Reimbursement Review

Talquetamab (Talvey)

Sponsor: Janssen Inc.

Therapeutic area: Relapsed or refractory multiple myeloma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance; SC = subcutaneous.

Introduction

Multiple myeloma (MM) is a plasma cell cancer characterized by clonal proliferation of malignant plasma cells (B cells) and overproduction of the abnormal immunoglobulin monoclonal protein (M protein).¹ In Canada in 2023, an estimated 3,900 individuals were diagnosed with MM and approximately 1,700 deaths due to MM occurred.² The 5-year survival rate for people with MM is estimated to be approximately 50%,³ and although survival rates have improved in recent years due to advances in therapeutic options, MM remains incurable.^4,5 The majority of patients with MM will experience relapse, and many patients will cease to experience response to commonly used therapies.⁶ Patients with relapsed or refractory r/r MM often undergo multiple rounds of treatment, with duration of remission, depth of response, progression-free survival (PFS), and overall survival (OS) decreasing with each subsequent line of therapy.⁷

The clinical expert and the clinician groups consulted for this review pointed out that the key treatment goals for patients with r/r MM are to delay progression, control the disease and associated symptoms, and prolong OS. Depending on drug sensitivity, patients can be treated with carfilzomib-dexamethasone (Kd) or pomalidomide-dexamethasone (Pd) in combination with isatuximab, carfilzomib-lenalidomide-dexamethasone, lenalidomide-dexamethasone, daratumumab-lenalidomide-dexamethasone, or daratumumab-bortezomib-dexamethasone. Alternative regimens with a different proteasome inhibitor (PI) or immunomodulator backbone can be used in the third and fourth lines. Cyclophosphamide may be added to some regimens, such as Pd, Kd, and lenalidomide-dexamethasone. According to the Provisional Funding Algorithm for Multiple Myeloma developed by CADTH,⁸ patients with drug resistance cannot be treated again with the same drug, except for dexamethasone, which is found in all regimens. There is no preferred therapy for r/r MM in the fourth-line setting or beyond, and at this stage of the disease patients may be treated with PIs, immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies and in some cases receive more than 1 PI or IMiD, further limiting treatment options in later lines of therapy.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of talquetamab 0.4 mg/kg of body weight weekly or 0.8 mg/kg of body weight every 2 weeks, administered subcutaneously, for the treatment of adult patients with r/r MM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, and who have experienced disease progression on or after the last therapy.

Patient and Clinician Perspectives

The information in this section is a summary of the input provided by the patient and clinician groups who responded to the review team’s call for input and from the clinical expert consulted for this review.

Patient Input

The review team received 1 patient group submission from Myeloma Canada, which conducted surveys with both patients and caregivers from April 17 to May 10, 2024, across Canada and internationally via email and social media. Eighty-six responses to the survey were received. Of these, 38 responses (32 patients and 6 caregivers; all from Canada except 1 patient) were recorded based on the eligibility criteria. Of these 38 respondents, 32 were eligible for the treatment under review (27 patients and 5 caregivers) and 6 had experience with it (5 patients and 1 caregiver). Nineteen of those 32 eligible respondents indicated that they had received 3 prior lines of therapy, 9 indicated that they had received 4 lines, and 4 indicated that they had received 5 lines of therapy or more. In addition, 97% of the 32 respondents indicated that they or the people they cared for had received an autologous stem cell transplant to treat the myeloma.

Respondents to the survey indicated that infections were the most important aspect related to myeloma to control, followed by fatigue, kidney problems, and pain. The respondents noted that among the elements of daily activity and quality of life, the ability to travel was the most significantly impacted by the symptoms associated with myeloma, followed by the ability to exercise and to conduct volunteer activities. The respondents felt that interruption of life goals or accomplishments had the greatest impact on quality of life, followed by loss of sexual desire and by anxiety or worry. Patient and caregiver respondents identified the following factors as the most important to myeloma treatment: quality of life, manageable side effects, effectiveness of treatment (especially in experiencing remission and having a durable response), and treatment accessibility or portability (including fewer or minimal visits to the hospital or cancer centre).

In terms of treatment outcomes, 21 of the 31 respondents eligible for the treatment under review and provided response to the question rated improved quality of life as extremely important, 9 as very important, and 1 as somewhat important. In addition, 21 of the 32 respondents eligible for the treatment under review indicated that an estimated minimum 1 year of extended life at this stage of myeloma was extremely desirable, and 9 indicated it was very desirable. When asked about tolerance of the most common side effects in patients who had received talquetamab, respondents perceived immune effector cell–associated neurotoxicity syndrome (ICANS), cytokine release syndrome (CRS), and infections to be the least tolerable side effects, followed by diarrhea and neutropenia. Six respondents having experience with talquetamab rated oral-related and nail-related issues as the least bearable of the most frequently experienced talquetamab side effects, followed by skin-related issues and infections. Most of the 6 respondents noted that the overall side effects while receiving talquetamab were manageable.

Clinician Input

Input From Clinical Expert Consulted for This Review

The clinical expert consulted for this review noted that fourth-line treatment for MM is challenging because there are limited available therapies. Moreover, tolerability of treatment is important as patients with r/r MM that can cause them to feel weak. The clinical expert noted that talquetamab could be appropriate to be used as a fourth-line or later-line treatment, being a potential treatment for patients who have received prior B-cell maturation antigen (BCMA)-directed therapy (e.g., belantamab, ciltacabtagene autoleucel [cilta-cel], teclistamab, elranatamab) or for patients who have not previously received BCMA-targeted therapy. The clinical expert indicated that patients treated with talquetamab would also be eligible for subsequent BCMA-targeted therapy. The clinical expert noted that the patients best suited to talquetamab would be those who need a fourth-line or later-line treatment and have an adequate performance status and reasonable hematologic function. The clinical expert indicated that there is no biomarker to predict treatment response and no companion test is necessary; however, the treatment centre must have an appropriate setup for the monitoring and treatment of CRS and should have access to infectious disease consultative services. The clinical expert indicated that treatment response is typically measured biochemically every 4 weeks. The clinical expert noted that the treatment discontinuation factors include disease progression according to the International Myeloma Working Group (IMWG) response criteria⁹ and intolerable adverse events (AEs) (e.g., severe dysgeusia, severe myelosuppression). The clinical expert noted that treatment with talquetamab should be initiated and supervised by a specialist (a hematologist or a medical oncologist with appropriate training). The clinical expert indicated that the first few doses of talquetamab treatment should be administered at a site with knowledge and expertise in managing CRS and that the subsequent doses could be administered in a community setting.

Clinician Group Input

Input on the review of talquetamab was received from 2 clinician groups: the Canadian Myeloma Research Group (CMRG) and the Ontario Health (Cancer Care Ontario) (OH-CCO) Hematology Cancer Drug Advisory Committee. Thirty-two clinicians (25 from CMRG and 7 from the OH-CCO Hematology Cancer Drug Advisory Committee) provided input for this submission.

Both CMRG and the OH-CCO Hematology Cancer Drug Advisory Committee emphasized that the overall treatment goals are to delay progression, improve OS, control the disease and associated symptoms, minimize adverse effects, and improve quality of life. CMRG highlighted that myeloma remains incurable and that patients eventually cease to experience response to all available funded drugs. CMRG emphasized that the highest unmet need is in patients with advanced disease who have received multiple lines of treatment and have already received the 3 major classes of drugs — PIs, IMiDs, and anti-CD38 monoclonal antibodies — (referred to here as patients with “triple-class exposed disease” or “triple-class refractory disease”). Another unmet need noted by the OH-CCO Hematology Cancer Drug Advisory Committee is to achieve ease of administration with talquetamab (i.e., subcutaneous [SC] injection and no need for apheresis) and a target than other bispecific antibodies.

Both clinician groups agreed that talquetamab could be another option for patients with triple-class exposed disease. CMRG indicated that patients with a good performance status, minimal or no comorbidities, relatively low tumour burden, adequate organ function, and satisfactory blood counts are the most likely to have the best outcomes with talquetamab. CMRG noted that, overall, patients with poor disease-related prognostic factors, such as extramedullary myeloma and high-risk cytogenetics, should be eligible for talquetamab.

CMRG added that clinically meaningful responses usually correlate with at least a partial remission according to IMWG consensus criteria. Both CMRG and the OH-CCO Hematology Cancer Drug Advisory Committee agreed that treatment discontinuation should be based on ongoing efficacy or response, disease progression, and long-term tolerability or significant toxicities. Given that prior exposure to anti-BCMA therapy does not preclude responsiveness to talquetamab, CMRG suggested that patients who had received prior anti-BCMA therapy or bispecific antibody treatment should be allowed access to talquetamab. The OH-CCO Hematology Cancer Drug Advisory Committee also noted that talquetamab might be helpful for patients who have previously received anti-BCMA treatment.

Drug Program Input

Input was obtained from the drug programs that participate in the reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a recommendation for talquetamab:

• relevant comparators

• considerations for initiation of therapy

• considerations for discontinuation of therapy

• considerations for prescribing of therapy

• generalizability

• funding algorithm

• care provision issues

• system and economic issues.

The clinical expert consulted for this review provided advice on the potential implementation issues raised by the drug programs. Refer to Table 4 for more details.

Clinical Evidence

Systematic Review

Description of Studies

One ongoing, phase I/II, single-arm, open-label, multicentre, dose escalation study, the MonumenTAL-1 study (total N = 501; N at either recommended phase II dose [RP2D] = 339), met the inclusion criteria for the systematic review conducted by the sponsor. The objectives of the MonumenTAL-1 study were to characterize the safety of talquetamab and the RP2Ds and schedule, to further characterize the safety of talquetamab at the RP2Ds (phase I), and to evaluate the efficacy of talquetamab at the RP2Ds (phase II) in adults with r/r MM. The trial enrolled adult patients with r/r MM who had not received prior T-cell redirection therapy (model cohort A [RP2D = 0.4 mg/kg weekly] and model cohort C [RP2D = 0.8 mg/kg every 2 weeks]) or who had received prior T-cell redirection therapy (model cohort B [either RP2D]). All patients had received at least 1 PI, 1 IMiD, and 1 anti-CD38 monoclonal antibody and had experienced disease progression on or after the last therapy. All patients had an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 in phase I and of less than or equal to 2 in phase II The 3 noncomparative cohorts were analyzed separately. Patients received 1 of the 2 RP2Ds: 0.4 mg/kg weekly SC on days 1, 8, 15, and 22 of a 28-day cycle (preceded by step-up doses of 0.01 mg/kg and 0.06 mg/kg) or 0.8 mg/kg every 2 weeks SC on days 1 and 15 of a 28-day cycle (preceded by step-up does of 0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg). The outcomes relevant to this review included the primary outcome of overall response rate (ORR) by independent review committee (IRC) per IMWG criteria and secondary outcomes of OS, PFS, duration of response (DOR), complete response (CR) or better rate, and safety. Health-related quality of life (HRQoL) was measured in phase II only, via the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), as a secondary outcome.

The trial population had a mean age of 61 to 65 years and a mean duration since MM diagnosis of 7.2 to 7.7 years across the model cohorts. There were more male patients (55% to 57% across the cohorts) than female patients (43% to 46%). Most enrolled patients were white (86% to 90%); the next largest groups by ethnicity were Black or African American, and Asian. Most patients (56% to 60%) had an ECOG Performance Status of 1, and less than 10% of the patients had an ECOG Performance Status of 2 (indicating good overall performance status). Most patients had a Revised International Staging System (R-ISS) disease stage of II (62% to 70%), standard cytogenetic risk (59% to 71%), and triple-class (PI, IMiD, and anti-CD38 monoclonal antibody) refractory disease (69% to 84%). The proportions of patients who had penta-drug (≥ 2 PIs, 2 IMiDs, and 1 anti-CD38 monoclonal antibody) refractory disease were 29% in model cohort A, 23% in model cohort C, and 41% in model cohort B.

As model cohort B was not included in the PE models and was more exploratory than the other 2 cohorts, the results summary is focused on model cohorts A and C. The results for model cohort B are presented in the main body of this report.

Efficacy Results

The key efficacy results from the MonumenTAL-1 study are summarized in Table 2, in descending order of the importance of the outcomes, as suggested by the clinical expert consulted for this review. The efficacy outcomes for this review were from the most recent analyses (clinical cut-off date: January 17, 2023) for the all-treated analysis set among the patients who received the RP2D in the MonumenTAL-1 study.

Overall Survival

At the data cut-off date, the OS data were immature. The median OS was not reached in any model cohort. The 12-month OS rate was 76% (95% confidence interval [CI], 68% to 83%) in model cohort A and 77% (95% CI, 69% to 84%) in model cohort C.

Progression-Free Survival

The median PFS was 7.5 months (95% CI, 5.7 to 9.4 months) in model cohort A and 14.2 months (95% CI, 9.6 months to not estimable) in model cohort C. The 12-month PFS rate in model cohort A (35%; 95% CI, 27% to 43%) appears lower than in model cohort C (54%; 95% CI, 45% to 63%).

Overall Response Rate

At the data cut-off date, the ORR was experienced by 74% (95% CI, 66% to 81%) and 72% (95% CI, 64% to 79%) of patients in model cohort A and model cohort C, respectively, with a 1-sided P value of less than 0.0001 for both cohorts. The results of prespecified clinically relevant subgroup analyses showed that the ORR seemed higher among patients with no extramedullary plasmacytomas at baseline (model cohort A: 81.8%; 95% CI, 73.3% to 88.5%; model cohort C: 81.5%; 95% CI, 72.9% to 88.3%) than among those with 1 or more baseline extramedullary plasmacytomas (model cohort A: 48.5%; 95% CI, 30.8% to 66.5%; model cohort C: 43.2%; 95% CI, 27.1% to 60.5%). It was not the intent of the study to formally test for subgroup differences.

Duration of Response

At the data cut-off date, the median DOR was reached among patients who experienced a partial response [PR] or better in model cohorts A and B, but not in model cohort C. The median DOR was 9.5 months (95% CI, 6.7 to 13.3 months) in patients who experienced a PR or better in model cohort A (n = 106) and not estimable (95% CI, 13.0 months to not estimable) in patients who experienced a PR or better in model cohort C (n = 104). The event-free rate for DOR was, at 6 months, 67% in model cohort A and 82% in model cohort C; at 9 months, 52% in model cohort A and 76% in model cohort C; and at 12 months, 44% in model cohort A and 69% in model cohort C.

CR or Better Rate

At the data cut-off date, a CR or better was experienced by 34% of patients (95% CI, 26% to 42%) in model cohort A and 39% of patients (95% CI, 31% to 47%) in model cohort C.

Health-Related Quality of Life

HRQoL, assessed via the EORTC QLQ-C30, was only reported for phase II of the MonumenTAL-1 study. In cohort A (talquetamab 0.4 mg/kg weekly SC in patients who had not received prior T-cell redirection therapy), the proportions of patients who experienced at least a 10-point improvement from baseline through cycle 7 day 1 (i.e., the first 6 months) in pain, fatigue, global health status (GHS), and physical functioning subscales were ████ ████ ████ ███ ███, respectively. In cohort C (0.8 mg/kg every 2 weeks SC in patients who had not received prior T-cell redirection therapy), the proportions of patients who experienced at least a 10-point improvement from baseline through cycle 7 day 1 in pain, fatigue, GHS, and physical functioning subscales were ████ ████ ████ ███ ███, respectively.

Harms Results

All patients in the study reported at least 1 treatment-emergent AE (TEAE). The most frequently reported TEAEs were CRS (79% in model cohort A and 75% in model cohort C), dysgeusia (50% and 49%), anemia (45% and 46%), weight decrease (41% and 41%), pyrexia (39% and 28%), and neutropenia (35% and 28%). Serious TEAEs occurred to 53% and 48% of patients in model cohorts A and C, respectively. The most frequently reported serious TEAEs were CRS (17% in model cohort A and 10% in model cohort C), pyrexia (6% and 5%), and ICANS (4% and 4%). In general, the proportions of patients with overall or specific TEAEs and with specific serious TEAEs were similar between the 2 cohorts, with a higher rate in model cohort A than in model cohort C for serious TEAEs and for pyrexia and neutropenia of any severity.

Likewise, the rates of AEs of special interest were similar between model cohort A and model cohort C: neurologic TEAEs (86% and 86%), neurotoxicity events (31% and 30%), and ICANS (11% and 11%). The rate of CRS was 79% in model cohort A and 75% in model cohort C. The proportion of patients who experienced an infection of any severity was 59% in model cohort A and 66% in model cohort C.

Critical Appraisal

The primary limitation of the MonumenTAL-1 study was the absence of a comparator group to assess the efficacy and harms of talquetamab compared to placebo or an active treatment; therefore, the interpretation of the results is limited by the study’s single-arm design. The open-label design introduces a potential performance bias and a bias in the assessment of PFS, ORR, DOR, CR or better rate, HRQoL, and some AEs. The assessment bias was mitigated by using the IRC, which performed tumour assessment per the IMWG criteria⁹ for the tumour response outcomes. The ORR and the 95% CI excluded the predetermined thresholds for null hypotheses for all 3 model cohorts (30% for model cohorts A and C; 15% for model cohort B) (P < 0.0001), and this effect can be attributed to talquetamab despite the single-arm study design. Despite a lack of multiplicity adjustment¹⁰ for the ORR analyses, P values were small, suggesting that these were not false-positive results. ORR was examined in prespecified clinically relevant subgroups; however, the sample sizes for the subgroup analyses were small and the analyses were not adjusted for multiplicity, limiting the interpretation of the data. The review team noted the smaller sample size (N = 51) of model cohort B (patients who had received prior T-cell redirection therapy and either of the 2 recommended dosing regimens), further limiting the interpretation of the results for these patients. At the data cut-off date and across the model cohorts, ██ ██ ██ of the patients were lost to follow-up for OS and | ██ ██ of the patients withdrew consent to study participation. It appears that the impact of missing data on OS and PFS is minimal. The data for OS in all 3 model cohorts were immature; therefore, the treatment benefit of OS based on the analysis at the latest data cut-off date would have been subject to a certain degree of uncertainty. At the data cut-off date and across the model cohorts, ███ ██ ███ of the patients had received 1 or more subsequent antimyeloma therapies, which may influence the assessment of efficacy of talquetamab on OS and PFS. The clinical expert commented that it is reasonable to use of 10-point improvement from baseline value¹¹ in the EORTC QLQ-C30 scores as the clinically meaningful improvement threshold in data analysis. The size of the HRQoL-evaluable population in phase II gradually decreased over time. At cycle 7 day 1, only ██ ██ ███ of all treated patients in cohort A, ██ ██ ██ in cohort C, and ██ ██ ██ in cohort B provided data for the EORTC QLQ-C30 assessment, which further increased risk of bias due to incomplete reporting or missing data for this outcome.

There is a lack of ethnic diversity in the MonumenTAL-1 study, as most patients were white (86% to 90% across the cohorts); the next largest groups by ethnicity were Black or African American (6% to 8%) and Asian (1% to 4%). Previous studies in the US have found that MM is twice as common in African American individuals than in white or Asian individuals.^7,12 The clinical expert pointed out that the patients in the MonumenTAL-1 study were generally younger and had less severe disease than the patients with r/r MM seen in clinical practice in Canada. These factors may potentially impact the generalizability of the study results, although the extent of such influence is uncertain.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and randomized controlled trials identified in the sponsor’s systematic review, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to assess the certainty of the evidence for the outcomes considered most relevant to inform the review team’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^13,14 Although GRADE guidance is not available for noncomparative studies, the review team assessed pivotal single-arm trials for study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for single-arm trials started at very low certainty with no opportunity for rating up.

The selection of outcomes for GRADE assessment was based on the sponsor’s summary of clinical evidence, consultation with the clinical expert, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: OS, PFS, ORR, DOR, CR or better rate, EORTC QLQ-C30, and notable harms, for patients in model cohort A and model cohort C separately. The outcomes in model cohort B were not assessed using GRADE due to the small sample size and the exploratory nature of that cohort.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for talquetamab in adult patients with r/r MM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, and have experienced disease progression on or after the last therapy.

Table 2: Summary of Findings for Talquetamab in Adult Patients With Refractory or Relapsed Multiple Myeloma

CI = confidence interval; CR = complete response; CRS = cytokine release syndrome; DOR = duration of response; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; ICANS = immune effector cell–associated neurotoxicity syndrome; NE = not estimable; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; q.2.w. = every 2 weeks; SC = subcutaneous; sCR = stringent complete response; VGPR = very good partial response.

Notes: Study limitations (which refers to internal validity or risk of bias), indirectness, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes. The data presented in this table are based on analyses at the clinical cut-off date of January 17, 2023, for the all-treated analysis set and for patients who received the recommended phase II dose. Model cohort A included patients who had not received prior T-cell redirection therapy and who were treated at the recommended phase II dose of 0.4 mg/kg weekly SC in phase I and phase II of the MonumenTAL-1 study. Model cohort C included patients who had not received prior T-cell redirection therapy and who were treated at the recommended phase II dose of 0.8 mg/kg q.2.w. SC in phase I and phase II of the MonumenTAL-1 study.

^aFollowing this value, there was a “+” symbol, denoting patients who died, in the sponsor’s submission.

^bIn the absence of a comparator arm, conclusions about efficacy relative to any comparator cannot be drawn, and the certainty of evidence started at very low without the opportunity to rate up.

^cDOR was calculated as the number of months from first documented response to progression or death due to any cause. The number of events referred to the number of patients who experienced a PR or better who experienced disease progression or died due to any cause.

^dMeasured using EORTC QLQ-C30: 0 (best) to 100 (worst) for pain and fatigue; 0 (worst) to 100 (best) for GHS and physical functioning.

^eRated down 2 levels for very serious risk of bias due to the open-label nature of the study and the subjective nature of the outcome (patient reported). There were substantial missing outcome data at cycle 7 day 1 (data were available for ██ ██ ██ patients compared to ███ patients at baseline for phase II cohort A, and data were available for ██ patients compared ██ ██ ██ patients at baseline for phase II cohort C for EORTC QLQ-C30 scales of pain, fatigue, GHS, and physical functioning).

Source: Clinical Study Report for MonumenTAL-1 (2023).¹⁵ The details included in the table are from the sponsor’s summary of clinical evidence.

Long-Term Extension Studies

There are no longer-term extension studies evaluating talquetamab for adults with r/r MM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, and who have experienced disease progression on the last therapy. Long-term follow-up of the MonumenTAL-1 trial is currently under way.^16,17

Indirect Comparisons

The sponsor provided nonrandomized comparative studies, which are summarized and appraised in the section on studies addressing gaps in the evidence from the systematic review.

Studies Addressing Gaps in the Evidence From the Systematic Review

Description of Studies

Three nonrandomized studies compared talquetamab in the MonumenTAL-1 trial to real-world physician’s choice of therapy (RWPC) in the LocoMMotion and MoMMent trials, to teclistamab in the MajesTEC-1 trial, and to cilta-cel in the CARTITUDE-1 trial to evaluate differences in ORR, CR or better rate, very good partial response (VGPR) or better rate, DOR, PFS, time to next treatment (TTNT), and OS. Each study separately compared MonumenTAL-1 study cohorts A and C, which received different dosing schedules of talquetamab (0.4 mg/kg weekly SC and 0.8 mg/kg every 2 weeks SC), to their respective cohorts. All included patients met similar key eligibility criteria, including specific serum or urine M-protein levels, an ECOG Performance Status of 0 to 2, receipt of at least 3 prior lines of therapy, and documented disease progression within 12 months of the last therapy. Using individual patient data (IPD) from each arm, propensity scores were derived through multivariable logistic regression to reduce the impact of bias due to confounding. Comparative efficacy was assessed using logistic regression for binary outcomes and Cox proportional hazards models for time-to-event outcomes. Sensitivity analyses included various weighting methods and propensity score matching, with e-values reported to estimate the impact of residual confounding. The studies aimed to determine the comparative effectiveness of talquetamab versus RWPC, teclistamab, and cilta-cel in treating r/r MM.

Efficacy Results

The studies comparing talquetamab to RWPC demonstrated that talquetamab improved ORR, PFS, OS, and TTNT in patients with triple-class exposed r/r MM. For the talquetamab 0.4 mg/kg weekly SC dosage, the adjusted response rate ratio for ORR was 2.67 (95% CI, 1.90 to 3.74; P < 0.0001). For the talquetamab 0.8 mg/kg every 2 weeks SC dosage, the adjusted response rate ratio for ORR was 2.62 (95% CI, 1.86 to 3.69; P < 0.0001). For PFS, the adjusted hazard ratio (HR) for the 0.4 mg/kg weekly dosage was 0.52 (95% CI, 0.39 to 0.71; P < 0.0001) and for the 0.8 mg/kg every 2 weeks dosage it was 0.40 (95% CI, 0.29 to 0.56; P < 0.0001). TTNT had an adjusted HR of 0.48 (95% CI, 0.36 to 0.64; P < 0.0001) for the 0.4 mg/kg weekly dosage and 0.39 (95% CI, 0.29 to 0.54; P < 0.0001) for the 0.8 mg/kg every 2 weeks dosage. Additionally, the DOR results favoured the talquetamab 0.8 mg/kg every 2 weeks dosage (HR = 0.43; 95% CI, 0.26 to 0.72; P = 0.0015).

When comparing talquetamab to teclistamab, talquetamab was favoured in ORR and OS but not in DOR or PFS. For the talquetamab 0.4 mg/kg weekly SC dosage, the adjusted response rate ratio for ORR was ████ ████ ███ █████ █████ ████████. For the talquetamab 0.8 mg/kg every 2 weeks SC dosage, the adjusted response rate ratio for ORR was ████ ████ ███ █████ █████ █████████. However, the adjusted HR for DOR was ████ ████ ███ █████ █████ ████████ for the 0.4 mg/kg weekly SC dosage, indicating that teclistamab was favoured. The HRs for PFS and TTNT showed no exclusion of the null between the treatments, while the adjusted HRs for OS in the 0.4 mg/kg weekly SC cohort were ████ ████ ███ █████ █████ █████████ and in the 0.8 mg/kg every 2 weeks SC cohort were ████ ████ ███ █████ █████ █████████.

In the comparison of talquetamab to cilta-cel, cilta-cel was favoured in ORR. For the talquetamab 0.4 mg/kg weekly SC dosage, the adjusted response rate ratio for ORR was ████ ████ ███ █████ █████ █████████. For the talquetamab 0.8 mg/kg every 2 weeks SC dosage, the adjusted response rate ratio was ████ ████ ███ █████ █████ █████████. Cilta-cel was also favoured in DOR, with an adjusted HR of ████ ████ ███ █████ █████ █████████ for the talquetamab 0.4 mg/kg weekly SC dosage, while the talquetamab 0.8 mg/kg every 2 weeks SC dosage ████ ███ █ ████ ██ ██████ ███ ████ ████ █████ ███ ███ █████ █████ ████████. In terms of PFS, the adjusted HR was ████ ████ ███ █████ █████ █████████ for the 0.4 mg/kg weekly SC dosage and ████ ████ ███ █████ █████ █████████ for the 0.8 mg/kg every 2 weeks SC dosage. ███ ███ ███ ███ ████████ ███ █████ ████ ████████ ███ ██ ████ ████ ███ █████ █████ █████████ ███ ████ ████ ███ █████ █████ █████████. Cilta-cel delayed the TTNT, with adjusted ███ ██ ████ ████ ███ █████ █████ █████████ for the talquetamab 0.4 mg/kg weekly SC dosage and ████ ████ ███ █████ █████ █████████ for the talquetamab 0.8 mg/kg every 2 weeks SC dosage.

Additionally, the observed CR or better rate for talquetamab in the 0.4 mg/kg weekly SC cohort was █████, versus ████ in the RWPC cohort, with an adjusted response rate ratio of █████ ████ ███ █████ ███████ █████████. For the 0.8 mg/kg every 2 weeks SC cohort, the CR or better rate was 38.6%, versus 0.6% in the RWPC cohort, with an adjusted r/r of ██████ ████ ███ █████ ████████ █████████. When compared to cilta-cel, talquetamab showed lower CR or better rates (█████ and █████ versus cilta-cel’s █████), with adjusted response rate ratios of ████ ████ ███ █████ █████ █████████ and ████ (███ ███ █████ █████ ████████), respectively, indicating that patients receiving cilta-cel were significantly more likely to experience CR or better.

Harms Results

Harms were not assessed in the nonrandomized studies.

Critical Appraisal

The 3 nonrandomized studies of talquetamab versus RWPC, teclistamab, and cilta-cel used IPD with inverse probability treatment weighting (IPTW) and average treatment effect in the treated (ATT) weighting to mitigate heterogeneity in prognostic factors, matching the MonumenTAL-1 trial criteria and outcome definitions. Despite these efforts, significant limitations remain, such as the lack of a predefined protocol and the lack of a systematic review for comparator data selection, resulting in a risk of selection bias and selective reporting, as well as unaddressed quality issues in the included studies. Pooling data from the LocoMMotion and MoMMent trials in the RWPC comparison without accounting for variability may have introduced bias or obscured differences that may have existed across the studies. The identification of prognostic factors relied on expert opinion without a systematic approach, and important factors like cytogenetic risk were excluded due to missing data, increasing the risk of residual confounding. The imputation of data for cytogenic risk as “missing” in sensitivity analyses is not able to fully account for the impact of this prognostic variable, had it been measured. After weighting, imbalances in some key prognostic variables remained in the RWPC and cilta-cel comparisons. Unknown confounders, methodological differences across studies (for the RWPC comparison) and potential deviations from the proportional hazards assumption further complicate the interpretation of the findings. Generalizability issues arise from outdated RWPC interventions and the inherent limitations in the clinical trial data (including that patients in the MonumenTAL-1 study were younger and fitter than in other trials and lacked ethnic diversity). The absence of safety or HRQoL measures also limits a comprehensive understanding of the treatments’ comparative effectiveness and safety.

Conclusions

One ongoing, phase I/II, single-arm, open-label study (MonumenTAL-1) provided evidence on the efficacy and safety of talquetamab for patients with r/r MM who have received at least 3 prior lines of therapy. The evidence for the treatment effect of talquetamab from the MonumenTAL-1 trial is very uncertain due to the single-arm design, which is not intended to be confirmatory of efficacy. The findings for ORR were clinically meaningful and durable according to the clinical expert consulted by the review team and can be attributed to talquetamab (rather than natural history or other factors) despite the single-arm design. However, causal conclusions regarding time-to-event end points were not possible given the lack of a comparator group, though the clinical expert indicated that based on the natural history of the disease and experience in clinical practice, the OS and PFS findings observed in the MonumenTAL-1 study appear promising in patients who have not had prior exposure to a T-cell redirection therapy at either the 0.4 mg/kg weekly SC or 0.8 mg/kg every 2 weeks SC dosing. The results for HRQoL were inconclusive due to the trial’s open-label design and the considerable amount of missing outcome data. Notable harms in the MonumenTAL-1 study, including CRS, ICANS, and infections, were consistent with the known safety profile of the drug.

Three nonrandomized studies assessed the efficacy of talquetamab against RWPC, teclistamab, and cilta-cel, using IPD with IPTW and ATT weights to reduce the impact of confounding. All these comparisons were impacted by methodological limitations, including a lack of predefined systematic review protocol, no systematic procedure for the identification of comparator studies, lack of quality assessment, lack of clarity on the appropriateness of pooling data from the LocoMMotion and MoMMent trials for the RWPC comparison, and a risk of bias due to residual confounding (particularly for comparisons to RWPC and cilta-cel). Nonetheless, the evidence suggested a benefit of talquetamab for all measured outcomes compared to RWPC. Though this comparison was the most impacted by the aforementioned limitations, the magnitude of the estimated benefit across multiple outcomes seems unlikely to be fully accounted for by these limitations. The true magnitude of the difference is less clear, and the relevance of this comparison was diminished by the mix of treatments included in the RWPC arm, many of which may not be widely used in current practice. Results for talquetamab versus teclistamab were inconsistent across outcomes, in many cases with CIs crossing the null, which caused uncertainty about which drug might be favoured. The evidence suggested that cilta-cel may have ████ ██████████ ████ ████ ███ ███ than the 0.4 mg/kg weekly dosage of talquetamab. Potential differences between treatments were uncertain for the 0.8 mg/kg every 2 weeks cohort, where only tumour response results excluded the null. The effect estimates were ███ █████████ ██ ████████ █████ ███ ██████████ ██ ██ between talquetamab and cilta-cel for any dose comparison. No comparative evidence for HRQoL or harms was available.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of talquetamab at 0.4 mg/kg of body weight, administered subcutaneously once weekly after receiving step-up doses of 0.01 mg/kg and 0.06 mg/kg of body weight, or at 0.8 mg/kg of body weight, administered subcutaneously every 2 weeks after receiving step-up doses of 0.01 mg/kg, 0.06 mg/kg, and 0.4 mg/kg of body weight, for the treatment of adult patients with r/r MM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, and have experienced disease progression on or after the last therapy.

Disease Background

The contents of this section have been informed by materials submitted by the sponsor and by clinical expert input. The following has been summarized and validated by the review team.

MM is a plasma cell cancer characterized by clonal proliferation of malignant plasma cells (B cells) and overproduction of the abnormal immunoglobulin M protein.¹ Older individuals and males (as opposed to females) are more likely to develop MM, and it is twice as common in African American individuals than in Caucasian or Asian individuals in the US.^7,12 In Canada in 2023, an estimated 3,900 individuals were diagnosed with MM and approximately 1,700 deaths due to MM occurred.² The 5-year survival rate for people with MM is estimated to be approximately 50%,³ and although survival rates have improved in recent years due to advances in therapeutic options, MM remains incurable.^4,5 The majority of patients with MM experience relapse, and many patients will cease to experience response to commonly used therapies.⁶ Patients with r/r MM often undergo multiple rounds of treatment, with the duration of remission, depth of response, PFS, and OS decreasing with each subsequent line of therapy.⁷

The most common symptoms of MM are fatigue and bone pain,⁷ with other symptoms including kidney conditions, recurrent infections, fever, and nervous system conditions.¹⁸ Disease stage, along with other factors, can impact MM prognosis. Commonly recognized factors that impact the prognosis of MM include beta2-microglobulin (high levels are associated with poor prognosis), serum albumin (low levels are associated with poor prognosis), lactate dehydrogenase (LDH) (high activity is predictive of poor prognosis), and chromosomal changes (shorter remission duration is associated with chromosome deletions or translocations).¹⁹ In addition to these factors, prognosis may be influenced by patient age, creatinine levels, and performance status. In general, patients older than 80 years, those with high creatinine levels, and those with poor overall function tend to have worse outcomes than younger individuals, those with lower creatinine levels, and those with better overall function.²⁰

Diagnosis of MM typically occurs during a visit to a primary care physician, occurring either incidentally when laboratory tests for other conditions are ordered or, if MM is suspected, based on signs and symptoms.²¹ Diagnosis of MM is based on the presence of 1 or more myeloma-defining events, along with either 10% or more clonal bone marrow plasma cells or biopsy-proven plasmacytoma.⁷ Myeloma-defining events include the presence of end-organ damage known as the CRAB criteria (hypercalcemia, renal insufficiency, anemia, and bone lesions), along with 3 specific biomarkers: clonal bone marrow plasma cell percentage of 60% or more, free light chain ratio of 100 or more, and more than 1 focal lesion on MRI studies.⁷

Several systems are used for staging MM: the International Staging System (ISS), the R-ISS, and the Durie-Salmon staging system.^1,22,23 The ISS is commonly used in Canada and uses blood tests that assess albumin levels and beta2-microglobulin levels to stage MM (advanced-stage MM is associated with lower albumin and higher beta2-microglobulin levels):²²

• Stage I: beta2-microglobulin less than 3.5 mg/L and serum albumin greater than or equal to 3.5 g/dL

• Stage II: beta2-microglobulin less than 3.5 mg/L and serum albumin less than 3.5 g/dL, or beta2-microglobulin 3.5 mg/L to 5.5 mg/L, irrespective of serum albumin

• Stage III: beta2-microglobulin greater than 5.5 mg/L.

The preferred staging system for MM is the R-ISS,²³ which combines elements of tumour burden (ISS) and disease biology (presence of high-risk cytogenetic abnormalities or elevated LDH level) to create a unified prognostic index that helps in clinical care as well as in comparison of clinical trial data. R-ISS uses serum beta2-microglobulin, serum albumin, serum LDH, and bone marrow fluorescence in situ hybridization results to stratify patients into 3 risk groups:^22,23

• Stage I: beta2-microglobulin less than 3.5 mg/L; serum albumin greater than or equal to 3.5g/dL; normal LDH; and no del(17p), t(4;14), t(14;16) by fluorescence in situ hybridization

• Stage II: neither stage I nor stage III

• Stage III: beta2-microglobulin greater than or equal to 5.5 mg/L; elevated LDH; and/or del(17p), t(4;14), t(14;16) by fluorescence in situ hybridization.

According to the IMWG criteria, a patient is considered to have refractory MM when they do not experience response to therapy or experience disease progression within 60 days of their last line of therapy.^24,25 A patient is considered to have relapsed MM if they experience disease progression after being previously treated and require a salvage therapy but do not meet the criteria for primary refractory MM or r/r MM.^24,25 A patient is considered to have r/r MM if they have experienced a minimal response or better at some point during previous treatments but the disease is currently nonresponsive on salvage therapy or if they experience disease progression within 60 days of their last therapy.^24,25

Standards of Therapy

The contents of this section have been informed by materials submitted by the sponsor and by clinical expert input. The following has been summarized and validated by the review team.

The clinical expert and clinician groups consulted for this review pointed out that the key treatment goals for patients with r/r MM are to delay progression, control the disease and associated symptoms, and prolong OS.²⁶ The choice of therapy depends on eligibility for autologous stem cell transplant at diagnosis, patient age, comorbidities, weakness, cytogenetics, previous treatments, response to prior therapy, prior toxicities, and line of therapy.^5,7

According to the American Society of Clinical Oncology and CCO Joint Clinical Practice Guideline, generally, the second-line treatment options available to a patient with r/r MM depend on their response to the therapy received in the first line, and the third-line treatment options depend on their response to the therapy received in the second line.²⁷ According to the Provisional Funding Algorithm for Multiple Myeloma developed by CADTH,⁸ patients with drug resistance cannot be treated again with the same drug, except for dexamethasone, which is found in all regimens. Depending on drug sensitivity, patients can be treated with Kd or Pd in combination with isatuximab, carfilzomib-lenalidomide-dexamethasone, lenalidomide-dexamethasone, daratumumab-lenalidomide-dexamethasone, or daratumumab-bortezomib-dexamethasone. Alternative regimens with a different PI or immunomodulator backbone can be used in the third and fourth lines, depending on drug sensitivity. Cyclophosphamide may be added to some regimens, such as Pd, Kd, and lenalidomide-dexamethasone. There is no preferred standard of care for the treatment of r/r MM in the fourth line and beyond, and at this stage of the disease patients may be exposed to PIs, IMiDs, and anti-CD38 monoclonal antibodies, in some cases receiving more than 1 PI or IMiD, further limiting treatment options in later lines of therapy.^8,27

Recent recommendations by the pan-Canadian Oncology Drug Review Expert Committee to reimburse drugs to treat triple-class exposed r/r MM (and have demonstrated disease progression on the last therapy) include Kd,²⁸ Pd,²⁹ selinexor-bortezomib-dexamethasone,³⁰ cilta-cel,³¹ teclistamab,³² and elranatamab.³³ According to the CADTH provisional funding algorithm for MM,⁸ selinexor-bortezomib-dexamethasone is recommended for third-line therapy and beyond in patients who are sensitive to bortezomib but not to anti-CD38 monoclonal antibodies and lenalidomide. In Canada, coverage for Pd with or without cyclophosphamide and for Kd with or without cyclophosphamide is determined on a case-by-case basis, while cilta-cel is under consideration for negotiation at the pan-Canadian Pharmaceutical Alliance.³⁴

Drug Under Review

The key characteristics of talquetamab are summarized in Table 3, along with those of other options available for the treatment of adult patients with r/r MM in fourth-line therapy and beyond, as indicated in CADTH’s provisional funding algorithm.⁸

Talquetamab is indicated for the treatment of adult patients with r/r MM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, and have experienced disease progression on or after the last therapy. The reimbursement request aligns with the Health Canada indication.³⁵

Talquetamab, a first-in-class bispecific antibody that targets a novel antigen, binds to both GPRC5D (on MM cells) and CD3 receptors (on T cells).³⁶ Talquetamab recruits and activates CD3-positive T cells to induce killing of GPRC5D-expressing myeloma cells.³⁶

Talquetamab is administered as a weekly or biweekly SC injection. The recommended dosage for talquetamab is 0.4 mg/kg of body weight once weekly after receiving step-up doses of 0.01 mg/kg and 0.06 mg/kg of body weight, or 0.8 mg/kg of body weight every 2 weeks after receiving step-up doses of 0.01 mg/kg, 0.06 mg/kg, and 0.4 mg/kg of body weight.³⁵

Table 3: Key Characteristics of Pharmacotherapies for Multiple Myeloma

BCMA = B-cell maturation antigen; cilta-cel = ciltacabtagene autoleucel DRESS = drug reaction with eosinophilia and systemic symptoms; DVT = deep venous thrombosis; ICANS = immune effector cell–associated neurotoxicity syndrome; IMiD = immunomodulatory drug; Kd = carfilzomib-dexamethasone; mAb = monoclonal antibody; MM = multiple myeloma; PI = proteasome inhibitor; PML = progressive multifocal leukoencephalopathy; SC = subcutaneous; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; TLS = tumour lysis syndrome.

^aHealth Canada–approved indication.

Sources: Product monographs for talquetamab,³⁵ teclistamab,³⁷ ciltacabtagene autoleucel,³⁸ selinexor,³⁹ pomalidomide,³² and carfilzomib;⁴⁰ Canadian Pharmacists Association.⁴¹

Patient Perspectives

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups. The full original patient input(s) received by the review team have been included in this section of the report.

The review team received 1 patient group submission from Myeloma Canada, which conducted surveys with both patients and caregivers from April 17 to May 10, 2024, across Canada and internationally via email and social media. Eighty-six responses to the survey were received. Of these, 38 responses (32 patients and 6 caregivers; all from Canada except 1 patient) were recorded based on the eligibility criteria (patient has r/r MM and has received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody). Of these 38 respondents, 32 aligned with the proposed indication and would be eligible for the treatment under review (27 patients and 5 caregivers) and 6 had experience with the treatment (5 patients and 1 caregiver). Nineteen of those 32 eligible respondents indicated that they had received 3 prior lines of therapy, 9 indicated that they had received 4 lines, and 4 indicated that they had received 5 lines of therapy or more. In addition, 97% of the 32 respondents indicated that they or the people they cared for had received an autologous stem cell transplant to treat the myeloma.

Respondents to the survey indicated that infections were the most important aspect related to myeloma to control, followed by fatigue, kidney problems, and pain. The respondents noted that among the elements of daily activities and quality of life, the ability to travel was the most significantly impacted by the symptoms associated with myeloma, followed by the ability to exercise and to conduct volunteer activities. Sixteen of the 38 respondents identified travel costs as the most significant financial implication of myeloma treatment for the respondents and their households, followed by parking costs (n = 15); lost income or pension funds due to absence from work, disability, or early retirement (n = 10); drug costs (n = 10); and accommodation costs (n = 9). Respondents felt that interruption of life goals or accomplishments had the greatest impact on quality of life, followed by loss of sexual desire and anxiety or worry. Patient and caregiver respondents identified the following factors as the most important to myeloma treatment: quality of life, manageable side effects, effectiveness of treatment (especially experiencing remission and having a durable response), and treatment accessibility or portability (including fewer or minimal visits to the hospital or cancer centre).

In terms of treatment outcomes, 21 of the 31 respondents eligible for the treatment under review and provided response to the question rated improved quality of life as extremely important, 9 as very important, and 1 as somewhat important. In addition, 21 of the 32 respondents eligible for the treatment under review indicated that an estimated minimum 1 year of extended life at this stage of myeloma was extremely desirable, and 9 indicated it was very desirable. When asked about tolerance of the most common side effects in patients who had received talquetamab, respondents perceived ICANS, CRS, and infections to be the least tolerable side effects, followed by diarrhea and neutropenia.

Six respondents (5 patients and 1 caregiver) indicated having experience with talquetamab. Of these 6 respondents, 2 had experience with talquetamab as monotherapy and 4 had experience with talquetamab in combination with another drug. Five of the 6 respondents who had received or were currently receiving treatment with talquetamab for themselves or the people they cared for indicated that they were admitted to the hospital at some point in the initial step-up dosing period. The 6 respondents rated oral-related and nail-related issues as the least bearable of the most frequently experienced talquetamab side effects, followed by skin-related issues and infections. Most of the 6 respondents noted that the overall side effects while receiving talquetamab were manageable.

Clinician Input

Input From Clinical Expert Consulted by the Review Team

All review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of MM.

Unmet Needs

The clinical expert consulted for this review noted that fourth-line treatment for MM is challenging because there are limited available therapies. The clinical expert noted that cilta-cel is not currently available in Canada and that teclistamab is only available in Canada through a compassionate access program. The clinical expert indicated that patients with r/r MM are usually weak and that, therefore, tolerability of treatment is also important.

Place in Therapy

The clinical expert noted that talquetamab (a GPRC5D-targeted therapy) could be appropriate to be used as a fourth-line treatment for patients with r/r MM, being a potential treatment for patients who have received prior BCMA-directed therapy (e.g., belantamab, cilta-cel, teclistamab, or elranatamab) or for patients who have not previously received BCMA-targeted therapy. The clinical expert noted that patients treated with talquetamab would also be eligible for subsequent BCMA-targeted therapy.

Patient Population

The clinical expert noted that the patients best suited to talquetamab would be those who need a fourth-line treatment and have an adequate performance status and reasonable hematologic function based on complete blood count parameters. The clinical expert indicated that there is no biomarker to predict treatment response and no companion test is necessary; however, the treatment centre must have an appropriate setup for the monitoring and treatment of CRS. The clinical expert indicated that the treatment centre should also have access to infectious disease consultative services given the known risk of serious infection among patients with r/r MM who are treated with talquetamab. The clinical expert noted that although the MonumenTAL-1 study only included patients with an ECOG Performance Status of 2 or less, talquetamab could be used in patients with central nervous system disease that is controlled and in patients with plasma cell leukemia or amyloidosis.

Assessing the Treatment Response

The clinical expert indicated that treatment response is typically measured biochemically every 4 weeks. The clinical expert noted that meaningful outcomes would be improved survival, reduced disease-related symptoms, and improved patient-reported HRQoL.

Discontinuing Treatment

The clinical expert noted that the factors to be considered when deciding whether a patient should discontinue treatment with talquetamab include disease progression according to the standard IMWG response criteria⁹ and intolerable AEs (e.g., severe dysgeusia, severe myelosuppression).

Prescribing Considerations

The clinical expert noted that treatment with talquetamab should be initiated and supervised by a specialist (a hematologist or a medical oncologist with appropriate training). The clinical expert indicated that the first few doses of talquetamab treatment should be administered at a site with knowledge and expertise in managing CRS and that the subsequent doses could be administered in a community setting.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups. The full original clinician group input(s) received by the review team have been included in the input section of this report.

Input on the review of talquetamab was received from 2 clinician groups: CMRG and the OH-CCO Hematology Cancer Drug Advisory Committee. Thirty-two clinicians (25 from CMRG and 7 from the OH-CCO Hematology Cancer Drug Advisory Committee) provided input for this submission.

Both CMRG and the OH-CCO Hematology Cancer Drug Advisory Committee emphasized that the overall treatment goals are to delay progression, improve OS, control the disease and associated symptoms, minimize adverse effects, and improve quality of life. CMRG highlighted that myeloma remains incurable and that patients eventually cease to experience response to all available funded drugs. CMRG emphasized that the highest unmet need is in patients with advanced disease who have received multiple lines of treatment and have already received the 3 major classes of drugs: PIs, IMiDs, and anti-CD38 monoclonal antibodies. Another unmet need noted by the OH-CCO Hematology Cancer Drug Advisory Committee is to achieve ease of administration with talquetamab (i.e., SC injection and no need for apheresis) and a different target than other bispecific antibodies.

Both clinician groups agreed that talquetamab could be another option for patients with triple-class exposed or refractory disease. CMRG further stated that, currently, talquetamab would be used late in the lines of myeloma treatment (i.e., after failure of multiple drugs). CMRG added that talquetamab is not expected to impact the sequencing of drugs earlier in the disease course or lead to a major change in treatment algorithms before the disease becomes triple-class exposed or refractory. Both clinician groups emphasized that the availability of talquetamab will complement access to the recently endorsed T-cell redirection therapies.

CMRG indicated that patients with a good performance status, minimal or no comorbidities, relatively low tumour burden, adequate organ function, and satisfactory blood counts are the most likely to have the best outcomes with talquetamab. CMRG further noted that, overall, patients with poor disease-related prognostic factors, such as extramedullary myeloma and high-risk cytogenetics, should be eligible for talquetamab.

The OH-CCO Hematology Cancer Drug Advisory Committee highlighted that treatment responses with talquetamab are assessed using standard myeloma response measures as well as CRS and ICANS toxicity grading scales. CMRG elaborated that responses are based on the M-protein markers in the serum and/or urine, bone marrow biopsy, and in some instances imaging studies (IMWG). CMRG added that clinically meaningful responses usually correlate with at least a partial remission by IMWG consensus criteria, including improvement in symptoms (cessation of bone destruction with less pain, fractures, and need for radiotherapy), improvement in energy, and better ability to perform activities of daily living. Both CMRG and the OH-CCO Hematology Cancer Drug Advisory Committee agreed that treatment discontinuation should be based on ongoing efficacy or response, disease progression, and long-term tolerability or significant toxicities.

Given that prior exposure to anti-BCMA therapy does not preclude responsiveness to talquetamab, CMRG suggested that patients who had received prior anti-BCMA therapy or bispecific antibody treatment should be allowed access to talquetamab. The OH-CCO Hematology Cancer Drug Advisory Committee also noted that talquetamab might be helpful for patients who have previously received anti-BCMA treatment.

Drug Program Input

The drug programs provide input on each drug being reviewed through the review team’s reimbursement review processes by identifying issues that may impact the drug programs’ ability to implement a recommendation. The implementation questions and corresponding responses from the clinical expert consulted for this review are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

BCMA = B-cell maturation antigen; cilta-cel = ciltacabtagene autoleucel; CNS = central nervous system; CRS = cytokine release syndrome; ECOG = Eastern Cooperative Oncology Group; ICANS = immune effector cell–associated neurotoxicity syndrome; MM = multiple myeloma; pERC = pan-Canadian Oncology Drug Review Expert Review Committee.

Clinical Evidence

The objective of the Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of talquetamab administered subcutaneously at a dosage of 0.4 mg/kg of body weight once weekly after receiving step-up doses of 0.01 mg/kg and 0.06 mg/kg of body weight or at a dosage of 0.8 mg/kg of body weight every 2 weeks after receiving step-up doses of 0.01 mg/kg, 0.06 mg/kg, and 0.4 mg/kg of body weight for the treatment of adult patients with r/r MM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, and have experienced disease progression on or after the last therapy. The focus will be placed on comparing talquetamab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of talquetamab is presented in 4 sections, with the review team’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes the pivotal studies and randomized controlled trials that were selected according to the sponsor’s systematic review protocol. The review team’s assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section would include sponsor-submitted long-term extension studies, but no studies were available for this submission. The third section would include indirect evidence submitted by the sponsor, but no indirect evidence was included in this submission. The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

Clinical evidence from the following studies is included in the review and appraised in this document:

• 1 pivotal study (phase I/II study) identified in the systematic review

• 3 studies addressing gaps in the systematic review evidence.

Systematic Review

The contents of this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Description of Studies

One pivotal study (MonumenTAL-1) met the inclusion criteria for the sponsor’s systemic review. The characteristics of the MonumenTAL-1 study are summarized in Table 5.

Table 5: Details of Study Included in the Systematic Review (MonumenTAL-1)

AE = adverse event; CAR = chimeric antigen receptor; CR = complete response; CRS = cytokine release syndrome; DLT = dose-limiting toxicity; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; FLC = free light chain; HRQoL = health-related quality of life; IMiD = immunomodulatory drug; IMWG = International Myeloma Working Group; mAb = monoclonal antibody; MM = multiple myeloma; MRD = minimal residual disease; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PI = proteasome inhibitor; POEMS = polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes; PR = partial response; PRO = patient-reported outcome; q.2.w. = every 2 weeks; RP2D = recommended phase II dose; SAE = serious adverse event; SC = subcutaneous; sCR = stringent complete response; TTR = time to response; VGPR = very good partial response.

^aPatients who were enrolled in the China and Japan cohorts were declared out of scope for the 2023 Clinical Study Report of the MonumenTAL-1 study, and data relating to those patients were not reported in this submission.

^bCriterion for progressive disease on or within 12 months of therapy does not apply to patients who received CAR T-cell therapy as the last line of therapy.

^cFor patients in phase I, disease response was assessed by the investigator using 2011 IMWG response criteria.²⁵ For patients who received RP2Ds in either phase of the study, the independent review committee provided the primary assessment of disease response using 2016 IMWG response criteria.⁹

Sources: Clinical Study Report for MonumenTAL-1 (2023);¹⁵ clinical protocol for MonumenTAL-1.⁴³ Details included in the table are from the sponsor’s summary of clinical evidence.

The MonumenTAL-1 study is a phase I/II, single-arm, open-label, multicentre, dose escalation study of talquetamab in adults with r/r MM. The primary objectives of the 3-part MonumenTAL-1 study were to characterize the safety of talquetamab and the RP2Ds and schedule (phase I dose escalation [i.e., part 1]); to further characterize the safety of talquetamab at the RP2Ds (phase I dose expansion [i.e., part 2]); and to evaluate the efficacy of talquetamab at the RP2Ds (phase II [i.e., part 3]). The most recent data cut-off date was January 17, 2023. Patients from 47 centres across 11 countries in Asia, Europe, and North America were included in the study. Randomization was not implemented in accordance with the single-arm study design.¹⁵

In the MonumenTAL-1 study, 501 patients were treated with talquetamab, and patients received talquetamab until disease progression, unacceptable toxicity, withdrawal of consent, death, or the end of the study (defined as 2 years after the last participant had received the initial dose of talquetamab or when the last participant had completed the last study assessment, whichever occurred first).¹⁵ The results of this clinical review were reported for 3 populations from phase I and phase II of the MonumenTAL-1 study who were treated with the RP2D of talquetamab of either 0.4 mg/kg weekly SC or 0.8 mg/kg every 2 weeks SC (Figure 1):

• Model cohort A (N = 143): all treated patients assigned to the RP2D of 0.4 mg/kg weekly SC in either phase I or phase II cohort A, who had not received prior T-cell redirection therapies such as chimeric antigen receptor (CAR) T-cell therapy or bispecific antibodies. This group corresponds to model cohort A in the pharmacoeconomic (PE) report and model.

• Model cohort C (N = 145): all treated patients assigned to the RP2D of 0.8 mg/kg every 2 weeks SC in either phase I or phase II cohort C, who had not received prior T-cell redirection therapy. This group corresponds to model cohort C in the PE report and model.

• Prior T-cell redirection (N = 51): all treated patients assigned to the 0.4 mg/kg weekly SC RP2D in phase II cohort B or to RP2D (either 0.4 mg/kg weekly SC or 0.8 mg/kg every 2 weeks SC) in phase I who had received prior T-cell redirection therapy. This group was not included in the PE model but was narratively addressed in the PE report.⁴⁴

Populations

Inclusion and Exclusion Criteria

The patients eligible for inclusion in the MonumenTAL-1 study were those aged 18 years or older who had a documented diagnosis of MM according to IMWG diagnostic criteria²⁵ and an ECOG Performance Status of 0 or 1 (phase I) or 0 to 2 (phase II). All patients were required to have measurable disease. All patients in phase II had been treated with at least 3 prior therapies and had been previously exposed to a PI, an IMiD, and an anti-CD38 monoclonal antibody. Patients were excluded from the MonumenTAL-1 study if they had previously experienced grade 3 or higher CRS related to a T-cell redirection therapy or prior GPRC5D-targeting therapy. Patients were excluded if they had received any of the following antitumour therapies before the first dose of the study drug: gene-modified adoptive cell therapy within 3 months, epigenetic therapy, monoclonal antibody treatment or cytotoxic therapy within 21 days, PI therapy or radiotherapy within 14 days, IMiD therapy within 7 days, CAR T-cell therapy or T-cell redirection therapy at any time (for phase II cohort A and cohort C only), and T-cell redirection therapy within 3 months (for phase II cohort B only).

Patients were also excluded if they had received a cumulative dose of corticosteroids equivalent to 140 mg or more of prednisone within the 14-day period before the first dose of the study drug, had received an allogeneic stem cell transplant within the past 6 months, or had received an autologous stem cell transplant 12 weeks or less before the first dose of the study drug.⁴³

Figure 1: MonumenTAL-1 Study Analysis Populations

Q2W = every 2 weeks; RP2D = recommended phase II dose; PE = pharmacoeconomic; SC = subcutaneous.

Notes: The group labelled with “*” corresponds to model cohort A in the PE report and model. The group labelled with “**” corresponds to model cohort C in the PE report and model.

Source: Sponsor’s submission.⁴⁵

Interventions

Phase I (Part 1 and Part 2)

During dose escalation (part 1 of phase I), the talquetamab dosing schedules were as follows: IV from 0.001 mg/kg to 0.00338 mg/kg every 2 weeks, IV from 0.0015 mg/kg to 0.18 mg/kg weekly, SC from 0.015 mg/kg to 0.8 mg/kg weekly, SC 0.8 mg/kg or 1.2 mg/kg every 2 weeks, or SC at 1.6 mg/kg monthly.⁴³

Dose escalation for biweekly IV treatment was initiated at the minimum anticipated biologic effect level–based starting dose of 0.0005 mg/kg, while dose escalation for weekly IV treatment was initiated at the dose deemed safe during the dose escalation assessment for biweekly IV dosing. Dose escalation for the SC treatment began at a cleared dose level that was approved by the study evaluation team. Most IV doses and all SC doses were preceded by step-up dosing.⁴³

During dose expansion (part 2 of phase I), patients received talquetamab at 0.405 mg/kg SC weekly on days 1, 8, and 15 of a 21-day cycle (preceded by step-up doses of 0.01 mg/kg and 0.06 mg/kg) or at 0.8 mg/kg SC every 2 weeks on days 1 and 15 of a 28-day cycle (preceded by step-up doses of 0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg).¹⁵

In phase I, patients could switch from a weekly to a biweekly or monthly dosing schedule if they experienced PR or better, had received at least 4 cycles of therapy, and had the sponsor’s approval. Dose modifications, including delays and reductions, were used to manage talquetamab-related toxicities at the investigator’s discretion.¹⁵

Phase II (Part 3)

Safety, efficacy, pharmacokinetic, and pharmacodynamic data from phase I (parts 1 and 2) were used to inform the 2 selected RP2Ds of 0.4 mg/kg SC weekly and 0.8 mg/kg SC every 2 weeks. The RP2D of 0.405 mg/kg (phase I) was adjusted to 0.4 mg/kg for operational convenience and is used herein to refer to the associated dose in both phase I and phase II.¹⁵ Cohorts A and B received 0.4 mg/kg SC weekly on days 1, 8, 15, and 22 of a 28-day cycle (preceded by step-up doses of 0.01 mg/kg and 0.06 mg/kg). Cohort C received 0.8 mg/kg SC every 2 weeks on days 1 and 15 of a 28-day cycle (preceded by step-up does of 0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg).¹⁵

In phase II, patients in cohort A or B could switch from weekly to biweekly dosing if they experienced CR or better for at least 6 months and had the sponsor’s approval.¹⁵

In all patients treated at the RP2Ds, talquetamab was administered until disease progression, unacceptable toxicity, withdrawal of consent, death, or the end of the study.¹⁵

Pretreatment Therapy

Patients in the MonumenTAL-1 study received pretreatment medication of glucocorticoid, antihistamine, and antipyretic at cycle 1 dose 1 and at all step-up doses. Histamine-2 receptor antagonists and antiemetics were administered as clinically indicated.^15,43

Concomitant Therapy

Permitted Medications

Patients in the MonumenTAL-1 study received full supportive care during the study. Examples of supportive therapies included standard supportive care therapies (antiemetics, antidiarrheals, anticholinergics, antispasmodics, antipyretics, antihistamines, analgesics, antibiotics and other antimicrobials, histamine receptor antagonists or proton pump inhibitors, and other medications intended to treat symptoms or signs of disease) as clinically indicated, as well as bisphosphonates, growth factor support, erythropoietin-stimulating drugs, platelet-stimulating factor, antibiotics or other anti-infective drugs, corticosteroids, and best supportive care to prevent potential toxicities.⁴³

Subsequent Anticancer Therapy

In parts 1 and 2, information on subsequent anticancer therapy (type of therapy and start date) administered up to 16 weeks after the last dose of talquetamab was recorded, according to the study protocol. In part 3, unless a patient experienced intolerance to talquetamab, subsequent antimyeloma therapy was not started before disease progression was established per the IMWG criteria^9,25 and confirmed by the sponsor. After confirmation of progressive disease, the choice of subsequent therapy was at the discretion of the investigator.⁴³

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 6, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review according to the clinical expert consulted for this review and input from the patient and clinician groups and public drug plans. Using the same considerations, the review team selected the end points that were considered to be most relevant to inform the expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. Select efficacy and notable harms outcomes that were considered important for informing the expert committee deliberations were assessed using GRADE.

Table 6: Outcomes Summarized From the Study Included in the Systematic Review

AE = adverse event; CR = complete response; DOR = duration of response; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; SAE = serious adverse event; sCR = stringent complete response; VGPR = very good partial response.

Note: ORR and CR or better rate were defined according to the International Myeloma Working Group criteria and were based on the independent review committee assessment.

Sources: Clinical Study Report for MonumenTAL-1 (2023);¹⁵ clinical protocol for MonumenTAL-1.⁴³ Details included in the table are from the sponsor’s summary of clinical evidence.

OS was defined as the time from the date of the first dose of the study drug to the date of the patient’s death. If the patient was alive or their vital status was unknown, then the patient’s data were censored at the date the patient was last known to be alive. If the patient had died, the date and cause of death were collected and documented on the electronic case report form, if or when available.

Disease evaluations were performed at the start of each cycle, as specified in the relevant time and event schedules.⁴³ Disease evaluations were performed by a central laboratory, unless otherwise specified, until disease progression. In phase I, response to treatment was evaluated by study investigators according to the 2011 IMWG response criteria²⁵ (for patients treated at a candidate or putative RP2D, response was additionally assessed by an IRC using the 2016 IMWG response criteria⁹).⁴³ In phase II, response to treatment was evaluated by the IRC and validated using a computerized algorithm (although the IRC assessment was used as the primary assessment). Response was additionally assessed by the investigator using the 2016 IMWG response criteria.^9,43

PFS was defined as the time from the date of the first dose of the study drug to the date of first documented disease progression, as defined in the IMWG criteria,⁹ or death due to any cause, whichever occurred first. For patients who had experienced progression and were alive, data were censored at the last disease evaluation before the start of any subsequent antimyeloma therapy. Disease progression and survival were assessed according to the relevant time and event schedules.⁴³

ORR was defined as the proportion of patients who have a PR or better (i.e., stringent CR, CR, VGPR, or PR) according to the IMWG criteria.⁹

DOR was calculated among patients who experienced a PR or better, from the date of initial documentation of a response to the date of first documented evidence of progressive disease (as defined by the IMWG criteria)⁹ or death due to progressive disease, whichever occurred first. Relapse from CR was not considered as disease progression. For patients who had not experienced progression, data were censored at the last disease evaluation before the start of any subsequent antimyeloma therapy.

The CR or better rate was defined as the proportion of patients who experienced a CR or better (i.e., CR or stringent CR) according to the IMWG criteria.⁹

Patient-reported outcome measures were administered according to the relevant time and event schedules⁴³ to assess the patient’s HRQoL (symptoms, functioning, and general well-being) after treatment and the change from baseline. The patient-reported outcome measures were completed by the patient. The EORTC QLQ-C30 version 3 includes 30 items, comprising 5 functional scales (physical, role, emotional, cognitive, and social), 1 GHS scale, 3 symptom scales (pain, fatigue, and nausea/vomiting), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The recall period is 1 week (“past week”), and responses are reported using verbal and numeric rating scales. The instrument contains 28 items using a Likert scale, with 4 response options: “not at all,” “a little,” “quite a bit,” and “very much” (scored 1 to 4). Two additional items use response options 1 to 7: 1 indicates “very poor,” and 7 indicates “excellent.” The item and scale scores are transformed to a 0 to 100 scale according to the algorithm in the EORTC QLQ-C30 scoring manual, version 3. A higher score represents greater HRQoL, better functioning, and more (worse) symptoms (Table 7). The sponsor used a 10-point change for improvement from baseline through cycle 7 day 1 (i.e., the first 6 months) in the EORTC QLQ-C30 scores as the clinically meaningful improvement threshold, based on the literature.^{11,15,43,45,46} Compliance rates for the patient-reported outcome instruments at each scheduled visit were provided based on the number and percentage of expected and received complete questionnaires.⁴⁷

AEs were reported by the patient (or, when appropriate, by a caregiver, a surrogate, or the patient’s legally acceptable representative).

The considerations that informed the selection of the efficacy outcomes to be summarized and assessed using GRADE include the following:

• Survival outcomes, which were identified by the patient and clinician group input and were specified by the clinical expert consulted for this review to include OS and PFS.

• ORR, which was identified as important by the patient and clinician group input (as response to treatment).

• DOR, which was identified as important by the patient group input and by the clinical expert consulted for this review.

• CR or better rate, which was identified as important by the patient group input and by Canadian Drug Expert Committee representatives and presenters.

• HRQoL outcomes, which were identified by the patient and clinician group input and were specified by the clinical expert to include the EORTC QLQ-C30 measure.

• CRS and ICANS, which were identified as important safety outcomes by the clinical expert and by the patient and clinician group input.

Table 7: Summary of Outcome Measures and Related Measurement Properties

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; HRQoL = health-related quality of life; HSCT = hematopoietic stem cell transplant; MID = minimal important difference; MM = multiple myeloma; QoL = quality of life; SRM = standardized response mean.

^aThe European Society for Blood and Marrow Transplantation criteria for response were used to determine the patients’ disease phase.

^bTo assess the magnitude of the difference in scores between patients whose disease improved, deteriorated, and remained stable, SRMs were calculated and compared against the Cohen rule of thumb for interpreting the magnitude of mean differences in HRQoL scores: 0.20 represents a small change, 0.50 a moderate change, and more than 0.80 a large change.

^cThe MIDs were estimated using an anchor-based approach, anchored to a structured QoL interview (response options were “improved,” “deteriorated,” or “unchanged”).

^dThe MIDs were estimated using an anchor-based approach, anchored to a structured QoL interview (response options were “improved,” “deteriorated,” or “unchanged”).

Statistical Analysis

Clinical Study End Points

The statistical analyses for the study end points are presented in Table 8.

Table 8: Statistical Analysis of Efficacy and Safety End Points in MonumenTAL-1 Study

CI = confidence interval; CR = complete response; DOR = duration of response; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; IRC = independent review committee; MCT = meaningful change threshold; NR = not reported; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; PRO = patient-reported outcome; sCR = stringent complete response; SD = standard deviation; VGPR = very good partial response.

^aThe dependent variable was change from baseline in score, and the independent variables were baseline value and time as fixed effects and patient as a random effect.

Source: Clinical protocol for MonumenTAL-1.⁴³ The details included in the table are from the sponsor’s summary of clinical evidence.

Sample Size and Power Calculation

Phase I (parts 1 and 2) of the MonumenTAL-1 trial did not include any formal statistical hypothesis testing.⁴³ In part 1, each dosing cohort required at least 1 participant, with at least 6 patients enrolled at each RP2D.¹⁵ In part 2, a maximum of 40 patients were treated at each RP2D to further assess safety and evaluate the preliminary antitumour activity of talquetamab.¹⁵

In phase II (part 3) of the MonumenTAL-1 trial, the sample size requirements were determined as follows:⁴³

• Cohort A: A target sample size of approximately 120 patients was determined using an assumed ORR of at least 45% for patients treated with talquetamab. This provided a power of approximately 90% or greater to conclude that the ORR is higher than 30% at the 1-sided significance level of 0.025.

• Cohort B: A target sample size of at least 60 patients and up to approximately 100 patients was determined by using an assumed ORR of at least 35% for patients treated with talquetamab. Initially, calculations revealed that 38 patients would provide a power of approximately 80% or greater to conclude that the ORR is higher than 15% at the 1-sided significance level of 0.025. The target sample size was further increased to at least 60 patients to determine the ORR with more precision (i.e., tighter CIs).

• Cohort C: A target sample size of approximately 100 patients was determined by using an assumed ORR of at least 45% for patients treated with talquetamab. This provided a power of more than 85% to conclude that the ORR is higher than 30% at the 1-sided significance level of 0.025.

According to the sponsor, for this single-arm trial, multiplicity adjustment(s) were not used in the analyses of ORR in the MonumenTAL-1 study.⁴⁷

Interim Analyses

A formal interim analysis was not planned for phase I nor for cohorts A and B in phase II.⁴³ For cohort B in phase II, the null hypothesis that ORR was at most 15% was tested using a 2-stage design against the alternative hypothesis that ORR was at least 35%. The first stage occurred when approximately 21 patients enrolled in cohort B were response evaluable and the response for the last patient in the first stage could be assessed. Once at least 3 responses were observed in the first stage, additional patients were enrolled to obtain at least 34 patients who were response evaluable across both stages. This was followed by an increase in sample size to at least 60 patients to calculate the ORR with more precision (i.e., tighter CIs).⁴⁵

Subgroup Analyses

Within each model cohort, the results of the MonumenTAL-1 study were also reported by subgroup. Prespecified subgroups included the following:

• sex (male or female)

• age (< 65 years, 65 to < 75 years, or ≥ 75 years)

• baseline renal function (≤ 60 mL/min/1.73 m² or > 60 mL/min/1.73 m² for efficacy outcomes; and < 30 mL/min/1.73 m², 30 to < 60 mL/min/1.73 m², 60 to < 90 mL/min/1.73 m², or ≥ 90 mL/min/1.73 m² for safety outcomes)

• for safety only: hepatic function (normal or impaired)

• race (African American, Black, white, or other)

• baseline ECOG Performance Status (0 or ≥ 1)

• number of lines of prior therapy (< 4 or ≥ 4)

• disease refractory to prior therapy (last line of prior therapy, PI and IMiD, triple class [PI, IMiD, and anti-CD38 monoclonal antibody], or penta-drug [at least 2 PIs, at least 2 IMiDs, and 1 anti-CD38 monoclonal antibody])

• prior autologous stem cell transplant (yes or no)

• type of myeloma (immunoglobulin G or non–immunoglobulin G)

• baseline ISS (I, II, or III); baseline ISS was derived based on the combination of serum beta2-microglobulin and albumin

• baseline R-ISS (I, II, or III); baseline R-ISS was derived based on the combination of serum beta2-microglobulin and albumin, genetic risk, and LDH level

• cytogenetic risk (high risk or standard risk); high risk was defined by patients having t (4; 14); t (14; 16) and/or 17p deletion

• bone marrow percentage of plasma cells (≤ 30%, > 30% to < 60%, or ≥ 60%)

• baseline tumour GPRC5D expression (≥ median value or < median value)

• baseline extramedullary plasmacytomas (0 or ≥ 1)

• prior antibody drug conjugate (yes or no)

• prior lines of therapy and refractory status (≥ 4 lines of therapy and triple refractory).

Analysis Populations

The key analysis populations are presented in Table 9.

Table 9: Analysis Populations of MonumenTAL-1 Study

CR = complete response; FLC = free light chain; HRQoL = health-related quality of life; IRC = independent review committee; MM = multiple myeloma; PR = partial response; q.2.w. = every 2 weeks; RP2D = recommended phase II dose; SC = subcutaneous.

Note: The analysis populations outlined in the table apply to each of the 3 model cohorts that received the RP2D: patients with no prior T-cell redirection therapy treated at the RP2D of 0.4 mg/kg weekly SC; patients with no prior T-cell redirection therapy treated at the RP2D of 0.8 mg/kg q.2.w. SC; and patients with prior T-cell redirection therapy treated at either RP2D (0.4 mg/kg weekly SC or 0.8 mg/kg q.2.w. SC).

Source: Clinical protocol for MonumenTAL-1.⁴³ The details included in the table are from the sponsor’s summary of clinical evidence.

Results

Patient Disposition

A summary of patient disposition in the MonumenTAL-1 study is given in Table 10. In total, 681 patients were screened, and 501 patients who met the inclusion and exclusion criteria and initiated treatment with talquetamab on or before April 20, 2022, were included in the MonumenTAL-1 study analyses.⁵⁷ A total of 180 patients did not meet the screening criteria, mainly because of not meeting the clinical laboratory (hematology or chemistry) values (n = 78).⁵⁷ At the January 17, 2023, data cut-off date, 62 patients (43.4%) in model cohort A and 41 patients (28.3%) in model cohort C had discontinued the study, mainly due to death (33.6% and 22.1% in model cohorts A and C, respectively). In total, 110 patients (76.9%) in model cohort A and 85 patients (58.6%) in model cohort C discontinued talquetamab due to progressive disease (58.0% and 34.5% in model cohorts A and C, respectively), physician decision (8.4% and 8.3%), AEs (5.6% and 8.3%), patient refusal (3.5% and 4.1%), and death (1.4% and 3.4%).

Table 10: Summary of Patient Disposition in MonumenTAL-1 Study

q.2.w. = every 2 weeks; RP2D = recommended phase II dose; SC = subcutaneous; SD = standard deviation.

Note: The data presented in this table were based on analyses at the clinical cut-off date of January 17, 2023, for the all-treated analysis set and patients who received the RP2D.

^aBased on Kaplan-Meier product limit estimate.

^bFollowing this value, there was a “+” symbol, denoting patients who died, in the sponsor’s submission.

^c“Patient refused further treatment” includes “withdrawal by patient” from phase I RP2D.

Sources: Clinical Study Report for MonumenTAL-1 (2023);¹⁵ sponsor’s submission.⁵⁷ The details included in the table are from the sponsor’s summary of clinical evidence.

Baseline Characteristics

A summary of the baseline patient demographics in the MonumenTAL-1 study is given in Table 11, and baseline patient disease characteristics are given in Table 12.

In model cohorts A and C of the MonumenTAL-1 study (i.e., patients with no prior T-cell redirection therapy), the median age of the patients was 67.0 years (range, 38 to 86 years), with 43.4% and 45.5% of the patients in those 2 model cohorts, respectively, aged younger than 65 years. There were more male patients (54.5% and 57.2%) than female patients (42.8% and 45.5%). Most patients were white (86.2% and 89.5%); the next largest categories by ethnicity were Black or African American (6.2% and 8.4%) and Asian (0.7% and 4.1%). Most patients had an ECOG Performance Status of 1 (55.9% and 60.1%), and less than 10% of patients had an ECOG Performance Status of 2, indicating good overall performance status.

In model cohorts A and C, the most common immunoglobulin isotypes were immunoglobulin G (53.1%) and immunoglobulin A (16.1% and 17.9%). The median time from diagnosis of MM to enrolment in the study was approximately 6.5 years (range, 0.8 to 25.4 years). Thirty-three patients (23.1%) in model cohort A and 37 patients (25.5%) in model cohort C had 1 or more extramedullary plasmacytomas at baseline. Of the 132 patients and 128 patients with baseline cytogenetic data reported in model cohorts A and C, 31.1% and 28.9% had at least 1 high-risk cytogenetic feature, including del(17p) (22.0% and 19.5%), t(4;14) (9.1% and 10.9%), and t(14;16) (3.8% and 4.7%). In patients with available baseline ISS or R-ISS data, most had ISS stage I disease (43.4% and 44.4% in model cohorts A and C, respectively), ISS stage II disease (37.1% and 31.3%), or R-ISS stage II disease (70.3% and 62.3%).

At baseline, all patients in the study populations had had disease that was refractory at some point to prior MM therapy. Most patients (94%) in model cohorts A and C had disease that was refractory to their last line of therapy. Approximately three-quarters (74.1%) of the patients in model cohort A and 69.0% of the patients in model cohort C had disease that was triple-class refractory (PI, IMiD, and anti-CD38 monoclonal antibody) (Appendix 1, Table 24).

Table 11: Summary of Baseline Characteristics in MonumenTAL-1 Study

ECOG = Eastern Cooperative Oncology Group; q.2.w. = every 2 weeks; SC = subcutaneous; SD = standard deviation.

Note: The data presented in this table were based on analyses at the clinical cut-off date of January 17, 2023, for the all-treated analysis set and patients who received the recommended phase II dose.

^aBased on data from 141 patients.

Source: Clinical Study Report for MonumenTAL-1 (2023).¹⁵ The details included in the table are from the sponsor’s summary of clinical evidence.

Table 12: Baseline Disease Characteristics of Patients in MonumenTAL-1 Study

FLC = free light chain; IMWG = International Myeloma Working Group; ISS = international staging system; MM = multiple myeloma; q.2.w. = every 2 weeks; R-ISS = Revised International Staging System; SC = subcutaneous; SD = standard deviation.

Note: The data presented in this table were based on analyses at the clinical cut-off date of January 17, 2023, for the all-treated analysis set and patients who received the recommended phase II dose.

^aIncludes patients without a positive immunofixation but with evidence of FLC-kappa by FLC testing.

^bIncludes patients without a positive immunofixation but with evidence of FLC-lambda by FLC testing.

^cISS staging is derived based on serum beta2-microglobulin and albumin.

^dR-ISS staging is derived based on the combination of serum beta2-microglobulin and albumin, genetic risk, and lactate dehydrogenase level.

^eThe maximum value from the bone marrow biopsy or bone marrow aspirate is selected if both the results are available.

Source: Clinical Study Report for MonumenTAL-1 (2023).¹⁵ The details included in the table are from the sponsor’s summary of clinical evidence.

Exposure to Study Treatments

Patient exposure to study treatments in the MonumenTAL-1 study is presented in Table 13. At the time of analysis, which used the data cut-off date of January 17, 2023, patients in model cohort A received a median of ███ ██████ ███████ ████ ██ ████ ████████ and patients in model cohort C received a median of ███ ██████ ███████ ████ ██ ████ ███████ of talquetamab.

The median dose intensity across all treatment cycles was █████ ██████████ ███████ ████ ██ █████ ███████████ in model cohort A and █████ ██████████ ███████ █████ ██ █████ ███████████ in model cohort C. The median number of doses received was ██ ███████ █ ██ ████ in model cohort A and ██ ███████ █ ██ ███ in model cohort C.

Table 13: Summary of Patient Exposure in MonumenTAL-1 Study

q.2.w. = once every 2 weeks; SC = subcutaneous; SD = standard deviation.

Note: The data presented in this table were based on analyses at the clinical cut-off date of January 17, 2023, for the all-treated analysis set and patients who received the recommended phase II dose.

^aDose intensity (mcg/kg/week) was calculated as the sum of total treatment doses (mcg/kg) received (excluding step-up doses before cycle 1) divided by the protocol-specified cycle length in weeks on talquetamab after the step-up dosing period.

Source: Clinical Study Report for MonumenTAL-1 (2023).¹⁵ The details included in the table are from the sponsor’s summary of clinical evidence.

Pretreatment Medications

All pretreatment medications (required and optional) administered at any time during the study are summarized in Table 14. In the MonumenTAL-1 study, all patients received corticosteroids and antipyretics (anilides), while most (94.5% to 100% across analysis cohorts) also received antihistamines (histamine-1 receptor antagonists). The use of corticosteroids as pretreatment medications decreased over the duration of treatment, while the use of anilides and histamine-1 receptor antagonists generally remained stable over time.¹⁵

Table 14: Pretreatment Medications in MonumenTAL-1 Study

ATC = Anatomical Therapeutic Chemical; q.2.w. = every 2 weeks; SC = subcutaneous.

Note: The data presented in this table were based on analyses at the clinical cut-off date of January 17, 2023, for the all-treated analysis set and patients who received the recommended phase II dose.

Source: Clinical Study Report for MonumenTAL-1 (2023).¹⁵

Concomitant Medications

Most patients treated with the RP2D received concomitant medication during treatment (█████ in model cohort A, and ████ of in model cohort C). The most frequently used concomitant medications were ███████████ ███ ███████████ █████████ ███████ █████████████ ██████████ ██████ ███ █████ ██ █████ ███████ █ ███ ██ ██████████████ ████████ ██ ████████ ██████ ███ ███████ ███ ██████ ████ ██████████ ██████ ███ ██████ (Table 15).

Table 15: Concomitant Medication Use in MonumenTAL-1 Study

ATC = Anatomical Therapeutic Chemical; q.2.w. = every 2 weeks; SC = subcutaneous.

Note: The data presented in this table were based on analyses at the clinical cut-off date of January 17, 2023, for the all-treated analysis set and patients who received the recommended phase II dose.

Source: Clinical Study Report for MonumenTAL-1 (2023).¹⁵

Subsequent Antimyeloma Treatment

For the patients who had not received prior T-cell redirection therapy, the median TTNT was ███ ██████ and ████ ██████ in patients treated at 0.4 mg/kg weekly SC (model cohort A) or at 0.8 mg/kg every 2 weeks SC (model cohort C), respectively. The median TTNT was ███ months in patients who had received prior T-cell redirection therapy treated at either RP2D (0.4 mg/kg weekly SC or 0.8 mg/kg every 2 weeks SC) (model cohort B).¹⁵ Subsequent antimyeloma therapy was recorded for ██ ████████ ███████ in model cohort A and ██ ████████ ███████ in model cohort C (Table 16).

Table 16: Subsequent Antimyeloma Therapies in MonumenTAL-1 Study

q.2.w. = every 2 weeks; SC = subcutaneous.

Note: The data presented in this table were based on analyses at the clinical cut-off date of January 17, 2023, for the all-treated analysis set and patients who received the recommended phase II dose.

Source: Clinical Study Report for MonumenTAL-1 (2023).¹⁵

Efficacy

Efficacy outcomes for this review were from the most recent analyses in the MonumenTAL-1 study (clinical cut-off date of January 17, 2023) for the all-treated analysis set among the patients who received the RP2D. Key efficacy outcomes are summarized in Table 17. The median follow-up periods for the all-treated analysis set were 18.8 months (range, 0.5+ to 32.9 months) for model cohort A, 12.7 months (range, 0.2+ to 26.1 months) for model cohort C, and 14.8 months (range, 1.0+ to 29.0 months) for model cohort B (“+” denotes patients who died).⁴⁷

Survival

Overall Survival

At the data cut-off date, the OS data were immature. The median OS was not reached in any model cohort. The 12-month OS rate was greater than 75% among patients who had not received prior T-cell redirection therapy: 76.4% (95% CI, 68.3% to 82.7%) in model cohort A and 77.4% (95% CI, 69.1% to 83.7%) in model cohort C. The main reason for censoring was being in follow-up without an event at the data cut-off date █████ ███ █████ in model cohorts A and C, respectively); the next most common reason was loss to follow-up ████ ███ █████.

Progression-Free Survival

At the data cut-off date, the median PFS was reached in all 3 model cohorts and was 7.5 months (95% CI, 5.7 to 9.4 months) in model cohort A and 14.2 months (95% CI, 9.6 months to not estimable) in model cohort C. █████ of the patients in model cohort A and █████ of the patients in model cohort C were progression-free and alive at 12 months.

In model cohort A, of the reported PFS events, █████ were progressive disease and ████ were death without progressive disease. Reasons for progressive disease in more than 10% of patients were ████████ ██ █████ █████████ ████████ ████████ ██ █████ ████ █████ █████ █████ ████████ ███ ██████████████ █████████████ ████████ ███ ████ ██████ ████████ ███ ████████ ██ ██████████████ ████████████ ████ ███████.

In model cohort C, of the reported PFS events, █████ were progressive disease and █████ were death without progressive disease. Reasons for progressive disease in more than 10% of patients were ████████ ██ █████ █████████ ████████ ████████ ██ █████ ███ ████████ ███ ██████████████ █████████████ ████████ ███ ████ ██████ ████████ ███ █████████ ██████████████ ████████████ ████ ███████.

The Kaplan-Meier plots for OS and PFS for model cohorts A and C are included in Appendix 1.

Tumour Response to Treatment

Overall Response Rate

In the MonumenTAL-1 study, ORR was the primary outcome for phase II and the secondary outcome for phase I.¹⁵

In model cohort A, ORR was experienced by 106 patients (74.1%; 95% CI, 66.1% to 81.1%). The P value for declaring that the ORR was higher than 30% was less than 0.0001. Most patients with reduced dosing frequency or dose reductions after an initial response maintained the response after the change:

• |██████ ████████ switched from 0.4 mg/kg weekly SC to 0.8 mg/kg every 2 weeks SC after experiencing a response of CR or better for 6 months, per protocol; however, monthly doses were maintained. ███ of these patients experienced disease progression or died by the January 17, 2023, clinical cut-off date.¹⁵

• |█████████ patients reduced the total monthly dose after a response (██ by reducing dose frequency to every 2 weeks or monthly, ██ by reducing the dose administered each week, and 2 by doing both), usually due to TEAEs. Ten of these patients experienced disease progression or died by the January 17, 2023, clinical cut-off date.¹⁵

In model cohort C, ORR was experienced by 104 patients (71.7%; 95% CI, 63.7% to 78.9%). The P value for declaring that the ORR was higher than 30% was less than 0.0001.

The results of prespecified clinically relevant subgroup analyses for ORR showed that in model cohorts A and C, talquetamab delivered consistent ORR by cytogenetic risk at baseline and across other clinically relevant subgroups, except among participants with baseline plasmacytomas. The ORR appeared higher (not tested statistically) among patients with no extramedullary plasmacytomas at baseline (n = 110) (██████ ███ ███ █████ ██ █████ in model cohort A; ██████ ███ ███ █████ ██ █████ in model cohort C) than among those with 1 or more baseline extramedullary plasmacytomas (n = 33) (██████ ███ ███ █████ ██ █████ in model cohort A; ██████ ███ ███ █████ ██ █████ in model cohort C) (Appendix 1, Figure 45, Figure 46).

The detailed treatment responses by category per the IRC (stringent CR, CR, VGPR, and PR, and so forth) and the forest plots of ORR subgroup analyses are given in Table 25 (Appendix 1).

Duration of Response

At the data cut-off date, the median DOR was reached among patients who experienced a PR or better in model cohorts A and B, but not in model cohort C.

Among patients who experienced a PR or better in model cohort A (n = 106), the median follow-up was 18.9 months (range, 2.7 to 32.9 months), with █████ patients having had at least 6 months of follow-up, █████ patients having had at least 9 months of follow-up, and █████ patients having had at least 12 months of follow-up. The median DOR was 9.5 months (95% CI, 6.7 to 13.3 months). The estimated probability of remaining in response at 6 months was █████ ████ ███ █████ ██ ██████ among the 48 patients who experienced CR or better, █████ ████ ███ █████ ██ ██████ among the 37 patients who experienced VGPR as the best response, and █████ ████ ███ ████ ██ ██████ among the 21 patients who experienced PR as the best response.¹⁵

Among patients who experienced a PR or better in model cohort C (n = 104), the median follow-up was 12.9 months (range, 4.1 to 26.1 months), with █████ patients having had at least 6 months of follow-up, █████ patients having had at least 9 months of follow-up, and █████ patients having had at least 12 months of follow-up. With █████ of patients who experienced a PR or better having been censored, DOR data were not yet mature. The estimated probability of remaining in response at 6 months was █████ ████ ███ █████ ██ ██████ among the 56 patients who experienced CR or better, █████ ████ ███ ██████ ██████ among the 32 patients who experienced VGPR as the best response, and █████ ████ ███ █████ ██████ among the 16 patients who experienced PR as the best response.¹⁵

CR or Better Rate

At the data cut-off date, a CR or better was experienced by 34% of patients (95% CI, 26% to 42%) in model cohort A and 39% of patients (95% CI, 31% to 47%) in model cohort C.

Results Summary of Additional Analyses to Tumour Response Outcomes

For all 3 model cohorts in the MonumenTAL-1 study, the sensitivity analyses and supplemental analyses of OS, PFS, ORR, DOR, and CR or better rate demonstrated similar results to the primary analyses.¹⁵

Table 17: Summary of Key Efficacy Results From MonumenTAL-1 Study

CI = confidence interval; CR = complete response; DOR = duration of response; FLC = free light chain; IMWG = International Myeloma Working Group; IRC = independent review committee; NE = not estimable; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; q.2.w. = every 2 weeks; SC = subcutaneous; sCR = stringent complete response; VGPR = very good partial response.

Notes: The data presented in this table were based on analyses at the clinical cut-off date of January 17, 2023, for the all-treated analysis set and patients who received the recommended phase II dose. Progressive disease was assessed by the IRC, based on IMWG consensus criteria (2016).

^aFollowing this value, there was a “+” symbol, denoting patients who died, in the sponsor’s submission.

^bA patient may show progressive disease based on more than 1 criterion.

^cPercentages were based on the number of patients with a PFS event.

^dPercentages were based on the number of patients with a progressive disease event.

^eOnly applicable to patients without measurable serum and urine M-protein levels.

^fPercentages were based on the number of patients censored in the all-treated analysis set.

^gStatistical testing was not adjusted for multiple comparisons.

^hResponse was assessed by the IRC, based on IMWG consensus criteria (2016).⁹ Percentages were calculated with the number of patients in the all-treated analysis set as a denominator. Exact 95% CIs were provided.

ⁱDOR was calculated as the number of months from first documented response to progression or death due to any cause. Number of events referred to the number of patients experiencing a PR or better who developed disease progression or died due to any cause.

Sources: Clinical Study Report for MonumenTAL-1 (2023);¹⁵ sponsor’s submission.⁴⁷

Health-Related Quality of Life

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30

HRQoL outcomes, assessed with the EORTC QLQ-C30, were only reported for phase II (i.e., part 3) of the MonumenTAL-1 study, and no HRQoL outcomes were assessed in phase I.^15,43,45 Scales of pain, fatigue, GHS, and physical functioning in the EORTC QLQ-C30 were considered important by the clinical expert consulted for this review and thus are reported in this section. Data on improvements of at least 10 points (the threshold of a meaningful improvement used by the sponsor)^11,46 in selected EORTC QLQ-C30 scales from baseline through cycle 7 day 1 (i.e., the first 6 months) are summarized in Table 18 for phase II cohort A, in Table 19 for phase II cohort C, and in Table 27 (Appendix 1) for phase II cohort B. In the all-treated analysis set and across the 3 cohorts, between █████ ███ █████ of patients experienced improvements of at least 10 points in GHS and physical functioning after the first cycle of talquetamab. Between █████ ███ █████ had at least a 10-point improvement after cycle 7. Similarly, between █████ ███ █████ of patients reported at least 10-point reductions in pain and fatigue symptoms after the first treatment cycle. Between █████ ███ █████ reported reductions of at least 10 points after cycle 7 across the 3 cohorts in phase II of the MonumenTAL-1 study.⁵⁸

A narrative summary of time to improvement (defined as an increase in score that was at least half of the standard deviation from baseline values) by the sponsor showed that the medians were between 0.3 months and 2.3 months for the selected EORTC QLQ-C30 scales across the 3 cohorts (Appendix 1, Table 28). Time-to-event analysis of the time to worsening for HRQoL showed a median between ███ ██████ ██ ████ ██████ for the selected EORTC QLQ-C30 scales across the 3 cohorts (Appendix 1, Table 28).¹⁵

Phase II Cohort A

In this patient population (patients in the phase II trial treated with talquetamab 0.4 mg/kg weekly SC who had received no prior T-cell redirection therapy), compliance in completing the EORTC QLQ-C30 was 97.5% at baseline (119 questionnaires received out of the 122 expected) and ranged from 78.3% to 92.3% at postbaseline assessments through cycle 15 day 1. The proportions of patients who experienced at least a 10-point improvement from baseline through cycle 7 day 1 (i.e., the first 6 months) in pain, fatigue, GHS, and physical functioning subscales were ████ ████ ████ ███ ███, respectively (Table 18).

Phase II Cohort C

In this patient population (patients in the phase II trial treated with talquetamab 0.8 mg/kg every 2 weeks SC who had received no prior T-cell redirection therapy), compliance in completing the EORTC QLQ-C30 was 97.2% at baseline (106 questionnaires received out of the 109 expected) and ranged from 69.2% to 93.7% at postbaseline assessments through cycle 15 day 1. Patients in phase II cohort C reported improvements in GHS and physical functioning compared to baseline, with the improvement likely due to the on-target, off-tumour effects, which seem to improve with time (Appendix 1, Figure 47).¹⁵

Phase II Cohort B

In this patient population (patients in the phase II trial treated at either RP2D who had received prior T-cell redirection therapy), compliance in completing the EORTC QLQ-C30 was 91.2% at baseline (31 questionnaires received out of the 34 expected) and ranged from 77.8% to 93.8% at postbaseline assessments through cycle 13 day 1. The proportions of patients who experienced at least a 10-point improvement from baseline through cycle 7 day 1 (i.e., the first 6 months) in pain, fatigue, GHS, and physical functioning subscales were ████ ████ ████ ███ ███, respectively (Appendix 1, Table 27).¹⁵

Table 18: Improvement of at Least 10 Points From Baseline in EORTC QLQ-C30 Scales in Phase II for Patients Receiving 0.4 mg/kg Weekly SC With No Prior T-Cell Redirection Therapy

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; NA = not applicable; SC = subcutaneous.

Note: The data presented in this table were based on analyses at the clinical cut-off date of January 17, 2023. Based on the literature, 10 points was used as the threshold for a meaningful change. Meaningful change indicates meaningful improvement.

Source: Sponsor’s submission.⁵⁸

Table 19: Improvement of at Least 10 Points From Baseline in EORTC QLQ-C30 Scales in Phase II for Patients Receiving 0.8 mg/kg q.2.w. SC With No Prior T-Cell Redirection Therapy

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; NA = not applicable; q.2.w. = every 2 weeks; SC = subcutaneous.

Note: The data presented in this table were based on analyses at the clinical cut-off date of January 17, 2023. Based on the literature, 10 points was used as the threshold for meaningful change. Meaningful change indicates meaningful improvement.

Source: Sponsor’s submission.⁵⁸

Harms

Refer to Table 20 for harms data for the MonumenTAL-1 study (all-treated analysis set), presented from the most recent safety analyses (clinical cut-off date of January 17, 2023).

Adverse Events

All patients in the study reported at least 1 TEAE. The most frequently reported TEAEs were CRS (79.0% in model cohort A and 74.5% in model cohort C), dysgeusia (50.3% and 49.0%), anemia (44.8% and 45.5%), weight decrease (41.3% and 41.4%), pyrexia (39.2% and 27.6%), and neutropenia (35.0% and 28.3%).

Serious AEs

Seventy-six patients (53.1%) in model cohort A and 70 patients (48.3%) in model cohort C reported at least 1 serious TEAE. The most common serious TEAEs occurring in at least 2% of patients were CRS (16.8% and 10.3% in model cohorts A and C, respectively), pyrexia (5.6% and 4.8%), and ICANS (4.1% and 3.7%).

Withdrawal Due to AEs

TEAEs led to discontinuation of talquetamab for 7 patients (4.9%) in model cohort A and 12 patients (8.3%) in model cohort C. In model cohort A, the TEAEs that led to treatment discontinuation for more than 1 patient were ICANS (1.6%) and skin exfoliation (████).¹⁵ In model cohort C, the only TEAE that led to treatment discontinuation for more than 1 patient was dysgeusia (1.4%), and study drug-related TEAEs leading to treatment discontinuation occurred in 4.8% of patients.¹⁵

Mortality

A TEAE with the outcome of death occurred in 5 patients (3.5%) in model cohort A and 6 patients (4.1%) in model cohort C. One patient (0.7%) in each of these 2 cohorts died due to COVID-19.

Notable Harms

CRS

In model cohort A, at least 1 event of CRS (any grade) was reported for 113 patients (79.0%), with the majority of CRS events occurring early during treatment (33.6% following step-up dose 1, 49.0% following step-up dose 2, and 26.6% following cycle 1 day 1). Using American Society for Transplantation and Cellular Therapy grading, the maximum severity of CRS was grade 1 (62.2% of patients), grade 2 (14.7%), or grade 3 (2.1%); no patients experienced grade 4 or grade 5 CRS. Forty-six patients (32.2%) experienced multiple CRS events, and the grade of CRS worsened at any subsequent event for 6 patients (4.2%).

In model cohort C, at least 1 event of CRS (any grade) was reported for 108 patients (74.5%), with the majority of CRS events occurring early during treatment (26.2% following step-up dose 1, 40.7% following step-up dose 2, and 34.5% following step-up dose 3). Using American Society for Transplantation and Cellular Therapy grading, the maximum severity of CRS was grade 1 (57.2%), grade 2 (16.6%), or grade 3 (0.7%); no patients experienced grade 4 or grade 5 CRS. Forty-six patients (31.7%) experienced multiple CRS events, and the grade of CRS worsened at any subsequent event for 6 patients (4.1%).

Neurologic TEAEs

In model cohort A, at least 1 neurologic TEAE was reported in 123 patients (86.0%), and the most commonly reported neurologic TEAEs (reported in at least 5% of patients) by preferred term were dysgeusia (50.3%), ageusia (19.6%), headache (18.9%), ICANS (10.7%, based on phase II only), dizziness (7.0%), taste disorder (7.0%), and insomnia (7.7%).¹⁵

In model cohort C, at least 1 neurologic TEAE was reported in 124 patients (85.5%), and the most commonly reported neurologic TEAEs (reported in at least 5% of patients) by preferred term were dysgeusia (49.0%), ageusia (20.7%), headache (20.7%), dizziness (14.5%), ICANS (11.0%, based on phase II only), paresthesia (5.5%), insomnia (11.0%), and anxiety (5.5%).¹⁵

Neurotoxicity

In model cohort A, at least 1 neurotoxicity TEAE was reported for 44 patients (30.8%), and the most commonly reported neurotoxicity TEAEs (reported in at least 5% of patients) by preferred terms were ICANS (10.7%, based on phase II only) and headache (9.1%). Grade 3 ICANS was reported for 2 patients (1.4%). No grade 4 or 5 neurotoxicity TEAEs were reported. Serious neurotoxicity events were reported for 4.2% of patients.

In model cohort C, at least 1 neurotoxicity TEAE was reported for 43 patients (29.7%), and the most commonly reported neurotoxicity TEAEs (reported in at least 5% of patients) by preferred terms were ICANS (11.0%, based on phase II only) and headache (9.0%). Grade 3 neurotoxicity events were reported for 4.8% of patients, including ICANS (3.7%), headache (0.7%), insomnia (0.7%), and nystagmus (0.7%). A single grade 4 neurotoxicity event of ICANS was reported (0.9% of patients), and no grade 5 neurotoxicity events were reported. Serious neurotoxicity events were reported for 4.8% of patients, including ICANS (3.7%), headache (0.7%), insomnia (0.7%), and nystagmus (0.7%).

Infection

In model cohort A, at least 1 infection TEAE (any grade) was reported for 84 patients (58.7%). The most frequently reported infections that were reported in more than 5% of patients were upper respiratory tract infection (12.6%), COVID-19 (10.5%), nasopharyngitis (9.8%), urinary tract infection (9.8%), bronchitis (8.4%), and pneumonia (7.7%). The maximum severity of infections was grade 3 or 4 for 19.6% of patients, with the following Grade 3 or 4 infections each in more than 1 patient: pneumonia (3.5%), urinary tract infection (2.1%), COVID-19 (1.4%), and sepsis (1.4%). Three patients (2.1%) had a grade 5 infection, including 1 patient each with COVID-19 pneumonia, fungal sepsis, and septic shock. Infections were reported as serious TEAEs in 18.9% of patients.

In model cohort C, at least 1 infection TEAE (any grade) was reported for 96 patients (66.2%). The most frequently reported infections that were reported in more than 5% of patients were COVID-19 (23.4%), upper respiratory tract infection (9.0%), nasopharyngitis (6.9%), and pneumonia (6.2%). The maximum severity of infections was grade 3 or 4 for 14.5% of participants, with grade 3 or 4 infections of COVID-19 (2.1%), pneumonia (2.1%), and cellulitis (1.4%) reported in more than 1 patient. Two patients (1.4%) had a grade 5 infection: 1 patient each with COVID-19 pneumonia and “infection” (unknown etiology).

Table 20: Summary of Harms Results From MonumenTAL-1 Study

AE = adverse event; CRS = cytokine release syndrome; ICANS = immune effector cell–associated neurotoxicity syndrome; MedDRA = Medical Dictionary for Regulatory Activities; NR = not reported; q.2.w. = every 2 weeks; SC = subcutaneous; TEAE = treatment-emergent adverse event.

Note: The data presented in this table were based on analyses at the clinical cut-off date of January 17, 2023, for the all-treated analysis set and patients who received the recommended phase II dose.

^aPhase I started before the American Society for Transplantation and Cellular Therapy consensus criteria for ICANS were implemented, and ICANS could not be identified or excluded prospectively for patients in phase I. Thus, all percentages for ICANS in this section are based on phase II cohorts only.

Source: Clinical Study Report for MonumenTAL-1 (2023).¹⁵ The details included in the table are from the sponsor’s summary of clinical evidence.

Critical Appraisal

Internal Validity

The primary limitation of the MonumenTAL-1 study was the absence of a comparator group to assess the efficacy and harms of talquetamab compared to another relevant treatment (e.g., PIs, IMiDs, or other drugs used to treat r/r MM in Canada); therefore, the interpretation of the results is limited by the single-arm design. A single-arm study design is usually used to provide preliminary evidence of the efficacy of a treatment and to collect safety data (e.g., dose finding) and is not intended to be confirmatory for efficacy.⁵⁹ According to the FDA, ORR is a direct measure of anticancer activity that may be attributed to the study drug and is evaluable with a single-arm design.⁶⁰ For other end points it is difficult to make causal conclusions, in particular to what extent the observed effects were attributable to talquetamab, because it is impossible to distinguish between the effects of talquetamab and a placebo effect or the natural history of the disease in the absence of a frame of reference for comparison. The open-label design introduces a potential performance bias and bias in the assessment of PFS, ORR, DOR, CR or better rate, HRQoL, and subjective AEs. This potential for bias was mitigated by using the IRC, which performed tumour assessment per the IMWG criteria⁹ for the response outcomes.

The sample size and power calculations (in phase II) were based on ORR, which had a prespecified hypothesis that was tested; analyses for all the other outcomes were descriptive. In the MonumenTAL-1 study, values of ORR and the 95% CI excluded the predetermined thresholds for the null hypotheses (30% for model cohorts A and C and 15% for model cohort B) for all 3 model cohorts (P values < 0.0001). Despite the lack of multiplicity adjustment¹⁰ for the ORR analyses, the P values were small, suggesting that these were not false-positive results. The review team noted the smaller sample size (N = 51) of model cohort B (patients who had received prior T-cell redirection therapy and who received either of the 2 recommended dosing regimens), further limiting the interpretation of results for these patients. Combining the 2 doses into 1 group in model cohort B does not allow for interpretation of dose-specific effects. According to the sponsor, the phase II prior T-cell redirection therapy cohort was designed at the same time as cohort A and therefore used the 0.4 mg/kg weekly dosing schedule. The phase I patients who had received prior T-cell redirection therapy were not from a specific cohort but were pooled based on prior T-cell redirection therapy; this pooled group therefore included patients receiving both the 0.4 mg/kg and the 0.8 mg/kg dose. Censoring rules for OS and PFS were prespecified and seem appropriate in the MonumenTAL-1 study. At the data cut-off date and across the model cohorts, ██ ██ ██ of the patients were lost to follow-up for OS and | ██ ██ of the patients withdrew consent to study participation. The impact of missing data on OS and PFS appears to be minimal. Patients with missing data or who were lost to follow-up were considered as not experiencing a PR or better for the response analyses, which is considered a conservative approach in this setting.

All planned efficacy and safety outcomes, including sensitivity analyses and supplementary analyses, were performed and reported in accordance with the prespecified statistical plan. Stopping rules were prespecified in the protocol. ORR was examined in prespecified clinically relevant subgroups; however, the sample sizes for the subgroup analyses were small and the analyses were exploratory in nature rather than designed to formally detect differences between subgroups.

The OS data in all 3 model cohorts were immature; therefore, the treatment benefit of OS based on the analysis at the latest data cut-off date would have been subject to a certain degree of uncertainty. At the data cut-off date and across model cohorts A and C, 39% to 58% of the patients received 1 or more subsequent antimyeloma therapy, with a median TTNT ranging from 9.2 months to 16.3 months, which may influence the assessment of the efficacy of talquetamab in relation to OS. In the analysis of PFS, patients were censored at the start of subsequent therapy.

The EORTC QLQ-C30 has been validated in patients with MM and showed evidence of reliability and responsiveness. The clinical expert consulted for this review commented that it is reasonable to use the literature-reported 10-point improvement from baseline value¹¹ in the EORTC QLQ-C30 scores as the clinically meaningful improvement threshold in data analysis. The size of the HRQoL-evaluable population in phase II gradually decreased over time. At cycle 7 day 1, only ██ ██ ███ of all treated patients in cohort A, ██ ██ ██ in cohort C, and ██ ██ ██ in cohort B provided data for the EORTC QLQ-C30 assessment. Thus, the results of the EORTC QLQ-C30 assessment were subject to bias due to incomplete reporting or missing data and, as EORTC QLQ-C30 score is a subjective outcome and due to the open-label study design, beyond the limitations of the study’s single-arm design.

External Validity

The review team noted some differences between the dosing of talquetamab used in the MonumenTAL-1 study and the recommended dosing in the final product monograph. In the product monograph for talquetamab,³⁵ 0.4 mg/kg is specified as step-up dose 3, following 2 preceding step-up doses of 0.01 mg/kg and 0.06 mg/kg. However, in the MonumenTAL-1 study, when 0.8 mg/kg SC every 2 weeks was the target dose (phase I part 2 dose expansion or phase II part 3 cohort C), 3 step-up doses of 0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg were used, with 0.3 mg/kg as step-up dose 3.^15,43 According to the sponsor, the change in the last step-up dose for the 0.8 mg/kg every 2 weeks SC dosing regimen from 0.3 mg/kg (as employed in the MonumenTAL-1 study) to 0.4 mg/kg was recommended to simplify drug labelling and harmonize the 2 RP2D dosing schedules (i.e., 0.4 mg/kg weekly SC and 0.8 mg/kg every 2 weeks SC).⁴⁷ The sponsor reported that the final population pharmacokinetic modelling report showed that the simulated talquetamab serum concentration-time profiles were comparable between the studied step-up dose schedule (0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg) and the proposed step-up dose schedule (0.01 mg/kg, 0.06 mg/kg, and 0.4 mg/kg) for the 0.8 mg/kg every 2 weeks SC dosing regimen, suggesting a similar safety and efficacy profile for the proposed dosing regimen as for the dosing regimen evaluated in the MonumenTAL-1 study. The sponsor further indicated that the safety profile of the proposed step-up dose schedule for the 0.8 mg/kg every 2 weeks SC regimen, particularly the CRS profile, has been established in the 0.4 mg/kg weekly SC cohort, as these proposed step-up doses (0.01 mg/kg, 0.06 mg/kg, and 0.4 mg/kg) are the same as the step-up doses in combination with the first treatment dose for the 0.4 mg/kg weekly SC dosing regimen, which was evaluated in the MonumenTAL-1 study.⁴⁷ The review team regards the sponsor’s explanations regarding the difference in the third step-up dose for the 0.8 mg/kg every 2 weeks SC dosing regimen of talquetamab as reasonable.

The inclusion and exclusion criteria and baseline characteristics of the MonumenTAL-1 study were generalizable to adults with r/r MM in clinical practice in Canada. However, there is a lack of ethnic diversity as most patients in the MonumenTAL-1 study were white (86% to 90%), with the next largest groups by ethnicity being Black or African American (6% to 8%) and Asian (1% to 4%). Previous studies in the US found that MM is twice as common in African American individuals than in Caucasian or Asian individuals.^7,12 The clinical expert pointed out that the patients in the MonumenTAL-1 study were younger (the mean age of patients who had and had not received prior T-cell redirection therapy was 65 years and 61 years, respectively) and had less severe disease than patients with r/r MM seen in clinical practice in Canada. The fact that the patient population in the MonumenTAL-1 study is not very diverse in ethnicity, is younger in age, and has milder disease severity than the general population of patients with r/r MM may impact the generalizability of the study results, although the extent of such influence is uncertain.

Dose adjustments were allowed in the trial, and the dose adjustment methods were outlined in the protocol. The clinical expert consulted for this review noted that the dose adjustments or modifications described in the MonumenTAL-1 study are also anticipated in a clinical practice setting to manage AEs while maintaining drug benefit. According to the inputs from the patient and clinician groups and the clinical expert, the MonumenTAL-1 study included outcomes that were regarded as relevant and important to patients, clinicians, and drug plans, including the survival, treatment response, HRQoL, and safety outcomes.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and randomized controlled trials identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for the outcomes considered most relevant to inform the review team’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^13,14

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Although GRADE guidance is not available for noncomparative studies, the review team assessed pivotal single-arm trials for study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for single-arm trials started at very low certainty with no opportunity for rating up.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for talquetamab in adult patients with r/r MM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, and have experienced disease progression on or after the last therapy. The selected outcomes for GRADE assessment include OS, PFS, ORR, DOR, CR or better rate, EORTC QLQ-C30, and notable harms for patients in model cohort A and model cohort C separately. The outcomes in model cohort B were not assessed using GRADE due to the small sample size and the exploratory nature of that population cohort.

Long-Term Extension Studies

The contents of this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

There are no longer-term extension studies evaluating talquetamab for adults with r/r MM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, and who have experienced disease progression on the last therapy. Long-term follow-up of the MonumenTAL-1 trial is currently under way.^16,17

Indirect Evidence

The sponsor provided nonrandomized comparative studies, which are summarized and appraised in the section on studies addressing gaps in the evidence from the systematic review.

Studies Addressing Gaps in the Systematic Review Evidence

The contents of this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team. The sponsor submitted evidence within the indirect treatment comparisons section of the submission that used IPD from included studies. These are therefore considered nonrandomized comparisons, thus the reference to them as such.

Objectives for the Summary of Studies Addressing Gaps

The objective of the submitted nonrandomized studies is to generate evidence comparing talquetamab to other key comparators in the PE model. The 3 nonrandomized studies presented in this section were commissioned and submitted by the sponsor as, at the time of this submission, there were no direct randomized comparisons of talquetamab to relevant comparators in Canada for the treatment of adult patients with triple-class exposed r/r MM with at least 3 prior lines of therapy who experienced disease progression on the last therapy.

Description of Studies Addressing Gaps

Sponsor-Submitted Nonrandomized Studies

Three nonrandomized studies were submitted that compared the efficacy of talquetamab to RWPC, teclistamab, and cilta-cel in patients with r/r MM who have received at least 3 prior lines of therapy. Studies were selected for inclusion in the comparisons if they assessed treatment for r/r MM, included patients (or a subset of patients) with triple-class exposed r/r MM who had received at least 3 prior lines of therapy, and reported sufficient efficacy outcome data. A systematic literature review was not conducted to identify studies informing the nonrandomized comparisons; however, key comparators were identified using the CADTH Provisional Algorithm.⁸ IPD from studies of talquetamab and the key comparators in the PE model (RWPC, teclistamab, and cilta-cel) were compared using IPTW, with the aim of balancing patient characteristics across groups. A summary of the study selection criteria is presented in Table 21.

Table 21: Study Selection Criteria and Methods for Nonrandomized Comparisons Submitted by the Sponsor

CR = complete response; DOR = duration of response; IMiD = immunomodulatory drug; IMWG = International Myeloma Working Group; mAb = monoclonal antibody; MM = multiple myeloma; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PI = proteasome inhibitor; RCT = randomized controlled trial; r/r MM = relapsed or refractory multiple myeloma; TCE = triple-class exposed; TTNT = time to next treatment; VGPR = very good partial response.

Source: The details included in the table are from the sponsor’s summary of clinical evidence.

Design of the Comparisons

Objectives

The following sponsor-submitted nonrandomized studies were conducted to generate relative efficacy data in support of the PE model:

• talquetamab (model cohort A and model cohort C) versus RWPC

• talquetamab (model cohort A and model cohort C) versus teclistamab

• talquetamab (model cohort A and model cohort C) versus cilta-cel.

Study Selection Methods

Best-available data, rather than a comprehensive systematic literature review, were used to select studies for the sponsor-submitted nonrandomized studies. Key comparators were identified using the CADTH Provisional Algorithm. Studies were included if they assessed treatment for r/r MM in patients who had received at least 3 prior lines of therapy and reported sufficient efficacy outcome data. As a full systematic review was not conducted, no information is available regarding the search strategy or methods used to screen articles. Data extraction was performed by a single reviewer and confirmed by a second reviewer to ensure accuracy and consistency. Quality assessment was not performed in this review. Consequently, no studies were excluded based on quality criteria, and potential risk of bias or quality issues in the comparator arms are unknown.

Analysis Methods for the Sponsor-Submitted Nonrandomized Studies

Talquetamab in MonumenTAL-1 Study Versus RWPC in LocoMMotion and MoMMent Studies^61,62

The study comparing talquetamab to RWPC used IPD from each treatment and IPTW methods, with ATT weights, to compare differences in ORR, CR or better rate, VGPR or better rate, DOR, PFS, TTNT, and OS. The 2 MonumenTAL-1 study cohorts, which received talquetamab at different dosing schedules (0.4 mg/kg weekly SC and 0.8 mg/kg every 2 weeks SC), were separately compared to the RWPC cohort derived from pooled data from 2 prospective cohort studies (LocoMMotion and MoMMent). Patients that received the following regimens were included in the LocoMMotion and MoMMent studies: pomalidomide-cyclophosphamide-dexamethasone; Pd; carfilzomib-cyclophosphamide-dexamethasone; Kd; carfilzomib-lenalidomide-dexamethasone; lenalidomide-dexamethasone; daratumumab-bortezomib-dexamethasone; belantamab mafodotin; panobinostat, bortezomib, and dexamethasone; elotuzumab, pomalidomide, and dexamethasone; ixazomib, lenalidomide, and dexamethasone; bortezomib, bendamustine, and dexamethasone; carfilzomib, pomalidomide, and dexamethasone; cyclophosphamide and dexamethasone; daratumumab, pomalidomide, and dexamethasone; melphalan and dexamethasone; and idecabtagene vicleucel.^61,62 Only patients from the RWPC cohort meeting the key eligibility criteria for phase II of the MonumenTAL-1 trial were included in the comparative effectiveness analyses. These criteria included having measurable disease defined by the IMWG criteria, at least 3 prior lines of therapy, documented evidence of progressive disease by IMWG criteria on or within 12 months of the patient’s last line of therapy, an ECOG Performance Status of 0 to 2, and no prior T-cell redirection therapy.^61,62

IPD were available for physician’s choice of therapy from the LocoMMotion and MoMMent studies and are outlined in Table 22.^63,64 Using IPD from the MonumenTAL-1 study and the LocoMMotion study combined with the MoMMent study, analyses were conducted using IPTW methods with ATT weights to compare the efficacy of talquetamab versus RWPC. The clinical cut-off dates were January 17, 2023, for the MonumenTAL-1 trial; October 27, 2022, for the LocoMMotion study; and March 13, 2023, for the MoMMent study. The median follow-up was 16.3 months in the MonumenTAL-1 study for both cohorts (18.8 months for the 0.4 mg/kg weekly cohort and 12.7 months for the 0.8 mg/kg every 2 weeks cohort), 26.4 months in the LocoMMotion study, and 9.3 months in the MoMMent study. The 2 MonumenTAL-1 study cohorts, which received talquetamab at different dosing schedules, were separately compared to the RWPC cohort.^61,62

The clinical experts consulted by the sponsor identified a priori a list of potential baseline factors that were important prognostic factors in the setting of later-line r/r MM (Table 22).^61,62 Multiple imputation by chained equations was used to impute missingness. Propensity scores were derived with a multivariable logistic regression using each cohort (the MonumenTAL-1 study versus the RWPC cohort) as the dependent variable and selected baseline prognostic variables as explanatory factors. To estimate the ATT population, patient weights were derived from the propensity scores using weighting formulas for the desired target population. The patients in the MonumenTAL-1 study were assigned a weight of 1, and the patients in the RWPC cohort were reweighted in terms of observed characteristics to become similar to the MonumenTAL-1 study population. Weightings were scaled such that they improved the balance of prognostic variables and summed to the original number of participants in the RWPC cohort. Baseline characteristics after weighting were provided for included IPD but were not broken down by analysis subsets.

The comparative efficacy of talquetamab versus RWPC was determined in terms of ORR, CR or better rate, VGPR or better rate, DOR, PFS, TTNT, and OS. Estimates of comparative efficacy were derived for both the unadjusted comparison (i.e., talquetamab versus RWPC before IPTW) and the adjusted comparison (i.e., with IPTW). For binary outcomes (i.e., ORR, CR or better rate, and VGPR or better rate), weighted logistic regression was used to estimate odds ratios, response rate ratios, and rate differences with the respective 95% CIs. For time-to-event outcomes (i.e., DOR, PFS, OS, and TTNT), a weighted Cox proportional hazards model was used to estimate HRs and respective 95% CIs.^61,62 Assessment of the assumption of proportional hazards for survival outcomes was based on visual inspection of the log-cumulative hazard plot, visual inspection of the Schoenfeld residuals plot, and performance of the Grambsch-Therneau test.

Sensitivity analyses included ATT with all variables, multivariable regression, average treatment effect in the overlap, average treatment effect, and ECOG Performance Status matching. E-values were also reported as a measure for estimating the impact of unmeasured confounders.

Talquetamab in MonumenTAL-1 Study Versus Teclistamab in MajesTEC-1 Study⁶⁵

The study comparing talquetamab to teclistamab used IPTW methods with ATT weights to compare differences in ORR, CR or better rate, VGPR or better rate, DOR, PFS, TTNT, and OS. The 2 MonumenTAL-1 study cohorts, which received talquetamab at different dosing schedules (0.4 mg/kg weekly SC and 0.8 mg/kg every 2 weeks SC), were separately compared to the teclistamab cohort, which was formed by the MajesTEC-1 phase I/II single-arm trial. Only patients from the MajesTEC-1 study meeting the key eligibility criteria for phase II of the MonumenTAL-1 trial were included in the comparative effectiveness analyses. These criteria include having measurable disease defined by the IMWG criteria, at least 3 prior lines of therapy, documented evidence of progressive disease by IMWG criteria on or within 12 months of the patient’s last line of therapy, an ECOG Performance Status of 0 to 2, and no prior T-cell redirection therapy.⁶⁵

Using IPD from both the MonumenTAL-1 trial and the MajesTEC-1 trial, comparisons were conducted using IPTW methods with ATT weights to compare the efficacy of talquetamab versus teclistamab in patients with triple-class exposed r/r MM. The MonumenTAL-1 study clinical cut-off date was January 17, 2023, with a median follow-up of 18.8 months for the 0.4 mg/kg weekly SC cohort and 12.8 months for the 0.8 mg/kg every 2 weeks SC cohort. The MajesTEC-1 study clinical cut-off date was January 4, 2023, with a median follow-up of 22.8 months. The 2 MonumenTAL-1 study cohorts, which received talquetamab at different dosing schedules, were separately compared with the all-treated population in the MajesTEC-1 trial.⁶⁵

To allow for the MajesTEC-1 cohort to be reweighted to align with the MonumenTAL-1 study cohort, IPTW with ATT was chosen as the statistical method for the main analysis, which included all known prognostic factors with sufficient data as identified by the sponsor’s clinical experts.⁶⁵ Propensity scores were derived through a multivariable logistic regression, using each cohort (the MonumenTAL-1 study versus the MajesTEC-1 study) as the dependent variable and selected baseline prognostic variables as explanatory factors. Missing data were imputed using multiple imputation by chained equations. To estimate the ATT population, patient weights were derived from the propensity scores using weighting formulas for the desired target population. The patients in the MonumenTAL-1 study were assigned a weight of 1, and the patients in the MajesTEC-1 cohort were reweighted to become similar to the MonumenTAL-1 study population. Weightings were scaled such that they improved the balance of prognostic variables and summed to the original number of participants in the MajesTEC-1 cohort. Baseline characteristics after weighting were provided for included IPD but were not broken down by analysis subsets.

The comparative efficacy of talquetamab versus teclistamab was determined in terms of ORR, CR or better rate, VGPR or better rate, DOR, PFS, TTNT, and OS. Estimates of comparative efficacy were derived for both the unadjusted comparison (i.e., talquetamab versus teclistamab before IPTW) and the adjusted comparison (i.e., with IPTW). For binary outcomes (e.g., ORR, CR or better rate, and VGPR or better rate), an unweighted logistic regression including the selected baseline characteristics as prognostic variables was used to estimate the odds ratio, and rate difference with the respective 95% CIs. For the time-to-event outcomes (e.g., DOR, PFS, OS, and TTNT), an unweighted Cox proportional hazards model including the selected baseline characteristics as prognostic variables was used to estimate the HR and its respective 95% CI. For all time-to-event analyses, observed and weighted survival curves were reported, including the number of participants at risk over time.⁶⁵ Assessment of the assumption of proportional hazards for survival outcomes was based on visual inspection of the log-cumulative hazard plot, visual inspection of the Schoenfeld residuals plot, and performance of the Grambsch-Therneau test.

Sensitivity analyses included ATT with all variables, multivariable regression, average treatment effect in the control, average treatment effect in the overlap, average treatment effect, and ECOG Performance Status matching. E-values were also reported as a measure for estimating the impact of unmeasured confounders.

Talquetamab in MonumenTAL-1 Study Versus Cilta-Cel in CARTITUDE-1 Study⁶⁶

The nonrandomized study comparing talquetamab to cilta-cel used IPTW methods with ATT weights to compare differences in ORR, CR or better rate, VGPR or better rate, DOR, PFS, TTNT, and OS. The 2 MonumenTAL-1 study cohorts, which received talquetamab at different dosing schedules (0.4 mg/kg weekly SC and 0.8 mg/kg every 2 weeks SC), were separately compared to the cilta-cel cohort, which was formed from the CARTITUDE-1 phase I/II single-arm trial.

Both the MonumenTAL-1 and CARTITUDE-1 trials included patients diagnosed with MM according to IMWG criteria, requiring measurable disease and specific serum or urine M-protein levels. The MonumenTAL-1 trial enrolled patients with an ECOG Performance Status of 0 to 2 and required patients to have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody. The CARTITUDE-1 trial had similar inclusion criteria but required patients to have disease that was double refractory to an IMiD and a PI or to have received at least 3 prior lines of therapy. Both trials mandated documented evidence of disease progression within 12 months of the last line of therapy, based on IMWG criteria, and included patients with disease progression within 6 months whose disease was refractory or nonresponsive to their most recent therapy. Additionally, both trials required patients to meet certain clinical laboratory values and had similar exclusion criteria.⁶⁶

Using IPD from the MonumenTAL-1 trial and from the CARTITUDE-1 trial, IPTW methods with ATT weights were used to compare the efficacy of talquetamab versus cilta-cel in patients with triple-class exposed r/r MM. The MonumenTAL-1 study clinical cut-off date was January 17, 2023, with a median follow-up of 18.8 months for the 0.4 mg/kg weekly SC cohort and 12.8 months for the 0.8 mg/kg every 2 weeks SC cohort. The CARTITUDE-1 trial clinical cut-off date was January 2022, with a median follow-up time of 29.0 months. The 2 MonumenTAL-1 study cohorts, which received talquetamab at different dosing schedules, were separately compared with the intention-to-treat population in the CARTITUDE-1 trial.⁶⁶

IPTW with ATT was chosen as the statistical method for the main analysis, which included all prognostic factors with sufficient data, as identified by the sponsor’s clinical expert (Table 22).⁶⁶ Propensity scores were derived through a multivariable logistic regression, using each cohort (the MonumenTAL-1 study versus the CARTITUDE-1 study) as the dependent variable and selected baseline prognostic variables as explanatory factors. Missing data were imputed using multiple imputation by chained equations. To estimate the ATT population, patient weights were derived from the propensity scores using weighting formulas for the desired target population. The patients in the MonumenTAL-1 study were assigned a weight of 1, and the patients in the CARTITUDE-1 study were reweighted to become similar to the MonumenTAL-1 study population. Weightings were scaled such that they improved the balance of prognostic variables and summed to the original number of participants in the CARTITUDE-1 study cohort. Baseline characteristics after weighting were provided for included IPD but were not broken down by analysis subsets.

The comparative effectiveness of talquetamab versus cilta-cel was determined in terms of ORR, CR or better rate, VGPR or better rate, DOR, PFS, TTNT, and OS. Estimates of comparative effectiveness were derived for both the unadjusted comparison (i.e., talquetamab versus cilta-cel before IPTW) and the adjusted comparison (i.e., with IPTW). For binary outcomes (e.g., ORR, CR or better rate, and VGPR or better rate), a weighted logistic regression was used to estimate odds ratios with the respective 95% CIs and rate differences. Response rate ratios were estimated using the same approach. For the time-to-event outcomes (e.g., DOR, PFS, OS, and TTNT), a weighted Cox proportional hazards model was used to estimate HRs and respective 95% CIs. For all time-to-event analyses, observed and weighted survival curves were reported, including the number of participants at risk over time.⁶⁶

Sensitivity analyses included ATT with all variables, multivariable regression, average treatment effect in the overlap, average treatment effect, average treatment effect in the control, and performance status matching. E-values were also reported as a measure for estimating the impact of unmeasured confounders.

Table 22: Sponsor-Submitted Indirect Treatment Comparison Analysis Methods

ATE = average treatment effect; ATO = average treatment effect in the overlap; ATT = average treatment effect in the treated; CI = confidence interval; cilta-cel = ciltacabtagene autoleucel; CR = complete response; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; IPD = individual patient data; IPTW = inverse probability treatment weighting; ISS = International Staging System; MM = multiple myeloma; NA = not applicable; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; q.2.w. = every 2 weeks; r/r MM = relapsed or refractory multiple myeloma; RWPC = real-world physician’s choice of therapy; SC = subcutaneous; SMD = standardized mean difference; TTNT = time to next treatment; VGPR = very good partial response; vs. = versus.

Sources: Janssen Research & Development, data on file;⁶¹ Einsele et al.(2024);⁶² Janssen Research & Development, data on file;⁶⁵ Janssen Research & Development, data on file.⁶⁶ The details included in the table are from the sponsor’s summary of clinical evidence.

Results of the Nonrandomized Comparisons

Summary of Included Studies: Sponsor-Submitted Nonrandomized Comparisons Supporting PE Model

Talquetamab in MonumenTAL-1 Study Versus RWPC in LocoMMotion and MoMMent Studies^61,62

The MonumenTAL-1 study is an ongoing phase I/II, open-label, multicentre clinical trial as described in earlier sections of this report. The LocoMMotion study (N = 248) is a prospective, multinational, observational study of RWPC treatments in patients with r/r MM who have received at least 3 prior lines of therapy or who have disease that is double refractory to an IMiD and a PI. It enrolled 248 participants from 76 sites across Europe and the US between August 2019 and October 2020, with a clinical cut-off date in October 2022 and a median follow-up of 26.4 months. The primary end point is ORR, with secondary end points including CR, VGPR, stringent CR, DOR, PFS, TTNT, and OS. The MoMMent study (N = 54), similar to the LocoMMotion study, is a prospective observational study documenting RWPC and outcomes in patients with triple-class exposed disease, with 2 periods: patients who received an PI, an IMiD, and an anti-CD38 monoclonal antibody (period 1); patients who additionally received BCMA-targeted therapy (period 2). Recruitment began in November 2021 across 51 sites in Europe, with a clinical cut-off date in March 2023 and a median follow-up of 9.3 months. The primary end point is ORR, with secondary end points mirroring those in the LocoMMotion study.

A total of 177 participants (58.6%) from the LocoMMotion and MoMMent studies met the MonumenTAL-1 study inclusion criteria and were eligible for analysis. The selected prognostic factors were refractory status, ISS stage, time to progression on the last regimen, presence of extramedullary plasmacytoma, number of prior lines of therapy, years since MM diagnosis, average duration of prior lines of therapy, age, hemoglobin levels, LDH levels, creatinine clearance, ECOG Performance Status, sex, type of MM, prior stem cell transplant, race, and cytogenetic profile. In the main analyses, no variables required imputation for the MonumenTAL-1 study population. For the RWPC cohort, the following proportions of the prognostic factors required imputation: ISS stage (19.8%), LDH levels (17.5%), type of MM (23.7%), and race (20.3%). Cytogenetic profile was excluded from the main analyses due to a high degree of missingness (44.1% missing). Additionally, race was not included in the main analyses due to extreme weights after imputation. However, both race and cytogenetic profile were adjusted for in a sensitivity analysis. Imputation was not done for cytogenetic profile; instead, “missing” was added as a categorical variable in the sensitivity analysis, including all variables, with multiple imputation by chained equations used to impute missingness for race.

Before weighting, both the 0.4 mg/kg weekly SC cohort and the 0.8 mg/kg every 2 weeks SC cohort in the MonumenTAL-1 study exhibited several baseline differences compared to the RWPC cohort. Compared with the 0.4 mg/kg cohort, more patients receiving RWPC had triple-refractory disease (22.9% versus 10.3%) and fewer had penta-refractory disease (21.4% versus 33.3%). Also, a higher percentage of patients receiving RWPC were in ISS stage III (23.7% versus 17.1%) and a lower percentage had extramedullary plasmacytomas (11.5% versus 23.9%). Fewer patients receiving RWPC had experienced disease progression in less than 3 months on their last regimen (16.8% versus 30.8%), and a smaller proportion were younger than 65 years (31.3% versus 43.6%). Similarly, compared with the 0.8 mg/kg cohort, the RWPC cohort had more patients with triple-refractory disease (22.9% versus 16.8%) and fewer patients with penta-refractory disease (21.4% versus 28.3%), along with a higher proportion of patients in ISS stage I (37.4% versus 42.5%). Also, fewer patients receiving RWPC had extramedullary plasmacytomas (11.5% versus 24.8%), fewer had experienced disease progression in less than 3 months on their last regimen (16.8% versus 30.1%), and fewer were younger than 65 years (31.3% versus 41.6%).

After ATT weighting, the balance between the MonumenTAL-1 study cohorts and the RWPC cohort improved. For the 0.4 mg/kg cohort, the standardized mean difference (SMD) for refractory status dropped to 0.141 and for ISS stage to 0.119. The overall balance improved, with the mean SMD decreasing from 0.209 to 0.093 and the percentage of SMDs that were less than or equal to 0.1 increasing from 20% to 47%. For the 0.8 mg/kg cohort, the SMD for refractory status reduced to 0.123 and for ISS stage to 0.058. The mean SMD decreased from 0.214 to 0.089, and the percentage of SMDs that were less than or equal to 0.1 increased from 7% to 53%.

A further summary of the characteristics of the studies used to generate the comparison is provided in Table 23.

Talquetamab in MonumenTAL-1 Study Versus Teclistamab in MajesTEC-1 Study⁶⁵

A total of 165 participants from the MajesTEC-1 study met the MonumenTAL-1 study inclusion criteria and were eligible for the main analysis. The prognostic factors were refractory status, ISS stage, time to progression on the last regimen, presence of extramedullary plasmacytoma, number of prior lines of therapy, years since MM diagnosis, average duration of prior lines of therapy, age, hemoglobin levels, LDH levels, creatinine clearance, ECOG Performance Status, sex, type of MM, prior stem cell transplant, race, and cytogenetic profile. Low-risk imputation was used to impute missingness. For the MonumenTAL-1 study 0.4 mg/kg weekly SC cohort, no variables required imputation, and for the MonumenTAL-1 study 0.8 mg/kg every 2 weeks SC cohort, ISS stage required imputation (0.7% missing). For the MajesTEC-1 study, low-risk imputation was used to impute missingness for ISS stage (1.8% missing), years since MM diagnosis (0.6% missing), time to progression on last regimen (1.2% missing), and average duration of prior lines of therapy (0.6% missing). Although data were missing for cytogenetic profile in both MonumenTAL-1 study cohorts (7.7% missing in 0.4 mg/kg weekly and 11.7% missing in 0.8 mg/kg every 2 weeks) and the MajesTEC-1 study cohort (10.3% missing), an imputation was not done for cytogenetic profile; instead, “missing” was added as a categorical variable.

Before weighting, both the 0.4 mg/kg weekly SC cohort and the 0.8 mg/kg every 2 weeks SC cohort in the MonumenTAL-1 study exhibited several baseline differences compared to the MajesTEC-1 study cohort. More patients were in ISS stage III in the MonumenTAL-1 study 0.4 mg/kg cohort (19.6% versus 12.1% in the MajesTEC-1 study cohort). Additionally, fewer patients in the MonumenTAL-1 study 0.4 mg/kg cohort had extramedullary plasmacytomas (23.1% versus 17%) and were younger than 65 years (45.5% versus 52.1%). Similar trends were observed for the MonumenTAL-1 study 0.8 mg/kg cohort, which had more patients in ISS stage III (24.1% versus 12.1% in the MajesTEC-1 study cohort) and a higher proportion of patients with extramedullary plasmacytomas (25.5% versus 17%). Differences in refractory status showed more patients with triple-class refractory disease in the MonumenTAL-1 study 0.8 mg/kg cohort than in the MajesTEC study cohort (16.6% versus 12.1%), and age distribution also varied, with more patients aged 65 years or older in the MonumenTAL-1 study 0.8 mg/kg cohort (56.6% versus 47.9%).

After ATT weighting, the balance between the MonumenTAL-1 study cohorts and the MajesTEC-1 study cohort improved. For the 0.4 mg/kg cohort, the SMD for refractory status dropped to 0.064 and for ISS stage to 0.036. The overall mean SMD decreased from 0.107 to 0.032, and the percentage of SMDs that were less than or equal to 0.1 increased from 41% to 100%. In the 0.8 mg/kg cohort, similar improvements were seen, with the SMD for refractory status reducing to 0.083 and for ISS stage to 0.054. The overall mean SMD decreased from 0.117 to 0.034, and the percentage of SMDs that were less than or equal to 0.1 increased from 47% to 100%. A further summary of the characteristics of the studies used to generate the indirect treatment comparison (ITC) are provided in Table 23.

Talquetamab in MonumenTAL-1 Study Versus Cilta-Cel in CARTITUDE-1 Study⁶⁶

The CARTITUDE-1 study intention-to-treat population had 113 participants, with 93 participants in the subgroup analysis for those who had received at least 4 prior lines of therapy. The participant numbers for each analysis are detailed in Table 22: the main analysis included 113 participants in the CARTITUDE-1 study, 143 in the MonumenTAL-1 study 0.4 mg/kg weekly cohort, and 145 in the MonumenTAL-1 study 0.8 mg/kg every 2 weeks cohort; the subgroup analysis included 93 participants from the CARTITUDE-1 study, 117 from the MonumenTAL-1 study 0.4 mg/kg weekly cohort, and 113 from the MonumenTAL-1 study 0.8 mg/kg every 2 weeks cohort.

The prognostic factors were refractory status, ISS stage, time to progression on the last regimen, presence of extramedullary plasmacytoma, number of prior lines of therapy, years since MM diagnosis, average duration of prior lines of therapy, age, hemoglobin levels, LDH levels, creatinine clearance, ECOG Performance Status, sex, type of MM, prior stem cell transplant, race, and cytogenetic profile. For the MonumenTAL-1 study 0.4 mg/kg weekly SC cohort, no variables required imputation, and for the MonumenTAL-1 study 0.8 mg/kg every 2 weeks SC cohort, low-risk imputation was used to impute missingness for ISS stage (0.7% missing in the 0.8 mg/kg every 2 weeks cohort). For the CARTITUDE-1 study, ISS stage had 4.4% missing data (at apheresis). Imputation was done by using ISS stage (at infusion) whenever available; if this variable was missing as well, then low-risk imputation was used to impute the remaining missingness.

Before weighting, the MonumenTAL-1 study 0.4 mg/kg weekly SC cohort (143 participants) and the 0.8 mg/kg every 2 weeks SC cohort (145 participants) displayed several baseline differences compared to the CARTITUDE-1 study intention-to-treat cohort (113 participants). The MonumenTAL-1 study 0.4 mg/kg weekly cohort had a higher percentage of patients in ISS stage III (19.6% versus 12.4% in the CARTITUDE-1 study) and a lower percentage in stage I (43.4% versus 59.3%), more patients with extramedullary plasmacytomas (23.1% versus 14.2%), and a higher proportion of patients who had experienced disease progression in less than 3 months on their last regimen (30.8% versus 41.6%). Similarly, the MonumenTAL-1 study 0.8 mg/kg every 2 weeks cohort had more patients in ISS stage III (24.1% versus 12.4% in the CARTITUDE-1 study) and fewer in stage I (44.8% versus 59.3%), more patients with extramedullary plasmacytomas (25.5% versus 14.2%), and fewer patients aged 65 years or older (56.6% versus 38.1%).

After ATT weighting, these differences were reduced in both cohorts. In the 0.4 mg/kg weekly cohort, the SMD for refractory status decreased from 0.453 to 0.051, for ISS stage from 0.329 to 0.095, and for extramedullary plasmacytomas from 0.231 to 0.134. The overall mean SMD improved from 0.275 to 0.094. For the 0.8 mg/kg every 2 weeks cohort, the SMD for refractory status dropped from 0.656 to 0.220, for ISS stage from 0.349 to 0.122, and for extramedullary plasmacytomas from 0.288 to 0.006. The overall mean SMD improved from 0.261 to 0.144, with the percentage of SMDs greater than 0.1 decreasing from 82% to 47% and the percentage of SMDs greater than 0.2 decreasing from 71% to 6%.

A further summary of the characteristics of the studies used to generate the observational comparisons is provided in Table 23.

Table 23: Assessment of Homogeneity Across Studies Informing Sponsor-Submitted Observational Comparisons for PE Model

ATT = average treatment effect in the treated; BCMA = B-cell maturation antigen; cilta-cel = ciltacabtagene autoleucel; CR = complete response; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; FLC = free light chain; HSCT = hematopoietic stem cell transplant; IMiD = immunomodulatory drug; IMWG = International Myeloma Working Group; ISS = international staging system; MM = multiple myeloma; NR = not reported; ORR = overall response rate; OS = overall survival; PE = pharmacoeconomic; PFS = progression-free survival; PI = proteasome inhibitor; PR = partial response; q.2.w. = every 2 weeks; RWPC = real-world physician’s choice of therapy; SC = subcutaneous; sCR = stringent complete response; TTNT = time to next treatment; VGPR = very good partial response; vs. = versus.

Sources: Sponsor’s submissions;^61,65,66 Einsele et al.(2024).^62f

Efficacy Results

Efficacy For Nonrandomized Studies Included in PE Model

Talquetamab in MonumenTAL-1 Study Versus RWPC in LocoMMotion and MoMMent Studies

The results of the nonrandomized studies conducted using IPTW with ATT weights to compare talquetamab versus RWPC suggest talquetamab is associated with better response and survival outcomes in patients with triple-class exposed r/r MM who received at least 3 previous lines of therapy. The comparisons demonstrate that talquetamab (at either dose) results in better ORR, PFS, OS, and TTNT. RWPC resulted in a numerically comparable DOR point estimate without excluding the null from the CI compared to 0.4 mg/kg weekly SC talquetamab; however, 0.8 mg/kg every 2 weeks SC talquetamab resulted in better DOR.^61,62 Details for each outcome are presented in the following subsections.

Overall Response Rate

The observed ORR for talquetamab in the 0.4 mg/kg weekly SC cohort was 74.1%, versus 37.3% in the RWPC cohort. After reweighting, the RWPC ORR was 27.8%. The adjusted response rate ratio for talquetamab versus RWPC was 2.67 (95% CI, 1.90 to 3.74; P < 0.0001), suggesting that treatment with talquetamab increased the likelihood of experiencing ORR. Figure 2 provides further details.

The observed ORR for talquetamab in the 0.8 mg/kg every 2 weeks SC cohort was 71.7%, versus 37.3% in the RWPC cohort. After reweighting, the RWPC ORR was 27.3%. The adjusted response rate ratio for talquetamab versus RWPC was 2.62 (95% CI, 1.86 to 3.69; P < 0.0001), suggesting that treatment with talquetamab increased the likelihood of experiencing ORR. Figure 2 provides further details.^61,62

The results of the sensitivity analyses for the 2 cohorts, including the analysis that adjusted for all variables, aligned with the main analyses.^61,62

Figure 2: Summary of Results for ORR for Talquetamab Versus RWPC [Redacted]

Duration of Response

The unadjusted HR in the 0.4 mg/kg weekly SC cohort for DOR was 0.92 (95% CI, 0.61 to 1.39; P = 0.6957) for talquetamab versus RWPC. Results from the main analysis using IPTW with ATT weights showed an HR of 0.77 (95% CI, 0.49 to 1.23; P = 0.2766) (Figure 3). The results of the sensitivity analyses, including the analysis that adjusted for all variables, aligned with the main analyses.^61,62

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of DOR for the 0.4 mg/kg weekly SC cohort are presented in Figure 4. For the MonumenTAL-1 study population, the median DOR for the 0.4 mg/kg weekly SC cohort was 9.49 months (95% CI, 6.67 to 13.34 months). In the unadjusted RWPC population, the median DOR was 9.00 months (95% CI, 5.75 to 14.42 months) compared to ████ ██████ ████ ███ █████ ██████ in the adjusted main analysis.⁶¹

The unadjusted HR in the 0.8 mg/kg every 2 weeks SC cohort for DOR was 0.45 (95% CI, 0.27 to 0.75; P = 0.0021) for talquetamab versus RWPC. Results from the main analysis using IPTW with ATT weights showed an HR of 0.43 (95% CI, 0.26 to 0.72; P = 0.0015) (Figure 3). The results of the sensitivity analyses, including the analysis that adjusted for all variables, aligned with the main analyses.^61,62

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of DOR for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 5.^61,62

Figure 3: Summary of Results for DOR for Talquetamab Versus RWPC [Redacted]

Figure 4: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of DOR for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 5: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of DOR for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

Progression-Free Survival

The unadjusted HR in the 0.4 mg/kg weekly SC cohort for PFS was 0.70 (95% CI, 0.53 to 0.92; P = 0.0093) for talquetamab versus RWPC. Results from the main analysis using IPTW with ATT weights showed an HR of 0.52 (95% CI, 0.39 to 0.71; P < 0.0001), suggesting talquetamab increases the time to progression or death (Figure 6). The results of the sensitivity analyses, including the analysis that adjusted for all variables, aligned with the main analyses.^61,62

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of PFS for the 0.4 mg/kg weekly SC cohort are presented in Figure 7.^61,62

The unadjusted HR in the 0.8 mg/kg every 2 weeks SC cohort for PFS was 0.49 (95% CI, 0.36 to 0.67; P < 0.0001) for talquetamab versus RWPC. Results from the main analysis using IPTW with ATT weights showed an HR of 0.40 (95% CI, 0.29 to 0.56; P < 0.0001), suggesting that treatment with talquetamab increased the time to progression or death (Figure 6). The results for the sensitivity analyses, including the analysis that adjusted for all variables, aligned with the main analyses.^61,62

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of PFS for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 8.^61,62

Figure 6: Summary of Results for PFS for Talquetamab Versus RWPC [Redacted]

Figure 7: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of PFS for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 8: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of PFS for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

Overall Survival

The unadjusted HR for OS in the 0.4 mg/kg weekly SC cohort was 0.50 (95% CI, 0.35 to 0.70; P < 0.0001) for talquetamab versus RWPC. Results from the main analysis using IPTW with ATT weights showed an HR of 0.36 (95% CI, 0.25 to 0.53; P < 0.0001), suggesting that treatment with talquetamab reduced the time to death compared with RWPC (Figure 9). The results for the sensitivity analyses, including the analysis that adjusted for all variables, aligned with the main analyses.^61,62

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of OS for the 0.4 mg/kg weekly SC cohort are presented in Figure 10.^61,62

The unadjusted HR for OS in the 0.8 mg/kg every 2 weeks SC cohort was 0.44 (95% CI, 0.30 to 0.66; P < 0.0001) for talquetamab versus RWPC. Results from the main analysis using IPTW with ATT weights showed an HR of 0.37 (95% CI, 0.23 to 0.60; P < 0.0001), suggesting that treatment with talquetamab reduced the time to death (Figure 9). The results for the sensitivity analyses, including the analysis that adjusted for all variables, aligned with the main analyses.^61,62

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of OS for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 11.^61,62

Figure 9: Summary of Results for OS for Talquetamab Versus RWPC [Redacted]

Figure 10: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of OS for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 11: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of OS for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

CR or Better Rate

The observed CR or better rate for talquetamab in the 0.4 mg/kg weekly SC cohort was 33.6%, versus 0.6% in the RWPC cohort. After reweighting, the RWPC CR or better rate was 0.4%. The adjusted response rate ratio for talquetamab versus RWPC was 78.05 (95% CI, 8.11 to 751.03; P = 0.0002). The observed CR or better rate for talquetamab in the 0.8 mg/kg every 2 weeks SC cohort was 38.6%, versus 0.6% in the RWPC cohort. After reweighting, the RWPC CR or better rate was 0.4%. The adjusted response rate ratio for talquetamab versus RWPC was 101.14 (95% CI, 9.19 to 1,113.06; P = 0.0002). The results of the sensitivity analyses for the 2 cohorts, including the analysis that adjusted for all variables, aligned with the main analyses, with the results remaining significantly in favour of talquetamab. As CR or better was not reported for patients receiving RWPC within the 4 or more prior lines of therapy subgroup, no analyses were conducted to compare talquetamab to RWPC for this subgroup.

Time to Next Treatment

The unadjusted HR in the 0.4 mg/kg weekly SC cohort for TTNT was 0.62 (95% CI, 0.48 to 0.81; P = 0.0003) for talquetamab versus RWPC. Results from the main analysis using IPTW with ATT weights showed an HR of 0.48 (95% CI, 0.36 to 0.64; P < 0.0001), suggesting that treatment with talquetamab increased the time to starting a subsequent treatment (Figure 12). The results for the sensitivity analyses, including the analysis that adjusted for all variables, aligned with the main analyses.^61,62

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of TTNT for the 0.4 mg/kg weekly SC cohort are presented in Figure 13.^61,62

The unadjusted HR in the 0.8 mg/kg every 2 weeks SC cohort for TTNT was 0.48 (95% CI, 0.36 to 0.64; P < 0.0001) for talquetamab versus RWPC. Results from the main analysis using IPTW with ATT weights showed an HR of 0.39 (95% CI, 0.29 to 0.54; P < 0.0001), suggesting that treatment with talquetamab increased the time to starting a subsequent treatment by 61% compared with RWPC (Figure 12).^61,62

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of TTNT for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 14.^61,62

Figure 12: Summary of Results for TTNT for Talquetamab Versus RWPC [Redacted]

Figure 13: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of TTNT for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 14: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of TTNT for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

Talquetamab in MonumenTAL-1 Study Versus Teclistamab in MajesTEC-1 Study

The results of the nonrandomized study conducted using IPTW with ATT weights to compare talquetamab versus teclistamab indicates that, in most outcomes, neither drug was more favourable than the other. In certain outcomes, specifically ORR and OS, the results suggest that talquetamab may be more favourable. However, it was noted that teclistamab showed a more favourable DOR than 0.4 mg/kg weekly talquetamab, and in all other outcomes the null was included in the CI.

Overall Response Rate

The observed ORR for talquetamab in the 0.4 mg/kg weekly SC cohort was ████% versus █████ in the teclistamab cohort. After reweighting, the ORR for teclistamab was ████%. The adjusted response rate ratio for talquetamab versus teclistamab was ████ ████ ███ █████ █████ █████████, suggesting that treatment with talquetamab increased the likelihood of experiencing ORR (Figure 15).⁶⁵

The observed ORR for talquetamab in the 0.8 mg/kg every 2 weeks SC cohort was ██████ versus █████ in the teclistamab cohort. After reweighting, the ORR for teclistamab was ██████ The adjusted response rate ratio for talquetamab versus teclistamab was ████ ████ ███ █████ █████ █████████, suggesting that treatment with talquetamab increased the likelihood of experiencing ORR (Figure 15). The results of the sensitivity analyses were similar to those of the primary analyses.⁶⁵

Figure 15: Summary of Results for ORR for Talquetamab Versus Teclistamab [Redacted]

Duration of Response

The unadjusted HR in the 0.4 mg/kg weekly SC cohort for DOR was ████ ████ ███ █████ █████ ████████) for talquetamab versus teclistamab. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ ██████████ (Figure 16).⁶⁵

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of DOR for the 0.4 mg/kg weekly SC cohort are presented in Figure 17.⁶⁵

The unadjusted HR in the 0.8 mg/kg every 2 weeks SC cohort for DOR was ████ ████ ███ █████ █████ ████████ for talquetamab versus teclistamab. Results from the main analysis using IPTW with ATT weights showed an HR of 1 ███ ████ ███ █████ █████ █████████████████ ███. The results of the sensitivity analyses are aligned with the main analyses.⁶⁵

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of DOR for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 18.⁶⁵

Figure 16: Summary of Results for DOR for Talquetamab Versus Teclistamab [Redacted]

Figure 17: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of DOR for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 18: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of DOR for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

Progression-Free Survival

The unadjusted HR in the 0.4 mg/kg weekly SC cohort for PFS was ████ ████ ███ █████ █████ █████████ for talquetamab versus teclistamab. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ █████████ (Figure 19). The results of the sensitivity analyses are aligned with the main analyses. The results of the 4 or more prior lines of therapy subgroup analyses aligned with the primary analyses.⁶⁵

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of PFS for the 0.4 mg/kg weekly SC cohort are presented in Figure 20.⁶⁵

The unadjusted HR in the 0.8 mg/kg every 2 weeks SC cohort for PFS was ████ ████ ███ █████ █████ █████████ for talquetamab versus teclistamab. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ █████████ (Figure 19).⁶⁵

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of PFS for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 21.⁶⁵

Figure 19: Summary of Results for PFS for Talquetamab Versus Teclistamab [Redacted]

Figure 20: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of PFS for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 21: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of PFS for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

Overall Survival

The unadjusted HR in the 0.4 mg/kg weekly SC cohort for OS was ████ ████ ███ █████ █████ ████████ for talquetamab versus teclistamab. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ ████████, suggesting that treatment with talquetamab increased the time to death (Figure 22). The results of the sensitivity analyses are aligned with the main analyses, favouring talquetamab over teclistamab for OS. The results of the 4 or more prior lines of therapy subgroup analyses are aligned with the primary analyses.⁶⁵

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of OS for the 0.4 mg/kg weekly SC cohort are presented in Figure 23.⁶⁵

The unadjusted HR in the 0.8 mg/kg every 2 weeks SC cohort for OS was ████ ████ ███ █████ █████ █████████ for talquetamab versus teclistamab. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ █████████, suggesting that treatment with talquetamab increased the time to death compared to teclistamab (Figure 22). The results of the sensitivity analyses are aligned with the main analyses.⁶⁵

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of OS for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 24.⁶⁵

Figure 22: Summary of Results for OS for Talquetamab Versus Teclistamab [Redacted]

Figure 23: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of OS for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 24: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of OS for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

CR or Better Rate

The observed CR or better rate for talquetamab in the 0.4 mg/kg weekly SC cohort was 33.6%, versus 45.5% in the teclistamab cohort. After reweighting, the CR or better rate for teclistamab was 41.1%. The adjusted response rate ratio for talquetamab versus teclistamab was ████ ████ ███ █████ █████ █████████. The observed CR or better rate for talquetamab in the 0.8 mg/kg every 2 weeks SC cohort was 38.6%, versus 45.5% in the teclistamab cohort. After reweighting, the CR or better rate for teclistamab was █████. The adjusted response rate ratio for talquetamab versus teclistamab was ████ ████ ███ █████ █████ █████████. The results of the sensitivity analyses for the 2 cohorts were similar to those of the main analyses, with no significant difference in the CR or better rate between treatment with talquetamab or teclistamab. The results of the 4 or more prior lines of therapy subgroup analyses for the 2 cohorts are aligned with the primary analyses.

Time to Next Treatment

The unadjusted HR in the 0.4 mg/kg weekly SC cohort for TTNT was ████ ████ ███ █████ █████ █████████ for talquetamab versus teclistamab. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ ████████ (Figure 25). The results of the sensitivity analyses are aligned with the main analyses, with the null included in the 95% CI between talquetamab and teclistamab. The results of the 4 or more prior lines of therapy subgroup analyses are aligned with the primary analyses.⁶⁵

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of TTNT for the 0.4 mg/kg weekly SC cohort are presented in Figure 26.⁶⁵ The unadjusted HR in the 0.8 mg/kg every 2 weeks SC cohort for TTNT was ████ ████ ███ █████ █████ █████████. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ █████████ for talquetamab versus teclistamab (Figure 25). The results of the sensitivity analyses are aligned with the main analyses. The results of the 4 or more prior lines of therapy subgroup analyses aligned with the primary analyses.⁶⁵

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of TTNT for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 27.⁶⁵

Figure 25: Summary of Results for TTNT for Talquetamab Versus Teclistamab [Redacted]

Figure 26: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of TTNT for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 27: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of TTNT for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

Talquetamab in MonumenTAL-1 Study Versus Cilta-Cel in CARTITUDE-1 Study

The results of the nonrandomized study conducted using IPTW with ATT weights to compare talquetamab versus cilta-cel suggest that cilta-cel is associated with better response outcomes in patients with triple-class exposed r/r MM who have received at least 3 previous lines of therapy. The comparisons suggest that cilta-cel resulted in better ORR compared to either dosage of talquetamab. Compared to 0.4 mg/kg weekly SC talquetamab, cilta-cel resulted in better DOR, PFS, and TTNT; however, the null was included in the 95% CI in these outcomes compared to the 0.8 mg/kg every 2 weeks SC dosage of talquetamab. Talquetamab (at either dosage) and cilta-cel resulted in OS that did not exclude the null from the 95% CI. Details for each outcome are presented in the following subsections.

Overall Response Rate

The observed ORR for talquetamab in the 0.4 mg/kg weekly SC cohort was 74.1%, versus 84.1% in the cilta-cel cohort. After reweighting, the ORR for cilta-cel was 90.5%. The adjusted response rate ratio for talquetamab compared to cilta-cel was ████ ████ ███ █████ █████ █████████, suggesting that patients treated with cilta-cel were more likely to experience overall response (Figure 28).⁶⁶ The observed ORR for talquetamab in the 0.8 mg/kg every 2 weeks SC cohort was 71.7%, versus 84.1% in the cilta-cel cohort. After reweighting, the ORR for cilta-cel was ██████. The adjusted response rate ratio for talquetamab compared to cilta-cel was ████ ████ ███ █████ █████ ████████), suggesting that patients treated with cilta-cel were ████ ██████ to experience overall response (Figure 28).⁶⁶

Figure 28: Summary of Results for ORR for Talquetamab Versus Cilta-Cel [Redacted]

Duration of Response

The unadjusted HR in the 0.4 mg/kg weekly SC cohort for DOR was ████ ████ ███ █████ █████ █████████ for talquetamab versus cilta-cel. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ █████████, suggesting that cilta-cel █████████ the time to progression or death compared to talquetamab (Figure 29). The results of the sensitivity analyses align with the main analysis. The results of the 4 or more prior lines of therapy subgroup analyses differed from the results of the primary analysis; the main ATT-adjusted and the average treatment effect in the control and performance status–matched sensitivity subgroup analyses did not exclude the null from the 95% CI.

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of DOR for the 0.4 mg/kg weekly SC cohort are presented in Figure 30.⁶⁶

The unadjusted HR in the 0.8 mg/kg every 2 weeks SC cohort for DOR was ████ ████ ███ █████ █████ █████████ for talquetamab versus cilta-cel. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ █████████ (Figure 29). The results of the sensitivity analyses align with the main analysis. The results of the 4 or more prior lines of therapy subgroup analyses are aligned with the results of the primary analysis.⁶⁶

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of DOR for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 31.⁶⁶

Figure 29: Summary of Results for DOR for Talquetamab Versus Cilta-Cel [Redacted]

Figure 30: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of DOR for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 31: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of DOR for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

Progression-Free Survival

The unadjusted HR in the 0.4 mg/kg weekly SC cohort for PFS was ████ ████ ███ █████ █████ █████████ for talquetamab versus cilta-cel. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ █████████, suggesting that cilta-cel █████████ the time to progression or death compared to talquetamab (Figure 32). The results of the sensitivity analyses are aligned with the main analyses. The results of the 4 or more prior lines of therapy subgroup analyses are aligned with the primary analyses.⁶⁶

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of PFS for the 0.4 mg/kg weekly SC cohort are presented in Figure 33.⁶⁶

The unadjusted HR in the 0.8 mg/kg every 2 weeks SC cohort for PFS was ████ ████ ███ █████ █████ ████████ for talquetamab versus cilta-cel. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ ████████ (Figure 32).⁶⁶

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of PFS for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 34.⁶⁶

Figure 32: Summary of Results for PFS for Talquetamab Versus Cilta-Cel [Redacted]

Figure 33: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of PFS for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 34: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of PFS for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

Overall Survival

The unadjusted HR for OS in the 0.4 mg/kg weekly SC cohort was ████ ████ ███ █████ █████ █████████ for talquetamab versus cilta-cel. Results from the main analysis using IPTW with ATT showed an HR of ████ ████ ███ █████ █████ █████████ (Figure 35). The results of the sensitivity analyses are aligned with the main analyses, with the null being crossed in all cases. The results for the 4 or more prior lines of therapy subgroup analyses are also aligned with the primary analyses.⁶⁶

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of OS for the 0.4 mg/kg weekly SC cohort are presented in Figure 36.⁶⁶

The unadjusted HR for OS in the 0.8 mg/kg every 2 weeks cohort was ████ ████ ███ █████ █████ █████████ for talquetamab versus cilta-cel. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ █████████ (Figure 35). The results of the sensitivity analyses are aligned with the main analyses, with the null being crossed in all cases. The results of the 4 or more prior lines of therapy subgroup analyses are aligned with the primary analyses.⁶⁶

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of OS for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 37.⁶⁶

Figure 35: Summary of Results for OS for Talquetamab Versus Cilta-Cel [Redacted]

Figure 36: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of OS for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 37: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of OS for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

CR or Better Rate

The observed CR or better rate for talquetamab in the 0.4 mg/kg weekly SC cohort was █████, versus █████ in the cilta-cel cohort. After reweighting, the CR or better rate for cilta-cel was █████. The adjusted response rate ratio for talquetamab compared to cilta-cel was ████ ████ ███ █████ █████ █████████. The results of the sensitivity analyses are aligned with the main analysis. The observed CR or better rate for talquetamab in the 0.8 mg/kg every 2 weeks SC cohort was █████, versus █████ in the cilta-cel cohort. After reweighting, the CR or better rate for cilta-cel was █████. The adjusted response rate ratio for talquetamab compared to cilta-cel was ████ ████ ███ █████ █████ █████████, suggesting that patients treated with cilta-cel were significantly more likely to experience a CR or better. The results of the sensitivity analyses were similar to the main analysis.

Time to Next Treatment

The unadjusted HR in the 0.4 mg/kg weekly SC cohort for TTNT was ████ ████ ███ █████ █████ █████████ for talquetamab versus cilta-cel. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ █████████ (Figure 38). The results of the sensitivity analyses are aligned with the main analyses, with cilta-cel being favoured. The results of the 4 or more prior lines of therapy subgroup analyses are also aligned with the primary analyses.⁶⁶

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of TTNT for the 0.4 mg/kg weekly SC cohort are presented in Figure 39.⁶⁶

The unadjusted HR in the 0.8 mg/kg every 2 weeks SC cohort for TTNT was ████ ████ ███ █████ █████ █████████ for talquetamab versus cilta-cel. Results from the main analysis using IPTW with ATT weights showed an HR of ████ ████ ███ █████ █████ █████████ (Figure 38). The results of the sensitivity analyses differed from those of the main analysis, with the results for the multivariable logistic regression, the weighted for average treatment effect in the overlap, the weighted for average treatment effect, and the performance status–matched sensitivity analyses all favouring cilta-cel.⁶⁶

The unadjusted and ATT-weighted Kaplan-Meier plots for the main analysis of TTNT for the 0.8 mg/kg every 2 weeks SC cohort are presented in Figure 40.⁶⁶

Figure 38: Summary of Results for TTNT for Talquetamab Versus Cilta-Cel [Redacted]

Figure 39: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of OS for the 0.4 mg/kg Weekly SC Cohort [Redacted]

Figure 40: Unadjusted and Adjusted (ATT-Weighted) Kaplan-Meier Plots of TTNT for the 0.8 mg/kg q.2.w. SC Cohort [Redacted]

Critical Appraisal of Sponsor-Submitted Nonrandomized Comparisons Informing the PE Model

The 3 comparative studies submitted by the sponsor employed similar approaches in using IPD with IPTW and ATT to reduce the extent of confounding due to heterogeneity in prognostic factors between any 2 data sources being assessed in a given comparative study. The studies included only patients who matched the inclusion and exclusion criteria of the MonumenTAL-1 study and compared outcomes that were defined similarly, and the studies successfully reduced the baseline clinical heterogeneity of most of the identified prognostic factors. However, some prognostic factors maintained discrepancy at a level of more than 0.1 SMD, especially in the comparison versus cilta-cel. In addition to using similar methods, the studies share similar limitations, as well as unique limitations per study, that affect the interpretation of the results. In addition, the limitations that are inherent within the MonumenTAL-1 trial also apply here; these limitations include the interim nature of the results and the immature OS data.

In all 3 studies, the choice of comparator data was not sufficiently justified. There was no systematic review approach to identify potential studies that may be eligible for these comparisons, and it was unclear if a protocol was established a priori to inform the analytical approach to the analysis and the conduct of the studies. These limitations increase the risk of selection bias and the possibility of missing important evidence that could have led to different results. This limitation is particularly important for the comparison against RWPC as a number of observational studies exist in the literature that could have been assessed for inclusion. Furthermore, no assessment of risk of bias from each study was reported and no attempt was described to deal with poor-quality data arising from said risk assessment.

In addition, a unique limitation to the comparison against RWPC is the pooling of data from the LocoMMotion and MoMMent studies without consideration of potential variability and error between the studies. This may have introduced bias to the analysis, and important differences across the studies might have been obscured in the pooling. However, the direction of such potential bias is unclear. Furthermore, although the study attempted to reduce clinical and methodological heterogeneity through statistical approaches and matching of the inclusion criteria and the end point definitions, certain heterogeneities cannot be adjusted for, such as the differences in the study design: the MonumenTAL-1 study is a clinical trial and the LocoMMotion and MoMMent studies are cohort studies. Variations in study design can lead to significant differences in the manner of enrolling, assessing, monitoring, and following-up with patients. These variations, in turn, can lead to variations in unobserved factors as well as measurement and human error — all factors that cannot be adjusted. In addition, the MonumenTAL-1 study had a shorter follow-up period than all the other studies. The magnitude and the direction of bias introduced by the differences in the study design are unclear.

Shared among the 3 studies is the approach to identifying prognostic factors for assessment and weighting. A list of possible prognostic factors that require adjustment was established in consultation with the sponsor’s clinical expert. Overall, the clinical expert consulted by Canada’s Drug Agency (CDA-AMC) concurred with the assessment of the sponsor’s expert. However, there was no systematic approach to establishing the prognostic factors beyond expert opinion, for example by consulting the available literature. The lack of evidence-informed prognostic choice may increase the uncertainty of the results by potentially missing important prognostic variables, leading to confounding, or by including variables that are not strongly related to the treatment assignment, which can cause overfitting and reduce generalizability.

Across the 3 studies, an important prognostic factor that was not adequately addressed due to missing data was the cytogenetic risk. Both the sponsor’s clinical experts and the clinical expert consulted by CDA-AMC considered it an important prognostic factor; however, it was not included in the main analyses due to a high level of missingness. A sensitivity analysis was conducted to assess the impact of missing data. However, that sensitivity analysis can only provide information on the potential effect of the missing data, rather than adjusting for cytogenetic risk as a prognostic factor. The limitations related to missing cytogenetic risk data were most pronounced in the comparison against RWPC. Based on the existing data, there seems to be a larger proportion of patients with a “high-risk” cytogenic profile in the MonumenTAL-1 study than in the RWPC data or in the data from the CARTITUDE-1 study. Finally, it was unclear how missing outcome values were handled. It is unclear how this discrepancy, coupled with the large proportion of missing data, could affect the direction of the results.

Across the 3 studies, unknown or unmeasured factors cannot be adjusted for, including those previously noted as being affected by large missingness in data. Although e-values were presented — and some of these values suggest that any unmeasured confounders would need to have a relatively large effect to fully explain away the observed effect size — e-values have important limitations that reduce⁶⁸ their utility in this regard. Specifically, e-values cannot account for other sources of bias, such as measurement error, selection bias, or information bias. They also rely on assumptions including effect homogeneity, and a single unmeasured confounder (or a composite of all unmeasured confounding variables or those unaccounted for). Additionally, interpretation of e-values is challenged when there is no frame of reference (i.e., values of known confounding variables) and the e-value for the bound of the CI closest to the null is not provided to understand the extent of residual confounding that would be needed for the CI to cross the null.

Visual inspection of the log-cumulative hazard plots and Schoenfeld residuals plots across the 3 studies indicated potential deviation from the proportional hazards assumption. However, the Grambsch-Therneau test for the proportional hazards assumption was conducted and found to be nonsignificant. The observed possible discrepancies in the approach to assess the assumption reduced certainty that the assumption had been met but did not conclusively reject the possibility that the assumption had been met. It was also unclear what number of events were driving the OS outcome. Based on the MonumenTAL-1 study interim results for OS, there is a concern that a low number of events may lead to unstable estimates.

The generalizability of the study comparing against RWPC is limited due to the changes in the treatment landscape. According to the clinical expert consulted by CDA-AMC, it is highly unlikely that any patient would be given the interventions pooled together in the RWPC cohort. This is largely due to the availability of new treatment approaches. This reduces the clinical value of the comparative results. Although the comparisons against cilta-cel and teclistamab are relevant, the data sources come from clinical trials, which pose their own limitations for generalizability to the patient population living in Canada. However, the clinical expert consulted by CDA-AMC did not identify any unusual clinical characteristics that would set the patients in these studies apart from those treated in general practice.

Finally, no safety or HRQoL measures were reported, and no clear justification was available. This reduces the review team’s ability to balance understanding of the comparative efficacy and safety of the treatments.

Discussion

Summary of Available Evidence

One ongoing, pivotal, phase I/II, noncomparative study, the MonumenTAL-1 study (total N = 501; N at either RP2D = 339), met the inclusion criteria for the sponsor-conducted systematic review. In the 3 model cohorts, patients received 1 of the 2 RP2Ds: 0.4 mg/kg SC weekly on days 1, 8, 15, and 22 of a 28-day cycle (preceded by step-up doses of 0.01 mg/kg and 0.06 mg/kg) or 0.8 mg/kg SC every 2 weeks on days 1 and 15 of a 28-day cycle (preceded by step-up does of 0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg). The objectives of the MonumenTAL-1 study were to characterize the safety of talquetamab and the RP2Ds and schedule, to further characterize the safety of talquetamab at the RP2Ds (phase I), and to evaluate the efficacy of talquetamab at the RP2Ds (phase II) in adults with r/r MM. The trial enrolled adults with r/r MM who had not received prior T-cell redirection therapy (model cohort A [RP2D = 0.4 mg/kg weekly] and model cohort C [RP2D = 0.8 mg/kg every 2 weeks]) or who had received prior T-cell redirection therapy (model cohort B [either RP2D]). All patients had an ECOG Performance Status of 1 or less in phase I and of 2 or less in phase II. The outcomes relevant to this review included the primary outcome of ORR by IRC per the IMWG criteria and secondary outcomes of OS, PFS, DOR, CR or better rate, and harms. HRQoL was measured in phase II only, via the EORTC QLQ-C30, as a secondary outcome. The trial population had a mean age of 61 to 65 years and a mean MM duration of 7.2 to 7.7 years across the model cohorts. There were more male patients (55% to 57% across the cohorts) than female patients (43% to 46%). Most enrolled patients were white (86% to 90%); the next largest groups by ethnicity were Black or African American, and Asian. Most patients had an ECOG Performance Status of 1 (56% to 60%), and less than 10% of the patients had an ECOG Performance Status of 2 (indicating good overall performance status). Most patients had an R-ISS disease stage of II (62% to 70% across the cohorts), standard cytogenetic risk (59% to 71%), and triple-class (PI, IMiD, and anti-CD38 monoclonal antibody) refractory disease (69% to 84%). The proportions of patients who had penta-drug (≥ 2 PIs, 2 IMiDs, and 1 anti-CD38 monoclonal antibody) refractory disease were 29% in model cohort A, 23% in model cohort C, and 41% in model cohort B.

In the absence of direct randomized comparisons between talquetamab and relevant comparators, 3 nonrandomized studies comparing 2 talquetamab cohorts in the MonumenTAL-1 trial (0.4 mg/kg weekly SC and 0.8 mg/kg every 2 weeks SC) to RWPC in the LocoMMotion and MoMMent studies, to teclistamab in the MajesTEC-1 study, and to cilta-cel in the CARTITUDE-1 study were submitted. Each of the studies used IPD from both arms and IPTW methods with ATT weights to reduce the impact of confounding in comparing ORR, CR or better rate, VGPR or better rate, DOR, PFS, TTNT, and OS. All patients included met similar key eligibility criteria, including specific serum or urine M-protein levels, an ECOG Performance Status of 0 to 2, at least 3 prior lines of therapy, and documented disease progression within 12 months of the last therapy. The studies aimed to determine the comparative effectiveness of talquetamab versus RWPC, teclistamab, and cilta-cel in treating r/r MM. No evidence was provided on the impact of talquetamab on HRQoL and harms compared to other relevant treatments. Comparisons to elranatamab were unavailable, which is understandable given that the drug was recently reviewed by the pan-Canadian Oncology Drug Review Expert Review Committee.³³

Interpretation of Results

Efficacy

The findings of the MonumenTAL-1 study need to be interpreted with consideration of the single-arm design, which typically cannot support causal conclusions about the effect of a drug versus any comparator. However, ORR is a surrogate end point that can be evaluated as a direct measure of anticancer activity in a single-arm design⁶⁰ by considering the magnitude of the effect and the proportion of CRs. Evidence for time-to-event end points (i.e., PFS, OS) is not possible to robustly evaluate in a single-arm design; therefore, the interpretation of findings for these end points from the MonumenTAL-1 study is informed primarily by expert opinion.

The MonumenTAL-1 study reached its primary outcome at the data cut-off (January 17, 2023) in the 3 model cohorts, demonstrating an ORR of 65% to 74% among patients with or without prior T-cell redirection therapy, at either of the RP2Ds. These analyses were uncontrolled for multiplicity. The clinical expert consulted for this review considered that the results were clinically meaningful. In both model cohorts A and C, subgroup analysis results for ORR appeared generally consistent with the primary analysis, but the ORR appeared higher among patients with no extramedullary plasmacytomas at baseline than among those with 1 or more baseline extramedullary plasmacytomas. This is an exploratory finding, but the clinical expert consulted for this review indicated that it may align with their observation in clinical practice. A CR or better rate was experienced in 34% to 39% of patients across the 3 model cohorts, which was considered clinically meaningful. Among patients experiencing a PR or better and at the data cut-off, the median DOR was reached in model cohorts A and B (with 39% to 49% of the patients censored) but not in model cohort C. The probability of patients remaining in response at 12 months was 44% in model cohort A, 69% in model cohort C, and 48% in model cohort B. The clinical expert considered these DOR results to demonstrate that the overall response was durable.

At the most recent data cut-off date, the OS data were immature, with medians and CIs not being reached. Also, for PFS, the upper bound of 95% CI in model cohort C is not estimable. The clinical expert commented that due to the lack of a control group, a causal conclusion about the clinically meaningful benefit on the 12-month OS rates (63% to 77% across the 3 model cohorts) is compromised. Moreover, whether the observed ORRs would be transferable to a meaningful treatment effect on OS or PFS remains unknown. HRQoL is an important outcome to patients and clinicians; however, interpretation of the EORTC QLQ-C30 results is limited, due to the lack of a control group, potential bias related to the open-label design, and the large amount of missing outcome data over time.

The studies comparing talquetamab to RWPC demonstrated that talquetamab improved ORR, PFS, OS, and TTNT in patients with triple-class exposed r/r MM. Additionally, the DOR showed a reduction in the risk of progression or death for the 0.8 mg/kg every 2 weeks SC dose.

When comparing talquetamab to teclistamab, talquetamab showed █████████ ███████ ██ ███ ███ ██ ███ ███ ██ ███ ██ ███. However, the adjusted HR for DOR was ████ ████ ███ █████ █████ █████████ for the 0.4 mg/kg weekly SC dose, indicating an increased risk for progression or death compared to teclistamab. The HRs for PFS and TTNT showed no exclusion of the null between the treatments, while the adjusted HRs for OS indicated a significant reduction in the risk of death for talquetamab.

In the comparison of talquetamab to cilta-cel, cilta-cel was ████ ██████ ██ ███████ ██ ███████ ████████. Cilta-cel also ███████ ███ ████ ██ ███████████ ██ █████ when compared against the 0.4 mg/kg weekly SC dose, while the 0.8 mg/kg every 2 weeks SC dose showed no significant difference. In terms of PFS, the adjusted HR was ████ ████ ███ █████ █████ █████████ for the 0.4 mg/kg weekly SC dose and ████ ████ ███ █████ █████ █████████ for the 0.8 mg/kg every 2 weeks SC dose. For OS, there was ██ ███████████ ██████████ between the treatments, with adjusted HRs of ████ ████ ███ █████ █████ █████████ ███ ████ ████ ███ █████ █████ █████████. Cilta-cel █████████████ ███████ the TTNT when compared with the 0.4 mg/kg weekly SC group but not with the 0.8 mg/kg every 2 weeks SC group.

The 3 nonrandomized studies of talquetamab compared with RWPC, teclistamab, and cilta-cel used IPD with IPTW and ATT to reduce the impact of confounding arising from the lack of randomization, matching the MonumenTAL-1 trial criteria and outcome definitions. Despite these efforts, significant limitations remain, such as the lack of systematic review for comparator data selection and the lack of clarity regarding an a priori protocol, increasing the risk of selection bias, as well as unaddressed quality issues in included studies. Pooling data from the LocoMMotion and MoMMent studies in the RWPC comparison without accounting for variability may introduce bias. The identification of prognostic factors relied on expert opinion without a systematic approach, and important factors like cytogenetic risk were excluded due to missing data, introducing increased risk of bias due to residual confounding. Additionally, even after weighting there were meaningful imbalances in known prognostic variables in the comparisons between talquetamab and both RWPC and cilta-cel. Additionally, unknown confounders and potential deviations from the proportional hazards assumption further complicate the findings. Generalizability issues arise from outdated RWPC interventions and the inherent limitations of clinical trial data. The absence of safety or HRQoL measures also limits a comprehensive understanding of the treatments’ comparative effectiveness and safety.

The evidence from the nonrandomized comparisons suggests that there is a benefit of talquetamab compared to RWPC. A benefit of talquetamab over RWPC seems plausible and given the large magnitude of effect for several outcomes (particularly CR or better rate and OS), it seems unlikely that bias and residual confounding can fully explain the result. However, the exact magnitude of benefit is not certain, and the relevance of the comparison is diminished by the mix of treatments included in the RWPC arm, many of which may not be relevant to current practice. The comparison of talquetamab versus teclistamab showed inconsistent results across outcomes ███ █████ ████ █████ ████ ███ ██████████ ███ █████, which resulted in uncertainty about which drug might be favoured. Finally, there is a consistency of effect in cilta-cel versus talquetamab for most outcomes when compared against the 0.4 mg/kg weekly cohort. The results suggest that cilta-cel has ████ ██████████ ████ ██ ██ ███████ ████ ███ ███ outcomes than talquetamab at a dosage of 0.4 mg/kg weekly. The potential difference between treatments was less evident for the 0.8 mg/kg every 2 weeks cohort, where only tumour response results excluded the null. The effect estimates for both dosages were ███ █████████ ██ ████ █ ██████████ █████ ███████ ███████████ ██ █████████ █████ ██ ████████ ███ ██.

The clinician group and the clinical expert consulted for this review pointed out that there are limited available options for patients with r/r MM receiving the fourth or later lines of therapy and that many of these patients would eventually cease to experience response to the available funded drugs. Being the first GPRC5D-targeted drug for r/r MM, talquetamab may help meet some of the unmet needs, because it would be an additional treatment option with a different mechanism of action. The clinical expert also noted that 23% to 41% of patients across the model cohorts in the MonumenTAL-1 study had penta-refractory disease and that the findings may have generalizability among these heavily treated patients. In the opinion of the clinical expert, it is likely that most patients would eventually be on the 0.8 mg/kg every 2 weeks SC dosing schedule after the initial step-up doses due to convenience. Both the clinical expert and the clinician group indicated that talquetamab could be used for patients who had and had not received prior anti-BCMA therapy.

Harms

Input from the patient and clinician groups and from the clinical expert consulted for this review all highlighted the importance of a tolerable treatment. The patient group considered ICANS, CRS, and infection as the most important harms associated with talquetamab treatment. The most common TEAEs were CRS (79% in model cohort A and 75% in model cohort C), dysgeusia (50% and 49%), and anemia (45% and 46%). Serious TEAEs occurred in approximately half the patients in model cohorts A and C, and the most frequently reported event was CRS (17% and 10%). TEAEs with the outcome of death occurred in 4% of the patients in model cohorts A and C, of which 1 patient (0.7%) in each cohort died due to COVID-19. The AEs of special interest were CRS (79% and 75% in model cohorts A and C), patients with 1 or more neurologic TEAEs (86% in both cohorts), neurotoxicity events (31% and 30% in model cohorts A and C), ICANS (11% in both cohorts), and infection of any severity (59% and 66% in model cohorts A and C). Rates of infections of grade 3 or 4 were 20% in model cohort A and 15% in model cohort C. The common reported TEAEs associated with talquetamab are related to T-cell activation (e.g., CRS). However, due to the lack of a comparator in the MonumenTAL-1 study, no causal association can be drawn for talquetamab regarding the risk of any particular harm or whether talquetamab is a more tolerable treatment than other treatment options. The clinical expert noted that patients in the pivotal study may have been healthier and younger than the broader population of patients in Canada who could receive talquetamab in practice. These patients enrolled in the MonumenTAL-1 study may be better able to tolerate an AE and be willing to remain on the study drug, thereby lowering the number of patients who withdrew from treatment compared to clinical practice. The clinical expert indicated that the reported AEs were reasonable for what is known about r/r MM and the study treatments (talquetamab and concomitant medications) and that with appropriate care the AEs would be manageable for most patients, as was described in the MonumenTAL-1 study.

The product monograph requires that patients “remain within proximity of a healthcare facility” and be monitored for 48 hours after all doses within the step-up dose regimen for either RP2D, in particular for CRS and/or ICANS.³⁵

Conclusion

One ongoing, phase I/II, single-arm, open-label study (MonumenTAL-1) provided evidence regarding the efficacy and safety of talquetamab for patients with r/r MM who had received at least 3 prior lines of therapy. The evidence for the treatment effect of talquetamab from the MonumenTAL-1 trial is very uncertain due to the single-arm design, which is not intended to be confirmatory for efficacy. The findings for ORR were clinically meaningful and durable according to the clinical expert consulted by the review team and can be attributed to talquetamab (rather than natural history or other factors) despite the single-arm design. However, causal conclusions regarding time-to-event end points were not possible given the lack of comparator group, though the clinical expert indicated that based on the natural history of the disease and the experience in clinical practice, the OS and PFS findings observed in the MonumenTAL-1 study appear promising in patients without prior exposure to a T-cell redirection therapy at either the 0.4 mg/kg weekly SC or the 0.8 mg/kg once every 2 weeks SC dosage. The results for HRQoL were inconclusive due to the open-label design and considerable missing outcome data. Notable harms in the MonumenTAL-1 study, including CRS, ICANS, and infections, were consistent with the known safety profile of the drug.

Three nonrandomized studies assessed the efficacy of talquetamab compared with RWPC, teclistamab, and cilta-cel, using IPD with IPTW and ATT weights to reduce the impact of confounding. All these comparisons were impacted by methodological limitations, including lack of a predefined systematic review protocol, no systematic procedure for the identification of comparator studies, lack of quality assessment, lack of clarity on the appropriateness of pooling the LocoMMotion and MoMMent studies for the RWPC comparison, and a risk of bias due to residual confounding (particularly for comparisons to RWPC and cilta-cel). Nonetheless, the evidence suggested a benefit of talquetamab for all measured outcomes compared to RWPC. Though this comparison was the most impacted by the aforementioned limitations, the large magnitude of estimated benefit across multiple outcomes seems unlikely to be fully accounted for by these limitations. The true magnitude of the difference is less clear, and the relevance of this comparison was diminished by the mix of treatments included in the RWPC arm, many of which may not be widely used in current practice. Results for talquetamab versus teclistamab were inconsistent across outcomes, in many cases with CIs crossing the null, which caused uncertainty about which drug might be favoured. Finally, the evidence suggested that cilta-cel may have ████ ██████████ ████ ████ ███ ███ than the 0.4 mg/kg weekly dosage of talquetamab. Potential differences between treatments were uncertain for the 0.8 mg/kg every 2 weeks cohort, where only tumour response results excluded the null. The effect estimates were ███ █████████ ██ ████████ █████ ███ ██████████ ██ ██ between talquetamab and cilta-cel for any dose comparison. No comparative evidence for HRQoL or harms was available.

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