Reimbursement Review

Elranatamab (Elrexfio)

Sponsor: Pfizer Canada ULC

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 on Application Submitted for Review

NOC = Notice of Compliance; NOC/c = Notice of Compliance with Conditions.

Introduction

Multiple myeloma (MM) is a plasma cell cancer characterized by the clonal proliferation of malignant plasma cells (B-cells) and the overproduction of the abnormal immunoglobulin M protein. In 2022, it was estimated that 4,000 individuals living in Canada were diagnosed with MM and that 1,650 patients living in Canada died from MM. The 5-year survival rate for patients with MM is estimated to be approximately 50%, and although survival rates have improved in recent years due to advances in therapeutic options, MM remains incurable. The majority of patients with MM will relapse and many patients will become refractory to commonly used therapies. Patients with relapsed or refractory multiple myeloma (RRMM) often undergo multiple rounds of treatment, with the duration of remission, depth of response, progression-free survival (PFS), and overall survival (OS) decreasing with each subsequent line of therapy. According to the clinical experts consulted by CADTH, the main treatment goals for patients with RRMM are to prolong survival, improve symptoms, minimize toxicities, and maintain or improve health-related quality of life (HRQoL). Therapies for the treatment of patients with RRMM, and the sequencing of these treatments, depend on eligibility for autologous stem cell transplant at diagnosis, age, comorbidities, previous treatments, beforexicities, and line of therapy. According to the joint clinical practice guideline of Ontario Health (Cancer Care Ontario) (OH-CCO) and the American Society of Clinical Oncology, treatment for RRMM includes triplet therapy consisting of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs). There is no preferred therapy for RRMM in the fourth-line and beyond settings, and at this stage of the disease, patients may be treated with PIs, IMiDs, and anti-CD38 mAbs, 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 elranatamab 76 mg, subcutaneous injection, for the treatment of adults with RRMM who have received at least 3 prior lines of therapy.

Stakeholder Perspectives

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

Patient Input

CADTH received 1 patient group submission from Myeloma Canada. Myeloma Canada conducted both patient and caregiver surveys from September 26 to October 23, 2023, across Canada and internationally via email and social media. A total of 67 complete responses to the patient survey were received, of which 38 responses were recorded based on the respondent’s eligibility criteria (receiving treatment with an IMiD, PI, and anti-CD38 antibody). Among these 38 patients, 24 patients were eligible for the drug under review and 14 patients had experience with it. A total of 32 caregivers responded to the caregiver survey, 11 of whose responses were recorded (8 based on eligibility and 3 based on experience with elranatamab).

Patient respondents indicated that among their daily activities and quality of life, their ability to work was the factor the most significantly impacted by symptoms associated with myeloma, followed by the ability to travel and to exercise. Regarding the most significant financial implication of myeloma treatment on patients and their household, 24 of 49 respondents (both patients and caregivers) identified loss of income or pension funds due to absence from work, disability, or early retirement as the most significant financial implication, and 20 of 49 respondents chose travel parking costs. Patient respondents felt that interruption of life goals or accomplishments had the greatest impact on their quality of life, followed by the 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 the treatment (especially in achieving remission and having a durable response), and treatment accessibility or portability (including fewer or minimal visits to the hospital or cancer centre). Infections were identified as the most important aspect to control identified by patients, followed by mobility and kidney problems.

In terms of treatment outcomes, 12 of the 23 respondents who would currently be eligible for treatment with elranatamab rated improved quality of life as extremely important, 6 of the respondents rated it as very important, and 5 of the respondents rated it as somewhat important. In addition, 17 of the 23 patients rated the aspect of life extension while considering a myeloma treatment as extremely important, and 4 patients rated it as very important. When asked about their tolerance of the most common side effects in patients who receive elranatamab, these patients perceived pneumonia, immune effector cell-associated neurotoxicity syndrome (ICANS), upper respiratory tract infections (URTIs), cytokine release syndrome (CRS), and infections to be the least tolerable side effects, followed by peripheral neuropathy, other infections, and COVID-19. Regarding the impact of the dosing schedule of elranatamab on the quality of life (weekly injections for at least 24 weeks, with the possibility of then switching to every 2 weeks), 11 of 24 patients chose the response of negative impact, indicating it would limit patients’ ability to travel or require a relocation (near their cancer centre) for the duration of treatment.

A total of 17 respondents (14 patients and 3 caregivers) indicated having experience with elranatamab. All 14 patients who had received or are currently receiving treatment with elranatamab mentioned they were admitted to the hospital at some point in the initial step-up dosing period. Regarding the most frequently experienced elranatamab side effects, all 14 patients rated cough as the least bearable side effect, followed by CRS, neutropenia, and URTI. Most of these patients mentioned the overall side effects while receiving elranatamab were manageable and found elranatamab effective in controlling their myeloma.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Unmet Needs

The clinical experts indicated that since almost all patients with RRMM will become refractory to their therapy and continue on to the next line of therapy, the unmet needs of patients would be new effective treatments, with curative potential, which are tolerable by targeting a different mechanistic pathway. Both clinical experts highlighted that the balance between treatment efficacy, minimizing toxicities, and quality of life would be important.

Place in Therapy

The clinical experts agreed that because of elranatamab’s novel mechanism of action, it would provide an additional treatment option for patients who are refractory to other standard of care (SOC) treatments. They noted that elranatamab is a new class of treatment for which there should be no existing drug resistance, and given its unique mechanism of action and toxicity profile, it should create a treatment synergy with other current families of myeloma treatments. However, they noted that given the lack of direct evidence, it is not known yet if elranatamab is more effective than other therapies.

Patient Population

The clinical experts agreed that the patients best suited for elranatamab would be those who are triple-class refractory (TCR). One of the clinical experts noted that patients most likely to respond to this therapy would be those with a stronger and more intact immune system, and patients with significant pre-existing cytopenias may not be ideal candidates as the cytopenias may worsen during treatment and predispose patients to infection. The experts did not note any issues or challenges related to the diagnosis or misdiagnosis of RRMM, and the identification of patients likely to respond. Patients would be identified during routine cancer follow-up based on biochemical assessment (serum protein electrophoresis, serum free light chain) or other evidence of relapse.

Assessing the Response Treatment

The clinical experts agreed that in clinical practice, standard clinical response criteria can be used to determine whether a patient with RRMM is responding or progressing on treatment. The clinical experts noted that achieving a durable objective response (OR) lasting 6 months to 12 months would be a sign of successful treatment, and such a response would be associated with a reduction in disease-related symptoms, bone pain, fatigue, and transfusion requirements. They noted that toxicities, especially cytopenias such as neutropenia, infections, CRS, and hypogammaglobulinemia, would need to be monitored.

Discontinuing Treatment

The clinical experts indicated that treatment with elranatamab should be discontinued if the patient experiences disease progression (as defined radiologically or biochemically), loss of response, unacceptable toxicity such as grade 3 or grade 4 infection or CRS, light chain or renal dysfunction, or increasing transfusion requirement.

Prescribing Considerations

The clinical experts noted that patients receiving elranatamab should be under the care of a specialist (e.g., hematologist, oncologist) familiar with myeloma and the use of bispecific antibodies, and who can manage toxicity associated with the therapy. They noted that elranatamab can be given in most centres experienced with myeloma therapy, and that the first few doses usually require hospitalization.

Clinician Group Input

Clinician group input on the review of elranatamab was received from 2 clinician groups: the Canadian Myeloma Research Group (CMRG) and Ontario Health -Cancer Care Ontario Hematology Cancer Drug Advisory Committee (OH-CCO’s Drug Advisory Committees). A total of 33 clinicians provided input for this submission (26 clinicians from CMRG and 7 clinicians from OH-CCO’s Drug Advisory Committees).

Both CMRG and OH-CCO’s Drug Advisory Committees emphasized that the overall treatment goals are to delay progression, improve OS, minimize adverse effects, control the disease and associated symptoms, and improve quality of life. While discussing the unmet needs of patients, CMRG highlighted that myeloma remains incurable and patients eventually become refractory to all available funded drugs, similar to the statements of the clinical experts consulted by CADTH. CMRG emphasized that the highest unmet need consists of patients with advanced disease who have received multiple lines of treatment and have already received the 3 major classes of drugs (triple-class exposed [TCE] or refractory), including an IMiD, PI, and anti-CD38 mAb.

As with the clinical experts consulted by CADTH, both clinician groups agreed that elranatamab could be another option for TCE patients. 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 those most likely to have the best outcomes with elranatamab. CMRG noted that overall, patients with poor disease-related prognostic factors, such as extramedullary myeloma and high-risk cytogenetics, should be eligible for the treatment under review.

CMRG added that clinically meaningful responses usually correlate with at least a partial remission as defined by International Myeloma Working Group (IMWG) consensus criteria. Both CMRG and OH-CCO’s Drug Advisory Committees agreed that treatment discontinuation is based on ongoing efficacy or response, disease progression, and long-term tolerability or significant toxicities. Given that prior anti–B-cell maturation antigen, or BCMA, exposure does not preclude responsiveness to subsequent anti-BCMA therapy, CMRG would suggest that patients with prior anti-BCMA therapy who did not progress during it (i.e., nonrefractory to anti-BCMA therapy) be allowed access to elranatamab.

Drug Program Input

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

• relevant comparators

• considerations for the initiation of therapy

• considerations for the discontinuation of therapy

• considerations for the prescribing of therapy

• generalizability

• funding algorithm

• care provision issues

• system and economic issues.

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs. Refer to Table 4.

Clinical Evidence

Systematic Review

Description of Studies

One ongoing trial, the MagnetisMM-3 study (N = 187), met the inclusion criteria for the systematic review conducted by the sponsor. The objective of the MagnetisMM-3 trial was to assess the efficacy and safety of elranatamab 76 mg, subcutaneous injection, in adults with RRMM. The trial enrolled adults who either had previous experience with BCMA-directed treatment (cohort B) or did not (cohort A), were disease-refractory to at least 1 PI, 1 IMiD, and 1 anti-CD38 antibody, and were disease-relapsed or disease-refractory to their last antimyeloma regimen. Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of less than or equal to 2, and adequate bone marrow, hepatic, and renal functions. The 2 noncomparative cohorts were analyzed separately. Patients received elranatamab 76 mg, subcutaneous injection, once a week on a 28-day cycle with a 2 step-up priming dose regimen of 12 mg on day 1 and 32 mg on day 4 during the first week. Patients who received dosing once a week for at least 6 cycles and attained a partial response or better persisting for at least 2 months had their dosing interval changed to once every 2 weeks. The outcomes relevant to the CADTH review included the primary outcome of the objective response rate (ORR) by blinded independent central review (BICR) per IMWG criteria, and secondary outcomes of PFS, OS, complete response rate (CRR), duration of response (DOR), and safety. HRQoL via the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20 (EORTC QLQ-MY20) tool was included as an exploratory outcome. The trial population was predominately white (███), with a similar proportion of male and female patients who had a mean age of ██ years. Most patients had an ECOG PS score of 1 (███) and 0 (███), indicating good overall performance, a Revised International Staging System (R-ISS) disease stage of II (███), standard cytogenetic risk (███), and a prior stem cell transplant (███). Patients had received an average of | prior lines of therapy, and ███ had penta-drug refractory disease (refractory to at least 2 PIs, 2 IMiDs, and 1 anti-CD38 antibody). Key characteristics were generally consistent between cohorts, although patients in cohort B had a longer mean time since first diagnosis ████████████████████████ and received on average more prior anticancer therapies ███████████████████████ than patients in cohort A.

Efficacy Results

Only those efficacy outcomes and analyses of subgroups identified as important to this review are reported. Efficacy and safety data were evaluated at a planned analysis data cut-off date of October 14, 2022, and additional follow-up data at a cut-off date of March 14, 2023.

Objective Response Rate

At the March 14, 2023, data cut-off, with a median follow-up of 14.7 months, the ORR in cohort A was 61.1% (95% confidence interval [CI], 51.8% to 69.6%; P < 0.0001) and ██████████████████████████████ in cohort B. In cohort A and cohort B, the ORR was greater than or equal to the prespecified alternative hypotheses of 48% and 34%, respectively. These findings were consistent with the results at the 9-month analysis (with a data cut-off date of October 14, 2022). In cohort A, the ORR results were consistent across subgroups by age, baseline cytogenetics risk, prior stem cell transplant, and number of prior lines of therapy. However, lower ORRs were observed in patients with R-ISS stage III. ███████████████████████████████████.

PFS by BICR

In total, ██ events had occurred in both cohorts by the March 14, 2023, data cut-off. The median follow-up for PFS was 14.7 months for cohort A and █████████ for cohort B. The median PFS was not reached (95% CI, 9.9 months to not estimable) in cohort A and █████████████████████████ in cohort B. The probability of being event-free at 12 months in cohort A was 56.6% (95% CI, 46.7% to 65.3%) ██████████████████████████ in cohort B.

Overall Survival

As of the March 14, 2023, data cut-off, the OS data were immature. A total of 55 (44.7%) patients in cohort A and █████████ patients in cohort B had died. Median OS had not yet been reached in cohort A and was █████████████████████████ ██████████ in cohort B. The probability of being alive at 12 months in cohort A ██████████████████████████████████████████████ in cohort B.

DOR and CRR

As of the March 14, 2023, data cut-off, the median DOR had not been reached among responders in both cohorts, with ███ of all patients censored at the time of the analysis. The probability of patients remaining in response at 12 months was 75.5% (95% CI, 58.8% to 80.9%) in cohort A ███ █████ ████ ███ ████ ██ █████ in cohort B. A complete response or better was attained in 43 patients (complete response = 35.0% [95% CI, 26.6% to 44.1%]) in cohort A ███ █ ██████ ███ ███ ███ ██ █████ patients in cohort B.

Harms Results

All patients in the trial reported at least 1 TEAE. The most frequently reported TEAEs in both cohorts were CRS █████, anemia █████, neutropenia █████ and diarrhea ██████ In both cohorts, ███ of patients experienced 1 or more serious TEAE. The type and number of events were similar in both cohorts, with the most frequently reported events being COVID-19 pneumonia ██████ and CRS ██████ Study treatment discontinuation due to TEAEs occurred in ███ of patients, and was similar in both cohorts. In cohort A and cohort B, 45% and ███ of patients died, respectively. Most deaths in both cohorts were attributed to disease progression. In the total population, the most frequently reported notable adverse events (AEs) were infections █████ and CRS ██████ followed by peripheral neuropathy ██████ hypogammaglobulinemia ██████ and ICANS (████ All CRS events were grade 1 or grade 2 in severity. The median time from the most recent elranatamab dose to CRS onset was | days and the median time to resolution was also | days. In general, the harms results of the MagnetisMM-9 trial were similar to those of the MagnetisMM-3 trial. According to the clinical experts, infection-related hospitalizations, hypogammaglobulinemia as measured by need for IV or subcutaneous immunoglobulin, and neurotoxicities were considered important outcomes, although they were not reported in the trials. As such, this represents a gap in the available evidence.

Critical Appraisal

The primary limitation of the MagnetisMM-3 trial was the absence of a comparator group to assess the efficacy and harms of elranatamab, and therefore the interpretation of the results is limited to its single-arm design. As such, it is difficult to make causal conclusions — in particular, to what extent the observed effects were attributable to elranatamab. The open-label design introduces a potential bias in the assessment of ORR, PFS, DOR, and CRR, and a potential reporting bias of the subjective outcomes HRQoL and safety. However, this bias was mitigated by the use of BICR for ORR, PFS, DOR, and CRR. To minimize the risk of differential measurement error, the trial performed tumour assessments using IMWG criteria and radiographic scans were assessed by BICR. Sample size and power calculations were based on ORR, which had a prespecified hypothesis that was tested; however, all other analyses were descriptive. These included PFS, OS, DOR, and CRR, and the exploratory HRQoL outcome (via the EORTC QLQ-MY20 tool), which are deemed clinically important outcomes for the disease. The sample sizes for the subgroup analyses were small, and not adjusted for multiplicity, which also made it difficult in interpreting the results. While the trial met its primary objective of assessing ORR, there was limited supporting evidence from important secondary outcomes — notably, the immature data for PFS and OS. Given the importance of these outcomes to patients and clinicians, longer follow-up for the PFS and OS analyses would have been preferred to determine the clinical value of treatment with elranatamab. In addition, patients were permitted to receive post-treatment anticancer medications after study treatment had been discontinued (33% of all patients), which may have influenced the assessment of OS. The results of the EORTC QLQ-MY20 questionnaire were subjected to bias potentially due to incomplete reporting or missing data, which could have influenced the results toward the null. Therefore, the potential differences regarding a patient’s quality of life remain uncertain.

In general, the population requested for reimbursement aligns with that of the Health Canada indication, and the dosing and administration of elranatamab were consistent with the Health Canada–approved product monograph. According to the clinical experts consulted by CADTH, the inclusion and exclusion criteria and baseline characteristics of the MagnetisMM-3 trial were generalizable to adults with RRMM in the Canadian setting. However, the clinical experts noted that the trial did not include patients with a poor ECOG PS score, which is not entirely representative of patients with RRMM in clinical practice. The trial included outcomes that were important to patients and clinicians. The patient group indicated that stopping disease progression, prolonging life, improving HRQoL, and reducing treatment side effects are important to them. However, assessing HRQoL as an exploratory outcome is a limitation to the evidence since no definitive conclusions can be drawn.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^1,2

Although GRADE guidance is not available for noncomparative studies, the CADTH 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 group 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 clinical experts, 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:

• response outcomes (ORR, DOR, CRR)

• survival outcomes (PFS, OS)

• HRQoL outcomes (EORTC QLQ-MY20 functional and symptom scale scores).

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for elranatamab.

Table 2: Summary of Findings for Elranatamab for Patients with RRMM

+= censored observation; CI = confidence interval; CR = complete response; DOR = duration of response; EORTC QLQ-MY20 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20; NE = not estimable; NR = not reported; OR = objective response; OS = overall survival; PFS = progression-free survival; PR = partial response; RRMM = relapsed or refractory multiple myeloma.

Notes: Data, including effect estimates are based on the MagnetisMM-3 trial data cut-off date of March 14, 2023.

^aIn the absence of a comparator arm, conclusions about efficacy relative to any comparator cannot be drawn and certainty of evidence started at the level of very low.

^bRated down 1 level for risk of bias due to a large amount of missing outcome data.

Source: MagnetisMM-3 Clinical Study Report.³[Details included in the table are from the sponsor’s Summary of Clinical Evidence].

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor.

Indirect Comparisons

Description of Studies

In the absence of direct comparative evidence of elranatamab versus relevant comparators, 2 unanchored matching-adjusted indirect comparisons (MAICs) were conducted by the sponsor. The objective of MAIC 1 was to assess the relative treatment effect of elranatamab, using data from cohort A of the MagnetisMM-3 trial, compared to physician’s choice of treatment based on aggregated data from the CMRG database in patients with TCE or RRMM. The outcomes assessed included PFS and OS.

The objective of MAIC 2 was to assess the relative treatment effect of elranatamab compared to teclistamab from the MajesTEC-1 trial, physician’s choice of treatment from prospective real-world evidence (RWE) studies (the LocoMMotion and MAMMOTH trials), idecabtagene vicleucel from the KarMMa trial, and ciltacabtagene autoleucel (cilta-cel) from the CARTITUDE-1 trial in patients with TCE or RRMM. Since idecabtagene vicleucel is not used in Canada, as per the participating drug plans and clinical experts consulted by CADTH, comparisons to this treatment were not included in this report. The outcomes assessed included ORR, PFS, OS, and CRR. Both MAICs used the same methods to match study populations and quantify the relative effect of treatments using HRs with 95% CIs. Prognostic variables (PVs) and effect modifiers (EMs) were identified through a systematic literature review and validated with clinical expert opinion.

Efficacy Results

The results of both MAICs were generally in favour of elranatamab compared to relevant comparators, except for cilta-cel. In MAIC 1, the PFS and OS favoured elranatamab versus physician’s choice of treatment, although the proportional hazards assumption was violated for both outcomes, which could have biased the estimates. In MAIC 2, the ORR favoured elranatamab versus teclistamab and physician’s choice of treatment. For PFS, the hazard ratio (HR) favoured elranatamab versus teclistamab and physician’s choice of treatment and crossed the null for elranatamab versus cilta-cel. For OS, the HR crossed the null for elranatamab versus teclistamab, favoured cilta-cel versus elranatamab, and favoured elranatamab versus physician’s choice of treatment. The proportional hazards assumption was violated in most comparisons for both OS and PFS, except for the comparison to teclistamab. For CRR, the effect crossed the null for elranatamab versus teclistamab, and favoured elranatamab versus physician’s choice of treatment.

Harms Results

The MAICs did not include harms, and therefore no conclusions could be drawn on the relative safety of elranatamab versus relevant comparators from this evidence.

Critical Appraisal

Both MAIC 1 and MAIC 2 used the same methods to indirectly compare treatments, and their rationale and objectives were reported. In the case of both MAICs, the authors did not report a systematic literature search, describe their methods for data extraction, or conduct quality assessment of the included studies. The MAICs included relevant outcomes identified by the CADTH team (ORR, PFS, OS, CRR); however, important outcomes such as DOR, HRQoL, and safety were not included in the comparisons. The CMRG database did not capture DOR, HRQoL and safety outcomes, and therefore these outcomes were not included in MAIC 1. As such, their indirect comparative assessment remains unknown.

Across the included studies, there were similarities and notable differences in study design, inclusion and exclusion criteria, outcome definitions, and patient characteristics. For MAIC 2, a key difference of comparing elranatamab to teclistamab, cilta-cel, and physician’s choice of treatment based on the LocoMMotion study was that these studies included patients who were TCE, while the MagnetisMM-3 trial enrolled patients who were TCR. As TCE patients are potentially in better health than TCR patients, the treatment comparisons against these drugs would have been subjected to a certain degree of uncertainty in favour of the comparators. To account for between-study differences in patient baseline characteristics, several relevant PVs and EMs were matched in the weighting process, with separate sets of variables used across treatment comparisons and outcomes. These variables were selected based on a systematic literature search and clinical expert input; however, the authors did not differentiate PVs from EMs, and used them collectively in the weighting process. For MAIC 1 (elranatamab versus physician’s choice), ISS disease stage and cytogenetic risk could not be adjusted in the analyses for PFS and OS, as the definitions did not align across the MagnetisMM-3 trial and the CMRG study, a multicentre, retrospective, real-world (RW) study. The authors noted that, at the feasibility stage, because the definitions of ISS disease stage and cytogenetic risk were not comparable between the 2 studies, they were not included in the indirect treatment comparison. In the CMRG study, patient-level data regarding these 2 variables were captured at diagnosis rather than at the start of the trial period, as it was defined in the MagnetisMM-3 trial. Additionally, extramedullary disease was not adjusted for in the analysis as it was not reported in the CMRG study. For MAIC 2, these 2 important variables were missing for 2 comparisons: in the comparison of physician’s choice of treatment from the MAMMOTH study, extramedullary disease was not adjusted for, and in the comparison of physician’s choice of treatment from the LocoMMotion study, cytogenetic risk was not adjusted for. Not adjusting for these differences could introduce residual confounding due to unreported or unobserved cross-study differences, although the direction or extent of bias is unclear. For MAIC 1, following the weighting process, the effective sample size (ESS) for OS declined by approximately 34% of the original sample size in the comparison with physician’s choice of treatment. For the PFS comparison with physician’s choice of treatment, the ESS declined by approximately 33% of the original sample size. For MAIC 2, following adjustment, the ESS for OS declined by 37% of the original sample size in the comparison with teclistamab, by 73% of the original sample size in the comparison with cilta-cel, by 45% of the original sample size in the comparison with physician’s choice of treatment (the LocoMMotion study), and by 20% of the original sample size in the comparison with physician’s choice of treatment (the MAMMOTH study). These reductions in the ESS meant that the final matched patient population was more selective than the original patient population, and may lead to large uncertainty in estimated treatment effects, although the magnitude and direction of potential bias is unclear. For MAIC 1, the proportional hazards assumption was violated for both the PFS and OS outcomes, and for MAIC 2, the assumption was violated in most comparisons for the PFS and OS outcomes. These violations could have led to biased treatment effect estimates. In addition, since both MAICs only included cohort A from the MagnetisMM-3 trial and the Health Canada indication is for patients with and without prior exposure to BCMA-directed therapies, there is no indirect comparative evidence for the use of elranatamab in patients who have received prior BCMA-directed therapy. Due to these limitations in the MAICs and uncertainty in their estimates, no definitive conclusions could be drawn on the relative treatment effects of elranatamab versus relevant comparators.

Studies Addressing Gaps in the Evidence From the Systematic Review

This section summarizes 2 retrospective cohort studies with external control arms (Study C1071024 and Study C1071031) and 1 phase I and phase II dosing study (the MagnetisMM-9 trial) that were submitted to provide comparative evidence of elranatamab versus other active treatments.

RWE External Cohort Studies (Study C1071024 and Study C1071031)

Description of Studies

A retrospective cohort study, Study C1071024, was conducted to compare the efficacy outcomes ORR, time to response, and DOR observed in the participants of the MagnetisMM-3 trial (with at least 9 months of follow-up) and RW patients selected from 2 US-based oncology electronic health record databases, the Flatiron Health and COTA databases. Study C1071031 is the continuation of Study C1071024 with an available follow-up of the MagnetisMM-3 study participants of approximately 15 months. Study C1071031 aimed to compare the PFS and OS in participants of the MagnetisMM-3 study treated with elranatamab versus RW patients with TCR MM treated with RW physician’s choice of therapy. Study C1071031 also assessed patient-reported outcomes (PROs) (via the EORTC QLQ-MY20 tool) using other studies, Study C1071013 and Study C1071014, as the data sources for the external cohort. Patients were considered eligible for selection in the external control arm if they had MM that was refractory to at least 1 PI, 1 IMiD, and 1 anti-CD38, and had started at least 1 new treatment since the documentation of TCR status. The date of initiation of the first regimen after TCR MM eligibility was defined as the index date in establishing the external control arms from the Flatiron Health and COTA databases. Patients were only eligible if they had an index date occurring between November 16, 2015, and June 30, 2022.

For the main analysis in Study C1071024 and Study C1071031, differences in baseline and key covariate characteristics between participants in the MagnetisMM-3 study and each external control arm were balanced using inverse probability of treatment weighting (IPTW).

Between February 2021 and January 2022, the MagnetisMM-3 trial, cohort A, enrolled 123 patients with TCR MM, who were included in the main analysis for Study C1071031. For the external control arms for Study C1071024 and Study C1071031, 239 patients with TCR MM were selected from the COTA database and 152 patients from the Flatiron Health database. Median follow-up times for included patients were 14.7 months in the MagnetisMM-3 trial, cohort A; 8.8 months for patients with TCR MM from the COTA database; and 7.7 months for patients with TCR MM from the Flatiron Health database.

A systematic literature review was conducted to identify variables most strongly and consistently correlated with outcomes in real-world database (RWD) studies conducted among patients with RRMM and some additional variables were included in the analysis as confounders. To control baseline confounding, propensity scores (PSs) were estimated using logistic regression models.

For the PROs analysis (EORTC QLQ-MY20), a total of 67 patients from prospective cohort studies C1071013 and C1071014 were included. Baseline characteristics were compared between participants of the MagnetisMM-3 study and Study C1071013 and Study C1071014. Most baseline characteristics between Study C1071013 and Study C1071014 were generally similar, although compared to the MagnetisMM-3 study’s population, the population from the observational studies, Study C1071013 and Study C1071014, had higher proportions of ISS stage III (18.3% and 37.8%, respectively), an ECOG PS score of 2 (5.6% and 20.0%, respectively), and high-risk cytogenetics (24.4% and 42.2%, respectively). A higher proportion of participants in the MagnetisMM-3 study had extramedullary disease compared to patients from the observational studies (38.9% and 13.3%, respectively).

Efficacy Results

PFS (Study C1071031): During the study periods, PFS events (disease progression or death) were identified for 53 (43%) patients in the MagnetisMM-3 trial’s population, 136 (57%) patients in the COTA database population, and 88 (58%) patients in the Flatiron Health database population. Median PFS was longer with elranatamab versus RW SOC in the COTA database population, both before weighting (HR = 0.51 [95% CI, 0.37 to 0.71; P < 0.0001]) and after IPTW (HR = 0.37 [95% CI, 0.22 to 0.64; P = 0.0003]). In the restricted mean survival time analyses, the average PFS was longer with elranatamab versus RW SOC in the COTA database population at 9 months, 12 months, 15 months, 18 months, and 24 months using both weighted and unweighted analyses. Similarly, the average PFS time was longer with elranatamab versus RW SOC in the Flatiron Health database population.

OS (Study C1071031): During the study periods, deaths were identified for 55 (45%) patients in the MagnetisMM-3 trial’s population, 171 (72%) patients from the COTA database population, and 90 (59%) patients from the Flatiron Health database population. Median OS was longer with elranatamab versus RW SOC in the COTA database population, both before weighting (HR = 0.65 [95% CI, 0.47 to 0.88; P = 0.0062]) and after IPTW (HR = 0.46 [95% CI, 0.27 to 0.77; P = 0.0032]). In the restricted mean survival time analyses, the average OS time was longer with elranatamab versus RW SOC in the COTA database population at 12 months, 15 months, 18 months, and 24 months using the unweighted analyses, and was also longer at 9 months, 12 months, 15 months, 18 months, and 24 months using the inverse probability of treatment (IPT)-weighted analyses. Similarly, the average OS time was longer with elranatamab versus RW SOC in the Flatiron Health database population at 9 months, 12 months, 15 months, 18 months, and 24 months using the unweighted analyses.

ORR (Study C1071024): The ORR was higher for elranatamab compared to RW SOC in both unweighted and IPT-weighted analyses. In the unweighted analyses, the ORR was 61% (95% CI, 51.8% to 69.6%) in the MagnetisMM-3 trial’s population, 31.3% (95% CI, 25.4% to 37.7%) in the COTA database population, and 30.3% (95% CI, 23.1% to 38.2%) in the Flatiron Health database population, with higher values observed in the MagnetisMM-3 trial versus the COTA database population (risk ratio [RR] = 1.95 [95% CI, 1.54 to 2.47; P < 0.0001]) and versus the Flatiron Health database population (RR = 2.01 [95% CI, 1.52 to 2.67; P < 0.0001]). Similarly, after adjusting for baseline confounding using IPTW, higher ORR was observed in the MagnetisMM-3 trial versus the COTA database population (RR = 2.22 [95% CI, 1.69 to 2.90; P < 0.0001]) and versus the Flatiron Health database population (RR = 1.79 [95% CI, 1.01 to 3.15; P = 0.0447]).

DOR (Study C1071024): Among patients who attained an OR, the median DOR was longer with elranatamab compared to RW SOC from both databases. In the unweighted analysis, improved DOR was observed with elranatamab in the MagnetisMM-3 trial compared with RW SOC in the COTA database population (HR = 0.17 [95% CI, 0.09 to 0.31; P < 0.0001]) and in the Flatiron Health database population (HR = 0.22 [95% CI, 0.11 to 0.43; P < 0.0001]). After accounting for the baseline confounding in the IPT-weighted analysis, improved DOR was still observed with elranatamab in the MagnetisMM-3 trial compared with RW SOC in the COTA database population (HR = 0.11 [95% CI, 0.06 to 0.22; P < 0.0001]) and in the Flatiron Health database population (HR = 0.21 [95% CI, 0.10 to 0.45; P < 0.0001]).

PROs (MagnetisMM-3 Trial Versus Study C1071013 and Study C1071014)

The least squares mean difference values for the disease symptoms and side effects of treatment modules were inconclusive.

Harms Results

Safety data were not evaluated.

Critical Appraisal

Patients were compared using IPTW and doubly robust methods in an attempt to minimize the impact of confounding on the results. It should be noted that this method cannot control for substantial differences resulting from different study designs between the 2 cohorts (RCT versus retrospective registry review). The MagnetisMM-3 trial is a phase II, open-label, single-arm trial whereas the external control arms were derived from longitudinal RW cohorts from electronic health records in the US. For the retrospective cohorts, there was concern of potential time-related bias (e.g., treatment changes, informative censoring) due to the likely possibility of unequal number of dropouts for outcome assessment. The definition of censoring in the PFS analysis was not equivalent between participants of the MagnetisMM-3 trial and patients identified from RW sources, which is a potential source of measurement error in PFS measurements that may have biased the comparative effectiveness estimates in favour of the SOC treatment group. There might be important unknown or unmeasured residual confounding in the external control arms that were either not documented or could not be accounted for. Although the sponsor conducted IPTW, a few characteristics were not well balanced in the comparison of the MagnetisMM-3 trial and the Flatiron Health database populations (i.e., ECOG PS score, time since the initial MM diagnosis, Charlson Comorbidity Index score, the number of lines of therapy before the index date, and history of stem cell transplant). Therefore, there remains also a potential risk of residual confounding. The sponsor recognized that unlike clinical trial settings, which use specifically defined outcomes and scheduled assessments, RW data are subject to inconsistent assessments and evaluations of treatment response. The sponsor noted that further limitations on the data quality of RWDs such as key variables were either unavailable or not similarly reported, that missing data and the accuracy of recorded data may introduce an information bias and residual confounding, and that applying eligibility criteria from a clinical trial to an RWD requires adjustments, which could impact the comparability of the populations. Well-defined, reliable, and clinically meaningful outcomes that are typically used in randomized trials may be particularly difficult to ascertain and evaluate in a RWD source that is being considered for an externally controlled trial. As a general consideration, outcomes of interest are more likely to be recorded in clinical records when events are objective and/or require immediate medical attention. This might have led to the omission of some important outcomes in the RWE cohort, which may bias the results. In addition, the sponsor did not evaluate the consistency of the timing of outcome assessments in the treatment arm compared to the external control arms. For the analysis of PROs (EORTC QLQ-MY20), participation in Study C1071013 and Study C1071014 was dependent on physicians’ and patients’ ability and willingness to participate, which may have impacted patient representativeness and be a source of self-selection bias.

The patients chosen from these RWDs to generate the external cohorts were highly selective in nature and may not reflect the general population. It is not possible to know whether the results may have differed if data from different RRMM studies or databases had been used. Numerous therapies were used in the RW clinical practice groups from the MagnetisMM-3 trial cohort and the external cohorts, many of which may not be relevant to Canadian clinical practice. Additionally, treatment regimens reported from these sources were included from November 16, 2015, until June 30, 2022 (the index date), and may not be reflective of current treatment standards. The clinical experts consulted by CADTH indicated that the patient population included in the external control arms based on the US-based COTA and Flatiron Health databases may differ from the Canadian general population. The sponsor conducted a subgroup analysis according to treatments, providing the rationale that treatments included in the analysis aligned with the “relevant comparators” for this submission. However, according to the clinical experts consulted by CADTH, some important comparators (e.g., pomalidomide, bortezomib, dexamethasone, belantamab) used in Canada are missing from the RW treatment list used for the subgroup analysis. Furthermore, the clinical experts also noted that some of treatments included are not commonly used in Canada.

MagnetisMM-9 Trial

Description of Studies

The phase I and phase II MagnetisMM-9 trial was conducted to evaluate a dosing regimen with 2 step-up priming doses and longer dosing intervals of elranatamab. The primary objective was to assess the safety of a priming dose regimen that involves premedication and 2 step-up priming doses administered within the first week of elranatamab treatment in RRMM participants who are refractory to at least 1 PI, 1 IMiD, and 1 anti-CD38 mAb. At the time of submission, data were only available for an interim analysis up to July 29, 2022, at which point patients had only been enrolled in part 1(76 mg elranatamab) and part 2A, dose level 1(> 76 mg with more than 1 week dosing interval); efficacy data were only available for patients from part 1 and safety data were only available for patients from part 1 and part 2A, dose level 1. Both sets of patients received the same first cycle (premedication, 2 step-up priming doses of elranatamab [4 mg and 20 mg], and 76 mg doses of elranatamab); patients in part 1 continued elranatamab 76 mg every week for 6 cycles while patients in part 2A, dose level 1, received elranatamab 116 mg every 2 weeks for cycle 2 to cycle 6. Additional doses were considered in the MagnetisMM-9 trial design but were not summarized because data for those groups were not yet available. The primary outcome of the MagnetisMM-9 trial was the rate of grade 2 or higher CRS during cycle 1 in adult patients with TCR MM, which was evaluated against an a priori assumption that the mean grade 2 or higher CRS rate would be 35%. Outcomes in the MagnetisMM-9 study were analyzed descriptively and without a hierarchical testing strategy; several efficacy outcomes (the duration of complete response, PFS, OS, and minimal residual disease) were immature at the time of submission and are not summarized because data were not available at the time of the interim data cut-off date. The main inclusion and exclusion criteria for the MagnetisMM-9 study were similar to the eligibility criteria of the pivotal MagnetisMM-3 trial. The baseline demographic characteristics and clinical characteristics of patients who enrolled in the MagnetisMM-3 and MagnetisMM-9 trials were generally consistent with the characteristics of patients who have heavily pretreated RRMM.

Efficacy Results

At the latest data cut-off date (July 29, 2022), efficacy data were not available for the MagnetisMM-9 study. At this time, the trial included ██ patients, █████ of patients were receiving treatment, and █████ were under follow-up. In the overall population, the median treatment duration was ████ months in the MagnetisMM-9 study; the median treatment duration in part 1 of the MagnetisMM-9 study (████ months) was comparable to that in the overall MagnetisMM-3 study population. The median cumulative dose was higher in the MagnetisMM-3 study than in the MagnetisMM-9 study (█████ ██ ███ ███ ███ ████████████), which reflects the shorter time on treatment in the MagnetisMM-9 study at the data cut-off dates. However, relative dose intensities were similar between the MagnetisMM-3 study (███████ and the MagnetisMM-9 study (████████ No major differences were observed in the proportions of patients with dose reductions or interruptions in the MagnetisMM-3 study (██████ and the MagnetisMM-9 study (███████ which were predominantly due to AEs. A smaller proportion of patients re-escalated to the 76 mg or 116 mg doses of elranatamab in the MagnetisMM-9 trial. Patients in the overall populations of the MagnetisMM-9 study had heavily pretreated MM (median = | previous lines) that was refractory to the last line of therapy. Most patients (█████) were classified as being TCR. Similar to the MagnetisMM-3 trial, infection prophylaxis was common in the MagnetisMM-9 trial, most frequently involving antiviral medication (██████ and medication to prevent Pneumocystis jiroveci pneumonia (███████

Harms Results

All harms data reported in this section are from the data cut-off date of July 29, 2022. All patients in the trial reported at least 1 TEAE. The most frequently reported TEAEs in part 1 were CRS (███), anemia (███), neutropenia (███), diarrhea (███), decreased appetite (███), pyrexia (███) and fatigue (███). The most frequently reported TEAEs in part 2A, dose level 1, were CRS (███), anemia (███), neutropenia (███), diarrhea (███), fatigue (███), decreased appetite (███), injection site reaction (███), thrombocytopenia (███) and pain in extremity (███). In the total population, ███ of patients experienced at least 1 serious TEAE. The most frequently reported serious AEs in both part 1 and part 2A, dose level 1, were CRS ████ ███ ████ ██████████████ Study treatment discontinuation due to TEAEs in part 1 were ███ and ███ in part 2A, dose level 1. The most common TEAEs leading to the discontinuation of elranatamab included septic shock (██) and peripheral sensory neuropathy (██) for part 2A, dose level 1, and neutropenia (██) for part 1. In part 1 and part 2A, dose level 1, ███ ███ ███ of patients died, respectively. Most deaths in both cohorts were attributed to other reasons ███ ██ ████ █ ███ ███ ██ ████ ██ ████ █████ ███ The primary end point of the MagnetisMM-9 trial was the rate of grade 2 or higher CRS during cycle 1 (combining patients from part 1 and part 2A), which was ███████

Critical Appraisal

The MagnetisMM-9 study was an open-label, single-arm, phase I and phase II trial. The primary limitation of the MagnetisMM-9 study was the absence of a comparator group against which the benefits and harms of elranatamab could be compared. Single-arm trials are subject to several limitations that complicate their interpretation. Efficacy outcomes in the MagnetisMM-9 study were analyzed descriptively. As the primary outcome for the MagnetisMM-9 study, the rate of grade 2 or higher CRS during cycle 1 was evaluated against an a priori assumption. Efficacy data were immature. The trial was open label, which can result in a risk of bias in the measurement of the outcomes, particularly for subjective harms.

The baseline demographic characteristics and clinical characteristics of patients who enrolled in the MagnetisMM-3 and MagnetisMM-9 trials were generally consistent with the characteristics of patients who have heavily pretreated RRMM. Dose adjustments were allowed in the trial and the methods were outlined in the protocol. Dose adjustments or modifications are anticipated in a clinical practice setting to manage AEs while maintaining drug benefit.

Conclusions

Evidence of efficacy and safety from 1 ongoing, phase II, noncomparative, open-label trial (the MagnetisMM-3 trial) in adults with RRMM who had received at least 3 prior lines of therapy was included in the review for elranatamab. The clinical experts consulted by CADTH indicated that based on their experience treating patients with RRMM and the natural history of the disease, the ORR observed in patients without prior exposure to BCMA-directed therapy (cohort A) is clinically meaningful. However, it remains unknown whether elranatamab could improve PFS, OS, and DOR in patients with prior exposure to BCMA-directed therapy (cohort B) and without prior exposure to BCMA-directed therapy (cohort A) because of the lack of a comparator group, because data were immature, and because no definitive conclusions can be drawn on HRQoL due to the open-label design and large amount of missing outcome data. Overall, the results for patients in cohort B were not as favourable as those for patients in cohort A. There were no new safety signals identified and the safety of elranatamab was consistent with the known safety profile of the drug. Results from the indirect treatment comparisons and RWE studies consistently favoured elranatamab over comparators, except for cilta-cel. However, due to limitations of these studies, no conclusions can be drawn regarding the relative efficacy and safety of elranatamab compared to relevant comparators, including physician’s choice of treatment, teclistamab, and cilta-cel. The evidence submitted to CADTH did not include indirect comparative evidence between elranatamab and any comparator for patients with prior exposure to BCMA-directed therapy; this represents a gap in the available indirect evidence.

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 elranatamab 40 mg/mL, subcutaneous injection, for the treatment of adults with RRMM who have received at least 3 prior lines of therapy.

Disease Background

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

MM is a plasma cell cancer characterized by the clonal proliferation of malignant plasma cells (B-cells) and the overproduction of the abnormal immunoglobulin M protein.⁴ Older individuals and men (as opposed to women) are more likely to develop MM and it is twice as common in African-American individuals compared to Caucasian or Asian individuals.^5,6 In 2022, it was estimated that 4,000 individuals living in Canada were diagnosed with MM and 1,650 patients living in Canada died from MM.⁷ The 5-year survival rate for patients with MM is estimated to be approximately 50%,⁸ and although survival rates have improved in recent years due to advances in therapeutic options, MM remains incurable.^9,10 The majority of patients with MM will relapse and many patients will become refractory to commonly used therapies.¹¹ Patients with RRMM often undergo multiple rounds of treatment, with the duration of remission, depth of response, PFS, and OS decreasing with each subsequent line of therapy.⁶

The most common symptoms of MM are fatigue and bone pain,⁶ with other symptoms including kidney problems, recurrent infections, fever, and nervous system problems.¹² Disease stage, along with other factors, can impact MM prognosis. Commonly recognized factors that impact the prognosis of MM include beta₂-microglobulin (B2M) (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).¹³ In addition to these factors, prognosis may be influenced by age, creatinine levels, and performance status. In general, older patients, those with high creatinine levels, and those with poor overall function tend to have worse outcomes compared to younger individuals, those with lower creatinine levels, and those with better overall function.¹⁴

The 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.¹⁵ The 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.⁶ 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: a clonal bone marrow plasma cell percentage of 60% or more, a free light chain ratio of 100 or more, and more than 1 focal lesion on MRI scans.⁶

Several systems are used for staging MM: the International Staging System (ISS), R-ISS, and the Durie-Salmon staging system.^4,16,17 The ISS is commonly used in Canada and uses blood tests that assess albumin levels and B2M levels to stage MM (advanced-stage MM is associated with lower albumin and higher B2M levels):¹⁶

• stage I — B2M of less than 3.5 mg/L; serum albumin of 3.5 g/dL or more

• stage II — B2M of less than 3.5 mg/L; serum albumin of less than 3.5 g/dL; or B2M of 3.5 mg/L to 5.5 mg/L, irrespective of serum albumin

• stage III — B2M of more than 5.5 mg/L.

The preferred staging system for MM is the R-ISS,¹⁷ which combines elements of tumour burden (ISS) and disease biology (the presence of high-risk cytogenetic abnormalities or elevated LDH levels), to create a unified prognostic index that helps in clinical care as well as in the comparison of clinical trial data. R-ISS uses serum B2M, serum albumin, serum LDH, and bone marrow fluorescence in situ hybridization (FISH) results to stratify patients into 3 risk groups:^16,17

• stage I — B2M of less than 3.5 mg/L, serum albumin of 3.5 g/dL or more, normal LDH, and with no del(17p), t(4;14), t(14;16) by FISH

• stage II — neither stage I nor stage III (There are 2 categories for stage II: serum 2-microglobulin 3.5 mg/L but serum albumin 3.5 g/dL; or serum 2-microglobulin 3.5 to 5.5 mg/L irrespective of the serum albumin level.

• stage III — B2M of 5.5 mg/L or more, elevated LDH, and/or del(17p), t(4;14), t(14;16) by FISH.

According to the IMWG criteria, a patient is considered to have refractory MM when they are nonresponsive to therapy or experience disease progression within 60 days of their last line of therapy.^18,19 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 RRMM.^18,19 Finally, a patient is considered to have relapsed and refractory MM if they have attained a minimal response or better at some point during previous treatments but the disease is currently nonresponsive on salvage therapy, or they experience disease progression within 60 days of their last therapy.^18,19

Standards of Therapy

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

According to the clinical experts consulted by CADTH, the main treatment goals for patients with RRMM are to prolong survival, improve symptoms, minimize toxicities, and maintain or improve HRQoL. Therapies for the treatment of patients with RRMM, and the sequencing of these treatments, depend on eligibility for autologous stem cell transplant at diagnosis, age, comorbidities, previous treatments, beforexicities, and line of therapy. According to the joint clinical practice guideline of OH-CCO and the American Society of Clinical Oncology, treatment for RRMM includes triplet therapy consisting of PIs, IMiDs, and mAbs.²⁰ There is no preferred therapy for RRMM in the fourth-line and beyond settings, and at this stage of the disease, patients may be treated with PIs, IMiDs, and anti-CD38 mAbs,^20,21 and in some cases receive more than 1 PI or IMiD, further limiting treatment options in later lines of therapy. According to the 2022 Provisional Funding Algorithm for MM developed by CADTH,²¹ 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 carfilzomib and dexamethasone or pomalidomide and dexamethasone in combination with isatuximab; carfilzomib, lenalidomide, and dexamethasone; lenalidomide and dexamethasone; daratumumab, lenalidomide, and dexamethasone; or daratumumab, bortezomib, and dexamethasone. Alternative regimens with a different PI or immunomodulator backbone can be offered in the third and fourth lines, depending on drug sensitivity. Cyclophosphamide may be added to some regimens, such as pomalidomide and dexamethasone; carfilzomib and dexamethasone; and lenalidomide and dexamethasone.

Recent recommendations to reimburse drugs to treat triple RRMM with conditions by the pan-Canadian Oncology Drug Review Expert Review Committee include carfilzomib and dexamethasone; pomalidomide and dexamethasone; selinexor, bortezomib, and dexamethasone; and cilta-cel. According to the CADTH Provisional Funding Algorithm for MM, selinexor, bortezomib, and dexamethasone is recommended for third-line therapy and beyond in patients who are sensitive to bortezomib but not to anti-CD38 mAbs and lenalidomide. In Canada, coverage for pomalidomide and dexamethasone with or without cyclophosphamide, and carfilzomib and dexamethasone 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. Coverage for selinexor varies across provinces and territories in Canada.

Drug Under Review

Elranatamab injection is indicated for the treatment of adults with RRMM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 mAb, and who have demonstrated disease progression on the last therapy. The reimbursement request aligns with the Health Canada indication for elranatamab.²²

Elranatamab is a bispecific antibody consisting of humanized anti-BCMA and anti–CD3-epsilon targeting arms paired on a immunoglobulin G2a backbone with nullified Fc binding function, which leads to a longer half-life.^23,24 Elranatamab binds to both BCMA-expressing MM cells and T-cells, effectively creating a bridge between them.^24,25 Activated T-cells release perforin and granzyme B, leading to cytolysis of MM cells.^23,25-27

The recommended dosing schedule for elranatamab, via subcutaneous injection, is 12 mg on day 1 and 32 mg on day 4 of week 1, followed by a full treatment dose of 76 mg administered weekly from week 2 to week 24.²² For patients who have received at least 24 weeks of treatment and have attained a response (i.e., an IMWG response category of partial response or better with responses persisting for at least 2 months), the dose interval should transition to a schedule of every 2 weeks.²²

Key characteristics of elranatamab and other therapies for the treatment of adult patients with RRMM in fourth-line therapy and beyond, as indicated in CADTH's Provisional Funding Algorithm for MM,²¹ are presented in Table 3.

Table 3: Key Characteristics of Pharmacotherapies for Multiple Myeloma

BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; DRESS = Drug Rash with Eosinophilia and Systemic Symptoms; DVT = deep venous thrombosis; ICANS = immune effector cell-associated neurotoxicity syndrome; IMiD = immunomodulatory drug; mAb = monoclonal antibody; MM = multiple myeloma; PI = proteasome inhibitor; PML = progressive multifocal leukoencephalopathy; RRMM = relapsed or refractory multiple myeloma; SC = subcutaneous; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis.

^aHealth Canada–approved indication.

Sources: Product monographs for Elrexfio,²² Carvykti,²⁸ Xpovio,²⁹ Pomalyst,³² and Kyprolis,³⁰ and Canadian Pharmacists Association.³¹

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by a patient group. The full original patient input received by CADTH has been included in the Stakeholder section of this report.

CADTH received 1 patient group submission from Myeloma Canada. Myeloma Canada conducted both patient and caregiver surveys from September 26 to October 23, 2023, across Canada and internationally via email and social media. A total of 67 complete responses to the patient survey were received, of which 38 responses were recorded based on the respondent’s eligibility criteria (receiving treatment with an IMiD, PI, and anti-CD38 antibody). Among these 38 patients, 24 were eligible for the drug under review and 14 had experience with it. A total of 32 caregivers responded to the caregiver survey, 11 of whose responses were recorded (8 based on eligibility and 3 based on experience with elranatamab). Upon verifying their eligibility for or experience with elranatamab, respondents were divided into 4 subsets. These included patients (n = 24) who would currently be eligible for treatment with elranatamab; patients (n = 14) who have received or are currently receiving treatment with elranatamab; caregivers (n = 8) of patients who would currently be eligible for treatment with elranatamab; and caregivers (n = 3) of patients who have received or are currently receiving treatment with elranatamab. Regarding receiving prior lines of therapy, 13 patients and 3 caregivers indicated receiving 3 lines of therapy, 6 patients and 5 caregivers indicated receiving 4 lines of therapy, 6 patients and 1 caregiver indicated receiving 1 line of therapy, and 5 patients and 2 caregiver respondents indicated receiving 5 lines of therapy or more.

Patient respondents indicated that among their daily activities and quality of life, their ability to work was the factor the most significantly impacted by symptoms associated with myeloma, followed by the ability to travel and to exercise. Regarding the most significant financial implication of myeloma treatment on patients and their household, 24 of 49 respondents (both patients and caregivers) identified loss of income or pension funds due to absence from work, disability, or early retirement as the most significant financial implication, and 20 of 49 respondents chose travel parking costs. Patient respondents felt that interruption of life goals or accomplishments had the greatest impact on their 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 the treatment (especially in achieving remission and having a durable response), and treatment accessibility or portability (including fewer or minimal visits to the hospital or cancer centre). Infections were identified by patients as the most important aspect to control, followed by mobility and kidney problems.

In terms of treatment outcomes, 12 of the 23 respondents who would currently be eligible for treatment with elranatamab rated improved quality of life as extremely important, 6 respondents rated it as very important, and 5 respondents rated it as somewhat important. In addition, 17 of the 23 patients rated the aspect of life extension while considering a myeloma treatment as extremely important, and 4 patients rated it as very important. When asked about their tolerance of the most common side effects in patients who receive elranatamab, these patients perceived pneumonia, ICANS, URTI, CRS, and infections as the least tolerable side effects, followed by peripheral neuropathy, other infections, and COVID-19. Regarding the impact of the dosing schedule of elranatamab on quality of life (weekly injections for at least 24 weeks, with the possibility of then switching to every 2 weeks), 11 of 24 patients chose the response of negative impact, indicating that it would limit patients’ ability to travel or require a relocation (near their cancer centre) for the duration of treatment.

A total of 17 respondents (14 patients and 3 caregivers) indicated having experience with elranatamab. Among these, 12 respondents (10 patients and 2 caregivers) received elranatamab as monotherapy, 4 patients received elranatamab in combination with another drug, and 1 caregiver was unsure. All 14 patients who had received or were currently receiving treatment with elranatamab mentioned that they were admitted to the hospital at some point in the initial step-up dosing period. Regarding the most frequently experienced elranatamab side effects, all 14 patients rated cough as the least bearable side effect, followed by CRS, neutropenia, and URTI. Most of these patients mentioned that the overall side effects while receiving elranatamab were manageable and found elranatamab effective in controlling their myeloma.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding 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, providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of RRMM.

Unmet Needs

The clinical experts indicated that since almost all patients with RRMM will become refractory to their therapy and continue on to the next line of therapy, the unmet needs of patients would be new effective treatments, with curative potential, which are tolerable by targeting a different mechanistic pathway. Both clinical experts highlighted that the balance between treatment efficacy, minimizing toxicities, and quality of life would be important.

Place in Therapy

The clinical experts agreed that due to elranatamab’s novel mechanism of action, it would provide an additional treatment option for patients who are refractory to other SOC treatments. The clinical experts noted that elranatamab is a new class of treatment for which there should be no existing drug resistance, and given its unique mechanism of action and toxicity profile, it should create a treatment synergy with other current families of myeloma treatments. However, they noted that given the lack of direct evidence, it is not known yet if elranatamab is more effective than other therapies.

Patient Population

The clinical experts agreed that the patients best suited for elranatamab would be those who are TCR. One of the clinical experts noted that patients most likely to respond to this therapy would be those with a stronger and more intact immune system, and that patients with significant pre-existing cytopenias may not be ideal candidates as the cytopenias may worsen during treatment and predispose patients to infection. The experts did not note any issues or challenges related to the diagnosis or misdiagnosis of RRMM, and the identification of patients likely to respond. Patients would be identified during routine cancer follow-up based on biochemical assessment (serum protein electrophoresis, serum free light chain) or other evidence of relapse.

Assessing the Response Treatment

The clinical experts agreed that in clinical practice, standard clinical response criteria can be used to determine whether a patient with RRMM is responding or progressing on treatment. The clinical experts noted that achieving a durable OR lasting 6 months to 12 months would be a sign of successful treatment, and such a response would be associated with a reduction in disease-related symptoms, bone pain, fatigue, and transfusion requirements. They noted that toxicities, especially cytopenias such as neutropenia, infections, CRS, and hypogammaglobulinemia, would need to be monitored.

Discontinuing Treatment

The clinical experts indicated that treatment with elranatamab should be discontinued if the patient experiences disease progression (as defined radiologically or biochemically), loss of response, unacceptable toxicity such as grade 3 or grade 4 infection or CRS, light chain or renal dysfunction, or increasing transfusion requirement.

Prescribing Considerations

The clinical experts noted that patients receiving elranatamab should be under the care of a specialist (e.g., hematologist, oncologist) familiar with myeloma and the use of bispecific antibodies, and who can manage toxicity associated with the therapy. They noted that elranatamab can be given in most centres experienced with myeloma therapy, and that the first few doses usually require hospitalization.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by clinician groups. The full original clinician group input received by CADTH has been included in the Stakeholder section of this report.

Clinician group input on the review of elranatamab was received from 2 clinician groups: the CMRG and OH-CCO’s Hematology Cancer Drug Advisory Committee (OH-CCO’s Drug Advisory Committees). A total of 33 clinicians (26 from CMRG and 7 from OH-CCO’s Drug Advisory Committees) provided input for this submission.

Both CMRG and OH-CCO’s Drug Advisory Committees emphasized that the overall treatment goals are to delay progression, improve OS, minimize adverse effects, control the disease and associated symptoms, and improve quality of life. While discussing the unmet needs of patients, CMRG highlighted that myeloma remains incurable and patients eventually become refractory to all available funded drugs, similar to the statements of the clinical experts consulted by CADTH. CMRG emphasized that the highest unmet need consists of patients with advanced disease who have received multiple lines of treatment and have already received the 3 major classes of drugs (TCE or refractory) including an IMiD, PI, and anti-CD38 mAb. Another unmet need noted by OH-CCO Drug Advisory Committees is to achieve ease of administration with elranatamab (i.e., subcutaneous injection and no need for apheresis).

Similar to the clinical experts consulted by CADTH, both clinician groups agreed that elranatamab could be another option for TCE patients. CMRG further stated that presently, this treatment would be used late in the current lines of myeloma treatment (i.e., after the failure of multiple drugs). Moreover, CMRG added that elranatamab is not expected to impact the sequencing of drugs earlier in the disease course or lead to a major change in treatment algorithms before patients becoming TCE or refractory.

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 patients most likely to have the best outcomes with elranatamab. CMRG noted that overall, patients with poor disease-related prognostic factors, such as extramedullary myeloma and high-risk cytogenetics, should be eligible for the treatment under review.

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

Given that prior anti-BCMA exposure does not preclude responsiveness to subsequent anti-BCMA therapy, CMRG suggests that patients with prior anti-BCMA therapy who did not progress during it (i.e., nonrefractory to anti-BCMA therapy) be allowed access to elranatamab.

Drug Program Input

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

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

BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; cilta-cel = ciltacabtagene autoleucel; CNS = central nervous system; CRS = cytokine release syndrome; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ICANS = immune effector cell-associated neurotoxicity syndrome; IMWG = International Myeloma Working Group; KCd = carfilzomib plus dexamethasone in combination with cyclophosphamide; Kd = carfilzomib plus dexamethasone; PCd = pomalidomide plus dexamethasone in combination with cyclophosphamide; Pd = pomalidomide plus dexamethasone; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; SC = subcutaneous; SVd = selinexor plus bortezomib and dexamethasone.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of elranatamab 40 mg/mL, subcutaneous injection, for the treatment of adults with RRMM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 mAb, and who have demonstrated disease progression on the last therapy. The focus will be placed on comparing elranatamab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of elranatamab is presented in 3 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. CADTH’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 includes indirect evidence from the sponsor. The third 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 is included in the CADTH review and appraised in this document:

• One pivotal trial

• Two indirect treatment comparisons

• Three additional studies addressing gaps in the pivotal and/or RCT evidence.

In addition, a multicentre retrospective cohort study that used the CMRG database to describe RW outcomes in patients with anti-CD38 mAb refractory MM subsequently treated with SOC regimens is summarized in Appendix 1.

Systematic Review

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Description of Studies

Characteristics of the included studies are summarized in Table 5.

The MagnetisMM-3 study is an ongoing, phase II, nonrandomized, noncomparative, open-label, multicentre trial that aims to assess the efficacy and safety of elranatamab 76 mg, subcutaneous injection, once weekly after 2 step-up priming doses followed by dosing every 2 weeks in adults with RRMM (Figure 1).³ The trial enrolled adults with a prior diagnosis of MM and measurable disease who either had previous experience with BCMA-directed treatment (cohort B) or did not (cohort A). Patients had to have been disease-refractory to at least 1 PI, 1 IMiD, and 1 anti-CD38 antibody, and disease-relapsed or disease-refractory to their last antimyeloma regimen. The 2 cohorts were analyzed separately.

The trial enrolled 187 patients (cohort A, n = 123; cohort B, n = 64) across 10 countries, including 13 patients from 5 Canadian centres. The trial included a screening phase up to 28 days, and a treatment phase that included 28-day cycles until discontinuation criteria were met, which included confirmed disease progression, unacceptable toxicity, withdrawal of consent, death, or study termination. All patients were followed up at 28 days to 35 days after treatment discontinuation, with long-term follow-up of 2 years or longer after enrolment.

The outcomes relevant to the CADTH review included the primary outcome of ORR by BICR per IMWG criteria, and secondary outcomes of PFS, OS, CRR, DOR, and safety. HRQoL measured via the EORTC QLQ-MY20 tool was included as an exploratory outcome.

Efficacy and safety data were evaluated at a planned analysis data cut-off date of October 14, 2022, and additional follow-up data to a cut-off date of March 14, 2023.

Table 5: Details of Studies Included in the Systematic Review

ADC = antibody-drug conjugate; ASTCT = American Society for Transplantation and Cellular Therapy; BCMA = B-cell maturation antigen; BICR = blinded independent central review; CAR = chimeric antigen receptor; CRR = complete response rate; CRS = cytokine release syndrome; DOCR = duration of complete response; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EMD = extramedullary disease; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-MY20 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20; GBS = Guillain-Barré syndrome; GVHD = graft-vs.-host disease; HBV = hepatitis B virus; HCV = hepatitis C virus; ICANS = immune effector cell-associated neurotoxicity syndrome; ICU = intensive care unit; IMiD = immunomodulatory drug; IMWG = International Myeloma Working Group; MM = multiple myeloma; MRD = minimal residual disease; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PI = proteasome inhibitor; POEMS = polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TTR = time to response; ULN = upper limit of normal.

Note: Details included in Table 5 are from the sponsor’s Summary of Clinical Evidence.

Source: MagnetisMM-3 Clinical Study Report.³[Details included in the table are from the sponsor’s Summary of Clinical Evidence].

Populations

Inclusion and Exclusion Criteria

A detailed description of the inclusion and exclusion criteria for the MagnetisMM-3 trial is provided in Table 5. Eligible patients were adults with MM with measurable disease as defined by IMWG criteria. Patients had to have disease that was refractory (defined as having disease progression while on therapy, or within 60 days of the last dose in any line, regardless of response) to at least 1 or more PI, IMiD, and anti-CD38 antibody, and disease-relapsed or disease-refractory to their last regimen. Patients eligible for cohort A must not have received prior BCMA-directed therapy, while patients eligible for cohort B must have received prior BCMA-directed antibody-drug conjugate or BCMA-directed chimeric antigen receptor (CAR) T-cell therapy. Patients were required to have an ECOG PS of less than or equal to 2, a left ventricular ejection fraction greater than or equal to 40%, and adequate bone marrow, hepatic, and renal functions. Patients were excluded if they had smouldering MM; active plasma cell leukemia; amyloidosis or polyneuropathy, organomegaly, endocrinopathy, myeloma protein, skin changes syndrome; a stem cell transplant 12 weeks or less before enrolment or active graft-versus-host disease; or any active, uncontrolled bacterial, fungal, or viral infection. Patients were also excluded if they had impaired cardiovascular function or clinically meaningful cardiovascular disease for 6 months or less.

Figure 1: Study Design of MagnetisMM-3 Trial

ADC = antibody-drug conjugate; ANC = absolute neutrophil count; BCMA = B-cell maturation antigen; BICR = blinded independent central review; BsAb = bispecific antibody; CAR t = chimeric antigen receptor T-cell therapy; CR = complete response; ECOG = Eastern Cooperative Oncology Group; IMWG = International Myeloma Working Group; min = minute; MM = multiple myeloma; MRD = minimal residual disease; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; POEMS = polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes; Q2W = every 2 weeks; QW = every week; RRMM = relapsed or refractory multiple myeloma; SC = subcutaneous.

Note: Details included in Figure 1 are from the sponsor’s Summary of Clinical Evidence.

Prior BCMA-directed treatments included ADC or CAR-Ts (no prior BCMA-directed BsAb).

* If a patient attained an IMWG response category of partial response or better persisting for at least 2 months, the dosage interval could be changed from QW to Q2W.

^a Refractory is defined as having disease progression while on therapy or within 60 days of the last dose in any line, regardless of response. MM with measurable disease is as defined by IMWG criteria. Patients with an active or clinically significant bacterial, fungal, or viral infection, POEMS syndrome, and those who received a stem cell transplant within 12 weeks before enrolment were excluded.

^b BICR assessment per IMWG response criteria.

^c Investigator assessment per IMWG response criteria.

Source: Bahlis et al. (2022).³³

Interventions

Patients received elranatamab 76 mg by subcutaneous injection once a week on a 28-day cycle with a 2 step-up priming dose regimen of 12 mg on day 1 and 32 mg on day 4 during the first week (4 patients received a single 44 mg priming dose). Hospitalization was required for 48 hours following the first step-up dose and for 24 hours after the second step-up dose. Premedication with acetaminophen (650 mg), diphenhydramine (25 mg), and dexamethasone (20 mg) were required before each step-up dose and before the first full dose of elranatamab. Patients who received once a week dosing for at least 6 cycles and attained a partial response or better persisting for at least 2 months had their dosing interval changed to once every 2 weeks. Dose reductions and interruptions were permitted for toxicity. Elranatamab treatment was to be continued until patient refusal, loss to follow-up, death, disease progression, or unacceptable toxicity.

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 experts consulted by CADTH and stakeholder input from patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected end points that were considered to be the most relevant to inform CADTH’s expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE.

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

BICR = blinded independent central review; CRR = complete response rate; EORTC QLQ-MY20 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20; ORR = objective response rate; PFS = progression-free survival.

Note: Details included in Table 6 are from the sponsor’s Summary of Clinical Evidence.

^aStatistical testing for this outcome was adjusted for multiple comparisons (e.g., hierarchical testing).

Source: MagnetisMM-3 Clinical Study Report.³

Objective Response Rate

The primary outcome for the MagnetisMM-3 trial was ORR assessed by BICR, defined as confirmed partial response or better according to IMWG criteria from the date of first dose until confirmed progressive disease, death, or the start of new anticancer therapy, whichever occurred first. Patients who did not have a postbaseline disease assessment due to early confirmed progressive disease, who received anticancer therapy other than the study intervention before achieving an OR, or who died, experienced confirmed progressive disease, or stopped disease assessments for any reason before achieving an OR were counted as nonresponders.

Progression-Free Survival

The secondary outcome of PFS was defined as the time from the date of first dose until confirmed progressive disease per IMWG criteria or death due to any cause, whichever occurred first, or censoring. PFS was censored on the date of the last adequate disease assessment for patients who did not have an event (i.e., confirmed progressive disease per IMWG criteria or death due to any cause), before the start of a new anticancer therapy, or when there were 2 consecutive missed disease assessments. Participants who did not have an adequate postbaseline disease assessment were censored on the date of the first dose unless death occurred on or before the time of the second planned disease assessment (i.e., ≤ 70 days after the date of the first dose), in which case the death was considered an event. Tumour assessments were done with CT or MRI at screening and at suspected complete response (if not performed within the prior 6 weeks), at the sign of progressive disease from extramedullary disease, and annually if not done within the past 12 months.

Overall Survival

The secondary outcome of OS was defined as the time from the first dose to death due to any cause or censoring. Patients not known to have died were censored at the last contact date.

Complete Response Rate

The secondary outcome of CRR assessed by BICR was defined as confirmed complete response or better according to IMWG criteria at any time from the first treatment dose until confirmed progressive disease or the start of new anticancer therapy.

Duration of Response

The secondary outcome of DOR was defined as the time from the first confirmed response to confirmed progressive disease or death due to any cause, whichever was earlier, or censoring. Patients were censored at the last valid assessment before the initiation of new anticancer therapy or when there were 2 consecutive missed efficacy assessments before an event.

Health-Related Quality of Life

The exploratory outcome HRQoL was measured by change in baseline in the EORTC QLQ-MY20 tool. A summary of its measurement properties is in Table 7. The EORTC QLQ-MY20 is an MM-specific module of the European Organisation for Research and Treatment of Cancer questionnaire that contains 20 items that use 4-point Likert scales, and are grouped into 2 functional scales (future perspective, body image) and 2 symptom scales (disease symptoms, side effects of treatment). Patients self-rate their current state for each item and scores are linearly transformed onto a scale of 0 to 100. Higher scores indicate worse symptoms (disease symptoms and side effects of treatment) or better support or functioning (future perspectives and body image). One study of patients with MM has estimated minimal important differences of 10 points for disease symptoms, 10 points for side effects of treatment, 13 points for body image, and 9 points for future perspective.³⁴ Assessments were performed at baseline (day 1 and day 15), end of treatment (28 days to 35 days post–final dose), and once every 3 cycles after year 1.

Safety Outcomes

The assessment of safety was based on the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, notable TEAEs, TEAEs leading to discontinuation, TEAEs leading to dose modification, and deaths. AEs were reported throughout the study period and coded to preferred term and system organ class using the Medical Dictionary for Regulatory Activities and classified by severity using the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0, except for CRS and ICANS, which were graded according to the criteria of the American Society for Transplantation and Cellular Therapy. TEAEs were defined as any event occurring from the first dose of elranatamab through the minimum of 90 days after the last elranatamab dose or the start of new anticancer therapy.

Table 7: Summary of Outcome Measures and Their Measurement Properties

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-MY20 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20; EORTC QLQ-MY24 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 24; MID = minimal important difference; MM = multiple myeloma.

Statistical Analysis

A summary of the statistical analysis of efficacy outcomes is provided in Table 8.

Sample Size and Power Calculation

Sample sizes were calculated separately for cohort A and cohort B. In cohort A, 120 treated patients would provide approximately 98% power at a 1-sided significance level of 0.025 to reject the null hypothesis (ORR by BICR ≤ 30%) if the observed ORR was greater than or equal to 48%. In cohort B, 60 treated patients would provide approximately 95% power at a 1-sided significance level of 0.025 to reject the null hypothesis (ORR by BICR ≤ 15%) if the observed ORR was greater than or equal to 34%. The rationale for these thresholds was not reported in the sponsor’s submission.

Statistical Testing

Point estimates of ORR by BICR in cohort A and cohort B were calculated along with the 2-sided exact 95% CIs using the Clopper-Pearson method. The null hypotheses were tested at a 1-sided alpha of 0.025 independently in the 2 cohorts. PFS and OS were analyzed using the Kaplan-Meier method and displayed graphically, and median PFS and OS times with 2-sided 95% CIs were calculated using the Brookmeyer-Crowley method. The CIs for the survival function estimates at different time points were derived using the log-log method according to the Kalbfleisch-Prentice method. Point estimates for CRR were calculated using the same method as for ORR. If at least 3 participants attained an OR and subsequently had an event, DOR was estimated using the same method as described for PFS and OS. The analysis of the EORTC QLQ-MY20 scales were summarized using descriptive statistics. Efficacy outcomes were not adjusted for covariates or baseline variables, and sensitivity analyses or analyses used to handle missing data were not performed. No adjustments for multiple comparisons were made for the included outcomes.

Cohort A crossed the efficacy boundary at the first planned interim analysis (data cut-off date of March 23, 2022) based on the first 94 patients while cohort B crossed the efficacy boundary at the final analysis (data cut-off date of June 17, 2022). Additional data were provided at the March 14, 2023, data cut-off date.

Subgroup Analysis

The following prespecified subgroups of interest were assessed for the primary outcome of ORR: age (< 65 years versus ≥ 65 years; < 75 years versus ≥ 75 years), baseline cytogenetics risk groups (high risk versus standard risk), prior stem cell transplant (yes versus no), disease stage (I to II versus III) according to the R-ISS, and the number of prior lines of therapy (≤ 5 versus > 5). The subgroup analyses were not adjusted for multiplicity.

Sensitivity Analyses and Data Imputation Methods

Sensitivity analyses and data imputation were not performed.

Analysis Populations

The efficacy and safety outcomes were analyzed based on the safety analysis set, defined as patients who received at least 1 dose of elranatamab. The HRQoL outcome was analyzed based on all patients from the safety analysis set who completed a baseline assessment and at least 1 postbaseline assessment.

Table 8: Statistical Analysis of Efficacy End Points — MagnetisMM-3 Trial

BICR = blinded independent central review; CI = confidence interval; CRR = complete response rate; DOR = duration of response; EORTC QLQ-MY20 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20; ORR = objective response rate; PFS = progression-free survival.

Note: Details included in Table 8 are from the sponsor’s Summary of Clinical Evidence.

Source: MagnetisMM-3 Clinical Study Report.³

Results

Patient Disposition

A summary of patient disposition is in Table 9. In total, 237 patients were screened, and 187 patients were assigned to elranatamab treatment (cohort A = 123; cohort B = 64). Reasons were not reported for the 45 patients who were screened out and 5 patients not enrolled. At the March 14, 2023, data cut-off, 82 (66.7%) patients in cohort A and 51 (79.7%) patients in cohort B discontinued treatment. The most common reason for discontinuation in both groups was disease progression (cohort A = 48; cohort B = 29), followed by AEs (cohort A = 17; cohort B = 7), and death (cohort A = 9; cohort B = 9).

Baseline Characteristics

A summary of baseline patient demographics and disease characteristics of the safety population are in Table 10. The characteristics outlined in the table are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. The trial population was predominately white (███), with a similar proportion of male and female patients who had a mean age of ██ years ████ ████ ███████ ██ ███ ██ █████). Most patients had an ECOG PS score of 1 (███) and 0 (███), indicating good overall performance, an R-ISS disease stage of II (███), standard cytogenetic risk (███), and a prior stem cell transplant (███). Patients had received an average of | prior lines of therapy, ███ had TCR disease, and ███ had penta-drug refractory disease (refractory to at least 2 PIs, 2 IMiDs, and 1 anti-CD38 antibody). ████████ ███ ███████████████ ████ █████████ ██████████ ███████ ████████ ████████ ██████ █ ███ █ ██████ ████ ████ █████ █████ █████████ ██████ ██████ ████ ████████ ███ ████████ ██ ███████ ████ █████ ██████████ █████████ ██████████ ███ ██████████ ████ ██████ ██

Table 9: Summary of Patient Disposition — MagnetisMM-3 Trial

NR = not reported; PRO = patient-reported outcome.

Note: Details included in Table 9 are from the sponsor’s Summary of Clinical Evidence.

Source: MagnetisMM-3 Clinical Study Report.³

Table 10: Summary of Baseline Characteristics — MagnetisMM-3 Trial

ADC = antibody-drug conjugate; BCMA = B-cell maturation antigen; BICR = blinded independent central review; CAR = chimeric antigen receptor; CrCl = creatinine clearance; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IgA = immunoglobulin A; IgD = immunoglobulin D; IgG = immunoglobulin G; R-ISS = Revised International Staging System; SD = standard deviation.

Note: Details included in Table 10 are from the sponsor’s Summary of Clinical Evidence.

^aThis included participants who had at least 1 of the following: an ECOG PS score of 2, an R-ISS score of 3, extramedullary disease at baseline by BICR, high cytogenetic risk, or bone marrow plasma cell involvement greater than or equal to 50%.

^bPenta-drug refractory disease is defined as being refractory to at least 2 proteasome inhibitors, 2 immunomodulatory drugs, and 1 anti-CD38 antibody.

Source: MagnetisMM-3 Clinical Study Report.³[Details included in the table are from the sponsor’s Summary of Clinical Evidence].

Exposure to Study Treatments

By the March 14, 2023, data cut-off, the median duration of treatment observed in the total population was ████ months ██████ █ ████ ██ ████ ████████ The median durations of treatment for cohort A and cohort B were 5.6 months (range, 0.03 months to 24.4 months) and ███ ██████ ██████ █ ████ ██ ████ ███████, respectively. The average dose intensity per week was █████ ██████████ █████ with █████ of patients experiencing 1 or more dose reduction or interruption, mostly (██████ due to AEs. The most common AEs leading to dose reduction or interruption were not reported. Most patients re-escalated to the 76 mg dose of elranatamab after requiring a dose reduction (██████ or dose interruption (███████ All patients received at least 1 or more concomitant medication, and almost all (██ ██ █████ received the first, second, and third doses of all 3 premedication drugs (antipyretics, antihistamines, and corticosteroids) as CRS prophylaxis. Infection prophylaxis was also commonly provided, most frequently involving antiviral medication (██████ and medication to prevent Pneumocystis jiroveci pneumonia ████████ Exposure to concomitant medications was generally consistent between cohorts.

Subsequent Treatment

A summary of subsequent anticancer therapy is in Table 11. Overall, ███ of patients received subsequent anticancer therapy after receiving elranatamab. The most common therapies included dexamethasone █████, cyclophosphamide ███ ██, or carfilzomib ██████ Two patients ██████ underwent subsequent transplants and no patients received follow-up radiation therapy. In general, subsequent treatments for patients in cohort A and cohort B were similar.

Table 11: Summary of Subsequent Treatment — MagnetisMM-3 Trial

Note: Details included in Table 11 are from the sponsor’s Summary of Clinical Evidence.

Source: MagnetisMM-3 Clinical Study Report.³

Efficacy

Only those efficacy outcomes and analyses of subgroups identified as important to this review were reported. The findings presented are from the 15-month analysis (March 14, 2023, data cut-off).

ORR by BICR

At the March 14, 2023, data cut-off, with a median follow-up of 14.7 months, the ORR in cohort A was 61.1% (95% CI, 51.8% to 69.6%; P < 0.0001) and █████ ████ ███ ████ ██ █████████████ in cohort B. These findings were consistent with the results at the 9-month analysis (data cut-off date of October 14, 2022).

ORR Subgroup Analyses

Forest plots of ORRs by BICR for cohort A and cohort B are in Figure 2 and Figure 3, respectively. In cohort A, the ORR results were consistent across subgroups by age, baseline cytogenetics risk, prior stem cell transplant, and number of prior lines of therapy. However, lower ORRs were observed in patients with R-ISS stage III. ██ ██████ ██ ███ ███ ███████ █████████████ ██████ ███ ██████████

PFS by BICR

Table 12 provides a summary of results for PFS by BICR. In total, 95 events had occurred in both cohorts by the March 14, 2023, data cut-off. The median follow-up for PFS was 14.7 months for cohort A and ███ months for cohort B. The median PFS was not reached (95% CI, 9.9 months to not estimable) in cohort A and ███ ██████ ████ ███ ███ ██ ████ in cohort B. The probability of being event-free at 12 months in cohort A was 56.6% (95% CI, 46.7% to 65.3%) and █████ ████ ███ ████ ████ in cohort B.

Table 12: Progression-Free Survival — MagnetisMM-3 Trial, Safety Analysis Set

BICR = blinded independent central review; CI = confidence interval; NE = not estimable.

Note: Details included in Table 12 are from the sponsor’s Summary of Clinical Evidence.

^aBased on Kaplan-Meier estimates.

Source: MagnetisMM-3 Clinical Study Report.³

Overall Survival

Table 13 provides a summary of OS findings. As of the March 14, 2023, data cut-off, the OS data were immature. A total of 55 (44.7%) patients in cohort A and ██ ███████ patients in cohort B had died. Median OS had not yet been reached in cohort A and was ████ ██████ ████ ██ ███ ██ ███ ██████████ in cohort B. The probability of being alive at 12 months in cohort A was 63.0% (95% CI, 53.7% to 70.9%) and █████ ████ ███ ████ ██ █████ in cohort B.

Table 13: Overall Survival — MagnetisMM-3 Trial, Safety Analysis Set

CI = confidence interval; NE = not estimable.

Note: Details included in Table 13 are from the sponsor’s Summary of Clinical Evidence.

^aBased on Kaplan-Meier estimates.

Source: MagnetisMM-3 Clinical Study Report.³

DOR and CRR by BICR

Table 14 provides a summary of DOR findings. By the March 14, 2023 data cut-off, the ██████ ███ ███ ███ ███████ █████ ██████████ ██ ████ ████████ ████ ███ ██ ███ ████████ ████████ ██ ███ ████ ██ ███ ████████. The probability of patients remaining in response at 12 months was 75.5% (95% CI, 58.8% to 80.9%) in cohort A and █████ ████ ███ ████ ██ █████ in cohort B. A complete response or better was attained in 43 patients (complete response or better = 35.0% [95% CI, 26.6% to 44.1%]) in cohort A and █████ ███ ███ ███ ██ █████ in cohort B.

Table 14: Duration of Response Among Confirmed Responders — MagnetisMM-3 Trial, Safety Analysis Set

CI = confidence interval; NE = not estimable; PR = partial response.

Note: Details included in Table 14 are from the sponsor’s Summary of Clinical Evidence.

^aBased on Kaplan-Meier estimates.

Source: MagnetisMM-3 Clinical Study Report.³

HRQoL by EORTC QLQ-MY20

███ ███████████ ███████ █████ ████████ █████ ██████ ███ ████████ ██ Table 15 ██ ███ █████ ███ ████ ████ ███ ████ ███ ████ █████ ██████ ████ ████████ ██ █████ ██ ██ ██████ █ ████ █████████ ███████████ █████ ██████ █████████ ██ ██████ █ ███ ████ ██ ██████ ██ ███ ███████ █████████ ██████████ █████ ██ ██ ███████ ██████ ███████████ ██████ █████████ ██ ████ ███████ ███ ███ ██████ ████ ████████ ████████ ███ ████████ ███ ██ █ ██████ ██ █████ ███ ███████ ███████ ██████ █████████ ██ ████ ███████ ███ ███ ███ ██████ ███ ████████ ███ ██ ██ ███████ ████ ███████ ██ █████████ ██████ █████████ ██ ████ ███████ ███ ███ ███ ██████ ███ ████████ ███ ██ ██ ██████.

Table 15: Mean Changes in EORTC QLQ-MY20 From Baseline to Cycle 15 — MagnetisMM-3 Trial, PRO Analysis Set [Redacted]

CFB = change from baseline; EORTC QLQ-MY20 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20; PRO = patient-reported outcome; SD = standard deviation.

Note: Details included in Table 15 are from the sponsor’s Summary of Clinical Evidence.

Source: MagnetisMM-3 Clinical Study Report.³

Harms

Harms data reported in this section are from the data cut-off date of March 14, 2023. The key harms results for the safety (i.e., as-treated) population are summarized in Table 16.

Adverse Events

All patients in the trial reported at least 1 TEAE. The most frequently reported TEAEs in cohort A were CRS (58%), anemia (49%), neutropenia (49%), diarrhea (42%), and fatigue (37%). ███ ████ ██████████ ████████ █████ ██ ██████ █ ████ ████████ ███████ ████████ ██████ ██████ ██████ ████████████████ ██████ ███████████████ ███ ███████████ ██████

Serious Adverse Events

In the total population, ███ of patients experienced 1 or more serious TEAE. The type and number of events were similar in both cohorts, with the most frequently reported events being COVID-19 pneumonia █████, CRS █████, pneumonia ██ ██, and disease progression ████.

Withdrawals Due to Adverse Events

Study treatment discontinuation due to TEAEs in cohort A was 20% and ███ in cohort B. The most common TEAEs leading to the discontinuation of elranatamab across both cohorts were similar, and included septic shock ████, neutropenia ████ COVID-19 pneumonia ████, and peripheral sensory neuropathy ████.

Mortality

In cohort A and cohort B, 45% and ███ of patients died, respectively. Most deaths in both cohorts were attributed to disease progression (30% in cohort A and ████ in cohort B).

Notable Harms

The incidence of notable harms in the total population was ███, and was similar in both cohorts. In the total population, the most frequently reported notable AEs were infections █████ and CRS█████, followed by peripheral neuropathy █████, hypogammaglobulinemia █████, and ICANS ████. All CRS events were grade 1 or grade 2 in severity. The median time from the most recent elranatamab dose to CRS onset was | ████ ███████ █ ██ █ █████ and the median time to resolution was | ████ ███████ █ ██ ██ ██████

Table 16: Summary of Harms Results — MagnetisMM-3 Trial, Safety Analysis Set

ICANS = immune effector cell-associated neurotoxicity syndrome; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TEAE = treatment-emergent adverse event.

Note: Details included in Table 16 are from the sponsor’s Summary of Clinical Evidence.

^aFrequency of 10% or more in at least 1 group.

^bFrequency of 5% or more in at least 1 group.

^cFrequency of 3 or more total patients.

Source: MagnetisMM-3 Clinical Study Report.³

Critical Appraisal

Internal Validity

The primary limitation of the MagnetisMM-3 trial was the absence of a comparator group to assess the efficacy and harms of elranatamab, and therefore the interpretation of the results is limited to its single-arm design. As such, it is difficult to make causal conclusions — in particular, to what extent the observed effects were attributable to elranatamab. The open-label design introduces a potential bias in the assessment of ORR, PFS, DOR, and CRR, and a potential reporting bias of the subjective outcomes HRQoL and safety. However, this bias was mitigated by the use of BICR for ORR, PFS, DOR, and CRR. To minimize the risk of differential measurement error, the trial performed tumour assessments using IMWG criteria and radiographic scans were assessed by BICR. Sample size and power calculations were based on ORR, which had a prespecified hypothesis that was tested; however, all other analyses were descriptive. These included PFS, OS, DOR, and CRR, and the exploratory HRQoL outcome (via the EORTC QLQ-MY20 tool), which are deemed clinically important outcomes for the disease. The sample sizes for the subgroup analyses were small and not adjusted for multiplicity, which also made it difficult in interpreting the results.

The median durations for PFS and OS were immature; therefore, the treatment benefit of PFS and OS based on the latest interim analysis would have been subjected to a certain degree of uncertainty. While the trial met its primary objective of assessing ORR, there was limited supporting evidence from important secondary outcomes — notably, the immature data for PFS and OS. Given the importance of these outcomes to patients and clinicians, longer follow-up for the PFS and OS analyses would have been preferred to determine the clinical value of treatment with elranatamab. In addition, patients were permitted to receive post-treatment anticancer medications after study treatment had been discontinued (33% of all patients), which may influence the assessment of OS. The EORTC QLQ-MY20 questionnaire has been validated in patients with RRMM with evidence of reliability, responsiveness, and minimal important difference. However, the results for this outcome were subjected to bias potentially due to incomplete reporting or missing data, which could have biased the results toward the null. Therefore, the potential differences regarding a patient’s quality of life remain uncertain.

External Validity

In general, the population requested for reimbursement aligns with that of the Health Canada indication, and the dosing and administration of elranatamab were consistent with the Health Canada–approved product monograph. According to the clinical experts consulted by CADTH, the eligibility criteria and baseline characteristics of the MagnetisMM-3 trial were generalizable to adults with RRMM in the Canadian setting, although the trial did not include patients with a poor ECOG PS. The clinical experts noted that enrolling patients with only an ECOG PS score of 0 and 1 is not entirely representative of patients with RRMM as they expect to encounter patients with higher ECOG PS scores in their practice.

Dose adjustments were allowed in the trial and the methods were outlined in the protocol. The clinical experts noted that dose adjustments or modifications are anticipated in a clinical practice setting to manage AEs while maintaining drug benefit.

The trial included outcomes that were important to patients and clinicians. The patient group indicated that stopping disease progression, prolonging life, improving HRQoL, and reducing treatment side effects are important to them. However, assessing HRQoL as an exploratory outcome is a limitation to the evidence since no definitive conclusions can be drawn. The clinical experts noted that the following safety outcomes were not reported in the trial: infection-related hospitalizations, hypogammaglobulinemia as measured by the need for IV or subcutaneous immunoglobulin, and neurotoxicities.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^1,2

• “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 CADTH review team assessed pivotal single-arm trials for study limitations (which refers to the 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 the level of very low certainty with no opportunity for rating up.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for elranatamab.

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor.

Indirect Evidence

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Objectives for the Summary of Indirect Evidence

The aim of this section is to summarize and critically appraise 2 sponsor-submitted unanchored MAICs used to inform the pharmacoeconomic model and to fill gaps in the comparative evidence versus other relevant treatments for adults with RRMM who have received at least 3 prior lines of therapy.

Description of MAICs

For both MAICs, the sponsor did not report a systematic literature search or describe the methods for study selection, data extraction, and quality assessment.

MAIC Design

Objectives

MAIC 1: Elranatamab Versus Physician’s Choice

The objective of MAIC 1³⁷ was to assess the relative treatment effect of elranatamab, using data from cohort A of the MagnetisMM-3 trial, compared to physician’s choice of treatment based on RWE from the CMRG database³⁸ and selinexor plus bortezomib in combination with dexamethasone treatment data from the BOSTON trial³⁹ in patients with TCE or RRMM. The outcomes assessed included PFS and OS.

MAIC 2: Elranatamab Versus Teclistamab, Cilta-Cel, and Physician’s Choice

The objective of MAIC 2⁴⁰ was to assess the relative treatment effect of elranatamab, using data from cohort A of the MagnetisMM-3 trial, compared to teclistamab from the MajesTEC-1 trial,⁴¹ physician’s choice of treatment from prospective RWE studies (the LocoMMotion⁴² and MAMMOTH^43,44 trials), idecabtagene vicleucel from the KarMMa trial,⁴⁵ and cilta-cel from the CARTITUDE-1 trial^46,47 in patients with TCE or RRMM.⁴⁰ Since idecabtagene vicleucel is not used in Canada, as per the participating drug plans and clinical experts consulted by CADTH, it was not included in this report. The outcomes assessed included ORR, PFS, OS, and CRR.

MAIC Analysis Methods

MAIC 1: Elranatamab Versus Physician’s Choice

A feasibility assessment was carried out to compare the study design, patient population, and outcome definitions between the MagnetisMM-3 trial, the CMRG study, and the BOSTON trial. Compatibility considerations focused on similarities and differences between the studies, and whether these could be adequately adjusted in an MAIC. Based on the feasibility assessment, an MAIC comparing elranatamab to physician’s choice of treatment from the CMRG study was feasible. Due to key differences in trial design, inclusion and exclusion criteria, patient population, and the definitions of outcome measures between the MagnetisMM-3 and BOSTON trials, an MAIC between elranatamab and selinexor plus bortezomib in combination with dexamethasone was deemed unfeasible, and therefore not reported.

The authors performed an unanchored MAIC by combining individual-level patient data (IPD) from the MagnetisMM-3 trial and aggregate data from a subgroup analysis of patients with TCE or RRMM from the CMRG RWE study to compare elranatamab to physician’s choice of treatment. The main indirect comparative analysis was conducted on cohort A (no prior BCMA-directed therapy) of the MagnetisMM-3 trial, with a median follow-up duration of 14.7 months (with a data cut-off date of March 14, 2023).

To identify potential PVs to adjust for in the comparative analyses, univariate Cox proportional hazards models were performed to identify any potential PVs based on the MagnetisMM-3 trial data. Any variable that exhibited a P value greater than 0.05 was removed as a PV. EMs and additional PVs were identified through a systematic literature review and validated with clinical expert opinion. The list of PVs and EMs for PFS and OS are in Table 17.

To conduct the MAIC, weights were assigned such that the average baseline characteristics after reweighting matched the published aggregate characteristics of the CMRG population. For variables where the means and the distributions were reported in the aggregated data, weights were generated so that the weighted means and the standard deviations in the IPD from the MagnetisMM-3 study matched those as reported in the aggregated data. For continuous variables where only the medians were reported, binary variables were generated using the IPD based on the reported medians from the aggregated data and the weights were generated so that the weighted means of the binary variables were 0.5 (i.e., to match the median reported in the aggregated data).

A PS-type logistic regression equation was used to estimate the balancing weights; this equation predicted whether a given type of patient originated from the index trial or the comparator trial as a function of baseline characteristics. More specifically, weights were estimated by the odds calculated as where is the vector of baseline variables included for matching. The beta coefficients were determined by the method of moments. Once the coefficients were estimated, the equation was applied to the patients from the MagnetisMM-3 trial to calculate the individual patient weights. These weights were then used to calculate the ESS, attained after weighting patients. The ESS was calculated by (∑w_i)² ÷ (∑w_i²). If the populations were perfectly balanced before adjustment, the ESS would equal the original size of the MagnetisMM-3 trial’s population. Adjustments for population differences assigned patients uneven weights, which led to the inevitable loss of ESS. A low ESS indicated an irregular distribution of weights across patients, meaning that only a small fraction of patients shared common characteristics. The relative effect of elranatamab versus physician’s choice of treatments was quantified as HRs with 95% CIs, as well as Kaplan-Meier curves. Differences were considered statistically significant at P values of less than 0.05. Sensitivity analyses were not performed.

The assessed outcomes PFS and OS were defined based on the MagnetisMM-3 trial as the time from the date of first dose until confirmed progression per IMWG criteria or death due to any cause, and as the time from the date of first dose until death due to any cause, respectively. The proportional hazards assumption for PFS and OS was assessed using the threshold of the Schoenfeld test set at a P value of 0.05, and through visual inspection of the log cumulative hazard plots and the Schoenfeld residual plots.

MAIC 2: Elranatamab Versus Teclistamab, Cilta-Cel, and Physician’s Choice

MAIC 2 used the same methods as MAIC 1, and is briefly described here. A compatibility assessment was performed and the results suggested notable heterogeneity between the included studies, particularly differences in patient populations. For elranatamab, IPD from the MagnetisMM-3 trial were used with the same data cut-off date of March 14, 2023, and for comparators, aggregated data were derived from their respective pivotal trial or study publications. The main indirect comparative analysis was conducted on cohort A (no prior BCMA-directed therapy) of the MagnetisMM-3 trial. The same PVs and EMs were used in MAIC 1 (Table 17) for both time-to-event and response-related outcomes. The methods to applying weights and quantifying the relative effects of treatment were the same as the methods used in MAIC 1, although it also included a naive comparison without any adjustment to treatment effects. The assessed outcomes of ORR, PFS, OS, and CRR were defined based on the MagnetisMM-3 trial. For ORR and CRR, results were reported as between-group rate differences (i.e., elranatamab and the comparator) and odds ratios with respective 95% CIs. A sensitivity analysis was performed using imputed data for variables in the MagnetisMM-3 trial where there were missing data (imputed based on a random sample of the observed data).

Results of MAIC 1 and MAIC 2

Summary of Included Studies

MAIC 1: Elranatamab Versus Physician’s Choice

A summary of study characteristics for the MagnetisMM-3 trial and CMRG study is in Table 18.

The CMRG database captures both legacy data and prospectively collected data from 2007 up to a data cut-off date of June 30, 2022, and reflects the outcomes seen with the basket of treatments used in RW clinical practice in Canada. The most prevalent regimens used in the CMRG basket were IMiDs and PIs. In the CMRG study, ISS disease stage and cytogenetic risk were reported for patients with MM at diagnosis. These baseline characteristics did not match the definition in the MagnetisMM-3 trial (where it was captured at the initiation of the trial period). As a result of this discrepancy, ISS disease stage and cytogenetic risk were not adjusted in the analysis. Other baseline characteristics that were reported in the CMRG study, such as exposure to prior therapies and being refractory to prior therapies, were not included in the analysis as these variables were not identified as key PVs and EMs.

To perform matching with the MagnetisMM-3 trial’s population, patients were selected from the CMRG database if they were adults (≥ 18 years), had MM that was refractory to an anti-CD38 mAb (progressed on therapy or within 60 days of the last dose of the anti-CD38 mAb), and had TCR disease (refractory to at least 1 IMiD, at least 1 PI, and 1 anti-CD38 mAb).

Table 17: Prognostic Variables and Effect Modifiers Identified for PFS and OS for MAIC 1 and MAIC 2

ECOG PS = Eastern Cooperative Oncology Group Performance Status; IgA = immunoglobulin A; IgD = immunoglobulin D; IgG = immunoglobulin G; ISS = International Staging System; MAIC = matching-adjusted indirect comparison; MM = multiple myeloma; OS = overall survival; PFS = progression-free survival; R-ISS = Revised International Staging System.

Note: Details included in Table 17 are from the sponsor’s Summary of Clinical Evidence.

Source: MAIC 1 technical report.³⁷

Table 18: Summary of Study Characteristics Included in MAIC 1 — Elranatamab Versus Physician’s Choice

BCMA = B-cell maturation antigen; CMRG = Canadian Myeloma Research Group; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IMiD = immunomodulatory drug; IMWG = International Myeloma Working Group; mAb = monoclonal antibody; MAIC = matching-adjusted indirect comparison; MM = multiple myeloma; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PI = proteasome inhibitor; TCR = triple-class refractory.

Note: Details included in Table 18 are from the sponsor’s Summary of Clinical Evidence.

Source: MAIC 1 technical report.³⁷

MAIC 2: Elranatamab Versus Teclistamab, Cilta-Cel, and Physician’s Choice

A summary of study characteristics is in Table 19.

Elranatamab Versus Teclistamab

Overall, the design of the pivotal trials of elranatamab (the MagnetisMM-3 study) and teclistamab (the MajesTEC-1 study) was similar except that in the MagnetisMM-3 study, enrolled patients were TCR whereas patients in the MajesTEC-1 study were TCE. Additionally, the MajesTEC-1 trial enrolled patients with an ECOG PS score of less than or equal to 1, which differs from the MagnetisMM-3 trial where patients with a performance score less than or equal to 2 were eligible for enrolment. To account for this difference, patients from the MagnetisMM-3 trial with an ECOG PS score greater than 1 were excluded from MAIC analyses. In the MajesTEC-1 trial, extramedullary disease was defined as the presence of 1 or more extramedullary soft-tissue lesions. This definition did not match the definition in the MagnetisMM-3 trial (defined as the presence of any plasmacytoma [extramedullary and/or paramedullary] with a soft-tissue component). To account for this, an additional baseline variable in the MagnetisMM-3 study’s IPD was created for the comparison versus teclistamab, which matched the definition of extramedullary disease in the MajesTEC-1 study. The definitions of PFS and OS were similar between the 2 trials.

Elranatamab Versus Cilta-Cel

A key difference between the designs of the MagnetisMM-3 and CARTITUDE-1 trials was patients in the MagnetisMM-3 trial were TCE, whereas patients in CARTITUDE-1 were TCR. There were notable differences between the number of patients with different disease stages, extramedullary disease, and creatine clearance. Other characteristics, including the definitions of PFS and OS, were similar between the 2 trials.

Elranatamab Versus Physician’s Choice

LocoMMotion Study

A key difference between the designs of the MagnetisMM-3 trial and the LocoMMotion study is that the latter is an observational, noninterventional study of patients who are TCE whereas the MagnetisMM-3 study is a single-arm, interventional clinical trial of patients who are TCR. In addition, the LocoMMotion study enrolled patients with an ECOG PS score of less than or equal to 1 (the MagnetisMM-3 trial enrolled patients with an ECOG PS score of 2 or less). However, when the baseline characteristics were captured, ECOG PS scores higher than 1 were recorded. As a result, ECOG PS score was not considered to be a discrepancy between the MagnetisMM-3 and LocoMMotion studies. Due to the large amount of missing data, cytogenetic risk was not included in the MAIC. This potentially led to bias as cytogenetic risk was identified as a PV and EM. Other characteristics, including the definitions of PFS and OS, were similar between the 2 studies.

Table 19: Summary of Study Characteristics Included in MAIC 2 — Elranatamab Versus Teclistamab, Cilta-Cel, and Physician’s Choice

BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; cilta-cel = ciltacabtagene autoleucel; ECOG PS = Eastern Cooperative Oncology Group Performance Status; GVHD = graft-vs.-host disease; IMiD = immunomodulatory drug; IMWG = International Myeloma Working Group; mAb = monoclonal antibody; MAIC = matching-adjusted indirect comparison; MM = multiple myeloma; NR = not reported; PI = proteasome inhibitor; SCT = stem cell transplant; TCE = triple-class exposed; TCR = triple-class refractory.

Note: Details included in Table 19 are from the sponsor’s Summary of Clinical Evidence.

^aThe LocoMMotion study is ongoing. Time-to-event data for this study were based on a data cut-off date of October 2022, after a median follow-up of 26.4 months.

Source: MAIC 2 technical report.⁴⁰

MAMMOTH Study

Similar to the LocoMMotion study, the MAMMOTH study reflects the outcomes seen with the basket of treatments used in RW clinical practice. A key difference between the designs of the 2 studies is that the MAMMOTH study was an observational, noninterventional study whereas the MagnetisMM-3 study is a single-arm, interventional clinical trial. Only data from the TCR subgroup were used for comparison in analyses. Differences between the studies included patients who were penta-exposed and penta-refractory. Other characteristics, including the definitions of ORR, PFS, OS, and CRR, were similar between the 2 studies.

Results

MAIC 1: Elranatamab Versus Physician’s Choice

In the comparison of PFS with elranatamab versus physician’s choice of treatment (the CMRG study), weights were generated based on adjustment for median age, median time since initial diagnosis in years, and median prior lines of therapy. The same adjustments were made for the OS comparison, with the addition of sex. The authors noted that the proportional hazards assumption was violated for both OS and PFS.

Progression-Free Survival

Following MAIC adjustment and an ESS of 82, the PFS HR was 0.36 (95% CI, 0.23 to 0.54; P = 0.000) in favour of elranatamab versus physician’s choice of treatment.

Overall Survival

Following MAIC adjustment and an ESS of 81, the OS HR was 0.48 (95% CI, 0.32 to 0.73; P = 0.000) in favour of elranatamab versus physician’s choice of treatment.

MAIC 2: Elranatamab Versus Teclistamab, Cilta-Cel, and Physician’s Choice

A summary of PVs and EMs adjusted in the MAICs is in Table 20, and results for ORR, PFS, OS, and CRR are in Table 21. The authors noted that the proportional hazards assumption was violated in most comparisons for both OS and PFS, except for the comparison to teclistamab (PFS and OS) and the LocoMMotion study (OS only).

Objective Response Rate

Following MAIC adjustment, the ORR difference favoured elranatamab versus teclistamab and physician’s choice of treatment (for both the LocoMMotion and MAMMOTH studies). The results of the sensitivity analyses were consistent with the primary base-case analyses.

Progression-Free Survival

Following MAIC adjustment, the PFS HR favoured elranatamab versus teclistamab and physician’s choice of treatment (for both the LocoMMotion and MAMMOTH studies), and crossed the null for elranatamab versus cilta-cel. The results of the sensitivity analyses were consistent with the primary base-case analyses.

Overall Survival

Following MAIC adjustment, the OS HR crossed the null for elranatamab versus teclistamab, favoured cilta-cel versus elranatamab, and favoured elranatamab versus physician’s choice of treatment (for both the LocoMMotion and MAMMOTH studies). The results of the sensitivity analyses were consistent with the primary base-case analyses.

Complete Response Rate

Following MAIC adjustment, the CRR difference between elranatamab and teclistamab crossed the null, and favoured elranatamab versus physician’s choice of treatment (for both the LocoMMotion and MAMMOTH studies). The results of the sensitivity analyses were consistent with the primary base-case analyses.

Table 20: Summary of Variables Adjusted in MAIC 2, per Outcome

Cilta-cel = ciltacabtagene autoleucel; CRR = complete response rate; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ESS = effective sample size; ISS = International Staging System; MAIC = matching-adjusted indirect comparison; NA = not applicable; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; vs. = versus.

Note: Details included in Table 20 are from the sponsor’s Summary of Clinical Evidence.

Source: MAIC 2 technical report.⁴⁰

Table 21: Summary of Adjusted MAIC 2 Results, per Outcome

CI = confidence interval; CRR = complete response rate; ESS = effective sample size; HR = hazard ratio; MAIC = matching-adjusted indirect comparison; NA = not applicable; OR = odds ratio; OS = overall survival; PFS = progression-free survival; RE = random effect; vs. = versus.

Note: Details included in Table 21 are from the sponsor’s Summary of Clinical Evidence.

Source: MAIC 2 technical report.⁴⁰

Critical Appraisal of MAIC 1 and MAIC 2

Both MAIC 1 and MAIC 2 used the same methods to indirectly compare treatments, and their rationale and objectives were reported. In the case of both MAICs, the authors did not report a systematic literature search, describe their methods for data extraction, or conduct quality assessment of the included studies. In addition, only cohort A from the MagnetisMM-3 trial was included in the primary analyses. As such, the indirect comparative assessment remains unknown for patients with prior BCMA-directed therapy (cohort B).

The MAICs included relevant outcomes identified by the CADTH team (ORR, PFS, OS, CRR); however, important outcomes such DOR, HRQoL, and safety were not included in the comparisons. Across the included studies, there were notable differences in study designs (single-arm, open-label, phase II trial versus multicentre retrospective or prospective cohort studies), inclusion and exclusion criteria, and patient characteristics (refractory or relapse status, prior history of treatments, ECOG PS). For MAIC 2, a key difference of comparing elranatamab to teclistamab, cilta-cel, and physician’s choice of treatment based on the LocoMMotion study was that these studies included patients who were TCE, while the MagnetisMM-3 trial enrolled patients who were TCR. Therefore, there is significant concern that the MAIC results would have been subjected to biases due to the large amount of heterogeneity across the included studies.

To account for between-study differences in patient baseline characteristics, several relevant PVs and EMs were matched in the weighting process, with separate sets of variables used across treatment comparisons and outcomes. These variables were selected based on a systematic literature search and clinical expert input.

For MAIC 1 (elranatamab versus physician’s choice), ISS disease stage and cytogenetic risk could not be adjusted in the analyses for PFS and OS, as the definitions did not align across the MagnetisMM-3 trial and CMRG study. In the CMRG study, patient-level data regarding these 2 variables were captured at diagnosis rather than at the start of the trial period, as it was defined in the MagnetisMM-3 trial. Additionally, extramedullary disease was not adjusted for in the analysis as it was not reported in the CMRG study.

For MAIC 2, the following variables were missing for 2 comparisons: in the comparison of physician’s choice of treatment from the MAMMOTH study, extramedullary disease was not adjusted for, and in the comparison with physician’s choice of treatment from the LocoMMotion study, cytogenetic risk was not adjusted for. The authors noted that both cytogenetic risk and extramedullary disease were found to be important PVs based on the IPD of the MagnetisMM-3 study. These limitations, and differences in study design that could not be adjusted for in the analysis, could introduce residual confounding due to unreported or unobserved cross-study differences, although the direction or extent of bias is unclear.

For MAIC 1, following the weighting process, the ESS for OS declined by approximately 34% of the original sample size in the comparison with physician’s choice of treatment. For the PFS comparison with physician’s choice of treatment, the ESS declined by approximately 33% of the original sample size. For MAIC 2, following adjustment, the ESS for OS declined by 37% of the original sample size in the comparison with teclistamab, by 73% of the original sample size in the comparison with cilta-cel, by 45% of the original sample size in the comparison with physician’s choice of treatment (the LocoMMotion study), and by 20% of the original sample size in the comparison with physician’s choice of treatment (the MAMMOTH study). These reductions in the ESS meant the final matched patient population was more highly selective than the original patient population, and may lead to large uncertainty in estimated treatment effects, although the magnitude and direction of potential bias is unclear.

For MAIC 1, the proportional hazards assumption was violated for both PFS and OS outcomes, and for MAIC 2, the assumption was violated in most comparisons for PFS and OS outcomes. The assumptions were based on the Schoenfeld test, and through visual inspection of the log cumulative hazard plots and the Schoenfeld residual plots. These violations could have led to biased treatment effect estimates.

Studies Addressing Gaps in the Systematic Review Evidence

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

This section summarizes 2 retrospective cohort studies with external control arms (Study C1071024⁴⁸ and Study C1071031⁴⁹) and 1 phase I and phase II dosing study (the MagnetisMM-9 trial).⁵⁰ The sponsor provided an article on a multicentre retrospective cohort study using the CMRG database,⁵¹ which has been included in Appendix 1. The following section summarizes the details of both Study C1071024 and Study C1071031.

Description of RWE External Cohort Studies (Study C1071024 and Study C1071031)

To help contextualize the results from the MagnetisMM-3 study, the sponsor provided 2 studies (Study C1071024⁴⁸ and Study C1071031⁴⁹) to retrospectively compare efficacy outcomes between elranatamab and 2 external control arms using a basket of RW treatments (refer to Table 22 for details) from the Flatiron Health and COTA databases.

A retrospective cohort study, Study C1071024, was conducted to compare the efficacy outcomes ORR and DOR observed in the participants of the MagnetisMM-3 study (with at least 9 months of follow-up) and RW patients selected from 2 US-based oncology electronic health record databases, the Flatiron Health and COTA databases. The Flatiron Health database is a longitudinally, demographically, and geographically diverse database covering more than 280 community cancer centres and academic institutions (approximately 800 sites of care) that represent more than 2.4 million active US cancer patients. The source population includes patients managed in at least 1 of the US oncology centres taking part in the Flatiron Health database network from January 1, 2011, onward. The COTA database is a longitudinal database derived from the electronic health records of more than 200 health care provider sites in the US (including academic institutions, community centres, and hospital systems) that represent 500,000 patients. Data elements were standardized across sources and ontologies to create a single, structured dataset to cover the full longitudinal history of a patient’s clinical care.

Study C1071031 is the continuation of Study C1071024 with an available follow-up of the MagnetisMM-3 study participants of approximately 15 months. Study C1071031 aimed to compare the PFS and OS in participants of the MagnetisMM-3 study treated with elranatamab versus RW patients with TCR MM treated with RW physician’s choice of therapy. Study C1071031 also assessed PROs (via the EORTC QLQ-MY20 tool) using other studies, Study C1071013 and Study C1071014, as the data sources for the external cohort. In Study C1071024 and Study C1071031, 2 external arms were constructed from these 2 cohorts of RW patients with TCR MM to maximize comparability to participants from the pivotal MagnetisMM-3 trial. The eligibility criteria for patients in the 2 external control arms were based on the eligibility criteria from the pivotal MagnetisMM-3 trial. Patients were considered eligible for selection in the external control arm if they had MM that was refractory to at least 1 PI, 1 IMiD, and 1 anti-CD38, and had started at least 1 new treatment since the documentation of TCR status. Refractory disease was defined as experiencing progression, according to IMWG criteria or clinical assessment, while on therapy or within 60 days of the last dose in any line of therapy, regardless of response.

The date of the initiation of the first regimen after TCR MM eligibility was defined as the index date in establishing the external control arms from the Flatiron Health and COTA databases for both Study C1071024 and Study C1071031. Patients were only eligible if they had an index date occurring between November 16, 2015 (the date that the US FDA approved the first anti-CD38 therapy), and March 31, 2022 (Study C1071024), or June 30, 2022 (Study C1071031). The study period comprised the baseline period (time preceding the index date) and the observational period (time following the index date). The observational period spanned from the index date to the date of death or the latest available patient record, whichever occurred first. The sequences of relevant study events are shown for the MagnetisMM-3 trial in Figure 2 and the external control arms in Figure 3.

Study C1071024 used the Flatiron Health and COTA databases as data sources for the external cohorts that were compared to the MagnetisMM-3 study for the outcomes ORR and DOR. Study C10710131 also used the Flatiron Health and COTA databases for the cohorts compared to the MagnetisMM-3 study for the outcomes of OS and PFS. In addition, study C1071031 assessed PROs (via the EORTC QLQ-MY20 tool) using other studies, Study C1071013 and Study C1071014, as the data sources for the external cohort. Data were extracted between November 16, 2015, and June 30, 2022. Similar inclusion and exclusion criteria from the MagnetisMM-3 trial were applied to the external control arms from Study C1071013 and Study C1071014 to maximize comparability to participants from the pivotal MagnetisMM-3 trial.

Figure 2: Baseline and Observation Periods in MagnetisMM-3 Trial

Sources: Study C1071024 and Study C1071031 technical reports.^48,49

Study C1071013 is a noninterventional, observational, prospective, multinational (the US, Canada, France, Germany) study collecting IPD from RW patients with TCR MM who started a new line of systemic therapy at any point after they were TCR eligible. PRO measures (via the EORTC QLQ-MY20 tool) were collected at the start of this new line of systemic therapy and then monthly for 12 months. Study C1071013 is ongoing and a data cut-off from March 31, 2023, was used for this analysis.

Study C1071014 is a noninterventional, observational, prospective study in the US collecting IPD from RW patients with TCR MM who started a new line of systemic therapy at any point after they were classified as eligible based on having TCR disease. PRO measures (via the EORTC QLQ-MY20 tool) were collected at the start of this new line of systemic therapy and then monthly for 6 months. Study C1071014 is ongoing and a data cut-off date from April 2023 was used for this analysis. Only patients using regimens that included treatment options available in RW clinical practice such as alkylating drugs, IMiDs, PIs, anti-CD38 therapies, anti–signalling lymphocytic activation molecule family member 7 therapies, BCMAs (except BCMA bispecifics), and other select anti-MM systemic therapies such as panobinostat and selinexor were included in the external control arms from both Study C1071013 and Study C1071014 for the PRO analysis.

Figure 3: Baseline and Observation Periods in the Flatiron Health and COTA Database External Control Arms

Source: Study C1071024 and Study C1071031 technical reports.^48,49

Patients with TCR MM were defined as patients with MM with disease-refractory to 1 or more IMiD, 1 or more PI, and 1 or more anti-CD38 antibody treatment based on the refractory status recorded in the COTA and Flatiron Health databases. Refractory status was defined using IMWG-derived progression events or health care provider -reported progression. To minimize potential misclassification and to enhance the comparability of patients identified from the COTA and Flatiron Health databases, IMWG-derived progressions were reallocated to a specific line of therapy using a sponsor-developed algorithm. Various time windows were tested while developing this algorithm.

For the comparative analysis of PFS and OS, units used in reported laboratory values in the populations identified from RWD sources were standardized to those used in the MagnetisMM-3 study to permit proper comparisons between treatment groups.

Populations

Two types of eligibility criteria (critical and expanded) were used for the efficacy analysis in Study C1071024 and Study C1071031. The critical eligibility criteria were applied for the main analysis and additional analysis, and expanded eligibility criteria were additional criteria added for sensitivity analyses to assess the potential influence of the selection process based on the eligibility criteria.

The critical inclusion criteria, based on the MagnetisMM-3 study, that were applied to the COTA and Flatiron Health databases were as follows:

• male or female patients aged 18 years or older

• a prior diagnosis of MM as defined according to IMWG criteria

• measurable disease, based on IMWG criteria

• TCR MM, defined as refractory to at least 1 IMiD, at least 1 PI, and at least 1 anti-CD38 antibody

• patient had started at least 1 anti-MM systemic therapy in the TCR MM setting

• an ECOG PS score of 2 or less.

The critical exclusion criteria, based on the MagnetisMM-3 study, that were applied to the COTA and Flatiron Health databases were as follows:

• active plasma cell leukemia

• amyloidosis

• previous treatment with an investigational drug within 30 days

• smouldering MM

• stem cell transplant within 12 weeks before enrolment or active graft-versus-host disease

• active malignancy within 3 years before enrolment (except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ)

• active infections.

The same critical eligibility criteria were applied to Study C1071013 and Study C1071014 for the analysis of PROs (via the EORTC QLQ-MY20 tool).

In addition to the critical criteria, there was also expanded eligibility criteria.

The expanded inclusion criteria were as follows:

• adequate hepatic function characterized by all of the following —

  • total bilirubin of 2 or less multiplied by the upper limit of normal (ULN) (≤ 3 × ULN if documented Gilbert syndrome)

  • aspartate aminotransferase of 2.5 or less multiplied by the ULN

  • alanine aminotransferase of 2.5 or less multiplied by the ULN

• adequate renal function, defined by an estimated creatinine clearance of 30 mL per minute or more

• adequate bone marrow function characterized by all of the following —

  • absolute neutrophil count of 1.0 or more multiplied by 10⁹/L

  • platelets of 25 or more multiplied by 10⁹/L

  • hemoglobin of 8 g/dL or more.

The expanded exclusion criteria were as follows:

• impaired cardiovascular function or clinically significant cardiovascular diseases, defined based on the history of any of the following conditions within 6 months before enrolment —

  • acute myocardial infarction or acute coronary syndromes

  • clinically significant cardiac arrhythmias

  • thromboembolic or cerebrovascular events

  • prolonged QT syndrome (or triplicate average QT interval corrected for heart rate using the Fridericia formula greater than 470 milliseconds)

• ongoing grade 2 or higher peripheral sensory or motor neuropathy

• a history of any grade of peripheral sensory or motor neuropathy with prior BCMA-directed therapy (cohort B)

• a history of Guillain-Barré syndrome or Guillain-Barré syndrome variants, or a history of any grade 3 or higher peripheral motor neuropathy.

Interventions

Patients were classified as having received elranatamab (in the MagnetisMM-3 trial) or any of the RW treatment options (in the COTA or Flatiron Health databases) in Study C1071024 and Study C1071031 that are described in Table 22. Only the first RW treatment option in the TCR setting during the index period was considered in the analyses; subsequent treatments were not considered.

Table 22: List of Treatments Available for MM Received by Patients in the COTA or Flatiron Health Databases

ADC = antibody-drug conjugate; anti-BCMA = anti–B-cell maturation antigen; CAR = chimeric antigen receptor; BCL2 = B-cell lymphoma 2; HDAC = histone deacetylase IMiD = immunomodulatory drug; mAb = monoclonal antibody; MM = multiple myeloma; PI = proteasome inhibitor ; Anti-SLAMF7 = anti-signalling lymphocytic activation molecule family member 7

Note: Details included in Table 22 are from the sponsor’s Summary of Clinical Evidence.

Sources: Study C1071024 and Study C1071031 technical reports.^48,49[Details included in the table are from the sponsor’s Summary of Clinical Evidence].

Outcomes

Mortality data in the COTA database are collected via a third-party obituary source while mortality data in the Flatiron Health database are collected through an amalgamation of structured data elements and unstructured documents, and by linking to external mortality sources and the Social Security Death Index. Table 23 compares the definitions of PFS, OS, ORR, and DOR used in the MagnetisMM-3 study, the COTA database, and Flatiron Health database populations.

Table 23: Definitions of Primary Outcomes in MagnetisMM-3 Trial, and COTA and Flatiron Health Databases

CR = complete response; DOR = duration of response; FLC = free light chain; IMWG = International Myeloma Working Group; MM = multiple myeloma; OR = objective response; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; sCR = stringent complete response; TCR = triple-class refractory; VGPR = very good partial response.

Note: Details included in Table 23 are from the sponsor’s Summary of Clinical Evidence.

The COTA database uses a third-party obituary data source to capture mortality data. COTA defines progression based on IMWG criteria. COTA defines a progression as an increase of 25% or more from the lowest response value in any 1 or more of the following criteria: Serum Protein Electrophoresis(SPEP) with an absolute increase of more than 0.5 g/dL; 24-hour Urine protein electrophoresis (UPEP) with an absolute increase of more than 200 mg per 24 hours; in patients without measurable serum and urine M protein, the absolute increase of more than 10 mg/dL in the difference between involved and uninvolved FLC levels; or an absolute bone marrow plasma cell percentage of more than 10%. The Flatiron Health database’s mortality variable is created through an amalgamation of structured data elements and unstructured documents, and by linking to external mortality sources and the Social Security Death Index. Flatiron Health defines progression based on IMWG criteria. Flatiron Health defines a progression as an increase of 25% or more from baseline or nadir value in any 1 or more of the following: an absolute increase in serum M protein by SPEP by 0.5 g/dL or more; serum M protein of 1 g/dL or more if the lowest M component was 5 g/dL or more; an absolute increase in urine M protein by UPEP by 200 mg or more per 24 hours; or in patients without measurable serum and urine M protein levels, an absolute increase in the difference between involved and uninvolved FLC levels of more than 10 mg/dL.

Sources: Study C1071024 and Study C1071031 technical reports.^48,49

Statistical Analysis for Study C1071024 and Study C1071031

Methods

No formal sample size estimates were calculated for these study. The study sample was identified from the analysis of secondary data that had already been collected. Accordingly, the sample size was limited by the duration of the observation window.

A total of 6 datasets and 7 datasets were created using the various sources based on critical eligibility criteria and expanded eligibility criteria (additional criteria were added for sensitivity analyses to assess the potential influence of the selection process based on the eligibility criteria) in Study C1071024 and Study C1071031, respectively. Each dataset used the same patients from the MagnetisMM-3 trial along with varying RW patients.

For the main analysis and sensitivity analyses to address the primary and secondary objectives:

• the MagnetisMM-3 trial, cohort A arm, plus the external control arm selected chose to use critical eligibility criteria from the COTA database

• the MagnetisMM-3 trial, cohort A arm, plus the external control arm selected using critical eligibility criteria from the Flatiron Health database.

For a sensitivity analysis based on alternative inclusion and exclusion criteria:

• the MagnetisMM-3 trial, cohort A arm, plus the external control arm selected using expanded eligibility criteria from the COTA database

• the MagnetisMM-3 trial, cohort A arm, plus the external control arm selected using expanded eligibility criteria from Flatiron Health database.

For the additional analyses based on the MagnetisMM-3 trial, cohort A and cohort B:

• the MagnetisMM-3 trial, cohort A and cohort B arms, plus the external control arm selected using critical eligibility criteria from the COTA database

• the MagnetisMM-3 trial, cohort A and cohort B arms, plus the external control arm selected using critical eligibility criteria from the Flatiron Health database.

For the analysis of PROs (via the EORTC QLQ-MY20 tool):

• the MagnetisMM-3 trial, cohort A and cohort B arms, plus the external control arm selected using critical eligibility criteria from the prospective observational Study C1071013 and Study C1071014.

For the main analysis in Study C1071024 and Study C1071031, differences in baseline and key covariate characteristics between participants in the MagnetisMM-3 trial and each external control arm, including treatment history and disease-related characteristics at the index date, were balanced using IPTW. In a sensitivity analysis, the robustness of the estimates from the primary analysis was assessed via doubly robust estimation using a semiparametric approach described by Yadlowsky et al.⁵² Furthermore, sensitivity analyses were conducted to evaluate the effect of alternative inclusion and exclusion criteria, and to evaluate any differences in the magnitude of treatment effect when also accounting for prior exposure to BCMA-directed therapy. Finally, a quantitative bias analysis (nullification analysis) was performed to evaluate the robustness of results in the presence of potential threats to internal validity.

A systematic literature review was conducted to identify variables most strongly and consistently correlated with outcomes in RWD studies conducted among patients with RRMM. Results from 57 identified studies supported adjustment for the following covariates that were strongly associated with outcomes in patients with RRMM:

• age

• sex

• cytogenic risk

• number of prior lines of therapy

• ECOG PS score

• time since initial MM diagnosis

• penta-refractory status

• ISS stage.

Additional confounders were identified and included in the analysis to optimize the balance between participants from the MagnetisMM-3 trial and each RW data source. The confounders identified were based on their clinical importance and relevance to disease prognosis and disease complications:

• disease prognosis, severity, and complications — the level of serum albumin, calcium, hemoglobin, and serum creatinine; the presence of bone lesions; and extramedullary disease

• liver dysfunction — the level of serum bilirubin, aspartate aminotransferase, and alanine aminotransferase

• burden of comorbid conditions — the Charlson Comorbidity Index score.

The value of each confounding variable was measured on or before the index date; if before, the most recent measurement was used. Of note, the presence of extramedullary disease was only available for the analyses using the combined datasets of the MagnetisMM-3 trial and COTA database patients, because this variable was unavailable in the Flatiron Health database. Next, due to the high percentage of missing values in the COTA database, bilirubin, calcium in serum or plasma, and serum albumin were included only in the analyses using the combined datasets of the MagnetisMM-3 study and Flatiron Health database patients. Information used to construct the Charlson Comorbidity Index was assessed up to 12 months before the index date, inclusive. For RW patients, the Charlson Comorbidity Index was obtained directly from the data source; for MagnetisMM-3 study participants, it was derived from the Medical Dictionary for Regulatory Activities classification of available patient comorbidity information. Values for other clinical covariates identified as potential confounders were measured on or up to 90 days before the index date; if before, the most recent measurement was used.

PSs and IPTW

To control baseline confounding, PSs were estimated using logistic regression models as the probability of initiating elranatamab versus SOC conditional on patient characteristics described earlier for both Study C1071024 and Study C1071031. Standardized mean differences (SMDs) were used to assess the balance in baseline prognostic characteristics between elranatamab and SOC-treated patients before and after applying IPTW. The SMDs were estimated for means (continuous variables) and prevalence (dichotomous variables), which were considered balanced across exposure groups if the corresponding SMD was 20% or less. To ensure that the estimated IPTW would allow for obtaining unbiased estimates of the treatment effect, several assumptions were verified.

Weighted Analyses Of PFS, OS, and Resposnse Rates

The proportional hazards assumption was tested based on the visual assessment of the Kaplan-Meier curves and using the Schoenfeld residuals test. Because the proportional hazards assumption was not adjusted for when comparing survival curves (PFS and OS) in participants of the MagnetisMM-3 study and patients from the Flatiron Health database, unadjusted and IPT-weighted restricted mean survival time models were applied instead of the Cox proportional hazards regression model.

ORR was compared between treatment groups using unadjusted and IPT-weighted log-binomial models. Robust standard errors were used for IPT-weighted analysis. DOR was compared between treatment groups using HRs estimated from unadjusted and IPT-weighted Cox proportional hazards models. Differences were considered statistically significant at P values of less than 0.05.

Subgroup Analysis for PFS and OS

The sponsor provided a rationale for the subgroup analysis, stating that the treatment patterns described in the COTA and Flatiron Health databases may not be generalizable to all non-US countries. Subgroup analyses were performed to only include treatments frequently available for this patient population in non-US countries. For subgroups with a sufficient sample size, PFS and OS were compared between participants of the MagnetisMM-3 trial and patients from the Flatiron Health and COTA databases using IPTW analysis.

Missing Values

For both Study C1071024 and Study C1071031, incomplete dates of death (i.e., missing day) were imputed in the RW data to match the rules of the MagnetisMM-3 study. The Flatiron Health database provides only the month and year of death. Therefore, the date of death was imputed as the middle of the month (i.e., the 15th), unless the patient’s last record date was within the month of death, in which case the date of death was imputed as the date of the last record. The COTA database provides the precise date of death for most patients. When the date of death is missing, the COTA database by default imputes the date of the death as the middle of the month when the month is known, and as the middle of the year when only the year is known. For patients whose month of death is known, the date of death was imputed as the last record date if it was within 15 days of the date of death provided by the COTA database (otherwise, the default date of death was kept). For patients whose year of death only was known, the date of death was imputed as the last record date if it fell within 182 days of the date of death provided by the COTA database (otherwise, the default date of death was kept).

For the baseline characteristics, a missing day component was imputed as the last day of the corresponding month to decide whether the measurement lay within the baseline period for qualifying as the baseline value. A missing month component was not imputed, but if it was clear from the year component that the covariate fell within the baseline period, the measurement was taken into consideration. A missing year component was not imputed.

For each baseline covariate, the proportion of missing values was assessed. For covariates with a proportion of missing values of 30% or less, multiple imputation was performed under the assumption of missingness at random. Multiple imputation by chained equations was performed to address missing values, using the fully conditional specification method. Variables included in the imputation model were baseline characteristics used to estimate the PS, measured covariates related to missingness and those correlated with the covariate of interest, as well as the cumulative baseline hazard for time-to-event models.

The convergence of imputation models obtained via multiple imputation by chained equations was assessed. The distributions of covariates in the observed and imputed data were visually assessed using plots. Convergence was evaluated by plotting the mean and variance of each imputation run across iterations, to confirm that there were no apparent trends.

Sensitivity Analyses

A conditional average treatment effect and its associated HR were estimated using a semiparametric approach. This estimator provided a doubly robust comparison for PFS and OS between treatment arms. Standard errors and 95% CIs were obtained for this estimator using the nonparametric bootstrap.

To evaluate the robustness of primary analysis results, a sensitivity analysis was conducted using the set of all participants within cohort A of the MagnetisMM-3 study who received at least 1 dose of elranatamab and RW patients selected using expanded eligibility criteria. The analyses were conducted to compare the PFS and OS using IPT-weighted analyses. A nullification analysis was applied to assess the potential influence of unmeasured confounding on the observed associations. A sensitivity analysis was conducted to assess the potential influence of unmeasured confounders on the estimates described in the main analyses.

Analysis of PROs (EORTC QLQ-MY20)

For each treatment group (elranatamab or SOC), the number and percentage of participants who completed the EORTC QLQ-MY20at each visit and the timing of PRO completion by treatment group were described. An instrument was considered completed if at least half of the item was answered by the participant. In this study, 2 symptom scales (disease symptoms and side effects of treatment) for the EORTC QLQ-MY20 module were assessed. For this analysis, the PROs (via the EORTC QLQ-MY20 tool) collected at baseline and at monthly follow-up visits up to month 6 were analyzed. The time points for the follow-up measurements were determined after the assessment of the data completion status.

PROs (EORTC QLQ-MY20) were compared among MagnetisMM-3 study participants and patients from the Study C1071013 and Study C1071014 prospective observational studies in unadjusted analyses and analyses adjusted for age, sex, baseline values of ECOG PS scores, extramedullary disease, and high cytogenetic risk, and time of PROs completion (EORTC QLQ-MY20). A higher score for the EORTC QLQ-MY20 disease symptoms and side effects of treatment scales represented a higher perceived level of symptoms or problems.

A mixed model of repeated measures was fitted to the data to examine the effects of time (visit) among patients treated with elranatamab versus SOC. Mixed models of repeated measures were also used for the domains of EORTC QLQ-MY20 to examine the effects of time (visit) by cohort and overall. In the model, outcomes were postbaseline scores (and change scores separately), the predictor was the treatment group (elranatamab versus SOC), and the controlling covariates were the corresponding baseline PROs score (EORTC QLQ-MY20), age (< 65 years versus ≥ 65 years), sex, ECOG PS score (0 versus 1+), extramedullary disease (yes versus no), high cytogenetic risk (yes versus no), and time (visit).

Results

Patient Disposition (Study C1071031)

Between February 2021 and January 2022, the MagnetisMM-3 trial, cohort A, enrolled 123 patients with TCR MM who were included in the main analysis for Study C1071031. Applying the critical eligibility criteria to the databases identified 239 patients with TCR MM in the COTA database who had initiated a new line of therapy between November 2015 and June 2022 (Figure 4), as well as 152 patients with TCR MM in the Flatiron Health database who had initiated a new line of therapy between November 2015 and August 2021 (Figure 5) to create external control arms for Study C1071024 and Study C1071031. The median follow-up times for included patients were 14.7 months in the MagnetisMM-3 trial, cohort A; 8.8 months for patients with TCR MM from the COTA database; and 7.7 months for patients with TCR MM from the Flatiron Health database. Study C1071024 had similar patient disposition, with slight differences in the cohort from the COTA database.

Baseline Characteristics

Table 24 shows the baseline demographic and clinical characteristics of included patients from the MagnetisMM-3 study, cohort A, and the COTA and Flatiron Health databases included in Study C1071031. The characteristics for participants included in Study C1071024 are not described here, as the numbers are the same for both the MagnetisMM-3 study, cohort A, and the Flatiron Health database, with a slight difference in the COTA database (N = 239 in Study C1071031 and N = 233 in Study C1071024). Some differences were noted in the baseline characteristics among patients. The MagnetisMM-3 study population was slightly more pretreated than the COTA or Flatiron Health database populations (the number of mean treatment lines were 5.2 versus 4.9 versus 4.0, respectively) and more likely to have previously received stem cell transplant (70.7% versus 57.3% versus 36.2%, respectively). The MagnetisMM-3 study population was more likely to have extramedullary disease compared to the COTA database population (30.9% versus 13.4%, respectively), while the COTA database population was more likely to have bone lesions than the MagnetisMM-3 study population or the Flatiron Health database population (50.6% versus 27.6% versus 11.8%, respectively). No major differences in cytogenetic risk were noted between the 3 different databases.

Figure 4: Flow Chart for Selection of Cohort From COTA DATABASE Using the Critical Eligibility Criteria (Study C1071031)

D = day; ECOG = Eastern Cooperative Oncology Group; HBV = hepatitis B virus; HCV = hepatitis C virus; IMiD = immunomodulatory drug; LOT = line of therapy; MM = multiple myeloma; PI = proteasome inhibitor; RW = real world; SMM = smouldering multiple myeloma; TCR = triple-class refractory.

¹ TCR eligibility is defined as the earliest date on which patients were identified as having MM refractory to 1 or more IMiD, 1 or more PI, and 1 or more anti-CD38.

Source: Study C1071031 technical report.⁴⁹

Figure 5: Flow Chart for Selection of Cohort from Flatiron Health Database Using the Critical Eligibility Criteria (Study C1071031)

ECOG = Eastern Cooperative Oncology Group; GVHD = graft-versus-host disease; HBV = hepatitis B virus; HCV = hepatitis C virus; IMiD = immunomodulatory drug; LOT = line of therapy; MM = multiple myeloma; PI = proteasome inhibitor; RW = real world; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TCE = triple-class exposed; TCR = triple-class refractory.

¹ The identification of patients in the Flatiron Health and COTA databases followed a different stepwise approach. TCE was defined as patients exposed to at least 1 PI, 1 IMiD, and 1 anti-CD38 monoclonal antibody.

² TCR eligibility was defined as the earliest date on which patients were identified as having MM refractory to 1 or more IMiD, 1 or more PI, and 1 or more anti-CD38.

Source: Study C1071031 technical report.⁴⁹

Multiple imputation by chained equations (for missing data) and IPTW were applied in an attempt to improve the balance of the 3 populations’ baseline demographic and disease characteristics. After applying these techniques, the SMDs were less than the prespecified threshold of 0.2 for all important prognostic factors in the comparison of the MagnetisMM-3 study and the COTA database populations, while a few characteristics were not balanced in the comparison of the MagnetisMM-3 study and the Flatiron Health database populations (ECOG PS score, time since initial MM diagnosis, Charlson Comorbidity Index score, the number of lines of therapy before the index date, and history of stem cell transplant). The details are in Table 25.

For the analysis of the PROs (EORTC QLQ-MY20), a total of 67 patients from prospective cohort studies Study C1071013 and Study C1071014 were included. Baseline characteristics were compared between participants of the MagnetisMM-3 trial and Study C1071013 and Study C1071014. Most baseline characteristics between Study C1071013 and Study C1071014 were generally similar, although compared to the MagnetisMM-3 trial’s population, the population from the observational studies had higher proportions of ISS stage III (18.3% for the MagnetisMM-3 trial participants and 37.8% for the Study C1071013 and Study C1071014 patients), an ECOG PS score of 2 (5.6% for the MagnetisMM-3 trial participants and 20.0% for the Study C1071013 and Study C1071014 patients), and high-risk cytogenetics (24.4% for the MagnetisMM-3 trial participants and 42.2% for the Study C1071013 and Study C1071014 patients). A higher proportion of participants in the MagnetisMM-3 trial had extramedullary disease compared to patients from the observational studies (38.9% for the MagnetisMM-3 trial participants and 13.3% for the Study C1071013 and Study C1071014 patients). Baseline demographic and clinical characteristics of the participants of the MagnetisMM-3 trial and patients in the prospective observational trials Study C1071013 and Study C1071014 are presented in Table 26.

Table 24: Baseline Demographics and Disease Characteristics of Participants of MagnetisMM-3 Trial, Cohort A, and RW Patients Identified From COTA and Flatiron Health Databases Before Matching (Study C1071031)

ECOG PS = Eastern Cooperative Oncology Group Performance Status; ISS = International Staging System; MM = multiple myeloma; RW = real world; SD = standard deviation; TCR = triple-class refractory.

Note: Details included in Table 24 are from the sponsor’s Summary of Clinical Evidence.

Source: Study C1071031 technical report.⁴⁹

Table 25: Baseline Demographics and Disease Characteristics of Participants of MagnetisMM-3 Trial, Cohort A, and RW Patients Identified From COTA and Flatiron Health Databases After Applying MICE and IPTW (Study C1071031)

ECOG PS = Eastern Cooperative Oncology Group Performance Status; IPT = inverse probability of treatment; IPTW = inverse probability of treatment weighting; ISS = International Staging System; LOT = line of therapy; MICE = multiple imputation by chained equation; MM = multiple myeloma; PS = propensity score; RW = real world; SCT = stem cell transplant; SMD = standardized mean difference; TCR = triple-class refractory.

Note: Details included in Table 25 are from the sponsor’s Summary of Clinical Evidence.

^aMICE using the fully conditional specification method was performed to address missing values in baseline covariates included in the PS model. Summary statistics and standardized difference values reported in this table were first calculated individually within each of the imputed datasets, and then were averaged across the datasets. Due to rounding of descriptive statistics, some standardized differences are greater than 0 when there appears to be no difference in the balance of covariates.

^bWeights used to produce these preliminary results were stabilized and truncated at the 99.5th percentile.

^cUnlike t tests and other statistical tests of hypothesis, the standardized difference is not influenced by sample size and can therefore be used to compare balance in observed covariates between large study cohorts. It also allows for the comparison of the relative balance of continuous variables measured in different units (e.g., age vs. number of immunosuppressant medications) by calculating each in standard deviation units. For the purposes of the current study, a standardized difference threshold of more than |0.2| was used to identify imbalanced covariates. The proposed threshold aligns with the literature, where authors generally proposed thresholds ranging from more than |0.10| to more than |0.20| to define covariate imbalance.

Source: Study C1071031 technical report.⁴⁹

Table 26: Baseline Demographics and Disease Characteristics of Participants of MagnetisMM-3 Trial, Cohort A and Cohort B, and Patients in Prospective Observational Studies C1071013 and C1071014 [Redacted]

BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FLC = free light chain; ISS = International Staging System; LOT = line of therapy; MM = multiple myeloma; SD = standard deviation; SOC = standard of care.

Note: Details included in Table 26 are from the sponsor’s Summary of Clinical Evidence.

^aThe SOC combined cohort included patients with no CAR T-cell therapy and no history of BCMA from either SOC Study C1071013 or SOC Study C1071014. When information on a given patient characteristic was unavailable for 1 of the 2 SOC studies, a missing value was reported for the combined cohort.

Source: Study C1071031 technical report.⁴⁹

Efficacy

PFS (Study C1071031)

During the study periods, PFS events (disease progression or death) were identified for 53 (43%) patients in the MagnetisMM-3 trial’s population, 136 (57%) patients in the COTA database population, and 88 (58%) patients in the Flatiron Health database population. In the unweighted analyses, the rate of PFS events per 1,000 patient-months were 49.4 events (95% CI, 37.8 events to 64.7 events) in the MagnetisMM-3 trial’s population, 110.9 events (95% CI, 93.7 events to 131.2 events) in the COTA database population, and 137.8 events (95% CI, 111.8 events to 169.9 events) in the Flatiron Health database population. The median PFS was not reached in the MagnetisMM-3 trial’s population, was 4.7 months in the COTA database population, and was 3.7 months in the Flatiron Health database population. The median PFS was longer with elranatamab versus RW SOC in the COTA database population, both before weighting (HR = 0.51 [95% CI, 0.37 to 0.71; P < 0.0001]) and after IPTW (HR = 0.37 [95% CI, 0.22 to 0.64; P = 0.0003]) (Table 27 and Figure 6). However, due to violations of the proportional hazards assumption, the unweighted and IPT-weighted comparisons between elranatamab and SOC in the Flatiron Health database population were conducted using restricted mean survival time analyses, as prespecified in the statistical analysis plan.

The results of the restricted mean survival time analyses for COTA and Flatiron Health databases are presented in Figure 7 and Figure 8, respectively. In the restricted mean survival time analyses, the average PFS was longer with elranatamab versus RW SOC in the COTA database population at 9 months, 12 months, 15 months, 18 months, and 24 months using both weighted and unweighted analyses. Similarly, the average PFS time was longer with elranatamab versus RW SOC in the Flatiron Health database population.

Table 27: PFS Comparison Between Elranatamab in MagnetisMM-3 Trial, Cohort A, and RW External Control Arms

CI = confidence interval; HR = hazard ratio; IPT = inverse probability of treatment; IPTW = inverse probability of treatment weighting; PFS = progression-free survival; RW = real world.

Note: Details included in Table 27 are from the sponsor’s Summary of Clinical Evidence.

^aHRs were estimated using unadjusted Cox proportional hazards models.

^bSignificant at the 5% level.

^cFor the MagnetisMM-3 trial vs. Flatiron study comparison, the proportional hazards assumption was violated, and the HR could not be estimated.

^dFor the IPTW analysis, IPTW HRs were estimated using weighted Cox proportional hazards models and CIs were estimated using robust error variances. Stabilized IPT weights truncated at the 99.5th percentile were used.

Source: Study C1071031 technical report.⁴⁹

Figure 6: Forest Plot Summarizing Hazard Ratios for PFS Analysis

CI = confidence interval; IPT = inverse probability of treatment; PFS = progression-free survival; PS = propensity score.

Source: Study C1071031 technical report.⁴⁹

OS (Study C1071031)

During the study periods, deaths were identified for 55 (45%) patients in the MagnetisMM-3 trial’s population, 171 (72%) patients from the COTA database population, and 90 (59%) patients from the Flatiron Health database population. In the unweighted analyses, the all-cause mortality rate (per 1,000 patient-months) was 37.7 (95% CI, 28.9 to 49.1) in the MagnetisMM-3 trial’s population, 52.9 (95% CI, 45.5 to 61.5) in the COTA database population, and 54.6 (95% CI, 44.4 to 67.1) in the Flatiron Health database population. The median OS was not reached in the MagnetisMM-3 trial and was 11.24 months in both the COTA and Flatiron Health database populations. The median OS was longer with elranatamab versus RW SOC in the COTA database population both before weighting (HR = 0.65 [95% CI, 0.47 to 0.88; P = 0.0062]) and after IPTW (HR = 0.46 [95% CI, 0.27 to 0.77; P = 0.0032]) (Table 28 and Figure 9). However, due to violations of the proportional hazards assumption, restricted mean survival time analyses were conducted for the COTA and Flatiron Health database populations (Figure 10 and Figure 11, respectively). In the restricted mean survival time analyses, the average OS time was longer with elranatamab versus RW SOC in the COTA database population at 12 months, 15 months, 18 months, and 24 months using the unweighted analyses, and was also longer at 9 months, 12 months, 15 months, 18 months, and 24 months using the IPT-weighted analyses. Similarly, the average OS time was longer with elranatamab versus RW SOC in the Flatiron Health database population at 9 months, 12 months, 15 months, 18 months, and 24 months using the unweighted analyses. A trend toward improved survival with elranatamab versus RW SOC in the Flatiron Health database population was observed using the IPT-weighted analyses, although the results did not reach statistical significance.

Figure 7: Kaplan-Meier Curves of PFS and RMST Estimates in MagnetisMM-3 Trial, Cohort A, and COTA Database External Control Arm Before IPTW (A) and After IPTW (B)

CI = confidence interval; IPT = inverse probability of treatment; IPTW = inverse probability of treatment weighting; PFS = progression-free survival; RMST = restricted mean survival time; RW = real world; TCR = triple-class refractory.

* Significant at the 5% level.

¹ The RMST estimates correspond to the number of months patients in each cohort remain progression-free on average over a specified period following the date of the first dose for Study C1071003 patients and following the initiation of the first-line therapy after TCR for RW patients.

² Unweighted RMST differences and P values were obtained using nonparametric Kaplan-Meier estimators, and IPT-weighted RMST differences and P values were obtained using adjusted RMST proposed by Conner et al. (Conner SC, Sullivan LM, Benjamin EJ, LaValley MP, Galea S, Trinquart L. Adjusted restricted mean survival times in observational studies. Stat Med. 2019 Sep 10;38(20):3832 to 3860.)

³ Kaplan-Meier estimates obtained from each of 5 imputed datasets were normalized using a complementary log-log transformation to satisfy the assumptions of Rubin’s pooling rules. The same transformation was applied to the standard errors for each Kaplan-Meier curve, which were obtained using the delta method. The transformed estimates and their standard errors were then analyzed as usual using the MIANALYZE procedure, and back-transformed to the original scale to produce a summary Kaplan-Meier plot.

⁴ Stabilized IPT weights truncated at the 99.5th percentile were used.

Source: Study C1071031 technical report.⁴⁹

Figure 8: Kaplan-Meier Curves of PFS and RMST Estimates in MagnetisMM-3 Trial, Cohort A, and Flatiron Health Database External Control Arm Before IPTW (A) and After IPTW (B)

CI = confidence interval; IPT = inverse probability of treatment; IPTW = inverse probability of treatment weighting; PFS = progression-free survival; RMST = restricted mean survival time; RW = real world; TCR = triple-class refractory.

* Significant at the 5% level.

¹ The RMST estimates correspond to the number of months patients in each cohort remain progression-free on average over a specified period following the date of the first dose for Study C1071003 patients and following the initiation of the first-line therapy after TCR for RW patients.

² Unweighted RMST differences and P values were obtained using nonparametric Kaplan-Meier estimators, and IPT-weighted RMST differences and P values were obtained using adjusted RMST proposed by Conner et al. (Conner SC, Sullivan LM, Benjamin EJ, LaValley MP, Galea S, Trinquart L. Adjusted restricted mean survival times in observational studies. Stat Med. 2019 Sep 10;38(20):3832 to 3860.)

³ Kaplan-Meier estimates obtained from each of 5 imputed datasets were normalized using a complementary log-log transformation to satisfy the assumptions of Rubin’s pooling rules. The same transformation was applied to the standard errors for each Kaplan-Meier curve, which were obtained using the delta method (Oehlert 1992). The transformed estimates and their standard errors were then analyzed as usual using the MIANALYZE procedure, and back-transformed to the original scale to produce a summary Kaplan-Meier plot.

⁴ Stabilized IPT weights truncated at the 99.5th percentile were used.

Source: Study C1071031 technical report.⁴⁹

Table 28: OS Comparison Between Elranatamab in MagnetisMM-3 Trial, Cohort A, and RW External Control Arms