Reimbursement Review

Isatuximab (Sarclisa)

Sponsor: Sanofi-Aventis Canada Inc.

Therapeutic area: 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

ASCT = autologous stem cell transplant; NOC = Notice of Compliance.

Introduction

Multiple myeloma (MM) is an incurable, malignant plasma cell disease that originates from multipotent hematopoietic cells in the bone marrow. It is characterized by clonal proliferation of plasma cells in the bone marrow and excess production of monoclonal immunoglobulin (Ig). As the malignant plasma or myeloma cells accumulate in the bone marrow, they may form localized tumours or plasmacytomas. They also may interfere with normal blood cell production. When multiple plasmacytomas form either inside or outside bone, the condition is called MM. MM is the second most common hematologic cancer worldwide and the 15th most diagnosed cancer in Canada. There is limited information on the prevalence of MM in Canada; however, in 2024, it was estimated that 4,100 individuals living in Canada were diagnosed with MM and 1,750 of them would die from it.¹ According to GLOBOCAN 2022 data, the 5-year prevalence for both sexes in North America was 117,011 cases or 21.7% of all prevalent cases worldwide. In Canada, the 1-year prevalence (2022 data for both sexes) was reported to be 4,044 cases or 10.5 cases per 100,000 population, whereas the 5-year prevalence was 14,553 cases or 37.9 cases per 100,000 population.

In eligible patients who were previously untreated, newly diagnosed MM is usually treated with an autologous stem cell transplant (ASCT) following induction therapy (i.e., typically with high-dose chemotherapy). However, the number of patients who may not be eligible for an ASCT is estimated to be as high as 81%. Further, not all patients who are eligible for an ASCT are willing to undergo therapy. Despite treatment advances over the past 2 decades, MM remains an incurable disease with the treatment options currently available.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of isatuximab (10 mg/kg infusion) combined with bortezomib-lenalidomide-dexamethasone (IsaVRd), for the treatment of adult patients with transplant-ineligible, newly diagnosed MM. In April 2021, isatuximab (10 mg/kg IV infusion) combined with pomalidomide-dexamethasone received a recommendation from Canada’s Drug Agency (CDA-AMC) to reimburse with clinical criteria and/or conditions for the treatment of patients with relapsed or refractory MM who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor. In February 2022, isatuximab (10 mg/kg IV infusion) combined with carfilzomib-dexamethasone also received a CDA-AMC recommendation to reimburse with clinical criteria and/or conditions for the treatment of adult patients with relapsed or refractory MM who have received at least 1 prior therapy.

Perspectives of Patients, Clinicians, and Drug Programs

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

Patient Input

Myeloma Canada, an advocacy group supporting individuals with MM, provided input for the CDA-AMC review of isatuximab. Information for this submission was gathered through an online survey of patients and caregivers conducted by Myeloma Canada from October 11 to November 10, 2024. The survey was distributed via email and social media by Myeloma Canada and the Leukemia & Lymphoma Society of Canada.

Of the 43 survey responses, 24 were complete and eligible and divided into 2 subsets; 1 subset (named subset C) had 22 respondents ineligible for or not receiving an ASCT as first-line therapy and the second subset (named subset T) had 2 patients who received IsaVRd as first-line therapy.

Respondents rated the most important myeloma symptoms to control as bone issues such as fractures or pain (extremely important), followed by infections, mobility, and neuropathy. Myeloma symptoms were reported to have a significant impact on daily activities and quality of life (QoL), with respondents indicating an extreme effect on their ability to travel, work, and carry out household chores. The factors that patients considered most important to myeloma treatment consisted of effectiveness and remission, overall QoL, manageable side effects, the minimization of hospital visits, and ease of access.

The 2 respondents with IsaVRd experience reported having received the treatment for 1 year to 2 years. They found supportive care very effective, with treatment side effects and hospital visits having a slight to moderate negative impact on QoL. Both respondents rated IsaVRd as effective in controlling myeloma and manageable in terms of side effects. Despite side effects like diarrhea, infections, and neuropathy, they reported overall improved QoL, with 1 respondent noting significant health improvements.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

According to the clinical experts consulted by CDA-AMC, newer and more cost-effective treatments are welcomed as the currently available options are limited.

Unmet Needs

In the absence of a cure for MM, the goal is to prevent disease progression and prolong QoL. Even so, a significant number of patients on the current standard of care in Canada (daratumumab-lenalidomide-dexamethasone [DRd]) progress after 8 months of treatment, therefore never reaching the landmark 5-year progression-free survival (PFS) average. The prognosis is even worse for patients with early relapses because no other therapy offers this duration of response. With the average age of individuals with MM being in the transplant-ineligible category, there is an unmet need for treatments that effectively delay first relapse, lessen frailty from progressive disease (PD), and minimize health care usage from the symptoms of PD.

Place in Therapy

According to the clinical experts, IsaVRd would be an alternative to the currently funded first-line therapy for patients with myeloma who are transplant-ineligible (e.g., DRd). It is expected that combinations using isatuximab would be equally considered for first-line treatment in this patient population. Subsequently, bortezomib-lenalidomide-dexamethasone (VRd) may be used more frequently due to starting patients on IsaVRd, given that some patients may not tolerate the side effects of isatuximab and remain on VRd only.

Patient Population

All patients requiring first-line therapy for transplant-ineligible MM would be eligible for treatment with IsaVRd.

Assessing the Response Treatment

Together with traditional measures of response as per International Myeloma Working Group (IMWG) response criteria, a reduction in the frequency and/or severity of symptoms such as bone pain and renal failure would be documented monthly with lab investigations. Improvement in QoL and function would be expected with better and faster response to therapy.

Discontinuing Treatment

The clinical experts consulted by CDA-AMC noted that treatment discontinuation is guided by IMWG response criteria or is clinically determined, and is also guided by PD and intolerable side effects (e.g., infusion reactions and infection).

Prescribing Considerations

IsaVRd would be considered as a first-line treatment option for individuals with transplant-ineligible MM. The clinical experts noted that a myeloma therapy expert would be needed to facilitate therapy.

Clinician Group Input

Two clinician groups comprising 19 clinicians provided input for this review: the Canadian Myeloma Research Group (CMRG) (13 clinicians contributed to the input) and the Ontario Health (Cancer Care Ontario) (OH [CCO]) Hematology Cancer Drug Advisory Committee (6 clinicians contributed to the input). Overall, the input was aligned with the input from the clinical experts consulted by CDA-AMC.

The OH (CCO) Hematology Cancer Drug Advisory Committee highlighted the lack of comparative data with DRd and noted that isatuximab’s IV administration may be less appealing than daratumumab’s subcutaneous option. The clinical experts consulted by CDA-AMC noted that this may be a less relevant issue once isatuximab evolves in the future to permit subcutaneous administration and this form of delivery is approved.

The CMRG pointed out that the key shift in treatment would involve adding bortezomib to the anti-CD38 monoclonal antibody, lenalidomide, and a steroid backbone, supporting IsaVRd as the new first-line standard of care for patients with newly diagnosed, transplant-ineligible MM due to its potential for greater efficacy than VRd alone. The CMRG also remarked that while isatuximab requires longer infusion times, shorter durations are feasible. Furthermore, patients who were refractory to bortezomib in the front-line setting could still benefit from carfilzomib-based regimens, making IsaVRd unlikely to alter the relapsed treatment landscape significantly.

Drug Program Input

The Provincial Advisory Group identified jurisdictional implementation issues related to relevant comparators, considerations for the initiation of therapy, considerations for the prescribing of therapy, generalizability, considerations for a funding algorithm, care provision issues, and system and economic issues. The clinical experts consulted by CDA-AMC weighed evidence from the pivotal IMROZ trial and other clinical considerations to provide responses to the Provincial Advisory Group’s implementation questions.

Clinical Evidence

Systematic Review

Description of Studies

The systematic review included 3 reports of 1 pivotal trial (the IMROZ study). The IMROZ study is an ongoing, prospective, international (no sites in Canada), multicentre, open-label, parallel-group, phase III randomized controlled trial (RCT) to assess the clinical benefit of IsaVRd compared to VRd alone in patients with newly diagnosed MM who are not eligible for an ASCT. A total of 446 patients were randomized in a 3:2 ratio to IsaVRd (N = 265) or VRd (N = 181). Randomization was stratified by country (China versus other countries), age (younger than 70 years versus 70 years or older), and Revised International Staging System (R-ISS) stage I to stage II versus stage III versus not classified (i.e., inconclusive fluorescence in situ hybridization [FISH] unless the randomization stratum could be determined based on lactate dehydrogenase [LDH], albumin, and beta2-microglobulin only). Patients in the IsaVRd group received isatuximab 10 mg/kg IV in 42-day cycles (cycle 1 to cycle 4) or 28-day cycles (after 4 cycles) in combination with VRd. Patients were treated until they died, experienced disease progression, experienced unacceptable toxicity, or decided to discontinue study treatment. The primary outcome was PFS, and the key secondary outcomes included minimal residual disease (MRD) and overall survival (OS). During the continuous treatment period, patients randomized to the VRd group who had confirmed PD during the VRd portion of the continuous treatment period (as assessed by the investigator) could cross over to the IsaVRd group. Harms including treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) of special interest (AESI) were also measured and reported. Patient-reported outcomes (e.g., health-related quality of life [HRQoL]) were measured as well.

Patients were aged an average of 71.5 years (SD = 4.8 years), and 53.1% of patients were male while 46.9% were female. Most patients (89.0%) had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1. The most common International Staging System (ISS) stage at study entry was stage I (53.0% of patients), followed by stage II (31.1% of patients), and stage III (15.2% of patients). The MM subtype at baseline was most frequently IgG (64.1% of patients) and the R-ISS stage at study entry was most frequently stage II (n = 286; 64.1% of patients). The median time from initial diagnosis to randomization was 1.18 months. The main reason for transplant ineligibility was being aged 65 years or older (95.7% of patients).

Unless otherwise specified, all data reported are from the second interim analysis for the IMROZ trial, corresponding with a data cut-off of September 26, 2023, and reported for the intention-to-treat (ITT) population. This data cut-off date corresponds with the planned second PFS interim analysis cut-off date (i.e., the date when 167 PFS events [with a 75% information fraction] from the global population were expected to be observed). By the September 26, 2023, data cut-off, a total of 162 PFS events had been observed, as determined by an independent review committee (IRC). The median follow-up at this data cut-off date was 59.73 months (range, 0.17 months to 68.99 months).

Efficacy Results

At the time of the September 26, 2023, data cut-off, 78 patients (43.1%) in the VRd group and 84 patients (31.7%) in the IsaVRd group experienced PFS events. The median PFS was 54.34 months (95% confidence interval [CI], 45.207 months to not calculated [NC]) in the VRd group and not reached in the IsaVRd group. The hazard ratio (HR) was 0.596 (98.5% CI, 0.406 to 0.876) in favour of the IsaVRd group compared to the VRd group. At 60 months, the PFS probability was 45.2% in the VRd group and 63.2% in the IsaVRd group. The risk difference at 60 months was 18.0% (95% CI, 6.5% to 29.5%). The results for sensitivity analyses (e.g., without censoring for further antimyeloma treatment, using investigator assessment of response, without censoring for progression or death occurring at least 13 weeks after the last valid disease assessment) and planned subgroup analyses (e.g., by age, sex, race, or geographic location) were consistent with those of the primary analysis.

At the time of the interim analysis, 128 deaths had occurred (VRd group = 59 deaths; IsaVRd group = 69 deaths), representing an OS information fraction of 63%. The median OS was not calculable at the data cut-off date for the IsaVRd or VRd group (HR = 0.776; 99.97% CI, 0.407 to 1.48). OS was not formally analyzed due to an earlier failure of the statistical hierarchy (the final OS analysis will be conducted once there have been 202 deaths). The OS event-free probability at 60 months was 66.3% in the VRd group and 72.3% in the IsaVRd group, representing an absolute risk difference of 5.9% (95% CI, –3.3% to 15.2%).

The overall response rate (ORR) was similar in the VRd group and the IsaVRd group at 92.3% versus 91.3%, respectively (odds ratio [OR] = 0.888; 95% CI, 0.439 to 1.794). The complete response (CR) rate (consisting of patients with stringent CR and CR) was statistically significant in favour of IsaVRd (OR = 1.656; 95% CI, 1.097 to 2.500) with a CR or better in 74.7% of patients in the IsaVRd group compared with 64.1% of patients in the VRd group. The MRD negativity rate for patients with a CR was statistically lower in the VRd group (40.9%) compared with the IsaVRd group (55.5%) (OR = 1.803; 95% CI, 1.229 to 2.646). The rate of very good partial response (VGPR) or better based on IRC assessment was 82.9% in the VRd group and 89.1% in the IsaVRd group (OR = 1.729; 95% CI, 0.994 to 3.008). The P value did not cross the multiplicity-adjusted efficacy boundary of 0.025. Most patients (> 90%) in both treatment groups achieved a tumour response.

HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Completion rates were more than 90% of patients to cycle 14, and more than 80% of patients at each cycle among patients remaining in follow-up; however, the total number of patients declined over time. Global health status remained stable throughout the treatment period, with no apparent differences between groups with regard to change from baseline.

Harms Results

Most patients had a TEAE (IsaVRd group = 99.6%; VRd group = 98.3%), with the most frequently reported TEAEs (≥ 10% of patients) in the IsaVRd and the VRd treatment groups being peripheral sensory neuropathy (54.4% versus 60.8%, respectively), diarrhea (54.8% versus 48.6%, respectively), constipation (35.7% versus 40.9%, respectively), upper respiratory tract infection (34.2% versus 33.7%, respectively), peripheral edema (32.7% versus 32.6%, respectively), fatigue (34.6% versus 26.5%, respectively), and cataracts (38.0% versus 25.4%, respectively).

More individuals in the IsaVRd group had a grade 3 or higher TEAE compared to those in the VRd group (91.6% versus 84.0%, respectively). Similarly, more patients in the IsaVRd group had treatment-emergent SAEs than those in the VRd group (70.7% versus 67.4%, respectively). The most frequently reported SAE (≥ 10% of patients in either treatment group) was pneumonia (29.7% in the IsaVRd group versus 21.0% in the VRd group).

TEAEs leading to definitive treatment discontinuation were reported in 22.8% of patients receiving IsaVRd and 26.0% of patients receiving VRd. The most frequent reason for definitive treatment discontinuation was due to COVID-19 pneumonia (3.0% in the IsaVRd group versus 0.6% in the VRd group).

There were 128 deaths reported (IsaVRd group = 26.2%; VRd group = 32.6%). AEs accounted for 11.0% in the IsaVRd group and 6.1% in the VRd group.

Infusion reactions and infections were notable harms of interest to this review. Infusion reactions were more frequent with IsaVRd compared to VRd (23.6% versus 1.1%, respectively). The rate of infections was similar across groups, occurring in 91.3% of patients in the IsaVRd group and 86.7% of patients in the VRd group; they consisted primarily of pneumonia, upper respiratory tract infections, and COVID-19 infections.

Critical Appraisal

The randomization method and allocation concealment of the IMROZ trial were considered adequate. However, the IMROZ study was an open-label trial, and a lack of blinding may have biased results, particularly for subjective, patient-reported outcomes (e.g., HRQoL), harms reporting, or willingness to remain in the trial. Objective outcomes like death and assessment of outcomes like PFS were conducted by a blinded IRC and therefore were unlikely to have been influenced by a lack of blinding. Even so, there was an exploratory component to this trial in which patients in the VRd control group were allowed to cross over to the IsaVRd group after disease progression was confirmed. Multiplicity was controlled in the key secondary outcomes with the use of a hierarchical testing procedure; however, an early failure of the hierarchy meant that statistical testing was not conducted for OS, 1 of the key secondary outcomes, and no inferences could be drawn about differences between groups for this outcome. HRQoL was not included in the hierarchy, and differences between groups were not tested statistically; therefore, no conclusions could be drawn about this outcome. While the IMROZ trial is still ongoing, the available results were based on a planned interim analysis, with an information fraction of 75% for PFS; therefore, there is a risk of overestimation of the primary effect for PFS. However, given the statistically significant difference observed between the groups and the calculation of the 98.5% CIs, the potential for overestimation is unlikely to alter the conclusions. In the analysis of PFS, 18.8% of patients in the VRd group and 23.8% of patients in the IsaVRd group were censored due to not having a valid disease assessment in the 13 weeks before the data cut-off date (i.e., missed 2 or more scheduled disease assessments). Because the reason for missed assessments is not known, there is potential for a risk of bias due to informative censoring. There was no sensitivity analysis addressing this issue and the direction of potential bias cannot be ascertained. At the data cut-off date, the OS information fraction was 63%. This is important because while PFS can be viewed as a surrogate for OS, death is not an immediate consequence of treatment failure as further lines of treatment can prolong life. Furthermore, the OS analysis is confounded by crossovers (the risk of bias may be toward the null). As the trial progressed, more patients discontinued treatment or died. This may have led to attrition bias for outcomes analyzed based on change scores like HRQoL or the incidence of AEs, which were only documented for patients still being followed. For the latter, results were additionally reported after adjustment for the duration of exposure.

The IMROZ trial excluded patients aged older than 80 years and those with an ECOG PS score greater than 2; however, some patients with an ECOG PS score of 2 or more were enrolled. The clinical experts noted that the efficacy of VRd in the trial was higher than would normally be expected, which could be the result of a learning curve in jurisdictions that use VRd regularly. Further, in the IMROZ trial, bortezomib was not dosed at the Canadian and international standard of once weekly. Finally, while the study was conducted in 96 sites (in 21 countries or regions), none of the sites were in Canada.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for the Grading of Recommendations Assessment, Development and Evaluations (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:

• PFS — median, 18 months, 36 months, and 60 months

• OS — median and 60 months

• HRQoL using the EORTC QLQ-C30 — change from baseline

• individuals with SAEs — up to the data cut-off date.

Table 2: Summary of Findings for IsaVRd Versus VRd for Patients With Multiple Myeloma

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; HRQoL = health-related quality of life; IRC = independent review committee; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; NA = not applicable; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial; RR = risk ratio; SAE = serious adverse event; VRd = bortezomib-lenalidomide-dexamethasone.

Note: Study limitations (which refer to internal validity or the risk of bias), inconsistency across studies, indirectness, the imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aNo threshold of clinical importance could be established. Effects were appraised using the null. Rated down 1 level for study limitations; 18.8% of patients in the VRd group and 23.8% in the IsaVRd group were censored due to not having a valid disease assessment in the 13 weeks before the data cut-off (i.e., missed 2 or more scheduled disease assessments). Because the reason for missed assessments was not known, there is a potential for a risk of bias due to informative censoring.

^bRated down 1 level for study limitations. Results are from an interim analysis where OS was not formally tested, there is a risk of bias due to confounding as a result of crossover of patients from the VRd group to the IsaVRd group postprogression, and there is a potential for a risk of bias due to informative censoring. No threshold of clinical importance could be established; effects were appraised using the null. Rated down 1 level for imprecision. The point estimate suggests benefit and the CI includes no difference and potential harm.

^cRated down 2 levels for study limitations. There is a risk of bias due to a lack of blinding and a subjective outcome, as well as due to substantial missing outcome data.

^dFor patients in the VRd group who crossed over, the follow-up was to the crossover date minus 1 day.

^eNo threshold of clinical importance could be established; effects were appraised using the null. Rated down 1 level for imprecision. The point estimate suggests harm and the CI includes no difference and potential benefit (i.e., lesser harm than VRd).

Source: IMROZ Clinical Study Report.³²

Long-Term Extension Studies

There is no long-term extension phase planned for the IMROZ trial. The IMROZ trial remains ongoing with an anticipated completion date of June 30, 2027. No other long-term extension studies were included in the submission.

Indirect Comparisons

Description of Studies

Unanchored matching-adjusted indirect comparisons (MAICs) were used as the source of indirect treatment comparison (ITC) to compare individual patient-level data (PLD) for IsaVRd from the IMROZ trial to aggregate data from studies of DRd, lenalidomide-dexamethasone (Rd), daratumumab-bortezomib-melphalan-prednisone (DVMP), and daratumumab-cyclophosphamide-bortezomib-dexamethasone (DCyBorD). For the comparison to cyclophosphamide-bortezomib-dexamethasone (CyBorD) (Flatiron Health data source), a nonrandomized comparison using inverse probability weighting (IPW) methods was used because individual PLD were available for each group.

Efficacy Results

Progression-Free Survival

The MAIC of IsaVRd versus DRd resulted in HRs of ████ ████ ███ ████ ██ █████ at 1 year and ████ ████ ███ ████ ██ █████ at 5 years.

The MAIC of IsaVRd versus DVMP resulted in HRs of ████ ████ ███ ████ ██ ████ at 1 year and ████ ████ ███ ████ ██ █████ at 5 years.

The MAIC of IsaVRd versus DCyBorD resulted in HRs of ████ ████ ███ ████ ██ █████ at 1 year and ████ ████ ███ ████ ██ █████ at 5 years.

The MAIC of IsaVRd versus Rd using data from the MAIA study resulted in HRs of ████ ████ ███ ████ ██ █████ at 1 year and ████ ████ ███ ████ ██ █████ at 5 years. Using data from the FIRST study, the HR was ████ ████ ███ ████ ██ █████ at 1 year and ████ ████ ███ ████ ██ █████ at 5 years.

The observational comparison of IsaVRd versus CyBorD resulted in HRs of ████ ████ ███ ████ ██ █████ at 1 year and ████ ████ ███ ████ ██ █████ at 5 years.

Overall Survival

The MAIC of IsaVRd versus DRd resulted in HRs of ████ ████ ███ ████ ██ █████ at 1 year and ████ ████ ███ ████ ██ █████ at 5 years.

The MAIC of IsaVRd versus DVMP resulted in HRs of ████ ████ ███ ████ ██ █████ at 1 year and ████ ████ ███ ████ ██ █████ at 5 years.

There were no data available to compare OS for IsaVRd versus DCyBorD.

The MAIC of IsaVRd versus Rd using data from the MAIA study resulted in HRs of ████ ████ ███ ████ ██ █████ at 1 year and ████ ████ ███ ████ ██ █████ at 5 years. Using data from the FIRST study, the HR was ████ ████ ███ █████ █████ at 1 year and ████ ████ ███ █████ █████ at 5 years.

The observational comparison of IsaVRd versus CyBorD resulted in HRs of ████ ████ ███ ████ ██ █████ at 1 year and ████ ████ ███ ████ ██ █████ at 5 years.

Harms Results

Harms were not evaluated in the submitted ITCs.

Critical Appraisal

The ITC analyses were preceded by a feasibility appraisal, and the decision to use MAICs and IPW as the ITC method of choice (instead of network meta-analysis [NMA]) was adequately justified. However, the unanchored nature of the comparisons imposes an unrealistic assumption that all prognostic factors and effect modifiers are adequately adjusted for. The choice of the adjustment factors was based on internal expert opinion and availability and completeness of data in the trials. An assessment of the potential magnitude of residual confounding was not presented for any comparison; therefore, the extent of potential bias is unknown. The adjustment methods used cannot overcome methodological or design differences across the comparators, which can introduce bias (e.g., region or setting, length of follow-up, outcome definitions [event and censoring rules, schedule and method of assessments], cointerventions, or subsequent treatments). Important outcomes for decision-making like HRQoL and AEs were not included in the analyses, even though the MAIC included real-world evidence (RWE) that could have provided important insights and the generation of hypotheses for future confirmation. The OS data from the IMROZ trial is still immature and final data will not be available until 2027, so any MAIC based on this is premature. Generalizability may be an issue due to the small sample size remaining after the exclusions and matching in some of the analyses.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies addressing gaps were submitted.

Conclusions

One multinational, ongoing, open-label, phase III RCT (the IMROZ study) was included in the CDA-AMC review. In a population of 446 patients with newly diagnosed MM who were ineligible for an ASCT, IsaVRd resulted in a statistically significant improvement in PFS compared to VRd. Though the median PFS was not reached in the IsaVRd group, the clinical experts consulted by the review team considered the findings clinically meaningful. There was some concern for the potential risk of bias in the analysis of PFS due to missed disease assessments. The IMROZ trial is an ongoing study and though the results suggest that IsaVRd may improve OS compared to VRd, conclusions are limited because the data for OS were based on an interim analysis and were not formally tested. Additionally, the median results for OS had not been reached and results were considered immature. Because the final analysis of OS is not yet available, the results are only considered supportive of the overall findings. The findings for OS are also limited by potential confounding by crossovers, and imprecision in the estimates (i.e., CIs crossed the null). The addition of isatuximab to VRd increased the incidence of patients with grade 3 or higher TEAEs but the clinical experts consulted by the review team noted that the side effects were considered manageable. HRQoL seemed to be similar between groups, suggesting no detriment to QoL, but there was no statistical testing and there was increased attrition as the trial progressed.

Time-varying MAICs and IPW were used to derive comparative effect estimates for IsaVRd versus relevant comparators that were not included in the IMROZ trial. Despite the fact that these analyses suggested improved PFS with IsaVRd compared to DVMP and Rd (there was no difference detected compared to DRd, DCyBorD, and CyBorD), multiple methodological limitations rendered the evidence insufficient to draw definitive conclusions. These limitations included a high risk of bias resulting from unaddressed prognostic and effect-modifying variables, differences in study design and/or conduct that could not be adjusted for in the analyses, important reductions in ESS, and in some cases, imprecision (i.e., CIs crossing the null). Findings for OS are subject to additional uncertainty as the data for OS from the IMROZ trial remain immature. The lack of consideration of HRQoL and harms in the indirect comparisons limits the ability to comprehensively assess the balance of comparative benefits and harms.

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 isatuximab, 10 mg/kg infusion in combination with VRd, for the treatment of adult patients with transplant-ineligible, newly diagnosed MM.

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 CDA-AMC review team.

MM is an incurable, malignant plasma cell disease that originates from multipotent hematopoietic cells in bone marrow.² It is characterized by clonal proliferation of plasma cells in the bone marrow and excess production of monoclonal Ig, usually of the IgG or IgA type, or free light chains (e.g., paraprotein, M protein, M component).² As the malignant plasma or myeloma cells accumulate in the bone marrow, they may form localized tumours or plasmacytomas, which, in turn, grow inside (intramedullary) or outside (extramedullary or soft-tissue) bone.³ They also may interfere with normal blood cell production. When multiple plasmacytomas form either inside or outside bone, the condition is called MM.³ The natural history of MM depicts a heterogenous course characterized by 3 clinical stages: monoclonal gammopathy of undetermined significance, smouldering MM, and active MM.³ The timeline for movement through these stages is not linear.^4,5 As myeloma cells proliferate and the disease progresses, patients face a heavy disease burden due to disease-related symptoms and complications such as hypercalcemia, anemia, weakness, fatigue, renal failure, exertional dyspnea, immunodeficiency, infection, bone destruction leading to pain and fractures, and treatment-related toxicities.⁶

MM is the second most common hematologic cancer worldwide and the 15th most diagnosed cancer in Canada.⁷ While there is limited information on its prevalence in Canada, in 2024, it was estimated that 4,100 individuals living in Canada would be diagnosed with MM and 1,750 would die from it.⁸ According to GLOBOCAN 2022 data, the 5-year prevalence of MM for both sexes in North America was 117,011 cases, or 21.7% of all prevalent cases of MM worldwide.⁹ In Canada, the 1-year prevalence (2022 data for both sexes) was reported to be 4,044 cases or 10.5 cases per 100,000 population, whereas the 5-year prevalence was 14,553 cases or 37.9 cases per 100,000 population.¹⁰

Timely diagnosis is key to prevent or limit irreversible injury to organs and to prolong survival.¹¹ For patients with suspected MM, the initial diagnostic work-up usually includes baseline blood studies (e.g., complete blood count), and biological assessments to differentiate symptomatic and asymptomatic MM.^11,12 Various serum and urine analyses are also conducted to evaluate the M protein components in serum (e.g., quantitative Ig tests for IgA, IgD, IgE, IgG, and IgM, serum protein electrophoresis and serum immunofixation electrophoresis) and in urine (e.g., 24-hour urine protein electrophoresis or urine immunofixation electrophoresis).¹² A serum free light chain assay along with serum protein electrophoresis and serum immunofixation electrophoresis provide high sensitivity and prognostic value.¹² Other evaluations include bone marrow aspiration and biopsy to detect quantitative and/or qualitative abnormalities of bone marrow plasma cells or whole body low-dose CT to identify lytic bone lesions.¹² Cytogenetic testing such as karyotyping or chromosome analysis by FISH is used to identify specific chromosomal abnormalities associated with MM such as translocations, deletions, or amplifications, and to assist with risk stratification.^11,12 Gene expression profiling also assists with prognosis and therapeutic decisions.^13-15 Additional diagnostic tests include bone marrow immunohistochemistry, flow cytometry, whole body MRI, or PET or PET-CT scans.¹²

The diagnosis of symptomatic MM is made on the basis of the IMWG criteria: clonal bone marrow cells of more than 10% (or biopsy-proven bony or extramedullary plasmacytoma), end organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions), or myeloma defining events (clonal bone marrow plasma cells of 60% or more, a serum involved or uninvolved free light chain ratio of 100 or more, or more than 1 focal lesion on an MRI).^16,17 Staging is then conducted using the Second Revision of the ISS.¹⁸ The ISS is based on serum beta2-microglobulin and serum albumin measurements.¹⁹ The ISS was revised in 2015 (R-ISS) and integrates high-risk chromosomal abnormalities detected by FISH and serum LDH as prognostic factors to better stratify patients who were newly diagnosed into homogeneous survival groups.²⁰ In Canada, MM is most often staged using the Second Revision of the ISS and genetic information.²¹ There are no confirmed or anticipated statements in the Canadian product monograph regarding specific diagnostic technology that is recommended for isatuximab.

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 CDA-AMC review team.

Pharmacotherapy regimens for MM are complex and evolving rapidly as novel drugs and multidrug combination regimens of various drug classes are increasingly being incorporated into clinical practice. In eligible patients who were previously untreated, newly diagnosed MM is usually treated with an ASCT following induction therapy (i.e., typically with high-dose chemotherapy). It should be noted that more than 50% of patients may not be eligible for an ASCT because of health risks or other issues.^22,23 Further, not all patients who are eligible for an ASCT are willing to undergo a transplant.

There are currently 3 main drug classes available for the treatment of MM: immunomodulatory drugs (e.g., thalidomide, lenalidomide, and pomalidomide), proteasome inhibitors (e.g., bortezomib, carfilzomib, and ixazomib), and monoclonal antibodies (e.g., anti-CD38 antibodies such as daratumumab and isatuximab). In 2019, the joint guideline from OH (CCO) and the American Society of Clinical Oncology recommended initial treatment of triplet therapy including a novel drug (e.g., immunomodulatory drugs) and steroids.²⁴ In 2024, CDA-AMC recommended the prioritization of first-line daratumumab (e.g., DCyBorD or DRd) in patients with MM who were ineligible for a transplant.²⁵ Despite treatment advances over the past 2 decades, MM remains an incurable disease, with the treatment options currently available reflecting the need for further innovative treatment options.

Drug Under Review

Isatuximab is a monoclonal antibody that binds to a specific extracellular epitope of CD38, triggering mechanisms that result in the death of CD38-expressing tumour cells.²⁶ CD38 is a transmembrane glycoprotein with ectoenzymatic activity that is expressed in hematologic malignancies as well as other cell types and tissues. Isatuximab acts through IgG fragment crystallizable-dependent mechanisms, including antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity, and may also trigger the death of tumour cells by inducing apoptosis through a fragment crystallizable-independent mechanism.²⁶

Isatuximab is administered as an IV infusion, at a dose of 10 mg/kg, in combination with bortezomib-lenalidomide-dexamethasone for the treatment of patients with newly diagnosed MM who are not eligible for an ASCT. It has a Health Canada indication for the treatment of adult patients with relapsed or refractory MM who have received 1 to 3 prior lines of therapy. Each treatment cycle is 28 days; in cycle 1, isatuximab is administered on day 1, day 8, day 15, and day 22 (weekly), and, in cycle 2 and beyond, it is administered every 2 weeks. Treatment continues until disease progression or unacceptable toxicity. The sponsor’s reimbursement request is consistent with past Health Canada schedules for isatuximab. In April 2021, isatuximab (10 mg/kg) IV infusion combined with pomalidomide and dexamethasone received a CDA-AMC recommendation to reimburse with clinical criteria and/or conditions for the treatment of patients with relapsed or refractory MM who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor. In February 2022, isatuximab (10 mg/kg) IV infusion combined with carfilzomib and dexamethasone received a CDA-AMC recommendation to reimburse with clinical criteria and/or conditions for the treatment of adult patients with relapsed or refractory MM who have received 1 to 3 prior lines of therapy.

Key characteristics of isatuximab are summarized in Table 3 with other treatments available for the first-line treatment of transplant-ineligible MM.

Table 3: Key Characteristics of Isatuximab, Proteasome Inhibitors, Immunomodulatory Drugs, and Daratumumab

ADCC = antibody-dependent cell-mediated cytotoxicity; ADCP = antibody-dependent cellular phagocytosis; ASCT = autologous stem cell transplant; CDC = complement-dependent toxicity; CHF = congestive heart failure; DKd = daratumumab-carfilzomib-dexamethasone; DRd = daratumumab-lenalidomide-dexamethasone; DRESS = drug reaction with eosinophilia and systemic symptoms; DVd = daratumumab-bortezomib-dexamethasone; DVMP = daratumumab-bortezomib-melphalan-prednisone; DVT = deep vein thrombosis; ER = endoplasmic reticulum; H₂ = histamine subtype 2; IMiD = immunomodulatory drug; Kd = isatuximab-dexamethasone; KRd = isatuximab-lenalidomide-dexamethasone; mAb = monoclonal antibody; MM = multiple myeloma; NOC = Notice of Compliance; PE = pulmonary embolism; PI = proteasome inhibitor; PML = progressive multifocal leukoencephalopathy; Rd = lenalidomide-dexamethasone; SCT = stem cell transplant; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; TLS = tumour lysis syndrome; VPd = bortezomib-pomalidomide-dexamethasone.

^aHealth Canada–approved indication.

Source: CADTH Reimbursement Review: Isatuximab (Sarclisa).²⁷

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received by CDA-AMC are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the CDA-AMC review team based on the input provided by patient groups.

Myeloma Canada, an advocacy group supporting individuals with MM, provided input for the CDA-AMC review of isatuximab. Information for this submission was gathered through an online survey of patients and caregivers conducted by Myeloma Canada from October 11 to November 10, 2024. The survey was distributed via email and social media by Myeloma Canada and the Leukemia & Lymphoma Society of Canada.

Among the 43 survey responses, 24 were complete and eligible and divided into 2 subsets; 1 subset (named subset C) had 22 respondents ineligible for or not receiving an ASCT as first-line therapy and the second subset (named subset T) had 2 patients who received IsaVRd as first-line therapy. Subset C included respondents primarily from British Columbia (n = 11), with others from across Canada and 2 international participants. Most were male (n = 15; female, n = 7), aged 70 years to 79 years (n = 15), and lived in urban areas (n = 19). Subset T included 2 patients from Ontario aged 70 years to 79 years, 1 male and 1 female. None of the respondents were currently eligible for the treatment under review.

Eligible respondents (n = 24) rated the importance of controlling myeloma symptoms on a scale of 1 (not important) to 5 (extremely important), with bone issues (e.g., fractures, pain) (n = 12) rated as extremely important, followed by infections (n = 10), mobility (n = 9), and neuropathy (n = 8). Myeloma symptoms were reported to have a significant impact on daily activities and QoL, with respondents indicating an extreme effect on their ability to travel (n = 5), work (n = 4), and carry out household chores (n = 3). Most respondents (n = 19) reported visiting the hospital or cancer centre monthly, with travel times of less than 30 minutes (n = 11) or 30 minutes to 1 hour (n = 9).

According to the survey, treatment costs were primarily linked to parking fees (n = 8), drug expenses (n = 5), and administration fees (n = 3). Furthermore, the psychological and social challenges associated with the disease that were reported to have an extreme impact on QoL included the loss of sexual desire (n = 4), followed by difficulty sleeping (n = 3) and anxiety or worry (n = 2). Of the 21 patient respondents, 11 reported needing caregiver support while 8 indicated they did not. When asked about the factors they consider most important to myeloma treatment, 22 respondents emphasized effectiveness and remission, overall QoL, manageable side effects, the minimization of hospital visits, and ease of access.

In subset C, 18 respondents were ineligible for an ASCT at diagnosis, and 4 were eligible but did not receive a transplant. The most used first-line treatments were dexamethasone (n = 21), lenalidomide (n = 18), and daratumumab (n = 13), with DRd being the most frequent treatment combination (n = 11), followed by Rd (n = 3). Respondents rated their treatment experience positively, with many reporting improved QoL, manageable side effects, and effective myeloma control, and stating that the experience completely or mostly met their expectations. When considering treatment, respondents from subset C rated infections and cataracts as the least bearable side effects, followed by neutropenia and fever.

The 2 respondents with IsaVRd experience reported having received the treatment for 1 to 2 years. They found supportive care very effective, with treatment side effects and hospital visits having a slight to moderate negative impact on QoL. Both respondents rated IsaVRd as effective in controlling myeloma and manageable in terms of side effects. Despite side effects like diarrhea, infections, and neuropathy, they reported overall improved QoL, with 1 respondent noting significant health improvements.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

All CDA-AMC 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, or 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 MM.

Unmet Needs

The clinical experts noted that MM is an incurable disease despite the treatments available today. In the absence of a cure, the goal is to prevent disease progression and prolong QoL. It should be noted that QoL in clinical practice may be determined by a combination of validated QoL scales, patient reports, and clinical determination. A significant number of patients receiving the current standard of care in Canada (DRd) progress after 8 months of treatment, therefore never reaching the landmark 5-year PFS average. Prognosis is even worse for patients with early relapses because no other therapy offers this duration of response. With active myeloma, it takes typically 6 months for the symptoms (e.g., renal failure and extreme bone pain) to settle and to begin to experience alleviation. With relapsed disease, the symptoms of myeloma persist, and death can occur, so having more effective therapy in first-line treatment that would delay progression for as long as possible and prevent these issues and attrition is essential. With the average age of individuals with MM being in the transplant-ineligible category, there is an unmet need for treatments that effectively delay first relapse, lessen frailty from PD, and minimize health care usage from the symptoms of PD.

Place in Therapy

According to the clinical experts, IsaVRd would be an alternative to the currently funded first-line therapy for patients with myeloma who are ineligible for transplant (e.g., DRd). It is expected that combinations using isatuximab would be equally considered for first-line treatment in this patient population. The clinical experts also noted that isatuximab may also provide an alternative for drug shortages to meet patient preferences and frailty status. The clinical experts noted that, in the future, the evolution of isatuximab delivery with subcutaneous administration at home may help to decrease chair time and minimize health disparities for patients in rural settings who do not live in an urban environment and would otherwise refuse daratumumab. Further, combined with a bortezomib home injection, this would allow for a 4-drug combination to be delivered in the home, decreasing the burden on the health care system and further reducing health disparities. Also, the addition of proteosome inhibitors has consistently added 8 months of OS compared to the control group in other phase III myeloma clinical trials.

Patient Population

All patients requiring first-line therapy for transplant-ineligible MM would be eligible for treatment with IsaVRd.

Assessing the Response Treatment

Together with traditional measures of response as per IMWG response criteria, a reduction in the frequency and/or severity of symptoms such as bone pain and renal failure would be documented monthly with lab investigations. Improvement in QoL and function would be expected with better and faster response to therapy.

Discontinuing Treatment

The clinical experts noted that treatment discontinuation is guided by IMWG response criteria or is clinically determined, and is also guided by PD and intolerable side effects (e.g., infusion reactions and infection). The clinical experts also noted that consideration for the discontinuation of therapy based on sustained negative MRD response may allow for treatment-free intervals, but research on drug stoppage trials is ongoing. It should also be noted that deep and durable responses are needed first before entertaining the idea of the discontinuation of drug therapy.

Prescribing Considerations

IsaVRd would be considered as a first-line treatment option for individuals with transplant-ineligible MM. The clinical experts noted that a myeloma therapy expert would be needed to facilitate therapy.

Clinician Group Input

This section was prepared by the CDA-AMC review team based on the input provided by clinician groups.

Two clinician groups comprising 19 clinicians provided input for this review: CMRG (13 clinicians contributed to the input) and the OH (CCO) Hematology Cancer Drug Advisory Committee (6 clinicians contributed to the input). Overall, the input was aligned with the input from the clinical experts consulted by CDA-AMC.

According to clinician groups, patients who are newly diagnosed in Canada with myeloma and who are transplant-ineligible typically receive daratumumab-based regimens, such as DRd, until disease progression. A small proportion of patients with renal impairment or poor bone marrow reserve may start treatment with DCyBorD. Less often, patients with transplant ineligibility due to frailty may receive Rd or VRd (typically “lite”), with single drug lenalidomide also used until disease progression.

Both groups underscored the primary treatment goals: prolonging PFS and OS and controlling disease symptoms and complications (e.g., bone damage, kidney failure, hypercalcemia, or low blood counts). Additionally, CMRG stressed minimizing treatment-related AEs and improving QoL by tailoring care to individual patient needs.

While acknowledging multiple therapy lines for myeloma, both groups reiterated its incurable nature. The CMRG stressed that long-term survival depends on maximizing disease control during first-line treatment, emphasizing deep and durable response — including MRD negativity — to achieve prolonged remission. They noted that 19% of patients who are transplant-ineligible in Canada do not receive second-line therapy due to disease progression or death.

The OH (CCO) Hematology Cancer Drug Advisory Committee highlighted the lack of comparative data for IsaVRd with DRd and noted that the IV administration of isatuximab may be less appealing than subcutaneous daratumumab. The CMRG pointed out that the key shift in treatment would involve adding bortezomib to the anti-CD38 monoclonal antibody, lenalidomide, and a steroid backbone, supporting IsaVRd as the new first-line standard of care for patients who are transplant-ineligible with newly diagnosed MM due to its potential for greater efficacy than VRd alone. They also remarked that while isatuximab requires longer infusion times, shorter durations are feasible. Furthermore, patients who were refractory to bortezomib in the front-line setting could still benefit from carfilzomib-based regimens, making IsaVRd unlikely to alter the relapsed treatment landscape significantly.

The OH (CCO) Hematology Cancer Drug Advisory Committee highlighted the use of standard myeloma response criteria and noted that PFS is a key outcome. The CMRG elaborated on using monoclonal protein markers, bone marrow biopsy, and imaging studies per IMWG criteria while clinical trials also assess marrow MRD. Clinically meaningful responses (defined as at least partial remission) were linked to improvements in symptoms such as reduced bone pain, fewer fractures, a decreased need for radiotherapy, increased energy, and enhanced daily functioning. Response evaluations are typically conducted every 1 month to 3 months based on clinical stability and treatment regimen.

Both groups agreed that treatment discontinuation should be considered for significant intolerance. The OH (CCO) Hematology Cancer Drug Advisory Committee added that disease progression could also warrant discontinuation, while CMRG emphasized that bortezomib-related toxicity might necessitate stopping treatment.

The clinician groups concurred that isatuximab should be administered in systemic therapy centres. The CMRG specified that IsaVRd is suitable for centres experienced in managing isatuximab and bortezomib and should be overseen by hematologists or oncologists proficient in managing potential AEs, including in community and tertiary facilities.

Drug Program Input

The drug programs provide input on each drug being reviewed through the CDA-AMC 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 CDA-AMC are summarized in Table 4.

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

DCyBorD = daratumumab-cyclophosphamide-bortezomib-dexamethasone; DRd = daratumumab-lenalidomide-dexamethasone; DVMP = daratumumab-bortezomib-melphalan-prednisone; ECOG PS = Eastern Cooperative Oncology Group Performance Status; G-CSF = granulocyte colony-stimulating factor; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; MRD = minimal residual disease; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; Rd = lenalidomide-dexamethasone; VRd = bortezomib-lenalidomide-dexamethasone.

Clinical Evidence

The objective of the CDA-AMC Clinical Review report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of isatuximab 20 mg/mL concentrate solution for IV infusion in the treatment of patients with newly diagnosed MM who are not eligible for an ASCT. The focus will be placed on comparing isatuximab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of isatuximab is presented in 2 sections with the CDA-AMC critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes the pivotal RCT that was selected according to the sponsor’s systematic review protocol. The CDA-AMC 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 and indirect evidence selected from the literature that met the selection criteria specified in the review. The third and fourth sections would normally include sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review. However, none were submitted by the sponsor.

Included Studies

Clinical evidence from the following is included in the CDA-AMC review and appraised in this document:

• 1 pivotal RCT identified in the systematic review (the IMROZ study)

• an ITC analysis.

Systematic Review

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

Description of Studies

One study (the IMROZ trial) was identified from the literature for inclusion in the systematic review. Characteristics of the included study are summarized in Table 5.

The IMROZ trial (ClinicalTrials.gov ID code NCT03319667) is an ongoing, prospective, international, multicentre, randomized, open-label, parallel-group, phase III trial to assess the clinical benefit of IsaVRd compared to VRd alone in patients with newly diagnosed MM who are not eligible for an ASCT. The IMROZ trial is being conducted at 96 sites in 21 countries or regions but there are no participating sites in Canada. A total of 446 patients who were enrolled were randomized using an interactive response technology (IRT) in a 3:2 ratio to IsaVRd (N = 265) and VRd (N = 181). Randomization was stratified by country (China versus other countries), age (younger than 70 years versus 70 years or older), and R-ISS stage I to stage II versus stage III versus not classified (i.e., inconclusive FISH unless the randomization stratum could be determined based on LDH, albumin, and beta2-microglobulin only). The primary objective of the IMROZ study was to demonstrate the benefit of IsaVRd in the prolongation of PFS using IMWG criteria. During the continuous treatment period, patients randomized to the VRd group who had confirmed PD during the VRd portion of the continuous treatment period (as assessed by the investigator) could cross over to the IsaVRd group. Unless otherwise specified, all data reported in this document are from the September 26, 2023, data cut-off. This corresponds with the second planned PFS interim analysis cut-off date (i.e., the date when 167 IRC-determined PFS events [information fraction of 75%] from the global population were expected to be observed). At the September 26, 2023, data cut-off (median follow-up = 59.73 months; range, 0.17 months to 68.99 months), a total of 162 PFS events had been observed.

Table 5: Details of Study Included in the Systematic Review

AE = adverse event; CR = complete response; CrCl = creatinine clearance; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; 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; EOT = end of treatment; Fc = fragment crystallizable; Ig = immunoglobulin; IgM = immunoglobulin M; IMWG = International Myeloma Working Group; IRC = independent review committee; IsaRd = isatuximab-lenalidomide-dexamethasone; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; MM = multiple myeloma; MRD = minimal residual disease; ORR = overall response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PFS2 = progression-free survival on next line of therapy; PK = pharmacokinetic; PRO = patient-reported outcome; q.4.w. = every 4 weeks; q.d. = every day; q.w. = every week; SAE = serious adverse event; SC = subcutaneous; SCT = stem cell transplant; TEAE = treatment-emergent adverse event; TT1R = time to first response; TTBR = time to best response; TTP = time to progression; VGPR = very good partial response; VRd = bortezomib-lenalidomide-dexamethasone.

Note: Outcomes were reported for a preplanned second interim PFS analysis (and interim analysis of OS) corresponding with a data cut-off date of September 26, 2023, with a median follow-up of 59.73 months.

Sources: IMROZ Clinical Study Report³²

Populations

Inclusion and Exclusion Criteria

Patients who were enrolled were newly diagnosed with MM as defined by the IMWG criteria and evidence of measurable disease.¹⁶ Patients were not considered for high-dose chemotherapy due to their age (i.e., 65 years or older, or younger than 65 years with important comorbidities likely to have a negative impact on the tolerability of high-dose chemotherapy with stem cell transplant), or where high-dose chemotherapy was not indicated. To be eligible for crossover, patients must have confirmed PD in the VRd group before crossover and have not received any systemic anticancer therapy other than VRd in the IMROZ study. Key exclusion criteria were those younger than 18 years or those older than 80 years, a diagnosis of peripheral neuropathy greater than grade 1 or grade 1 with pain, amyloidosis, monoclonal gammopathy of undetermined significance, smouldering MM, Waldenström disease, or other conditions in which Ig M protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions. Patients were also excluded if they had prior or current systemic therapy or a stem cell transplant for MM (except for emergency use of a short course of corticosteroids if completed 14 days before randomization), concomitant plasma cell leukemia, a major procedure within 14 days of study initiation, an ECOG PS score greater than 2, or clinical laboratory parameters outside predefined limits.

Interventions

Isatuximab was supplied as a 20 mg/mL concentrate for solution for parenteral infusion. The appropriate volume of isatuximab based on patient weight was diluted in 250 mL of a 0.9% sodium chloride solution or a 5% dextrose solution to achieve the appropriate drug concentration for IV infusion. Infusion via a central line was preferred, if available; however, if patients experienced local intolerance after peripheral IV infusion, the decision to use a central line was at the discretion of the investigator. The length of infusion corresponded with the amount of time for the total dose to be administered and the presence or absence of infusion-related (IR) reactions. The dose of isatuximab administered was 10 mg/kg according to the following schedule. For cycle 1 (a 42-day cycle), the dose was administered once weekly on day 1, day 8, day 15, day 22, and day 29; for cycle 2 to cycle 4 (42-day cycles), the dose was administered every 2 weeks on day 1, day 15, and day 29; for cycle 5 to cycle 17 (28-day cycles), the dose was administered every 2 weeks on day 1 and day 15; and for cycles 18 and beyond (28-day cycles), the dose was administered every 4 weeks on day 1 in combination with the following:

• bortezomib 1.3 mg/m²: Day 1, day 4, day 8, day 11, day 22, day 25, day 29, and day 32 of the first 42-day cycles only by subcutaneous injection; patients with a body surface area greater than 2.2 m² were to use 2.2 m² for the determination of the bortezomib dose

• lenalidomide 25 mg: Once daily on day 1 to day 14 and day 22 to day 35 in a 42-day cycle (10 mg once daily if creatinine clearance was 30 mL or more per minute to less than 60 mL per minute) in induction period and 25 mg once daily on day 1 to day 21 of a 28-day cycle in the continuous treatment period and crossover by oral capsule

• dexamethasone 20 mg: Once daily on day 1, day 2, day 4, day 5, day 8, day 9, day 11, day 12, day 15, day 22, day 23, day 25, day 26, day 29, day 30, day 32, and day 33 if aged younger than 75 years, or otherwise day 1, day 4, day 8, day 11, day 15, day 22, day 25, day 29, and day 32 for cycle 1 to cycle 4 and 20 mg once daily on day 1, day 8, day 15, and day 22 during the continuous treatment period by IV infusion on isatuximab infusion days or otherwise by oral tablet; dexamethasone was to be administered 15 minutes to 30 minutes (but no longer than 60 minutes) before isatuximab.

The dosing of VRd in the control group followed the same regimen as for the IsaVRd group. For both groups, there was no limitation on the number of treatment cycles to be administered in the absence of major toxicity, PD, or any other discontinuation criteria. Dose adjustments (i.e., dose delay, dose omission, or — specifically for VRd — dose reduction) were permitted for subsequent treatment cycles based on individual patient tolerance. No dose reductions were permitted for isatuximab.

Patients allocated to the IsaVRd group received premedications before the isatuximab infusion to reduce the risk and severity of IR reactions commonly observed with monoclonal antibodies. Recommended premedication included diphenhydramine 25 mg to 50 mg IV (or equivalent), dexamethasone IV or oral (as per previous dosing), ranitidine 50 mg IV (or equivalent), and acetaminophen 650 mg to 1,000 mg orally before isatuximab. The isatuximab infusion was to start immediately after completion of the premedication regimen. Patients who did not experience an IR reaction upon 4 consecutive administrations of isatuximab could have their subsequent premedication reconsidered at the investigator’s discretion. Thromboprophylaxis was applied continuously throughout the study period as per local practice.

Patients in the VRd group eligible for crossover treatment were dosed as follows:

• dexamethasone 20 mg by IV infusion on the days of isatuximab administration and orally otherwise on day 1, day 8, day 15, and day 22 of each cycle between 15 minutes and 30 minutes (but not longer than 60 minutes) before isatuximab

• isatuximab 10 mg/kg by IV infusion on day 1, day 8, day 15, and day 22 of the first crossover cycle, and then 10 mg/kg on day 1 and day 15 for subsequent cycles.

Outcomes

Disease assessments (e.g., M protein measurements) were performed by a central laboratory. An IRC, blinded to study treatment groups, determined disease response and progression according to efficacy MM laboratory data (central laboratory results), bone marrow assessment for plasma cell infiltration (based on local laboratory results), and centrally reviewed imaging as per IMWG criteria and in line with the IRC charter up to the final PFS analysis.³³

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 CDA-AMC and input from patient and clinician groups and public drug plans. Using the same considerations, the CDA-AMC review team selected end points that were most relevant to informing the CDA-AMC 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 the GRADE tool. Select notable harms outcomes considered important for informing the CDA-AMC expert committee deliberations were also assessed using GRADE. The outcomes selected for GRADE appraisal were PFS, OS, HRQoL, and SAEs. Infusion reactions and infections were also noted as important by the clinical experts consulted for this review. The following outcomes were included in the text of the report as supportive information: ORR (and its components, including CR and VGPR), the MRD negativity rate, and time to first response (TT1R).

Table 6: Outcomes Summarized From the IMROZ Trial

CR = complete response; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; VGPR = very good partial response.

^aStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchical testing). The hierarchy failed after VGPR or better rate. An interim analysis of OS for futility and overwhelming efficacy was planned at the time of the interim analysis of PFS. The final analysis will be performed when there have been approximately 202 deaths.

Source: IMROZ Clinical Study Report.³²

Progression-Free Survival

The primary outcome was PFS, defined as the time from the date of randomization to the date of first documented PD (determined by the IRC per IMWG criteria) or death from any cause, whichever came first. If PD and death were not observed before the data cut-off date or the date of initiation of further antimyeloma treatment, PFS was censored at the date of the last valid disease assessment not showing PD or the analysis cut-off date, whichever came first. Progressions or deaths occurring more than 13 weeks after the last valid disease assessment (i.e., after > 2 consecutive missed scheduled disease assessments) were to be censored at the date of the last valid disease assessment without evidence of progression before initiation of new antimyeloma treatment (if any) or the PFS analysis cut-off date, whichever came first. Patients without an event and without any valid postbaseline assessment were censored at the date of randomization. Responses (including progression) were evaluated by a blinded IRC according to IMWG criteria using central laboratory results and central radiological review. Response and progression based on serum and/or urine M protein were confirmed by 2 consecutive assessments.

Overall Survival

OS, a key secondary outcome, was defined as the time from the date of randomization to death from any cause. Patients without an event at the data cut-off date were to be censored at the last date that the patient was known to be alive or at the analysis cut-off date, whichever came first.

Clinical Response

ORR was defined as the proportion of patients with best overall response of stringent CR, CR, VGPR, and partial response, as assessed by the IRC using IMWG response criteria. The following assessments were considered for derivation of the best overall response:

• Randomized groups: From the randomization date until the first documentation of PD, death, initiation of antimyeloma treatment, or crossover, whichever came first.

• Crossover group: The best sequential response, from the first isatuximab drug intake until the first documentation of PD, death, or initiation of antimyeloma treatment, whichever came first.

Minimal Residual Disease

The MRD negativity rate, a key secondary outcome, was defined as the negativity rate for patients with a CR or better response, deemed as the proportion of patients for whom MRD is negative. Bone aspirates were collected at screening and for patients with a CR or VGPR at the end of the induction period, then every 6 months during the first 2 years (i.e., at 12 months, 18 months, and 24 months after randomization), and then once a year until PD or until the final PFS analysis cut-off date, whichever occurred first. The threshold for negativity by means of next-generation sequencing was assessed at 10^-5 sensitivity.

Time to First Response

TT1R was defined as the time from randomization to the first IRC-determined response (partial response or better) that is subsequently confirmed.

Health-Related Quality of Life

HRQoL was assessed using EORTC QLQ-C30 (Table 7), a 30-item instrument with 15 items related to function (physical, role, cognitive, emotional, social), 7 questions related to symptoms (7 questions), single-item symptom scales (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and 2 items related to global QoL. All except global QoL are scored from 1 (“not at all”) to 4 (“very much”).^34,35 The EORTC QLQ-C30 score range is 0 to 100, with higher scores indicating better functioning or global health status or QoL, and lower scores indicating a higher symptom burden. It was administered before treatment on day 1 of every cycle, at the end of treatment visit, and at 90 (± 5) days after the last study treatment administration.

Responses were not expected at a given visit for any of the following reasons: death, progression, dropout due to an AE, poor protocol compliance, or withdrawal by a patient. A questionnaire could be expected but not received for other reasons as well (e.g., failure to distribute the questionnaire, patient did not have the time to complete questionnaire).

Safety Outcomes

Safety outcomes included AEs, SAEs, and AESIs, including IR reactions.

Table 7: Summary of Outcome Measures and Their Measurement Properties

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; HRQoL = health-related quality of life; MID = minimal important difference; MM = multiple myeloma; QoL = quality of life; SEIQoL = Schedule for the Evaluation of Individual Quality of Life; SRM = standardized response mean.

Statistical Analysis

Sample Size and Power Calculation

In determining sample size, the sponsor assumed that there would be a median PFS of 40 months in the VRd group, that the IsaVRd group would have an HR of 0.64 compared to the VRd group, and that, assuming proportional hazards, this was expected to correspond to an improvement in median PFS from 40 months to 62.5 months. The sponsor planned to perform a stratified log-rank test at a 1-sided significance level of 2.5% power and planned for a 3:2 randomization ratio, IsaVRd to VRd, as well as an interim analysis for PFS when 60% of the PFS events had been observed. Based on these assumptions, a total of 222 events were needed to achieve 90% power, and 440 patients (264 patients in the IsaVRd group and 176 patients in the VRd group) were needed to achieve the targeted number of PFS events. Assuming a uniform accrual of 30 patients per month, the final PFS cut-off date was expected to be approximately 60 months after the first patient had been enrolled. With the addition of 1 interim analysis when 75% of PFS events were observed, the power was to be decreased from 90.1% to 89.7 %. With the addition of a third interim analysis once 85% of PFS events had been observed, the power was to be decreased to 89.4%.

Statistical and Analytical Plans

Continuous data were summarized using the number of available data, the mean, standard deviation (SD), the median, quartile 1 and quartile 3, and minimum and maximum values for each treatment group, as applicable. Categorical and ordinal data were summarized using the number and percentage of patients in each treatment group.

All efficacy analyses were performed in the ITT population. All analyses using the stratification factors employed the stratification factors as per IRT; however, due to the low number of patients randomized in the stratum R-ISS not classified (N = 5), stratification factors R-ISS stage III and R-ISS not classified were pooled together. Statistical testing was only conducted for the induction and continuous portions of the IMROZ trial. Of note, the purpose of the crossover group was exploratory and no formal statistical testing was performed. The results of the crossover phase are not reported here.

The analyses presented in this document correspond with the preplanned second PFS interim analysis (Table 8).

Primary Outcome

Testing of the primary end point (PFS) was via a log-rank test stratified by age and R-ISS. The estimates for HR and corresponding 95% CI were provided using a Cox proportional hazards model stratified by the same stratification factors. The Kaplan-Meier (KM) method was used to estimate median PFS and probabilities of being progression-free at different time points, as well as corresponding CIs.

Testing of all relevant end points as well as adjustment factors, methods of handling missing data, and sensitivity analyses are described in Table 8.

Data Imputation Methods

If a postbaseline disease assessment of response was determined to be “not evaluable” based on IMWG criteria or the date of assessment was missing, the disease assessment was considered invalid. For PFS and OS, the trial reported nonmissing observations in the considered population.

Subgroup Analyses

The consistency of the results of the primary analysis was evaluated across the following predefined subgroups (if there were 10 patients in each treatment group within each subgroup):

• age by IRT (aged younger than 70 years versus 70 years)

• age (aged younger than 70 years versus 70 years; aged younger than 75 years versus 75 years)

• sex (male versus female)

• race (white versus other)

• geographical region of the world (Europe versus North America versus Asia versus other countries or regions)

• ECOG PS score at baseline (0 or 1 versus greater than 1)

• ISS staging at study entry (stage I versus stage II versus stage III)

• R-ISS staging at study entry by IRT (stage I or stage II versus stage III or not classified)

• chromosomal abnormality (17p deletion, t[4;14], t[14;16]) (at least 1 versus none)

• chromosomal abnormality 1q21+ (yes versus no)

• MM type at study entry (IgG versus non-IgG)

• extramedullary or paramedullary plasmacytoma at baseline by IRC (yes versus no)

• plasmacytoma disease by IRC (both extramedullary and paramedullary disease versus only extramedullary disease versus only paramedullary disease versus no plasmacytoma disease)

• baseline estimated glomerular filtration rate (modification of diet in renal disease formula) (less than 60 mL per minute per 1.73 m² versus 60 mL per minute per 1.73 m²)

• hemoglobin at baseline (less than 10 g/dL versus 10 g/dL).

For each predefined subgroup, the treatment effect HR and associated 2-sided 95% CI was estimated and a forest plot summarizing the results for the predefined subgroups was constructed. For each subgroup, PFS was analyzed using a nonstratified Cox proportional hazards model with terms for the factor, treatment, and their interaction. A test of the interaction was performed at the 10% alpha level. The prespecified subgroups were not included in the statistical hierarchical testing strategy nor adjusted for multiplicity.

Multiplicity Adjustment

Hypothesis testing of the key secondary outcomes was carried out using a closed test procedure to control the type I error rate. Testing on key secondary outcomes was performed only if the significance level had been reached on PFS and testing on subsequent outcomes continued only if the null hypothesis for the previously tested outcome was rejected. The hierarchical procedure was performed according to the following order:

1. CR rate at the time of the primary PFS analysis and/or the final PFS analysis

2. MRD negativity rate at the time of the primary PFS analysis and/or the final PFS analysis

3. VGPR or better rate at the time of the primary PFS analysis and/or the final PFS analysis

4. OS.

Three interim analyses for PFS were planned to be conducted after 60%, 75%, and 85% of events had been observed. The primary analysis of PFS corresponded to the positive interim analysis or the final PFS analysis. At the time of the positive PFS interim analysis, key secondary end points were tested sequentially up to the null hypothesis that failed to be rejected for a key secondary end point. At the final PFS analysis, the testing procedure will resume where it stopped at interim analysis. Except for OS and PFS on next line of therapy, other secondary end points were analyzed at the time of the primary analysis and/or the final analysis of PFS. The OS analysis will be conducted with up to 5 looks, including at the time of the interim and final analysis of PFS, and at the final OS analysis when approximately 202 deaths have occurred. In addition, up to 3 nonbinding futility analyses of OS will be performed; the data monitoring committee may have considered stopping the trial at the time of interim analysis 2 if the HR for OS was higher than 1.1. Control for multiplicity across the interim analyses of PFS was achieved using an O’Brien-Fleming alpha spending function. The efficacy boundaries were determined based on the actual number of events at each analysis. At the time of interim analysis 2, the P value boundary for PFS was 0.007423. Similarly, for key secondary end points, significance levels were determined based on alpha spending functions specific to each end point (O’Brien-Fleming alpha spending functions for CR and the MRD negativity rate and a user-defined alpha spending function for OS). Other end points were unadjusted for multiplicity.

Sensitivity Analyses

Ten different sensitivity analyses of the primary outcome were conducted and included: a PFS analysis without censoring for further antimyeloma treatment; a PFS analysis using investigator assessment of response and considering symptomatic deterioration; a PFS analysis using investigator assessment of response and ignoring symptomatic deterioration; initiation of further antimyeloma treatment considered as a PFS event; a PFS analysis without censoring of progression or death occurring greater than 13 weeks after the last valid disease assessment; analysis based on scheduled assessment dates instead of actual assessment dates; a final PFS analysis using the date of the last observed event as the cut-off date; an unstratified PFS analysis; a PFS analysis using stratification factors as per an electronic case report form (if relevant); and a PFS analysis censoring death events due to COVID-19 infections. Sensitivity analyses for other end points are described in Table 8.

Table 8: Statistical Analysis of Efficacy End Points of IMROZ Study

CMH = Cochran-Mantel-Haenszel; eCRF = electronic case report form; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; HRQoL = health-related quality of life; ITT = intention to treat; KM = Kaplan-Meier; MRD = minimal residual disease; ORR = overall response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; R-ISS = Revised International Staging System; TT1R = time to first response.

^aAnalyses and summaries of continuous and categorical variables were based on observed data only. Percentages were calculated using as denominator the number of patients with nonmissing observations in the considered population.

^bPatients in the ITT population without MRD assessment were to be considered as having positive MRD.

Source: IMROZ Clinical Study Report and Statistical Analysis Plan.³²

Analysis Populations

Analysis populations of the IMROZ trial are summarized in Table 9.

Table 9: Analysis Populations of IMROZ Trial

ADA = antidrug antibody; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; ITT = intention to treat; VRd = bortezomib-lenalidomide-dexamethasone.

Source: IMROZ Clinical Study Report and Statistical Analysis Plan.³²

Results

Patient Disposition

In the IMROZ trial, a total of 512 patients were screened and 446 patients (87.1%) were randomized (Table 10). Among patients who were randomized, the reason for transplant ineligibility was being aged 65 years or older (427 patients [95.7%]) and comorbidities (19 patients [4.3%]); these were not substantially different between the groups. The IMROZ study is an ongoing trial and at the time of the second PFS interim analysis data cut-off (September 26, 2023), 275 patients had discontinued treatment (137 patients [75.7%] in the VRd group and 138 patients [52.1%] in the IsaVRd group), mainly due to AEs (50 patients [27.6%] in the VRd group and 60 patients [22.6%] in the IsaVRd group). More patients in the VRd group (67 patients [37.0%]) than the IsaVRd group (38 patients [14.3%]) had discontinued treatment due to PD. As of the data cut-off date, 25 patients in the VRd group had crossed over to receive IsaVRd.

Table 10: Summary of Patient Disposition From the IMROZ Trial

IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; ITT = intention to treat; NA = not applicable; VRd = bortezomib-lenalidomide-dexamethasone.

^aTreatment discontinuation reported in Table 10 refers to definitive treatment discontinuation, which was defined as the discontinuation of all study interventions. Per protocol, patients could discontinue only 1 component of combination therapy and continue the other(s).

Source: IMROZ Clinical Study Report.³²

Baseline Characteristics

The baseline characteristics outlined in Table 11 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. At baseline, the 2 groups were balanced with regard to patient demographic and disease characteristics in the ITT population. Patients were aged an average of 71.5 years (SD = 4.8 years). Most patients (89.0%) had an ECOG PS score of 0 or 1. The most common ISS stage at study entry was stage I (53.0%), followed by stage II (31.1%) and stage III (15.2%). The MM subtype at baseline was most frequently IgG (64.1%) and the R-ISS stage at study entry was most frequently stage II (n = 286; 64.1%). The median time from initial diagnosis to randomization was 1.18 months. The main reason for transplant ineligibility was being aged 65 years or older (95.7%). It should be noted that there were fewer patients with kidney dysfunction (estimated glomerular filtration rate < 60 mL per minute per 1.73 m²) in the IsaVRd group at baseline compared to the VRd group (24.9% versus 34.3%, respectively).

Table 11: Summary of Baseline Characteristics From IMROZ Study

1q21+ = chromosome arm 1q21; Del(17p) = 17p deletion; ECOG PS = Eastern Cooperative Oncology Group Performance Status; GFR = glomerular filtration rate; IgA = immunoglobulin A; IgD = immunoglobulin D; IgE = immunoglobulin E; IgG = immunoglobulin G; IgM = immunoglobulin M; IRC = independent review committee; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; ISS = International Staging System; MM = multiple myeloma; R-ISS = Revised International Staging System; SD = standard deviation; VRd = bortezomib-lenalidomide-dexamethasone.

^aHigh cytogenetic risk was defined as the presence of del(17p), t(4;14), t(14;16), or a combination of these.

^bAbnormality was defined as present in at least 30% of abnormal bone marrow plasma cells for t(4;14), t(14;16), and 1q21+ (at least 3 copies) and at least 50% of abnormal plasma cells for del(17p). One patient in the IsaVRd group had 2 high-risk chromosomal abnormalities (del[17p] and t[4;14]).

^cThe 1q21+ abnormality was defined as at least 3 copies of 1q21. The amplification 1q21 abnormality was defined as at least 4 copies of 1q21.

Sources: IMROZ Clinical Study Report³² and Facon et al. (2024).³⁰

Exposure to Study Treatments

The median duration of overall exposure to study treatments was 31.28 months (range, 0.6 months to 67.2 months) in the VRd group and 53.16 months (range, 0.5 months to 68.8 months) in the IsaVRd group, as detailed in Table 12. The median number of cycles started was 29.00 cycles (range, 1 cycle to 69 cycles) in the VRd group and 52.00 cycles (range, 1 cycle to 69 cycles) in the IsaVRd group. The median duration of exposure to the IsaVRd regimen after exposure in the crossover population was 8.02 months (range, 2.0 months to 49.2 months) and the median number of cycles started was 9.00 cycles (range, 2 cycles to 53 cycles). At the time of data cut-off, 4 patients (16.0%) were still on crossover treatment, with the most common reason for treatment discontinuation being disease progression in 16 patients (64.0%).

Table 12: Summary of Patient Exposure From Studies Included in the Systematic Review

IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; SD = standard deviation; VRd = bortezomib-lenalidomide-dexamethasone.

Source: IMROZ Clinical Study Report.³²

Concomitant Medications and Cointerventions

Concomitant medications are those the patient used at any time during the treatment period (from the first dose of study treatment to the last dose + 30 days). Most patients in both treatment groups received at least 1 concomitant medication (IsaVRd group = 99.2%; VRd group = 100%). The most common medications were anti-infectives for systemic use (IsaVRd group = 99.2%; VRd group = 100%) and blood and blood-forming organs (IsaVRd group = 99.2%; VRd group = 100%).

Subsequent Treatment

In the ITT population, the time to the next treatment in the IsaVRd group was delayed compared with the VRd group (stratified HR = 0.376; 95% CI, 0.265 to 0.534). The median time to the next treatment was 63.57 months (range, 48.624 months to NC) for the VRd group and was not reached in the IsaVRd group.

Among patients who received further antimyeloma treatment (80 patients [44.2%] and 52 patients [19.6%] in the VRd and IsaVRd groups, respectively), the most frequent subsequent therapy given was corticosteroids (90.0% and 100% in the VRd group and the IsaVRd group, respectively) and immunomodulators (72.5% and 76.9% in the VRd group and the IsaVRd group, respectively). This included not only the second line of therapy, but all further lines of therapy received by the patients. Further antimyeloma treatment also included anti-CD38 drugs (monoclonal antibodies) in twice as many participants in the VRd group (68.8%) than in the IsaVRd group (34.6%) — primarily, daratumumab (37.5% and 28.8%, respectively). Patients treated with subsequent isatuximab (36.3% and 5.8% in the VRd and IsaVRd groups, respectively) included 25 patients (13.8%) in the VRd group opting to cross over to the IsaVRd group.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the CDA-AMC review protocol are reported in this section. The median follow-up at the September 26, 2023, data cut-off was 59.73 months (range, 0.17 months to 68.99 months). A summary of the key efficacy results for the IMROZ trial is presented in Table 13.

Table 13: Summary of Key Efficacy Results From Studies Included in the Systematic Review

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; CR = complete response; HR = hazard ratio; IRC = independent review committee; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; ITT = intention to treat; KM = Kaplan-Meier; MRD = minimal residual disease; NC = not calculated; OR = odds ratio; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; R-ISS = Revised International Staging System; sCR = stringent complete response; TT1R = time to first response; VGPR = very good partial response; VRd = bortezomib-lenalidomide-dexamethasone.

Note: Median follow-up time is 59.73 months. An HR of less than 1 or an OR of more than 1 favours the IsaVRd treatment group.

^aTested according to a prespecified statistical hierarchy and P value has been adjusted for multiple testing.

^bPatient is considered as lost to follow-up if the reason for censoring is last valid disease assessment before the cut-off date and if the time from the last disease assessment to the cut-off date is longer than 13 weeks.

^cStratified by age (< 70 years versus ≥ 70 years) and R-ISS stage (stage I or stage II versus stage III or not classified) according to interactive response technology.

^dThe 1-sided significance level was 0.007423 using the O’Brien-Fleming alpha spending function to control overall 1-sided type I error at 2.5%.

^eEstimated using the KM method.

^fNoninferential (nominal P value) due to break in statistical hierarchical testing procedure at VGPR rate or better.

^gFor analysis purposes, patients in the ITT population but without MRD assessment by next-generation sequencing were considered as having positive MRD. Sensitivity of 1 in 10^-5 nucleated cells.

Sources: IMROZ Clinical Study Report³² and Facon et al. (2024).³⁰

Progression-Free Survival

There were 78 patients (43.1%) in the VRd group and 84 patients (31.7%) in the IsaVRd group in the ITT population who experienced PFS events after a median follow-up of 59.73 months as per Table 13. The HR was 0.596 (98.5% CI, 0.406 to 0.876; P = 0.0005), corresponding with a 40.4% reduction in the hazard of disease progression or death in the IsaVRd group compared to the VRd group. An early separation between the VRd and IsaVRd groups was observed in the KM PFS curves as depicted in Figure 1. The median PFS was 54.34 months (95% CI, 45.207 months to NC) in the VRd group and not reached in the IsaVRd group. At 60 months, the PFS probability was 45.2% in the VRd group and 63.2% in the IsaVRd group. The risk difference at 60 months was 18.0% (95% CI, 6.5% to 29.5%).

A number of sensitivity analyses of the primary outcome were performed (refer to Table 8). All results were consistent with those of the primary analysis. There were also several subgroup analyses, with most also demonstrating no significant interaction at the 10% level between treatment groups and subgroups of stratification factors, demographic characteristics, or baseline disease characteristics supporting an overall consistent treatment effect (Figure 2). Most subgroup analyses, including those of poor prognosis subgroups, showed a treatment effect that favoured IsaVRd over VRd, consistent with the primary PFS analysis. However, in the subgroup of MM type at study entry (IgG versus non-IgG), the subgroup of plasmacytoma disease per IRC (extramedullary disease versus only paramedullary disease versus no plasmacytoma disease), and the subgroup of chromosomal 1q21+ abnormality, the P value for interaction was less than 10%, suggesting there is some difference in the treatment effect across those subgroups. The effect of IsaVRd over VRd seems to be stronger, respectively, in the IgG subgroup and extramedullary disease subgroup, and in participants with chromosomal 1q21+ abnormality.

Figure 1: IMROZ Trial KM Curves for PFS by IRC (ITT Population)

IRC = independent review committee; ITT = intention to treat; IVRd [IsaVRd] = isatuximab-bortezomib-lenalidomide-dexamethasone; KM = Kaplan-Meier; PFS = progression-free survival; R-ISS = Revised International Staging System; VRd = bortezomib-lenalidomide-dexamethasone.

Note: Log-rank test procedure stratified by age (< 70 years versus ≥ 70 years) and R-ISS stage (stage I or stage II versus stage III or not classified) according to interactive response technology. The 1-sided significance level was 0.007423.

Source: IMROZ Clinical Study Report.³²

Figure 2: IMROZ Trial Forest Plot of Subgroup Analyses of PFS by IRC by Baseline Demographic Characteristics (ITT Population)

CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; eGFR = estimated glomerular filtration rate; IRC = independent review committee; ITT = intention to treat; IVRd [IsaVRd] = isatuximab-bortezomib-lenalidomide-dexamethasone; MDRD = Modification of Diet in Renal Disease; PFS = progression-free survival; VRd = bortezomib-lenalidomide-dexamethasone.

Source: IMROZ Clinical Study Report.³²

Overall Survival

The interim analysis of OS for futility and overwhelming efficacy was planned at the time of the interim analysis of PFS. After a median follow-up of 59.73 months, there were 59 deaths (32.6%) in the VRd group and 69 deaths (26.0%) in the IsaVRd group as per Table 13. This represents an OS information fraction of 63% because the final OS analysis is to be conducted once there have been 202 deaths. The HR was 0.776 (99.97% CI, 0.407 to 1.48), which passed the prespecified futility threshold that was set to an HR of more than 1.1. The 1-sided nominal P value was 0.076. The KM curves follow a similar trajectory (and consequently crossed at times) and do not begin to separate until after 54 months. Median OS was not reached in either treatment group. The risk difference at 60 months was 0.059 (95% CI, –0.033 to 0.152). The KM curves for OS are provided in Figure 3.

Figure 3: IMROZ Trial KM Curves for OS (ITT Population)

ITT = intention to treat; IVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; KM = Kaplan-Meier; OS = overall survival; VRd = bortezomib-lenalidomide-dexamethasone.

Source: IMROZ Clinical Study Report.³²

The effect of death due to COVID and crossover from the VRd group to the IsaVRd group were tested in sensitivity analyses for OS. In addition, a sensitivity analysis of OS adjusted by the switch to anti-CD38 therapies showed that the stratified HR was 0.837 (95% CI, 0.585 to 1.198) using the rank-preserving structural failure time model and 0.803 (95% CI, 0.557 to 1.158) using the inverse probability of censoring weighting (IPCW) method. These results were consistent with those of the primary analysis.

Clinical Response

Overall Response Rate

Most patients (> 90%) in both treatment groups obtained a tumour response. An ORR (i.e., total patients with stringent CR, CR, VGPR, or PR) were experienced by 167 patients (92.3%) in the VRd group and 242 patients (91.3%) in the IsaVRd group (OR = 0.888; 95% CI, 0.439 to 1.794). Subgroup analyses (e.g., poor prognosis subgroups) were consistent with the primary findings.

Complete Response

The CR rate was statistically significant in favour of IsaVRd (OR = 1.656; 95% CI, 1.097 to 2.500; P = 0.0080) with a CR or better in 74.7% of patients in the IsaVRd group compared with 64.1% of patients in the VRd group.

Very Good Partial Response

The rate of VGPR or better based on IRC assessment was 82.9% in the VRd group and 89.1% in the IsaVRd group (OR = 1.729; 95% CI, 0.994 to 3.008; P = 0.0259). The P value did not cross the multiplicity-adjusted efficacy boundary of 0.025.

MRD Negativity Rate

The MRD negativity rate for patients with a CR was statistically lower in the VRd group (40.9%) compared with the IsaVRd group (55.5%) (OR = 1.803; 95% CI, 1.229 to 2.646; P = 0.0013).

MRD Negativity Rate for Patients With a CR

The percentage of patients with at least 1 evaluable on-treatment sample was lower in the VRd group than in the IsaVRd group (75.7% and 84.2%, respectively) (Table 13). Sensitivity analyses of tipping point analysis and multiple imputations were conducted to assess the impact of missing data in the analysis of MRD negativity rate in patients with a CR or better. These results were consistent with those of the primary analysis.

Time to First Response

In the ITT population, the median TT1R was short in both treatment groups. In the VRd group, the median TT1R by IRC assessment was 1.48 months (95% CI, 1.478 months to 1.511 months) and 1.51 months (95% CI, NC to NC) in the IsaVRd group.

Health-Related Quality of Life

HRQoL was assessed using the EORTC QLQ-C30 tool. More than 90% of patients completed the questionnaire for at least the first 14 cycles and more than 80% of patients did so at each cycle. Results were reported for change from baseline in each treatment group, but no statistical analyses were planned. Figure 4 shows that at most time points, the results of the EORTC QLQ-C30 tool were similar between groups with overlapping CIs.

Figure 4: IMROZ Trial EORTC QLQ-C30 Mean (SD) Scores for GHS QoL Over Time (ITT Population Evaluable)

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EOT = end of treatment; FU = follow-up; GHS = global health status; HRQoL = health-related quality of life; IVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; ITT = intention to treat; QoL = quality of life; SD = standard deviation; VRd = bortezomib-lenalidomide-dexamethasone.

Note: A higher score represents better QoL. Cycles with fewer than 20 patients were not presented. EOT was 30 days after the last study treatment administration. FU was 90 days after the last study treatment administration.

Source: IMROZ Clinical Study Report.³²

Harms

Safety outcomes for the IMROZ trial were reported for the safety population (i.e., all patients who received at least 1 dose of study treatment). A summary of the overall TEAEs experienced by patients in the IMROZ trial is provided in Table 14.

Adverse Events

In the study, 99.6% of patients in the IsaVRd group and 98.3% of patients in the VRd group had at least 1 TEAE; the percentage of patients who had at least a grade 3 AE was 70.7% versus 67.4%, respectively (Table 14). The most common AE in the IsaVRd group was diarrhea; it occurred in 54.8% of patients in the IsaVRd group and 48.6% of patients in the VRd group. Other common AEs in the IsaVRd group versus the VRd group, included peripheral sensory neuropathy (54.4% versus 60.8%), cataracts (38.0% versus 25.4%), constipation (35.7% versus 40.9%), fatigue (34.6% versus 26.5%), and upper respiratory tract infection (34.2% versus 33.7%).

Serious Adverse Events

SAEs occurred in 70.7% of patients in the IsaVRd group and 67.4% of patients in the VRd group (Table 14). The most common SAE was pneumonia (29.7% in the IsaVRd group versus 21.0% in the VRd group).

Withdrawal Due to Adverse Events

Overall, 26.0% of patients in the IsaVRd group and 22.8% of patients in the VRd group had an AE leading to definitive treatment discontinuation, which was defined as discontinuing all treatments (Table 14). The most frequent reason for definitive treatment discontinuation was due to COVID-19 pneumonia (3.0% in the IsaVRd group versus 0.6% in the VRd group).

Deaths

There were 128 deaths recorded in the IMROZ trial; death occurred in 26.2% of patients in the IsaVRd group and 32.6% of patients in the VRd group (Table 14). Death due to disease progression occurred more frequently in the VRd group (12.2%) while death due to an AE occurred more frequently in the IsaVRd group (11.0%).

Notable Harms

Infusion reactions and infections were notable harms of interest to this review. Infusion reactions were more frequent with IsaVRd compared to VRd (23.6% versus 1.1%, respectively). The rate of infections was similar across groups, occurring in 91.3% of patients in the IsaVRd group and 86.7% of patients in the VRd group; they consisted of pneumonia, upper respiratory tract infections, and COVID-19 infections. Among other AESIs in the trial, other than deaths, were primary malignancies, which occurred in 16.0% of patients in the IsaVRd group and 8.8% of patients in the VRd group, with squamous cell carcinoma of the skin being the most common (4.9% in the IsaVRd group versus 2.2% in the VRd group). There were no hematologic malignancies reported in either treatment group. Events of decreased neutrophil count occurred in 30.0% of patients in the IsaVRd group versus 21.5% of patients in the VRd group.

Table 14: Summary of Harms Results From the IMROZ Trial

AE = adverse event; IsaRd = isatuximab-lenalidomide-dexamethasone; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; SAE = serious adverse event; TEAE = treatment-emergent adverse event; VRd = bortezomib-lenalidomide-dexamethasone.

^aTEAEs reported are all-grade TEAEs in at least 20% of patients in either treatment group.

^bSAEs reported are all-grade SAEs in at least 2% of patients in either treatment group.

^cDefinitive treatment discontinuations are all-grade TEAEs leading to definitive treatment discontinuation in 2% or more of patients in either treatment group. Definitive treatment discontinuation is defined as the discontinuation of all study interventions or the last ongoing study drug.

^dTotal deaths during the treatment and posttreatment periods (including the crossover period for patients in the VRd group who switched to IsaRd).

^eOther deaths mainly comprised the primary System Organ Class of infections and infestations (7.2% [n = 13] in the VRd group and 13.7% [n = 36] in the IsaVRd group).

Source: IMROZ Clinical Study Report.³²

Critical Appraisal

Internal Validity

The IMROZ trial was planned with adequate power to meet the goals of the study’s primary outcome (PFS), randomizing 446 patients in a 3:2 ratio to the addition of isatuximab to VRd or VRd only. The assumptions made when performing power calculations were considered reasonable. The randomization method, and allocation concealment, appeared adequate. Further, the randomization was stratified based on important prognostic factors to minimize important differences in baseline characteristics between groups and to allow for the maintenance of randomization for exploratory subgroup analyses based on these baseline characteristics. The use of IRC assessments for the important outcomes provides objectivity to the outcome assessments. There were, however, some limitations and potential sources of bias, which are outlined in this section.

The reported results to date were based on a preplanned second PFS interim analysis (i.e., the date when 167 PFS events [with a 75% information fraction] were expected to be observed in the global population). The interim data cut-off date for these analyses occurred when 162 PFS events had been observed. Interim analyses are typically at risk of overestimating the true magnitude of benefit. However, given the statistical and clinical significance of the difference observed between the IsaVRd and VRd groups, and the relatively large information fraction, this is likely not a major concern. In the analysis of PFS, 18.8% of patients in the VRd group and 23.8% of patients in the IsaVRd group were censored due to not having a valid disease assessment in the 13 weeks before the data cut-off date (i.e., missed 2 or more scheduled disease assessments). Because the reason for missed assessments is not known, there is a potential for the risk of bias due to informative censoring. There was no sensitivity analysis addressing this issue and the direction of potential bias cannot be ascertained. Other sensitivity analyses of the primary end point were supportive of the primary analysis. At the data cut-off date, the OS information fraction was 63%. This is important because while PFS can be viewed as a surrogate for OS, death is not an immediate consequence of treatment failure as further lines of treatment can prolong life. Furthermore, the OS analysis is confounded by crossovers (the risk of bias may be toward the null). To account for this potential bias, the sponsor performed several sensitivity analyses of OS results, including IPCW and rank-preserving structural failure time models. However, these analyses are limited by unverifiable underlying assumptions (i.e., a key assumption of no unmeasured confounding for IPCW and a common treatment effect for IPCW). As the follow-up continues, the potential bias from treatment crossovers may increase, including the use of newer, highly effective therapies that delay death (e.g., chimeric antigen receptor T-cell therapy).

The IMROZ study is open-label, and a lack of blinding may bias results, particularly for subjective, patient-reported outcomes. HRQoL self-reporting and the reporting of more subjective AEs (e.g., injection-related AEs) may also be influenced by a lack of blinding because patients may anticipate known adverse effects of IsaVRd and thus may be more likely to report them when they do occur. Physician knowledge of their patient’s assigned treatment may also affect the way they manage their patient, and patient knowledge of their assigned treatment may make them more or less likely to remain in the study. Objective clinical outcomes such as PFS and OS are less likely to be influenced by a lack of blinding, especially when they are evaluated by a blinded IRC. Assessment of radiological and laboratory-related outcomes (such as ORR) were also conducted by a blinded IRC and therefore would not be less likely to be directly biased from a lack of blinding.

Multiplicity was controlled in the study by using a hierarchical testing procedure. The hierarchy was planned for 4 consecutive analyses following the testing of PFS (CR rate, MRD negativity rate, VGPR or better rate, then OS) and failed at the third analysis. Therefore, as described in the protocol, OS was not formally analyzed and is only expected in the final analysis in 2027. Additionally, the trial was not stratified for most subgroup analyses, and the subgroup analyses were not adjusted for multiplicity or powered to detect effect modification. As such, the conclusions of the subgroup analyses should only be used for hypothesis generation. Even so, the results of most sensitivity and subgroup analyses for the primary outcome, PFS, were generally consistent with the primary analysis supporting the consistency of the effect across subgroups.

By the time of the second interim analysis, most patients had discontinued treatment, mainly due to AEs or PD. This large level of treatment discontinuation may influence any potential comparative evaluation and interpretation of HRQoL and harms outcomes, which were not done in this study. Relatively few patients discontinued the study due to reasons other than death (7.2% in the VRd group and 6.8% in the IsaVRd group). However, the number of patients remaining to complete HRQoL assessments declined over time, resulting in a risk of bias due to missing outcome data given that only complete cases were reported.

External Validity

The IMROZ trial excluded patients older than 80 years and those with an ECOG PS score of greater than 2; however, some patients with an ECOG PS score of 2 or more were enrolled. In a real-world setting, these individuals may be eligible for treatment. The clinical experts noted that the efficacy of VRd in the trial was higher than would normally be expected, which could be the result of a learning curve in jurisdictions that use VRd regularly. For example, in the phase III SWOG S0777 trial, the median PFS for VRd was only 43 months⁴⁰ compared to 54 months in the IMROZ trial. Further, in the IMROZ trial, bortezomib was not dosed at the Canadian and international standard of once weekly. In addition, the most commonly used drug in Canada for this population is based on daratumumab, which was not evaluated in this trial. This brings uncertainty with regard to the anticipated true effect relative to relevant comparators in a Canadian population, but it is expected to be more effective than the historic use of VRd and with a better side-effect profile due to once weekly dosing of bortezomib. Finally, while the IMROZ study was conducted in 96 sites (21 countries), none of the sites were in Canada. As such, data from patients in Canada cannot be directly compared to those of individuals from other countries to determine if the results were homogeneous or if there were uncontrolled factors related to geography or the health care system that could have affected the results, although the clinical experts considered that this may be a minor factor that could affect external validity in the context in Canada.

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 the CDA-AMC expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group^41,42:

• “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.’”

Following the GRADE approach, evidence from the RCT started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or a risk of bias), indirectness, the imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. Certainty in the effects for OS, PFS, and SAEs was based on the presence or absence of any effect because a threshold of clinical importance could not be established. A literature-based minimal important difference was available for HRQoL; however, the difference between groups was not tested statistically. Therefore, a narrative description of the findings was used.

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:

• PFS — median, 18 months, 36 months, and 60 months

• OS — median and 60 months

• HRQoL using the EORTC QLQ-C30 — change from baseline

• individuals with SAEs — up to the data cut-off date.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for IsaVRd versus VRd in patients with newly diagnosed MM.

Long-Term Extension Studies

There is no long-term extension phase planned for the IMROZ trial. The IMROZ trial remains ongoing with an anticipated completion date of June 30, 2027. No other long-term extension studies were included in the submission.

Indirect Evidence

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

Objectives for the Summary of Indirect and Nonrandomized Evidence

Currently, the only head-to-head randomized comparison of IsaVRd is the IMROZ trial. Given that there are several other treatment options in the setting in Canada, and given a recent recommendation by the Formulary Management Expert Committee to prioritize daratumumab, the sponsor submitted an ITC report in which an NMA and unanchored MAICs were conducted for most comparators for the outcomes PFS and OS. The MAICs used individual PLD from the IMROZ study and aggregate data for the comparator studies. Individual PLD were used in both groups in the comparison of IsaVRd (the IMROZ study) and CyBorD (the Flatiron Health database), which were considered as a nonrandomized study and compared using IPW methods.

Description of the ITCs and Nonrandomized Comparison

The sponsor-provided ITC report describes the proposed NMA, MAICs, and nonrandomized comparisons that were performed. A systematic review and feasibility assessment were done to identify studies to include in the ITC, the eligibility criteria for which are summarized in Table 15.

Table 15: Study Selection Criteria and Methods for ITCs Submitted by the Sponsor

ASCO = American Society of Clinical Oncology; ASH = American Society of Hematology; BSH = British Society for Haematology; CDSR = Cochrane Database of Systematic Reviews; CENTRAL = Cochrane Central Register of Controlled Trials; CTd = cyclophosphamide-thalidomide-dexamethasone; CyBorD = cyclophosphamide-bortezomib (Velcade)-dexamethasone; DCyBorD = daratumumab (Darzalex)-cyclophosphamide-bortezomib (Velcade)-dexamethasone; DRd = daratumumab-lenalidomide (Revlimid)-dexamethasone; DVMP = daratumumab-bortezomib (Velcade)-melphalan-prednisone; DVRd = daratumumab (Darzalex)-bortezomib (Velcade)-lenalidomide (Revlimid)-dexamethasone; EHA = European Hematology Association; EKRd = elotuzumab-carfilzomib (Kyprolis)-lenalidomide (Revlimid)-dexamethasone; ERd = elotuzumab-lenalidomide (Revlimid)-dexamethasone; ESMO = European Society for Medical Oncology; HSCT = hematopoietic stem cell transplant; ITC = indirect treatment comparison; IsaVRd = isatuximab (Sarclisa)-bortezomib (Velcade)-lenalidomide (Revlimid)-dexamethasone; MM = multiple myeloma; MPR = melphalan-prednisone-lenalidomide (Revlimid); MPT = melphalan-prednisone-thalidomide; NICE = National Institute for Health and Care Excellence; NMA = network meta-analysis; RCT = randomized controlled trial; Rd = lenalidomide (Revlimid)-dexamethasone; SLR = systematic literature review; Vd = bortezomib (Velcade)-dexamethasone; VMP = bortezomib (Velcade)-melphalan-prednisone; VRd = bortezomib (Velcade)-lenalidomide (Revlimid)-dexamethasone; VTd = bortezomib (Velcade)-thalidomid-dexamethasone.

^aStudies assessing mixed populations with more than 80% of the population of interest or reporting separate subgroup data for the population of interest were included and extracted.

^bMPR and MPT were newly added to the list of included interventions for the SLR update.

Source: Clinical Systematic Literature Review Update for Treatments in Newly Diagnosed Multiple Myeloma.⁴⁴

ITC and Nonrandomized Study Design

Objectives

In the absence of direct comparison between IsaVRd and other available treatments in Canada, the overall aim of the ITC was to estimate the relative efficacy of IsaVRd compared with currently funded alternative treatments (DVMP, DRd, Rd, DCyBorD, and CyBorD) in patients with transplant-ineligible newly diagnosed MM.

Study Selection Methods

Three sources of data informed the ITC analyses. The first source was a systematic literature review (SLR) of RCTs that were used to compare IsaVRd with DVMP, DRd, and Rd in patients with untreated MM. DCyBorD and CyBorD were identified as being used in clinical practice but no RCTs were identified from the clinical SLR to support ITCs. Thus, 2 alternative sources were considered, including PLD from the real-world Flatiron Health Electronic Medical Record database, and a clinical SLR of non-RCTs and observational studies.

The RCT SLR was last updated in April 2024. Bibliographies of key systematic reviews and meta-analysis articles (identified in the update from 2023) were also screened to ensure that the initial searches done by CDA-AMC captured all the relevant clinical studies. Bibliographic searching was also conducted as per the original SLR (from 2023 onward) for the National Institute for Health and Care Excellence (NICE) (including the National Health Services Cancer Drugs Fund), the Scottish Medicines Consortium, the All Wales Medicines Strategy Group, CDA-AMC (including the pan-Canadian Oncology Drug Review), and the Pharmaceutical Benefits Advisory Committee to identify primary publications (i.e., completed trials whose results were available and published as full-text articles reporting primary end points).

To determine the final set of studies eligible for the clinical SLR of non-RCT and observational studies, explicit inclusion and exclusion criteria were applied to the literature search results. The criteria used for the inclusion and exclusion of studies in the systematic review are described in Table 16. These criteria were applied to the literature search results to identify the final set of studies that form the main body of the clinical evidence included in the review update.

Table 16: Inclusion and Exclusion Criteria for the Non-RCT and Observational SLR for the ITCs Submitted by the Sponsor

ASCO = American Society of Clinical Oncology; ASCT = autologous stem cell transplant; BSH = British Society for Haematology; CDA-AMC = Canada’s Drug Agency; CDSR = Cochrane Database of Systematic Reviews; CENTRAL = Cochrane Central Register of Controlled Trials; CyBorD = cyclophosphamide-bortezomib-dexamethasone; DCyBorD = daratumumab-cyclophosphamide-bortezomib-dexamethasone; HSCT = hematopoietic stem cell transplant; ITC = indirect treatment comparison; MM = multiple myeloma; NA = not applicable; OS = overall survival; PFS = progression-free survival; PFS2 = progression-free survival on next line of therapy; RCT = randomized controlled trial; RRMM = relapsed or refractory multiple myeloma; SLR = systematic literature review; SOC = standard of care; Te = transplant-eligible; Ti = transplant-ineligible.

^aStudies assessing mixed populations with more than 80% of the population of interest or reporting separate subgroup data for the population of interest were included and extracted. The studies were retained for information purposes only and the focus of the review in terms of data extraction and reporting of results was studies in the Ti population.

^bNon-English citations that were potentially relevant to the SLR were to be flagged.

Source: Clinical Systematic Literature Review Update for Treatments in Newly Diagnosed Multiple Myeloma.⁴⁴

All retrieved studies were assessed against the eligibility criteria. Primary screening (level 1, title and abstract) and secondary screening (level 2, full text) was conducted by 2 independent reviewers against the eligibility criteria. Any uncertainty regarding the inclusion of a study was checked by a third reviewer. Included studies were categorized according to the transplant status of the study participants (who were newly diagnosed with MM and were transplant-eligible or transplant-ineligible). Studies that included both populations were categorized as “both” and consideration was given as to whether the results of each population were reported separately. Studies were categorized as “unclear” where the transplant eligibility status of participants was not reported. Data were extracted by a single reviewer. All extracted data were quality-checked against the original source article by a second senior reviewer. All included studies were subject to a quality appraisal using the standard NICE checklist as per the original SLR.⁴³ Quality assessment was done by a single independent reviewer and checked by a second senior reviewer.

Feasibility Assessment

A total of 76 RCTs were identified in the SLR; 30 studies included patients who were transplant-eligible, 33 studies included patients who were transplant-ineligible, 6 studies included patients who were both transplant-eligible and transplant-ineligible, and in 7 studies the transplant status was unclear. The 30 studies that included only patients who were transplant-eligible were not further considered (not relevant to the comparison of interest). The feasibility assessment considered the remaining 46 RCTs plus the IMROZ trial (47 studies).

The feasibility of conducting ITCs was based on the connectivity of the evidence base and the evaluation of the plausibility of key assumptions (similarity, homogeneity, and consistency). This was accomplished via qualitative evaluation of the comparability of study design, inclusion and exclusion criteria, treatment regimens, patient demographics, and outcome data. Following review, 31 studies were deemed not suitable for inclusion in ITCs and were excluded based on transplant status (n = 8), a lack of network connectivity (n = 17), study design (n = 4), differences in patient characteristics (n = 1), and a lack of relevant outcome data (n = 1). In total, 16 studies (including the IMROZ study) were deemed suitable for ITCs.

The potential to conduct an NMA was explored. The IMROZ study was connected to the network via the SWOG S0777 study, which compared VRd to Rd. There were potential imbalances in patient characteristics and differences in the administration of bortezomib between the SWOG S0777 study and the IMROZ study. Therefore, it was determined that the inclusion of the SWOG S0777 study to anchor the IMROZ study to the network would likely lead to substantial bias and unreliable relative efficacy estimates for IsaVRd compared to other treatments. As a suitable network of evidence could not be formed for comparisons, an unanchored MAIC (and IPW for the comparison to CyBorD) was deemed the most appropriate approach to assess comparative efficacy for IsaVRd versus relevant comparators.

Summary of Included Studies

SLR of RCTs in patients with untreated MM: Three comparator trials were identified that were deemed relevant suitable for unanchored MAICs — the MAIA study (DRd and Rd), the ALCYONE study (DVMP), and the FIRST study (Rd).

SLR of non-RCTs and observational studies: The SLR identified 1 single-arm study that assessed DCyBorD, in which only PFS data were available. Further, for the comparison with CyBorD, the SLR did not identify any study that was deemed suitable for ITCs. Therefore, RWE was required to fill this gap.

RWE using Flatiron Health data: RWE data from the Flatiron Health database was identified as the most appropriate source for the comparison with CyBorD. The Flatiron Health Electronic Medical Record database is a retrospective, observational cohort study that uses real-world PLD for patients with MM who received VRd and did not receive an ASCT in first-line therapy. The study period was from April 30, 2011, to January 31, 2022. A cohort of patients who underwent VRd followed by lenalidomide maintenance was used to extrapolate survival outcomes.

ITC and Nonrandomized Study Analysis Methods

MAIC Methods

Given that a common comparator was not available between the IMROZ trial and the comparator studies, an unanchored MAIC was required for comparisons between IsaVRd and other treatments. In the analysis, individual patients treated with IsaVRd from the IMROZ trial were assigned statistical weights that adjusted for their over-representation or under-representation relative to the average prognostic factors and treatment effect modifiers observed in each comparative evidence source. These weights were then incorporated into the analyses of PFS and OS outcomes.

IPW Methods

IPW was used to adjust for observed differences in patient characteristics between the IMROZ study population and the patients treated with CyBorD at first-line therapy from the Flatiron Health data source. Propensity scores for patients receiving IsaVRd in the IMROZ study and patients receiving CyBorD from the Flatiron Health data source were derived using logistic regression (known as the propensity score model). Statistical weights were derived for the average treatment effect on the treated estimand, with the target population being patients in the IMROZ study. The final propensity score model adjusted for the following covariates: age (continuous), ECOG PS score (0, 1, 2, or 3), ISS stage (stage I, stage II, stage III, or stage IV), time from MM diagnosis to treatment (continuous), cytogenetic risk (standard or high), and chromosomal abnormality 1q21+ (present or absent). Multiple imputation was used to impute missing baseline characteristics in the Flatiron Health data source, assuming that the data were missing at random.

Comparisons with DCyBorD were informed by aggregate data from a single-arm trial (the Yimer et al. study⁵⁰); the single-arm nature of the Yimer et al. study meant an unanchored MAIC was required. This was the only source of evidence available for DCyBorD. Additionally, only PFS could be analyzed because OS data were not reported.

Identification of Prognostic Factors and Treatment Effect Modifiers

Unanchored MAICs require that all prognostic factors and treatment effect modifiers be adjusted for. The following sources were used to identify prognostic factors and treatment effect modifiers.

• Clinical expertise: Consultations with clinicians indicated that the following characteristics were prognostic and/or effect-modifying for OS and PFS (ranked in descending order of importance) — age, frailty, ISS stage, cytogenetic risk, ECOG PS score, LDH levels, and renal impairment.

• PLD analyses of the IMROZ clinical trial data:

  • PFS subgroup analyses³² conducted in the IMROZ trial indicated that there was some evidence (P value < 0.1) of a difference in the treatment effect across 2 subgroups — MM type IgG and chromosomal abnormality 1q21+

  • Cox proportional hazards models fitted to the IMROZ trial PLD indicated that ISS stage, chromosomal abnormality 1q21+, LDH levels, and creatinine clearance have a statistically significant effect on PFS outcomes.

• PLD analyses of Flatiron Health data: Cox proportional hazards models fitted to the Flatiron Health data identified age, ECOG PS score, ISS stage, cytogenetic risk, and chromosomal abnormality 1q21+ as potential prognostic factors for OS and ISS stage, cytogenetic risk, and chromosomal abnormality 1q21+ as potential prognostic factors for PFS.⁴⁵

Based on the aforementioned details, 9 patient characteristics were considered for adjustment in the MAICs: age, frailty, ISS stage, cytogenetic risk, chromosomal abnormality 1q21+, ECOG PS score, LDH levels, creatinine clearance (a proxy for renal impairment), and MM type IgG. Inclusion of these characteristics in the matching depended on data availability as reported in the clinical trials. Note that frailty was not reported in any comparator study so could not be adjusted for in analyses. Table 17 presents the characteristics included in the matching for each comparator study.

Statistical Analysis Methods

Following the estimation of statistical weights for the MAICs and IPW, adjusted and unadjusted KM curves as well as the mean difference in restricted mean survival time (RMST) were reviewed. Adjusted log-cumulative hazard (LCH) curves, Schoenfeld residual plots, and the Schoenfeld residual test were used to assess the proportional hazards assumption. In all cases, potential violations to the proportional hazards assumption resulted in time-varying models being preferred over constant HR models. Weighted parametric survival models were fit for each of the 7 standard distributions (exponential, gamma, generalized gamma, log-normal, log-logistic, Gompertz, and Weibull) with a multivariate treatment effect parameter. Relative effects were applied to 1 parameter (exponential) or 2 parameters (remaining distributions). A bootstrapping approach was used to estimate time-varying HRs and 95% CIs over time.

In the absence of justification for fitting different parametric models for each group, the same distribution was used for both groups for all comparisons. In the IMROZ trial ITT analysis, the gamma distribution was preferred for modelling PFS and the Gompertz distribution was preferred for modelling OS. For consistency, the same distributions were preferred in this ITC analysis, although all distributions were analyzed.

Table 17: Matching Variables Used in the MAICs

1q21+ = chromosome arm 1q21; CSR = Clinical Study Report; DCyBorD = daratumumab-cyclophosphamide-bortezomib-dexamethasone; DRd = daratumumab-lenalidomide-dexamethasone; DVMP = daratumumab-bortezomib-melphalan-prednisone; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IgG = immunoglobulin G; ISS = International Staging System; LDH = lactate dehydrogenase; MAIC = matching-adjusted indirect comparison; Rd = lenalidomide-dexamethasone.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

Results of ITC and Nonrandomized Study

Results

Overview of Included Studies and Data Sources to Support the ITC and Nonrandomized Study

An overview of the set of studies used to support ITCs between IsaVRd and each of DRd, DVMP, DCyBorD, Rd, and CyBorD is provided in Table 18. An unanchored MAIC was required for comparisons with all treatments except CyBorD, in which IPW was conducted. A summary of the sources of heterogeneity between each trial and the IMROZ study is available in Table 19.

Evidence Networks

Given multiple MAICs were performed to compare IsaVRd and relevant comparators, there are no networks available. Networks were created for NMAs performed as exploratory analyses and are not presented herein.

Table 18: Summary of Data Sources Used for MAIC and IPW

CyBorD = cyclophosphamide-bortezomib-dexamethasone; DCyBorD = daratumumab-cyclophosphamide-bortezomib-dexamethasone; DRd = daratumumab-lenalidomide-dexamethasone; DVMP = daratumumab-bortezomib-melphalan-prednisone; IPW = inverse probability weighting; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; MAIC = matching-adjusted indirect comparison; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial; Rd = lenalidomide-dexamethasone.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

Table 19: Summary of Heterogeneity Between IMROZ Study and Data Sources Used for MAIC and IPW

ASCT = allogeneic stem cell transplant; CyBorD = cyclophosphamide-bortezomib-dexamethasone; DCyBorD = daratumumab-cyclophosphamide-bortezomib-dexamethasone; DRd = daratumumab-lenalidomide-dexamethasone; DVMP = daratumumab-bortezomib-melphalan-prednisone; IPW = inverse probability weighting; ISS = International Staging System; MAIC = matching-adjusted indirect comparison; OS = overall survival; Rd = lenalidomide-dexamethasone; SCT = stem cell transplant; vs. = versus.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

Efficacy

IsaVRd Versus DRd (MAIA Study)

Baseline Characteristics

The unanchored MAIC of IsaVRd compared to DRd using the MAIA study was conducted employing the following matching characteristics: age, ISS stage, ECOG PS score, cytogenetic risk, creatinine clearance, and MM type. Chromosomal abnormality 1q21+, LDH levels, and frailty were not reported in the MAIA study so were not included in the weighting. The effective sample size (ESS) of the weighted IsaVRd population was ███ patients after matching, which is ███ of the original sample size (N = 265).

Table 20 shows the patient baseline characteristics for IsaVRd and DRd before and after matching. Characteristics reported for the MAIC that were not included in the matching included sex, race, and time since diagnosis.

Table 20: Baseline Characteristics Before and After Matching — IsaVRd (IMROZ Study) Versus DRd (MAIA Study)

DRd = daratumumab-lenalidomide-dexamethasone; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ESS = effective sample size; IgG = immunoglobulin G; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; ISS = International Staging System; LDH = lactate dehydrogenase; NR = not reported.

Note: Matching characteristics included age, ISS stage, ECOG PS score, cytogenetic risk, and multiple myeloma type.

^aAssumed based on the median.

^bMissing ISS stage was grouped into ISS stage II because this was the largest group.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

Progression-Free Survival

The MAIC of IsaVRd versus DRd suggests that the relative treatment effect between IsaVRd and DRd is slightly less when adjusting for differences in patient characteristics. This is shown by the smaller difference in the KM curves and the corresponding change in the difference in restricted mean survival from ████ months (95% CI, ████ ██ ████ months) before weighting to ████ months (95% CI, █████ ██ ████ months) after weighting.

Proportional hazards between the adjusted IsaVRd and DRd PFS data were tested using LCH plots and Schoenfeld residual plots. The LCH curves overlapped initially and were not approximately parallel, indicating hazards are nonproportional. This is also reflected in the Schoenfeld plot, which showed a slight arc in the log HR. However, the Schoenfeld test was not statistically significant (P = 0.721). Findings suggest that the proportional hazards assumption may not be valid, meaning a constant HR may provide a biased estimate of the relative treatment effect. As such, time-varying HRs estimated from weighted parametric survival models are preferred.

Associated landmark HRs show an HR of ████ (95% CI, ████ ██ ████) at 1 year and ████ (95% CI, ████ ██ ████) at 5 years (Table 21). Following the end of the IMROZ trial follow-up (5.67 years), the HR was ████ (95% CI, ████ ██ ████). However, the 95% CIs overlap 1 throughout the time period, suggesting no statistically significant treatment effect.

Overall Survival

Similar to PFS, the relative treatment effect between IsaVRd and DRd was reduced following adjustment, shown by the smaller difference in the KM curves and by the smaller difference in restricted mean survival, which reduced from ████ months (95% CI, ████ ██ ████) before matching to ████ months (95% CI, █████ ██ ████) following adjustment.

Similar to PFS, the assessment of LCH and Schoenfeld residual plots showed that the proportional hazards assumption may not be appropriate for OS. As such, constant HRs may be subject to bias and not provide reliable relative effect estimates. Because of this, time-varying HRs estimated from weighted parametric survival models are preferred.

Results for all distributions suggest that IsaVRd provides a lower hazard of death (HR < 1) throughout the entire time period; however, results are not statistically significant. For the Gompertz distribution, the HR decreases linearly over time with an estimated HR of ████ (95% CI, ████ ██ ████) at 1 year and ████ (95% CI, ████ ██ ████) at 5 years (Table 22).

Table 21: Landmark HRs for PFS — IsaVRd (IMROZ Study) Vs. DRd (MAIA Study)

CI = confidence interval; DRd = daratumumab-lenalidomide-dexamethasone; HR = hazard ratio; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; PFS = progression-free survival; vs. = versus.

Notes: An HR of less than 1 indicates a reduced hazard of progression or death for IsaVRd. Bolded values indicate the preferred model.

^aMaximum IMROZ study follow-up.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

Table 22: Landmark HRs for OS — IsaVRd (IMROZ Study) Vs. DRd (MAIA Study)

CI = confidence interval; DRd = daratumumab-lenalidomide-dexamethasone; HR = hazard ratio; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; OS = overall survival; vs. = versus.

Notes: An HR of less than 1 indicates reduced a hazard of death for IsaVRd. Bolded values indicate the preferred distribution.

^aMaximum IMROZ study follow-up.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

IsaVRd Versus DVMP (ALCYONE Study)

Baseline Characteristics

The MAIC for IsaVRd versus DVMP was initially conducted using the following matching characteristics: age, ISS stage, ECOG PS score, cytogenetic risk, MM type, and creatinine clearance. However, the ESS of the weighted population was very low (██ █████████ ████ of the original sample size). Additionally, extreme weights were estimated for some patients (e.g., | ███████ ███ █ ██████ ██ ████). To preserve the ESS, creatinine clearance was excluded from the weighting as it was the variable ranked lowest (of those adjusted for) by clinicians. Additionally, chromosomal abnormality 1q21+, LDH levels, and frailty were not reported in the ALCYONE study, so they were not included in the weighting. The ESS of the weighted IsaVRd population following the exclusion of creatinine clearance was ███ █████████ █████ ██ ███ of the original sample size.

Table 23 shows the patient baseline characteristics before and after matching. Patient populations with respect to the matching variables were well balanced following adjustment. Characteristics reported for the ALCYONE study that were not part of the weighing included sex, race, time since diagnosis, and creatinine clearance. The matched IsaVRd population has a greater proportion of patients who were male, a lower proportion of patients who were white, and a marginally longer time since diagnosis compared with the DVMP population. Creatinine clearance was removed from the analyses to preserve ESS, so there is an imbalance between treatments for this characteristic. The matched IsaVRd population has a greater proportion of patients with creatinine clearance of more than 60 mL per minute compared with the DVMP population.

Progression-Free Survival

The MAIC of IsaVRd versus DVMP suggests that the relative treatment effect between IsaVRd and DVMP is less when adjusting for differences in patient characteristics. This is shown by the smaller difference in the KM curves and the corresponding change in the difference in restricted mean survival from █████ months (95% CI, ████ ██ █████ months) before matching to █████ months (95% CI, ████ ██ █████ months) after matching.

Proportional hazards between the adjusted IsaVRd and DVMP PFS data were tested using LCH plots and Schoenfeld residual plots. The LCH curves overlapped during the █████ ██ ██████ before separating, indicating hazards were nonproportional. This is also reflected in the Schoenfeld plot, which showed the log HR did not form an approximate straight line. However, the Schoenfeld test was not statistically significant (P = 0.687). Overall, findings suggest the proportional hazards assumption may not be valid, meaning a constant HR may provide a biased estimate of the relative treatment effect. As such, time-varying HRs estimated from weighted parametric survival models are preferred.

Results for the gamma distribution suggest IsaVRd provides a lower hazard of progression or death (HR < 1). The HR is estimated to be ████ (95% CI, ████ ██ ████) at 1 year and ████ (95% CI, ████ ██ ████) at 5 years (Table 24).

Overall Survival

The MAIC of IsaVRd versus DVMP suggests that the relative treatment effect between IsaVRd and DVMP is less when adjusting for differences in patient characteristics. This is shown by the smaller difference in the KM curves and the corresponding change in the difference in restricted mean survival from ████ months (95% CI, ████ ██ ████ months) before matching to ████ months (95% CI, █████ ██ ████ months) after matching.

Similar to PFS, the assessment of LCH and Schoenfeld residual plots showed the proportional hazards assumption may also not be appropriate for OS. The LCH curves were not approximately parallel, crossing at approximately ██ ██████ and overlapping from approximately ██ ██████. Furthermore, the Schoenfeld plot showed an arc in the log HR over time, suggesting nonproportional hazards, although the Schoenfeld test was not statistically significant (P = 0.191). As the proportional hazards assumption is questionable, constant HRs may be subject to bias and not provide reliable relative effect estimates. Because of this, time-varying HRs estimated from weighted parametric survival models are preferred.

For the Gompertz distribution, the time-varying HR was monotonically decreasing and tended toward 0 over time. The estimated HR was ████ (95% CI, ████ ██ █████ at 1 year and ████ (95% CI, ████ ██ █████ at 5 years. The extrapolated HR estimates toward the end of the time period are implausible, with an estimate of ████ (95% CI, ████ ██ █████ at 28 years (Table 25).

Table 23: Baseline Characteristics Before and After Matching — IsaVRd (IMROZ Study) Versus DVMP (ALCYONE Study)

DVMP = daratumumab-bortezomib-melphalan-prednisone; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ESS = effective sample size, IgG = immunoglobulin G; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; ISS = International Staging System; LDH = lactate dehydrogenase; NR = not reported.

Note: Matching characteristics included age, ISS stage, ECOG PS score, cytogenetic risk, and multiple myeloma type.

^aMissing ISS stage was grouped into ISS stage II because this was the largest group.

^bAssumed based on the median.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

Table 24: Landmark HRs for PFS — IsaVRd (IMROZ Study) Vs. DVMP (ALCYONE Study)

CI = confidence interval; DVMP = daratumumab-bortezomib-melphalan-prednisone; HR = hazard ratio; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; PFS = progression-free survival; vs. = versus.

Notes: An HR of less than 1 indicates a reduced hazard of death for IsaVRd. Bolded values indicate the preferred distribution.

^aMaximum IMROZ study follow-up.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

Table 25: Landmark HRs for OS — IsaVRd (IMROZ Study) Vs. DVMP (ALCYONE Study)

CI = confidence interval; DVMP = daratumumab-bortezomib-melphalan-prednisone; HR = hazard ratio; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; OS = overall survival; vs. = versus.

Notes: An HR of less than 1 indicates a reduced hazard of death for IsaVRd. Bolded values indicate the preferred distribution.

^aMaximum IMROZ study follow-up.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

IsaVRd Versus DCyBorD

Baseline Characteristics

The MAIC for IsaVRd versus DCyBorD could only be conducted for PFS as OS data were not reported for the Yimer et al. study.⁵⁰ Analyses were conducted using the following matching characteristics: age, ECOG PS score, ISS stage, cytogenetic risk, and MM type. Chromosomal abnormality 1q21+, LDH levels, creatinine clearance levels, and frailty were not reported in the Yimer et al. study, so were not included in the weighting. The ESS of the weighted IsaVRd population was ██ █████████ █████ ██ ███ of the original sample size. In addition, there was evidence of extreme (very high or very low) weights. This low ESS is likely due to the small overlap in cytogenetic risk distributions, where ███ of the IsaVRd population were high-risk compared with ███ in the Yimer et al. study.

Table 26 shows the patient baseline characteristics for IsaVRd and DCyBorD before and after weighting. Patient populations with respect to the matching variables were well balanced following adjustment. Characteristics reported for the Yimer et al. study that were not part of the matching included sex and time since diagnosis. The weighted IsaVRd population had a lower proportion of patients who were male and shorter mean time since diagnosis.

Table 26: Baseline Characteristics Before and After Matching — IsaVRd (IMROZ Study) Versus DCyBorD (Yimer et al. Study⁵⁰)

DCyBorD = daratumumab-cyclophosphamide-bortezomib-dexamethasone; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IgG = immunoglobulin G; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; ISS = International Staging System; LDH = lactate dehydrogenase; NR = not reported.

Notes: Matching characteristics included age, ISS stage, ECOG PS score, cytogenetic risk, and multiple myeloma type.

^aAssumed based on the median.

^bMissing ISS stage was grouped into ISS stage II because this was the largest group.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

Progression-Free Survival

The MAIC of IsaVRd versus DCyBorD suggests that the relative treatment effect between IsaVRd and DCyBorD is greater when adjusting for differences in patient characteristics. This is shown by the larger difference in the KM curves and the corresponding change in the difference in restricted mean survival from ████ months (95% CI, █████ ██ ████ months) before matching to ████ months (95% CI, █████ ██ ████ months) after matching.

Proportional hazards between the adjusted IsaVRd and DCyBorD PFS data were tested using LCH plots and Schoenfeld residual plots. The LCH curves crossed once initially but appeared approximately proportional thereafter. The Schoenfeld plot showed a decreasing log HR over time, suggesting nonproportionality. However, the Schoenfeld test was not statistically significant (P = 0.241). There is some doubt that the proportional hazards assumption may not be valid given the shape of the Schoenfeld plot; however, the LCH curves did not show obvious signs of nonproportional hazards.

Results for the gamma distribution suggest IsaVRd provides a lower hazard of progression or death (HR < 1) over time; however, results are not statistically significant because the 95% CI overlaps 1 throughout time. The HR is estimated to be ████ (95% CI, ██████ ████) at 1 year and ████ (95% CI, ████ ██ █████ at 5 years (Table 27).

Table 27: Landmark HRs for PFS — IsaVRd (IMROZ Study) Vs. DCyBorD (Yimer et al. study⁵⁰)

CI = confidence interval; DCyBorD = daratumumab-cyclophosphamide-bortezomib-dexamethasone; HR = hazard ratio; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; PFS = progression-free survival; vs. = versus.

Notes: An HR of less than 1 indicates a reduced hazard of progression or death for IsaVRd. Bolded values indicate the preferred distribution. Gompertz has been removed due to implausible estimates of survival.

^aMaximum IMROZ study follow-up.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

IsaVRd Versus Rd (MAIA Study)

Baseline Characteristics

For analyses versus Rd using the MAIA study, the following characteristics were adjusted for in analyses: age, ISS stage, ECOG PS score, cytogenetic risk, creatinine clearance, and MM type. Chromosomal abnormality 1q21+, LDH levels, and frailty were not reported in the MAIA study, so were not included in the weighting. The ESS of the weighted IsaVRd population was ███ ████████ after weighting, which is ███ of the original sample size (N = 265). Table 28 shows the patient baseline characteristics for IsaVRd and Rd before and after weighting. Patient populations with respect to the matching variables were well balanced following adjustment. Characteristics reported for the MAIA study that were not included in the weighting included sex, race, and time since diagnosis. Patients receiving IsaVRd and Rd had similar proportions of patients who were male and mean time since diagnosis before and after weighting. Patients receiving Rd had a greater proportion of patients who were white than patients receiving IsaVRd.

Table 28: Baseline Characteristics of IsaVRd and Rd Before and After Matching

ECOG PS = Eastern Cooperative Oncology Group Performance Status; ESS = effective sample size, IgG = immunoglobulin G; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; ISS = International Staging System; LDH = lactate dehydrogenase; NA = not applicable; NR = not reported; Rd = lenalidomide-dexamethasone.

Note: Matching characteristics included age, ISS stage, ECOG PS score, cytogenetic risk, creatinine clearance, and multiple myeloma type.

^aMissing patients were grouped into the largest category.

^bAssumed based on the median.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

Progression-Free Survival

The MAIC of IsaVRd versus Rd suggests that the relative treatment effect between IsaVRd and Rd is slightly less when adjusting for differences in patient characteristics. This is shown by the smaller difference in the KM curves and the difference in restricted mean survival. Following adjustment, the difference in restricted mean survival reduces from █████ months (95% CI, █████ ██ █████ months) before matching to █████ months (95% CI, ████ ██ █████ months) after matching. Proportional hazards between the adjusted IsaVRd and Rd PFS data were tested using LCH plots and Schoenfeld residual plots. The Schoenfeld plot suggests a mostly horizontal log HR with no statistical significance on the Schoenfeld test (P > 0.05); however, the LCH curves cross at approximately | ██████ indicating nonproportional hazards. Therefore, constant HRs may provide a biased estimate of the relative treatment effect. As such, time-varying HRs estimated from weighted parametric survival models are preferred.

Results suggest IsaVRd provides a significantly lower hazard of progression or death (HR < 1). Associated landmark HR estimates show an HR of ████ (95% CI, ████ ██ ████) at 1 year and ████ (95% CI, ████ ██ ████) at 5 years for the gamma distribution (Table 29).

Table 29: Landmark HRs for PFS — IsaVRd (IMROZ Study) Vs. Rd (MAIA Study)

CI = confidence interval; HR = hazard ratio; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; PFS = progression-free survival; Rd = lenalidomide-dexamethasone; vs. = versus.

Notes: An HR of less than 1 indicates a reduced hazard of progression or death for IsaVRd. Bolded values indicate the preferred model.

^aMaximum IMROZ study follow-up.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

Overall Survival

Similar to PFS, the relative treatment effect between IsaVRd and Rd is reduced following adjustment as shown by the smaller difference in KM curves and restricted mean survival. Following adjustment, the difference in restricted mean survival reduced from ████ months (95% CI, ████ ██ █████ months) to ████ months (95% CI, ████ ██ ████ months).

Similar to PFS, the assessment of LCH and Schoenfeld residual plots showed the proportional hazards assumption may not be appropriate for OS. Results suggest a potential violation of the proportional hazards assumption. The Schoenfeld plot suggests a mostly horizontal log HR with no statistical significance on the Schoenfeld test (P > 0.05); however, the LCH curves cross at approximately ██ ██████. As such, constant HRs may provide a biased estimate of the relative treatment effect; time-varying HRs estimated from weighted parametric survival models are preferred.

Landmark HR estimates show an HR of ████ (95% CI, ████ ██ ████) at 1 year and ████ (95% CI, ████ ██ ████) at 5 years (Table 30). The HR for the Gompertz distribution is monotonically decreasing and tends toward 0 at 28 years, meaning results at later time points may be implausible.

Table 30: Landmark HRs for OS — IsaVRd (IMROZ Study) Vs. Rd (MAIA Study)

CI = confidence interval; HR = hazard ratio; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; OS = overall survival; Rd = lenalidomide-dexamethasone; vs. = versus.

Notes: An HR of less than 1 indicates a reduced hazard of death for IsaVRd. Bolded values indicate the preferred distribution.

^aMaximum IMROZ study follow-up.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

IsaVRd Versus Rd (FIRST Study)

Baseline Characteristics

For analyses versus Rd using the FIRST study, the following characteristics were adjusted for in analyses: age, ISS stage, ECOG PS score, cytogenetic risk, creatinine clearance, MM type, and LDH level. Chromosomal abnormality 1q21+ and frailty were not reported in the FIRST study, so they were not included in the weighting. The ESS of the weighted IsaVRd population was ███ █████████ ███ of the original sample size (N = 265). Table 31 shows the patient baseline characteristics for IsaVRd and Rd before and after weighting. Patient populations with respect to the matching variables were well balanced following adjustment. Characteristics reported for the FIRST study that were not used in the weighting included sex. The IsaVRd and Rd patients had similar proportions of male patients before and after weighting.

Table 31: Baseline Characteristics of IsaVRd and Rd Before and After Matching

ECOG PS = Eastern Cooperative Oncology Group Performance Status; ESS = effective sample size, IgG = immunoglobulin G; IsaVRd = isatuximab-bortezomib-lenalidomide-dexamethasone; ISS = International Staging System; LDH = lactate dehydrogenase; NR = not reported; Rd = lenalidomide-dexamethasone.

Note: Matching characteristics included age, ISS stage, ECOG PS score, cytogenetic risk, creatinine clearance, and multiple myeloma type.

^aMissing patients were grouped into the largest category.

^bAssumed based on the median.

Source: Indirect Treatment Comparisons for Isatuximab Combined with Bortezomib, Lenalidomide and Dexamethasone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma.⁴⁶

Progression-Free Survival

The relative treatment effect between IsaVRd and Rd reduces when adjusting for differences in patient characteristics, shown by the smaller difference in the KM curves. The difference in RMST following adjustment decreases from ██ months (95% CI, █████ ██ █████ months) to █████ months (95% CI, █████ ██ █████ months).

Proportional hazards between the adjusted IsaVRd and Rd PFS data were tested using LCH plots and Schoenfeld residual plots. Results suggest a potential violation of the proportional hazards assumption. The Schoenfeld plot suggests a mostly horizontal log HR with no statistical significance on the Schoenfeld test (P > 0.05); however, the LCH curves cross up to approximately | ██████. Therefore, constant HRs may provide a biased estimate of the relative treatment effect. As such, time-varying HRs estimated from weighted parametric survival models are preferred.

Results suggest IsaVRd provides a significantly lower hazard of progression or death (HR < 1). Associated landmark HR estimates (Table 32) show an HR of ████ (95% CI, ████ ██ ████) at 1 year and ████ (95% CI, ████ ██ ████) at 5 years for the gamma distribution.

Overall Survival

Similar to PFS, the relative treatment effect between IsaVRd and Rd is reduced following adjustment, as shown by the KM curve and the difference in RMST. Following adjustment, the difference in RMST reduced from ████ months (95% CI, ████ ██ █████ months) to ████ months (95% CI, ████ ██ █████ months).

Proportional hazards between the adjusted IsaVRd and Rd PFS data were tested using LCH plots and Schoenfeld residual plots. Results suggest a potential violation of the proportional hazards assumption. The Schoenfeld plot suggests a mostly horizontal log HR with no statistical significance on the Schoenfeld test (P > 0.05); however, the LCH curves are not parallel throughout the time period. Therefore, constant HRs may provide a biased estimate of the relative treatment effect. As such, time-varying HRs estimated from weighted parametric survival models are preferred.

Landmark HR estimates (Table 33) show an HR of ████ (95% CI, █████ ████) at 1 year and ████ (95% CI, █████ ████) at 5 years for the Gompertz distribution. The HR for the Gompertz distribution is monotonically decreasing, meaning results at later time points may be implausible.

Table 32: Landmark HRs for PFS — IsaVRd (IMROZ Study) Vs. Rd (FIRST Study)