Efficacy of Isatuximab Combination Regimens in Patients with Relapsed and Refractory Multiple Myeloma: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Abstract

Introduction: Management of relapsed refractory multiple myeloma (RRMM), which accounts for 1% of all cancers, is an area in dire need of therapeutic innovation. In recent years, the introduction of anti-CD 38 monoclonal antibody is one of the major advances in the management of patients with multiple myeloma both in newly diagnosed and relapsed refractory settings. Isatuximab is an anti-CD38 antibody recently approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone for RRMM. The purpose of our study is to explore and consolidate the efficacy of isatuximab combination regimens in patients with RRMM. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing isatuximab in patients with relapsed or refractory multiple myeloma were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratios (RR) for overall progression free survival (PFS) and PFS in different subgroups based on cytogenetics, del (17 p) or t (4,14) statuses, overall survival (OS), overall response rate (ORR), including MRD negativity and complete response (CR). Heterogeneity was assessed with Cochran's Q -statistic. Fixed and random effects models were applied in assessing PFS, OS, and ORR, CR and MRD negativity. Results: Two phase III RCTs (ICARIA-MM and IKEMA) including a total of 609 patients with RRMM were eligible. ICARIA-MM and IKEMA compared isatuximab (I) + pomalidomide (P) + dexamethasone (d) vs Pd, and isatuximab (I) + Carfilzomib (K) + dexamethasone (d) vs Kd respectively. The randomization ratios were 1:1 in ICARIA-MM, and 3:2 in IKEMA studies. Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. The pooled HR for overall PFS was statistically significant at 0.59 (95% CI: 0.47-0.73; P < 0.00001). The PFS benefit was observed in different subgroups of cytogenetics, del (17 p) and t(4,14) statues; non-high-risk cytogenetic cohort (HR, 0.55; 95% CI: 0.40- 0.75; P = 0.0001), non del (17 p) cohort (HR, 0.55; 95% CI: 0.41- 0.72; P < 0.0001), t(4,14) cohort (HR, 0.52; 95% CI: 0.28- 1.0; P = 0.05), and non t(4,14) cohort (HR, 0.54; 95% CI: 0.41- 0.72; P < 0.0001). The pooled HR for PFS was not statistically significant in high-risk cytogenetic cohort at 0.68 (95% CI: 0.42- 1.11; P = 0.13) and del (17 p) cohort at 0.79 (95% CI: 0.39- 1.60; P = 0.52). The pooled HR for OS was 0.77 (95% CI: 0.61- 0.96; P = 0.02). The pooled RRs for ORR, MRD negativity and CR were not statistically significant at 1.39 (95% CI: 0.69-2.82; P = 0.36), 1.02 (95% CI: 0.24-4.33; P = 0.98), and 2.29 (95% CI: 0.8-6.51; P = 0.12). Conclusions: Isatuximab based combination regimens significantly improved overall PFS and OS compared to control arm in patients with RRMM while benefits to ORR, MRD negativity and CR were not statistically significant. The improvement in PFS was noted in non-high-risk cytogenetic, non t(4,14), and non del (17p) cohorts and there was a trend towards PFS benefit in t(4,14) cohort. However, there were no PFS benefits in high-risk cytogenetic and del (17p) cohorts. More randomized studies are required to explore further novel agents and to formulate optimal combination regimen to improve survival in these high-risk cytogenetic and del (17p) subsets.