Efficacy of Isatuximab Combination Regimens in Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials
Authors: Aboaid Hazem , Srinivasmurthy Ramaditya , Jones Daniel Thomas , Nguyen Kevin , Nanda Rishi Kumar , Thein Kyaw Zin , Htut Thura Win 
Published: December 2024

Introduction:
Treatment paradigm for multiple myeloma (MM) has evolved rapidly since the introduction of anti-CD 38 monoclonal antibody, isatuximab. Previously, the studies and meta-analysis demonstrated the effectiveness of isatuximab combination therapies in patients with relapsed and refractory MM. The purpose of this analysis is to explore and consolidate the efficacy of isatuximab combination regimens in patients with newly diagnosed MM.
Methods:
We systematically conducted a comprehensive literature search using MEDLINE, EMBASE, and COCHRANE databases and from inception through July 22nd, 2024. Phase III RCTs utilizing isatuximab in patients with newly diagnosed multiple myeloma (NDMM) were incorporated in the analysis. We also performed a subgroup analysis to evaluate the efficacy of isatuximab in patients with NDMM who were transplant ineligible (TI). Mantel-Haenszel (MH) method was used to calculate the estimated pooled odd ratios (OR) for minimal residual disease (MRD) negativity and/ or complete response (CR) as well as very good partial response (VGPR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects models were applied.
Results:
A total of 1376 patients from 3 phase III RCTs were eligible (transplant-ineligible patients with NDMM from BENEFIT and IMROZ trials + transplant-eligible [TE] patients with NDMM from GMMG-HD7 trial). IMROZ and GMMG-HD7 both compared isatuximab (Isa) + bortezomib (V) + lenalidomide (R) + dexamethasone (d) vs VRd. BENEFIT compared Isa-Rd vs Isa-VRd, Isa-VRd was considered as the isatuximab (experimental) group and Isa-Rd was considered as the control group. Randomization ratios were 1:1 in BENEFIT and GMMG-HD7 studies, and 3:2 in IMROZ study. The efficacy parameters included MRD negativity, CR or better (≥ CR), VGPR or better (≥ VGPR), and ≥CR with MRD negativity. Odds ratio (OR) for MRD negativity in NDMM was statistically significant at 2.21 (95% CI: 1.47-3.33; P=0.0001). The benefit of MRD negativity was also observed in the TI cohort (OR, 2.56; 95% CI: 1.22-5.36; P=0.01). OR for ≥ CR in NDMM was not statistically significant at 1.78 (95% CI: 0.99-3.18; P=0.05), however, it was statistically significant in the TI cohort (OR, 2.35; 95% CI: 1.08-5.11; P=0.03). OR for ≥ VGPR was statistically significant in both NDMM overall and TI cohort at 1.98 (95% CI: 1.53-2.56; P=&lt;0.00001) and 1.79 (95% CI: 1.21-2.66; P=0.004), respectively. Achieving ≥ CR with MRD negativity was higher in the isatuximab group in both NDMM overall and TI cohort with OR at 1.80 (95% CI: 1.21-2.69; P=0.004) and 2.21 (95% CI: 1.25-3.91; P=0.006), respectively.
Conclusion:
Isatuximab based combination regimens significantly improved achieving MRD negativity, VGPR or better, andCR or better with MRD negativity compared to the control arm in patients with NDMM in general and in the TI subgroup. The benefit of achieving CR or better was only statistically significant in the TI cohort. More studies are necessary to explore further novel agents and to formulate optimal combination regimen to improvethe rates of CR or better in all patients with NDMM regardless of their eligibility for autologous stem cell transplant.