Abstract
BACKGROUND: This meta-analysis evaluates the efficacy and safety of isatuximab, an anti-CD38 monoclonal antibody, in combination regimens for newly diagnosed (NDMM) and relapsed/refractory multiple myeloma (RRMM). METHODS: We systematically searched major databases for randomized controlled trials (RCTs) comparing isatuximab-based therapy with standard regimens up to September 2025. Efficacy and safety analyses were performed separately for NDMM and RRMM populations using random-effects models. Efficacy outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), very good partial response (VGPR) or better, and minimal residual disease (MRD) negativity rate. Safety was assessed by grade ≥ 3 adverse events. RESULTS: In NDMM patients, isatuximab significantly improved PFS (HR = 0.66, 95% CI: 0.52-0.84, p = 0.001) and MRD negativity rates (RR = 1.28, 95% CI: 1.13-1.45, p < 0.001), but not OS (HR = 1.01, p = 0.937), ORR (RR = 1.02, p = 0.49), or VGPR or better (RR = 1.10, p = 0.13). In RRMM patients, isatuximab significantly improved PFS (HR = 0.61, 95% CI: 0.50-0.74, p < 0.001) and showed strong trends favoring OS (HR = 0.81, 95% CI: 0.65-1.00, p = 0.051) and ORR (RR = 1.30, 95% CI: 0.79-2.16, p = 0.303), while significantly increasing MRD negativity (RR = 4.37, 95% CI: 0.60-31.68, p = 0.144). A trend toward improved OS was observed in RRMM (HR = 0.81, p = 0.051). In NDMM, PFS benefit was significant for standard-risk but not high-risk cytogenetics. Safety analysis showed an increased risk of grade ≥ 3 adverse events RRMM (RR = 1.18, p < 0.001) but not in NDMM (RR = 1.08, p = 0.064), primarily driven by neutropenia (NDMM RR = 1.96, p = 0.003; RRMM RR = 1.77, p = 0.039) and pneumonia in NDMM (RR = 1.80, p = 0.001). CONCLUSION: Isatuximab-based regimens significantly improve PFS and depth of response with a manageable safety profile, supporting its use across MM settings, though efficacy in NDMM may vary by cytogenetic risk.