# Efficacy and Safety of Isatuximab Combination Therapy in Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials

## TL;DR

This study confirms that isatuximab, when combined with standard treatments, delays cancer progression in multiple myeloma patients and is generally safe.

## Contribution

The study provides a comprehensive meta-analysis of isatuximab's efficacy and safety in both newly diagnosed and relapsed multiple myeloma.

## Key findings

- Isatuximab significantly improves progression-free survival in both newly diagnosed and relapsed multiple myeloma patients.
- The treatment increases minimal residual disease negativity rates, especially in relapsed patients.
- Grade ≥ 3 adverse events are more common in relapsed patients, mainly due to neutropenia and pneumonia.

## Abstract

Multiple myeloma is a type of blood cancer that often returns after initial treatment, creating a need for more effective therapies. Isatuximab is a newer antibody drug that helps the patient’s own immune system attack the cancer cells. While several clinical trials have shown that adding isatuximab to standard treatments can be beneficial, the overall picture from these individual studies can be unclear. Our research combined the results of all relevant high-quality trials to provide a definitive answer. We found that treatment regimens containing isatuximab significantly delay cancer progression and lead to deeper responses in both newly diagnosed and relapsed patients, with side effects that are generally manageable. This analysis helps confirm the value of isatuximab, giving doctors and patients greater confidence in using it as part of their treatment strategy.

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.