The introduction of anti-CD38 monoclonal antibodies (mAb) has significantly advanced treatment of multiple myeloma (MM). Both daratumumab (D) and isatuximab (I) have demonstrated substantial efficacy and improved outcomes in newly diagnosed and relapsed/refractory MM. Although widely evaluated with similar backbone regimens, direct comparative evidence between these agents remains unavailable. In the absence of head-to-head trials, network meta-analysis (NMA) provides a rigorous framework for indirect comparisons to support evidence-based selection of CD38-targeted strategies.

We conducted a systematic review (SR) and NMA of randomized clinical trials (RCT) to compare efficacy and survival outcomes of daratumumab- versus isatuximab-based regimens in MM.

A structured search of Cochrane Library, Embase, Google Scholar, Medline, PubMed, Scopus, Web of Science, clinical trial registries, and major conference abstracts (2022–2025) was performed in January 2025. Eligible phase II/III RCT evaluated either antibody in combination with a shared therapeutic backbone and reporting progression-free survival (PFS) as endpoint. Two authors extracted and quality-checked data. We estimated hazard ratios (HR) for PFS and overall survival (OS) using a frequentist NMA model based on aggregate-level data, for each indirect comparison between regimens sharing a common backbone. Subsequently, we pooled the results using a random-effect model to summarize the overall treatment effect. Heterogeneity was assessed using Cochran's Q and I2 statistics.

Six phase III trials comprising 2,587 patients met inclusion criteria. To enable an indirect comparison between D and I, studies were grouped into three networks based on identical backbone regimens: carfilzomib and dexamethasone (Kd), pomalidomide and dexamethasone (Pd), and bortezomib, lenalidomide and dexamethasone (VRd). No significant differences in PFS were observed across regimens: D-Kd vs. I-Kd (HR 1.10, 95% CI: 0.73–1.66), D-Pd vs. I-Pd (HR 1.11, 95% CI: 0.75–1.63), and D-VRd vs. I- VRd (HR 0.95, 95% CI: 0.60–1.49). Similarly, no differences in OS were detected: D-Kd vs. I-Kd (HR 0.91, 95% CI: 0.59–1.40), D-Pd vs. I-Pd (HR 1.05, 95% CI: 0.70–1.58), and D-VRd vs. I-VRd (HR 1.09, 95% CI: 0.65–1.82). In the pooled analysis, no significant differences were found between daratumumab- and isatuximab-based regimens for either PFS (HR 1.06, 95% CI: 0.86–1.30; p = 0.36) or OS (HR 1.01, 95% CI: 0.79–1.28; p = 0.91). Heterogeneity was low in both analyses (PFS: Cochran's Q, p = 0.86; I2 = 0%; and OS: Cochran's Q, p = 0.84; I2 = 0%). Risk of bias was low across all studies, and effect modifiers were sufficiently balanced to support transitivity.

This is the first NMA to indirectly compare daratumumab and isatuximab in MM using RCT-level evidence. In absence of significant differences in PFS or OS between these two anti-CD38 mAbs, therapeutic choice should be based on factors other than efficacy. Protocol Registration: CRD420250618823.