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    Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)

    Category: Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)

    A Network Meta-Analysis of Randomized Clinical Trials Comparing the Efficacy of Daratumumab Versus Isatuximab in the Treatment of Multiple Myeloma

    (PA-436) A Network Meta-Analysis of Randomized Clinical Trials Comparing the Efficacy of Daratumumab Versus Isatuximab in the Treatment of Multiple Myeloma

    Thursday, September 18, 2025
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    Introduction: 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.

    Methods: 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.

    Results: 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.

    Conclusions: 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.