Abstract
Frontline therapy for transplant-ineligible newly diagnosed multiple myeloma (TI-NDMM) has advanced with anti-CD38 monoclonal antibody (mAb)-based regimens. Although quadruplet combinations incorporating daratumumab and isatuximab have demonstrated improved response rates and progression-free survival (PFS), comparative overall survival (OS) data remain limited. We performed a systematic review, network meta-analysis (NMA), and reconstructed individual patient data meta-analysis comparing survival outcomes of quadruplet versus triplet regimens in TI-NDMM. This study adhered to Cochrane and PRISMA guidelines and was registered prospectively (PROSPERO CRD420251033401). A comprehensive literature search through April 2025 identified randomized clinical trials (RCT) evaluating quadruplet and triplet regimens involving daratumumab, isatuximab, bortezomib, lenalidomide, and dexamethasone in any combination, compared to their backbone regimens, reporting OS and PFS. Four RCT (n = 2,038) were included. At 60 months, estimated PFS rates were: D-VRd (66.4%), I-VRd (63.2%), D-Rd (51.9%), and VRd (42.6%). Both D-VRd and I-VRd significantly improved PFS compared with D-Rd (HR 0.65; 95% CI 0.48-0.87; and HR 0.68; 95% CI 0.52-0.89) and VRd (HR 0.51; 95% CI 0.39-0.67; and HR 0.53; 95% CI 0.41-0.67). D-Rd also showed superior PFS over VRd (HR 0.77, 95% CI 0.64-0.93; P = 0.007). At 60 months, OS rates were: D-VRd (72.8%), I-VRd (72.2%), D-Rd (67.1%), and VRd (67.0%). Pooled analyses demonstrated that quadruplets significantly improved both PFS (64.7% vs. 46.3%; HR 0.57, 95% CI 0.47-0.69; P < 0.0001) and OS (72.5% vs. 67.1%; HR 0.78, 95% CI 0.63-0.96; P = 0.02) compared to triplet regimens. The OS benefit of quadruplets was consistent in comparisons against both D-Rd (HR 0.77; 95% CI: 0.60-0.98; P = 0.04) and VRd (HR 0.77; 95% CI: 0.62-0.97; P = 0.02). In the NMA, quadruplet regimens ranked highest for complete response, PFS, and OS. This meta-analysis supports anti-CD38 mAb-based quadruplet regimens as superior frontline therapy in TI-NDMM, significantly improving overall survival.