Anti-CD38-based quadruplet versus triplet induction regimens in transplant-ineligible newly diagnosed multiple myeloma: A systematic review and meta-analysis

Abstract Introduction Triplet induction therapy with either daratumumab, lenalidomide, and dexamethasone (D-Rd) or bortezomib, lenalidomide, and dexamethasone (VRd) has long been the standard of care for transplant-ineligible patients with newly diagnosed multiple myeloma (TIE-NDMM). In recent years, anti-CD38-containing quadruplet induction regimens have increasingly been adopted as frontline therapies, with studies indicating their potentials to enhance treatment responses and improve survival outcomes. This meta-analysis aims to evaluate the efficacy and safety of these quadruplet regimens as initial treatment for this population. Methods We conducted a comprehensive literature search across PubMed, Embase, and Cochrane databases from inception to April 30, 2025. Included studies consisted of randomized controlled trials (RCTs) comparing anti-CD38-based quadruplet induction regimens to triplet induction regimens among TIE-NDMM patients. Outcomes of interest were progression free survival (PFS), overall survival (OS), rates of minimal residual disease (MRD) negativity, rates of stringent complete response and complete response (sCR/CR), rates of very good partial response (VGPR) or better, overall response rates (ORR), rates of severe adverse events (SAEs), grade 3 to 4 infections, neutropenia and thrombocytopenia. Statistical analyses were performed using Review Manager version 5.4.1. Heterogeneity was assessed using Cochran's Q test and I² statistics. Results A total of six RCTs involving 2,023 patients were identified, with sample sizes ranging from 121 to 706 participants and median follow-up durations between 34 and 59.7 months. 1088 participants received quadruplet induction while 935 received triplet induction. The quadruplet regimens comprised an anti-CD38 monoclonal antibody (daratumumab or isatuximab), a proteasome inhibitor (bortezomib or carfilzomib), an immunomodulatory drug (lenalidomide) or alkylator (melphalan or cyclophosphamide), and a corticosteroid. Triplet regimens consisted of the same backbone without the anti-CD38 agent. Quadruplet induction regimens significantly improved PFS (HR 0.49, 95% CI 0.39-0.61, P<0.00001, I²=56%) and OS (HR 0.63, 95% CI 0.52-0.76, P<0.00001, I²=0%) compared to triplet regimens. Quadruplets were associated with enhanced rates of MRD negativity at a threshold of 10⁻⁵ (RR 1.97, 95% CI 1.29-2.99, P=0.002, I²=92%), rates of sCR/CR (RR 1.46, 95% CI 1.01-1.98, P=0.02, I²=90%) and VGPR or better (RR 1.33, 95% CI 1.10-1.61, P=0.003, I²=88%). ORR was similar between patients receiving quadruplets and triplets (RR 1.12; 95% CI 1.00-1.26, P=0.04, I²=86%). There was a slight increase in the rates of SAEs (RR 1.14, 95% CI 1.01-1.29, P=0.03, I²=17%) and grade 3 to 4 infections (RR 1.36, 95% CI 1.14-1.6, P=0.0004, I²=0%) associated with quadruplets. There were no significant differences in the rates of grade 3-4 neutropenia (RR 1.23, 95% CI 0.97-1.74, I²=87%) and thrombocytopenia (RR 0.99, 95% CI 0.86-1.14, I²=0%) between the two groups. A subgroup analysis of frail patients revealed that the benefits of quadruplet therapy extend to this population, with significant improvements in both PFS (HR 0.51, 95% CI 0.4-0.65, P<0.0001, I²=0%) and OS (HR 0.69, 95% CI 0.51-0.93, P=0.02, I²=0%). Conclusion Our study provides compelling evidence that anti-CD38-based quadruplet induction regimens are a more effective upfront treatment option compared to triplet regimens for TIE-NDMM patients, demonstrating improvements in PFS, OS, MRD negativity, rates of sCR/CR, and VGPR, with manageable safety concerns. While quadruplet regimens were associated with higher rates of SAEs and grade 3-4 infections, no significant differences were observed in the rates of grade 3-4 neutropenia or thrombocytopenia. Careful patient selection is essential to optimize outcomes and mitigate treatment-related toxicity.