Abstract
Introduction: Frontline therapy for transplant-ineligible newly diagnosed multiple myeloma (TI-NDMM) has evolved significantly. Although triplet regimens have long constituted the standard of care, recent quadruplet combinations incorporating anti-CD38 monoclonal antibodies (mAb), daratumumab and isatuximab, have demonstrated improved response rates and progression-free survival (PFS). However, the impact on long-term outcomes, particularly overall survival (OS), remains uncertain.
Methods: We conducted a systematic review, network meta-analysis (NMA), and reconstructed individual patient data meta-analysis (RIPDMA) to evaluate survival outcomes of quadruplet versus triplet lenalidomide-containing regimens in TI-NDMM. This study adhered to Cochrane and PRISMA guidelines and was prospectively registered on 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. The NMA employed a frequentist random-effects model with P-scores for treatment ranking. Individual patient data were reconstructed from published Kaplan-Meier curves using the IPDfromKM method to enable pooled survival analyses. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were calculated to estimate comparative efficacy. Statistical analyses, along with forest plots and pooled survival curves, were conducted using and R Statistical Software (version 4.4.1).
Results: Four RCT (CEPHEUS, IMROZ, MAIA, SWOG S0777) comprising 2,038 patients were included: D-VRd (n=197), I-VRd (n=265), D-Rd (n=368), VRd (n=614), and Rd (n=598). Median follow-up ranged from 58.7 to 89.3 months. Estimated 60-month 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 vs. D-Rd (HR 0.65, 95% CI 0.48–0.87, P=0.003; and HR 0.68, 95% CI 0.52–0.89, P=0.004) and vs. VRd (HR 0.51, 95% CI 0.39–0.67, P<0.0001; and HR 0.53, 95% CI 0.41–0.67, P<0.0001). 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%). When analyzed as grouped strategies, quadruplets achieved significantly superior outcomes at 60 months compared with triplets, with higher PFS (64.7% vs. 46.3%) and OS (72.5% vs. 67.1%). Pooled analysis confirmed improved PFS (HR 0.57, 95% CI 0.47–0.69, P<0.0001) and OS (HR 0.78, 95% CI 0.63–0.96, P=0.02) for quadruplets. The OS benefit of quadruplets remained consistent when compared with each triplet regimen: against D-Rd (HR 0.77; 95% CI: 0.60–0.98; P=0.04) and against VRd (HR 0.77; 95% CI: 0.62–0.97; P=0.02). In a sensitivity analysis excluding patients aged <65 years from SWOG S0777 and those who deferred transplant in CEPHEUS, the OS advantage of quadruplet regimens persisted (73.5% vs. 65.4%; HR 0.69, 95% CI 0.55–0.87; P = 0.001). Robustness analyses confirmed the OS benefit, with bootstrap-derived HR (0.64; 95% CI 0.62–0.83) aligning with the primary estimate and minimal impact observed in leave-one-out analyses. In the NMA, D-VRd and I-VRd ranked highest in probability of achieving complete response or better (P-scores: 0.9876 and 0.7318), PFS (0.8668 and 0.8114), and OS (0.7043 and 0.8328).
Conclusions: This meta-analysis provides the first comprehensive comparative assessment of anti-CD38-mAb based quadruplet versus triplet regimens in TI-NDMM, demonstrating a significant overall survival advantage and supporting quadruplet regimens as the most effective frontline treatment.
