Efficacy and safety of daratumumab-based quadruplet therapy vs non-daratumumab-based triplet therapy in newly diagnosed multiple myeloma patients: A GRADE assessed systematic review and meta-analysis of randomized controlled trials

Abstract

Background Multiple myeloma (MM) is the second most common hematologic malignancy worldwide. Recent therapeutic innovations, including the addition of daratumumab to standard regimens, have shown promising improvements in patient outcomes. Objectives This study aims to compare the efficacy and safety of daratumumab-based quadruplet therapy regimens with standard triplet therapy regimens in newly diagnosed multiple myeloma (NDMM) patients. Design Systematic review and meta-analysis of randomized controlled trials. Data sources and Methods A comprehensive literature search was conducted on PubMed, Cochrane Library, Embase, and ClinicalTrials.gov from inception to April 2026. Primary outcomes were Progression-free survival (PFS) and Minimal residual disease (MRD) negativity. Subgroup analysis based on cytogenetic risk was performed. The statistical assessment was done using The Review Manager (RevMan, Version 5.4). Results Our meta-analysis included 7 RCTs, comprising 3 studies in transplant-eligible multiple myeloma (TE-MM) and 4 in transplant-ineligible multiple myeloma (TIE-MM) patients, containing 3,443 patients (1,759 in the daratumumab group and 1684 in the non-daratumumab group). The median age across studies ranged from approximately 59 to 76 years. Daratumumab-based therapy demonstrated significantly higher PFS (HR 0.50, 95%CI: 0.43- 0.58, p < 0.00001). The analysis showed statistically significant high MRD negativity with daratumumab based quadruplet therapy compared to non-Dara triplet arm (RR 1.99, 95%CI 1.59-2.50, P<0.00001). Subgroup analysis based on cytogenetic risk demonstrated significant improved PFS in standard-risk (HR 0.45) as well as high-risk (HR 0.67), whereas MRD negativity increased significantly only in standard-risk (RR 1.76) but not high-risk (RR 1.23). Daratumumab-based quadruplet therapy was associated with increased neutropenia (56.2% vs 40.3%), thrombocytopenia (40.7% vs 32.5%), and infections (33.1% vs 23.3%). Conclusion The meta-analysis shows higher efficacy yet higher adverse events in Daratumumab-based quadruplet therapy for NDMM patients (TE, and TIE).