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

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).