Safety and efficacy of daratumumab plus bortezomib, lenalidomide, and dexamethasone (D-VRd) vs bortezomib, lenalidomide, and dexamethasone (VRd) in patients with multiple myeloma: A systematic review and meta-analysis.

Abstract Background Bortezomib, lenalidomide, and dexamethasone (VRd) remains a cornerstone in the treatment of multiple myeloma. Incorporating daratumumab into frontline therapy (D-VRd) has shown promising results in improving disease control. This systematic review and meta-analysis evaluates the safety and efficacy of D-VRd versus VRd in patients with multiple myeloma. Methods A comprehensive search of PubMed, Embase, and Cochrane CENTRAL databases was conducted from inception to July 2025. We included three randomized controlled trials (RCTs) and one retrospective cohort study comparing D-VRd to VRd in newly diagnosed patients of multiple myeloma patients. Primary outcomes included progression-free survival (PFS), minimal residual disease (MRD) negativity, and complete response (CR) rates. Secondary outcomes included grade 3–4 hematologic adverse events. Data were synthesized using Review Manager (RevMan) version 5.4, employing a random-effects model. Results A total of 2,637 patients were included across all studies, with 982 patients receiving Daratumumab-VRD (D-VRD) and 1,655 receiving VRD alone. D-VRD significantly improved progression-free survival (PFS) compared to VRD, with a pooled Hazard ratio (HR) of 2.50 [95% CI: 2.01–3.11], p < 0.00001, and no observed heterogeneity (I² = 0%). No statistically significant difference was observed in complete response (CR) rates between the two groups, with a pooled risk ratio (RR) of 0.89 [95% CI: 0.56–1.44], p = 0.64, and substantial heterogeneity (I² = 97%). Minimal residual disease (MRD) negativity was significantly higher in the D-VRD group, with a pooled RR of 1.98 [95% CI: 1.49–2.62], p < 0.00001, and moderate heterogeneity (I² = 74%). The incidence of grade 3–4 neutropenia was significantly increased with D-VRD (RR: 1.64 [95% CI: 1.34–2.01], p < 0.00001; I² = 0%), as was grade 3–4 thrombocytopenia (RR: 1.60 [95% CI: 1.29–1.98], p < 0.00001; I² = 0%). However, there was no significant difference in grade 3–4 anemia between groups (RR: 1.09 [95% CI: 0.76–1.57], p = 0.62; I² = 0%). Conclusion D-VRD significantly improves progression-free survival and minimal residual disease negativity compared to VRD, indicating deeper and more durable responses in newly diagnosed multiple myeloma patients. However, this benefit comes with an increased risk of grade 3–4 neutropenia and thrombocytopenia. No significant differences were observed in complete response or grade 3–4 anemia. Keywords: Multiple Myeloma, Daratumumab, VRd, D-VRd, Progression-Free Survival, Minimal Residual Disease