Daratumumab in the frontline management of newly diagnosed multiple myeloma: An overview of systematic reviews and meta-analyses.

248 Background: We conducted an overview of systematic reviews and meta-analyses (SRMAs) to evaluate daratumumab’s effect on overall survival (OS) in frontline newly diagnosed multiple myeloma (NDMM), as OS benefit remains uncertain despite improved progression-free survival. Methods: Registered in PROSPERO (CRD420261298985), we searched 4 databases from inception to January 31, 2026 for SRMAs evaluating daratumumab-based induction regimens reporting OS estimates. Method quality assessed using AMSTAR-2 and certainty of evidence using GRADE. Results: 8 SRMAs (2019–2025) were included, synthesizing a mean of 8.2 daratumumab-specific RCTs per review. Across regimens, daratumumab-containing therapy consistently reduced mortality vs. standard regimens, with varied certainty. The most robust OS benefit was observed with D-VTd (CASSIOPEIA: HR 0.55, 95% CI 0.42–0.73; high certainty) and D-Rd (MAIA: HR 0.67, 95% CI 0.55–0.82; high certainty). D-VMp also showed survival improvement (ALCYONE: HR 0.56, 95% CI 0.46–0.68; moderate certainty). For D-VRd, OS favored daratumumab but was imprecise (GRIFFIN: HR 0.90, 95% CI 0.31–2.56; moderate certainty). Evidence for D-VCd was limited (HR 1.33, 95% CI 0.69–2.55; low), and no mature OS data for D-KRd (very low certainty). Overall OS evidence was rated moderate, primarily downgraded for imprecision. Conclusions: Adding daratumumab improves OS in NDMM, supported by moderate-to-high certainty evidence with the most mature benefit seen for D-VTd, D-Rd, and D-VRd, supporting routine use; however, comparator arms are often inferior (quadruplets vs triplets vs doublets), limiting incremental inference. Longer follow-up is needed to clarify optimal sequencing. OS outcomes associated with frontline daratumumab-based regimens in newly diagnosed multiple myeloma (NDMM). Hazard ratios (HRs) <1.0 favor daratumumab-containing therapy over standard-of-care comparator regimens. Treatment Regimen Trial Name/Patients OS Hazards Ratio [95% CI] Quality of Evidence D-VTd vs. VTd CASSIOPEIA/543 0.55 (0.42–0.73) High D-VRd vs. VRd GRIFFIN/104CEPHEUS/197PERSEUS/358 0.90 (0.31–2.56)0.85 (0.58–1.24)0.73 (0.47–1.14) Moderate a, b D-Rd vs. Rd MAIA/368 0.67 (0.55–0.82) High D-VMd vs. VMd ALCYONE2017/350OCTANS/146 0.56 (0.46-0.68)0.60 (0.35-1.03) Moderate b D-VCd vs. VCd AMaRC 03-16 (64) 1.33 (0.692- 2.549) Low a, c D-KRd vs. KRd GEM2017FIT NR Very Low d D, daratumumab; V, bortezomib; T, thalidomide; R, lenalidomide; M, melphalan; C, cyclophosphamide; K, carfilzomib; d, dexamethasone; HR, hazard ratio; CI, confidence interval; NR, not reported. a Imprecision; 95% CI around the HR is wide and crosses unity. b Imprecision; contributing trial reporting reported interim OS data. c Imprecision; limited number of OS events across contributing trials. d Absence of reported overall OS from the trial.