Background. Daratumumab-bortezomib-melphalan-prednisone (DVMP) and daratumumab-lenalidomide-dexamethasone (DRd) are standard treatments for transplant-ineligible (NTE) newly diagnosed multiple myeloma (NDMM) patients (pts). No prospective randomized trial has directly compared DVMP vs DRd. Moreover, real-life older NTE pts are underrepresented in clinical trials. Aims. We conducted a randomized multicenter phase IV trial (NCT03829371; funded by the Italian Medicines Agency AIFA - Independent Research) to compare safety and efficacy of VMP +/- daratumumab (DVMP) vs Rd +/- daratumumab (DRd) in an unselected real-life population of NTE NDMM pts. Methods. In the first part of the trial,NDMM pts who were NTE due to age ≥65 years or comorbidities were randomized 1:1 to 9 VMP cycles vs continuous Rd (standard approved schedule). As of July 2022, the protocol was amended to randomize 1:1 pts to DVMP vs DRd. Pts were enrolled regardless of performance status, comorbidities, renal function or baseline laboratory values. Stratification was based on IMWG frailty score and cytogenetic risk [high risk: del(17p), t(14;16) or t(4;14)]. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population. Key secondary endpoints included overall survival (OS) and safety. Centralized measurable residual disease by next-generation flow (NGF-MRD) was analyzed by the ITT principle in daratumumab-treated pts. Results. At data cut-off (July 9, 2025), 231 pts received VMP (n=114) or Rd (n=117), and 170 pts received DVMP (n=87) or DRd (83). Results of the VMP vs Rd comparison were recently published (Bringhen et al. Haematologica 2025; median follow-up: 28.9 months). With an extended follow-up (median: 45.8 months), the median PFS in the ITT population was 29 vs 31 months with VMP vs Rd (HR 1.41, 95% CI 0.95–2.09, p=0.09). A significantly better OS was observed with VMP vs Rd, with 3-year OS rates of 82% vs 68% in the ITT population (HR 0.57, 95% CI 0.33–0.98, p=0.04). The difference in OS between VMP and Rd was particularly evident in high–cytogenetic-risk pts (median: not reached vs 19 months, p=0.067). Regarding the second part of the study (DVMP vs DRd), baseline characteristics were balanced between the DVMP and DRd arms: median age was 76 (range 64–90) vs 76 years (range 63–87), respectively; 18% vs 13% of pts were aged >80 years; 37% vs 34% were frail; 27% vs 32% had high-risk cytogenetics. Median follow-up was 19.3 months. PFS was significantly better in the daratumumab (DVMP + DRd) vs non-daratumumab (VMP + Rd) cohorts (HR 0.57, 95% CI 0.36–0.89, p=0.01). Despite the short follow-up, an OS advantage was already observed with the addition of daratumumab to Rd (DRd vs Rd: HR 0.26, 95% CI 0.09–0.77, p=0.02) but not to VMP (DVMP vs VMP: HR 1.71, 95% CI 0.74–3.94, p=0.20), suggesting a synergistic effect of daratumumab with Rd. Regarding the comparison DVMP vs DRd in the ITT population, the 6-month and 1-year PFS rates were 90% vs 97% and 83% vs 90%, respectively, with no significant differences (HR 1.56 95% CI 0.72–3.33, p=0.30). In the first 6 months, 9 PFS events (2 progressive disease and 7 deaths) were observed [7/9 (78%) pts were frail; 7/9 (78%) events were observed in the DVMP arm]. No significant differences in PFS with DVMP vs DRd were observed across the age (> or ≤80 years), IMWG frailty score or cytogenetic-risk subgroups. In the ITT population, the 12-month NGF-MRD negativity rate was 25% with DVMP vs 30% with DRd (OR 1.79, 95% CI 0.81–3.94, p=0.15). Reaching a MRD-negative vs -positive status within 12 months led to an improved PFS (HR 0.12, 95% CI 0.03–0.50, p=0.004) with no significant differences between the two arms in MRD-negative or -positive pts. No new safety concerns were reported. Conclusion. The extended follow-up of the VMP vs Rd cohorts confirmed an OS advantage of VMP over Rd, highlighting a possible detrimental effect of lenalidomide refractoriness at relapse. In the second part of the study, we confirmed the efficacy of DVMP and DRd in an older real-life NTE NDMM population including ~35% of frail pts. Centralized MRD assessment in this real-life setting was feasible, and MRD negativity rates were comparable to those in registrational trials. The addition of daratumumab to VMP and Rd led to improved PFS with DRd, already showing an OS benefit vs Rd. The benefit of VMP vs Rd in high–cytogenetic-risk pts was not observed when daratumumab was added to both regimens.
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