Adding daratumumab to VRd therapy significantly improves survival outcomes in transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma (NDMM), supporting its use as a new standard of care.
Multiple myeloma is a complex and incurable haematological malignancy, with frontline treatment strategies playing a critical role in prolonging survival. In transplant-ineligible NDMM, triplet therapies such as daratumumab plus lenalidomide and dexamethasone (D-Rd) or bortezomib, lenalidomide, and dexamethasone (VRd) have been established as standard treatments. However, the potential benefits of adding daratumumab to the VRd regimen required further investigation. This Phase III clinical trial assessed the efficacy and safety of daratumumab plus VRd (D-VRd) in patients who were either ineligible for transplant or had deferred transplantation as an initial approach.
A total of 395 patients were randomly assigned to receive eight cycles of either D-VRd or VRd, followed by D-Rd or Rd until disease progression. The primary endpoint was minimal residual disease (MRD) negativity at 10⁻⁵, assessed using next-generation sequencing. At a median follow-up of 58.7 months, the MRD negativity rate was significantly higher in the D-VRd group (60.9%) compared to the VRd group (39.4%) (odds ratio: 2.37; 95% CI: 1.58–3.55; P<0.0001). The complete response (CR) rate or better was also significantly improved with D-VRd (81.2% versus 61.6%; P<0.0001), as was the sustained MRD negativity rate of at least 12 months (48.7% vs 26.3%; P<0.0001). Additionally, the risk of disease progression or death was 43% lower in the D-VRd group (hazard ratio: 0.57; 95% CI: 0.41–0.79; P=0.0005). The safety profile of D-VRd was consistent with the known adverse events associated with daratumumab and VRd.
These findings reinforce the clinical benefit of incorporating daratumumab into VRd therapy, leading to deeper and more durable responses. The significantly improved MRD negativity rates suggest that D-VRd can enhance long-term disease control in patients with transplant-ineligible or transplant-deferred NDMM. Clinicians may now consider this quadruplet regimen as a frontline treatment option, potentially improving patient outcomes and delaying disease progression.
Jenna Lorge, EMJ
Reference
Usmani SZ et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. 2025;DOI:10.1038/s41591-024-03485-7.
