With almost 5 years of follow-up, results from a phase III CEPHEUS study show that the addition of daratumumab to triplet therapy of bortezomib, lenalidomide and dexamethasone (VRd) significantly increased depth of response, including rates of overall minimal residual disease (MRD) negativity, complete response (CR) or better and sustained MRD negativity, which translated to significantly improved progression-free survival (PFS) versus VRd regimen in transplant-ineligible or transplant-deferred patients with newly diagnosed multiple myeloma.
The results add further validity to the use of MRD negativity as an accelerated approval endpoint to predict PFS outcomes in patients with newly diagnosed multiple myeloma. Findings from the use of this quadruplet regimen were published by Dr. Saad Z. Usmani of the Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues on 5 February 2025 in the Nature Medicine.
Daratumumab was the first anti-CD38 monoclonal antibody approved in newly diagnosed multiple myeloma. The authors wrote in the background that for transplant-ineligible patients, significant PFS benefit was observed with frontline daratumumab plus Rd triplet therapy versus Rd regimen in the phase III MAIA study. The phase III PERSEUS study demonstrated that frontline treatment with daratumumab across the treatment continuum (induction/consolidation/maintenance) significantly improved PFS and increased the depth of the response versus the standard-of-care (SoC) in the transplant-eligible setting.
The phase III CEPHEUS study evaluated quadruplet daratumumab plus VRd versus VRd alone in patients with newly diagnosed multiple myeloma who were transplant ineligible or for whom transplant was not planned as the initial therapy (transplant deferred). At the time the study was designed, triplet VRd was a SoC based on the SWOG S0777 study, with CEPHEUS implementing the same VRd dosing with subcutaneous bortezomib. In the article published in the Nature Medicine, the study team reported the results from CEPHEUS after the final PFS analysis.
About 395 patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma were randomly assigned to eight cycles of daratumumab plus VRd or VRd followed by daratumumab plus Rd or Rd until progression. The primary endpoint was overall MRD negativity rate at 10−5 by next-generation sequencing. Major secondary endpoints included CR or better rate, PFS and sustained MRD negativity rate at 10−5.
At a median follow-up of 58.7 months, the MRD negativity rate was 60.9% with daratumumab plus VRd versus 39.4% with VRd (odds ratio 2.37; 95% confidence interval (CI) 1.58-3.55; p < 0.0001). Rates of CR or better (81.2% versus 61.6%; p < 0.0001) and sustained MRD negativity (≥12 months; 48.7% versus 26.3%; p < 0.0001) were significantly higher with daratumumab plus VRd versus VRd. Risk of progression or death was 43% lower with daratumumab plus VRd versus VRd (hazard ratio 0.57; 95% CI 0.41-0.79; p = 0.0005).
Overall survival (OS) data, although immature, showed a trend favouring daratumumab plus VRd. Sensitivity analyses provided stronger evidence of the treatment effect of daratumumab plus VRd on OS after adjusting for the impact of COVID19. Adverse events were consistent with the known safety profiles for daratumumab and VRd.
The authors concluded that these data, together with data from the phase III PERSEUS study, demonstrate the consistent benefit of quadruplet daratumumab plus VRd compared with triplet VRd treatment and support daratumumab plus VRd quadruplet therapy as a new SoC for patients with newly diagnosed multiple myeloma, regardless of transplant eligibility.
The study was sponsored by Johnson & Johnson.
Reference
Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS study. Nature Medicine; Published online 5 February 2025. DOI: https://doi.org/10.1038/s41591-024-03485-7