The addition of daratumumab to bortezomib, lenalidomide, and dexamethasone (VRd) significantly improves treatment outcomes for patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for or have deferred autologous stem cell transplant (ASCT). The phase 3 CEPHEUS trial (NCT03652064) demonstrated that the daratumumab quadruplet regimen achieved a 60.9% rate of minimal residual disease (MRD) negativity compared with 39.4% with VRd alone (OR, 2.37; P < .0001) at a 10-5 sensitivity. Complete response (CR) or better rates also favored the daratumumab arm (81.2% vs 61.6%; OR, 2.73; P < .0001).
The study, which enrolled 395 patients, randomly assigned participants to receive either the daratumumab quadruplet or VRd alone. Daratumumab was administered weekly for the first two 21-day cycles, every 3 weeks during cycles 3 to 8, and monthly in maintenance. Both groups followed a VRd induction regimen, with lenalidomide and dexamethasone maintenance for the control arm.
Efficacy Results
The primary endpoint of the trial was MRD-negativity rate with a CR or better. Secondary endpoints, including sustained MRD negativity and progression-free survival (PFS), also improved with the daratumumab regimen. At a median follow-up of 58.7 months, the median PFS had not been reached in the daratumumab plus VRd arm, whereas it was 52.6 months in the VRd arm. At month 54, the PFS rates were 68.1% vs 49.5%, with a hazard ratio of 0.57, indicating a statistically significant improvement (P = .0005).
According to Sonja Zweegman, MD, PhD, Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Netherlands, the 54-month PFS rates were 68.1% and 49.5%, respectively, reducing the risk for disease progression or death by 43% (HR, 0.57; 95% CI, 0.41-0.79; P = .0005).
Safety Profile
Hematologic adverse events were more common in the daratumumab-containing arm compared with the VRd alone arm. However, the duration of treatment on the daratumumab VRd arm was almost 2 years longer than VRd, which may account for the increased incidence of adverse events. Infections were also noted, but the rates of upper respiratory tract infections (grade 3 or higher) and peripheral sensory neuropathy were similar in both arms.
Impact on Treatment Options
These results signify that adding daratumumab to VRd improves the depth of response in terms of overall MRD negativity and sustained MRD negativity. The PFS benefit also favors the daratumumab plus VRd arm. According to Saad Z. Usmani, MD, MBA, FACP, FASCO, chief of the myeloma service at Memorial Sloan Kettering Cancer Center, the overall survival appears to be showing a trend in favor of the experimental arm, despite the fact that the study actually enrolled during the height of the COVID pandemic. This complements the use of daratumumab as a quadruplet for this patient population in the frontline setting.
Implications for Future Treatment
Quadruplet induction regimens are becoming the mainstay of care for newly diagnosed patients, whether they are transplant eligible or ineligible. The CEPHEUS trial results complement the use of daratumumab, which was already demonstrated to show better survival outcomes in the MAIA clinical trial. Now, with the quadruplet regimen, there is further evidence for its use in transplant-ineligible patients.
