Daratumumab Plus Bortezomib, Lenalidomide, and Dexamethasone (D-VRd) Versus VRd in Patients With Newly Diagnosed Multiple Myeloma: Final Analysis of Transplant-Ineligible Patients in the Phase 3 CEPHEUS Study
The phase 3 CEPHEUS study (NCT03652064) established that D-VRd improved overall minimal residual disease (MRD)-negativity rates and progression-free survival (PFS) versus VRd in patients with transplant-ineligible (TIE) or transplant-deferred newly diagnosed multiple myeloma (NDMM). Analysis of the D-VRd TIE subpopulation at a median follow-up of 58.7 months showed a complete response or better (≥CR) rate of 80.6% and MRD-negativity rate of 60.4%, with ~70% of patients alive and progression free. Here, we describe the final analysis of the CEPHEUS TIE subpopulation with a median follow-up of 76.0 months.
Materials and Methods/Case Presentation/Objective:
The primary endpoint of MRD-negativity rate (10-5 threshold and ≥CR) and secondary endpoints, including investigator-assessed PFS, ≥CR rate, and sustained MRD negativity (confirmed MRD negativity ≥12 months [+/-1 month] apart without MRD positivity in between and ≥CR), were assessed in the TIE subpopulation. The impact of treatment on health-related quality of life (HRQoL) was evaluated via the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) global health status (GHS) score using a mixed model for repeated measures. Patients provided informed consent.
Results/Description/Main Outcome Measure(s): Of 395 patients enrolled, 289 patients with TIE NDMM received D-VRd (n=144) or VRd (n=145). MRD-negativity rate at the 10-5 threshold was 61.1% for D-VRd and 40.0% for VRd (OR, 2.35 [95% CI, 1.47-3.77]; P=0.0004) and at the 10-6 threshold was 46.5% and 27.6% (OR, 2.27 [95% CI, 1.39-3.71]; P=0.0010). Sustained MRD-negativity rate at the 10-5 threshold was 49.3% for D-VRd and 29.0% for VRd (OR, 2.40 [95% CI, 1.47-3.91]; P=0.0005) and at the 10-6 threshold was 37.5% and 16.6% (OR, 3.01 [95% CI, 1.73-5.24]; P 0.0001). Overall ≥CR rate was 80.6% for D-VRd and 61.4% for VRd (OR, 2.64 [95% CI, 1.54-4.51]; P=0.0003). Median PFS was not estimable (NE; 95% CI, 74.81-NE) for D-VRd and 50.20 months (95% CI, 41.95-62.95) for VRd (HR, 0.55 [95% CI, 0.39-0.78]; P=0.0007); 59.3% of D-VRd patients and 38.3% of VRd patients were alive and progression free at 72 months. Overall survival favored D-VRd over VRd (HR, 0.84 [95% CI, 0.57-1.24]), particularly when censoring for COVID-19 (HR, 0.74 [95% CI, 0.49-1.12]). MRD-negativity and PFS treatment effects were consistent across most subgroups, including ISS stage III disease and ECOG performance status ≥1. Least squares mean change from baseline in EORTC QLQ-C30 GHS scores showed consistent improvement from baseline in both treatment arms from Cycle 9 onward, with mean changes on Cycle 72 Day 1 of +4.1 (95% CI, −0.9-9.1) for D-VRd (n=36) and +7.6 (95% CI, 1.6-13.6) for VRd (n=24).
Conclusion(s).: After median follow-up of >6 years, D-VRd continued to deliver deep and durable responses compared with VRd, a key consideration for patients with TIE NDMM. Importantly, the addition of daratumumab to VRd did not negatively affect HRQoL. Together, these data continue to reinforce D-VRd as a standard-of-care treatment for patients with TIE NDMM.
Trademarked Items: This abstract was accepted and previously presented at the 2026 ASCO and EHA Annual meetings. ©2026 American Society of Clinical Oncology, Inc. Reused with permission. All rights reserved.
References:
