Daratumumab Plus Bortezomib, Lenalidomide, and Dexamethasone (D-VRd) in Patients With Newly Diagnosed Multiple Myeloma: Subgroup Analysis of Transplant-ineligible Patients in the Phase 3 CEPHEUS Study
Introduction/Background/Significance: D-VRd is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). In CEPHEUS (NCT03652064), D-VRd improved minimal residual disease (MRD) negativity and progression-free survival (PFS) versus VRd in transplant-ineligible (TIE) or transplant-deferred patients with NDMM. As transplant deferral is uncommon in many regions, we report a post hoc analysis of D-VRd efficacy in TIE-only patients
Materials and Methods/Case Presentation/Objective: CEPHEUS enrolled TIE or transplant-deferred patients with NDMM, ECOG performance status 0-2, and an International Myeloma Working Group (IMWG) frailty score of 0-1. Patients who provided informed consent were randomized 1:1 to D-VRd or VRd. The primary endpoint was overall MRD-negativity rate (10–5 threshold with complete response or better [≥CR]); secondary endpoints included PFS and sustained MRD negativity (confirmed MRD negativity ≥12 months without MRD positivity).
Results/Description/Main Outcome Measures: Of 395 patients, 289 were TIE (D-VRd, n=144; VRd, n=145). Baseline characteristics were generally balanced between treatment groups. In the TIE versus intent-to-treat populations, median age was older (72 vs 70 years) and a higher percentage was intermediate fit per IMWG criteria (41.2% vs 35.2%) among TIE patients. In TIE patients, overall MRD-negativity rate (10−5) was 60.4% for D-VRd and 39.3% for VRd (odds ratio [OR], 2.37 [95% CI, 1.47-3.80]; P< 0.0001); MRD-negativity rate at 10–6 was 45.8% versus 26.9% (OR, 2.28 [95% CI, 1.40-3.73]; P=0.001). Sustained MRD-negativity rate (10−5) was 46.5% versus 27.6% (OR, 2.27 [95% CI, 1.39-3.70]; P=0.0010). Overall ≥CR rate was 80.6% versus 61.4% (OR, 2.73 [95% CI, 1.71-4.34]; P< 0.0001). At a median follow-up of 58.7 months, median PFS was not reached for D-VRd versus 49.6 months for VRd (54-month rates: 69.0% vs 48.0%; hazard ratio [HR], 0.51 [95% CI, 0.35-0.74]; P=0.0003). Of TIE patients who achieved MRD negativity (10–5; D-VRd, n=87; VRd, n=57), median PFS was not reached in either treatment group (54-month rates: 79.5% for D-VRd vs 70.6% for VRd; HR, 0.62 [95% CI, 0.33-1.17]; P=0.1382). Of TIE patients who remained MRD positive (10–5; D-VRd, n=57; VRd, n=88), median PFS was not reached for D-VRd versus 34.5 months for VRd (54-month rates: 51.0% vs 30.2%; HR, 0.62 [95% CI, 0.38-1.02]; P=0.0569). Overall survival favored D-VRd versus VRd (HR, 0.66 [95% CI, 0.42-1.03]; censored for COVID-19–related deaths, HR, 0.55 [95% CI, 0.34-0.90]). Treatment effect was consistent across subgroups. Safety results aligned with the known safety profiles for subcutaneous daratumumab and VRd.
Conclusions: In CEPHEUS TIE patients, the ≥CR rate was 80.6%, overall MRD-negativity rate (10−5) was 60.4%, and 12-month sustained MRD-negativity rate was 46.5%, all strongly favoring D-VRd over VRd. In addition, nearly 70% of TIE patients in the D-VRd group were alive and progression-free at 4.5 years. These data demonstrate the strong efficacy of D-VRd over VRd in TIE patients with NDMM.
©2025 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2025 ASCO and EHA annual meetings. All rights reserved
