DARATUMUMAB PLUS BORTEZOMIB, LENALIDOMIDE, AND DEXAMETHASONE (DVRD) IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM): SUBGROUP ANALYSIS OF TRANSPLANT- INELIGIBLE (TIE) PATIENTS IN THE PHASE 3 CEPHEUS STUDY

After reading out of the PERSEUS and CEPHEUS trials, daratumumab-based therapy + VRd is emerging as the standard of care in NDMM treatment. In CEPHEUS (NCT03652064), DVRd improved minimal residual disease negativity (MRD neg) and progression-free survival (PFS) vs VRd in patients (pts) with TIE or transplant-deferred (TD) NDMM. As transplant deferral is not a common clinical pathway in many regions, here we report a post hoc analysis of DVRd efficacy in TIE pts. In this analysis, the primary endpoint of overall MRD neg rate (MRD neg at 10-5 and complete response or better [≥CR]), and key secondary endpoints, including PFS and sustained MRD neg (confirmed MRD neg ≥12 months [mo] apart without MRD positivity in between) were assessed. CEPHEUS enrolled pts with TIE or TD NDMM, ECOG performance status (PS) 0–2, and an International Myeloma Working Group (IMWG) frailty score of 0 or 1. Pts were randomized (1:1) to DVRd or VRd. Of 395 pts, 289 were TIE (DVRd, n = 144; VRd, n = 145). TIE population baseline (BL) characteristics were generally well balanced between DVRd vs VRd. In the TIE vs intent-to-treat (ITT) population, median age was older (72 vs 70 years [y]), and a higher percentage of pts were intermediate fit per IMWG criteria (41.2% vs 35.2%). In TIE pts, overall MRD neg rate at 10−5 was 60.4% for DVRd and 39.3% for VRd (odds ratio [OR] 2.37; 95% CI 1.47–3.80; p < 0.0001); at 10−6, it was 45.8% vs 26.9% (OR 2.28; 95% CI 1.40–3.73; p = 0.001). Sustained MRD neg rate (10−5) was 46.5% vs 27.6% (OR 2.27; 95% CI 1.39–3.70; p = 0.0010). Overall ≥CR rate was 80.6% vs 61.4% (OR 2.73; 95% CI 1.71–4.34; p < 0.0001). At 58.7-mo median follow-up, median PFS was NR for DVRd and 49.6 mo for VRd, and the 54-mo PFS rate was 69.0% vs 48.0% (HR 0.51; 95% CI 0.35–0.74; p = 0.0003); OS favored DVRd vs VRd (HR 0.66; 95% CI 0.42–1.03); after censored for deaths due to COVID-19, HR 0.55; 95% CI 0.34–0.90). Treatment effect was generally consistent across subgroups MRD neg(10-5) rate, %: DVRd, VRd: ISS Stage III (55 vs 30), Cytogenetic risk high(50 both), ECOG ≥1 (621 vs 36.4) Median PFS, mo VRd: 60.6 Stage 1 and 33.6 Stage III, Cytogenetic risk High: 31.7, Standard:60.6. ECOG 0:60.6, ECOG ≥1:47.2. Safety profile was consistent with ITT and the known profile for daratumumab subcutaneous and VRd. In CEPHEUS TIE pts, the ≥CR rate was 80.6% and overall MRD neg rate (10−5) was 60.4%, with ∼50% of pts sustaining MRD neg for ≥1 y. Nearly 70% of pts were alive and progression free at 4.5 y. These subgroup data reinforce the strong efficacy of DVRd in the TIE population.