In the phase 3 CEPHEUS study, daratumumab plus bortezomib/lenalidomide/dexamethasone (D‑VRd) increased overall MRD-negativity rates versus VRd in transplant-ineligible/transplant-deferred patients with NDMM. We present an expanded MRD analysis of CEPHEUS. Patients who were transplant-ineligible, or deferred transplant as initial therapy, were randomized 1:1 to receive D-VRd or VRd. Overall MRD negativity (NGS) was defined as the proportion of patients achieving ≥CR and MRD-negative status assessed at 10-5 (primary endpoint) and 10-6 thresholds. A total of 395 patients were randomized (D-VRd, n=197; VRd, n=198). With 58.7-months median follow-up, overall MRD-negativity rates were significantly higher with D-VRd versus VRd (10-5, 60.9% vs 39.4%; OR, 2.37; 95% CI, 1.58-3.55; 10-6, 46.2% vs 27.3%; OR, 2.24; 95% CI, 1.48-3.40; P0.0001 and P=0.0001, respectively). Sustained MRD negativity (≥12 months) was also significantly higher with D-VRd versus VRd (10-5: 49.2% vs 27.3%; 10-6: 34.0% vs 16.2%; each P0.0001), with similar benefits at ≥24 and ≥36 months. MRD-negativity rates were higher at all pre-specified timepoints, and cumulatively, with D-VRd versus VRd (10-5 and 10-6). Among patients who achieved MRD negativity, PFS trended in favor of D-VRd versus VRd (10-5, HR, 0.61; 95% CI, 0.35-1.06; P=0.0755; 10-6, 0.66; 95% CI, 0.31-1.41; P=0.2811). Responses with D-VRd are deeper and more durable versus VRd, increasing overall, sustained, and landmark MRD-negativity rates, translating into improved overall PFS for patients treated with D-VRd versus VRd (intent-to-treat), with the potential to improve PFS even among patients who achieve MRD negativity. D-VRd is therefore a new standard-of-care treatment for transplant-ineligible/transplant-deferred NDMM. Registered at www.clinicaltrials.gov: NCT03652064.
Zweegman et al. (Wed,) studied this question.