Daratumumab in transplant-ineligible or -deferred newly diagnosed multiple myeloma: minimal residual disease in CEPHEUS

In the phase 3 CEPHEUS study, D-VRd (daratumumab/bortezomib/lenalidomide/dexamethasone) increased overall minimal residual disease (MRD)-negativity rates vs VRd in patients who were transplant ineligible/deferred with newly diagnosed multiple myeloma (NDMM). We present an expanded MRD analysis of CEPHEUS. Patients who were transplant-ineligible or deferred transplant as initial therapy were randomized to D-VRd or VRd. Overall MRD negativity (next-generation sequencing) was defined as the proportion of patients achieving complete response or better and MRD-negative status assessed at 10⁻⁵ (primary end point) and 10⁻⁶ thresholds. In total, 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 vs VRd (10⁻⁵: 60.9% vs 39.4%; odds ratio [OR], 2.37; 95% confidence interval [CI], 1.58-3.55; P < .0001; 10⁻⁶: 46.2% vs 27.3%; OR, 2.24; 95% CI, 1.48-3.40; P = .0001). Sustained MRD negativity (≥12 months) was significantly higher with D-VRd vs VRd (10⁻⁵: 49.2% vs 27.3%; 10⁻⁶: 34.0% vs 16.2%; each P < .0001), with similar benefits at ≥24 and ≥36 months. MRD-negativity rates were higher at all prespecified time points and cumulatively with D-VRd. Among patients who achieved MRD negativity, progression-free survival (PFS) trended in favor of D-VRd vs VRd (10⁻⁵: hazard ratio, 0.61; 95% CI, 0.35-1.06; P = .0755; 10⁻⁶: 0.66; 95% CI, 0.31-1.41; P = .2811). Responses with D-VRd were deeper and more durable vs VRd, with increased overall, sustained, and landmark MRD-negativity rates, translating into improved overall PFS with D-VRd vs VRd (intent-to-treat), with potential to improve PFS even among patients with MRD negativity. D-VRd is therefore a new standard-of-care treatment for transplant-ineligible/transplant-deferred NDMM. This trial was registered at www.clinicaltrials.gov as NCT03652064.