Combination of daratumumab, ixazomib, and lenalidomide with or without dexamethasone for initial therapy of newly diagnosed myeloma.

Quadruplets incorporating anti-CD38 monoclonal antibody have led to improved outcomes, potentially allowing limited-duration therapy and reduction in steroid doses. We designed this trial to examine the efficacy of the quadruplet regimen containing daratumumab, ixazomib, lenalidomide, and dexamethasone (Dara-IRd) given for fixed duration and to evaluate early discontinuation of steroids. Patients with untreated MM were enrolled, irrespective of their transplant eligibility. The primary objective was to determine the ≥complete response (CR) rate. Treatment involved 28-day cycles of ixazomib 4 mg days 1, 8, 15; lenalidomide 25 mg days 1-21, dexamethasone 40 mg, weekly and daratumumab 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and every 4-weeks thereafter during induction (12-cycles) followed by daratumumab and ixazomib maintenance (24-cycles). Seventy-eight patients were enrolled into two sequential cohorts: cohort A (n = 38) and B (N = 40), with dexamethasone given only for two cycles in Cohort B. At the time of the data cut-off, all patients had completed the treatment. The overall response rate was 96%, including a ≥CR rate of 32%, similar in both cohorts. Responses deepened over time; 32% achieved a marrow MRD negative status and 29% MRDneg-CR. After a median follow-up of 37.9 months, the median PFS or OS has not been reached. A grade ≥3 adverse event, at least possibly attributed to the study drugs, was seen in 55% of patients. The most common toxicities included fatigue, neutropenia, lymphopenia, peripheral neuropathy, diarrhea, and nausea. Stem cells were collected in 55 patients; the median sCD34+ cell yield (range) was 7.8 (2.8-15.9) × 106/kg. Dara-IRd is an active regimen in newly diagnosed MM, with high overall response rate as well as deep responses. Nearly a third of the patients attained MRDneg status, which improved over time. The PFS with finite-duration therapy is comparable to other studies in NDMM. Early discontinuation of dexamethasone did not impact efficacy.