Phase 1/2 study of carfilzomib, pomalidomide, dexamethasone with and without daratumumab in relapsed multiple myeloma.

We conducted a phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone (KPd) followed by another cohort of KPd with daratumumab (Dara-KPd) in relapsed/refractory multiple myeloma. The primary endpoints were identification of a maximum tolerated dose (MTD) of KPd for phase 1, and rates of overall response (ORR) and near complete response (nCR) after 4 cycles of KPd and Dara-KPd, respectively, for phase 2. The MTD for KPd was carfilzomib 20/27 mg/m2 on days 1, 2, 8, 9, 15, 16 (cycles 1-8) and days 1, 2, 15, 16 for cycles 9+; oral pomalidomide 4 mg on days 1-21; and oral dexamethasone 40 mg weekly in 28-day cycles. Sixty-six patients received KPd, including 34 at the MTD. The ORR after 4 cycles of KPd at the MTD was 27/34 (79%, 95% CI 62%-91%), meeting the statistical threshold for efficacy. At a median follow-up of 44 months, the median PFS and OS were 13 and 44 months, respectively. Twenty-eight patients received Dara-KPd. The rate of nCR or better after 4 cycles was 11/28 (39%, 95% CI 22%-59%), meeting the statistical threshold for efficacy. As best response to Dara-KPd, the ORR was 25/28 (89%) and the rate of measurable residual disease negativity by flow cytometry (10-5) was 17/26 (65%). At a median 26 months follow-up, the median PFS and OS for Dara-KPd were not reached. Dara-KPd induced deeper and more durable responses than KPd without compromising safety in a predominantly high risk, lenalidomide-refractory population, warranting further evaluation of this quadruplet for this patient population. This trial is registered at www.clinicaltrials.gov as NCT01665794.