Weekly Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab (wKRd-D) Combination Therapy in Newly Diagnosed Multiple Myeloma: Final Results from a Clinical and Correlative Phase 2 Study

INTRODUCTION. Recent studies show that ~25% of newly diagnosed multiple myeloma patients treated with 8 cycles of bortezomib, lenalidomide and dexamethasone (VRd) achieve minimal residual disease (MRD) negativity. Recently, 42% stringent complete response (sCR) rates were reported with the use of VRd combined with the CD38-targeted monoclonal antibody daratumumab (VRd-D). Here, we present the final results from a phase 2 study using weekly dosing of carfilzomib 56 mg/m2 with lenalidomide and dexamethasone in combination with daratumumab (wKRd-D). The primary endpoint of our study was to demonstrate >60% and to target up to 80% MRD negativity rate with wKRd-D. METHODS. This phase II clinical trial is based on Simon's optimal two-stage design. The wKRd-D dosing schedule is as follows: 8 cycles of treatment; 28-day cycles with IV carfilzomib 20/56 mg/m2 days 1, 8, and 15; PO lenalidomide 25 mg days 1-21; PO/IV dexamethasone 40 mg weekly cycles 1-4, 20 mg after cycle 4; and IV daratumumab 16 mg/kg days 1, 8, 15, and 22 cycles 1-2, days 1 and 15 cycles 3-6, and day 1 cycles 7-8. For fit patients, stem cell collection is recommended after 4 to 6 cycles of therapy; wKRd-D therapy resumed after collection to a total of 8 cycles wKRd-D. Treatment response is being assessed with parallel bone marrow-based MRD assays (10-color single tube flowcytometry and invivoscribe IGHV sequencing); per IMWG guidelines both MRD assays allows detection of 1 myeloma cell in 100,000 cells (10^-5). Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE). RESULTS. The study is fully enrolled; between October 2018 and November 2019 a total of 41 evaluable patients were enrolled. Baseline characteristics include; median age 59 years (range 30-70 years); 25 (61%) females;16 (39%) males; 20 (49%) patients had high-risk FISH/SNP signature defined as one or more of the following: 1q+, t(4;14), t(14;16), t(14;20), and 17p-. At submission of this abstract, 39 out of 41 patients have completed 8 cycles of treatment and end of treatment evaluations. Of those 39, 29 patients were MRD negative and 10 patients MRD positive. Two patients are pending end of treatment evaluations for response (currently receiving cycle 8 of wKRd-D). Thus, among patients treated on the weekly cohort (wKRd-D) and who were evaluable for the MRD primary endpoint at this analysis, we found 29/39 (74%) to be MRD negative. We further show no added