Depth of response and MRD in newly diagnosed ultra high-risk myeloma and plasma cell leukemia treated with Dara-CVRd and V-MEL ASCT: results of the molecularly stratified UK OPTIMUM/MUKnine trial

Background Outcome for patients with ultra high-risk (UHiR) newly diagnosed multiple myeloma (NDMM) or plasma cell leukemia (PCL) continues to be adverse, and UHiR patients are underrepresented in clinical trials. Recently, deepened responses have been reported for anti-CD38 monoclonal antibody combination therapy in NDMM. We report here protocol defined endpoints for the risk-stratified OPTIMUM/MUKnine (NCT03188172) trial for UHiR NDMM and PCL. Patients received daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction and bortezomib-augmented HDMEL and ASCT. Early endpoints response and MRD from induction to day 100 post ASCT are reported. Methods Between Sep 2017 and Jul 2019, 472 patients with suspected NDMM from 39 UK hospitals were centrally molecularly screened. Of these, 107 patients were identified as having UHiR NDMM by trial genetic (≥2 high-risk lesions (double-hit): t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with PCL (circulating plasmablasts >20%) and enrolled in OPTIMUM. Induction consisted of 6 cycles of Dara-CVRd, HDMEL and ASCT augmented with bortezomib, followed by Dara-VR(d) consolidation for 18 cycles and Dara-R maintenance. Primary trial endpoints are minimal residual disease (MRD) status post ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. Results Median follow-up for the 107 patients in the safety population was 22.2 months (95% CI: 20.6 – 23.9). At baseline, 27% of patients were ISS stage I, 40% stage II and 32% stage 3 with 1.0% missing data and patient median age was 60 (range 35 to 78) years. 53% of patient tumors carried double-hit genetics and 77% a SKY92 high-risk signature. Two patients died early during induction due to myeloma-related infection. Bone marrow aspirates suitable for MRD assessment by flow (10-5 sensitivity) were available for 81% of patients at end of induction and 78% at D100 post ASCT. Responses in the ITT population at end of induction were 94% ORR with 22% CR, 58% VGPR, 15% PR, 1% PD, 5% timepoint not reached (TNR; withdrew, became ineligible or died) and at D100 post ASCT 83% ORR with 47% CR, 32% VGPR, 5% PR, 7% PD, 10% TNR. For PCL patients, response post ASCT was lower with 22% CR, 22% VGPR, 22% PR and 22% PD, 11% TNR. MRD status was 41% MRD-neg, 40% MRD-pos and 19% not evaluable post induction and 64% MRD-neg, 14% MRD-pos and 22% not evaluable at D100 post ASCT. Most frequent induction grade 3/4 AEs were neutropenia (21%), thrombocytopenia (12%) and infection (12%). Conclusions We report here high response and MRD-negativity rates with Dara-CVRd quintuplet induction and augmented ASCT in difficult-to-treat UHiR NDMM and PCL patients, with good tolerability and all-oral/subcutaneous deliverability. However, some early progressors highlight the ongoing need for innovation in UHiR MM and PCL.