Primary Endpoint Analysis from a Response Adaptive Phase II Clinical Trial of Carfilzomib, Lenalidomide, Dexamethasone Plus Daratumumab (KRd-Dara) in Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Background Minimal residual disease (MRD) status has prognostic significance for progression-free survival (PFS) and overall survival (OS) in NDMM, but its value in guiding therapy remains unclear. We conducted a 2-stage, phase II trial evaluating the quadruplet regimen of KRd-Dara as induction therapy followed by MRD adapted KRd consolidation +/- autologous stem cell transplantation (ASCT) and maintenance versus observation. We previously reported the results of our stage I analysis at ASH 2022 (n=23; Blood 2022;140:4440-4441). Here we provide an updated analysis of the primary endpoint after completed enrollment of stage 2. Methods Eligible patients had NDMM with measurable disease. The induction phase allowed 8 cycles of KRd-Dara. Post-induction treatment assignment was informed by ASCT eligibility and MRD status by next generation sequencing (NGS at 10 -5), and included Group A (MRD negative, transplant-eligible and -ineligible, optional lenalidomide maintenance), Group B (MRD positive, transplant eligible, ASCT) and Group C (MRD positive, transplant ineligible, KRd consolidation for up to 12 cycles). Patients in Group B could receive up to 12 cycles of KRd consolidation therapy after ASCT if MRD positive. All groups could receive optional lenalidomide maintenance therapy after achievement of MRD negativity after induction ± consolidation. The primary endpoint was ≥complete response (CR) rate at the end of induction. The secondary endpoints were safety, MRD status, stem cell mobilization failure, and survival outcomes. Efficacy endpoints including MRD were evaluated with the intent to treat principle. Results Thirty-nine patients were enrolled: 23 in stage 1 and 16 in stage 2. Median age was 62 (range 34-78), 31% were female and 31% were African American. R-ISS stage 3 was present in 4 (10%), high-risk cytogenetics (including 1q21 gain) in 15 (39%). At the end of induction, ≥CR was achieved in 22/39 (56%, 90% CI: 42%-70%) patients including stringent CR (sCR) in 17 (44%), VGPR in 14 (36%) and PR in 1(3%). Of note, 2 patients did not complete induction therapy; one died during cycle 2, while another was withdrawn from study after an SAE during cycle 1. Evaluating by NGS, 62% achieved MRD negativity at 10 -5 and 41% MRD negativity at 10 -6 post-induction. MRD negativity by next generation flow cytometry (NGF) was 74% at 10 -5 and 31% at 10 -6. Concordance of MRD by NGS/ NGF at 10 -5 was 26/34 (76% in agreement and 24% disagreement, Cohen's kappa: 0.436), and by NGS/ NGF at 10 -6 was 17/25 (68% in agreement and 32% disagreement, Cohen's kappa: 0.351). 39 patients (100%) experienced treatment emergent AE, with grade ≥ 3 AE in 31 (80%). The most common (≥ 25%) any grade treatment related AE (TRAE) were diarrhea (39%), fatigue (36%), neutropenia (28%), and constipation (26%). Grade 3-4 TRAE (≥10% of patients) included neutropenia (21%) and hypophosphatemia (13%). Covid infection occurred in 10 (26%); only one patient needed hospitalization. Other infections (any grade) were seen in 20 (51%) patients. Fourteen (36%) patients experienced at least one SAE, of which 8 patients had a treatment-related SAE, including one death. Thromboembolic events were observed in 3 (8%) patients. Of 23 patients who collected stem cells upon completion of induction (7-8 cycles of KRD-Dara), 7 (30%) failed to collect an optimal target (3 million CD34+ cells/kg) on first attempt. Comparatively, 0 of 11 patients who collected after 3-5 cycles experienced stem cell collection failure (Fisher's exact: p=0.07). Post-induction, 24 patients were assigned to Group A, 8 to Group B, and 5 to Group C. After a median follow up of 26 months (95% CI: 17 - 27; data cut off 7/6/2023), 28 remain on treatment, 9 are in follow up, and 2 are off study. The 2-year PFS is 85.3% (95% CI: 71.6% - 99.1%); median PFS is not reached. Updated data on the best MRD/ CR/ sCR responses achieved post-induction will be presented at the meeting. Conclusions Our data confirm high rates of sCR and MRD negativity of the quadruplet regimen of KRd-Dara in NDMM. The safety data was in alignment with known safety profile of investigational products. With modification of the protocol to allow earlier stem cell collection, we were able to reduce the rate of stem cell mobilization failure from 30% to 0%. Based on our results, we recommend further testing of this MRD-based platform in randomized studies with stem cell collection after 3-4 cycles of KRd-Dara. Clinical trial: NCT04113018