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)

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.3380-3380
• Main Authors: Bhutani, Manisha, Robinson, Myra, Atrash, Shebli, Paul, Barry, Pineda-Roman, Mauricio, Foureau, David, Varga, Cindy, Friend, Reed, Begic, Xhevahire, Norek, Sarah, Drennan, Tiffany, Anderson, Michelle B, Symanowski, James, Voorhees, Peter M., Usmani, Saad Z
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-174972

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),