The MASTER study (NCT03224507) and GRIFFIN study (NCT02874742) evaluated the efficacy of daratumumab-containing regimens in transplant-eligible newly diagnosed patients with multiple myeloma (NDMM) with high-risk cytogenetic abnormalities (HRCAs). The post hoc analysis included 123 patients from MASTER treated with daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) and 120 patients from GRIFFIN treated with daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd). Results showed that complete response rates were higher in patients with 0 or 1 HRCA compared with those with ≥2 HRCAs, with D-KRd achieving 90.6%, 89.1%, and 70.8%, respectively, and D-RVd achieving 90.9%, 78.8%, and 61.5%, respectively. Minimal residual disease (MRD)-negativity rates were similar for patients with D-KRd regardless of HRCA status but were highest in patients with 1 HRCA (86.4%). Progression-free survival was superior in patients with 0 or 1 HRCA compared to those with ≥2 HRCAs in both studies. 

These findings suggest that daratumumab-based quadruplet regimens are effective in patients with 0 or 1 HRCA but highlight the need for additional strategies for those with ≥2 HRCAs. The analysis underscores the importance of initial CAR T cell expansion and effective lymphodepletion in achieving better outcomes. It also indicates that MRD-directed therapy and autologous stem cell transplant are beneficial in maintaining clinical responses. However, for ultra-high–risk patients with multiple HRCAs, innovative approaches beyond current CD38 antibody therapies are necessary to improve outcomes. 

Reference: Callander NS, Silbermann R, Kaufman JL, et al. Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk. Blood Cancer J. 2024;14(1):69. doi: 10.1038/s41408-024-01030-w.