Daratumumab-Containing Quadruplet Therapy for Newly Diagnosed Multiple Myeloma Patients With High Cytogenetic Risk Who Are Eligible for Transplantation

Daratumumab is a human IgGκ monoclonal antibody that specifically targets CD38, exhibiting both direct on-tumor effects and immunomodulatory properties. It has been shown to possess superior cytotoxicity against multiple myeloma cells in ex vivo studies when compared with other CD38 antibody analogs. Findings from the MASTER study (NCT03224507) indicated that the treatment regimen of daratumumab in conjunction with carfilzomib, lenalidomide, and dexamethasone (D-KRd) demonstrated notable efficacy in transplant-eligible patients diagnosed with newly diagnosed multiple myeloma (NDMM). In the GRIFFIN study (NCT02874742), the combination of daratumumab with lenalidomide, bortezomib, and dexamethasone (D-RVd) demonstrated enhanced outcomes for transplant-eligible patients with NDMM. A post-hoc analysis of patients from the MASTER and GRIFFIN studies is summarized here for patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]).

In the multicenter, single-arm, phase 2 MASTER study, D-KRd was evaluated in transplant-eligible patients with NDMM. Patients received up to 4 D-KRd induction cycles; high-dose therapy and autologous stem cell transplant (ASCT); and up to 2 phases of D-KRd consolidation therapy. The primary endpoint of the MASTER study was the achievement of minimal residual disease (MRD) negativity at any time during therapy. In the multicenter, randomized, open-label, phase 2 GRIFFIN study, D-RVd was evaluated versus RVd alone in transplant-eligible patients with NDMM. Patients received 4 D-RVd or RVd induction cycles, followed by high-dose therapy and ASCT, then 2 D-RVd or RVd consolidation cycles, followed by ≤2 years of maintenance therapy consisting of daratumumab plus lenalidomide or lenalidomide alone. The primary endpoint of GRIFFIN was the stringent complete response (CR) rate by the end of post-ASCT consolidation treatment.

Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs, respectively. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs, respectively. The rates of CR or better for patients with 0, 1, or ≥2 HRCAs were recorded as 90.6%, 89.1%, and 70.8% for the D-KRd regimen; the D-RVd regimen showed rates of 90.9%, 78.8%, and 61.5%, respectively. At median follow-up, MRD-negativity rates as assessed by next-generation sequencing (10^–5) were 80.0%, 86.4%, and 83.3% for patients with 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd, respectively. Progression-free survival (PFS) was similar between studies and superior for patients with 0 or 1 HRCA versus ≥2 HRCAs: 36-month PFS rates for the D-KRd regimen were 89.9%, 86.2%, and 52.4%; and 96.7%, 90.5%, and 53.5% for the D-RVd regimen.

This post-hoc analysis of transplant-eligible patients with NDMM, categorized by cytogenetic risk status from the MASTER and GRIFFIN studies, demonstrated that patients with high cytogenetic risk gain clinical benefits from the use of frontline daratumumab-based quadruplet therapy.

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;1:69.