Daratumumab Plus Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) Improves Depth of Response in Transplant-eligible Newly Diagnosed Multiple Myeloma: GRIFFIN Primary Analysis

Purpose of the Study: Daratumumab (DARA), a human CD38 mAb, is approved as monotherapy and in combination with standard-of-care (SoC) regimens for MM. In phase 3 studies, DARA-based regimens improved response rates, depth of response including stringent complete response (sCR) and minimal residual disease (MRD) negativity, and progression-free survival (PFS). In autologous stem cell transplant (ASCT)-eligible NDMM patients, RVd followed by high-dose therapy (HDT), ASCT, and consolidation is SoC in the US. GRIFFIN is a phase 2, randomized, active controlled, US study of DARA plus RVd (D-RVd) in ASCT-eligible NDMM patients. A safety run-in showed no safety concerns. Here we present the primary analysis of the randomized portion of GRIFFIN.

Summarized Description of the Project: Patients were randomized 1:1 to RVd ± DARA, stratified by ISS stage and creatinine clearance. Patients received 4 induction cycles, stem cell mobilization, HDT, ASCT, 2 consolidation cycles, and maintenance with R ± DARA for 24 months. During induction/consolidation (Cycles [C] 16), patients received V 1.3 mg/m2 SC on Days 1, 4, 8, and 11; R 25 mg PO on Days 114; and d 40 mg QW every 21 days. DARA 16 mg/kg IV was administered on Days 1, 8, and 15 of C14 and on Day 1 of C56. During maintenance (C7-32), patients received R 10 mg (15 mg in C10+ if tolerated) on Days 121 every 28 days ± DARA 16 mg/kg IV Q8W (or Q4W per patient decision after Amendment 2). The primary endpoint was the sCR rate by the end of consolidation per IMWG computer algorithm. The study had 80% power to detect a 15% improvement with a 1-sided alpha of 0.1 (equivalent to 2-sided alpha of 0.2).

Results: A total of 207 patients were randomized. Baseline characteristics were well balanced between arms. Median (range) age was  60 (29-70) years, and 48%, 37%, and 14% of patients were ISS stage I, II, and III, respectively. The study met its primary endpoint; D-RVd improved the sCR rate by end of consolidation (42.4% vs 32.0%; odds ratio 1.57; 95% CI, 0.87-2.82; P=0.1359) at the pre-set 2-sided alpha of 0.2. D-RVd achieved higher overall response (99% vs 92%), VGPR (91% vs 73%), and CR (52% vs 42%) rates vs RVd. The rate of MRD negativity (10^5 NGS) among patients achieving CR was higher with D-RVd (59% vs 24%). At median follow-up of 13.5 months, duration of response, PFS, and OS data are immature. Median stem cell yield was 8.1 vs 9.4 × 106 cells/kg for D-RVd vs RVd. Grade 3/4 TEAEs (10%) included neutropenia, lymphopenia, thrombocytopenia, and leukopenia. There was no difference in the rate of grade 3/4 infections between arms. Infusion reactions occurred in 41% of DARA-treated patients (mainly grade 1-2 and with the first infusion).

Conclusion: D-RVd induces higher response rates and greater depth of response, including sCR and MRD negativity, than RVd. The overall safety profile of D-RVd is consistent with previous reports of DARA and RVd, and stem cell mobilization and ASCT are feasible with D- RVd. Assessment of the effect of DARA maintenance on sCR improvement and MRD rates is ongoing.