The efficacy and safety of daratumumab (DARA), a human IgGκ monoclonal antibody targeting the CD38 antigen, was tested in transplant-eligible, newly diagnosed patients with multiple myeloma. The updated results of the phase 2 study are reported here.
In the primary analysis of the phase 2 GRIFFIN study (NCT02874742) in patients with transplant-eligible, newly diagnosed multiple myeloma, DARA plus lenalidomide, bortezomib, and dexamethasone (D-RVd) significantly improved rates of stringent complete response (sCR) by the end of post-transplant consolidation therapy versus RVd (Voorhees P, Blood. 2020). In this updated analysis, a total of 207 patients who were eligible for high-dose therapy (HDT) and autologous stem-cell transplant (ASCT) were randomized to RVd ± DARA in a 1:1 ratio. Patients were stratified by International Staging System (ISS) stage and creatinine clearance rate. The primary end point was rate of sCR at the end of post-ASCT consolidation per International Myeloma Working Group (IMWG) criteria. Key secondary end points included progression-free survival (PFS) and rate of minimal residual disease (MRD) negativity (10-5 threshold per IMWG criteria) assessed by next-generation sequencing.
Patients received 4 induction cycles, HDT, ASCT, 2 consolidation cycles, and maintenance with lenalidomide ± DARA for 24 months. During induction and consolidation, patients received lenalidomide 25 mg orally on days 1 to 14; bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11; and dexamethasone 40 mg once weekly every 21 days. Intravenous DARA 16 mg/kg was given on days 1, 8, and 15 of cycles 1‐4 and day 1 of cycles 5‐6. During maintenance (cycles 7-32), patients received lenalidomide 10 mg (15 mg in cycles 10+ if tolerated) on days 1‐21 every 28 days ± intravenous DARA 16 mg/kg once every 8 weeks.
At the end of post-transplant consolidation, with a median follow-up of 13.5 months in the response-evaluable population, the sCR rate favored the D-RVd cohort versus RVd (42.4% [42/99] vs 32.0% [31/97]; 1-sided P = .0680). With additional D-R (lenalidomide) or lenalidomide maintenance therapy, responses continued to deepen and remained higher for the D-RVd group versus the RVd group. At the 12-months-of-maintenance therapy data cut (median follow-up, 26.7 months), the sCR rate still favored D-RVd versus RVd (63.6% [63/99] vs 47.4% [46/97]; 2-sided P = .0253). MRD-negativity (10-5) rates favored D-RVd treatment versus RVd (62.5% [65/104] vs 27.2% [28/103]; P <.0001), as well as among patients who achieved complete response (CR) or better at that time (76.5% [62/81]. Similarly, MRD-negativity (10-6) rates favored D-RVd versus RVd (26.9% [28/104] vs 12.6% [13/103]; P = .0140), as well as among patients who achieved CR or better at that time (34.6% [28/81] vs 18.6% [11/59]; P = .0555). Estimated 24-month PFS rates were 94.5% and 90.8% for the D-RVd and RVd groups, respectively. In total, 14 deaths occurred (n = 7 per group), and 9 were due to progressive disease (D-RVd, n = 5; RVd, n = 4). With the longer follow-up period, no new safety concerns were observed. A total of 84.8% (84/99) of patients in the D-RVd group and 79.4% (81/102) in the RVd group had grade 3/4 treatment-emergent adverse events (TEAEs). One grade 5 TEAE occurred in the RVd group, which was unrelated to study therapy. Infusion-related reactions occurred in 43.4% (43/99) of patients, with the majority being grade 1 or 2 and occurring in the first cycle.
After >2 years of median follow-up, the updated analysis demonstrated that the addition of DARA to RVd induction and consolidation, followed by D-R maintenance resulted in durable responses, including higher sCR and MRD-negativity rates, compared with lenalidomide alone. No new safety concerns were observed with the longer follow-up.
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