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Phase 2 GRIFFIN Study Update: Daratumumab + Lenalidomide, Bortezomib, and Dexamethasone in Transplant-Eligible NDMM

Conference Correspondent  - ASH Highlights

Daratumumab (DARA) + lenalidomide, bortezomib, and dexamethasone (D-RVd) was shown to significantly improve stringent complete response (sCR) rates by the end of posttransplant consolidation therapy versus RVd in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) in the primary analysis of the phase 2 GRIFFIN study. Updated efficacy and safety data after 12 months of R ± DARA (D-R) maintenance therapy are now available.

In GRIFFIN, patients with NDMM eligible for high-dose therapy (HDT) and autologous stem-cell transplant (ASCT) were randomized 1:1 to RVd and D-RVd. Following the sequential regimen of 4 induction cycles, HDT, ASCT, and 2 consolidation cycles, patients were given 24 months of maintenance with lenalidomide (R) or D-R. Patients were given oral lenalidomide 25 mg on days 1 to 14; subcutaneous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; and dexamethasone 40 mg weekly every 21 days for induction and consolidation; intravenous (IV) DARA 16 mg/kg was administered on days 1, 8, and 15 of cycles 1 to 4 and day 1 of cycles 5 to 6. For maintenance (cycles 7-32), patients were given lenalidomide 10 mg (15 mg in cycles 10+ if tolerated) on days 1 to 21 every 28 days ± DARA 16 mg/kg IV every 8 weeks (or every 4 weeks if the patient desired following study protocol Amendment 2). The primary end point was sCR rate following ASCT consolidation; key secondary end points were progression-free survival (PFS), overall response rate, and rate of minimal residual disease (MRD)-negativity.

A total of 207 patients were randomized, 104 to D-RVd and 103 to RVd. With a median follow-up of 13.5 months following ASCT consolidation in the response-evaluable population, 42.4% (42/99) versus 32.0% (31/97) of patients achieved sCR with D-RVd versus RVd, respectively. Responses continued to deepen with additional lenalidomide or D-R maintenance therapy, and at the data cutoff following 12 months of maintenance therapy (median follow-up, 26.7 months), the sCR rate remained higher with D-RVd than with RVd (63.6% [63/99] vs 47.4% [46/97]; 2-sided P = .0253). Both MRD-negativity (10–5) and (10–6) rates in the intention-to-treat (ITT) population favored D-RVd versus RVd. Indeed, MRD-negativity (10–5) was observed in 62.5% (65/104) versus 27.2% (28/103) of patients receiving D-RVd versus RVd, respectively (P <.0001), and MRD-negativity (10–6) was observed in 26.9% (28/104) versus 12.6% (13/103) of patients receiving D-RVd versus RVd, respectively (P = .0140). Similarly, in the ITT population, MRD-negativity rates at both the 10–5 and 10–6 levels favored D-RVd versus RVd among patients who achieved complete response or better, and 76.5% (62/81) versus 42.4% (25/59) of this subset of patients receiving D-RVd versus RVd, respectively, achieved MRD-negativity at the 10–5 level (P <.0001). The estimated 24-month PFS rate was 94.5% for D-RVd and 90.8% for RVd.

Seven deaths occurred in each study group, with 5 in the D-RVd group and 4 in the RVd group resulting from progressive disease. No additional concerns regarding safety were observed at follow-up. Grade 3/4 treatment-emergent adverse events occurred in 84.8% (84/99) and 79.4% (81/102) of patients in the D-RVd and RVd groups, respectively. The most common grade 3/4 adverse events were neutropenia (43% vs 24% for D-RVd and RVd, respectively), lymphopenia (23% vs 23%, respectively), leukopenia (16% vs 8%, respectively), and thrombocytopenia (15% vs 9%, respectively). A total of 43.4% (43/99) of patients experienced infusion-related reactions, but the majority were grade 1/2 and occurred in Cycle 1.

This updated analysis of the phase 2 GRIFFIN study, with 26.7 months of median follow-up, showed that adding DARA to RVd induction and consolidation, followed by maintenance with D-R for transplant-eligible patients with NDMM elicits deep and improving responses, including higher rates of sCR and MRD-negativity. No additional safety concerns were noted at longer follow-up.


Reference

Abstract 549. ASH 2020. December 7, 2020. Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM):Updated Analysis of Griffin after 12 Months of Maintenance Therapy.

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