Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) Alone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of the Phase 3 Alcyone Study

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody that targets CD38 with a direct on-tumor and immunomodulatory mechanism of action. DARA is approved across multiple lines of therapy for patients with multiple myeloma. In the primary analysis of the phase 3 ALCYONE study (median follow-up, 16.5 months), a significant progression-free survival (PFS) benefit was achieved with D-VMP versus VMP alone (median not reached vs 18.1 months; hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.38-0.65; P <0.001) in transplant-ineligible patients with NDMM, with no increase in overall toxicity (Mateos MV, N Engl J Med 2018). With longer follow-up (median follow-up, 40.1 months), D-VMP significantly prolonged overall survival (OS) compared to VMP alone (median not reached in either arm; HR, 0.60; 95% CI, 0.46-0.80; P = 0.0003). The rate of minimal residual disease (MRD) negativity was also higher with D-VMP versus VMP (28% versus 7%; P <0.0001; Mateos MV, Lancet 2020). Here, we present an updated analysis of ALCYONE after a median follow-up of 74.7 months. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplant were randomized 1:1 to receive VMP ± DARA. Randomization was stratified by International Staging System disease stage (I vs II vs III), region (Europe vs other), and age (<75 vs ≥75 years). All patients received up to nine 6-week cycles of VMP (V: 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; M: 9 mg/m2 PO on Days 1-4 of Cycles 1-9; P: 60 mg/m2 PO on Days 1-4 of Cycles 1-9) ± DARA (16 mg/kg IV given once weekly in Cycle 1, once every 3 weeks in Cycles 2-9, and once every 4 weeks in Cycles 10+ until disease progression). OS, MRD-negativity rate (10-5 sensitivity: clonoSEQ® version 2.0), and safety were secondary endpoints. Results: In total, 706 patients were randomized (D-VMP, n = 350; VMP, n = 356). Baseline characteristics were well balanced between treatment arms. After a median follow-up of 74.7 months, a 37% reduction in the risk of death was observed with D-VMP versus VMP; median OS was 82.7 months with D-VMP versus 53.6 months with VMP (HR, 0.63; 95% CI, 0.51-0.78; P <0.0001). The estimated 72-month OS rate was 55.8% with D-VMP versus 39.2% with VMP (Figure A). The observed OS benefit of D-VMP versus VMP alone was generally consistent across pre-specified patient subgroups (Figure B). The MRD-negativity rate was higher for D-VMP versus VMP (28.3% vs 7.0%; P <0.0001), as was the rate of sustained MRD negativity lasting ≥12 months (14.0% vs 2.8%; P <0.0001). The most common (occurring in ≥30% of patients in either arm) any grade treatment-emergent adverse events (TEAEs; D-VMP/VMP) were neutropenia (50.6%/52.5%), thrombocytopenia (50.0%/53.7%), anemia (32.4%/37.0%), upper respiratory tract infection (30.9%/14.1%), and peripheral sensory neuropathy (28.9%/34.5%). Grade 3/4 TEAEs occurred in 82.9% of D-VMP patients and 77.4% of VMP patients, with the most common (occurring in ≥15% of patients in either arm) being neutropenia (D-VMP/VMP; 40.2%/39.0%), thrombocytopenia (34.7%/37.9%), anemia (18.2%/19.8%), and pneumonia (15.6%/4.5%). Grade 3/4 infection rates were 29.8%/15.0%. Conclusions: In this updated analysis of ALCYONE, the addition of DARA to VMP continued to prolong OS versus VMP alone in transplant-ineligible patients with NDMM; median OS was reached in both arms for the first time after a median follow-up of >6 years. D-VMP also achieved a 4-fold higher MRD-negativity rate and a 5-fold higher ≥12-month sustained MRD-negativity rate versus VMP alone. No new safety concerns were observed with longer follow-up. Our results continue to support the use of D-VMP in transplant-ineligible patients with NDMM. Updated OS results based on extended follow-up will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal