Daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) shows a significant improvement in overall survival (OS) over bortezomib, melphalan, and prednisone (VMP) regimen in patients with transplant-ineligible, newly diagnosed multiple myeloma. The results from the ALCYONE study are presented at the 61st American Society of Hematology (ASH) Annual Meeting in Orlando, Florida, USA (7–10 December 2019) and published in The Lancet. For the first time, a daratumumab-based combination therapy has shown a significant improvement in OS
The primary results of ALCYONE have been previously published and showed a remarkable benefit in progression-free survival (PFS) for patients with transplant-ineligible, newly diagnosed multiple myeloma treated with D-VMP versus VMP alone. However, the OS results were not mature at that time. Now the study team report updated efficacy and safety results from a prespecified, interim, OS analysis with more than 36 months of follow-up.
The ALCYONE is a multicentre, randomised, open-label, active-controlled, phase III trial that enrolled patients between February 2015 and July 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region.
Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities.
Patients were randomly assigned in a 1:1 ratio to receive D-VMP or VMP. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments.
All patients received up to nine 6-week cycles of subcutaneous bortezomib (1.3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of body weight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity).
The primary endpoint was PFS, which has been reported previously. The results presented now are from a prespecified interim analysis for OS.
The primary analysis population (including for OS) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment.
The study team randomized 706 patients to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40.1 months, a significant benefit in OS was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0.60 (95% CI 0.46–0.80; p = 0.0003). The 36-month rate of OS was 78.0% (95% CI 73.2–82.0) in the D-VMP group and 67.9% (62.6–72.6) in the VMP group.
The PFS remained significantly improved for the D-VMP group (HR 0.42 [0.34–0.51]; p < 0.0001).
The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (19% upper respiratory tract infections, 15% bronchitis, 12% viral upper respiratory tract infections), cough (12%), and diarrhoea (10%).
Updated analysis of the ALCYONE trial shows that the addition of daratumumab to a standard-of-care regimen significantly prolonged OS in patients with multiple myeloma. At a median follow-up of 40.1 months, D-VMP showed a 40% reduction in the risk of death versus VMP alone. The daratumumab regimen continued to show significant PFS benefit and sustained negative status for minimal residual disease, with no new safety concerns.
This study and other ongoing studies have shown that daratumumab-based combination regimens enable deep and durable responses, including negative status for minimal residual disease. The authors concluded that although longer-term follow-up of OS with daratumumab in other phase III studies is ongoing, the current efficacy and safety findings from the ALCYONE study strongly support the addition of daratumumab to standard-of-care regimens for patients with newly diagnosed, transplant-ineligible multiple myeloma.
The study was funded by the Janssen Research & Development.
References
Mateos M-V, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. The Lancet; Published online 10 December 2019. DOI: https://doi.org/10.1016/S0140-6736(19)32956-3
Mateos M-V, Cavo M, Blade J, et al. Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Overall Survival in Alcyone. 61st ASH Annual Meeting; Orlando, Florida, USA: 7–10 December 2019.