An updated analysis from the ALCYONE trial has found that adding daratumumab to a standard-of-care regimen significantly prolonged survival in patients with transplant-ineligible multiple myeloma, according to a recent paper in The Lancet.
An updated analysis from the ALCYONE trial has found that adding daratumumab (Darzalex) to a standard-of-care regimen significantly prolonged survival in patients with transplant-ineligible multiple myeloma, according to a recent paper inThe Lancet.
Newly diagnosed patients who received daratumumab in addition to bortezomib (Velcade), melphalan, and prednisone (D-VMP) showed a 40% reduction in the risk of death versus bortezomib, melphalan, and prednisone (VMP) alone.
After a median follow-up of 40.1 months (Interquartile Range [IQR], 37.4-43.1), the median overall survival (OS) was not reached in either 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= .0003). The 36-month OS rate was 78.0% (95% CI, 73.2%-82.0%) in the D-VMP group compared with 67.9% (95% CI, 62.6%-72.6%) in the VMP group.
Progression-free survival (PFS) remained significantly improved for the D-VMP group with a median of 36.4 months versus 19.3 months without daratumumab (HR, 0.42; 95% CI, 0.34-0.51;P<.0001).
The overall response rate was 90.9% in the D-VMP group compared with 73.9% in the patients who received VMP alone (P<.0001), with complete responses (or better) seen in 46% and 25% of patients, respectively.
“For the first time, a daratumumab-based combination therapy has shown a significant improvement in overall survival. 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,” wrote the authors, led by Maria-Victoria Mateos, MD, PhD, of the University Hospital of Salamanca, Spain. “Although longer-term follow-up of overall survival with daratumumab in other phase 3 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.”
ALCYONE is a global, randomized, open-label phase III trial that enrolled patients from 162 sites in 25 countries in North America, South America, Europe, and Asia. With a primary end point of PFS, ALCYONE was originally published in theNew England Journal of Medicinein 2018.2
Newly diagnosed patients were eligible to participate in ALCYONE if they were ineligible for high-dose chemotherapy and autologous stem cell transplantation because of their age (≥65 years) or because of substantial comorbidities. Participants received up to nine 6-week cycles of subcutaneous bortezomib at 1.3 mg/m2on days 1, 4, 8, 11, 22, 25, 29, and 32 of the first cycle and on days 1, 8, 22, and 29 of later cycles. Patients also received oral melphalan (9 mg/m2once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2once daily for the first 4 days of each cycle).
Patients in the D-VMP group also received intravenous daratumumab at a rate of 16 mg/kg once weekly during cycle 1. Later cycles included the drug once every 3 weeks. After completing the protocol’s 9 cycles, patients in this group could then continue to receive the study drug once every 4 weeks until disease progression or unacceptable toxicity. Patients in this group also received steroids with daratumumab to mitigate infusion-related reactions.
Of 706 total patients, 350 were randomized to the D-VMP arm and 356 to the VMP group. Data from the 700 patients who received at least one dose of the study treatment were included in the intention-to-treat population. The median patient age was 71 (range, 40-93), and about one-third of the total cohort was at least 75 years of age (n = 211, 30%). Close to 100 patients had a high-risk cytogenetic profile (n = 98, 14%).
Data cutoff for the current study occurred in June 2019. At that time, all 700 patients had completed or discontinued treatment. Nearly half of the experimental-group patients continued to receive daratumumab monotherapy (n = 146, 42%).
Mateos et al found that sustained negative status for minimal residual disease for at least 12 months was associated with significantly improved PFS and OS. “Patients who did not sustain negative status for minimal residual disease for at least 12 months frequently had a missing or indeterminate sample (21 in the D-VMP group and 7 in the VMP group), or became positive for minimal residual disease before disease progression or death (17 in the D-VMP group and 7 in the VMP group),” they wrote.1
The authors found that responses with daratumumab continued to improve over time from the primary analysis, which had a median follow-up of 16.5 months. They observed slight improvements in rates of “stringent” complete response from 63 patients (18%) in the primary analysis to 81 patients (23%) in the current analysis. Similarly, the number of patients who showed no minimal residual disease increased over time from 78 patients (22%) to 99 (28%).
No new safety signals emerged during follow-up. The most common treatment-emergent adverse events (AEs) of grade 3/4 during the first 9 cycles of treatment were neutropenia (D-VMP, 40%; VMP, 39%), thrombocytopenia (D-VMP, 34%; VMP, 38%), and anemia (D-VMP, 15%; VMP, 20%). The most common grade 3/4 AEs with daratumumab monotherapy were anemia, pneumonia, hypertension, neutropenia, and thrombocytopenia.
Mateos et al noted that one limitation of ALCYONE is that only patients in the daratumumab group were allowed to continue with the drug following completion of the 9-cycle protocol.
The current OS analysis was performed as a prespecified interim analysis after 209 deaths, or 63% of planned events, occurred. The authors will perform the final OS analysis after 330 deaths have been observed.