Results from a prespecified interim analysis from the phase III ALCYONE study found that the addition of daratumumab to standard care (bortezomib, melphalan, prednisone [VMP]) halved the risk of disease progression or death, compared with standard of care alone. However, while toxicity profiles were similar between the two treatment regimens, the addition of daratumumab was associated with more frequent grade 3 or 4 infections, the authors reported in The New England Journal of Medicine.
“[This combination] was associated with a 50-percent lower risk of disease progression or death among patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic cell transplantation (HCT),” wrote María‑Victoria Mateos, MD, from the University Hospital of Salamanca in Spain, and co-authors.
The multicenter, randomized, open-label, active-controlled study enrolled 706 patients from 162 sites in 25 countries between February 9, 2015, and July 14, 2016. ALCYONE included patients with newly diagnosed myeloma who were not eligible for high-dose chemotherapy with HCT because of coexisting conditions or age ≥65 years, but had adequate hepatic and renal function and an Eastern Cooperative Oncology Group performance status score of 0-2.
Patients were randomized 1:1 based on International Staging System (I, II, or III), geographic region (Europe vs. other), and age (<75 years vs. ≥75 years). All patients received a maximum of nine, six-week cycles of VMP with or without daratumumab:
VMP: bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle 1, and days 1, 8, 22, and 29 thereafter; melphalan 9 mg/m2 twice-daily; and prednisone 60 mg/m2 twice-daily on days 1-4 (n=356)
D-VMP: VMP regimen plus daratumumab 16 mg/kg intravenously once-weekly during cycle 1, every 3 weeks for cycles 2-9, and once-monthly thereafter (n=350)
The median age in both cohorts and the entire patient population was 71 years (range = 40-93 years).
The study protocol specified that all patients in the control cohort discontinue treatment after nine cycles, but patients in the D-VMP group could continue daratumumab monotherapy.
The median duration of treatment was 14.7 months in the daratumumab group and 12.0 months in the control cohort (ranges not provided). Most patients in each group (276 D-VMP patients [79.8%] and 220 VMP patients [62.1%]) completed all nine cycles of VMP, and 17 in each group were still receiving VMP at last follow-up.
During the first nine treatment cycles, 19.4 percent of daratumumab-treated patients and 33.1 percent of the control cohort discontinued treatment, most often due to disease progression (n=23/350 [6.6%] vs. 47/356 [13.3%]; p values not reported). After cycle nine, the most common reasons for daratumumab discontinuation were progressive disease (n=30/350 [8.7%]) and death (n=2/350 [0.6%]).
As of June 12, 2017 (clinical cutoff), more patients in the control group experienced disease progression or death (143 patients [40.2%] vs. 88 patients [25.1%]), which translated to a 50-percent reduction in the risk of these outcomes in patients who received daratumumab (hazard ratio [HR] = 0.50; 95% CI 0.38-0.65; p<0.001).
Median progression-free survival (PFS; primary endpoint) was significantly longer in the D-VMP group: not reached versus 18.1 months in the control group (95% CI 16.5-19.9; p<0.001). The 18-month rate of PFS also was higher among the daratumumab group: 71.6 percent vs. 50.2 percent (p<0.001).
“The superiority of daratumumab with [VMP] was consistent across all subgroups, including [participants] 75 years of age or older and those with a poor prognosis,” the authors wrote. They added that “although the [risk] for disease progression or death in the daratumumab group was higher among patients with a high-risk cytogenetic profile than among those with a standard-risk cytogenetic profile (0.78 vs. 0.39), the results still favored the daratumumab group over the control group.”
The overall response rate was 90.9 percent in the daratumumab group and 73.9 percent in the control cohort (p<0.001). The authors also noted that a significantly greater portion of patients in the D-VMP group achieved minimal residual disease–negative status (78 [22.3%] vs. 22 [6.2%]; p<0.001). See TABLE 1 for all response data.
The most common any-grade AEs (occurring in ≥20% of patients) in the daratumumab and control cohorts were neutropenia (49.7% and 52.5%), thrombocytopenia (48.8% and 53.7%), peripheral sensory neuropathy (28.3% and 34.2%), anemia (28.0% and 37.6%), upper respiratory– tract infection (26.3% and 13.8%), diarrhea (23.7% and 24.6%), pyrexia (23.1% and 20.9%), and nausea (20.8% and 21.5%).
The most common grade 3 or 4 AEs (occurring in ≥10% of patients) included neutropenia (39.9% with D-VMP vs. 38.7% with VMP), thrombocytopenia (34.4% vs. 37.6%), and anemia (15.9% vs. 19.8%).
Daratumumab treatment was associated with a higher incidence of grade 3 or 4 infections, compared with VMP alone: 23.1 percent versus 14.7 percent.
Despite this increased risk of infection, the authors noted, AE-related discontinuations were lower in the daratumumab cohort (4.9% vs. 9.0%). “Most infections, including pneumonia, resolved (in 87.9% of the patients in the daratumumab group and 86.5% of those in the control group), and rates of discontinuation of trial treatment owing to infections did not differ substantially between the two groups (0.9% and 1.4%, respectively),” the authors reported.
After a median follow-up of 16.5 months (range not reported), 45 deaths occurred in the D-VMP group and 48 occurred in the control group. Death from infection occurred in five patients (1.4%) in the daratumumab group and in four patients (1.1%) in the control group.
Follow-up for long-term, overall survival is ongoing. The study’s findings are limited by its unblinded design, which may have introduced bias, and the allowance of continued monotherapy in the D-VMP arm.
Janssen provided support for the study.
The corresponding authors report financial support from Janssen, Celgene, Takeda, Amgen, and Bristol-Myers Squibb. MedErgy provided editorial support.
Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378:518-28.