Results from the first randomized, phase III trial to evaluate frontline use of a monoclonal antibody in transplant-ineligible patients with newly diagnosed multiple myeloma (MM) show that daratumumab added to standard of care reduced the risk of disease progression or death by 50 percent, compared with standard of care alone. People who received the daratumumab combination also experienced deeper responses, according to lead author María Victoria-Mateos, MD, PhD, of the University Hospital of Salamanca in Spain, who presented the findings in a late-breaking abstract at the 2017 ASH Annual Meeting.
“Daratumumab is an anti-CD38 monoclonal antibody that has shown high activity as a single agent in highly refractory patients, and is extremely active in combination with other drugs – but always in the relapsed setting,” said co-author Jesús San-Miguel, MD, PhD, from Clínica Universidad de Navarra in Pamplona, Spain, who spoke with the press about results of the ALCYONE trial.
In this study, 706 patients were randomized 1:1 to receive bortezomib, melphalan, and prednisone (VMP; standard of care), with or without the anti-CD38 monoclonal antibody daratumumab (D-VMP). Participants received a maximum of nine, six-week cycles of VMP or D-VMP in the following dosing:
- 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
- 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
All patients (median age = 71 years; range = 40-93 years) had newly diagnosed disease and were 65 years or older or were ineligible for high-dose chemotherapy with autologous hematopoietic cell transplantation (AHCT). Patients were stratified by International Staging System (ISS; I, II, III), region (Europe vs. other), and age (<75 vs. ≥75 years).
This patient population represented “real-life patients with active, advanced disease,” Dr. San-Miguel noted. Most patients (74.9%) had an Eastern Cooperative Oncology Group performance status score of ≥1, 29.9 percent were 75 years or older, and 80.8% had ISS stage II or III disease. Of the 616 patients with cytogenetic information available, 15.9 percent were high risk (positive for del(17p), t[14;16], or t[4;14]).
By June 12, 2017 (prespecified date of analysis), patients had received a median of 12 treatment cycles (range = 1-24 cycles) in the D-VMP group and nine cycles (range = 1-9 cycles) in the VMP group. At a median follow-up of 16.5 months (range not provided), patients who received the daratumumab combination had a 50 percent reduction in the risk of progression or death, compared with standard care alone (hazard ratio [HR] for progression-free survival [PFS] = 0.50; 95% CI 0.38-0.65; p<0.0001).
The median PFS was not reached in the D-VMP group and was 18.1 months in the VMP group (ranges not provided). “The PFS treatment benefit of D-VMP versus VMP was consistent across all prespecified subgroups, including age ≥75 years, ISS stage III, and high-risk cytogenetics,” the authors noted. See TABLE for all treatment outcomes.
The benefit appeared to be driven by deeper responses in the D-VMP group, according to Dr. San-Miguel.
More patients in the D-VMP group attained minimal residual disease (MRD)-negative status compared to patients in the control group (22.3% vs. 6.2%; HR=4.36; 95% CI 2.64-7.21; p<0.0001).
“We know now that [MRD] has become probably the most relevant marker for prognosis in MM,” Dr. San-Miguel said. “As we saw in the PFS curve, patients achieving MRD-negative status – in the non-daratumumab arm, as well as the daratumumab arm (in which MRD-negativity was three times easier to obtain) – show a significantly longer PFS.”
Toxicity profiles were similar between study cohorts, Dr. San-Miguel reported, except for the high incidence of any-grade upper respiratory tract infection (26.3% vs. 13.8%) and grade 3/4 pneumonia (11.3% vs. 4.0%) in the D-VMP group.
Other common any-grade treatment-related adverse events (AEs) occurring in the D-VMP and VMP groups included neutropenia (49.7% vs. 52.5%), thrombocytopenia (48.8% vs. 53.7%), anemia (28.0% vs. 37.6%), and peripheral sensory neuropathy (28.3% vs. 34.2%). Common grade 3/4 AEs included neutropenia (39.9% vs. 38.7%), thrombocytopenia (34.4% vs. 37.6%), and anemia (15.9% vs. 19.8%).
One patient in each cohort discontinued treatment because of pneumonia. Grade 3/4 infections occurred in 23.1 percent of patients in the D-VMP cohort and 14.7 percent of the VMP cohort; these infections led to treatment discontinuation in 0.9 percent and 1.4 percent of patients, respectively.
Infusion-related reactions from daratumumab appeared in 27.7 percent of patients, “but occurred mainly in the first course of treatment, and were usually grade 1 or 2,” he added. Tumor lysis syndrome occurred in ˂1 percent of patients in each arm, and second primary malignancy occurred at similar rates (2.3% for D-VMP and 2.5% for VMP).
When asked if the results from ALCYONE are strong enough to potentially replace AHCT with the D-VMP combination, Dr. San-Miguel said the goal is instead to expand treatment choices for all patients with MM. “Use of monoclonal antibodies is going to challenge the role of transplant,” he explained. “Nevertheless, our goal is to cure MM, and we want to use all possible treatments to achieve this goal.”
The study’s findings are limited by the open-label design, which may have introduced bias. Overall survival data were also not presented. Dr. San-Miguel added that, while promising, the results may not be generalizable to the U.S. patient population, where VMP is not the standard of care for newly diagnosed, transplant-ineligible patients.
The authors report financial relationships with Takeda, Amgen, Celgene, and Janssen, which provided funding support for the study.
Mateos MV, Dimopoulos MA, Cavo M, et al. Phase 3 randomized study of daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for transplant (ALCYONE). Abstract LBA-4. Presented at the 2017 American Society of Hematology Annual Meeting, December 12, 2017; Atlanta, GA.