In patients with newly diagnosed multiple myeloma (MM) who are ineligible for high-dose chemotherapy and transplantation, adding daratumumab to bortezomib, melphalan, and prednisone (VMP) halved the risk of disease progression or death, compared with VMP alone, according to updated results from the phase III ALCYONE trial.
The findings, which were published in The Lancet, also point to an overall survival (OS) advantage with the investigational regimen, making it "the first daratumumab-based combination that has shown an OS benefit," commented lead study author MarÃa-Victoria Mateos, MD, PhD, from the University Hospital of Salamanca in Spain.
This report updates earlier data from the phase III, multicenter ALCYONE trial, in which daratumumab plus VMP led to improvements in progression-free survival (PFS) but was associated with more frequent grade 3 or 4 infections.
The trial enrolled 706 patients with newly diagnosed MM from 162 sites in 25 countries. All were considered ineligible for high-dose chemotherapy with transplantation because of co-existing conditions or older age (â‰¥65 years) but had adequate hepatic and renal function and an Eastern Cooperative Oncology Group performance status score of 0-2.
Patients were stratified by age (<75 years vs. â‰¥75 years), International Staging System (ISS) score (I, II, or III), and geographic region (Europe vs. other), then randomized 1:1 to receive either:
- 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)
- daratumumab plus 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)
Each treatment cycle lasted 6 weeks, and patients received up to 9 cycles during the study.
Patient demographics and baseline characteristics were well balanced between the 2 study groups. The median age in the overall study population was 71 years (range = 40-93), and 211 patients (30%) were â‰¥75 years. About one-third of patients (n=271; 38%) had ISS stage III disease and 98 (14%) had a high-risk cytogenetic profile.
After a median follow-up of 40.1 months (interquartile range = 37.4-43.1), 83 patients (24%) in the daratumumab group and 126 in the VMP group (35%) had died. This translated to a 40% reduction in the risk of death with frontline daratumumab treatment (hazard ratio [HR] = 0.60; 95% CI 0.46-0.80; p=0.0003).
In the primary endpoint analysis, comparing PFS between the two groups, the researchers found that a significantly higher proportion of patients in the VMP group had progressive disease or died during follow-up: 74% vs. 50% (HR=0.42; 95% CI 0.34-0.51; p<0.0001).
In addition, the 3-year OS and PFS rates also were significantly higher in the daratumumab-treated group than the standard-of-care group:
- OS: 78.0% vs. 67.9%
- PFS: 50.7% vs. 18.5%
The median PFS also was higher for patients in the daratumumab group (36.4 months vs. 19.3 months), and, while neither group reached the median OS, the researchers reported that follow-up is ongoing.
Consistent with the initial results from ALCYONE, the addition of daratumumab was associated with higher overall response rates, compared with the VMP group (90.9% vs. 73.9%; p<0.0001), including higher rates of very good partial response or better (73% vs. 50%; p<0.0001) and complete response or better (46% vs. 25%; p<0.0001). These responses also appeared to deepen over time, Dr. Mateos and colleagues reported. Those assigned to the daratumumab plus VMP group had a significantly higher rates of measurable residual disease–negativity: 28% vs. 7%, respectively (p<0.0001).
No new safety concerns were identified during the longer-term follow-up, the researchers added. During cycles 1 through 9, serious adverse events (AEs) occurred in 132 patients (38%) in the daratumumab group and in 117 patients (33%) in the VMP group. Pneumonia was the most commonly reported serious AE (10% in the daratumumab group and 3% in the VMP group). In addition, fewer daratumumab-treated patients discontinued treatment due to AEs, compared with the VMP-treated patients (7% vs. 9%).
In the maintenance phase, which included 278 patients initially treated with daratumumab, the most common AEs included:
- respiratory infections (upper respiratory tract infections [19%]; bronchitis [15%], and viral upper respiratory tract infections [12%])
- cough (12%)
- diarrhea (10%)
While other frontline combinations, including dexamethasone (Rd) plus daratumumab as well as bortezomib, lenalidomide, and dexamethasone (RVd), are available for this population, the daratumumab plus VMP combination has the advantage of not containing lenalidomide, Dr. Mateos told ASH Clinical News. "Together with efficacy results, physicians have to consider patient features, patient preference, comorbidities, and disabilities, in addition to how we are going to rescue these patients if their disease relapses," she explained. The daratumumab plus VMP combination represents a frontline option that will still allow for the use of lenalidomide- and dexamethasone-based combinations at relapse.
"Another possible approach to improve efficacy would be to add bortezomib to daratumumab as part of the maintenance phase," she added.
The study's findings are limited by its unblinded design, which may have introduced bias, and the continual use of maintenance monotherapy after the combination approach in patients randomized to daratumumab plus VMP.
Study authors reported relationships with Janssen, which sponsored the study.
Mateos MV, 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. Lancet. 2020;395:132-41.