A two-year daratumumab maintenance regimen administered every eight weeks significantly reduced the risk of disease progression or death, compared with observation alone, in patients with newly diagnosed multiple myeloma (MM). This is according to findings from the open-label CASSIOPEIA trial published in The Lancet Oncology.
The two-part trial included patients with newly diagnosed MM who were recruited across 111 academic and community practice centers in Europe. All patients were eligible for high-dose therapy and autologous hematopoietic cell transplant (AHCT).
In the first part of the trial, patients were randomized to receive induction and consolidation with either:
- daratumumab, bortezomib, thalidomide, and dexamethasone (n=543)
- bortezomib, thalidomide, and dexamethasone (n=542)
Patients who experienced a partial response or better following AHCT were then randomly assigned to receive either intravenous daratumumab 16 mg/kg every eight weeks (n=442) or observation only (n=444) for up to two years.
After the second randomization, progression-free survival (PFS) represented the primary endpoint. Researchers led by Philippe Moreau, MD, of the University Hospital of Nantes in France, performed an interim analysis of PFS after 281 events. The investigators also performed efficacy analyses in the maintenance-specific intention-to-treat population, which consisted of all the patients who underwent the second randomization protocol. Safety analyses were conducted in all patients in the daratumumab arm who were treated with one or more doses as well as all patients in the observation-only group.
The median age of each group was 59 years. The majority of patients in the daratumumab group (59%) and the group that received observation only (57%) were male. At baseline, most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (57% vs. 59%) or 1 (39% vs. 39%). Most patients had a standard-risk cytogenetic profile (87% for daratumumab vs. 84% for observation only).
During the maintenance period, the median number of daratumumab doses received was 14. In the daratumumab and observation-only groups, the median durations of treatment or observation during maintenance were 24 months and 24.2 months, respectively.
The median PFS at the median follow-up of 35.4 months was not reached in the daratumumab group and 46.7 months (95% CI 40.0–not estimable) in the observation-only group (hazard ratio = 0.53; 95% CI 0.42-0.68; p<0.0001). In a prespecified analysis of PFS, the investigators found a significant interaction between maintenance therapy and prior use of daratumumab in induction and consolidation treatment (p<0.0001).
According to the researchers, significant PFS benefit was only observed in patients who were naïve to treatment with daratumumab. “This raises questions about the precise strategy for how to implement daratumumab in the maintenance setting,” they wrote.
Common grade 3 or 4 adverse events (AEs) in the daratumumab and observation-only groups included lymphopenia (4% vs. 2%, respectively), hypertension (3% vs. 2%), and neutropenia (2% vs. 2%). A proportionally higher rate of serious AEs was reported in the daratumumab arm (23%) versus the observation-only arm (19%). A total of two AEs in the daratumumab group resulted in death. The deaths were attributable to septic shock (n=1) and natural killer-cell lymphoblastic lymphoma (n=1) and were related to treatment.
The investigators noted that the limitations of the study included the use of observation rather than lenalidomide as a comparator group as well as the “finite duration of the maintenance” phase. While the use of eight-week dosing intervals were supported by available data at the time of the study, subsequent data from the phase II CENTAURUS trial indicated that once-every-eight-week dosing “could be insufficient to maintain target suppression, and as a result, dosing every four weeks has become the preferred daratumumab regimen in ongoing maintenance studies.”
Study authors report relationships with Janssen, which funded the study.
Moreau P, Hulin C, Perrot A, et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): An open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(10):1378-1390.