As reported in The Lancet Oncology by Philippe Moreau, MD, and colleagues, an interim analysis of part 2 of the phase III CASSIOPEIA trial has shown significantly prolonged progression-free survival with maintenance daratumumab vs observation following induction and consolidation with or without daratumumab in addition to autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma.
![Philippe Moreau, MD](/media/14018055/23-moreau.jpg)
Philippe Moreau, MD
Study Details
In part 1 of the European multicenter open-label trial, 1,085 patients aged ≤ 65 years were randomly assigned to receive daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd; n = 543) or bortezomib, thalidomide, and dexamethasone (VTd; n = 542) as induction and posttransplantation consolidation. As previously reported, D-VTd was associated with improved depth of response and significantly better progression-free survival.
In part 2, 886 patients still on study postconsolidation (day 100 post-ASCT) who had experienced partial response or better (458 [84%] of the D-VTd group; 428 [79%] of the VTd group) were randomly assigned between May 2016 and June 2018 to receive daratumumab maintenance (n = 442; 229 from the D-VTd group, 213 from the VTd group) or observation only (n = 444; 229 from the D-VTd group, 215 from the VTd group). Daratumumab maintenance was given at 16 mg/kg every 8 weeks for up to 2 years. The part 2 primary endpoint was progression-free survival from second random assignment.
Progression-Free Survival
The preplanned interim analysis is considered the primary analysis of progression-free survival based on recommendation of the independent data monitoring committee.
At a median follow-up of 35.4 months (interquartile range = 30.2–39.9 months) from second random assignment, median progression-free survival was not reached (95% confidence interval [CI] = not evaluable–not evaluable) in the daratumumab group vs 46.7 months (95% CI = 40.0 months–not evaluable) in the observation group (hazard ratio [HR] = 0.53, 95% CI = 0.42–0.68, P < .0001).
A prespecified analysis showed a significant interaction between maintenance and induction and consolidation therapy (P < .0001). Median progression-free survival was 33.6 months (95% CI = 27.2–37.4 months) in the VTd plus observation group, and not reached in the D-VTd plus daratumumab, D-VTd plus observation, or VTd plus daratumumab groups (95% CI = not evaluable–not evaluable for all). A significant progression-free survival benefit was found for the VTd plus daratumumab group vs VTd plus observation group (HR = 0.32, 95% CI = 0.23–0.46, nominal P < .0001) but not for the D-VTd plus daratumumab group vs the D-VTd plus observation group (HR = 1.02, 95% CI = 0.71–1.47, nominal P = .91).
The daratumumab group had significantly higher rates of:
- Complete response or better (73% vs 61%, odds ratio [OR] = 2.17, P < .0001)
- Improved response (62% vs 47%, OR = 1.95, nominal P < .000)
- Measurable residual disease (MRD) negativity and complete response or better (59% vs 47%, OR = 1.80, P = .0001)
- Conversion to MRD negativity (44% vs 30%, OR = 1.84, nominal P = .0004).
Median overall survival was not reached in either group; at the time of analysis, 29 deaths had occurred in the daratumumab group and 27 had occurred in the observation group.
Adverse Events
Grade ≥ 3 adverse events occurred in 28% of patients in the daratumumab group vs 24% of the observation group, with the most common being lymphopenia (4% vs 2%), hypertension (3% vs 2%), and neutropenia (2% vs 2%). Infusion-related reactions following the first maintenance daratumumab infusion occurred in 55% of patients (90% grade 1–2) in the VTd plus daratumumab group and 2% of those (all grade 1–2) in the D-VTd plus daratumumab group. Serious adverse events occurred in 23% vs 19% of patients. Secondary primary malignancies occurred in 5% vs 3%. Infections occurred in 78% (89% grade 1–2) vs 64% of patients (89% grade 1–2). Adverse events led to death in two patients in the daratumumab group, due to septic shock and lymphoblastic lymphoma, respectively; both deaths were considered related to treatment.
KEY POINTS
- Maintenance daratumumab significantly prolonged progression-free survival vs observation.
- Median progression-free survival was not reached vs 46.7 months.
The investigators concluded, “Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy.”
Dr. Moreau, of the Hematology Clinic, University Hospital Hôtel-Dieu, Nantes, France, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development. For full disclosures of the study authors, visit thelancet.com.