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

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.

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.