As reported in The Lancet Oncology by Philippe Moreau, MD, of the University Hospital Hôtel-Dieu, Nantes, and colleagues, an interim analysis of part 2 of the phase III CASSIOPEIA trial has showed significantly prolonged progression-free survival with maintenance daratumumab vs observation following induction and consolidation with or without daratumumab and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma.¹

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 an 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 a 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 alone (n = 444; 229 from the D-VTd group, 215 from the VTd group). Randomization was stratified by the type of induction treatment and the depth of response to induction and consolidation therapy determined by minimal residual disease (MRD) status and postconsolidation response. 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 randomization.

Progression-Free Survival

The preplanned interim analysis is considered the primary analysis of progression-free survival based on the 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 randomization, median progression-free survival was not reached (95% confidence interval [CI] = not evaluable to not evaluable) in the daratumumab group vs 46.7 months (95% CI = 40.0 months to 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 to not evaluable for all). A significant progression-free survival benefit was found for the VTd-plus-daratumumab group vs the 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).

In other subgroup analyses, hazard ratios were 0.46 (95% CI = 0.31–0.67) among MRD-positive patients and 0.61 (95% CI = 0.44–0.83) among MRD-negative patients, 0.58 (95% CI = 0.45–0.75) among those with a very good partial response or better and 0.39 (95% CI = 0.21–0.73) among those with a partial response, and 0.43 (95% CI = 0.25–0.73) among those with high and 0.62 (95% CI = 0.48–0.82) among those with standard cytogenetic risk.

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 < .0001), MRD negativity and complete response or better (59% vs 47%, OR = 1.80, P = .0001), and 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 in the observation group. At least one subsequent antimyeloma treatment was received by 16% of patients given daratumumab and 41% of patients on observation who received VTd induction/consolidation and by 19% and 18% who received D-VTd.

Adverse Events

The most common grade 1 or 2 adverse events in the daratumumab group were bronchitis (38% vs 29% in the observation group), cough (18% vs 9%), and nasopharyngitis (17% vs 11%). Grade ≥ 3 adverse events occurred in 28% of 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 or 2) in the VTd-plus-daratumumab group and 2% of those (all grade 1 or 2) in the D-VTd-plus-daratumumab group. Infections occurred in 78% (89% grade 1 or 2) vs 64% of patients (89% grade 1 or 2).

Serious adverse events occurred in 23% vs 19% of patients. Second primary malignancies occurred in 24 vs 12 patients (solid tumor in 19 vs 11, hematologic malignancy in 5 vs 1). Adverse events led to discontinuation of daratumumab in 3% of patients. Adverse events led to death in two patients in the daratumumab group, due to septic shock and lymphoblastic lymphoma; 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.”

DISCLOSURE: The study was funded by the Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development. Dr. Moreau has received honoraria from and served on advisory boards for Celgene, Janssen, Amgen, AbbVie, and Sanofi.

REFERENCE

1. 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 22:1378-1390, 2021.