Clinicians currently treat patients with high-risk smoldering multiple myeloma (SMM) by actively monitoring them. However, new results indicate that these patients not only tolerate daratumumab (D) monotherapy well, but compared with active monitoring, they experience a delay to progression or prevention of active MM. Meletios-Athanasios Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece, presented this finding from the phase III Aquila study at the 66th American Society of Hematology Annual Meeting and Exposition in San Diego.
The study enrolled 390 patients randomized to D (n=194) or active monitoring (n=196). The two groups were balanced for median age (64 years) and time from initial SMM diagnosis to randomization (0.72 years). The median treatment duration in the D group was 38 cycles (35 months).
At a median follow-up of 65.2 months, patients receiving D had a significantly better progression-free survival (PFS) than those receiving active monitoring (hazard ratio [HR] = 0.49; 95% CI 0.36-0.67; p<0.001). While the median PFS was not reached in the D group, the active monitoring group had a PFS of 41.5 months. The investigators estimated the 60-month PFS rates to be 63.1% for those treated with D and 40.8% for those who received active monitoring. Lastly, prespecified analyses revealed consistent PFS improvement across subgroups with D versus active monitoring.
“Based on the improved PFS in favor of daratumumab compared to placebo, this study may be practice changing as far as patients with SMM and high-risk features are concerned,” Dr. Dimopoulos said. “The importance of the study is reinforced further with the improved survival data that we also observed.”
Treated patients also had a significantly higher overall response rate than untreated patients (63.4% vs. 2.0%, p<0.0001). The time to first-line MM treatment was prolonged with D compared with active monitoring such that, at the time of clinical cutoff, 33% of patients in the D group and 52% of patients in the active monitoring group had started first-line MM treatment. When the researchers calculated a median time from randomization to the date of first-line MM treatment, they found that while such time was not reached in the D group, patients in the active monitoring group achieved that median time at 50.2 months. The investigators also noticed a positive trend favoring D for PFS2 and overall survival.
Dr. Dimopoulos concluded that the results strongly support the benefit of early intervention with D monotherapy versus active monitoring in patients with high-risk SMM. “I was expecting that the study would be positive as far as PFS is concerned, but I was pleasantly surprised to see an overall benefit as well,” he said. Patients with SMM who are most likely to benefit from D monotherapy are those who fulfilled the inclusion criteria of the study, which means they have clonal bone marrow plasma cells (BMPCs) of at least 10% and at least one of the following risk factors: serum M-protein at least 30 g/L, IgA SMM, immunoparesis with reduction of two uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio greater than or equal to 8 and less than 100, and clonal BMPCs greater than 50% and less than 60%.
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Dimopoulos M-A, Voorhees PM, Schjesvold F, et al. Phase 3 randomized study of daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma: primary results of the Aquila Study. Abstract 773. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 9, 2024; San Diego, California.
