Daratumumab Offers Hope for Delaying Progression to Active MM: Peter Voorhees, MD

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The management of smoldering multiple myeloma (MM) is intensely focused on strategies that can change its natural history of smoldering multiple myeloma, that intermediate stage between monoclonal gammopathy of undetermined significance and full-fledged active MM.

On November 6, the FDA approved daratumumab and hyaluronidase-fihj (Darzalex Faspro; Janssen Biotech Inc) as a subcutaneous monotherapy for high-risk smoldering multiple myeloma based on results from the randomized phase 3 AQUILA trial (NCT03301220). This subcutaneous formulation, at a dose of 1800/30,000 units, requires only 3 to 5 minutes for administration.

AQUILA enrolled 390 high-risk patients. High risk was defined by the following criteria: having clonal bone marrow plasma cells of at least 10%, an M spike of 3 g/dL or higher, or an involved-to-uninvolved free light chain ratio of at least 8 but less than 100. Patients were randomized 1:1 to receive either active monitoring (the prior standard of care) or daratumumab for up to 36 months.

The trial’s primary end point was progression-free survival (PFS), defined as progression to active multiple myeloma based on the International Myeloma Working Group SLiM-CRAB Criteria, not just biochemical progression. Daratumumab demonstrated superior efficacy in delaying progression. The median PFS for the active monitoring arm was 41.5 months, while the median PFS in the daratumumab arm was not reached. Patients treated with daratumumab and hyaluronidase-fihj experienced a 51% reduced mortality risk vs the active monitoring cohort, achieving a 63.1% PFS rate vs 40.8% among those actively monitored. The overall response rate was 60%, double that previously seen in relapsed/refractory MM.

Secondary end points also favored the treatment. The median time to first treatment was not reached in the daratumumab arm compared with 50.2 months for active monitoring. Furthermore, patients on the daratumumab arm outperformed the control group regarding PFS on their first subsequent treatment (PFS2).

In an interview with The American Journal of Managed Care^® about the daratumumab approval, Peter Voorhees, MD, hematologist, Medical Oncology, Atrium Health Levine Cancer Institute, noted, “I don't necessarily think that there was anything that was all that surprising, to be honest with you. We know that the CD38 antibodies are very active in multiple myeloma. We figured that daratumumab monotherapy would perform better in patients with smoldering multiple myeloma compared to those who have relapsed/refractory disease.”