Dr Voorhees on the Significance of the FDA Approval of Subcutaneous Daratumumab for Smoldering Multiple Myeloma

“AQUILA was the first larger phase 3 randomized study rigorously conducted with advanced imaging techniques to show a benefit with regards to progression-free survival in this patient population.”

Peter Voorhees, MD, member of the Hematology Department at Atrium Health Levine Cancer Institute and a professor of Cancer Medicine at the Wake Forest University School of Medicine, discussed the clinical and regulatory significance of the FDA approval of daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) for the treatment of adult patients with high-risk smoldering multiple myeloma, highlighting how this decision reflects a maturation of evidence supporting early therapeutic intervention in a carefully selected population.

According to Voorhees, interest in treating high-risk smoldering multiple myeloma has existed for more than a decade, driven by the recognition that this subset of patients faces a substantial risk of progression to symptomatic disease. Earlier studies, including trials evaluating lenalidomide (Revlimid)–based approaches, demonstrated improvements in progression-free survival (PFS) and, in some cases, overall survival compared with observation. However, limitations related to study size, evolving definitions of high-risk disease, and advances in imaging and risk stratification prevented these data from translating into regulatory approvals at the time.

The November 2025 approval was supported by findings from the phase 3 AQUILA trial (NCT03301220), a large, randomized study designed to rigorously evaluate early intervention using contemporary diagnostic standards. In AQUILA, patients with high-risk smoldering multiple myeloma were randomly assigned to receive subcutaneous daratumumab or active monitoring. At the time of analysis, the median PFS was not reached in the daratumumab arm compared with 41.5 months in the observation arm, corresponding to a statistically significant reduction in the risk of progression (HR, 0.49; 95% CI, 0.36-0.67; P < .0001). Voorhees emphasized that this degree of benefit represents a clinically meaningful delay in progression to active myeloma.

Voorhees noted that AQUILA distinguishes itself from earlier studies by its scale, its randomized design, and its use of modern imaging and risk-assessment techniques to define high-risk smoldering disease. These methodological strengths increase confidence that the observed benefit is attributable to therapy rather than stage migration or under-recognition of early active disease, he explained. Importantly, the trial establishes that a single-agent, immunotherapy-based approach can delay progression in high-risk smoldering multiple myeloma without requiring combination cytotoxic therapy, Voorhees concluded.

From a clinical perspective, Voorhees underscored that this approval does not mandate treatment for all patients with smoldering myeloma but instead reinforces the importance of precise risk stratification. Identifying patients with truly high-risk biology remains essential to ensure that the benefits of early intervention outweigh the risks of overtreatment. He concluded that the approval of subcutaneous daratumumab marks a meaningful step forward, providing a regulatory-endorsed option for clinicians and patients seeking to delay progression while preserving quality of life through a well-tolerated, outpatient therapy.