FDA Approves Daratumumab for High-Risk Smoldering Multiple Myeloma Following Landmark AQUILA Trial Results
核心洞察
The FDA approved subcutaneous daratumumab (Darzalex Faspro) in November 2025 for treating high-risk smoldering multiple myeloma, marking the first regulatory approval for this indication.
The phase 3 AQUILA trial demonstrated that daratumumab monotherapy reduced the risk of progression to active multiple myeloma by 51% compared to active monitoring.
Patients at highest risk showed even greater benefit with a 64% reduction in progression risk when applying IMWG 20/20 criteria for defining high-risk disease.
The FDA has approved subcutaneous daratumumab and hyaluronidase-fihj (Darzalex Faspro) for the treatment of high-risk smoldering multiple myeloma (HR-SMM) in November 2025, marking the first regulatory approval for this indication. The approval was based on results from the landmark phase 3 AQUILA study (NCT03301220), which demonstrated that daratumumab monotherapy significantly reduced the risk of progression to active multiple myeloma by 51%.
Addressing an Unmet Medical Need
Prior to the AQUILA study, there was no clear standard of care nor regulatory approvals for therapy in smoldering multiple myeloma. The approval targets patients with HR-SMM who have a 50% likelihood of developing active multiple myeloma during the first two years of monitoring, addressing a critical gap in cancer care.
The foundation for investigating early intervention in SMM was established by two precursor randomized trials. The Spanish Myeloma Group (搜索)'s phase 3 QUIREDEX study (NCT00480363) compared lenalidomide with dexamethasone for two years versus active monitoring, showing that lenalidomide treatment reduced the risk of progression to active multiple myeloma and conferred an overall survival advantage. Similarly, the phase 3 ECOG-ACRIN study (NCT01169337) comparing lenalidomide monotherapy versus active monitoring demonstrated a reduction in progression risk, with patients with HR-SMM deriving the most benefit.
AQUILA Trial Design and Results
The AQUILA trial evaluated daratumumab monotherapy versus active monitoring in patients with HR-SMM. Patients in the daratumumab arm received the agent for three years, while those in the active monitoring arm followed standard protocol. Both arms underwent rigorous follow-up to ensure that progression to active disease would be detected early and uniformly regardless of treatment arm.
The study's primary endpoint was progression-free survival (PFS) to active multiple myeloma, defined by the International Myeloma Working Group (搜索) (IMWG) SLiM-CRAB criteria. Daratumumab monotherapy significantly reduced the risk of progression from smoldering to active multiple myeloma by 51% (HR, 0.49). This benefit was statistically significant and observed across various subgroups by age, cytogenetics, and performance status.
Enhanced Benefit in Highest-Risk Patients
When applying the IMWG 20/20 criteria for defining HR-SMM, the benefit was even more pronounced with a hazard ratio of 0.36, indicating that patients at highest risk of progression derived the greatest PFS benefit. This represents a 64% reduction in progression risk for the most vulnerable patient population.
Secondary Endpoints and Long-term Outcomes
Daratumumab also significantly delayed the need for first-line treatment for active multiple myeloma among the trial's secondary endpoints. The median time to first-line treatment was not reached in the daratumumab arm, compared with 50 months for the active monitoring arm. Secondary analysis regarding PFS on first-line treatment for active multiple myeloma (PFS2) was also improved in the daratumumab arm.
While the formal overall survival analysis had not been triggered due to a low number of events, an interim analysis showed promising results. At five years, 93% of patients in the daratumumab arm remained alive, compared with 87% in the active monitoring arm (HR, 0.52).