Pune, India | November 07, 2025
The FDA recently approved daratumumab combined with hyaluronidase-fihj (Darzalex Faspro) for adults diagnosed with high-risk smoldering multiple myeloma. Previously, patients within this category often waited until the disease progressed into full multiple myeloma before receiving any treatment. Consequently, early intervention was largely unavailable. According to the FDA’s official announcement, the approval is based on results from the pivotal AQUILA trial. That is compared to the new therapy against standard active monitoring practices in this patient population.
The randomized AQUILA trial enrolled 390 patients, who either received daratumumab and hyaluronidase-fihj or continued active monitoring without treatment. Those in the treatment group received a subcutaneous dose of 1,800 mg of daratumumab combined with 30,000 units of hyaluronidase weekly initially, then bi-weekly, and later every four weeks. Meanwhile, the control group underwent routine monitoring until disease progression occurred. The study defined high-risk smoldering multiple myeloma using precise clinical markers, including serum monoclonal protein levels exceeding 2 g/dL, an involved-to-uninvolved serum-free light chain ratio greater than 20, and bone marrow plasma cells surpassing 20%.
The trial’s primary endpoint measured progression-free survival (PFS) using the International Myeloma Working Group diagnostic criteria, as assessed by an independent review committee. In patients receiving only active monitoring, median PFS reached 41.5 months. Conversely, median PFS in the treatment arm remained unevaluable at the time of analysis, yielding a hazard ratio of 0.49, a 95% confidence interval between 0.36 and 0.67, and a p-value below 0.0001. These results clearly indicate a substantial reduction in the risk of disease progression or death among treated patients.
Additionally, prescribing information emphasizes important safety considerations that clinicians must address. Healthcare providers should monitor for hypersensitivity reactions and other risks related to subcutaneous administration. Other warnings include potential cardiac toxicity, particularly in patients with light chain amyloidosis, as well as infections, neutropenia, thrombocytopenia, and embryo-fetal toxicity. Furthermore, this therapy may interfere with red blood cell antibody screening and cross-matching. The recommended administration involves 1,800 mg of daratumumab combined with 30,000 units of hyaluronidase, delivered subcutaneously over three to five minutes.
This FDA approval represents a major milestone for treating high-risk smoldering multiple myeloma. Historically, clinicians followed a “watch-and-wait” approach, deferring therapy until symptomatic myeloma developed. With this new option, patients and providers can proactively treat the disease at an earlier stage, potentially delaying or preventing the transition to overt multiple myeloma. Consequently, this treatment could reshape disease management and improve long-term outcomes for high-risk patients.
However, the approval is limited strictly to adults with high-risk smoldering multiple myeloma and does not extend to those with lower-risk disease. The FDA has clearly indicated that benefit-risk assessments apply exclusively to this subgroup. Therefore, accurate risk stratification is essential, and physicians must ensure that patients meet the defined criteria before prescribing this therapy.
Clinicians, particularly oncologists and hematologists, should incorporate this approval into shared decision-making discussions with eligible patients. Conversations should cover potential clinical benefits, tolerability, logistics of subcutaneous administration, and ongoing monitoring requirements. Because the therapy is delivered subcutaneously, treatment burden may be lower compared to intravenous alternatives, enhancing patient convenience. Nonetheless, continuous vigilance regarding safety remains critical to optimize outcomes.
In practice, integrating daratumumab and hyaluronidase-fihj into treatment plans requires careful planning. Providers should emphasize early recognition of adverse events, adherence to dosing schedules, and coordination with laboratory monitoring. Additionally, real-world evidence will be essential in confirming trial results and informing long-term treatment strategies. As clinicians gain experience with this therapy, they will better understand its practical implications for patient care.
In conclusion, daratumumab combined with hyaluronidase-fihj establishes a new standard for treating adults with high-risk smoldering multiple myeloma. This FDA approval may transform clinical management by extending progression-free survival and encouraging earlier therapeutic intervention. As physicians implement this therapy, continued collection of long-term data will clarify its overall clinical impact. Patients and providers must engage in thoughtful discussions to weigh benefits, risks, and appropriate timing for early treatment under this approved indication.
