Pune, India | November 07, 2025
The U.S. Food and Drug Administration (FDA) has approved the combination of daratumumab and hyaluronidase-fihj (Darzalex Faspro) for adults with high-risk smoldering multiple myeloma. It marks a transformative development in early myeloma management. Until now, most individuals with smoldering multiple myeloma had to wait until their disease advanced into active multiple myeloma before initiating treatment. However, this decision now enables earlier therapeutic intervention and potentially better long-term outcomes. The approval arises from data presented in the pivotal AQUILA clinical trial. That is compared to daratumumab and hyaluronidase-fihj against standard active monitoring.
The AQUILA trial, a randomized study involving 390 participants, evaluated the efficacy and safety of the subcutaneous regimen. Patients who received daratumumab and hyaluronidase-fihj were administered a subcutaneous dose of 1,800 mg/30,000 units, first weekly. Then every two weeks, and finally every four weeks as maintenance. In contrast, those in the active monitoring group continued follow-up without any therapeutic intervention until disease progression occurred. High-risk smoldering multiple myeloma was characterized by one or more of the following criteria: serum monoclonal protein levels above 2 g/dL. An involved-to-uninvolved serum-free light chain ratio exceeding 20, or bone marrow plasma cell infiltration greater than 20%, as per standardized diagnostic definitions.
Progression-free survival (PFS) served as the primary endpoint, judged by an independent review committee using the diagnostic guidelines of the International Myeloma Working Group (IMWG). In the monitoring arm, the median PFS was 41.5 months. On the other hand, the median PFS had not been reached in the treatment arm at the time of analysis. The statistical data showed a hazard ratio of 0.49, with a 95% confidence interval ranging between 0.36 and 0.67, and a p-value below 0.0001. These findings illustrate a nearly 50% reduction in the risk of disease progression or death, underscoring the therapy’s promising impact.
Furthermore, the prescribing information outlines essential safety precautions. Healthcare professionals should watch for hypersensitivity and administration-related reactions during treatment. The drug label also includes warnings about potential cardiac toxicity, infections, neutropenia, thrombocytopenia, and embryo-fetal risks. It is especially in patients with light chain amyloidosis. Additionally, daratumumab may interfere with red blood cell antibody testing and cross-matching, necessitating careful pre-treatment evaluation. The recommended dosage remains 1,800 mg of daratumumab with 30,000 units of hyaluronidase, administered subcutaneously over three to five minutes.
This approval represents an essential milestone in managing smoldering multiple myeloma. It is particularly for those identified as having a high risk of progression. Traditionally, clinical management of smoldering myeloma relied heavily on observation and deferred treatment until symptoms or active disease appeared. Now, physicians and patients can adopt a more proactive stance, targeting the disease earlier in its development. Consequently, this shift might delay or even prevent the transition into symptomatic multiple myeloma. Thereby enhancing patients’ long-term survival and quality of life.
Nevertheless, the FDA emphasizes that the new indication applies strictly to high-risk smoldering myeloma and not to individuals with lower-risk or intermediate disease. The agency notes that it performed the benefit-risk evaluation exclusively for this specific subgroup. Therefore, careful and precise risk stratification becomes vital to ensure appropriate patient selection. Physicians must confirm eligibility through validated criteria before administering the therapy, ensuring that the treatment benefits outweigh potential risks.
In practice, oncologists and hematologists should incorporate this approval into collaborative treatment discussions with their patients. They should address the treatment’s possible advantages, administration methods, tolerability, and post-treatment monitoring requirements. Because the therapy uses a subcutaneous route, many patients may find it less burdensome than conventional intravenous regimens, which often require longer infusion times. Nonetheless, clinicians must maintain diligent safety monitoring and educate patients regarding possible adverse effects. The importance of laboratory follow-up throughout the treatment course.
The broader implications of this approval extend beyond immediate clinical outcomes. As more patients receive daratumumab-hyaluronidase for high-risk smoldering myeloma, future studies and real-world data will refine the understanding of its long-term efficacy, durability of response, and cost-effectiveness. These continuous insights may help refine treatment protocols and further personalize therapeutic decisions.
In conclusion, the FDA’s approval of daratumumab and hyaluronidase-fihj marks a major advancement in the management of high-risk smoldering multiple myeloma. This combination introduces a new therapeutic standard aimed at delaying disease progression and potentially improving overall prognosis. By offering clinicians a validated option for early intervention, it shifts clinical practice toward more proactive disease control. As this therapy becomes integrated into patient care, ongoing observation and evidence collection will determine its ultimate role in shaping the treatment landscape for smoldering and active multiple myeloma alike.
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