The U.S. Food and Drug Administration (FDA) has recently approved DARZALEX FASPRO® (hyaluronidase-fihj + daratumumab) as a single medication to treat adults with high-risk smoldering multiple myeloma (HR-SMM). DARZALEX FASPRO® is marketed by Janssen Biotech, Inc., a Johnson & Johnson company. It is the first and only FDA-approved treatment for HR-SMM. This approval offers an opportunity for earlier intervention to prevent or delay progression to active multiple myeloma (MM).
SMM is an asymptomatic precursor stage of multiple myeloma characterized by abnormal plasma cells in the bone marrow. However, patients did not experience typical symptoms like anemia, kidney problems, bone pain, slow organ damage, or bone fractures. Approximately 15% of MM cases are classified as SMM, and about half of HR-SMM patients progress to active disease within two years. In 2025, 36,000 U.S. people are expected to be diagnosed with MM, and over 12,000 may die due to it. Currently, management of HR-SMM involves active monitoring, but recent clinical studies highlight that early therapeutic intervention could help prevent or slow the progression of the disease.
This approval was supported by results data from the AQUILA (NCT03301220) clinical study. It was a multicenter, open-label, and Phase-3 randomized trial design. This study aimed to evaluate the safety and efficacy of subcutaneous DARZALEX FASPRO® compared with active monitoring in HR-SMM patients. A total of 390 patients (age ≥18 years) with HR-SMM were included and received DARZALEX FASPRO® for 36 months. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), complete response (CR) rate, progression-free survival on first-line treatment for MM (PFS2), overall response rate (ORR), and time to diagnostic or biochemical (SLiM-CRAB) progression. The median follow-up of the study was found to be 65.2 months. Around 41% of patients exhibited two or more key indicators of HR-SMM, including a serum monoclonal protein concentration of more than 2 g/dL, bone marrow plasma cells of greater than 20%, and a ratio of involved to uninvolved serum free light chain exceeding 20.
This Phase 3 clinical trial demonstrated that 63.1% of patients treated with DARZALEX FASPRO® remained progression-free at 5 years compared to 40.7% in the active monitoring group, with a hazard ratio (HR) of 0.49, 95% confidence interval (CI): 0.36-0.67, and P < 0.001. According to Mayo 2018 (20/2/20) criteria, 41% of the patients were classified as HR-SMM. In sub-group analysis, median PFS was not reached for the DARZALEX FASPRO® group compared to 22.1 months for the active monitoring group with an HR: 0.36, 95% CI: 0.23-0.58. ORRs were significantly higher with DARZALEX FASPRO® patients compared to the monitoring group (63.4% vs 2% and P < 0.001).
The most common adverse effects were reported in ≥20% of patients who received DARZALEX FASPRO®, including diarrhea, sensory neuropathy, musculoskeletal pain, injection site reactions, rash, upper respiratory tract infection, sleep disorder, and fatigue.
Dr. Jordan Schecter, Vice President, R&D, Oncology, Johnson & Johnson, said that “DARZALEX FASPRO® remains a milestone therapy in MM, reflecting our commitment to improving outcomes across all disease stages. The AQUILA study reinforces its significant impact, and this approval enables earlier treatment for HR-SMM patients as well as potentially transforming care and offering hope to people with MM.”
Reference: Johnson & Johnson. DARZALEX FASPRO® is the first and only treatment approved by the U.S. FDA for patients with high-risk smoldering multiple myeloma. Published November 6, 2025. Accessed November 11, 2025. DARZALEX FASPRO® is the first and only treatment approved by the U.S. FDA for patients with high-risk smoldering multiple myeloma
