FDA Approves Daratumumab and Hyaluronidase-fihj for High-Risk MM

A new option is now approved to treat adults living with high-risk smoldering multiple myeloma (MM).1 The FDA has greenlit daratumumab and hyaluronidase-fihj (Darzalex Faspro; Janssen Biotech Inc) as a subcutaneous monotherapy at a dose of 1800/30,000 units, respectively. Administration is expected to take between 3 and 5 minutes.

Data from an ongoing phase 3 randomized multicenter study served as the basis of this approval, and they show that median progression-free survival (PFS)—the investigation’s primary efficacy outcome measure—was not evaluable in the study arm of the AQUILA trial (NCT03301220) but was 41.5 months in the active monitoring comparator arm (HR, 0.49; 95% CI, 0.36-0.67; P < .0001). This means those who received daratumumab and hyaluronidase-fihj have a 51% reduced mortality risk from receiving the CD38 monoclonal antibody (also an antineoplastic agent) and the endoglycosidase, which conveys staying power to daratumumab so that it can exert greater effect within the body.2

PFS was defined as time from randomization to active MM per International Myeloma Working Group criteria, and secondary end points were time to biochemical or diagnostic progression, overall response rate, complete response rate, time to frontline treatment for MM, PFS on first-line treatment for MM, overall survival (OS), duration of response, and time to response.3

Data from the ongoing phase 3 AQUILA trial serve as the basis of this approval, and they show that median progression-free survival was not evaluable in the treatment arm but was 41.5 months in the active monitoring comparator arm. | Image Credit: © muh-stock.adobe.com

The patient population was 390 for the AQUILA trial, and the regimens for the treatment arm following 1:1 randomization (n = 194, treatment arm; n = 196, active monitoring) were daratumumab and hyaluronidase-fihj 1800 mg/30,000 units once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24, and once every 4 weeks starting with week 25 until 39 cycles or up to 36 months or until MM diagnosis or unacceptable toxicity. In both arms, patients were followed for 3 years or confirmed progressive disease.4

The FDA previously approved daratumumab and hyaluronidase-fihj as part of a quadruplet regimen with bortezomib, lenalidomide, and dexamethasone for induction and consolidation therapy in patients with MM eligible for autologous stem cell transplant,5 and alone in newly diagnosed or relapsed/refractory MM.6 The combo is also used with bortezomib, melphalan, and prednisone to treat newly diagnosed disease in patients ineligible for autologous stem cell transplant.7

In the AQUILA trial,1 taking place in the US and globally (Argentina, Greece, Israel, Mexico, Russia, and the UK were among the many countries), 41% of the overall patient population displayed 2 or more criteria of the criteria necessary for a diagnosis of high-risk smoldering MM:

• Serum monoclonal protein level greater than 2 g/dL
• Involved-to-uninvolved serum-free light chain ratio greater than 20 mg/L
• Bone marrow plasma cells greater than 20%

Trial inclusion criteria included diagnosis of high-risk smoldering MM for 5 or fewer years with measurable disease at randomization, clonal bone marrow plasma cells of at least 10%, Eastern Cooperative Oncology Group performance status score of 0 or 1, and requirements of pregnancy prevention (either abstain altogether from heterosexual intercourse or use proven highly effective contraception) and to not donate eggs during the study and for at least 3 months after.4 Patients were excluded if they had bone lesions, hypercalcemia, renal insufficiency, anemia, clonal bone marrow plasma cells of 60% or more, serum free light chain ratio of involved:uninvolved of at least 100 mg/L, 1 or more focal lesions measuring 5 mm or larger per MRI, primary systemic amyloid light-chain amyloidosis, or had been treated for other malignancies within 3 years of study randomization.

As recently as 2024, in AQUILA data presented at the American Society of Hematology Annual Meeting and Exposition, significant reductions were seen in risk of smoldering MM advancing to active MM following treatment with daratumumab and hyaluronidase-fihj.8 Most notably, the treated patients demonstrated a 63.1% PFS rate vs 40.8% seen in the active monitoring cohort. Respective 5-year OS rates were 93.0% and 86.9%, and median times to frontline treatment were not reached and 50.2 months (HR, 0.46; 95% CI, 0.33-0.62; P < .0001).

References

1. FDA approves daratumumab and hyaluronidase-fihj for high-risk smoldering multiple myeloma. News release. FDA. November 6, 2025. Accessed November 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-high-risk-smoldering-multiple-myeloma
2. Daratumumab and hyaluronidase-fihj injection. MedlinePlus. Updated September 20, 2024. Accessed November 6, 2025. https://medlineplus.gov/druginfo/meds/a620040.html#:~:text=Daratumumab%20and%20hyaluronidase%2Dfihj%20injection%20is%20used%20alone%20or%20in,Expand%20Section
3. Conroy R. FDA OKs subcutaneous daratumumab in high-risk smoldering multiple myeloma. CancerNetwork®. November 6, 2025. Accessed November 6, 2025. https://www.cancernetwork.com/view/fda-oks-subcutaneous-daratumumab-in-high-risk-smoldering-multiple-myeloma
4. A study of subcutaneous daratumumab versus active monitoring in participants with high-risk smoldering multiple myeloma. ClinicalTrials.gov. Updated October 10, 2025. Accessed November 6, 2025. https://clinicaltrials.gov/study/NCT03301220
5. Caffrey M. On the path to greater precision in treating multiple myeloma. AJMC®. August 18, 2025. Accessed November 6, 2025. https://www.ajmc.com/view/on-the-path-to-greater-precision-in-treating-multiple-myeloma
6. FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. News release. FDA. May 1, 2020. Accessed November 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-multiple-myeloma
7. Daratumumab and hyaluronidase-fihj (subcutaneous route). Mayo Clinic. Updated August 1, 2025. Accessed November 6, 2025. https://www.mayoclinic.org/drugs-supplements/daratumumab-and-hyaluronidase-fihj-subcutaneous-route/description/drg-20489593
8. Inman S. Daratumumab significantly delays smoldering multiple myeloma progression. AJMC. December 9, 2024. Accessed November 6, 2025. https://www.ajmc.com/view/daratumumab-significantly-delays-smoldering-multiple-myeloma-progression