FDA, EMA Receive Applications for Subcutaneous Daratumumab in High-Risk Smoldering Myeloma

The FDA and European Medicines Agency (EMA) have received applications seeking the approval of subcutaneous daratumumab (daratumumab and hyaluronidase-fihj [Darzalex Faspro] in the United States; daratumumab [Darzalex] in Europe) as monotherapy for the treatment of patients with high-risk smoldering multiple myeloma.¹

Both applications are supported by data from the phase 3 AQUILA trial (NCT03301220). Initial findings from the study will be presented at the 2024 ASH Annual Meeting in December.

“There remains an unmet need for early interventions and treatments that are both effective and well tolerated in people living with smoldering multiple myeloma at high risk of progressing to active multiple myeloma,” Yusri Elsayed, MD, MHSc, PhD, the global therapeutic area head of Oncology and Innovative Medicine at Johnson & Johnson, stated in a news release. “Daratumumab has changed the standard of care in multiple myeloma, and with these submissions to the FDA and EMA, this therapy could become the first approved treatment for patients with high-risk smoldering multiple myeloma, potentially shifting the treatment paradigm.”

AQUILA was a multicenter, randomized, open-label study that evaluated subcutaneous daratumumab vs observation in patients at least 18 years of age who had high-risk smoldering multiple myeloma for no more than 5 years.² Patients were required to have measurable disease at randomization, which was defined as a serum M protein level of at least 10 g/L.

Patients were also required to have a clonal bone plasma cells (BMPCs) level of at least 10% and at least 1 of the following risk factors: a serum M protein level of at least 30 g/L; immunoglobulin (Ig)A smoldering multiple myeloma; immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes; an uninvolved free light chain ratio of at least 8 and less than 100; or clonal BMPCs of more than 50% and less than 60% with measurable disease. An ECOG performance status of 0 or 1 was also required.

Patients with multiple myeloma that required treatment, including those with bone lesions, hypercalcemia, renal insufficiency, and anemia, were excluded. Other key exclusion criteria consisted of primary systemic amyloid light-chain amyloidosis; prior exposure to daratumumab or other anti-CD38 therapies, or investigational treatments for smoldering multiple myeloma or multiple myeloma; ongoing treatment with corticosteroids; ongoing treatment with other monoclonal antibodies; and treatment for another malignancy within 3 years of enrollment, other than squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesions.

Patients (n = 390) who were randomly assigned to the experimental arm received 1800 mg of daratumumab plus 2000 U/mL of recombinant human hyaluronidase subcutaneously once per week in the first 2 28-day cycles, once every 2 weeks in cycles 3 to 6, and once every 4 weeks thereafter.^1,2 Treatment continued for up to 39 cycles or 36 months, or until disease progression, unacceptable toxicity, or patient withdrawal. Patients in the control arm underwent observation and received the same disease evaluations as those in the experimental arm.²

Progression-free survival per International Myeloma Working Group criteria served as the trial’s primary end point. Secondary end points included time to biochemical or diagnostic progression; overall response rate; complete response rate; time to first-line treatment for multiple myeloma; time to second progression; overall survival; the proportion of patients whose disease progresses to multiple myeloma with adverse prognostic features; duration of response; time to response; and pharmacokinetics.

References

1. Johnson & Johnson submits applications in the U.S. and EU seeking approval of Darzalex Faspro/Darzalex (daratumumab) as subcutaneous monotherapy for high-risk smouldering multiple myeloma. News release. Johnson & Johnson. November 8, 2024. Accessed November 8, 2024. https://www.jnj.com/media-center/press-releases/johnson-johnson-submits-applications-in-the-u-s-and-eu-seeking-approval-of-darzalex-faspro-darzalex-as-subcutaneous-monotherapy-for-high-risk-smoldering-multiple-myeloma
2. A study of subcutaneous daratumumab versus active monitoring in participants with high-risk smoldering multiple myeloma. ClincialTrials.gov. Updated October 26, 2024. Accessed November 8, 2024. https://clinicaltrials.gov/study/NCT03301220