The FDA and the European Medicines Agency (EMA) are reviewing applications for subcutaneous daratumumab (Darzalex Faspro in the US, Darzalex in Europe) as a monotherapy for patients with high-risk smoldering multiple myeloma. These submissions are supported by data from the phase 3 AQUILA trial (NCT03301220), with initial results slated for presentation at the 2024 ASH Annual Meeting.
Johnson & Johnson's Global Therapeutic Area Head of Oncology and Innovative Medicine, Dr. Yusri Elsayed, emphasized the existing need for effective and well-tolerated early interventions for individuals with smoldering multiple myeloma who are at high risk of progressing to active disease. Daratumumab has already significantly impacted the treatment of multiple myeloma, and this submission aims to potentially establish it as the first approved treatment for high-risk smoldering multiple myeloma, potentially reshaping the treatment approach.
The AQUILA Trial
AQUILA is a multicenter, randomized, open-label study comparing subcutaneous daratumumab to observation in patients (age 18+) with high-risk smoldering multiple myeloma diagnosed within the past 5 years. Key inclusion criteria included measurable disease, defined as a serum M protein level of at least 10 g/L, and a clonal bone marrow plasma cell (BMPC) level of at least 10%, along with at least one additional risk factor. These risk factors included a serum M protein level of at least 30 g/L, IgA smoldering multiple myeloma, immunoparesis, an abnormal free light chain ratio, or clonal BMPCs between 50% and 60% with measurable disease. Patients were also required to have an ECOG performance status of 0 or 1.
Exclusion criteria encompassed patients requiring multiple myeloma treatment (e.g., those with bone lesions, hypercalcemia, renal insufficiency, or anemia), primary systemic amyloid light-chain amyloidosis, prior exposure to anti-CD38 therapies (including daratumumab), ongoing corticosteroid or monoclonal antibody treatment, and a history of other malignancies within 3 years (excluding certain skin cancers and non-invasive lesions).
The trial randomized 390 patients to either the experimental arm (1800 mg subcutaneous daratumumab plus 2000 U/mL recombinant human hyaluronidase) or the observation arm. Daratumumab was administered weekly for the first two 28-day cycles, every two weeks for cycles 3-6, and every four weeks thereafter, for up to 39 cycles (36 months), until disease progression, unacceptable toxicity, or patient withdrawal. The control arm underwent observation with the same disease evaluations as the experimental arm.
The primary endpoint of the AQUILA trial is progression-free survival (PFS) as defined by the International Myeloma Working Group criteria. Secondary endpoints include time to biochemical or diagnostic progression, overall response rate (ORR), complete response rate (CRR), time to first-line treatment for multiple myeloma, time to second progression, overall survival (OS), the proportion of patients whose disease progresses to multiple myeloma with adverse prognostic features, duration of response, time to response, and pharmacokinetics.
