Johnson & Johnson has submitted an application to the U.S. Food and Drug Administration (FDA) seeking approval for daratumumab (Darzalex) as a subcutaneous monotherapy for patients with high-risk smoldering multiple myeloma (SMM). This submission aims to provide the first approved treatment option for individuals at high risk of progressing to multiple myeloma (MM). The applications, also submitted in Europe, are based on data from the phase 3 AQUILA study (NCT03301220).
MM is the second most common hematologic malignancy, characterized by the proliferation of dysfunctional B lymphocytes, leading to renal failure, brittle bones, and immune suppression. Patients with SMM face a 10% annual risk of progressing to MM, with the highest risk occurring in the first five years post-diagnosis. Approximately 15% of newly diagnosed MM cases are classified as SMM, and half of those diagnosed as high-risk will progress to active MM.
Unmet Need in Smoldering Multiple Myeloma
Currently, there is no approved treatment for SMM. Clinical practice focuses on active monitoring, identifying signs of biochemical progression or end-organ damage. However, studies suggest that earlier therapeutic intervention with agents like daratumumab may benefit patients at high risk of progression.
Daratumumab's Mechanism and Prior Approvals
Daratumumab is a monoclonal antibody that targets CD38, a glycoprotein highly expressed on malignant plasma cells. CD38 compromises treatment response and enhances the proliferation of diseased cells. Initially approved in November 2015, daratumumab has received nine indications, including treatment for MM in the frontline setting and for newly diagnosed patients eligible or ineligible for transplant.
AQUILA Study Details
The phase 3, randomized, open-label, multicenter AQUILA study evaluated whether subcutaneously administered daratumumab prolongs progression-free survival (PFS) in 390 patients with high-risk SMM. Patients were randomized to receive daratumumab (1,800 mg DARA + rHuPH20 [2,000 U/mL] administered subcutaneously every week for Cycles 1 and 2, every 2 weeks for Cycles 3 to 6, and every 4 weeks thereafter for up to 39 cycles or 36 months) or active monitoring. The primary endpoint was progression-free survival, with secondary endpoints including time to progression, overall response rate, and overall survival.
Expert Commentary
"There remains an unmet need for early interventions and treatments that are both effective and well tolerated in people living with [SMM] at high-risk of progressing to active [MM]," said Yusri Elsayed, MD, MHSc, PhD, global therapeutic area head in oncology for innovative medicine at Johnson & Johnson, in a news release. "[Daratumumab] has changed the standard of care in [MM], and with these submissions to the FDA and EMA, this therapy could become the first approved treatment for patients with high-risk [SMM], potentially shifting the treatment paradigm."
