Johnson & Johnson's Darzalex (daratumumab) is poised to become the first approved treatment for smoldering multiple myeloma (SMM), an early-stage precursor to multiple myeloma, following positive Phase 3 AQUILA trial results. The data, presented at the American Society of Hematology (ASH) annual meeting and published in The New England Journal of Medicine, support regulatory applications submitted to both the FDA and EMA for Darzalex Faspro, a subcutaneous formulation.
The AQUILA study randomized 390 patients with high-risk SMM to either Darzalex Faspro or active monitoring. After a median follow-up of 65.2 months, Darzalex Faspro demonstrated a statistically significant improvement in progression-free survival (PFS), the trial's primary endpoint. Specifically, the data showed a 51% reduction in the risk of disease progression or death compared to active monitoring (HR=0.49, 95% CI: 0.34-0.70). The estimated 60-month PFS rate was 63.1% in the Darzalex Faspro arm versus 40.8% in the active monitoring arm.
Clinical Impact and Expert Opinions
The potential approval of Darzalex for SMM has sparked debate among myeloma experts. Dr. Ola Landgren from the University of Miami, who was not involved in the study, anticipates regulatory approval. However, Dr. Hearn Jay Cho, CMO of the Multiple Myeloma Research Foundation, raises concerns about potentially undertreating patients on the cusp of developing active myeloma with a less intensive therapy like Darzalex monotherapy.
Conversely, Dr. Irene Ghobrial from the Dana-Farber Cancer Institute argues that the data definitively demonstrate the benefit of early treatment in high-risk SMM, stating, "You can’t argue anymore that there is no benefit from early treatment." She plans to incorporate Darzalex into her treatment approach for select SMM patients.
Additional Trial Data
Beyond PFS, the AQUILA trial also reported an overall response rate (ORR) of 63.4% in the Darzalex Faspro group compared to 2.0% in the active monitoring group. Overall survival (OS) was also extended with Darzalex Faspro, with five-year survival rates of 93% versus 86.9% for active monitoring. At the data cutoff, 33.0% of patients in the Darzalex Faspro group and 52.0% of the active monitoring group had initiated first-line treatment for multiple myeloma.
Darzalex's Existing Market and Competition
Darzalex is already a blockbuster drug for Johnson & Johnson, approved for various multiple myeloma indications since 2015. In 2023, it generated approximately $9.7 billion in sales, and $8.6 billion in the first nine months of 2024. An SMM approval could further solidify its market position and potentially create distance from competitors like Sanofi's Sarclisa (isatuximab), which recently gained approval as a first-line multiple myeloma treatment in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for transplant-ineligible patients.
Smoldering Multiple Myeloma: An Unmet Need
Smoldering multiple myeloma accounts for approximately 15% of newly diagnosed multiple myeloma cases. Currently, SMM is typically monitored until the development of active multiple myeloma, at which point treatment is initiated. The AQUILA trial suggests that early intervention with Darzalex Faspro may delay or prevent progression to active disease in high-risk patients, potentially improving long-term outcomes.
