FDA Panel Backs First Treatment for High-Risk Smoldering Multiple Myeloma
An FDA advisory committee has recommended approval of the first-ever treatment specifically targeting high-risk smoldering multiple myeloma, potentially transforming how oncologists approach this precursor condition that frequently progresses to full-blown cancer.
In a significant vote on Tuesday, the Oncologic Drugs Advisory Committee endorsed Johnson & Johnson's DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) for patients with high-risk smoldering multiple myeloma , acknowledging its favorable benefit-risk profile. The subcutaneous therapy, if approved by the FDA, would replace the current "watch and wait" standard that leaves patients monitoring their condition until it worsens into active multiple myeloma.
"This represents a paradigm shift in how we approach precursor myeloma conditions," said an oncology specialist familiar with the clinical trial data. "Rather than waiting for organ damage to occur, we could potentially intervene early enough to change the disease trajectory."
Breaking the "Watch and Wait" Paradigm
Smoldering multiple myeloma occupies an unsettling middle ground—patients have abnormal plasma cells and protein levels but lack the symptoms and organ damage that define active disease. While approximately 15% of newly diagnosed multiple myeloma cases initially present as smoldering, those classified as high-risk face a sobering outlook: about half will progress to active disease within just two to three years.
Currently, these patients face a frustrating reality. Despite knowing they have a high probability of developing cancer, the standard approach involves regular monitoring without intervention—a "watch and wait" approach that continues until progression markers appear or symptoms develop.
The Phase 3 AQUILA trial, which provided the foundation for J&J's application, enrolled 390 patients and randomly assigned them to either receive DARZALEX FASPRO or undergo standard monitoring. The results were compelling: treatment reduced the risk of progression to active myeloma or death by 51% compared to observation alone. After five years, 63.1% of treated patients remained progression-free versus 40.8% in the monitoring group.
Even more striking was the difference in median time to progression—44.1 months for treated patients compared to just 17.8 months for those under observation. This translates to more than two additional years before disease advancement.
Moving Upstream in the Treatment Cascade
DARZALEX FASPRO is already a cornerstone therapy for multiple myeloma, with FDA approvals spanning eight indications across newly diagnosed and relapsed settings. The antibody targets CD38, a protein abundantly expressed on myeloma cells, and is administered as a subcutaneous injection that takes approximately 15 minutes.
"High-risk smoldering multiple myeloma remains a challenging clinical conundrum with no approved therapies, and earlier intervention may delay or even prevent progression to active multiple myeloma," said Peter Voorhees, M.D., of Atrium Health/Levine Cancer Institute in Charlotte, N.C., who was quoted in Johnson & Johnson's announcement.
If approved by the FDA, which typically follows advisory committee recommendations, DARZALEX FASPRO would become the first treatment specifically indicated for HR-SMM. Johnson & Johnson submitted its application to the FDA in November 2024, and a final decision is anticipated in the third quarter of 2025.
Balancing Benefits Against Treatment Burden
The advisory committee's deliberations focused on a critical question: Does treating an asymptomatic condition justify exposing patients to potential side effects and the burden of therapy?
The AQUILA data showed that grade 3-4 adverse events occurred in 40.4% of patients receiving DARZALEX FASPRO compared to 30.1% in the observation group. Most side effects aligned with the therapy's established safety profile, including fatigue and infections, which were generally manageable with standard care approaches.
An emerging survival advantage may have influenced the committee's decision. Five-year overall survival favored the treatment arm (93.0% versus 86.9%), suggesting that early intervention could potentially extend lives rather than simply delay disease progression.
Market Implications and Access Considerations
The stakes are considerable. Multiple myeloma affects over 35,000 Americans annually, with approximately 5,300 new HR-SMM cases diagnosed each year. Globally, improving diagnostic capabilities may identify even more candidates for early intervention.
Financial analysts estimate that this new indication could generate $1-1.5 billion in annual sales at peak for Johnson & Johnson, adding to the DARZALEX franchise that already exceeds $11 billion in global sales. The therapy's subcutaneous formulation holds patent protection until 2035, potentially insulating it from biosimilar competition.
However, questions remain about insurance coverage and access. The cost of the therapy—approximately $180,000 per treatment course—could face scrutiny from insurers reluctant to cover treatment for an asymptomatic condition without robust cost-effectiveness data.
Implications for Patients and Providers
For patients diagnosed with HR-SMM, the prospect of active treatment represents both hope and complexity. While many may welcome an option to potentially prevent or significantly delay progression to symptomatic disease, others might hesitate to begin therapy when they feel well.
"The key will be precise risk stratification," noted a hematology researcher not involved in the trial. "We need to confidently identify which patients truly have high-risk disease to ensure we're treating the right population."
The Mayo Clinic's 2018 risk assessment model has become a widely accepted method for identifying high-risk patients, though consistent application across community oncology practices will be essential to avoid overtreatment.
Looking Ahead
The FDA's final decision on DARZALEX FASPRO for HR-SMM is expected in the coming months. If approved, medical societies such as the National Comprehensive Cancer Network and International Myeloma Working Group would likely update their clinical practice guidelines to incorporate this new treatment approach.
Meanwhile, researchers continue exploring combination strategies that might further improve outcomes. Earlier intervention with DARZALEX FASPRO alongside immunomodulatory drugs or newer bispecific antibodies could potentially deepen responses and extend the window before active disease emerges.
As Sen Zhuang, M.D., Vice President of Oncology Clinical Research at Johnson & Johnson Innovative Medicine, stated: "The proactive approach demonstrated in the AQUILA study is an example of Johnson & Johnson's aspiration to get in front of cancer by providing a platform to treat disease before progression to active disease."
For patients caught in the uncertain space between health and cancer, this shift from watchful waiting to active prevention could transform what has long been a clinical conundrum into a manageable condition—potentially changing not just when we treat multiple myeloma, but fundamentally altering its natural history for thousands of patients each year.