FDA Advisory Panel Supports Daratumumab for High-Risk Smoldering Multiple Myeloma

An FDA Advisory Panel voted 6-2 in favor of approving daratumumab as a treatment for high-risk smoldering myeloma (SMM) at this week's Oncologic Drugs Advisory Committee (ODAC) meeting. If the FDA follows the panel's recommendations and approves the therapy, it will be the very first treatment approved for high-risk smoldering myeloma. To date, the protocol for SMM has been to "watch and wait," with close monitoring regardless of whether it is low, intermediate, or high-risk.

Understanding High-Risk Smoldering Multiple Myeloma

High-risk SMM is a precursor condition to multiple myeloma, meaning it is usually without symptoms but has an 80% chance of progressing to active myeloma within five years. Once a high-risk smoldering myeloma patient develops any of the CRAB criteria (high calcium, renal issues, anemia, or bone lesions), the diagnosis changes to active multiple myeloma. 

What is an ODAC Meeting and Why Does This Matter? 

When the FDA needs expert advice about the risks and benefits of a treatment, it holds an Oncologic Drugs Advisory Committee (ODAC) meeting. At this meeting, doctors review data and vote on whether to recommend the treatment. The FDA considers this vote when making its final approval decision.

In a 6 to 2 vote in favor of the approval, ODAC decided that the AQUILA study provided enough evidence to support using subcutaneous daratumumab (Darzalex Faspro, Johnson & Johnson) in treating high-risk SMM. 

AQUILA Study Results

The phase 3 AQUILA study compared three years of daratumumab therapy to active monitoring in patients with high-risk SMM. Key findings included:

• Median progression-free survival (time without disease progression) was not reached in patients taking daratumumab versus 41.5 months for the monitoring group.
• At five years, 63.1% of daratumumab-treated patients had not progressed compared to 40.8% of individuals under active monitoring.
• Daratumumab reduced the risk of progressing to multiple myeloma or death by 51%.

These outcomes suggest that daratumumab could significantly delay or prevent progression to active myeloma.

Side effects were higher in patients treated with daratumumab (40.4%) compared to active monitoring (30.1%). Hypertension (high blood pressure) was the most common side effect, but it was generally manageable. Eleven patients stopped treatment due to side effects, and 90 required dose adjustments, though effectiveness was unaffected by these changes.

FDA Perspectives

The FDA's core concerns were the following: 

• The risk criteria are evolving, and the study included low, intermediate, and high-risk smoldering patients. The FDA cited the fact that at the time the study began (2017), the risk criteria for smoldering myeloma had not yet been updated. This update happened in 2018 (called the Mayo 20/2/20 model). The FDA noted that more than half of the AQUILA study participants would not be considered high-risk today by any of the updated risk models (from 2018 or 2020). 
• Not all patients may need treatment. Even for patients who progressed to active myeloma during the study (on either trial arm), 20% of them were not immediately treated. The main reason cited for no treatment in 58% of patients was "controlled disease or no progression." Perhaps these patients were experiencing a rise in their monoclonal protein levels, but they were not at high enough levels for treatment or the development of CRAB criteria. 
• Does delaying progression have a meaningful benefit in the long-term? If a patient is treated early, do they live longer even after they progress to multiple myeloma? 
• Is this the right endpoint? The FDA prefers overall survival (OS) as an endpoint, but noted that if this trial had been powered for OS, it would have required 2,487 study participants, which they understood would be impossible. 

Expert Perspectives

Vincent Rajkumar, MD, spoke at the ODAC meeting to provide a myeloma specialist's perspective. He noted that because high-risk smoldering myeloma patients are very likely to progress, they are the best patients to get treated and are not always closely and sufficiently monitored to watch for organ damage that can come when patients develop active disease.

He emphasized that many patients with high-risk smoldering myeloma want to understand and access treatment options if they know they are at high risk of progression and that receiving treatment may also reduce anxiety. Dr. Rajkumar stated: 

• The study showed a meaningful delay in disease progression
• There was no negative impact on patients' quality of life
• There were understandable side effects
• Patients may want to be treated to take action or reduce anxiety
• In the future, we may want to consider more than a single-agent therapy for the treatment of high-risk smoldering myeloma

Several myeloma specialists joined during the comments portion to advocate for the approval of daratumumab for smoldering myeloma, highlighting the fact that monitoring can be challenging, especially in the community oncology setting.

One commenter noted that although close follow-up is needed for high-risk smoldering myeloma, the time commitment to do that is deeply challenging for community and rural offices. While imaging is required for close monitoring, some rural clinics lack the equipment to do this, and sometimes, insurance companies reject imaging. 

In the comments portion, Irene Ghobrial, MD, of the Dana-Farber Cancer Institute, stated, "This is a true cancer. There is nothing pre-malignant in smoldering myeloma." 

ODAC Committee Perspectives

ODAC committee members are typically not myeloma specialists—they are individuals who treat a variety of cancers and include both physicians and industry representatives. They debated what they heard from the company, the FDA, and the comments portion.

• They wanted to be assured that smoldering myeloma is indeed a cancer and not just a pre-cancerous condition. Smoldering myeloma is a cancerous condition.
• Some patients who will never progress may be overtreated.
• Some patients who need to be treated may be undertreated if only a single therapy is used.
• Is the goal to prevent myeloma from happening or delay myeloma from occurring?
• We need a better identification of patients who are more likely to progress to active disease.
• Patient anxiety isn't a reason for approval. Physicians should do an adequate job in patient monitoring and discussions to alleviate anxiety.
• The trial was sufficiently long and met its primary endpoint.
• Let patients decide with their doctors what is best.

Ultimately, the majority found the benefits sufficient for recommendation, with Daniel Sprett, MD, of the University Hospital Seidman Cancer Center, saying, "All the endpoints effectively favor intervention." 

Next Steps and The Importance of Shared Decision-Making for Patients

This study is breaking new ground in the debate about the treatment of smoldering myeloma. Following the ODAC recommendation, the FDA will now decide whether to officially approve daratumumab for high-risk SMM. Approval could offer a vital early treatment option to prevent or delay progression to multiple myeloma, potentially changing standard care practices.

This is clearly not a "one size fits all" situation, and there are pros and cons with early treatment, especially using a single drug. If you have high-risk smoldering myeloma, we strongly suggest that you have an educated discussion with your doctor that could include the following questions: 

• Do I have high-risk smoldering myeloma? What criteria are you using?
• How are you monitoring my high-risk smoldering myeloma? (What frequency and using what tools)
• If I have high-risk smoldering myeloma, should it be treated? 
• What is the treatment goal? Delay of progression or myeloma cell elimination?
• What side effects can I anticipate? 
• If I should be treated for my high-risk smoldering myeloma, what is my best treatment choice? Should I receive daratumumab, join a clinical trial, or consider another option? 
• How will this affect my future care? 

Conclusion

The ODAC's favorable decision on daratumumab represents a significant change in approach for high-risk SMM patients and may completely revolutionize the future of smoldering myeloma care. Patients should stay informed on the FDA's upcoming decision and participate in ongoing research opportunities to advance treatment understanding.

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Sources: 

• FDA ODAC Meeting Notes
• FDA ODAC Meeting Recording on Youtube (starts at 5:37:56)