ODAC finds sufficient evidence that benefits outweigh risks; supports treating HR-SMM patients with daratumumab and hyaluronidase-fihj
On Tuesday, May 20, the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) “voted (6-2) in favor of the benefit-risk profile of single agent DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) for the treatment of adult patients with high-risk smoldering multiple myeloma (HR-SMM),” states Johnson & Johnson in a press release. Darzalex Faspro for use in treating HR-SMM is still being reviewed by the FDA, who will make the final decision.
Summary
The ODAC vote (6-2) was based on positive results from the Phase 3 AQUILA trial—a major study which showed that the drug could lower the risk of the disease getting worse or causing death. The committee found sufficient evidence that the benefits of using Darzalex Faspro (daratumumab and hyaluronidase-fihj) to treat people with HR-SMM outweigh the risks.
Among the presenters of the Johnson & Johnson applicant presentation was IMF Chairperson of the Board S. Vincent Rajkumar, MD, FRCPC (Mayo Clinic—Rochester, MN).
IMF Board Director and Scientific Advisory Board Member Sagar Lonial, MD, FACP (Winship Cancer Institute, Emory University —Atlanta, GA) also shared his expert views about SMM and unmet needs during the presentation.
In 2024, it was estimated that approximately 15% of those with newly diagnosed multiple myeloma (NDMM) were classified as having SMM. About 50% with HR-SMM may develop full multiple myeloma within 2 to 3 years. By treating those diagnosed with HR-SMM earlier, the combination of daratumumab and hyaluronidase-fihj could help prevent the disease from advancing to active MM.
Currently, there are no approved treatments for HR-SMM. The standard of care for is active monitoring (“watch and wait”) until the disease progresses, whereby therapeutic intervention only happens after end-organ damage is detected.
Experts say this could be a big step forward in treating myeloma earlier and possibly stopping it from progressing.
What is the purpose of the ODAC meeting?
The ODAC is a committee of experts that the FDA brings together to help review how safe and effective cancer drugs are. They look at the data and give their opinion on whether a drug should be approved. However, their advice is not final—the FDA makes the official decision.
Approving treatment for high-risk SMM could help stop the disease from becoming more serious. The ODAC meeting was conducted because it was unclear if the benefits of the treatment outweigh the risks, and there are questions about how patients are grouped by risk level. Some ODAC members were worried that, with the current available data, it might be difficult to ensure that patients will get the right level of care.
What is Johnson & Johnson’s position?
According to applicant Johnson & Johnson, results of the AQUILA study demonstrated that early with daratumumab helped patients with high-risk smoldering multiple myeloma. The study showed clear and meaningful improvements in progression-free survival (PFS). There were also other benefits, including early signs that patients might live longer overall. Most importantly, daratumumab helped delay the progression of the disease.
Dr. Rajkumar and Dr. Lonial shared their expert views during the applicant presentation.
“[SMM patients] feel like they’re sitting on a ticking time bomb, waiting for a complication. Myeloma therapy impacts quality of life while trying to save lives. Our goal is to prevent the development of these symptoms so we can prevent the need for intensive therapy,” said Dr. Lonial.
At the end of the presentation, Dr. Rajkumar said: “In my experience, the benefits of daratumumab far outweigh the risks.”
What is the FDA’s position?
FDA Clinical Reviewer Dr. Payal Agarwal, who presented for the agency, noted an issue with the AQUILA study: even though SMM happens more often in Black patients, very few Black people were included—only 2% in the daratumumab group and 4% in the monitoring group.
The FDA also questioned whether the way the study defined “high-risk” SMM matched other accepted definitions.
Dr. Agarwal stated that about 20% of patients in the study (who were later diagnosed with multiple myeloma) didn’t start treatment right away. Additionally, the time it took to start treatment was different for each patient. These raised questions about how meaningful the results on progression-free survival (PFS) really were.
Also, the study didn’t show a big difference in delaying the need for second-line treatment, and data on overall survival (OS) seemed inadequate. On top of that, patients on daratumumab experienced more side effects/toxicities.
ODAC Panel Discussion and Voting Process
During the panel discussion, ODAC members addressed this question: Do the results from the AQUILA trial provide sufficient evidence to support a favorable benefit-risk profile for Dara SC for patients with high-risk SMM?
Because data showed that some patients may have gotten too much treatment, while others may have been undertreated, some committee members found it difficult to weigh the benefits and risks of the drug daratumumab.
Christopher Lieu, MD (Co-Director of GI Medical Oncology, University of Colorado — Boulder, CO) said that even though the study followed patients for over 5 years, the results still might not be fully clear.
He also expressed: “Right when you use this agent up front in smoldering multiple myeloma, then what is the efficacy in the frontline setting for active multiple myeloma? So, you’re looking at PFS2 to try and see if there's a detriment. At least from that signal—and I agree that PFS2 is very difficult to interpret…but you're not seeing shortened PFS2 in the treatment arm. I think that that is telling that you're not actually, at least in the data that we have, harming patients by giving them daratumumab.” Dr. Lieu voted Yes during the voting process.
Other members were concerned about how SMM patients were sorted into high-risk groups.
Daniel Spratt, MD (Chair and Professor of Radiation Oncology, University Hospitals Seidman Cancer Center and Case Western Reserve University —Cleveland, Ohio) said that “these risk groups are phenomenal, but I think they’re terrible for regulatory approval. These are prognostic risk groups. These are not predictive.”
According to Dr. Spratt, “a couple of more years of follow-up would be extremely valuable.” Dr. Spratt voted Yes, saying that “My vote comes down to all the endpoints effectively favoring the intervention.”
Dr. Spratt asked if SMM can be classified as cancerous or precancerous.
Dr. Rajkumar responded that SMM is “asymptomatic but not premalignant,” adding that SMM patients are “genomically indistinguishable from those with multiple myeloma.”
“Thinking of smoldering multiple myeloma as being a malignancy, and that we're just waiting and watching for a metastatic disease to show. So, I guess what I'm still struggling with is if we're really preventing cancers or if we're just delaying cancers being diagnosed,” said oncologist Heidi McKean, MD (Avera Health — Sioux Falls, SD).
“When we intervene, we're recommending lifelong therapy [to be] started earlier, and so that lifelong therapy better be not increasing toxicity [nor] harming quality of life. So, that's still the space that I’m struggling in, with the data,” she further added.
Dr. McKean pointed out that “in terms of HR-SMM, intermediate, low risk and [MGUS], patients are being identified as similar based on genomic features. But those are present in low risk, intermediate risk, throughout.” She thinks that “there is a need for better identification of patients that are more likely to progress.” Ultimately, Dr. McKean voted Yes.
For Toni K. Choueiri, MD (Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute; Jerome and Nancy Kohlberg Chair and Professor of Medicine, Harvard Medical School—Boston, MA), making a decision proved to be challenging. But after listening to all the evidence and thinking about the patients, he voted Yes.
“This was a very tough decision…I listened carefully to the sponsor, to the FDA, I did my homework, and I listened to the patients that are the real heroes here. I listened to some of the best key opinion leaders in myeloma [whom] I have the utmost respect for,” he said.
However, Dr. Choueiri also expressed some concerns: “we may be overtreating patients that have MGUS for 3 years, and we may have some real multiple myeloma patients that we are undertreating, but the thing today is that we do not have today an ideal classification on whom to treat for sure with high certainty.”
Ravi A. Madan, MD (Senior Clinician, National Cancer Institute—Bethesda, MD) and Neil Vasan, MD, PhD (Assistant Professor, Division of Hematology & Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center —New York, NY) voted No.
“I think we have to ask ourselves, just because we can treat, should we?” said Dr. Madan.
The rest of the ODAC members, Mark R. Conway, MD (Professor, Division of Translational Research and Applied Statistics, Department of Public Health Sciences, The University of Virginia School of Medicine — Charlottesville, VA); and myelodysplastic syndrome (MDS) patient Joan Durnell Powell (MDS Patient Representative and Advocate—Orange County, CA) voted Yes.
At the end of the meeting, the ODAC members voted in favor (6-2) of using Darzalex Faspro (daratumumab and hyaluronidase-fihj) as treatment for adult HR-SMM patients.
Please note that the ODAC’s recommendation is non-binding; it is still up to the FDA to make the final decision.
In case you missed it, you can still watch the recorded video of the ODAC Meeting on YouTube.
Event and presentation materials can be viewed and downloaded from the FDA website.
What is smoldering multiple myeloma?
Smoldering multiple myeloma (SMM) is an early stage of multiple myeloma where people don’t exhibit symptoms yet. It happens when abnormal cells grow in the bone marrow and there are high levels of M-protein in the blood. Even though there are no symptoms at first, the disease can get worse over time.
Each year, about 10% of people with SMM develop full multiple myeloma or a similar disease. For those with high-risk SMM, about half will see their disease become active within two years, which can lead to serious symptoms and damage to organs.
What is Darzalex Faspro?
Darzalex Faspro (daratumumab and hyaluronidase-fihj) is a drug that was approved by the U.S. FDA in May 2020 for nine different uses, including treating newly diagnosed patients whether they can have a stem cell transplant or not. It’s the only subcutaneous shot of its kind that targets a protein called CD38 on myeloma cells and contains a special ingredient that helps the drug absorb better under the skin.
DARZALEX® (daratumumab), a similar version given intravenously (IV), was approved in 2015 and is also used in newly diagnosed myeloma patients. It's the first CD38-targeting drug approved for multiple myeloma and has been used by more than 618,000 people worldwide.
What is the AQUILA Study?
Published in Blood and the New England Journal of Medicine, the AQUILA study is a large Phase 3 clinical trial that compares two groups of people with smoldering multiple myeloma (SMM). One group receives Darzalex Faspro, while the other group is closely and actively monitored.
The main goal of the study is to see how long patients can go without their disease getting worse or without dying—this is called progression-free survival (PFS). The study checks for signs that the disease has turned into active multiple myeloma using specific medical guidelines.
Other important things the study looks at include how well the drug works (response rate), how long patients stay healthy after starting treatment for active multiple myeloma (PFS2), and how long they live overall.
