ODAC Votes Daratumumab Benefits Smoldering MM
In a 6 to 2 vote, the Oncologic Drug Advisory Committee determined that findings from the phase 3 AQUILA trial do support a positive benefit-risk ratio for patients with smoldering multiple myeloma.
Microscopic, photorealistic image of myeloma cells - Generated with Adobe Firefly
In a 6 to 2 vote, the FDA’s Oncologic Drug Advisory Committee (ODAC) voted that results from the AQUILA study (NCT03301220) provides sufficient evidence to support a favorable benefit-risk ratio for subcutaneous daratumumab (Darzalex Faspro) for patients with high-risk smoldering multiple myeloma (SMM).1
Daratumumab is an approved therapy for several myeloma indications, and this new proposed indication is for the treatment of adult patients with high-risk SMM, a precursor condition that is typically asymptomatic. Patients with high-risk SMM have a 5-year risk of progression to multiple myeloma of about 80%, according to recent models. There are no approved therapies for SMM, and a watch-and-wait strategy is typically employed.
The significance of approving a therapy for high-risk SMM could prevent patients from progressing to serious disease, but the benefit-risk balance is uncertain, as well as how the risk groups are classified. ODAC members expressed concerns with being able to provide patients with the adequate level of treatment with the current availability of data.
After much debate, 6 members ultimately voted that the end point data was favorable and supported treatment in this indication.
“I think that my vote comes down to all the end points effectively are favoring the intervention here. I think that because this is cancer, a malignant condition, albeit maybe at an earlier stage…this is something that is a real entity with high rates of progression,” Daniel Spratt, MD, ODAC member and chairman and professor of radiation oncology at University Hospital Seidman Cancer Center, when explaining his yes vote. "I think that my vote comes down to all the end points effectively are favoring the intervention here."
About the AQUILA Study
The phase 3 AQUILA study compared 3 years of daratumumab therapy vs active monitoring in patients with intermediate- and high-risk SMM. After a median follow-up of 65.2 months (range, 0-76.6), the median progression-free survival—which was defined as progression to multiple myeloma or death—was not reached with daratumumab monotherapy compared with 41.5 months with active monitoring.2 Further, 60-month PFS rates were 63.1% and 40.8%, respectively, reducing the risk for disease progression or death by 51% (HR, 0.49; 95% CI, 0.36-0.67; P <.001) with subcutaneous daratumumab.
As expected, more adverse events were observed in the daratumumab arm, with 40.4% patients in the daratumumab arm compared with 30.1% of those undergoing active monitoring, with the most common being hypertension (5.7% vs 4.6%, respectively). The risk of hypertension was highest in the first year and was most often in patients with a history of or predisposed to it. The safety profile observed in AQUILA was in line with what has been previously reported with daratumumab in other indications. Eleven patients discontinued daratumumab treatment due to TEAEs, whereas 90 patients underwent dose modifications as a result; however, there were no differences in efficacy observed in patients with and without dose modifications.1,2
Applicant’s Stance
Johnson & Johnson, the applicant, identified that AQUILA strongly favored early intervention with daratumumab in patients with high-risk SMM, with statistically significant and clinically meaningful improvements in PFS and benefits observed across secondary end points, including early evidence of a positive trend in overall survival (OS).1 Importantly, daratumumab offered an opportunity to delay disease progression.
“[Patients with SMM] feel like they’re sitting on a ticking time bomb, waiting for a complication,” said Sagar Lonial, MD, FACP, medical oncologist specializing in multiple myeloma at the Winship Cancer Institute of Emory University. Lonial provided background on the disease and unmet needs during the applicant presentation.
“Myeloma therapy impacts quality of life while trying to save [patients’] lives,” Lonial said. “Our goal is to prevent the development of these symptoms so we can prevent the need for intensive therapy.”
“In my experience, the benefits of daratumumab far outweigh the risks,” said S. Vincent Rajkumar, MD, FRCPC, Edward W. and Betty Knight Scripps professor of medicine at Mayo Clinic, during the conclusion of the applicant presentation.
FDA’s Stance
Bone marrow aspirate cytology of multiple myeloma: © David A Litman - stock.adobe.com
Payal Agarwal, DO, MS, clinical reviewer in the Division of Hematologic Malignancies II, delivered the FDA’s presentation. The FDA identified issue with the AQUILA trial’s patient demographics, identifying that there is a higher incidence of SMM in Black patients; however, only 2% of patients in the daratumumab arm and 4% in the active monitoring arm were Black. Additionally, the FDA questioned if the protocol-defined definition of high-risk SMM aligned with the available high-risk models.
Agarwal noted in her presentation that about 20% of patients who were diagnosed with multiple myeloma in AQUILA did not initiate treatment immediately, and there was variable time to therapy initiation, raising uncertainties about the clinical meaningfulness of the PFS end point. Additionally, there was no meaningful impact on delaying initiation of second-line therapy and a lack of robust OS data with a higher rate of toxicities with daratumumab.
ODAC Discussion and Decision
Several members of the ODAC expressed the struggle with the benefit-risk calculations, with the data showing some patients getting overtreated and some undertreated.
“It’s crazy to say with a follow-up time of 5 and a half years that the data may be immature, but it might actually be a little immature here,” said Christopher Lieu, MD, ODAC member and co-director of gastrointestinal medical oncology at the University of Colorado.
“There's also a concern 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,” Lieu added.
Other ODAC members expressed a conflict with the risk stratification in SMM.
“I think these risk groups are phenomenal, but I think they're terrible for regulatory approval. These are prognostic risk groups. These are not predictive,” said Spratt.
“I think a couple of more years of follow-up, to me, would be extremely valuable,” Spratt said, echoing Lieu’s thoughts.
“In terms of high-risk smoldering [multiple myeloma,] intermediate, low risk and [monoclonal gammopathy of undetermined significance (MGUS)], and these patients are being identified as similar based on genomic features. But those are present in low risk, intermediate risk, throughout,” Heidi McKean, MD, ODAC member and oncologist at Avera Health in Sioux Falls, South Dakota. “I think there is a need for better identification of patients that more likely to progress.”
Spratt questioned if SMM is considered cancerous or precancerous. Rajkumar clarified that SMM is “asymptomatic but not premalignant,” and patients with SMM 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 McKean. “When we intervene, we're recommending lifelong therapy started earlier, and so that lifelong therapy better be not increasing toxicity and not harming quality of life. So, that's still the space that I’m struggling in with the data.”
“I think we have to ask ourselves, just because we can treat, should we?” said Ravi A. Madan, MD, ODAC member and senior clinician at the National Cancer Institute. Madan along with Neil Vasan, MD, PhD, physician-scientist in the Department of Medicine and the Herbert Irving Comprehensive Cancer Center at Columbia University Irving Medical Center, voted no.
Toni Choueiri, MD, ODAC member and professor at Harvard Medical School, Dana-Farber Cancer Institute, expressed his difficulty at making a decision, but ultimately 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 [that] I have the utmost respect for,” Choueiri said. “I have 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.”
“For me, [the change] was thinking of smoldering multiple myeloma as a malignancy and allowing the physician and the patient to look at this data and intervene earlier,” said McKean when explaining her yes vote.
