After a short delay and concerns of potential intervention from senior officials, the FDA has issued a draft guidance for the industry on the potential use of minimal residual disease (MRD) and complete response (CR) to support accelerated approval of drugs to treat multiple myeloma.
The draft guidance provides recommendations for designing clinical trials that use MRD or CR as endpoints for accelerated approval. The policy would open a path for faster approval of multiple myeloma drugs, especially for earlier lines of treatment, compared with traditional reliance on progression-free survival (PFS) and overall survival (OS).
Issuance of the guidance on Tuesday came after the FDA’s Oncologic Drugs Advisory Committee (ODAC) unanimously agreed during an April 2024 meeting that MRD could be used as a new endpoint to facilitate accelerated approvals in multiple myeloma. That was after meta-analyses by two separate research groups linked MRD negativity to improved PFS outcomes for patients.
But recent leadership changes at the FDA added some uncertainties to the agency’s receptiveness to MRD as an approvable endpoint. The FDA originally listed the guidance on its agenda for 2025.
The draft is “practical and to the point,” Ola Landgren, M.D., Ph.D., from the Sylvester Comprehensive Cancer Center, who led one of the two teams that presented during the ODAC meeting, said in an email to Fierce.
“We applaud the FDA’s acceptance of MRD as an endpoint for accelerated approval and their guidance for its application in multiple myeloma clinical trials,” Hearn Jay Cho, M.D., Ph.D., chief medical officer of the Multiple Myeloma Research Foundation, said in a statement to Fierce. “This forward-thinking approach will undoubtedly bring novel agents to all myeloma patients sooner.”
Calls for the adoption of MRD have grown recently as multiple myeloma therapies have become very effective, making it increasingly difficult for new therapies to show an advantage based on PFS or OS. As of 2022, the median OS is anticipated to be around seven years to 10 years for patients with newly diagnosed multiple myeloma, the FDA noted in the document.
The agency defined MRD at a minimum sensitivity to detect one tumor cell in 100,000 normal cells (10-5), while “alternate thresholds for assessing MRD negativity should be appropriately justified.”
The FDA recommends that an MRD-negative response should be assessed at the time of complete response, or within a three-month window of CR. But Landgren noted that for novel CAR-T therapy and T-cell engagers, CR takes a long time to achieve, while the patients may be MRD-negative in the bone marrow very quickly.
“Having bone marrow-based MRD testing as an independent variable (i.e., independent of CR/VGPR) seems like the way to go in the near-coming future,” he said.
The timepoint for assessing MRD negativity rate as a trial endpoint “should be prespecified and justified,” the FDA said, raising nine months and 12 months after randomization as two examples.
Here, Landgren suggested that the windows may need to be shortened for CAR-T therapies, although he noted that data here are currently lacking.
The 2024 ODAC also touched on whether sustained MRD negativity over a period of time—versus a specific timepoint—is more appropriate to reflect a drug’s efficacy. In the draft, the FDA suggested that “there are limited data on the use of imaging-based MRD response endpoints or sustained MRD negativity rate to support their use as a primary MRD endpoint.” Sponsors are therefore asked to consider those only as secondary or exploratory endpoints.
In addition, patients with missing MRD information should be included in the denominator for the MRD response calculation in the primary MRD analysis, the agency said.
Citing insufficient evidence, the FDA also excluded MRD’s application in the maintenance setting, and in smoldering multiple myeloma, monoclonal gammopathy of undetermined significance and extramedullary disease. But Landgren argued that the guidance should cover smoldering multiple myeloma following the FDA’s recent breakthrough approval of Johnson & Johnson’s Darzalex in this asymptomatic precursor condition.
Besides MRD, the agency also supported CR as a potential endpoint to back an accelerated approval. While most principles for MRD-based trial design apply to CR, the FDA made a few more considerations specific to CR, including that the endpoint should be assessed “as overall CR rate rather than CR rate at a specific timepoint,” and that “adequate follow-up is needed in order to establish that the durability of CR is meaningful.”
Related
The ODAC meeting on April 12, 2024, was remarkably cordial. Discussions around the relationship between MRD and longer-term endpoints such as PFS and OS, as well as potential detailed implementation of MRD—rather than whether it should be adopted—largely replaced the palpable tension between drugmakers and regulators that are a typical hallmark of these meetings.
That was until Speaker No. 6 dialed in.
“I’m Vinay Prasad,” the speaker introduced himself. “I’m a practicing hematology doctor. I see myeloma every week at San Francisco General Hospital, and I’m a professor here at UCSF. And I’m going to give you a different point of view on this decision for MRD for accelerated approval.”
About a year later, Prasad would become director of the FDA’s Center for Biologics Evaluation and Research and later chief medical and scientific officer at the agency as well.
During the ODAC meeting, Prasad laid out five reasons why he thinks MRD as an endpoint for accelerated approval is “an error.” Because patients with newly diagnosed multiple myeloma are already doing well on existing therapies, Prasad argued that there simply is not an unmet medical need that warrants an accelerated approval pathway.
While MRD could expedite approval timelines, fast approvals may overlook safety problems, he said. And while the two meta-analyses linked MRD negativity to positive PFS for patients, they did not establish a trial-level correlation between MRD and the gold-standard OS.
Now, the publication of the guidance suggests that the FDA remains open to granting approvals based on MRD, despite Prasad’s installment and the recent departure of the longtime FDA oncology chief Richard Pazdur, M.D.
“MRD- as an approval endpoint could offer even more dramatic benefits in frontline [multiple myeloma] studies, and we’d expect it to cut the time needed for players like” Arcellx/Gilead Sciences and Regeneron to catch up with current market leader Johnson & Johnson/Legend Biotech, Evercore ISI analysts wrote in a Jan. 20 note.
However, the draft guidance, even if finalized, does not guarantee an approval. As the guidance document reminds readers on every page, it “contains nonbinding recommendations.” In general, the FDA’s guidance documents “do not establish legally enforceable responsibilities and thus are not binding on FDA or the public,” according to the agency.
Bristol Myers Squibb recently reported that a phase 3 multiple myeloma trial of its CELMoD agent iberdomide met MRD as one of the dual primary endpoints. The company said in a September release that it plans to discuss the results with health authorities, while it expects the PFS endpoint to read out this year. BMS did not immediately respond to Fierce’s request for an update on whether the MRD data alone were deemed sufficient to support a filing.
