The FDA has issued a draft guidance for industry on use of minimal residual disease (MRD) and complete response rates as primary trial endpoints for accelerated approval of multiple myeloma drugs.

In multiple myeloma, accelerated approvals based on the early, surrogate endpoint of overall response rate (ORR) have expedited the availability of new therapies. However, as myeloma therapies have advanced, recent trials have seen ORRs surpassing 60%-70% in the relapsed or refractory setting and 90% in the newly diagnosed setting.

“With the improved outcomes observed in this disease area, demonstrating statistically significant differences in ORR may require infeasibly large clinical trials,” the FDA said in a notice outlining the reasons for the proposed new recommendations.

MRD is a more sensitive efficacy measure than ORR, and in April 2024, the Oncologic Drugs Advisory Committee unanimously agreed that MRD is an “acceptable” endpoint to support accelerated approval of multiple myeloma therapies. That was based on pooled analyses of clinical trial data showing correlations between MRD and progression-free and overall survival.

When finalized, the FDA said, the new guidance will provide specific recommendations for designing clinical trials with an MRD endpoint — defined as the MRD negativity rate as assessed in the bone marrow, by either flow cytometry- or sequencing-based methods, in patients who’ve achieved a complete response.

The draft guidance also covers the use of complete response as an endpoint because this biomarker has a demonstrated association with long-term outcomes. 

The guidance is open for public comments until March 23, 2026, according to a Federal Register notice.

Commenting on the FDA move, multiple myeloma expert Manni Mohyuddin, MD, said that MRD is a “good surrogate” for progression-free survival. But he noted that progression-free survival does not always correlate with overall survival in myeloma.

“So this isn’t a perfect arrangement, but it definitely can help expedite trial results,” Mohyuddin, of the University of Utah Huntsman Cancer Institute in Salt Lake City, told Medscape Medical News.

He also applauded the FDA’s guidance on not using MRD or complete response as endpoints in the maintenance setting or in trials of patients with smoldering myeloma.

However, Mohyuddin expressed doubts about how well the industry will ultimately comply with the finalized guidance, based on history.

As an example, he pointed to a statement in the draft that trial control arms should use “a US standard of care and have equipoise” — in other words, they should have a “fair control arm for the endpoint being utilized,” Mohyuddin noted.

In reality, he said, “[T]hat is very often not the case, and there are many recent examples that prove this phenomenon.”

In a 2021 systematic review evaluating the quality of control groups in randomized controlled trials (RCTs) of multiple myeloma drugs, Mohyuddin and his colleagues found that out of 49 RCTs, seven trials (14%) enrolled patients into inferior control groups after a superior regimen had been identified, while nine (18%) continued enrollment on substandard control arms after data on the inferiority of the control emerged.

Another 2021 study by Mohyuddin and his colleagues looked at the reporting of postprotocol therapies in RCTs of multiple myeloma drugs. The study found that such therapies are often not reported: Of 103 RCTs identified, only 43.7% overall and 55.3% of those funded by pharmaceutical companies reported on subsequent treatments. The findings underscored a need for reporting guidelines for postprotocol therapies, the investigators concluded.

If followed appropriately, the FDA’s proposed recommendations provide “enough guardrails for safe use” of MRD as an endpoint, Mohyuddin said.

“Unfortunately,” he added, “the past predicts for the future, and I suspect in myeloma, industry will continue to use unethical control arms and poor postprotocol therapy.”

As with other accelerated approvals, the FDA said that therapies granted such approval using MRD or complete response data will still be required to verify clinical benefit using traditional survival outcomes.

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape Medical News, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on X: @SW_MedReporter.