New draft guidance from the FDA on multiple myeloma endpoints reflects the new technology available to assess disease and how patient journeys have changed with better treatments.
Once a dire prognosis, the outlook for multiple myeloma has shifted dramatically over the past decade—so much so that the FDA is leveling up on its requirements for novel therapies seeking approval.
In a new draft guidance issued earlier this month, the agency recommended that drug sponsors seeking accelerated approval of multiple myeloma therapies use the endpoint minimal residual disease (MRD). Specifically, the FDA suggested that in addition to complete response rates, clinical trials rely not on overall response rate (ORR) but on MRD negativity rate, at least for this first level of approval.
The guidance follows a unanimous April 2024 vote by the FDA’s Oncologic Drugs Advisory Committee to approve MRD as a viable endpoint for myeloma clinical trials.
Nicholas Richardson, vice president of clinical development at the CRO Precision for Medicine and the former deputy director of the FDA’s Division of Hematologic Malignancies 2, explained the rationale behind this new thinking.
“Therapies in myeloma are reaching 80–90% ORR,” he told BioSpace in an interview. “So if you’re thinking about new therapies, it’s harder to tell if there’s an improvement.”
MRD is an “intermediate endpoint,” Richardson added, something that is assessed earlier in a patient’s journey. This is why the draft guidance is focused on accelerated approval, he said, to get drugs with early or intermediate benefits to patients more quickly. “It is also “known to confer a more positive outcome.”
But MRD comes with “a degree of uncertainty,” because it is evaluated on a shorter time frame than other metrics like five- or 10-year survival, Richardson said. Thus, full approval still might require more standard measures like ORR down the line.
A More Precise Bar
If a tumor shrinks or if the number of cancer cells in the blood goes down, then that patient is considered to have responded to treatment. A partial response occurs if some cancer remains, while a complete response is if signs of cancer are eradicated completely. Both are counted in overall response.
Patients who reach long-term treatment goals like five-year survival often hit “complete response,” where they have no detectable signs of disease, Richardson explained. However, the National Cancer Institute is careful to note that a complete response is not a cure, and patients can still relapse due to some small but meaningful population of cells that persists even in this state. That population of cells is considered the “minimal residual disease.”
Therefore, MRD is more precise than overall response rate, Richardson said. Specifically, the FDA in its new guidance has proposed a standard level that qualifies as MRD negative: one cancer cell per one hundred thousand healthy cells. This biomarker can then be used as an endpoint to support accelerated approvals in multiple myeloma based on single-arm and randomized trials.
Research points to MRD as an accurate predictor of long-term survival in patients with blood cancers. A meta-analysis published in Blood Advances in 2025 showed that 64% of MRD-negative patients with another blood cancer, acute lymphoblastic leukemia, had no detectable traces of disease after 10 years, compared to only 21% those who were MRD positive after initial treatment. This indicated that MRD was a good predictor of eradicating disease, the study’s authors concluded.
For Richardson, the push by both clinicians and regulators toward MRD shows confidence that the biomarker “represents a deeper level of remission” than ORR, which is assessed by more qualitative techniques like CT or PET scans. “This is a push towards more advanced analyses,” he said.
MRD has been used to assess other malignancies, particularly acute leukemia, where it was first used to support the accelerated approval of Amgen’s Blincyto in 2018, Richardson said. But the new guidance, which resulted from a unique public/private partnership between the University of Miami, an independent research group called i2TEAMM and the FDA, seeks to codify MRD into approvals for multiple myeloma.
“Multiple myeloma is really the pioneer from an MRD standpoint,” Richardson said.
Trial Considerations
In introducing new possibilities for endpoints in clinical trials, the FDA also presents new considerations for conducting these trials, Richardson said. The new guidance makes clear that randomized trials are preferred—though the agency did leave open the possibility for single-arm trials to support MRD-based approvals in multiple myeloma.
Randomized trials are recommended, according to the guidance, partly because a drug sponsor can conduct one study evaluating MRD for accelerated approval, while also evaluating later time-to-event endpoints such as progression-free survival (PFS) and overall survival for a future traditional approval. This type of trial is also preferred for assessing combination regimens, the FDA wrote.
However, there are careful considerations, Richardson noted.
“If [MRD] is used in a randomized trial, durability becomes an important metric in that setting,” he said, and a strong control arm is needed to compare the treatment durability to. Randomized trials should therefore be fully enrolled before any assessments of patients are made, he continued, so results of those assessments don’t lead to placebo-group dropouts that could impact the trial’s integrity.
“It’s important to have clarity,” Richardson said.
