Once considered a disease with poor outcomes, multiple myeloma has seen significant advances in treatment over the past decade. The U.S. Food and Drug Administration (FDA) is now updating its guidance for drug developers, reflecting these improvements by recommending new criteria for accelerated approval of therapies.
In a draft guidance released earlier this month, the FDA advised that companies seeking accelerated approval for multiple myeloma treatments should use minimal residual disease (MRD) negativity rate as a primary endpoint, rather than relying solely on overall response rate (ORR). This recommendation follows an April 2024 unanimous vote by the FDA’s Oncologic Drugs Advisory Committee supporting MRD as an appropriate endpoint in clinical trials for this condition.
Nicholas Richardson, vice president of clinical development at Precision for Medicine and former deputy director of the FDA’s Division of Hematologic Malignancies 2, explained the reasoning behind this shift. “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.”
Richardson described MRD as an “intermediate endpoint,” which can be assessed earlier during a patient’s treatment journey. He noted that the focus on MRD aims to bring drugs with early or intermediate benefits to patients more quickly. “It is also known to confer a more positive outcome.”
However, Richardson cautioned that MRD carries “a degree of uncertainty” because it is measured over a shorter period compared to long-term metrics like five- or ten-year survival rates. As a result, full approval may still require traditional measures such as ORR at later stages.
He further clarified distinctions between response types: if tumors shrink or cancer cell counts drop, patients are considered responders; partial responses indicate some remaining cancer, while complete responses mean no detectable disease. Yet even after achieving complete response, some patients relapse due to small populations of remaining cells—termed minimal residual disease.
Richardson emphasized that MRD provides a more precise assessment than ORR. The FDA's new guidance proposes defining MRD negativity as having one cancer cell per one hundred thousand healthy cells—a benchmark that could support accelerated approvals based on single-arm or randomized trials.
Research supports MRD as a strong predictor of long-term survival in blood cancers. A meta-analysis published in Blood Advances in 2025 found that 64% of MRD-negative acute lymphoblastic leukemia patients remained disease-free after ten years, compared to only 21% among those who were MRD-positive after initial treatment.
According to Richardson, both clinicians and regulators see MRD as indicating "a deeper level of remission" than ORR, which relies on imaging techniques like CT or PET scans. He stated: “This is a push towards more advanced analyses.”
MRD has already been used for other blood cancers; it supported the accelerated approval of Amgen’s Blincyto for acute leukemia in 2018. The current guidance—resulting from collaboration between the University of Miami, research group i2TEAMM and the FDA—aims to formally integrate MRD into multiple myeloma drug approvals.
“Multiple myeloma is really the pioneer from an MRD standpoint,” Richardson said.
The updated guidelines also affect how clinical trials are conducted. Randomized trials are preferred since they allow sponsors to evaluate both early endpoints like MRD and longer-term outcomes such as progression-free survival (PFS) and overall survival within one study. Single-arm trials remain possible but less favored under the new recommendations.
Richardson highlighted challenges with trial design: “If [MRD] is used in a randomized trial, durability becomes an important metric in that setting,” he said. He added that strong control arms are necessary and warned against assessing patients before full enrollment is completed to avoid bias from potential placebo-group dropouts.
“It’s important to have clarity,” Richardson said.
