Commenters seek clarity, expansion of multiple myeloma accelerated approval draft guidance

Stakeholders responding to recent draft guidance from the US Food and Drug Administration (FDA) on the use of minimal residual disease (MRD) and complete response (CR) primary endpoints for multiple myeloma accelerated approval products say they want more examples of appropriate use of these endpoints, and for the agency to consider expanding the draft guidance to drugs and biologics for other hematologic malignancies.

FDA’s draft guidance, released in January, outlines the agency’s thinking on when to use MRD and CR endpoints in the context of multiple myeloma products being considered for accelerated approval. While randomized controlled trials are preferred, FDA said that single-arm studies can use MRD as an endpoint for multiple myeloma products under consideration for accelerated approval (RELATED: FDA proposes guidance on endpoints for multiple myeloma therapeutics accelerated approval trials, Regulatory Focus 20 January 2026).

Writing in response to the draft guidance, the International Myeloma Foundation (IMF) said including MRD negativity rates as a treatment endpoint could help improve patient access to treatments, reduce the time to identifying whether a treatment is effective, encourage innovation, and improve clinical trial feasibility and efficiency.

“All the analyses and publications so far have clearly identified, in each and every disease and treatment setting, including all published studies utilizing newer immunotherapeutic approaches, the applicability of MRD as a treatment endpoint reflecting survival outcome,” they wrote. “In an era of increasingly effective therapies, including cellular therapies, bispecific antibodies, and novel immunotherapies, the ability to measure deep responses through MRD assessment provides an essential tool for evaluating treatment impact.”

Clarity on endpoint definitions

The American Association for Cancer Research (AACR) said more clarity would be welcome on how MRD outcomes could be used to support product approval. “While we appreciate the draft guidance’s mention of clinical settings in which MRD is currently not supported, including precursor conditions, extramedullary disease, and maintenance settings, it would be valuable for FDA to explicitly state whether the existing data supports use across therapeutic modalities,” they wrote.

As of now, it is unclear whether the outcome timepoints the agency has provided are meant as examples or general targets for sponsors of multiple myeloma products to focus on, they explained. “It would be helpful if FDA clearly stated some considerations sponsors could take into account when determining these timepoints,” AACR said.

AACR also noted the MRD rate calculations in the draft guidance should be aligned with FDA’s March 2023 draft guidance on clinical trial considerations to support accelerated approval of oncology therapeutics. Alternatively, the agency should explain the discrepancy between the response-based endpoint analysis definition in that draft guidance and the current multiple myeloma draft guidance, they said.

In their comment, the American Society of Hematology (ASH) said FDA’s suggestion of overall response rate as a long-term endpoint should be clarified. “[W]e believe that [overall response rate] and MRD are achieved at similar intervals and thus do not make a good long-term endpoint,” they explained. “The FDA could consider including [overall survival] as a more appropriate long-term clinical endpoint as a key objective along with [progression-free survival].”

Clinical trial designs and evidence

GSK said that they would like to see more information in the draft guidance on expectations for evidence in single-arm trials.

“The guidance notes a preference for randomized trials but acknowledges the possibility of single-arm trial designs,” they wrote. “We request clarity regarding the level of evidence and magnitude of treatment effect (“delta”) that FDA would consider sufficiently compelling for MRD- or CR-based accelerated approval in such cases.”

There should also be more clarity on the circumstances under which FDA would accept single-arm trials, GSK noted. “In several sections, the guidance references the two-trial model for accelerated approval,” they said. “Further clarity would be helpful on circumstances in which single-arm trials may be appropriate—particularly for rare diseases or highly unmet-need populations where randomization may not be feasible.”

In their comment, Novartis said that while single-arm trials “are critical in settings of high unmet need, the guidance offers limited clarity on when such designs are considered acceptable for MRD-based accelerated approval.”

“More explicit examples would help support the appropriate use of these trial designs,” they said.

Novartis also sought clarification on when it would be appropriate to consult with the Center for Devices and Radiological Health regarding validated platforms or accepted endpoints.

AACR pointed out that FDA’s request that sponsors consider the toxicity of a therapy in a single-arm trial in their proposed MRD negativity rate for single-arm trials may be difficult to implement because sponsors may not yet know the toxicity of the therapy at that point of drug development. “More detail regarding how to take toxicity into account to determine these rates at the design stage would be welcomed,” they said.

ASH said that FDA should consider allowing other trial designs to address the toxicity concerns of these therapies. “The Society encourages FDA to consider amending the guidance to emphasize the importance of long-term follow-up for patients treated with novel therapies, given the potential for delayed toxicities and refractory disease,” they said. “The Agency should also ensure that both short- and long-term toxicities are fully captured, which may not occur in the context of MRD-driven studies.”

Expansion of draft guidance

While FDA stated the guidance was only intended for multiple myeloma drugs and biologics, some organizations said it should include other hematologic malignancies.

“We suggest that FDA expand the scope of this guidance beyond patients with multiple myeloma, particularly given the broader applicability of MRD across hematologic malignancies,” Novartis wrote.

AstraZeneca said that the draft guidance “does not explicitly address whether its recommendations apply uniformly across all therapeutic modalities used in multiple myeloma.”

“AstraZeneca believes that based on the robustness of current meta-analysis data, sufficient data exists to allow for extrapolation to modalities that may not have been included in the datasets, such as targeted radiotherapy and antibody-drug conjugates,” they explained. “We respectfully request clarification as to whether the guidance is intended to apply broadly to all drug classes (other than CAR-T therapies).”

Draft guidance