FDA Draft Guidance Proposes CR, MRD to Accelerate MM Drug Approval

New draft guidance from the FDA positions minimal residual disease (MRD) and complete response (CR) as the end points to use to support drug and biologic product approval under the agency’s accelerated approval pathway in the multiple myeloma (MM) space.¹ Within these draft recommendations, MRD is defined as an MRD negativity seen in the patient’s bone marrow via flow cytometry– or sequencing-based methods following a CR, and CR is defined as including a CR or stringent CR.

Being MRD negative means a patient has less than 1 myeloma cell per 1 million bone marrow cells.² The measure has been used in clinical trials for many years to assess patient response, and recent research underlies its strengths when used to guide treatment decisions and patient response not only in MM,³ but also acute myeloid leukemia,⁴ chronic lymphocytic leukemia,⁵ and mantle cell lymphoma.⁶ One of several levels of treatment response in myeloma, a CR is when testing cannot detect any monoclonal protein (M-protein) in the blood.^7,8

With newer, modern therapeutics significantly improving survival rates, the FDA believes that data on MRD and CR, biomarkers that indicate deep treatment response and long-term clinical benefit, can expedite new drug delivery compared with long-term survival indicators. In this new draft guidance,¹ the FDA sets out a framework that encompasses clinical trial design, randomized studies, validated assays, predefined statistical analyses, and regulatory considerations, collectively meant to quantify treatment depth under rigorous standards. Several agencies collaborated on these guidelines: the Oncology Center of Excellence, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Devices and Radiological Health.

The caveat? This is the agency’s current thinking at the time of publication, not anything legally enforceable, “and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.” Confirmatory trials are still required for full approval, and these should be progressing concurrent with the manufacturer seeking the accelerated approval, according to the draft guidance.

MRD and CR as End Points

Under the draft guidance, randomized trials are the preferred method of investigation for accelerated approval in which MRD and CR are used as end points, but single-arm trials are also acceptable (just not preferred). Randomized trials are preferred because progression-free survival (PFS) and overall survival (OS) are also investigated.

The guidance drills down to several particular instructions for drug development. Some of these are having 1 trial to evaluate MRD, with a confirmatory investigation of time-to-event end points, such as PFS and OS; still investigate OS as a secondary or safety end point, if it is not a primary end point; have trial enrollment complete before analyzing the targeted end point for accelerated approval; allow cross-trial comparisons with historical controls; and in instances of combination regimens, specify how each part of the regimen will be evaluated for its contribution to MRD negativity.

When considering patients for enrollment, sponsors should justify deciding to use MRD in the particular MM setting. This is especially important when selecting patients at either end of the disease spectrum: do they have a higher risk of recurrence, or is a favorable outcome more likely? Also, patients should be enrolled who have measurable disease according to standard criteria and data collection needs to be robust. The guidance calls on trial designs to minimize potential for bias by having methods of patient assessment be similar across trial arms, include clear instructions on bone marrow aspirate assessment, assess MRD-negative responses when a CR is indicated or within a prespecified window, and prespecify an MRD negativity response of at least 1 in 10^–5 residual tumor cells.

Further, a detailed statistical analysis plan should contain key assumptions and justification for each assumption, and multiple supplementary and/or sensitivity analyses of MRD are recommended as applicable. Sponsors should also validate their choice of MRD assay (eg, next-generation sequencing vs next-generation flow) “to support regulatory decisions.”

Specifically for CR only, the guidance recommends measuring this in its entirety and not at a specific point; adequate follow-up establishing that CR is meaningful, since it can be similar to overall response rate; and considering durability of CR as time between achievement of CR and disease progression or death.

This draft guidance was also entered into the Federal Register.⁹ Comments are welcome through March 23, 2026.

References

1. Minimal residual disease and complete response in multiple myeloma: use as endpoints to support accelerated approval: guidance for industry. FDA. January 20, 2026. Accessed January 21, 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/minimal-residual-disease-and-complete-response-multiple-myeloma-use-endpoints-support-accelerated
2. What is minimal residual disease negativity for multiple myeloma? Dana-Farber Cancer Institute. March 20, 2018. Accessed January 21, 2026. https://blog.dana-farber.org/insight/2018/03/minimal-residual-disease-negativity-multiple-myeloma/
3. Caffrey M. On the path to greater precision in treating multiple myeloma. Am J Manag Care. 2025;31(Spec. No. 9):SP548-SP552. https://www.ajmc.com/view/on-the-path-to-greater-precision-in-treating-multiple-myeloma
4. Joszt L. NPM1 MRD status is a dominant predictor of AML relapse after alloHCT. AJMC^®. November 30, 2025. Accessed January 21, 2026. https://www.ajmc.com/view/npm1-mrd-status-is-a-dominant-predictor-of-aml-relapse-after-allohct
5. Klein HE. Personalized CLL therapy with MRD guidance improves survival outcomes. AJMC. February 6, 2025. Accessed January 21, 2026. https://www.ajmc.com/view/personalized-cll-therapy-with-mrd-guidance-improves-survival-outcomes
6. AJMC contributor. MRD-guided therapy shows promise as a time-limited frontline strategy for MCL. AJMC. December 9, 2025. Accessed January 21, 2026. https://www.ajmc.com/view/mrd-guided-therapy-shows-promise-as-a-time-limited-frontline-strategy-for-mcl
7. What are myeloma treatment response levels? HealthTree Foundation. May 2, 2024. Accessed January 21, 2026. https://healthtree.org/myeloma/community/articles/multiple-myeloma-remission
8. Stages of multiple myeloma. International Myeloma Foundation. Reviewed July 20, 2021. Accessed January 21, 2026. https://www.myeloma.org/phases-disease
9. Minimal residual disease and complete response in multiple myeloma: use as endpoints to support accelerated approval; draft guidance for industry; availability. Federal Register. January 21, 2026. Accessed January 21, 2026. https://www.federalregister.gov/documents/2026/01/21/2026-01068/minimal-residual-disease-and-complete-response-in-multiple-myeloma-use-as-endpoints-to-support