FDA Issues Draft Guidance on MRD and CR End Points in Multiple Myeloma

The FDA released a draft guidance document that provides a regulatory framework for sponsors to utilize minimal residual disease (MRD) and complete response (CR) as primary end points in clinical trials to support accelerated approval for multiple myeloma (MM) therapeutics.

The document, entitled “Minimal Residual Disease and Complete Response in Multiple Myeloma: Use as Endpoints to Support Accelerated Approval,” follows a unanimous decision from an April 2024 ODAC meeting and signals a shift in the drug development timeline, potentially bringing novel therapies to patients faster by utilizing early markers of efficacy rather than traditional, long-term survival data.^1,2

The Shift Toward Early End Points

Traditional approval for oncology drugs has relied on clinical benefit end points such as overall survival (OS). In the context of MM—a disease often characterized by long periods of remission—waiting for OS or even progression-free survival (PFS) data can significantly delay the availability of promising new treatments. Overall response rate (ORR) has been used as a surrogate end point for accelerated approval, but as myeloma therapies are advancing, new therapies are reaching 60% to 70% ORR in the relapsed setting and above 90% in the front line, making it difficult to confirm statistically significant differences in ORR vs existing therapies within small patient populations.¹

The FDA’s new draft guidance allows MRD and CR to serve as surrogate end points or intermediate clinical end points that are reasonably likely to predict clinical benefit. Highly sensitive assays like next-generation sequencing (NGS) or next-generation flow (NGF) can assess MRD to determine if a small number of malignant plasma cells remain in the body and could lead to relapse.

Key Study Design Considerations

The guidance outlines several critical considerations for sponsors designing trials that incorporate these end points.

The FDA encourages the use of MRD and CR in trials for both newly diagnosed and relapsed or refractory MM, but not in the maintenance setting or in other disease states such as smoldering MM, monoclonal gammopathy of undetermined significance (MGUS), and extramedullary disease. The primary end point to support accelerated approval is defined as the MRD-negative CR rate which represents the proportion of patients who achieve both a CR as defined by International Myeloma Working Group (IMWG) criteria and MRD negativity at a prespecified sensitivity level, typically 10⁻⁵ or better.

The FDA emphasizes that the assays used to measure MRD must be validated and highly sensitive, and the proposed MRD negativity threshold cutoff should be discussed with the FDA. Generally, they encourage trial sponsors to meet with the appropriate therapeutic product center early in trial development to ensure the assay is capable of adequate data collection and analytical validation. Trial investigators should account for missing MRD data caused by calibration failure or other reasons, and patients with missing MRD data must be included in the denominator when calculating MRD rates.

The draft notes that bone marrow aspirate assessment is required to assess achievement of CR to determine MRD negativity. However, since this requires frequent bone marrow biopsies, the guidance suggests this would not be more practical than standard disease monitoring for progression. Additionally, as imaging-based MRD and sustained MRD negativity lack supporting data as a primary end point, these should only be used as secondary or exploratory end points.

As survival end points must still be used for regular approval, sponsors may choose between 2 main trial designs:

• Two-Trial Approach: One trial uses the MRD-negative CR rate to support accelerated approval, while a separate, concurrent trial or a second stage of the same trial uses a clinical benefit end point such as PFS or OS to confirm the benefit and support traditional approval.
• Single Randomized Trial Approach: A single trial is designed to use MRD-negative CR for initial accelerated approval but remains powered for clinical benefit end points with continued follow-up to support traditional approval.

Complete Response as End Point

CR, which demonstrates the depth of response beyond overall response, has been shown to correlate to improved long-term outcomes. An FDA analysis of pooled clinical trial data supported the association between CR and PFS/OS.

The FDA stated that “the general principles for the design and analysis of clinical trials that use MRD as an [end point] for accelerated approval…also apply to trials that propose CR rate as an end point for accelerated approval.” Additionally, the document stated that the CR end point should be assessed as overall CR instead of at a specific time point, and that adequate follow-up must be used to confirm that the CR is durable. They also recommended use of an independent monitoring committee to evaluate CR.

Clinical Implications

This guidance could lead to future clinical trial results being reported earlier, based on deep molecular responses rather than years of survival follow-up. A review published in Blood Cancer Discovery in support of the MRD end point gave the example of a trial in newly diagnosed disease where the standard of care achieved an 84% 4-year PFS rate. In such a study, a 30% PFS improvement would not be confirmed with mature data until 11.5 years, whereas MRD would read out at 3.7 years.³ This accelerates the approval process at the same time emphasizes the depth of the response.

The FDA notes that although a deep response as indicated by MRD negativity is a strong prognostic indicator, it must still be verified by long-term clinical outcomes.¹ Therefore, even after a drug receives accelerated approval based on MRD data, sponsors are required to complete confirmatory trials to prove that the initial response translates into a meaningful extension of life or time without disease progression.

The Evolving Landscape

The FDA acknowledges that the use of MRD in MM is an evolving area. Complexities remain regarding trial and statistical design, drug development, and assay standardization. As such, the agency encourages sponsors to meet with the appropriate review division early in the development process to discuss trial designs that incorporate these end points.

This draft guidance reflects the oncology community’s growing consensus that achieving the deepest possible responses is a valuable outcome for treatment of multiple myeloma.

REFERENCES

1. Minimal residual disease and complete response in multiple myeloma: use as endpoints to support accelerated approval: guidance for industry. US FDA. January 20, 2026. Accessed January 21, 2026. https://tinyurl.com/4m5v6zwv

2. Oncologic Drugs Advisory Committee (ODAC) Meeting. US FDA. April 12, 2024. Accessed January 20, 2026. https://tinyurl.com/2rexatkp

3. Landgren O, Devlin SM. Minimal residual disease as an early endpoint for accelerated drug approval in myeloma: a roadmap. Blood Cancer Discov. 2025;6(1):13-22. doi:10.1158/2643-3230.BCD-24-0292