FDA Issues Guidance on MRD, CR Outcomes for Multiple Myeloma Approvals

The FDA has issued a draft guidance specifying the conditions in which minimal residual disease (MRD) and complete responses (CRs) can serve as primary end points in trials intended to support the accelerated approval of novel therapies and biological products for patients with multiple myeloma.¹

What is the Verdict on MRD?

Previously, investigators have conducted pooled analyses demonstrating the association between MRD and long-term outcomes such as progression-free survival (PFS) and overall survival (OS) among patients with multiple myeloma. In April 2024, the FDA’s Oncologic Drug Advisory Committee (ODAC) convened to discuss these analyses and unanimously voted in support of MRD as an acceptable end point for supporting the accelerated approval of investigational treatments for those with multiple myeloma.²

According to the draft guidance, investigators may use MRD as an end point to support accelerated approval in multiple myeloma based on single-arm or randomized studies, although the agency noted a preference for randomized trials that robustly evaluate comparative safety. Additionally, investigators should design the control arm in a way that ensures equipoise and consistency with established standards of care in the US. Randomized trials should also adequately evaluate long-term end points like PFS and overall response rate (ORR) as key objectives, along with OS as a secondary or safety end point.

In trials assessing novel therapeutic combinations, sponsors should outline a strategy for demonstrating the contribution of each individual agent to the impact of the regimen on MRD negativity. Studies assessing multiple phases of therapy—including induction, consolidation, and maintenance—should elucidate the contribution of each phase to changes in MRD negativity.

The agency highlighted insufficient evidence supporting the use of MRD as an end point to bolster accelerated approval in the maintenance setting and among certain patient populations, including those with smoldering multiple myeloma, monoclonal gammopathy of undetermined significance, and extramedullary disease. Additionally, trials seeking accelerated approval for products among biomarker-selected populations may need additional information related to the natural history and anticipated outcomes associated with said populations to determine the appropriateness of employing MRD as an end point.

Regarding assessments, the agency noted that trials evaluating MRD as a primary end point should include patients with measurable disease per standard criteria, with study protocols specifying and justifying the assessment schedule for MRD end points. Trials should also evaluate MRD negativity at a minimum threshold of 1 in 10⁵ residual tumor cells and employ prespecified and justified timepoints for MRD negativity. The draft guidance also described various statistical considerations, noting that a primary analysis of MRD should be founded on stated study objectives and described in a study protocol and statistical analysis plan for defining the primary metric for decision-making based on this end point.

In its draft guidance, the FDA stated that sponsors should appropriately validate the assay used to assess MRD as part of supporting regulatory decisions. Additionally, sponsors should consider the MRD assay methodology and validation data when including an MRD assay for the purpose of evaluating MRD as an end point. Sponsors are also encouraged to convene with therapeutic product centers early in development regarding the MRD assay to help adequately collect and analytically validate data.

What is the Verdict on CRs?

After conducting a pooled analysis of clinical trial findings, the FDA determined that CRs may correlate with long-term outcomes like PFS and OS in multiple myeloma. Consequently, the agency allowed the use of CR rate as an appropriate end point for supporting accelerated approval in trials assessing new drugs and biological products among those with multiple myeloma.

All general principles for trial design and analysis that the FDA outlined for MRD as an end point in the draft guidance also apply to trials proposing CR rate as an outcome intended to support accelerated approval. However, the agency described a few additional considerations for using CR as a key end point.

According to the draft guidance, trials should evaluate the CR end point as overall CR instead of CR rate at specific period. Additionally, adequate follow-up is necessary to determine the meaningful durability of CR; this durability should be assessed from time of achievement of CR to death or progression.

Trials that support accelerated approval based on MRD or CR end points will typically require verification of clinical benefit as part of one or more confirmatory trials. As part of verifying clinical benefit, sponsors may follow a 2-trial model for accelerated approval, in which a single-arm study evaluating MRD and CR end points for accelerated approval precedes a randomized trial employing an end point like PFS or OS that directly measures long-term clinical benefit. Alternatively, sponsors may follow a single randomized trial approach, in which a trial supporting an initial accelerated approval based on MRD or CR is also powered for clinical end points like PFS and OS, with follow-up from the same study to support traditional approval.

“While this guidance outlines important considerations when proposing to include MRD or CR as a primary end point to support accelerated approval in [multiple myeloma], this is an evolving area with complex trial/statistical design, drug development, and assay considerations,” the agency concluded in its draft guidance.¹ “Therefore, we encourage sponsors to meet with the appropriate review division to discuss [multiple myeloma] trials that incorporate MRD or CR assessment as a primary end point.”

References

1. FDA. Minimal residual disease and complete response in multiple myeloma: use as endpoints to support accelerated approval guidance for industry. January 2026. Accessed January 21, 2026. https://tinyurl.com/545wznuw
2. April 12, 2024. Meeting of the Oncologic Drugs Advisory Committee (ODAC). Streamed live April 12, 2024. Accessed January 21, 2026. https://tinyurl.com/2tbe3f4k