FDA Acceptance of Minimal Residual Disease as an Endpoint or Supportive Evidence

As MRD assays become analytically mature and clinically validated, sponsors increasingly seek to incorporate MRD response data into regulatory submissions — whether as a primary efficacy endpoint, a secondary endpoint, or supportive evidence of depth of response. Understanding precisely where and how FDA has accepted MRD in past approvals is essential for trial design decisions, endpoint negotiation with the agency, and label strategy across hematologic malignancies.

The analysis below surveys FDA approval actions in which MRD played a formal or supportive role, organized by disease area. It also examines the assay performance standards and evidentiary frameworks the agency has applied across these settings, drawing on labeling, approval letters, and agency guidance to characterize current regulatory expectations.

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Where FDA has accepted minimal residual disease (MRD) as an endpoint or supportive evidence

Minimal residual disease (MRD, also written measurable residual disease) is now embedded in FDA hematology decision-making, but the way the agency uses it varies sharply by disease and by the strength of the underlying assay. In one setting FDA has treated an MRD response as the actual approval endpoint; in most others MRD has functioned as supportive depth-of-response evidence layered on top of conventional endpoints such as complete remission (CR), overall response rate (ORR), or progression-free survival (PFS). The picture below organizes the accepted uses by disease area, then draws out the cross-cutting assay expectations FDA applies whenever MRD is submitted.

Acute lymphoblastic leukemia: the clearest case of MRD as the approval endpoint

Blinatumomab (Blincyto) in MRD-positive B-cell precursor ALL is the landmark example of FDA accepting MRD as the efficacy endpoint itself, not merely as supportive data. FDA approved the MRD-positive B-cell precursor ALL indication on March 29, 2018 1341014. The pivotal trial was Study MT103-203, an open-label, multicenter, single-arm confirmatory study in adults with MRD-positive B-cell precursor ALL (n=116) 29. The primary endpoint was the proportion of patients achieving a complete MRD response after one treatment cycle, defined as absence of detectable MRD by PCR at a minimum sensitivity of 10^-4 (0.01%) 293101417. Roughly 78% of patients achieved a complete MRD response after the first cycle 29. This is the setting where the disease state being treated is defined by MRD and the approval endpoint is an MRD response.

Blinatumomab's other ALL indications used MRD as reinforcing evidence rather than the primary basis:

  • Relapsed/refractory Ph-negative B-cell precursor ALL: efficacy rested on CR, duration of CR, and the proportion achieving an MRD-negative CR/CRh* within two cycles; 75.3% of CR/CRh* responders were MRD responders, and FDA's review states the conclusion of effectiveness was strengthened by patients achieving remission plus a reduction of MRD to below 10^-4 121126128136. The pediatric review similarly reported MRD response among CR and CRh* responders as part of the efficacy package 132133.
  • Philadelphia chromosome-positive B-cell precursor ALL (ALCANTARA): MRD response for CR/CRh* was reported as a secondary efficacy measure (64% of responders were MRD responders), i.e. supportive rather than primary 127130.

Ponatinib (Iclusig) in newly diagnosed Ph-positive ALL is a second ALL example where MRD carried the approval. FDA granted accelerated approval based on the MRD-negative complete remission rate at the end of induction 151152153194. The labeling also ties dose reduction to achieving MRD-negative (<0.01% BCR::ABL1/ABL1) CR at end of induction 152153194. The relevant labeling decision date shown is March 19, 2024, on a product first approved in 2012 150152191193194. As an accelerated approval, it remains subject to confirmatory evidence 151152.

Multiple myeloma: MRD as a secondary/supportive endpoint, moving toward a formal accelerated-approval endpoint

In myeloma, MRD negativity has appeared repeatedly as a key secondary endpoint and depth-of-response measure, but FDA has generally not relied on it as the basis for the effectiveness conclusion in the single-arm bispecific approvals reviewed:

  • Teclistamab (Tecvayli): MRD negativity was a key secondary endpoint in MajesTEC-1 alongside ORR, DOR, PFS, and OS, but FDA did not rely on the MRD data because the MRD-negativity rate had substantial calibration failure and missing data and was not robust enough for the prescribing information 858789.
  • Elranatamab (Elrexfio): MRD negativity was a secondary endpoint; FDA reported that among CR/sCR patients with evaluable samples most were MRD-negative at 10^-5, presented as supportive depth-of-response information 8386.
  • Talquetamab (Talvey): MRD negativity was a key secondary endpoint in MonumenTAL-1, but the efficacy assessment rested on ORR and DOR, with MRD treated as exploratory/supportive in the single-arm setting 81889091.

The direction of travel is captured in FDA's draft guidance, Minimal Residual Disease and Complete Response in Multiple Myeloma: Use as Endpoints to Support Accelerated Approval, dated January 21, 2026 6140. It recommends using the MRD negativity rate, assessed in bone marrow in patients who have achieved CR, by either flow cytometry-based or sequencing-based methods, as a primary endpoint (together with CR) in trials intended to support accelerated approval 6. The assay should have a minimum sensitivity to detect 1 tumor cell in 100,000 normal cells (10^-5) 140. Notably, the guidance is explicitly scoped to multiple myeloma and states it does not address other disease settings 6.

Chronic lymphocytic leukemia: MRD as supportive depth-of-response evidence

All the CLL examples center on venetoclax (Venclexta) combinations, where undetectable/MRD negativity was reported in labeling as supportive evidence rather than the formal approval endpoint (which remained PFS or ORR):

  • Venetoclax + obinutuzumab, first-line CLL (CLL14): MRD evaluated by ASO-PCR, MRD-negative defined as <1 CLL cell per 10^4 leukocytes, reported three months after treatment completion in both bone marrow and peripheral blood. Reported ITT rates were 57% vs 17% (bone marrow) and 76% vs 35% (peripheral blood) versus chlorambucil-obinutuzumab; among CR patients, 69% vs 45% and 87% vs 62% respectively 9293949899101104105. MRD was presented as supportive evidence, with the efficacy basis remaining PFS/ORR 101103104108.
  • Venetoclax + rituximab, relapsed/refractory CLL (MURANO): MRD by ASO-PCR; peripheral-blood MRD negativity among patients with PR or better three months after the last rituximab dose was 53% (103/194) versus 12% (23/195) for bendamustine-rituximab, used as supportive evidence of depth of response alongside the PFS benefit 110114116.
  • Venetoclax monotherapy in previously treated del(17p) CLL (M13-982): 3% (3/106) achieved MRD negativity in both peripheral blood and bone marrow among CR/CRi patients, presented as supportive data while the formal efficacy basis was ORR by IRC 109111112113115.

AML and MDS: MRD accepted as supporting evidence, not an established endpoint

FDA's disease-specific guidances set the tone here. For AML, FDA has accepted marrow MRD <0.01% as supporting evidence of efficacy for new drugs demonstrating durable CR in relapsed/refractory acute leukemia, and states that CR is the preferred timing to assess MRD as a response endpoint; MRD-based relapse definitions for time-to-event endpoints are viewed as impractical absent a validated peripheral-blood assay 1. In labeling, the AML MRD content retrieved is limited to venetoclax (Venclexta), where MRD was evaluated in peripheral blood and bone marrow among CR/CRi patients and 3% (3/106) achieved MRD negativity in both compartments 149.

For myelodysplastic syndromes (MDS), FDA states MRD is not an established endpoint at this time but may be considered as supporting evidence of efficacy for new drugs with durable CR 3.

Cross-cutting assay and methodology expectations

Across these guidances, FDA applies a consistent set of analytical expectations whenever MRD data are submitted 2:

  • Assay validation: accuracy, precision, limit of detection, limit of blank, limit of quantitation, linearity, reagent/sample stability, analytical specificity, and appropriate DNA input for sequencing assays.
  • Sensitivity relative to the cutoff: analytical sensitivity should generally be at least one log below the prespecified MRD-negativity threshold, with precision at the threshold considered when setting the cutoff.
  • Data quality: for sequencing assays, high baseline calibration failure rates can undermine interpretation; sponsors should minimize calibration failures and missing data. This is precisely the issue that led FDA to set aside the teclistamab MRD data 87.
  • Timing: CR is the preferred point to assess MRD; assessing at lesser responses requires justification 1.
  • Data submission specifications (AML): FDA expects capture of specimen type, lab method, specific MRD marker, assay used, input quantity, assay sensitivity (LOD/LOQ), evaluability, and result 5.
  • Early engagement: FDA encourages sponsors to meet early with the review center regarding the MRD assay and its analytical validation 2.

Bottom line

The strongest precedent for MRD as a standalone approval endpoint is blinatumomab in MRD-positive B-cell precursor ALL, where complete MRD response was the primary endpoint 29. Ponatinib's Ph-positive ALL accelerated approval likewise rests on MRD-negative CR at end of induction 151152153194. In multiple myeloma and CLL, MRD negativity has served mainly as supportive, secondary depth-of-response evidence rather than the formal basis for approval 83858892110, though FDA's January 2026 draft guidance signals a shift toward accepting MRD negativity (with CR) as a primary endpoint for accelerated approval specifically in myeloma 6140. In AML and MDS, FDA treats MRD as supporting evidence of efficacy rather than an established endpoint 13. Throughout, acceptance is conditioned on a validated assay with sensitivity at least one log below the negativity threshold and on clean, well-calibrated data 287.