FAQ: Using Minimal Residual Disease (MRD) in Multiple Myeloma Clinical Trials

Minimal residual disease (MRD) has emerged as a valuable tool in evaluating the efficacy of multiple myeloma drugs, reflecting the field’s shift toward deeper, more sensitive measures of treatment response. As therapies have become increasingly effective, traditional end points such as overall response rate and complete response are no longer sufficient to distinguish meaningful clinical benefit in feasible trial designs. The FDA’s draft guidance on the use of MRD and complete response (CR) as end points provides a regulatory framework for leveraging MRD to support accelerated approval.¹

The following FAQs summarize key elements of the guidance while incorporating expert perspective on its implications and limitations from C. Ola Landgren, MD, PhD, of the University of Miami Sylvester Comprehensive Cancer Center, explained in an interview with Targeted Oncology.

1. What is minimal residual disease (MRD), and why is it important in multiple myeloma trials?

Minimal residual disease (MRD) refers to the small number of myeloma cells that may remain after treatment and are not detectable using conventional response criteria. In multiple myeloma, MRD provides a much deeper and more sensitive measure of treatment response than overall response rate (ORR) or complete response (CR).

MRD has consistently been shown to correlate with long-term outcomes, particularly progression-free survival (PFS).² As treatments have become more effective and response rates higher, MRD has emerged as a critical tool to distinguish meaningful clinical benefit.

Landgren stressed that, “In order for drugs to be developed with a curative intent, and also for newly diagnosed patients, where you have the best long-term outcome, you need a surrogate end point such as MRD for early accelerated approval.”

2. Why did the FDA issue draft guidance on using MRD as an end point for accelerated approval?

The FDA issued the draft guidance in response to substantial advances in multiple myeloma therapy and the growing body of evidence supporting MRD as a prognostic biomarker. Progression-free survival (PFS) data can take too long to mature, but looking at short-term response end points is difficult as many modern regimens achieving response rates above 90%.

The guidance reflects years of pooled analyses, advisory committee discussions, and stakeholder input, culminating in a unanimous Oncology Drug Advisory Committee (ODAC) vote supporting MRD as an end point for accelerated approval.

Landgren noted: “I think this guidance document summarizes the core of what we have been trying to do for a very long time. It helps to create that framework that will allow new drugs to be developed for patients with multiple myeloma.”

3. Does the FDA require multiple trials for accelerated and regular approval?

The FDA draft guidance allows MRD to be used as a primary end point in both single-arm and randomized trials and allows a two-trial model with a single-arm trial for accelerated approval followed by a separate randomized study measuring PFS or OS. Alternately, a single randomized trial could be performed with a design that uses MRD initially followed by longer follow-up for PFS or OS for regular approval.

According to Landgren: “You can still use a single-arm study followed by a randomized trial along the same lines, or you could do that randomized trial right out of the gate, and capture MRD at half a year, or 1 year, or 9 months from randomization, and then you get your accelerated approval, and then the study just keeps on going. When your PFS data come back, then you get your full approval.”

4. How should MRD be measured according to the draft guidance?

MRD should be assessed in the bone marrow using appropriately validated assays, such as next-generation sequencing (NGS) or next-generation flow cytometry (NGF). The recommended sensitivity threshold is at least 1 tumor cell in 100,000 normal cells (10⁻⁵), with justification required for alternative thresholds.

The guidance emphasizes the importance of assay validation, analytical performance, and consistency across trial arms.

Landgren highlighted: “You shall apply a reproducible, validated assay… and you also need to show correlation to clinical outcome.”

5. When should MRD be assessed in a clinical trial?

MRD negativity should be assessed at the time of CR or within a prespecified time window around CR. The draft guidance provides examples such as 9 or 12 months from treatment initiation or randomization but allows flexibility if scientifically justified.

This flexibility is particularly relevant as newer, more potent therapies may achieve deep responses earlier in the treatment course.

As Landgren explained: “Because it uses ‘for example,’ you could imply that if you have a shorter window, 6 months, that would be good as well.”

6. Why is MRD favored over CR as a clinical trial end point?

Although CR is a recognized prognostic biomarker, its usefulness as a primary end point is diminishing as therapies become more effective. In many contemporary trials, CR rates are already very high, leaving little room to demonstrate incremental improvements without extremely large sample sizes.

MRD provides a more granular measure of depth of response and remains discriminatory even when CR rates approach saturation.

Landgren described this challenge: “Between 80% and 100%, you still have a very narrow window to improve upon… the size of the study becomes so large, it’s just not a feasible end point to use.”

7. Why does the draft guidance not support sustained MRD negativity as a primary end point?

Although sustained MRD negativity is clinically meaningful and may be relevant for treatment individualization or curative strategies, the FDA draft guidance does not currently support it as a primary end point for accelerated approval due to limited data.

Importantly, a single MRD-negative assessment has already been shown to predict longer PFS, making it sufficient for early regulatory decision-making.

As Landgren stated: “If you show continued, sustained MRD negativity, that is equal to cure. Everyone wants that. That doesn’t change the fact that a single data point is predictive of longer PFS… For drug development, you don’t need sustained MRD.”

8. How does the draft guidance address smoldering myeloma?

The draft guidance is explicitly limited to multiple myeloma and does not address the use of MRD as an end point in smoldering multiple myeloma. This exclusion reflects the scope of the document rather than a lack of biological rationale for MRD in earlier disease states.

Landgren has identified this as a key area needing clarification, particularly given recent regulatory progress in smoldering myeloma: “In November of 2025, the first drug for the indication of smoldering myeloma was approved by the FDA, and this document only talks about multiple myeloma.”

He has argued that MRD negativity should retain prognostic relevance across the disease spectrum: “There is no reason to believe that the relationship between no detectable disease and long PFS would be excluded in that setting.”

According to Landgren, excluding smoldering myeloma from MRD-based frameworks could hinder innovation: “That would not be fair to those patients, and it will completely stop the field for smoldering myeloma.”

9. How does using MRD as an end point accelerate drug development and patient access?

MRD enables earlier assessment of treatment benefit compared with traditional time-to-event end points such as PFS or OS. By serving as a surrogate end point correlated with long-term outcomes, MRD can substantially shorten development timelines.

This approach allows promising therapies to reach patients sooner while confirmatory trials continue to verify clinical benefit.

Landgren emphasized: “If you want to develop a drug, you [had to] wait for the clinical end point from randomization to 15 years out. You can shrink that to a year or less. That saves you many years, and you can get access to the drugs much sooner.”

10. How will the FDA draft guidance on MRD be finalized, and what changes may still needed?

The FDA draft guidance is currently open for public comment and will be reviewed and refined before being finalized. Stakeholder input from clinicians, academic investigators, industry sponsors, and patient advocates is an important part of the process. The final document may incorporate clarifications, refinements, or additional context based on submitted comments and evolving data.

Landgren views the draft guidance as strong and data-driven overall but believes several areas would benefit from further clarification. In particular, he has emphasized the need to more explicitly address smoldering myeloma and to allow greater flexibility around MRD assessment timepoints as newer, more potent therapies achieve deep responses earlier.

As he explained: “I think the document is very well written overall… but these are just small nuances. Overall, the document is very well written, and I applaud the FDA’s work putting it together.”

He also underscored that MRD-based regulation is an evolving framework rather than a fixed end point: “Every time you answer questions, there will be new questions. This is the nature of life.”

This FAQ reflects current thinking based on the FDA draft guidance and ongoing expert discussion. As the science and regulatory landscape evolve, further refinements are expected.

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. Landgren O, Devlin SM. Minimal residual disease as an early endpoint for accelerated drug approval in myeloma: a roadmap. Blood Cancer Discov. 2025 Jan 8;6(1):13-22. doi: 10.1158/2643-3230.BCD-24-0292. PMID: 39630969