One Year After ODAC Decision: Myeloma Studies Move to Adopt MRD End Point

Bone marrow aspirate cytology of multiple myeloma: © David A Litman - stock.adobe.com

One year since the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor of using minimal residual disease (MRD) as an end point to support accelerated approval of drugs, changes are taking place in ongoing clinical trials and cancer research.¹

The groundbreaking decision led to new trials designed with MRD end points from the start and amendments to existing trial protocols that will enable these trials to report results and submit to the FDA for approval much more quickly.

“If the study is successful in showing higher rates of MRD negativity for a new therapy, that treatment could be approved based on accelerated approval, so patients can get access to new drugs 10 years sooner than just waiting for the clinical outcome. That's a huge step forward for the field and for all the patients,” C. Ola Landgren, MD, PhD, said in an interview with Targeted Oncology^TM.

Landgren, professor of medicine and chief of the myeloma division and the Myeloma Institute at the Sylvester Comprehensive Cancer Center at the University of Miami, led the research efforts to support the use of MRD for over a decade.

Additionally, in the past year, the ODAC vote sparked new interest for using MRD more actively in other disease types and improving MRD assays for patients.

Updates to Trial Design

MRD serves as a surrogate for clinical outcomes and can be assessed much more rapidly than progression-free survival (PFS). Investigators in ongoing trials have amended their protocols to use both MRD negativity and PFS as coprimary end points for accelerated approval. Investigational therapies that could be evaluated based on MRD include cell therapies, T-cell engagers, antibody-drug conjugates, and small molecule compounds.

“We have also seen that all the companies that have ongoing trials that used to have only PFS as the primary end point have…negotiated with the FDA to revise or amend their protocols to also include MRD as a coprimary end point,” said Landgren. “Everything is ongoing has been updated, and all the new trials have been including [MRD].”

Landgren and other researchers have also presented data to the European Medicines Agency. He said it may take longer for other regulatory agencies to review the data and authorize MRD as an approval end point.

Additionally, researchers in other disease types such as chronic lymphocytic leukemia and lymphoma have expressed interest in following the same path, though they will need to collect the data to support it.

A Roadmap for MRD

Landgren and Sean M. Devlin, PhD, a biostatistician at Memorial Sloan Kettering Cancer Center in New York, published a review in Blood Cancer Discovery outlining the long process of developing supporting evidence, which led to the acceptance of MRD by the FDA.² Two research groups, one from the National Cancer Institute and National Heart, Lung, and Blood Institute and the a second made up of other researchers, developed studies that provided evidence for the use of MRD.

The review noted the utility of overall response rate [ORR] as a meaningful end point in myeloma has decreased as current standard therapies are showing high ORRs comparable to investigational agents with superior PFS. Evaluating MRD during trials provides an alternative that can still yield results more rapidly than mature PFS. MRD at 10^-5 sensitivity—detecting 1 malignant cell in 100,000 cells—is supported by the FDA as the minimum threshold for MRD analysis, with 10^-6 sensitivity also being evaluated in trials.

They provided a set of meta-analyses showing MRD negativity was associated with superior PFS and OS outcomes and described their methodology for making meta-analyses to establish it as a surrogate end point for PFS or OS using both trial-level data and patient-level data. Collecting individual patient data was necessary to demonstrate the association between MRD and long-term outcomes was established regardless of patient population, disease setting, or treatment history. This required researchers to gather individual patient data from industry-sponsored trials.

To emphasize the impact of using MRD vs PFS for approval, Landgren and Devlin showed a trial in newly diagnosed multiple myeloma (NDMM) with a comparator arm that had an 84% 4-year PFS rate would require 11.5 years to read out a significant PFS difference with an HR of 0.7, as opposed to only 3.7 years to show a difference in MRD negativity.

Expanding the Potential of MRD

There are more avenues to develop MRD in myeloma in the future. Landgren said there have been improvements in the use of bone marrow–based MRD assays as well as the development of blood-based assays and imaging-based technologies that could change how trials are performed.

Additionally, using MRD status to guide further treatment is another approach yielding results. The phase 3 ADVANCE trial (NCT04268498) is investigating the addition of daratumumab (Darzalex) to KRd (carfilzomib [Kyprolis], lenalidomide [Revlimid], and dexamethasone) in NDMM. Patients could receive autologous stem cell transplant if they were MRD-positive and otherwise go directly to maintenance therapy. This trial’s outcomes will be presented at the 2025 American Society of Clinical Oncology Annual Meeting and European Hematology Association Congress.

Read the full interview with Dr Landgren on the changes taking place in myeloma research.

_REFERENCES:

_{1. Cancer research in the wake of a key FDA decision on minimal residual disease. University of Miami. April 10, 2025. Accessed May 13, 2025. https://tinyurl.com/44hnphha}

_{2. 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}