MRD Takes Center Stage: Accelerating Drug Approvals for Multiple Myeloma

Over the past decade, minimal residual disease (MRD) has emerged as a crucial biomarker in multiple myeloma (MM) clinical trials, with MRD-negative status strongly linked to better clinical responses and longer progression-free survival (PFS) and overall survival (OS). Recognizing its value, the FDA's Oncologic Drugs Advisory Committee (ODAC) recently voted to use MRD-negative complete response (CR) as a primary endpoint in MM trials to support accelerated FDA approvals, paving the way for faster patient access to novel therapies.

The ODAC vote addresses the challenge of evaluating treatment efficacy as therapeutic advances have led to much longer PFS and OS. The analysis presented to the ODAC supported the relationship between MRD status and existing endpoints, making it an ideal surrogate endpoint that can accelerate development of life-extending therapies for patients.

Nikhil Munshi, MD, of Dana-Farber Cancer Institute and Carl Ola Landgren, MD, PhD, professor of medicine, chief of the myeloma division, and co-leader of the Translational and Clinical Oncology (TCO) Program at NCI-designated Sylvester Comprehensive Cancer Center of the University of Miami participated in a panel in September at the International Myeloma Society 21st Annual Meeting & Exposition, discussing the implications of the decision on the future of MM drug development. Specifically, the ODAC vote for use of MRD-CR as an endpoint in drug development supported the following:

• MRD-negative CR is acceptable as an endpoint to support accelerated approval across all patient populations and treatment modalities – newly diagnosed transplant eligible, newly diagnosed transplant ineligible and relapsed/refractory patients.
• The acceptable standard threshold for MRD assay sensitivity is 10^-5 or at least one myeloma cell in 100,000 healthy bone marrow cells.
• MRD negativity to predict treatment outcomes can be assessed at timepoints ranging from 6-15 months.

It was noted that in the absence of formal guidance, sponsors are encouraged to work directly with FDA on applications.

Standardization and validation are critical

Integrating MRD within a surrogate endpoint in a clinical trial requires a highly accurate assay that can deliver consistent results at the sensitivity required by regulatory authorities. Single site MRD testing has the advantage of ensuring standardization of testing across all sites. Using an FDA-cleared and CE-marked technology like clonoSEQ® means that the results are more likely to be trusted and accepted by the scientific and medical communities for future submissions.​

Sensitivity specifications may evolve

FDA has determined 10^-5 as the acceptable standard threshold for MRD assay sensitivity. However, studies have demonstrated that the more sensitive the MRD assessment, the better the prediction of clinical benefit.¹ Assessing MRD at 10^-6 maximizes the potential of understanding the full effect of a drug regimen versus the standard of care. For example, the PERSEUS study supporting daratumumab, which used MRD as a secondary endpoint in the assessment of upfront quad regimens in newly diagnosed MM, highlighted the utility of deeper thresholds of analysis and the necessity of using a tool which can reliably reach these levels of assessment.² Further, the Phase 3 IMROZ study supporting approval for isatuximab-irfc and Phase 3 CEPHEUS study evaluating daratumumab show how the field is moving toward measuring depth of response or sustained MRD negativity to characterize efficacy in addition to PFS and OS.^3,4

Sensitivity standards will likely evolve as more data and real-world evidence evaluating the benefit of deeper MRD detection become available. An increasing number of drug developers are including analyses at 10^-6 in their studies to ensure future admissibility of data and that they are prepared as the basis of competition shifts.

Extending MRD as a best practice in lymphoid malignancies

The FDA's endorsement of MRD as an endpoint for accelerated approval will significantly expedite drug development in MM. Similar efforts are underway with global regulators, like the European Commission, and MRD may soon emerge as a universal standard in MM care.

The progress made in MM has laid a roadmap for the use of MRD as an endpoint across other lymphoid malignancies with similar unmet needs, as well as solid tumors.

clonoSEQ is the gold standard MRD test for MM clinical trials

clonoSEQ is a next-generation sequencing-based assay for MRD detection in MM and is the only FDA-cleared and European Union IVDR-certified assay for the assessment of MRD in MM. clonoSEQ is a preferred testing option for researchers, with sensitivity of 10^-6 and backed by more than 150 peer-reviewed publications. It has been used by more than 60 biopharma companies across hundreds of clinical trials.

Data generated using clonoSEQ have supported IND submissions, including high profile approvals for CAR-T cell therapies, bispecific T-cell engagers (BiTEs), other monoclonal antibodies and BCL2 inhibitors. Results from the BENEFIT study were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, marking the first publication from a Phase 3 trial in MM in which MRD status via clonoSEQ was used as a primary endpoint—with PFS and OS as secondary endpoints. Today, clonoSEQ is used as an endpoint in more than 60 MM trials, and as a primary endpoint in nine ongoing studies, helping differentiate the treatment response for novel agents or therapeutic regimens from standard of care. Additionally, MRD status is being used in some trials (like the Phase 3 AURIGA trial) to tailor treatment decisions, including intensifying or de-escalating therapy.^2,5

Best-in-class technology can accelerate innovation while enabling more personalized and effective treatment strategies. ODAC’s decision will undoubtedly lead to earlier availability of life-extending therapies for MM patients. The use of MRD in clinical studies seamlessly translates into direct patient care, and it is increasingly becoming a crucial tool for shaping treatment decisions and improving long-term patient outcomes. clonoSEQ is at the forefront of this important paradigm shift.

If you are interested in learning more about the use of clonoSEQ testing for MRD in a clinical trial, contact MRDBiopharma@adaptivebiotech.com.