Minimal residual disease (MRD) assessment has emerged as a game-changing biomarker in the multiple myeloma (MM) treatment landscape. Over the past decade, MRD negativity has consistently demonstrated strong correlation with improved clinical outcomes, including extended progression-free survival (PFS) and overall survival (OS). Recognizing the clinical utility of MRD, the FDA’s Oncologic Drugs Advisory Committee (ODAC) recently voted to accept MRD-negative complete response (CR) as a primary endpoint in MM clinical trials. This landmark decision paves the way for accelerated approvals of next-generation MM therapies, providing earlier patient access to life-saving treatments. The ODAC vote addresses a critical challenge in MM drug development: evaluating efficacy in the context of significantly improved PFS and OS achieved by novel therapeutic modalities. Data presented to the ODAC validated the robust relationship between MRD status and traditional clinical endpoints, solidifying MRD as a reliable surrogate endpoint for expedited drug development. Leading experts, including Dr. Nikhil Munshi (Dana-Farber Cancer Institute) and Dr. Carl Ola Landgren (Sylvester Comprehensive Cancer Center), discussed the far-reaching implications of this decision at the International Myeloma Society 21st Annual Meeting. They emphasized the broad applicability of MRD-CR as a primary endpoint across all MM patient populations and treatment modalities, from newly diagnosed transplant-eligible patients to those with relapsed/refractory disease. The ODAC also established a standardized sensitivity threshold of 10⁻⁵ (one myeloma cell per 100,000 healthy bone marrow cells) and recommended assessment timepoints between 6-15 months. While formal guidance is pending, sponsors are encouraged to engage in proactive dialogue with the FDA.
Integrating MRD as a surrogate endpoint demands highly sensitive and standardized assays. Centralized, single-site MRD testing using FDA-cleared and CE-marked technologies, such as clonoSEQ®, enhances reliability and bolsters confidence in data integrity for regulatory submissions.
While the FDA currently recognizes 10⁻⁵ as the standard threshold, ongoing research suggests that greater sensitivity (e.g., 10⁻⁶) may offer even more precise prognostic value and deeper insights into treatment efficacy. Studies like the PERSEUS trial, evaluating daratumumab, underscore the clinical utility of higher sensitivity MRD assessment. Further, trials like IMROZ (isatuximab-irfc) and CEPHEUS (daratumumab) demonstrate the growing trend of incorporating sustained MRD negativity as a key measure of therapeutic efficacy. As real-world evidence accumulates, sensitivity standards are likely to evolve, driving the development of increasingly potent and personalized treatment strategies. The FDA’s endorsement of MRD as a surrogate endpoint has transformative potential, not just for MM, but also for other lymphoid malignancies and potentially even solid tumors. Global regulatory bodies, including the European Commission, are also exploring the adoption of MRD-based endpoints, signaling a paradigm shift in oncology drug development.
As a next-generation sequencing (NGS)-based assay, clonoSEQ® stands as the only FDA-cleared and EU IVDR-certified assay for MRD assessment in MM. With unparalleled sensitivity (10⁻⁶), robust validation across >150 peer-reviewed publications, and extensive use in hundreds of clinical trials by over 60 biopharma companies, clonoSEQ® has become a trusted tool for researchers and clinicians alike. Data generated using clonoSEQ® have supported numerous IND submissions and high-profile approvals, spanning CAR-T cell therapies, bispecific T-cell engagers (BiTEs), monoclonal antibodies, and BCL2 inhibitors. Shaping the Future of Personalized MM Care: The BENEFIT study, presented at ASCO 2024, marked a historic milestone as the first Phase 3 MM trial to utilize clonoSEQ® MRD status as a primary endpoint. Currently, clonoSEQ® serves as an endpoint in over 60 MM trials, including nine ongoing studies where it is the primary endpoint. Moreover, MRD status is being incorporated into adaptive trial designs (e.g., the AURIGA trial) to personalize treatment strategies through therapy intensification or de-escalation.
Conclusion: The convergence of cutting-edge technologies like clonoSEQ® and evolving regulatory paradigms centered around MRD assessment is ushering in a new era of personalized and effective MM therapies. The ODAC’s landmark decision promises to expedite drug development, ultimately delivering life-extending treatments to patients sooner. clonoSEQ® stands at the forefront of this revolution, empowering researchers and clinicians to make more informed treatment decisions and improve long-term patient outcomes.
