Historic Turning Point in Myeloma
ODAC unanimously votes in favor of MRD testing
On April 12, 2024, the U.S. Food and Drug Administration (FDA) held the Oncologic Drugs Advisory Committee (ODAC) meeting to evaluate available data to support the use of minimal residual disease (MRD) status as an early endpoint in myeloma clinical trials, including considerations regarding timing of assessment, patient populations, and design of studies that intend to use MRD to support accelerated approval of a new product or a new indication.
ODAC panelists answered the question: “Does the evidence support the use of MRD as an accelerated approval endpoint in MM trials?” with a unanimous YES: 12-0. The FDA generally follows the ODAC recommendations but is not legally bound to do so. The implementation strategies for incorporating MRD testing into ongoing and future clinical trials are now being established.
MRD is a measure of tumor burden assessed in the bone marrow sample. MRD as a biomarker has multiple regulatory uses including for response assessments and as a prognostic marker in both frontline and relapse settings. MRD testing has affirmed progression free survival (PFS) results that are used as basis for several FDA approvals in phase III clinical trials.
The FDA briefing document notes that while overall response rate (ORR) has generally supported accelerated approval of myeloma therapies, the improved understanding of the impact of MRD on long-term outcomes has increased interest in evaluating it as an endpoint. Technologies that detect the presence of malignant cells at orders of magnitude below the limit of conventional ORR have allowed an assessment of MRD in myeloma.
The IMF’s International Myeloma Working Group (IMWG) has established uniform response criteria for MRD in myeloma and it has been included as an exploratory endpoint and secondary endpoint to assess response to therapies in clinical trials. Sustained MRD-negativity is an important category, which the ODAC meeting confirmed.
Several studies and meta-analyses have reported the prognostic value of MRD, and the achievement of MRD-negativity has been associated with depth of clinical response and prolongation of PFS and overall survival (OS).
The two key applicants to the ODAC proceedings were the IMF with the collaborative International Independent Team for Endpoint Approval of Myeloma MRD (i2TEAMM) as well as a team headed by Dr. Carl Ola Landgren (Sylvester Comprehensive Cancer Center of the University of Miami – Miami, FL). Both applicants provided comprehensive presentations.
i2TEAMM representatives in attendance included Brian G.M. Durie, MD (former IMF Chief Scientific Officer), Bruno Paiva, PhD (CIMA Laboratory Diagnostics, University of Navarra – Pamplona, Spain), Qian Shi, PhD (Mayo Clinic – Rochester, MN), and Kenneth C. Anderson, MD (Dana-Farber Cancer Institute
and Harvard Medical School – Boston, MA). Unfortunately, i2TEAMM members Prof. Jesús San Miguel, MD, PhD (Clinica Universidad de Navarra – Pamplona, Spain) and Nikhil Munshi, MD (Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute – Boston, MA) were unable to attend.
Using strong data, the i2TEAMM affirmed that MRD-negativity can be immediately applied. ODAC members indicated that careful study design and monitoring of new therapies can be assessed to make the application of MRD-negative complete response (CR) valid and usable. The accepted early endpoints were at 9 and 12 months from start of treatment, meaning MRD can be used in the early assessment of new drugs. Because MRD can be evaluated early, it may save months or years for a randomized clinical trial to demonstrate the PFS benefit.
This is the result of nearly 10 years of research and dedication by the i2TEAMM. The IMF would also like to thank Saad Z. Usmani, MD, MBA, FACP (Memorial Sloan Kettering Cancer Center – New York, NY) and myeloma patient and advocate Linda Huguelet for their participation during the oral testimonials.
The ODAC vote is historic. MRD testing will considerably expedite the development of FDA-approved myeloma drugs and therapies and bring them to patients sooner than later. This is a turning point in myeloma clinical trials; it moves us steadily toward much improved outcomes. Expectations for new therapies and combinations are that they will produce durable long-term benefits with excellent quality of life.
To stay in the know about the key developments in the field of myeloma, sign up at subscribe.myeloma.org for our quarterly journal Myeloma Today and weekly e-newsletter Myeloma Minute, and contact the IMF InfoLine with your myeloma-related questions and concerns. Phone lines are open 9 a.m. to 4 p.m. (Pacific) Monday through Friday at 1.800.452.CURE in the U.S. and Canada and 1.818.487.7455 worldwide. To submit your query electronically, email [email protected].
(This article was published in the 2024 Summer Edition of the IMF's quarterly publication, Myeloma Today. Read the full publication here.)