Prof. Jesús San Miguel is currently Senior Consultant at the University of Navarra Clinic and Professor of Medicine. He has been Director of Clinical and Translational Medicine at the University of Navarra and Medical Director of the Clínica Universidad de Navarra from 2013 until last August 2023. Previously he was Head of the Hematology Service at the University Hospital (for 22 years) and professor of said University. He has been President of the International Myeloma Society.
Dr. San Miguel is one of the three Spanish scientists with the highest H index (127) and the first clinician for his contributions to clinical research, having contributed to the approval of five drugs by the FDA. His scientific production has been translated into more than 900 international publications.
He has received numerous awards, including the most important awards from European and American societies of hematology and International Myeloma Societies as well as the most prestigious recognitions in his country: the Gregorio Marañón National Research Award and the King James I Award.
With the recent news in the United States of the April 12, 2024, Oncologic Drugs Advisory Committee (ODAC)’s unanimous vote in favor of using minimal residual disease as an early endpoint for accelerated approval in multiple myeloma clinical trials, I’d like to elaborate on what this vote means for patients and clinicians.
What Is Minimal Residual Disease?
Minimal residual disease, or MRD, is a measure of tumor burden assessed in a 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.
Do I Think MRD Testing Is Valuable in Evaluating Treatment Response?
I always discuss the MRD results with my patients and explain to them that MRD is the most sensitive technique to evaluate treatment response. Why is this? It allows us to detect up to one residual tumor cell among one million bone marrow cells. So yes, for patients to achieve MRD negativity, that is excellent news! Therefore, they know that the tumor load has been reduced to a maximum level, which is associated with longer survival and better quality of life.
Nevertheless, I also explain to my patients that an MRD negative result does not mean cure. We cannot exclude the persistence of residual cells at other sites. For this reason, we need to continue treatment to consolidate the MRD negative status.
What Does MRD Mean to a Myeloma Doctor?
Although MRD negativity is my goal, the driver is MRD positivity. MRD positivity reflects the persistence of residual cells that I must eradicate if I want to prolong the survival and eventually to cure my patient.
Therefore, MRD is the best available marker for tailoring treatment. It allows me to ascertain whether to intensify treatment if residual cells persist—particularly with adverse genetics. It also helps me judge when to stop treatment if an MRD negative status is maintained for more than two years.
In summary, MRD-driving therapeutic strategy will avoid both “under-treating” patients or “overtreating” them.
What Does the Future Hold for MRD Testing?
Today, we have two well-standardized techniques for MRD evaluation at bone marrow level:
- Next-Generation sequencing and
- Next Generation Flow.
Both these techniques provide identical results at the same sensitivity level. Both show that the lower the level of residual tumor cells (10-5, or even 10-6), the longer the survival.
The good news is that ongoing efforts are showing that assessment of MRD at peripheral blood level (by Mass Spectrometry or Blood-Flow) may soon be a reality. These methods will provide complementary information that will allow us to spare the frequency of bone marrow exams.
What Is My Overall Outlook on the Unanimous ODAC Vote in Favor of MRD as an Early Endpoint in Multiple Myeloma Clinical Trials?
The ODAC was the result of a longstanding effort of academic centers and industry that worked together under the umbrella of the I2TEAMM project, and in parallel with the University of Miami group. The new MRD endpoint will represent a sensitive early readout for drug approval, allowing patients timely access to newer treatment options. Learn more about the historic ODAC in this article from the Summer 2024 edition of Myeloma Today.