Clinicians treating patients with multiple myeloma (MM) are familiar with the concept of measurable, or minimal, residual disease (MRD) and most of them are assessing it, whether in clinical trials or in standard-of-care settings. Fewer than four in 10, however, are making treatment decisions based on MRD results.
Those are the top-line findings of an international online survey of clinician attitudes and practices concerning MRD measurement in MM, recently published in the British Journal of Haematology. Lead author Benjamin A. Derman, MD, an assistant professor of medicine at the University of Chicago Medical Center, spoke with Nucleus about the survey and the current role of MRD in the care of patients with MM.
MRD measured at a sensitivity of 10-6 has been shown to predict superior progression-free survival (PFS) in patients with MM compared with 10-5 or 10-4. Moreover, MRD at 10-6 sensitivity was a strong prognostic biomarker for both PFS and overall survival. As a guide to treatment decision making for patients with MM, however, MRD remains unproven, Dr. Derman said.
“The use of MRD in decision making is by far the most controversial aspect of MRD in MM,” he said. “There is no consensus about it. We don’t know if it’s necessary to treat MRD-positive disease. Opponents point out that there is a lack of data to support basing treatment decisions on MRD. The reason for that, in part, is that clinical trials have assessed and reported MRD in varying ways, which has made it difficult to interpret the data.
“Our goal in conducting this survey was to assess how clinicians are actually using this technology. Are they using it purely as a prognostic tool, or are they using it as a basis for treatment decisions?”
The survey was distributed by email and Twitter in the fall of 2018 to 255 oncologists located on six continents, of whom 84 responded. Most of those responding practiced in North America (65.5%) or Europe (22.6%), but clinicians in Asia, South America, Africa, and Australia were also represented. A preponderance of respondents (89%) self-identified as clinicians at academic medical centers; the remainder worked in private practice or hybrid settings.
The finding that surprised him the most, Dr. Derman said, was that more than 80% of respondents working in private practice said they were assessing MRD in their patients, although just 12.5% said they used the results to make treatment decisions. Among clinicians at academic medical centers, 93% said they assessed MRD and 38% said they used the results in treatment decision making.
Dr. Derman cautioned, however, that clinicians who are using MRD may have been more highly motivated to respond to the survey and thus may have been overrepresented among the respondents. For this reason, the survey results may not accurately reflect the overall level of MRD use among clinicians treating patients with MM.
The absence of consensus in the MM community concerning the role of MRD in treatment decision making was mirrored in the survey responses, which revealed a lack of agreement about how to optimally incorporate MRD into patient care. Respondents were narrowly divided between those measuring MRD with multiparameter flow cytometry (49%) and next-generation sequencing (45%). Half of respondents reported assessing MRD at a sensitivity of 10-6. Clinicians indicated uncertainty about the most appropriate time to assess MRD. Preferred time points included during standard response assessment (62%), at the first evaluation after a stem cell transplant (51%), and after one or two years of maintenance therapy (30% for both).
Dr. Derman is now preparing to repeat the 2018 survey to look at how clinicians’ use of MRD has changed in the past two years. One issue he hopes to probe in the second survey is whether clinicians’ knowledge of patients’ MRD status influences their decision making in ways they may be unaware of.
“It’s a bit of a Pandora’s box,” he said. “Once the clinician has that information, it may subconsciously influence their decision making. So in this next survey we want to explore the potentially hidden influences of MRD on decision making by inquiring about common situations in which myeloma patients and clinicians might find themselves and how knowledge of MRD results might affect management decisions.”
Identifying Patients Who Can Discontinue Therapy – An “Appealing” Possible Application of MRD?
One of Dr. Derman’s interests is in whether MRD could ultimately be used to identify patients who can safely discontinue MM therapy.
“Because MM is considered incurable, the current standard of care is to continue maintenance therapy indefinitely,” he said. “But we have patients who continue to be MRD negative at multiple time points and by multiple measurement modalities. If they could come off treatment, they would be freed from the toxicities associated with maintenance therapy. However, we need clinical trials to determine at what point it might be safe to do that. To me this is a very appealing possible application of MRD.”
Derman BA, Jasielec JK, Jakubowiak AJ. Clinician attitudes and practices toward measurable residual disease in multiple myeloma. Br J Haematol. 2020 Aug;190(3):470-472. doi: 10.1111/bjh.16805.
Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132(23):2456-2464. doi:10.1182/blood-2018-06-858613