New MRD Assay Helps Move Testing Forward in Multiple Myeloma Research

Brian G.M. Durie, MD

Specialist, Multiple Myeloma and Related Disorders, Cedars-Sinai Comprehensive Cancer Center

Chairman, International Myeloma Foundation, North Hollywood, CA

An improved assay for assessing minimal residual disease (MRD) status in patients with multiple myeloma is contributing to the momentum for using MRD as a surrogate endpoint for survival in clinical trials and as a tool with the potential to help guide therapy choices, according to Brian G.M. Durie, MD.

In March, the International Myeloma Foundation (IMF) launched a new, automated flow cytometry test that is sensitive to 10^-6 (1 cell in a million) and provides a computerized printout of MRD levels. The new test offers a more reliable method of assessing MRD status in an area that currently lacks standardization, said Durie, who is cofounder and chair of the IMF.

Durie also participated in an internal symposium at FDA headquarters in Bethesda, Maryland, where regulators and National Cancer Institute (NCI) scientists discussed standards for the use of flow cytometry for assessing MRD.

“Broadly, there was a degree of consensus that MRD detection has reached a level where it is a valuable endpoint,” said Durie in an interview with OncologyLive.

“This is something that needs to be, I’m sure, further discussed internally and they’ll come out with recommendations and guidelines. Obviously, these are things that take time. But it’s absolutely up for consideration and discussion, and it’s very much on the radar.”

Utility of MRD Status

Durie said pharmaceutical companies already are incorporating MRD assessment into clinical trials in an effort to speed up development of new therapies for patients with multiple myeloma. He said there are two ways in which MRD status is being used in studies: (1) to compare therapeutic combinations based on which regimen is better able to produce an MRD zero result, and (2) to attempt to cure multiple myeloma by enhancing therapeutic regimens so that patients achieve MRD zero.A growing body of evidence has demonstrated that MRD-negative status is an achievable goal that is “predictive of superior outcomes” for patients with multiple myeloma, researchers have concluded.¹

“There have been important correlations between negative or low-level MRD status and progression-free and overall survival,” said Durie. “If you take a low-risk status patient and then that patient achieves MRD zero, it’s pretty clear that those patients do a whole lot better.”

Durie, who helped develop the first staging system for multiple myeloma in the mid-1970s, said MRD status represents another level of information beyond stringent complete response, the current measure of whether myeloma proteins are no longer present in the blood and the urine. Ultimately, Durie said, clinicians would use MRD status in the context of the patient’s risk stratification and in conjunction with PET CT scans and immunoglobulin heavy/light chain ratios.

“We are now taking it to the next level,” Durie said. “We’re saying that to have an MRD response that we think is worthwhile, you need to have both the bone marrow and the blood-negative [status] with our new flow method, and also we’re saying you need to have a negative PET CT scan and a normal heavy/light ratio.”

More Reliable Testing Needed

Durie said additional research into the clinical utility of MRD status must still be conducted before practicing oncologists and hematologists can use the test to make treatment recommendations for individual patients.For the research to continue to advance, however, Durie said there is a pressing need for a more reliable method of assessing MRD status. He noted that NCI researchers found that major medical centers in the United States vary considerably in MRD flow cytometry definitions and standards.²

Flanders et al found “considerable variation” in the number of bone marrow cells analyzed and the number of abnormal plasma cells used to define MRD status, as well as a 100-fold difference in sensitivity methods, among the 11 centers (out of 26 surveyed) that conduct MRD testing by flow cytometry.

“Quite frankly, the flow methodology that is being used across the US right now is just not reliable enough for this to be recommended” as a clinical trial endpoint, said Durie.

IMF’s New Assay Has Unique Attributes

As a result of such disparities, Durie identified improved testing as an important component of the IMF’s Black Swan Initiative. The initiative, which takes its name from the discovery of black swans at a time when all swans were believed to be white, aims to establish a cure for the disease through discoveries made in international research collaborations.Although researchers are exploring molecular- based testing, Durie believes enhancements to existing flow cytometry will be an efficient means to wide implementation of MRD standards.

This multiparameter flow cytometer was used to demonstrate the new minimal residual disease testing system at the IMF-EuroFlow Workshop in March.

The IMF has been working in partnership with the EuroFlow Consortium, which includes experts in the field of flow cytometry from 13 countries, to improve upon currently available technology. The new test that the group developed was unveiled in March at the Cancer Research Center at the University of Salamanca in Spain, where Alberto Orfao, MD, PhD, headed the studies.

Durie said the new test differs from current technology in that it uses a panel of 8 antigens chosen after months of research for reliability and sensitivity, and because it employs a unique, computerized algorithm.

“It’s linked in with a computer software program so that instead of needing a clinical pathologist sitting there in front of the machine and spending 45 minutes to an hour trying to figure out the results of the flow test, the results go automatically through the computer and you get a software printout and it tells you if there’s MRD zero or not,” explained Durie. “This is huge both in terms of efficiency and reliability. You are using a computer, not the variability of the individual investigator at a particular site.”

Durie said plans call for rolling out the new test kit and accompanying software in the United States starting in June. He estimated the cost of testing at $150 to $200 per test.

References

1. Munshi NC, Anderson KC. Minimal residual disease in multiple myeloma. [editorial] J Clin Oncol. 2013;31(20): 2523-2526.
2. Flanders A, Stetler-Stevenson M, Landgren O. Minimal residual disease testing in multiple myeloma by flow cytometry: major heterogeneity [letter]. Blood. 2013;122(6): 1088-1089.