Minimal Residual Disease in Myeloma Suggested as Clinical Trial Endpoint, but Experts Disagree

Minimal residual disease, a measurement that shows a low level of disease detected, should be used as an endpoint in myeloma clinical trials, a study exploring previously published data suggests.

The study, “Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis,” published in the journal JAMA Oncology, showed that those who do not have minimal residual disease after treatment are likely to survive longer, and that such measurements are better than currently used response classifications.

But researchers from the U.S. Food and Drug Administration (FDA) countered the suggestion in an editorial, stating that it is premature and that minimal residual disease needs more evaluation before being used in clinical trials.

Many myeloma treatments today lead to a remission of the cancer. However, the remission is often temporary, as it is common for myeloma patients to relapse, suggesting that a small but clinically relevant number of multiple myeloma cells not detected by current techniques persists in those patients.

As a result, researchers suggested that measurements of minimal residual disease may improve prognosis and the evaluation of treatment.

Methods for detecting minimal residual disease are also improving. Numerous studies exist that look at how such measurements relate to various outcomes of myeloma, but most studies have been small.

To get a better view of the findings, researchers at the Dana-Farber Cancer Institute in Boston analyzed data from previously published studies — 14 studies with 1,273 patients that analyzed how minimal residual disease impacted progression-free survival, and 12 studies with a total of 1,100 patients, that looked at overall survival. In total, the analysis included 1,259 patients without, and 1,114 with, minimal residual disease.

Some of the studies also looked specifically at patients who had a complete response. Five studies investigated progression-free survival and six explored overall survival, totaling 1,190 patients.

Researchers found that having no minimal residual disease was linked to a better progression-free survival, both in the entire group and among patients who had a complete response to treatment. The same was true when looking at overall survival.

The study found that minimal residual disease was a better measurement to predict survival than the presence of a complete response, and even better survival predictions could be attained if minimal residual disease status was combined with cancer genetic analysis.

Two of the studies also explored how maintenance treatment impacted minimal residual disease. One reported that maintenance treatment increased the proportion of patients without minimal residual disease, while the other did no comparison, but reported high rates.

Also, five studies of stem cell transplants all showed that more patients had no minimal residual disease after the transplant than before.

In a linked editorial, Dr. Nicole Gormley, MD; Dr. Ann Farrell, MD; and Dr. Richard Pazdur, MD, from the FDA Office of Hematology and Oncology Products applauded the study as a first crucial step toward the establishment of minimal residual disease as a surrogate marker used to assess treatment in clinical trials.

Still, the trio said several crucial questions remain. Such issues relate to how minimal residual disease status should be used in relation to other measurements, such as genetic and drug response, and which patient groups should be evaluated using this approach.

They also suggested that the timing of measurements and the impact of new drugs such as antibodies also need to be evaluated before minimal residual disease can be accepted as a clinical trial endpoint.