Minimal Residual Disease Testing: What Does it Mean?

The goal in treating myeloma is to cure the patient or achieve longterm remission. But there is always the chance that some myeloma cells remain, despite the patient being in complete remission. One test that may indicate that myeloma is not completely eradicated is to check for what doctors call minimum residual disease (MRD).

“MRD testing detects myeloma cells on a much more sensitive level inside the bone marrow,” Carolina Schinke, M.D., said. “MRD is a hot topic right now in the scientific myeloma community.”

During treatment, all myeloma patients at UAMS undergo testing for minimal residual disease with results being either positive for the disease or negative. The Myeloma Center uses two types of MRD testing — flow cytometry and next generation sequencing.

With flow cytometry, a laser light beam measures physical and chemical characteristics of cells. The test studies the difference in the proteins on the surface of a cell to distinguish regular plasma cells from myelomatous plasma cells. The Myeloma Center began MRD testing in early 2014. It is conducting a study with the flow cytometry tests and is still gathering data.

“The flow cytometry can detect one myeloma cell in 100,000 cells which

is pretty sensitive,” Schinke said. “The pathologist would never be able to see that.”

With next generation sequencing, a baseline sample is taken when the patient has active myeloma to identify unique DNA markers in the myeloma cells. These DNA sequences can then be searched for in the marrow when the patient is in remission by standard criteria. The test, conducted off site by Adaptive Biotechnologies, can detect one myeloma amidst a million normal cells.

The criteria of complete remission are no detectable myeloma protein in the blood and less than 5% plasma cells in the bone marrow. The presence of a negative MRD test either by flow or sequencing means that the patient has achieved a so-called stringently defined complete remission.

In addition, the Myeloma Center looks for active disease by imaging studies such as MRI and PET-scan.

“Achieving complete remission may mean just the tip of the iceberg has been treated and there may be a lot more tumor burden that wasn’t able to be identified,” Schinke said. “There is the potential for relapse if there are remaining cancer cells as detected by MRD testing.”

New MRD offer greater insight

“The goal is to try to get each patient to an MRD negative state because over time we see those patients don’t relapse or have overall better outcomes with less relapses,” Schinke said.

However, the interpretation of MRD testing is complex and depends on whether the patient’s disease is characterized as low risk or high risk. Some patients have more indolent, non-aggressive myeloma and these patients can remain MRD positive without ever relapsing.

On the other end of the spectrum there are patients with high-risk disease, 15% to 20% of the myeloma population, where MRD positivity after transplantation indicates a high risk of relapse. These patients remain a challenge and the question is how to best alter therapy. Patients with standard or low risk may take longer to achieve MRD negativity after transplant.

“We have found that those low risk patients who are MRD positive more than two years after transplant have an increased risk of relapse.”

Schinke said there is a lot of information available on MDR testing but few, if any, other treatment centers have systematically examined the difference between wlow-risk and high-risk disease.

“I believe we were the first ones to publish on that, but there are important questions we are trying to answer,” she said. “How do you guide your treatment around being MRD negative? If a patient achieves MRD negativity does that mean you can stop the three-year maintenance treatment early? How long does the patient need to be MRD negative to be safe? Can one use the flow test or does one need to use the more sensitive sequencing test?”

The other side of the coin is the positive MRD test.

“We will now actually change a treatment regimen based on positive MRD testing, especially in high-risk patients, even if everything else looks good,” Schinke said. “We have definitely become more proactive in preventing relapses when we see the MRD tests trending up.” “The goal is to try to get each patient to an MRD negative state because over time we see those patients don't relapse or have overall better outcomes with less relapses.”

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behind the scenes

Fenghuang “Frank” Zhan, M.D., Ph.D.

Frank Zhan is a professor of medicine with the UAMS College of Medicine. He earned his doctorate in cancer molecular genetics from Hunan Medical University in Changsha, China. He began his postdoctoral fellowship in neuroscience at the University of Louisville in Louisville, Kentucky. In 2000, he joined UAMS where he completed his postdoctoral fellowship and later was promoted as assistant professor. Zhan’s research focuses on translational research in multiple myeloma and aims to identify treatment approaches to overcome drug resistance in myeloma. His projects include molecular genetics and biology of tumor cells and microenvironment, genes and drug resistance, genomic classification, and identifying and targeting myeloma stem cells.

Sarah K. Johnson, Ph.D.

Sarah K. Johnson is a research assistant professor with the UAMS College of Medicine. She earned her doctorate in biochemistry from UAMS. She completed her postdoctoral fellowship in pharmaceutical sciences from the Medical University of South Carolina in Charleston, South Carolina. In 2002, she joined UAMS as a research assistant professor in the Myeloma Center. Johnson’s research focuses on the characterization of residual disease gene expression, epigenetic and metabolic profiles to identify resistant myeloma cells at any stage of the disease and to identify novel targets for the eradication of resistant tumor cells. Johnson studies myeloma cells and their interaction with the immune environment in the bone marrow. The goal is to learn how this interaction affects resistance to treatments to improve existing therapies as well design novel, especially immune-based therapies.