Most people with multiple myeloma need to undergo treatment. How do you know if these treatments are effective? Doctors use different methods to analyze whether any cancer cells remain in the body. One such method involves measuring minimal residual disease (MRD) — or measurable residual disease. A person with MRD still has a detectable small number of myeloma cells left in their body following treatment. Some of these cells may have become resistant to treatment, whereas others may just have escaped the effect of chemotherapy.
Doctors may measure MRD for people with blood cancers such as myeloma, leukemia, and lymphoma. In addition to showing whether treatments are working, testing for MRD may accurately show whether a person is in remission (meaning most or all signs of the cancer have disappeared). Additionally, undergoing MRD testing over the course of many follow-up appointments may show when a person experiences a relapse (their cancer has come back).
If a person has no signs of disease after treatment, they are said to have had a complete response or complete remission (CR). However, achieving CR doesn’t mean that the myeloma is cured — some people have a relapse after going into remission. Even just a few cancer cells remaining after treatment could begin growing again and eventually cause relapse.
In the past, doctors measured CR by looking at cells within the bone marrow — the soft, spongy tissue found inside certain bones, where plasma cells grow. If less than 5 percent of a person’s bone marrow cells were plasma cells, the person was said to have reached CR.
However, CR doesn’t give you the full picture. It means treatments have eradicated most cancer, but it doesn’t say exactly how much cancer is left in the body. Some people who have reached CR may have no remaining myeloma cells. Others may continue to have low levels of cancer, or minimal residual disease. Doctors use extra-sensitive tests to look for remaining cancer cells and to determine a person’s MRD status. Someone is MRD-positive if they still have a small number of cancer cells in the body following treatment. Someone is MRD-negative if sensitive tests can’t detect any cancer cells.
Usually, doctors say that a person is MRD-negative or MRD-zero if they test 1 million bone marrow cells and don’t find any cancerous cells. This doesn’t necessarily mean that there are no myeloma cells in the body — just that there are so few cancer cells that they can’t be detected. It’s safe to assume that the few remaining cells that go undetected by MRD testing methods will not survive and repopulate the cancer.
In the past, most doctors did not recommend that people with myeloma be tested for MRD. Only participants in research studies (called clinical trials) for myeloma treatments routinely underwent MRD testing. This is because researchers still had questions about what MRD test results meant for people with myeloma. For instance, if MRD is negative (no remaining myeloma cells), is it safe to stop treatment? And if MRD is positive (some remaining myeloma cells), does it mean treatment isn’t working?
In other words, doctors understand what MRD is and how to test for it, but they do not always know the best way to use this information. There are not yet guidelines for how doctors should consider MRD test results when making treatment plans. As such, some doctors may choose not to use MRD results until this measure is better understood.
In the meantime, studies are gradually uncovering more information about MRD. Some researchers now believe that MRD should start being more widely used, and some doctors have begun incorporating MRD testing into clinical practice. In the future, experts may develop guidelines that more clearly show how doctors can best take MRD results into account.
Expense is also a consideration in MRD assessment. Some health insurance carriers consider MRD specialized testing and will not pay for it. Additionally, not all labs can test for MRD, and this test may incur extra fees if samples need to be sent to an out-of-network lab. If your doctor has recommended you undergo MRD testing, your insurance provider can help you understand what your cost will be.
Once guidelines are established for measuring and using MRD results in myeloma, they may provide doctors with knowledge about how well myeloma treatments are working and help them tailor your treatment plan.
MRD may be able to provide information about a person’s outlook. Research has found that people who are MRD-negative are less likely to have a relapse than people who still have detectable myeloma cells following treatment. Additionally, we now know that MRD more accurately predicts outlook compared to CR.
In the near future, it is expected that doctors will be able to use MRD results to make treatment decisions. For example, doctors could use a person’s MRD status to know when to recommend effective but expensive immunotherapy drugs. High-risk people who still have MRD after treatment could take these drugs to help improve their prognosis, while those without MRD could avoid or delay unneeded treatments and drug costs. However, more research is needed before doctors fully understand how best to recommend treatment options based on MRD.
Most commonly, tests look for intramedullary disease (remaining myeloma cells inside the bones). For these tests, doctors use a bone marrow aspirate or biopsy, in which samples of fluid or cells are taken from inside the bone. The samples are sent to a laboratory, where they may undergo flow cytometry or gene testing.
Researchers are still improving these techniques and learning more about which tests are most helpful.
Flow cytometry is a test that identifies which proteins are found on a cell’s surface. Different types of blood cells contain different proteins. Normal, healthy cells also have a different set of proteins compared with cancer cells. Flow cytometry can help tell apart cell types and identify how many cancerous cells are in a sample. Doctors may also use an improved technique called next-generation flow cytometry to measure MRD.
Myeloma cells contain gene changes that set them apart from healthy plasma cells. Doctors can test a sample of plasma cells for these gene changes in order to determine how many cells within the sample are cancerous.
Traditionally, doctors used a technique called polymerase chain reaction (PCR) to look for MRD. This assay creates many copies of a small part of a gene, which helps doctors detect whether a particular gene or gene change is present.
In more recent years, many doctors have switched to using next-generation sequencing (NGS) for MRD detection. NGS “reads” many different genes found within a cell sample. NGS tests are more sensitive than PCR — they are more likely to detect tiny numbers of cancer cells. The U.S. Food and Drug Administration (FDA) has approved an NGS test called clonoSEQ for MRD testing for people with multiple myeloma.
In some cases, people may not have any myeloma cells inside the bone marrow but will have one or more tumors remaining outside of the bone marrow. Because flow cytometry and gene testing use blood or bone marrow samples, they may show that a person is MRD-negative despite having extramedullary disease (located outside of the bone marrow). For this reason, some doctors recommend using PET/CT scans along with other MRD tests. These imaging tests can detect myeloma cells around the body.
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