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Multiple myeloma cells. About 80% of adults with the disease achieve complete remission, but the majority of those will relapse.Credit: Shutterstock
Hematologist-oncologist Leonard Klein had good news for his patient, a 65-year old woman with multiple myeloma. After chemotherapy and a stem-cell transplant, her disease was in complete remission.
But Klein, who works for Illinois Cancer Specialists in Niles, about 20 miles outside Chicago, also knew that his patient’s battle was probably not over. About 80% of adults with myeloma achieve complete remission, but the majority of those will relapse at some point1.
“That tells us that there are residual cancer cells that are beyond what we can detect visually or by the scans used for testing traditionally defined complete remission,” says Klein.
New technologies are enhancing the ability of oncologists and hematologists to detect these lingering malignant cells. Clinicians can use this measurement, known as minimal residual disease (MRD), to help predict a patient’s prognosis, make treatment choices, and monitor for early signs of relapse.
Residual disease can now be tracked in hematological malignancies, including leukemia, lymphoma and myeloma, and the benefits of these MRD tests have grown in tandem with their sensitivity and reliability. There are several ways to measure MRD. The most recent advance uses next-generation sequencing (NGS), which is poised to become a critical part of patient care. NGS was initially used primarily by physicians at major academic centers, but it is rapidly moving out into the broader community of cancer treatment.
A short history of MRD
Testing for MRD in cancer care was first done regularly by the Children’s Oncology Group (COG), a global clinical trials network, two decades decade ago. COG made residual disease assessment a standard prognostic indicator in clinical trials of treatments for pediatric acute lymphoblastic leukemia (ALL).
While the overall relapse rate for pediatric ALL within five years of remission is about 20%2, a patient’s prognosis was found to vary considerably depending on MRD status at each phase of therapy. For instance, a prospective study3 by COG tracked about 2,000 children with B cell ALL from 2000 to 2005. The researchers recorded the children’s MRD levels at multiple points during their treatment regimens. Among the study’s findings was that 83% of patients who were MRD-negative after the consolidation phase of chemotherapy (generally 22–30 weeks into treatment) avoided relapse within 5 years, compared to just 43% of patients who were MRD-positive at that juncture.
To test for MRD, the study’s researchers used flow cytometry to assess fluorescently tagged antibodies bound to specific markers on the surface of cancer cells. The sensitivity of conventional flow cytometry for MRD is around 0.01%, meaning it can spot 1 cancer cell in 10,000 cells, but results can vary significantly from lab to lab4. An alternative MRD test using polymerase chain reaction (PCR) amplification identifies unique DNA sequences specific to cancer cells. PCR is more sensitive than flow cytometry, but is less widely used, in part because the test is technically complex and time-consuming to perform5.
The most recently developed test for MRD uses NGS. This technique first assesses a sample taken at diagnosis to determine the patient’s cancer-specific DNA sequences. Throughout treatment, subsequent samples are assessed for the cancer-specific DNA to see how many cancer cells remain. It is powerful enough to find a single cancer cell in a million cells, provided sufficient sample input.
The rapid improvement of MRD tests made possible by NGS technologies has helped move MRD beyond the realm of clinical trials, into regular patient care as a tool to guide clinical management decisions.
“The oncology field is trying to move towards finding ways of detecting residual disease after patients have received therapy, so that we can predict who is more or less likely to relapse,” says Aaron Logan, a hematologist-oncologist at the University of California, San Francisco who uses NGS MRD monitoring for his leukemia patients.
Logan describes NGS MRD as one of the most important prognostic indicators for the patient. “It gives you a snapshot of what the patient’s actual response was to treatment,” he explains. “And that allows you to tailor the therapy plan to the patient.”
An MRD-negative patient is usually safe to stay on their current course of treatment, says Logan. “Whereas, with patients who are MRD positive, you know some elements of their leukemia are not adequately responsive to the chemotherapy, so we have the opportunity to intervene with other treatments.”
In addition, says Klein, if being MRD-negative allows a patient to stop treatment, that avoids not only toxicity but also more cost. “In the community,” he adds, “that’s incredibly important.”
A more personalized treatment plan
Cancer treatment is a long road, lined with decision points where clinicians need to weigh potential risks and benefits. Should you stay with the current treatment regimen or switch to another? Should you consider a stem-cell transplant? Can you take a break from therapy altogether? In all of these choices, MRD assessment can be a critical data point for personalized care.
Raya Mawad, a hematologist-oncologist at the Swedish Cancer Institute in Seattle, has made frequent use of MRD testing to help inform the care decisions for her leukemia patients.
A few years ago, one of Mawad’s adult ALL patients had achieved remission following induction with a combination therapy of hyper-CVAD and tyrosine kinase inhibitors. Mawad and her patient were weighing up the benefits of a stem-cell transplant.
While stem cell transplants are a potentially effective, long-term option for cancer treatment, they can have serious, even fatal, side effects. “Committing somebody to an allogeneic stem cell transplant is a big decision,” says Mawad. Further research linking MRD assessment with relapse risk over the course of treatment could, she says, “help doctors identify patients who might benefit from a stem cell transplant versus those who might be willing to defer that step with close monitoring afterwards”.
Mawad and her patient opted against the transplant after their MRD was negative according to flow cytometry, PCR and NGS. Instead, they continued to check the bone marrow for residual disease every three months. About a year later, the NGS test revealed a low level of MRD, while all the other tests continued to be negative, which was still the case at follow-up a month later, when the NGS assessment showed an uptick.
“We started to put in motion treatment planning for impending relapse,” including preparations for a stem-cell transplant, says Mawad. They also sought insurance approval for the leukemia drug blinatumomab, the first treatment indicated for MRD-positive patients in ALL.
According to Mawad, the key to truly unlocking the power of NGS MRD testing in cancer care will be large-scale prospective studies that integrate it with other test results at important clinical time points linked with specific treatment options. “I anticipate that data will come in the next few years and change the landscape of MRD assessment for lymphoid malignancies and treatment decision-making,” she says.
The ultimate goal, of course, is improved patient outcomes, and Klein believes that as NGS monitoring of residual disease becomes a part of standard care, it raises the bar for treatment success. “We’ve known for a long time that the definition of complete remission is unsatisfactory, because the expectation is that you’re cured of your malignancy. We know that a large fraction of patients who enter traditionally defined complete remission will relapse,” he says. “With MRD, people are testing upfront to help guide management and treatment, and they’re now trying to treat patients not just to complete remission but until they are MRD negative.”
Indeed, tracking residual cancer was critical for Klein’s multiple myeloma patient. To ward off relapse, she started by taking lenalidomide as a maintenance therapy, but this led to serious complications, including low red-blood cell and platelet counts. He took samples of cells from the patient’s bone marrow and had them sent to the lab that performed the NGS MRD assay. A week later, he received a report indicating that his patient was MRD negative. Klein felt comfortable stopping her maintenance therapy and relieving the dangerous side effects.
“As a community oncologist, I need to be able to offer my patients the types of very helpful testing offered by university cancer centers that may be very far away,” he says. “No matter where your practice is, you still have a patient with a disease.”