Uncovering the Enemy Within

Kevin Richards with his wife, Dale, is living with IgM multiple myeloma, a rare subtype of the disease.

After Kevin Richards received a diagnosis of IgM multiple myeloma, a rare subtype of the disease, in August 2009, he was treated successfully with a standard chemotherapy regimen, followed by a bone marrow transplant. Then, to reduce the risk of relapse, his oncologist put him on a low dose of Revlimid (lenalidomide), an immunomodulatory drug, monitoring him monthly the first year, and bi-monthly the second year with blood or bone marrow tests that can find minuscule amounts of cancer long before they would show up in any other routine test. Testing for traces of cancer, or minimal residual disease (MRD), is becoming part of the standard of care in multiple myeloma, and it’s starting to catch on in the treatment of several other blood cancers, too. MRD tests give oncologists the opportunity to detect cancer cells hiding out in the body and try to eliminate those cells before they explode into a full-blown relapse.

Richards’ MRD test came up clear in 2012, prompting his oncologist to take him off Revlimid for good. Every MRD scan since has been clean — a huge relief to Richards, 65, who works as an estate planner in Paso Robles, California. Richards used to call “relapse” a four-letter word, he says. “That’s what’s hanging over a patient’s head. With MRD testing, I know my doctors will find out early enough to make the next set of treatments more effective and easier for me,” Richards says. “For a myeloma survivor, that is a huge relief. It allows me not to just exist, but to get involved with my regular activities, pursuits and passions.” MRD can be measured using a variety of technologies. A cell-counting tool called flow cytometry can find one tumor cell in 10,000 cells in bone marrow samples. A more advanced technology, polymerase chain reaction testing, can pick out one cancer cell in 100,000 cells. “Now we are entertaining multiple MRD technologies that might even be able to measure one cancer cell out of one million cancer cells,” says Luhua “Michael” Wang, M.D., a professor of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center in Houston.

What’s more, advanced MRD tests can reveal details about the remaining cancer cells that point oncologists to personalized treatments, Wang says. “This is a huge advantage, not only to detect when the disease is starting to come back, but also to track its evolution,” he says. “We’ll know which mutations are in the cells. That means we’ll know at a very early stage whether the relapse will be sensitive to (targeted) treatments.”

In October 2018, the Food and Drug Administration (FDA) approved the first test that can do just that: clonoSEQ, for monitoring patients with multiple myeloma or acute lymphoblastic leukemia (ALL). What makes it different from other technologies for monitoring MRD is that it identifies specific gene sequences in T and B cells — immune cells in the blood that have become cancerous. That lowers the amount of MRD that the test can detect to the coveted one-in-a-million level, in addition to revealing changes in cancerous mutations over time.

The FDA approved the test based on data from 273 patients with ALL and more than 1,000 with multiple myeloma. Patients who were MRD negative when tested with clonoSEQ had longer event-free, progression-free and disease-free survival rates than those with measurable MRD.

Several trials are examining whether clonoSEQ can improve the monitoring of patients with other types of blood cancer. For example, Memorial Sloan Kettering (MSK) Cancer Center in New York City is leading a trial of the technology in predicting relapses in aggressive B-cell non-Hodgkin lymphoma. The study, which will enroll 500 patients who have already undergone treatment, will assess whether clonoSEQ better detects MRD than traditional methods like CT scans, physical exams and symptoms reported by patients.

Extending the Use of MRD Tests

When monitoring patients with blood cancers for MRD that can’t be detected by clonoSEQ, oncologists select the technology that’s best suited to the patient’s diagnosis. In acute myeloid leukemia (AML), for example, a technology called multi-parameter flow cytometry is gaining ground, says Mary-Elizabeth Percival, M.D., assistant professor at the University of Washington and assistant member at Fred Hutchinson Cancer Research Center in Seattle. It uses fluorescent antibodies to label and count cells based on specific immunophenotypes, or abnormalities in patients’ cancers, before treatment. “Once (abnormalities) are characterized, they can be measured post-treatment,” Percival says. “It’s an extremely sensitive test.” It’s also a major improvement over older tests that merely count cancerous blood cells in bone marrow, she adds.

The increasing ability to personalize MRD testing helps oncologists better predict which patients are most likely to relapse. A 2016 study of patients with AML who underwent bone marrow transplants between 1988 and 2013 examined a commonly used polymerase chain reaction test for detecting MRD based on a single gene that’s overly active in most patients. That test was just 14 percent effective at predicting relapses. But in patients whose MRD was measured based on several genetic abnormalities that were detected using multi-gene panels, those who were MRD negative after transplant had no relapses in the first year. By contrast, there was an 83 percent relapse rate among patients who were MRD positive after transplant, as determined by the more sensitive MRD test.

MRD tracking is becoming more prevalent in clinical trials, and the results can provide valuable information for oncologists treating blood cancers. For example, one trial tracked patients with multiple myeloma who were treated with either two drugs or three drugs to prevent relapses after achieving MRD negativity. The three-drug regimen was superior. But after the primary endpoint of the study was reached, researchers noticed that some patients who got the less aggressive treatment had outcomes — namely MRD negativity — similar to those who received three drugs. And all patients who were MRD clear had similar progression-free survival regardless of which treatment they received.

That’s important insight, particularly for treating patients who may not be able to tolerate the more aggressive three-drug therapy, says Ola Landgren, M.D., Ph.D., chief of the myeloma service at MSK. “MRD negativity appears to be more important than what therapy that was given to reach MRD negativity,” he says. “Genomically, multiple myeloma is a very heterogenous disease, so it is not unexpected that some patients with (less aggressive) disease could achieve negative MRD with less active therapy. We are seeing the exact same patterns in newly diagnosed patients with multiple myeloma; modern combination therapy can deliver high rates of MRD negativity in the absence of bone marrow transplant and data suggest that MRD negative patients — with or without transplant — have the same progression-free survival and overall survival. The multiple myeloma treatment field is changing very fast.”

The idea of monitoring and treating MRD has been slow to catch in the realm of some blood cancers — most notably, Hodgkin lymphoma. But several clinical trials underway could help change that, says Alex Herrera, M.D., an assistant professor of hematology at City of Hope in Los Angeles. Most patients can be cured, but when Hodgkin lymphoma does recur, positron emission tomography (PET) scans often fail to detect it, he says. “There are very few malignant cells in a (Hodgkin lymphoma) tumor, so it’s been difficult for many years to figure out how to test for MRD,” Herrera says. “Now sequencing-based technology looks like it could be a powerful tool.”

One emerging technology that Herrera is watching closely is cancer personalized profiling by deep sequencing (CAPP-Seq), which tests the blood for tiny bits of genetic material that cancer cells release as tumors grow. Developed at Stanford University, the tool can detect multiple genetic mutations in a tumor and track them over time. In a study published in 2017, CAPP-Seq detected relapses in the most common type of non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), more than six months earlier than PET/CT scans could.

In another study — this one involving patients with Hodgkin lymphoma — a group of scientists led by the Institute of Oncology Research in Switzerland demonstrated that CAPP-Seq could not only detect MRD early but also be used throughout therapy to track how tumors were evolving over time.

Such precise MRD testing could help fine-tune treatment strategies, Herrera says. “CAPP-Seq can investigate hundreds of mutations at the same time, which allows us to track a patient’s disease,” he says. For example, some patients with B-cell lymphomas are treated with the targeted drug Imbruvica (ibrutinib), which inhibits an enzyme that causes B cells to grow out of control. CAPP-Seq can detect the formation of genetic mutations that cause patients to become resistant to the drug. “That could be used to guide decision-making about how to treat the disease going forward,” Herrera says.

From Testing to Treatment

With MRD testing, oncology researchers have turned to a pressing question: Once MRD has been detected, what is the best way to clear the remaining cancer cells and lessen the probability of a relapse? Several therapies are being explored in clinical trials aimed at clearing MRD, including targeted drugs and engineered cell treatments that are intended to boost the immune system’s ability to recognize and defeat cancer.

Percival is leading a trial of Mylotarg (gemtuzumab ozogamicin), an antibody attached to a cancer-fighting compound. The drug was initially approved to treat some patients with AML but was removed from the market due to safety concerns. It was re-approved in 2017 with different dosing recommendations for patients with new diagnoses or who had relapsed, and now Percival hopes to learn if it might also prevent relapses in patients with AML who also are MRD positive. Trial participants are receiving the drug intravenously three times a month, after which they will be followed for six months.

Rituxan (rituximab) is also in clinical trials for treating MRD in several types of lymphoma, including mantle cell and follicular lymphoma. In one study, the drug was shown to clear MRD in patients with mantle cell lymphoma who relapsed after undergoing drug treatments and bone marrow transplants.

In March 2018, the FDA approved Blincyto (blinatumomab) to treat patients with B-cell precursor ALL who are in remission but are MRD positive, marking the agency’s first approval of an ALL drug based on MRD status. In a clinical trial, 70 of 86 patients returned to MRD-free status after being treated with the drug. More than half of the participants were still in remission nearly two years later. Ongoing trials are investigating whether Blincyto is equally effective at clearing MRD in patients with other blood cancers, including DLBCL.

As MRD testing evolves, many oncologists hope it will point to treatments that can prevent relapses and at the same time allow patients to maintain a good quality of life. MSK recently opened a clinical trial that is recruiting patients with multiple myeloma who achieved MRD-negative status and were put on Revlimid but later converted back to MRD-positive status. Participants will stay on Revlimid and receive an additional six months of another multiple myeloma drug, Darzalex (daratumumab), to see if very early and short-term treatment can return them to MRD-free status.

Several trials are examining personalized cell therapies for treating MRD in different blood cancers. Fred Hutchinson is recruiting for one such trial, designed for patients with high-risk AML, many of whom have MRD and are not currently candidates for bone marrow transplant. The trial involves removing the immune system’s T cells from patients’ blood, then engineering them so they can recognize WT1, a molecule produced by leukemia cells. T cell receptor (TCR) therapy is similar to chimeric antigen receptor (CAR)-T cell treatment used in some blood cancers. But instead of targeting protein markers on the surface of cancer cells, like CAR-T therapy does, TCRs are engineered to recognize telltale markers inside of the cells. The Fred Hutch investigators hope to find that when the TCRs are put back into the body, they will home in on leukemia cells and kill them.

Deborah Sims with her children, Cameron, 14, Natasha, 9, and Marlowe, 12, who were only 7, 2 and 5, respectively, when she received her diagnosis and was given five years to live. She says every year is a blessing.

Advances in MRD testing are benefiting patients like Deborah Sims, who received a diagnosis of chronic lymphocytic leukemia (CLL) in 2011 and was found to be MRD positive after undergoing a standard chemotherapy regimen. In 2015, Sims enrolled in a clinical trial of Venclexta (venetoclax), which inhibits BCL-2, a protein associated with cancer cell survival and chemotherapy resistance. Sims traveled to London from her home in Melbourne, Australia, to get the drug. A little over a year after she started the trial, her MRD test showed she was clear of her disease, and she has been on Venclexta ever since — an easy regimen of four pills a day that have not caused her any side effects, she says.

In September 2018, the FDA updated Venclexta’s label to include MRD data. More than half of patients treated with a combination of the drug and Rituxan were MRD negative after nine months compared with 12 percent of patients taking a standard treatment of Rituxan with the chemotherapy drug bendamustine.

MRD results can help physicians and patients work together to figure out the best time to stop treatment altogether. Sims has been MRD negative for three years and continues to have her blood checked every two months for signs of the disease. Even though some research suggests that patients with CLL can stop treatment after testing negative for MRD, Sims opted to continue taking Venclexta. “I hope this is a cure. It’s looking good,” says Sims, 45, a mother of three who works for a public policy think tank. “But I like taking my four tablets a day. It’s a safety net.”