The interest in using quantitative tests to measure residual cancer cells—called measurable residual disease (MRD)—continues to expand in the arena of hematologic malignancies. Tests to measure MRD take a “snapshot” of a patient’s current status and provide clinicians with a yes or no answer to the question, “is disease still present in the body?” at a time when cancer cannot be detected using other traditional methods.
Applications of MRD vary depending on the disease state but can include providing prognostic information, acting as a measure of clinical efficacy, guiding therapeutic decisions, and serving as a clinical endpoint.
Blood Cancers Today spoke with experts in acute lymphoblastic leukemia (ALL), multiple myeloma (MM), and chronic lymphocytic leukemia (CLL) for a status update on the use of MRD in each of these diseases.
ALL Update
MRD is highly predictive and prognostic in ALL, explained Elias Jabbour, MD, a Professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston.
“You cannot treat ALL if you do not measure and act on MRD,” Dr. Jabbour said. “MRD is a critical part of management of ALL.”
In its requirements for the diagnosis of ALL, the National Comprehensive Cancer Network (NCCN) guidelines include a “baseline flow cytometric and/or molecular characterization of leukemic clone to facilitate subsequent” MRD analysis, and many of its treatment algorithms recommended therapy based on MRD status.1
There has been mounting evidence of the prognostic value of MRD in ALL, with much of the data for adult patients building on already-established evidence for pediatric populations.
For example, data from patients with ALL from two large transplant centers showed that detection of MRD even at a low level increased a patient’s risk for post-transplant relapse. Any MRD detection post-transplant also increased the risk for relapse. In contrast, patients with undetectable MRD prior to transplant and through the first year of monitoring have excellent post-transplant outcomes.2
Transplant-eligible patients who are MRD positive can receive blinatumomab prior to transplant. Blinatumomab was the first drug to receive US Food and Drug Administration (FDA) approval for the treatment of B-ALL.3
There is also early evidence that MRD status could predict relapse after chimeric antigen receptor (CAR) T-cell therapy in patients with B-ALL. Data from the pediatric and young adult populations showed that next-generation sequencing (NGS) MRD from bone marrow was highly predictive of relapse after tisagenlecleucel therapy, possibly enabling clinicians to consider additional treatment to prevent relapse.4
Dr. Jabbour and colleagues have presented results of a meta-analysis evaluating associations between MRD and long-term outcomes in Philadelphia chromosome-positive (Ph+) ALL. Study-level and individual patient data showed that deeper molecular response at end of induction yielded better long-term event-free survival (EFS) and overall survival (OS), that MRD-negative complete remission (CR) was associated with long-term EFS and OS, and that MRD-negative CR had a greater prognostic value than CR alone.5
“We are very close to considering MRD as a finite way to tailor therapy in ALL,” Dr. Jabbour said.
There are still multiple methods for measuring MRD use—flow cytometry, polymerase chain reaction, or NGS—each with its own level of sensitivity. However, Dr. Jabbour said that he feels the field will soon adopt NGS as a standard of care. Currently, ClonoSEQ assay, an NGS-based test, is the only FDA-approved test for the measurement of MRD in ALL or MM.6
In ALL, the high sensitivity of NGS, which can measure to a depth of 10-6, allows for measurement of MRD in peripheral blood. Studies have shown that there is concordance between blood and bone marrow assessment in adult patients.7
When clinicians choose to measure MRD by NGS, they must obtain the baseline patient-specific clonotype and then measure it again after induction therapy, consolidation therapy, and regularly throughout maintenance therapy.
“At my practice, I measure MRD every month until a patient becomes MRD negative,” Dr. Jabbour said. “Once a patient is MRD negative, then I measure it every three months throughout treatment, and once treatment is finished, every three to six months for the first couple of years.”
The use of MRD to guide therapeutic decisions is becoming more and more standard, Dr. Jabbour said.
“Eventually, with very effective therapy, the MRD response will trump the basic biologic features [of ALL],” Dr. Jabbour said. “The field is evolving and MRD assessment will carry a bigger and bigger weight moving forward.”
Myeloma Update
The biggest recent advance in the use of MRD in MM is the April 2024 Oncologic Drugs Advisory Committee (ODAC) 12-0 vote in favor of using MRD as an early endpoint to support accelerated approval,8 an achievement that was more than 15 years in the making according to C. Ola Landgren, MD, PhD, professor of Medicine, Chief of the Myeloma Division, and Co-Leader of the Translational and Clinical Oncology Program at the University of Miami Sylvester Comprehensive Cancer Center.
“Progression-free survival (PFS) is a surrogate endpoint for OS, and it is used for full approval of new drugs. But to have a surrogate endpoint you have to have strong correlations, and you have to have many datasets to prove your case with sufficient statistical power,” Dr. Landgren explained. “We developed a model where we tested the hypothesis that MRD was reasonably likely to predict clinical benefit, which is the level of statistical evidence you need to have for an endpoint to qualify as an endpoint for accelerated approval.”
The gathering of data and creation of this model began many years ago. When Dr. Landgren realized that while the drug companies had the data that might correlate MRD with clinical benefit and the FDA would review the data, a third party would be required to gather datasets from a wide range of classes of drugs and to develop statistical models designed to evaluate MRD as an early endpoint in MM.
This culminated in the publication of the EVIDENCE meta-analysis, which included eight phase II or III randomized studies of newly diagnosed MM and four studies of relapsed or refractory MM. Individual-level associations between 12-month MRD negativity and PFS yielded a global odds ratio of 4.02 for newly diagnosed disease and 7.67 for relapsed or refractory disease.9
These data, combined with similar data from the collaborative research group I2TEAMM (International Independent Team for Endpoint Approval of Myeloma MRD), led to the unanimous ODAC recommendation for the use of MRD as an early endpoint for accelerated approvals.
Dr. Landgren explained why this recommendation could be a big step forward.
“In a trial of MM, if you enroll 500 patients—which can take two years and then one year after the last patient is enrolled—you have MRD data for every patient,” Dr. Landgren said. “However, you would have to wait more than 10 years for the dataset to mature (ie, to obtain sufficient statical power) for PFS outcomes.”
This new evidence validates that MRD was able to predict PFS benefits.
“The deliverable is that you shrink those 12 years down to three,” Dr. Landgren said. “This makes it attractive to develop drugs in a disease where otherwise–with traditional endpoints–it isn’t because the patent would be almost over by the time the drug was approved.”
Additionally, trials designed to cure patients with MM can have an answer about whether it works in less than three years—one to two years for enrollment and one year for MRD measurement.
Best of all, this approach can be adapted to other diseases, Dr. Landgren said.
In addition to its use as an early clinical endpoint, evidence continues to grow in support of using MRD to guide therapeutic decisions in patients with MM.
Results of the PERSEUS trial published earlier in 2024 compared bortezomib, lenalidomide, and dexamethasone (VRd) plus lenalidomide maintenance or VRd plus daratumumab (D-VRd) plus daratumumab and lenalidomide maintenance. After two years of maintenance, patients who were MRD-negative for at least 12 months could discontinue daratumumab; recurrence of MRD prompted the return to daratumumab maintenance.10
Taking it a step further, the MRD2STOP trial looked at complete discontinuation of maintenance therapy in patients with sustained multimodal MRD negativity. Results showed that maintenance discontinuation resulted in a high rate of sustained MRD negativity and lack of disease progression.11
Dr. Landgren is also part of the ADVANCE study, which randomly assigned patients to eight cycles of carfilzomib, lenalidomide, and dexamethasone with or without daratumumab with autologous hematopoietic stem cell transplant offered to patients who remain MRD positive after eight cycles.12 Results are expected in 2025.
“There is not yet a trial that has definitely proven that [measuring MRD] is the way to do it,” Dr. Landgren said. “The reality is that it’s also probably true for all other markers; we use serum protein electrophoresis (SPEP) or light chains, but there are very few randomized trials that formally have proven their use.”
The biggest roadblock for increased use of MRD in MM is that it is measured using bone marrow biopsy, Dr. Landgren said. Blood-based techniques exist but have not yet been validated to fully replace bone marrow biopsies in myeloma.
“A blood-based MRD test for MM would very likely change the whole treatment field in the future,” Dr. Landgren said. “I could see some patients going off therapy and being tested every few months. In other patients, the therapy will be stepped up or down based on the MRD results.”
CLL Update
The utility of MRD measurement in CLL is not all that different than in ALL or MM, according to Talal Hilal, MD, a hematologist oncologist and bone marrow transplant physician at the Mayo Clinic in Phoenix, Arizona.
Similar to ALL and MM, MRD detection in CLL uses similar assays, with six or eight color flow cytometry detecting MRD to 10-4, and the same NGS assay–ClonoSeq–detecting to 10-6.
“One thing that makes MRD a little more versatile in CLL is that MRD can be easily tested in the peripheral blood as compared with ALL and MM, where it is still tested primarily from bone marrow samples,” Dr. Hilal explained.
Within CLL though it remains to be seen if MRD is a surrogate endpoint for clinical outcomes. Recently, Dr. Hilal and colleagues published a meta-analysis looking at associations between MRD and PFS in CLL using data from 11 prospective clinical trials of targeted agents or obinutuzumab-based regimens.
Undetectable MRD measured at 10-4 was associated with significantly improved PFS (hazard ratio [HR]=0.28) compared with MRD positivity, with improved outcomes noted for patients treated in the firstline, relapsed or refractory setting, or in trials using time-limited therapy.13
Researchers from the German CLL Study Group presented a similar analysis using patient- and trial-level data to look at correlations between PFS and MRD, and confirmed a correlation of MRD status with PFS.14
“These data showed if you achieve undetectable MRD at 10-4 after time-limited therapy—whether chemoimmunotherapy or venetoclax-based treatment—your PFS is going to be better than someone who does not achieve that endpoint,” Dr. Hilal said. “The hard part is understanding whether improving undetectable MRD rates can predict clinical benefit as defined by the FDA.”
Dr. Hilal noted that some clinicians may be hesitant to use MRD in practice because progression of CLL does not always mean a patient needs more treatment. Instead, “it may be necessary to correlate undetectable MRD to something more clinically meaningful like time to next treatment and, if possible, OS,” he said.
It also remains to be seen if MRD has clinical utility and if it can be used to guide therapeutic decisions.
In Dr. Hilal’s practice, a patient being treated with time-limited venetoclax plus obinutuzumab will typically have MRD tested at one year and possibly at six months.
“I often don’t do anything with the results though, which is sort of the issue,” Dr. Hilal said. “It is just an extra data point that provides prognostic information. It doesn’t change my approach to treatment.”
However, researchers are looking to change that. In December 2023, results of the FLAIR study showed that MRD-directed ibrutinib plus venetoclax resulted in significantly better PFS compared with fludarabine, cyclophosphamide, and rituximab.15 The duration of ibrutinib plus venetoclax was defined by MRD assessed in peripheral blood and bone marrow, and was double the time taken to achieve undetectable levels.
The phase III MAJIC study comparing acalabrutinib plus venetoclax versus venetoclax plus obinutuzumab will also use MRD to guide therapy duration.16
“If we can show in MAJIC that there is an improvement in PFS by extending the duration of therapy in someone who is MRD positive, then I think that is something people will start doing in practice,” Dr. Hilal said.
In contrast to extending the duration of therapy, there are times when MRD is undetectable by the six month mark, Dr. Hilal added. However, little is known about using MRD to shorten the duration of treatment, and it is difficult to fund studies looking at shortening duration.
“Let’s say though that a patient is having side effects from venetoclax and they are pushing through to get the maximum benefit. If they are MRD negative at six months, I would feel better about stopping therapy and would not push as hard as I would with someone who still has significant disease,” Dr. Hilal said. This could also be a strategy used in older patients who do not tolerate the regimen, he noted.
Additional research is needed to establish best practices for the method and timing of MRD testing. The use of flow cytometry may have a bit more uptake, since the use of NGS for MRD requires sequencing at diagnosis, Dr. Hilal said.
Another unanswered question is whether the use of peripheral blood to measure MRD in CLL is adequate. MRD negativity in the blood does not always mean MRD negativity in the bone marrow, Dr. Hilal said. There is a correlation between the samples 90% of the time, but bone marrow remains the most sensitive method.
“When it comes to MRD practices, there is no standardization. That is true across many hematologic malignancies,” Dr. Hilal said. “It varies by institution; Mayo Arizona may even do things different than Mayo Rochester.”
Finally, Dr. Hilal said that there are ongoing discussions about the best upfront combination therapy for patients with CLL.
“There is a lot of argument in favor of targeted therapy with a Bruton tyrosine kinase and B-cell lymphoma 2 inhibitor, which is not currently FDA approved,” Dr. Hilal said. “If we get that approval, that regimen will compete with time-limited therapy like venetoclax plus obinutuzumab. A lot of the argument for the use of one versus the other will hinge on differences in rates of MRD between those two strategies.”
Clinicians may not have answers to many of these questions any time soon, Dr. Hilal noted. Nevertheless, MRD will continue to be a large part of the conversation whenever a novel therapy approval rolls out.
Leah Lawrence is a freelance health writer and editor based in Delaware.
References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Acute Lymphoblastic Leukemia. Version 2.2024. July 19, 2024. Accessed November 1, 2024. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf
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3. US Food and Drug Administration. FDA granted accelerated approval to blinatumomab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia. March 29, 2018. Accessed November 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-accelerated-approval-blinatumomab-blincyto-amgen-inc-treatment-adult-and-pediatric
4. Pulsipher MA, Han X, Maude SL, et al. Next-generation sequencing of minimal residual disease for predicting relapse after tisagenlecleucel in children and young adults with acute lymphoblastic leukemia. Blood Cancer Discov. 2022;3(1):66-81. doi:10.1158/2643-3230.BCD-21-0095.
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6. US Food and Drug Administration. FDA authorizes first next generation sequencing-based test to detect very low levels of remaining cancer cells in patients with acute lymphoblastic leukemia or multiple myeloma. September 28, 2018. Accessed November 1, 2024. https://www.fda.gov/news-events/press-announcements/fda-authorizes-first-next-generation-sequencing-based-test-detect-very-low-levels-remaining-cancer
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8. Cancer Letter. ODAC unanimously upholds MRD as early endpoint across all settings in multiple myeloma. April 26, 2024. Accessed November 1, 2024. https://cancerletter.com/regulatory-news/20240426_1/
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