Getting to Zero: MRD Yardstick for Myeloma Inches Closer

C. Ola Landgren, MD, PhD

Minimal residual disease (MRD) is routinely used to monitor treatment response in hematologic malignancies such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).^1,2 Now, researchers and oncologists are excited about the prospect of MRD becoming equally useful in the assessment and management of patients with multiple myeloma, particularly in light of the development of new, more effective therapies and the current limited ability to assess their effectiveness.

The rapid rate of research into myeloma treatments has outpaced testing. Ten new drugs have been approved during the past decade, giving physicians hundreds of possible combinations to work with.³ For the 50 years before that, there were only two drugs for usual treatment: melphalan and steroids.

From 1975 to 1999, the 5-year survival rate for myeloma ranged from 26.6% to 31.1%^.4 By 2007, the rate had reached 45.1%. So until recently, there was no real push to study for response in myeloma as there was for the leukemias, C. Ola Landgren, MD, PhD, said in an interview with OncologyLive. Very few patients with myeloma even reached a complete response, he said. Landgren is chief of Myeloma Service at Memorial Sloan Kettering Cancer Center (MSK) in New York City.

Landgren predicts that with the new therapies, myeloma survival will double. “We recently did a simulation model that we are going to present at the AACR [American Association for Cancer Research] in 2016,” he explained. “Five years ago, we were at around 23,000 newly diagnosed patients in 1 year in the United States. This past year, we were at about 25,000, and in 5 years, we project that it will be about 26,000 or 27,000.” Five years ago, the number of people in the United States living with myeloma was around 50,000 to 55,000, Landgren said. “This year, the estimation is that there are around 80,000. We think that in 5 years, there will be more than 120,000 people in the United States living with myeloma. It’s going to skyrocket.”

The new drugs used to treat myeloma have become so effective that achieving a complete remission in the newly diagnosed patient population is expected, Blake A. Morrison, PharmD, vice president, Medical and Scientific Affairs, Multiple Myeloma Research Foundation (MMRF), said in an interview.

“In clinical trials, we’re now achieving complete remissions along the line of 60% to 80% of the time, and in general practices, it’s probably closer to 40% to 50%. What we find, though, is that for some patients who achieve a complete remission, the remission will last for 3 years, and for some of them, it will last for less than a year. There’s great variation in terms of the complete remission and what it ultimately achieves.”

Testing for MRD

But without the ability to assess patient response to treatment, physicians are limited in trying different new drug combinations and in determining which patients will fall into which remission category after treatment.A growing body of evidence has demonstrated that MRD-negative status is an achievable goal that is “predictive of superior outcomes” for patients with multiple myeloma,⁵ but development of the technical standards for measuring and defining that status has proved complex. National Cancer Institute researchers have found that major medical centers in the United States vary considerably in MRD flow cytometry definitions and standards. Flanders et al reported “considerable variation” in the number of bone marrow cells analyzed and the number of abnormal plasma cells used to define MRD status, as well as a 100-fold difference in sensitivity methods, among 11 centers (out of 26 surveyed) conducting MRD testing by flow cytometry.⁶

Researchers have been working to standardize testing methods and MRD definitions. The International Myeloma Foundation (IMF) has partnered with a consortium of 13 countries to create an automated flow cytometry test that is sensitive to 10-6 (1 cell in a million).⁷ The organization believes both the patient’s bone marrow and blood should be MRD negative by that standard, confirmed by a negative PET CT scan and a normal heavy/light ratio.⁷

Trends in Multiple Myeloma

SEER Stat Fact Sheets: Myeloma. National Cancer Institute; Surveillance, Epidemiology, and End Results Program. http://goo.gl/Na2WVg. Accessed January 18, 2016.

The ASCENT clinical trial, expected to be launched in the United States this year, will utilize the IMF test to correlate the effectiveness of an aggressive treatment strategy for patients with high-risk smoldering myeloma, which the group believes could result in cures for as many as 30% to 50% of participants.⁸ A similar clinical trial started in Spain last year.

The only commercial test for MRD currently available in the United States, the clonoSEQ Process, is not yet commonly used in the community setting, according to Morrison. The test uses next-generation sequencing technology and is able to detect cancer cells at a level as low as 1 per 1 million white blood cells, according to Adaptive Biotechnologies, which acquired the technology from Sequenta Inc in January 2015. The uptake for the test has been relatively slow, because it has not yet been validated in terms of providing value to the clinician, or for its use as a prognostic test for the patient, Morrison added.

Research presented at the 2015 American Society of Hematology Annual Meeting indicated that the clonoSEQ process was able to predict progression-free survival among nearly 250 patients who participated in a clinical trial evaluating myeloma regimens.⁹

The test was used to classify patients into three categories: negative (<10-6), low-positive (between 10-4 and 10-6), and positive (>10-4). “My belief is MRD testing continues to be somewhat of an experimental procedure, but at this last ASH meeting, there were data produced by a large study that had MRD testing built into the protocol, and this was utilized in the population,” said Morrison, referring to the clonoSEQ data. “The results were fairly conclusive that the MRD test was indicative of and had prognostic value in terms of being able to differentiate patients who achieved a complete remission. Those who had an MRD-negative complete remission did live longer than those who achieved a complete remission but were still MRD positive.”

“An increasing number of clinical trials use MRD as a secondary endpoint,” Landgren added. “These are primarily clinical trials that are focusing on patients who are newly diagnosed with myeloma, because that is where the vast majority of complete responders are.”

Currently, there are 34 trials evaluating myeloma treatment that include MRD, and there are 424 papers reviewing MRD testing.¹⁰

There is a push to have MRD testing as a possible study endpoint in designing future studies. Daniel Auclair, PhD, senior vice president of research at the MMRF, is part of a panel that is evaluating this. However, a thorough process is still needed to bring MRD to the next level, where it can be used as a surrogate marker for new drug approvals.

Utility of MRD Testing

“The FDA has laid out pathways through prospective clinical studies to get to that next level and has been working closely with the various players in the myeloma community to make those trials happen in an expedited fashion,” he said.Auclair believes that MRD could act as an early warning sign. “MRD comes back up even before the M-protein comes up in a patient, which is a universal marker in myeloma,” he said. “The potential is there. It would probably be an earlier warning sign, more sensitive, but it’s not quite there yet.”

Regular testing may not be the norm in community practice, but it is available in some academic settings. For example, MSK has implemented the testing across the board, Landgren said. All patients with multiple myeloma are worked up for MRD negativity/positivity if they obtain a complete response.

Aside from helping determine which patients may relapse, routine MRD testing could also speed up myeloma therapy development even more, as the testing would evaluate drug effectiveness. In March 2014, the FDA held a roundtable symposium on MRD in myeloma to review its utility and to discuss the standardization of assays used for flow cytometry.¹¹

At this point, standardization of testing is necessary, and the MMRF has been in discussions with the FDA and regulatory authorities for the past 18 months, Auclair said. “We’re in this climate where there’s going to be so many new drugs, and how are we going to be able to keep continuing the investment and finding more agents, more new treatments for our patients? How can we accelerate the development of these new treatments for patients?”

MRD Testing Not Yet Optimal

The FDA had earlier participated in workshops addressing MRD testing in ALL, CLL, and acute myeloid leukemia (AML). The evolution of MRD testing resulted from the chronic leukemia space, Morrison said. “It has been used more for a longer period of time in those diseases, and that’s a reflection of the improvements in therapy, which has been more advanced for a longer period of time,” he explained. “They had that need of being able to differentiate to a complete remission earlier than in myeloma.”Researchers know that MRD testing in myeloma is an important tool, but controversy remains about which techniques are the best for determining MRD levels and how the results should be interpreted.

Multicolor flow cytometry is the most commonly used technique, available for a few decades when testing for MRD in leukemia. The testing is accurate to 10-3 to 10-5 sensitivity depending on which test is used, it is broadly available, has a short turnaround time, and has a relatively low cost.10 However, there are some drawbacks, such as the need for fresh sample material, the lower number of parameters that can be measured, and issues related to the test performance itself.

“The problem with flow cytometry is it’s somewhat user dependent,” Morrison said. “A person has to be experienced with the technology. The laboratory technician has to be skilled in the technique of doing flow, and then be able to read and interpret the results. It’s a very technical test. I don’t see it being used by a general practitioner, for example.”

But improvements are in the works. “They use different color palettes to identify and differentiate the targets that they’re trying to look for and right now, the most sensitive flow cytometry testing is what they call 8-color flow, and I think they’re working on a 10-color flow now that will perhaps get the sensitivity down to 10-6, so 1 cell in a million is the goal, and that would be great.”

Next-generation sequencing looks at samples of bone marrow to find genetic sequences and signatures that code for myeloma, and is more sensitive than conventional flow cytometry, at 10-6. “The ability to be more sensitive does make a difference and the ability to predict whether a patient is really in complete response or not, or has a chance to progress,” Auclair said.

Another drawback to both flow cytometry and next-generation sequencing is the need for bone marrow samples, which can be traumatic for the patients. As well, the aspirations have associated risks, such as infection and excessive bleeding, and samples must be obtained every 6 months, if durable complete remission is to be established.¹²

“The ultimate goal would be to find a blood test, where you could get a sample of blood and be able to look for the myeloma signature,” Morrison said. “It would be more patient friendly.” Landgren agrees. “I think in 2 years, we will have the first clinically available test in our practice, a liquid biopsy for the purpose of MRD testing,” Landgren said. “Our goal is to go away from bone marrow tests and do either blood- or urine-based MRD testing. We at Memorial are driving that very fast.”

Who Benefits From MRD Testing?

Positron emission tomography (PET) can be a useful addition to the two invasive tests to help identify patients who would likely continue to do well following treatment.¹³ If patients have both a negative PET scan and are found to be MRD negative by flow cytometry or gene sequencing, they have a much higher rate of overall survival than patients who have negative MRD but positive PET findings.¹⁴Testing for MRD would benefit most patients with myeloma, but some patient groups may have more to gain from this advance, especially those with high-risk features, such as those whose genomic signature codes them for having a rapid relapse. “Knowing the MRD status would be very helpful in terms of being able to guide therapy.

But quite frankly, I think it applies to all patients, and especially in the newly diagnosed setting, particularly if the test is a blood-based procedure versus a bone marrow-based procedure,” Morrison said.

Others who could benefit most from MRD testing are the patients who have smoldering myeloma— very early disease—that leads to myeloma within 6 to 9 months. While previous therapies were quite toxic, the new agents are much less so and, through early identification, they could help patients whom physicians believe would go on to develop myeloma otherwise. Early detection not only helps increase the chances of complete responses, it also often leads to less severe complications, such as kidney failure, fractures, and cord compression.¹⁵

At the same time, MRD testing could also be valuable to patients who may not need to continue myeloma therapy following initial treatment. In North America, patients with myeloma who receive a transplant follow posttransplant maintenance until progression.

“For some of those patients, it may turn out that they don’t need to receive these drugs in perpetuity,” Auclair said. “There’s probably 10% of patients at least who can go many decades without having a recurrence of the disease. If you could identify those low-risk patients who basically show no traces of the disease, maybe you don’t need to expose these patients to such regimens.”

Landgren suggested that transplants may even be avoided in some cases, if MRD indicates that a transplant is not necessary. However, he stressed that he is not saying that transplants are going away.

What to Watch For

“Until there is a cure for the disease, there is nothing that should go away, but I think that if we can treat patients with drugs that are highly efficacious and not so toxic, then we can monitor them. We can safely follow them and explore whether a transplant is needed up front or if the patients should collect their stem cells and, in the event of a relapse, it could be done at a later time.”So what should physicians take away from the new advances in MRD testing? According to Landgren, the whole treatment paradigm is changing. “Myeloma used to be a very bad disease in terms of outcomes, when there were no drugs,” he said. “People died within 2 to 3 years after diagnosis, and they had a horrible quality of life.”

This is no longer the case and it is important that oncologists remain on top of the latest research. Auclair suggested that oncologists who steer their patients toward clinical trials for myeloma should make sure that MRD testing is an active component of the trial. “It is an important element that can bring important information, and it should be part of every trial,” he said. He believes that any patient who is involved in a clinical trial should undergo an MRD assessment.

“We’re getting closer to a point where eventually MRD testing for patients who achieve a complete remission should be considered standard care,” Morrison concluded. “I don’t know that it’s just yet ready for that. We still need a bit more evidence of the prognostic value, but [physicians should] watch this space.”

References

1. Campana D. Minimal residual disease in acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2010; 2010:7-12.
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3. Drugs approved for multiple myeloma and other plasma cell neoplasams. National Cancer Institute. http://goo.gl/88QaEI. Updated December 10, 2015. Accessed January 18, 2016.
4. SEER Stat Fact Sheets: Myeloma. National Cancer Institute; Surveillance, Epidemiology, and End Results Program. http://goo.gl/ Na2WVg. Accessed January 18, 2016.
5. Munshi NC, Anderson KC. Minimal residual disease in multiple myeloma. [editorial]. J Clin Oncol. 2013;31(20):2523-2526.
6. Flanders A, Stetler-Stevenson M, Landgren O. Minimal residual disease testing in multiple myeloma by flow cytometry: major heterogeneity [letter]. Blood. 2013;122(6):1088-1089.
7. Shaffer AT. New MRD assay helps move testing forward in multiple myeloma research. OncLive.com. http://goo.gl/TT9mO1. Published April 18, 2014. Accessed January 18, 2016.
8. Black Swan Research Initiative update [press release]. International Myeloma Foundation; November 15, 2015. http://goo.gl/IeN1b1. Accessed January 18, 2016.
9. Avet-Loiseau H, Corre J, Lauwers-Cances V, et al. Evaluation of minimal residual disease (MRD) by next generation sequencing (NGS) is highly predictive of progression free survival in the IFM/DFCI 2009 Trial. Presented at: 57th Annual American Society of Hematology Meeting & Exposition; December 5-8, 2015; Orlando, FL. Abstract 191.
10. Landgren O. MRD testing in myeloma: next steps. Presented at: Canadian Hematology Conference; October 2-3, 2015. Toronto, Canada.
11. FDA-NCI roundtable: symposium on flow cytometry detection of minimal residual disease in multiple myeloma, March 24, 2014. US Food & Drug Administration. http://goo.gl/TJAVlP. Accessed December 28, 2015.
12. Bone marrow biopsy and aspiration. Mayo Clinic. http://goo.gl/ D0LyXL. Updated November 27, 2014. Accessed December 28, 2015.
13. Nooka AK, Kaufman JL, Karagulle Kendi AT, et al. Role of PET/CT as a measure of minimal residual disease (MRD) negativity among patients with myeloma post autologous stem cell transplant (ASCT). Presented at: 57th Annual American Society of Hematology Meeting & Exposition; December 5-8, 2015; Orlando, FL. Abstract 4202.
14. Lonial S, Ghobrial I, Kumar S, et al. Multiple myeloma breakthroughs: highlights from Orlando 2015. Medscape. http://goo.gl/rOVX5t. Posted December 23, 2015. Accessed December 28, 2015.
15. Landgren O. Webinar: Newly updated IMWG criteria for the diagnosis of multiple myeloma; the importance of biomarkers in early stage disease. LabRoots. http://labroots.com/webinar/id/77. Posted March 10, 2015. Accessed December 28, 2015.