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[PODCAST] Ep 80: The Promise of MRD Testing in Multiple Myeloma & CLL

March 29, 2022

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While not yet mainstream in the community setting, measurable residual disease (MRD) testing has the potential to become more fully integrated into clinical practice as one of the reliable markers of treatment response for patients with multiple myeloma and chronic lymphocytic leukemia.

Our guests—Drs. Rafael Fonseca and Tara Graff—discuss the benefits of MRD testing for these specific patient populations, the importance of training the multidisciplinary care team, and the promise of MRD testing to improve patient outcomes as its adoption continues to grow.


Rafael FonsecaRafael Fonseca, MD
Professor of Medicine, Mayo Clinic
Scottsdale, Arizona

“If our wildest dreams come true because of MRD testing, I can see a future where the best therapies accompanied by the best diagnostics will not only save lives but will also save money.”


Tara GraffTara Graff, DO
Medical Oncologist, Mission Cancer and Blood
Des Moines, Iowa

“With more sensitive MRD testing and newer assays, we can detect way before any laboratory value, scan, or patient would have a clinical inkling... it’s like having a magic 8-ball into the future. That's a huge change that has occurred in the past few years.”


This podcast is produced as part of the MRD Testing Implementation Roadmaps education project. It is funded by Adaptive Biotechnologies.

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Tara Graff, DO: So, it's almost like, you know, having a, a magic eight ball and being able to, you know, see into the future. So that's the huge change that has occurred, you know, just in the last couple of years.

CANCER BUZZ: That's Dr. Tara Graff, a Medical Oncologist for Mission Cancer and Blood. She'll be back later in the show. Today on CANCER BUZZ, measurable residual disease testing (MRD), and the promising outlook for its broader applicability. What you need to know is next.

CANCER BUZZ: Welcome back to CANCER BUZZ. I'm your host Summer Johnson. Assays for measurable residual disease, or MRD—can identify extremely small numbers of remaining malignant cells after treatment and are ideal for blood cancers, such as multiple myeloma—or CLL—detecting one in 100,000 or even one in 1 million using next generation sequencing or next generation flow cytometry.

There's a growing interest in using MRD testing as a more effective prognostic biomarker, although its applicability to additional cancers is being studied. Dr. Rafael Fonseca, MD, is a professor of medicine at the Mayo Clinic in Scottsdale, Arizona. He specializes in multiple myeloma. Dr. Fonseca, how long has MRD testing been available for patients with cancer?

Rafael Fonseca, MD: When we talk about the MRD, we're talking about, one of the various tools that are available to measure with great sensitivity, the presence of residual cancer cells. In many ways, this has been available for many years for individuals who treat patients with various conditions where this is applicable, but truly the refinements that have occurred over the last five or 10 years have brought it to the forefront. And also in a very timely way, because now we have the treatments that are able to reach those very deep responses where the question matters for many of the cancers in the old days, we, you know, we would treat, and we would be happy with a partial response.

And we know the patients, you know, deriving some benefits, but measuring things like MRD was of no value. But now as we have patients that go into complete responses, some of them which are very durable with, or without the immunotherapy, we clearly needed better tools to measure the depth of that response. So, I would say it has to come to the forefront in the last 10 years, but very intensely now in the last five years. And I think it's here to stay.

CANCER BUZZ: What's the most frequent use of MRD testing in practice?

Rafael Fonseca, MD: Depending on the disease that you're applying the MRD for, you will have different questions, but in general, you would do MRD to first gauge the depth of the response after a line of treatment. So, in my particular case in multiple myeloma, we do that after induction therapy, for instance, and or, you know, after the stem cell transplant, where we just want to have very precise information of how deep down we were able to attain a response. So that would be the first one that has various uses widely accepted and supported by three meta-analysis unquestionable, it's the most important prognostic factor for multiple myeloma.

There's a growing field where people use that information to think about additional therapy, myself included. So, I use this in my standard clinical practice in such a way that if someone remains positive, I have a conversation with patients about the pros and cons of additional and particularly different type of therapy as we go through those steps. So that, that would be kind of the first one. The other big one is to use it in patients who have long-term sustained complete responses.

First for the, the reason that we can discuss this with patients is important information. But second, also to think about, you know, part of a more informed conversation where we can think about therapy discontinuation. So those are the two big uses that we have right now for this MRD testing. I'm sure they will expand this, as we go into the future.

CANCER BUZZ: Has the testing been incorporated widely into clinical decision-making?

Rafael Fonseca, MD: Not yet. I think we have significant room for improvement on how this can be integrated into the decision making in our clinical practices. Part of this is it's a little bit strange, but MRD has been treated somewhat as an exceptional thing where it's just a better tool, right? It would be like, we would need to have a conversation when we went from MRIs that were 3T versus the, I don't know, 5T or 7T, whatever it is that radiologists use. Now the same happened with myeloma. We kind of went from the protein electrophoresis and we measure free light chain. And it's just that sometimes there's this perception that it needs to be treated differently, but it doesn't. It's just merely a more sensitive tool that can help us gauge how deep the responses are occurring for our patients.

And of course, you know, we need to understand all the implications. I think there's research going on and understanding, okay, what do you do if this happens or that, but the reality is like, this is no different from any other biomarker we use to in oncology.

CANCER BUZZ: How does this differ from previous assays you use to detect cancer cells? Rafael Fonseca, MD: You know, if you think about cancer and how we monitor it, and you go to the most, you know, crude or, you know, rough way to do that, it would be through imaging. And the reason is that an imaging you might see nodules, or you might see masses. And what you're measuring is usually things that are in the range of about, you know, half an inch, sometimes bigger. You can sometimes see smaller nodules and you would describe them as such, but you, essentially have no ability to measure that, and we really have to move forward towards measurements that are more precise and our deeper. We have other biomarkers, some of which are helpful, but oftentimes they don't provide a whole set of information that we need, you know, tumor markers, like, you know, PSA CA, etc. In reality, what MRD does is it brings together the specificity of what we're measuring alongside with sensitivity.

CANCER BUZZ: What's the current evidence of usefulness of MRD testing in myeloma patients?

Rafael Fonseca, MD: You know, I have been doing this now for several years, probably more than five years now. And if you were to ask me, you know, do you know what you were doing before? And I would say, boy, my practice is so different. And it is so different because of the understanding that it's provided to me, by the ability to measure this. One could think about it this way, think about, you know, the ocean. And when we use our traditional methods of measuring proteins, we kind of are left at the surface of the water, but there's a lot of depth underneath that. And that's what MRD allows you to discern. Importantly, by the way, I should say the MRD testing provides a quantitative and continuous variable number that you can use to track progress or perhaps even recurrence.

So, when, when I talk about someone who has a complete response, that I have no protein markers that I can measure and you know, 10, 15 years ago, we would tell that patient boy, this is great. You know, we have a complete response, no evidence of cancer, but we know where you're touching the surface of that ocean. Now that we go deeper, we know if indeed we're at the bottom of the ocean, or if we are somewhere in between that again, it might disturb additional treatment or might indicate if over time it progresses. And it goes upwards that perhaps that's the early sign of a relapse.

CANCER BUZZ: Is there anything that we should keep in mind when we're thinking about MRD testing?

Rafael Fonseca, MD: The one word of caution, and this is important for people to know, and this just stems from very simple logic. You cannot prove a negative. Even though you have an MRD test that is zero. You cannot categorically state that there is evidence that there is no further deceased. What you just have is a test that it's negative, but you cannot a hundred percent say that there couldn't be deceased for multiple reasons sampling or, you know, there's tumors in other areas and so forth. But we know very well that if you reach this very deep level of responses, you actually are prognosticating a future that will be much better for those patients.

So again, I think there's quite a range of opinions on how much you can act on this. I think it's clearly moving more and more towards being fully integrated with our clinical practice. But if at the very least, and this is unquestionable, if at the very least you have a conversation with a patient that has this MRD negativity, and you explained to them what it means. And you're familiar with the data that comes out from this three-med analysis. I mean, this is incredibly useful information. I can't tell you the number of times patients have told me, you know, I cherish my MRD negativity.

You don't know what peace of mind I have knowing that I am MRD negative. Now there's another side of that coin too, as well as because the conversation is very explicit. There are some patients that, you know, become disappointed because they don't reach that point. But even then I would always argue more information is better. And, you know, the ability that we have to tailor that to the individual situation is quite unique with a measurement of MRD.

CANCER BUZZ: Some have said that MRD has become the most reliable marker of treatment response in patients with myeloma. What's your reaction to that?

Rafael Fonseca, MD: Completely agree with that. You know, we know that it's high levels of tumor burden. We can still measure the proteins like we do with the protein electrophoresis we do with the quantitative immunoglobulins. We do the free light chain, but then very quickly they go into a range where they no longer hold ability to discriminate further response or not. That's usually around 0.1 or 0.2 grams per deciliter on the protein electrophoresis, and usually in the normal range for the free light chain. So that's about two milligrams per deciliter. Once you go to that level, then you're navigating in the dark.

If you're not doing something like MRD testing. In fact, I have seen our cases where I know our pathology colleagues, the expert pathology colleagues may have a hard time knowing where there's some monoclonal protein or what we call an M-spike or not in patients who are previously known to have a monoclonal protein. And that subsequently, you know, through things like mass spec or through MRD testing, we know the patient does not have evidence over residual disease. And that just speaks to the difficulty that the standard laboratory technique has in differentiating those very deep level of responses.

So, you can use that as we get going. We use that all the time. It's part of routine clinical practice. I would never advocate that we don't use that because it's an important first set of steps. But then once you reach that very deep response, then you must use the MRD to continue to guide and assess the worth of your therapy.

CANCER BUZZ: Well, what about cost? Is it even covered?

Rafael Fonseca, MD: Yes. So, there's various test and, you know, flow cytometry for instance, is a test that it's available widely at different laboratories. In fact, people can have access to that, and if they have multiple colors, they can even use the EuroFlow at high sensitivity. Some of this out of this laboratory developed tests, but for the sequencing one, so we have an FDA approved test, which is a clonoSEQ assay and this clonoSEQ assay is FDA approved and it's covered by CMS. So, you know, that is there. I will argue that when we talk about costs, which is by the way, another one of my favorite topics, as we were just talking with some of our friends before, one has to look not at the unit cost of the intervention, the treatment or the diagnostic, but at the total cost of care.

And if indeed our wildest dreams come true because of MRD testing, I can see where there's a future that ‘A’, we have the treatments that achieve MRD negativity in the majority of patients, but ‘B’ also those treatments will allow discontinuation of therapy, and ‘C’, they will prevent complications such as, you know, disease progression, fractures, need for surgery, and need for hospitalization. So, it was not too farfetched to put a hypothesis that the best therapies accompanied by the best diagnostics will ultimately not only save lives, but it will also save money.

CANCER BUZZ: You heard from Dr. Tara Graff earlier in the show, she's a Medical Oncologist at Mission Cancer and Blood in Des Moines, Iowa—and she specializes in CLL.

Tara Graff, DO: Prior to just recently, we had MRD testing available, but it wasn't as sensitive. So, you were talking about 10 to the minus four, which is still a lot of the traditional assays use tied in the minus four. But now with some of the newer app phase like Kronos seat, we can detect minimal residual disease down to 10 to the minus six. So, we're talking way before any laboratory value would pick up at day before every scan would pick up anything heck before a patient would probably even have a clinical inkling that something was going on.

So, it's almost like, you know, having a, a magic eight ball and being able to, you know, see into the future. So that's, you know, the huge change that's occurred, you know, just in the last couple of years, you know, I have a big background in bone marrow transplant, and we were doing MRD testing back then, you know, for our transplant patients, but it was nothing compared, you know, to the assays that we have now.

CANCER BUZZ: How are you currently using MRD testing specifically for patients with CLL?

Tara Graff, DO: I would say for CLL, it's being used more in ALL and in multiple myeloma as well, but for CLL, you know, we are in this day and age of fixed duration of treatment. So, for some of our patients, we're choosing regimens that, you know, actually they can get off of in a year if they're MRD negative versus, you know, treating to progression or intolerance with other drugs. Now, a lot of that goes into selection. We choose our treatment for different patients for different reasons, but, you know, it's a good assay to use when you're talking about a fixed duration therapy.

It's also used, and I don't want to speak too much about the other disease states because those are not my areas of expertise, but in multiple myeloma, it's helpful, you know, prior to MRD testing, you know, for myeloma, we relied on marrow and we relied on these, you know, VGPRs, or VGPR (very good partial response)—and now with using the MRD, you know, we can really see, okay, if a patient's laboratory values show that they're like light chains, for example, are going up, well, are they going up because of something else going on in the body, are they going up because they're on REVLIMID or they're going up because there are truly plasma cell clones back in the marrow.

And so, you can do an MRD tests, and you can find that out without having to, you know, do a bone marrow every three to six months, if something's going on in the labs. So, it's really sparing our patients, you know, unnecessary scans and procedures, you know, in the right setting and not saying one size fits all, but in the right setting with the right question in mind, you know, it is helping us, you know, make those decisions.

CANCER BUZZ: Is MRD testing very common or is it even being utilized in the community setting?

Tara Graff, DO: It's not mainstream, not every clinic or lab is doing MRD testing and all of their myeloma and ALL and CLL patients, because it's just not something that's being readily used by community oncologists and such. It's, you know, used a lot more on trials. And I think it's just starting to make its way into, you know, mainstream in different practices. But I know that I practice in a large community oncology group and I traditionally practice more like an academic position, which is where my background is and where I came from.

So, I rely on it a lot more, but I know that out of the 17 of us, you know, there would be three of us that will do it. And me more than anybody else.

CANCER BUZZ: Has it been shown to improve outcomes?

Tara Graff, DO: I don't think we know that yet—is the problem. I don't think we know that yet. I mean, in a trial setting ‘yes’. In mainstream, you know, just everyday use, we don't know that yet. And it's not being used widely enough off trial to really say that right now. And I think that's what the argument is. And that's what we are having these meetings on is how do we get it used more? How do we get physicians more comfortable with using it? How do we interpret it? Do we know how to interpret the data? How are we going to use this data? You know, is it going to be useful? Is it going to make an impact? Is it going to change outcomes? And I think from a basic science setting, yeah, it's going to change outcomes because you're going to be able to catch disease progression and make a decision on your patient before it's all over.

CANCER BUZZ: When you're having discussions with your colleagues—how to better utilize MRD testing—what are some of the solutions that have come up in terms of training or education that's necessary for the members of the multidisciplinary team?

Tara Graff, DO: Knowing when it's appropriate to do it, you know, not everybody who walks in say, I've, you know, stage zero's CLL patient with good prognostic factors comes in. You're not going to do MRD testing on that person. The likelihood of them having disease progression or any kind of concern is very, very low. So, you have to know when to utilize. You know, there has to be a question, okay, is this patient progressing? Let's do this test to see. So, what happens is if I have a patient with high-risk disease, well, I'm using CLL as an example, you know, they have an unmutated IGHV.

I expect that they're going to need treatment either right away, or sometime in the near future, I'll get like a baseline test on them to measure clones, to measure clonality and to measure sequences. And then if I start them on treatment, I may do a test at three months and maybe a six month, but I'm not getting one every single time. I see that, you know, you can't, over-utilize the task. So, you have to let me know what your question is, who your patient is, and how to follow it.

CANCER BUZZ: How have you trained your staff?

Tara Graff, DO: So, there's some training of the care team in terms of who the pinpoint people are, who are going to be sending the test out how to do it, you know, where it goes, how it's stored the proper way to send it, temperatures, you know, all of those things. So, you know, we had a lot of education in our office led by me, my nurse manager, lab manager, and a couple other people to really get the facility on board with knowing the right top and you know, just the storage, all of that stuff. And then really I did MRD training.

So, I know how to interpret like the clonogenic assay, I actually, and one of the people who was trained on how to help other physicians across the country to interpret. So, for me, I helped my partners when they ordered, if they have questions, but you know, you usually have a pinpoint person, not so much necessarily in, within your group, but you know that you can contact, if you have questions.

CANCER BUZZ: You can check out the show notes for more information and resources on MRD testing. We know your time is valuable and we want to thank you for supporting CANCER BUZZ. Until next time for the entire CANCER BUZZ team, I'm Summer Johnson.

CANCER BUZZ: CANCER BUZZ is a resource of the Association of Community Cancer Centers (ACCC).

The views and opinions expressed herein are those of the author(s)/faculty member(s) and do not reflect the official policy or position of their employer(s) or the Association of Community Cancer Centers.