Learn what Minimal Residual Disease (MRD) testing is, how it should be used and why you should be talking to your doctor about it in this insightful show with myeloma expert Rafael Fonseca, MD, Chief Innovation Officer at the Mayo Clinic. 

Dr. Fonseca shares how the test has evolved from a research tool to gain helpful insights in routine clinic care. In this show he explains how MRD testing is even changing the way clinical trials are run. Find answers to the most common questions about MRD testing in this valuable HealthTree for Multiple Myeloma podcast episode. 

Join us on March 11 (virtual meeting) to learn more about MRD testing. 

 

Jenny: Welcome to today's episode of the HealthTree Podcast for Multiple Myeloma, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom.

During Myeloma Awareness Month, I was reflecting on the progress in myeloma that's been made over the last 15 years that I've been a patient. And I'm really wildly grateful for the incredible advances that have been made, but I'm also aware of the progress we still need to make. And I want to invite your help in helping us find faster myeloma cures.

In the last 75 years, 25 new drugs have been approved for the treatment of multiple myeloma, and many patients are living longer, achieving 10 or 15 year remissions compared to what used to be five year remissions. This is terrific and reflects the hard work from the myeloma research community, as well as patients who participated in these trials. Yet 40 % of patients are still dying in under five years, and you have the power to change that.

Only about 7% of myeloma patients join clinical trials, and this is a key way that the field advances with the development of new drugs. This needs to continue and more patients need to join trials, but not everyone can join. You may not be able to travel or you might not qualify for a study, but there's a way for all of you to contribute to research. HealthTree Cure Hub is a platform that puts patients at the center, not as a research subject, but as a research partner.

It's a place where you can securely connect your medical records and create a single unified profile that's yours. It's also a place where your experiences, your treatments, side effects, and outcomes become real data that helps researchers like Dr. Fonseca drive real discovery. And it's not just about advancing science, it's also personal. As you may have heard during our Myeloma Awareness Month announcements, we introduced a clinical trial finder where you can find personalized clinical trials you are eligible to join.

If I had to do that manually to review all 300 open clinical trials, it would take me about 300 hours to do that (if I even knew how to find all my data). We've automated that to be five steps in less than five minutes with a medical records connection. So we hope you use this clinical trial finder when you're looking for clinical trials you could join. It's remarkable advancements like these that will continue to make your myeloma life better and provide anonymous data researchers need to cure us faster.

So I invite you to join HealthTree Cure Hub today and be part of the 100% of patients fueling your own cure because in the end, the most powerful innovation in medicine is you.

Now onto our show. Minimal residual disease testing is a deeper level of testing that identifies the depth of your remission following treatment. I'm thrilled to have Dr. Rafael Fonseca with us today to share more about this important test. Dr. Fonseca, welcome to the program.

Dr. Fonseca: Jenny, thank you for having me and I look forward to our conversation.

Jenny: Yes, it's going to be exciting. Let me give an introduction for you before we get started. Dr. Rafael Fonseca is the Chief Innovation Officer at Mayo Clinic in Arizona. He is a consultant in the Division of Hematology-Oncology, Department of Internal Medicine, and Professor of Medicine.

Dr. Fonseca has a broad range of research interests, including clinical trials for the treatment of myeloma, a better understanding of the genetics of myeloma and related conditions, new drug development, including harnessing the cells metabolism to develop effective therapies.

myeloma bone disease, the economics of drugs, and policy. His research lab is currently composed of five full-time technologists and three postdoctoral fellows. In terms of highlights and awards, he is an inductee in the Giants of Cancer Care for OncLive in 2024 and is the Getz Family Cancer Professor at the Mayo Clinic in 2009. Dr. Fonseca, thank you so much for joining the show today.

I think we should just start with some basics. What is MRD testing?

Dr. Fonseca: Thank you, Jenny. So MRD testing refers to the new mechanisms by which we can test to much greater depth the level of the responses we see with therapeutics in myeloma. So it's said to be MRD, which stands for measurable residual disease or minimal residual disease. You'll hear those two terms used.

In reality, what we're doing is we're trying to measure if there's any detection whatsoever of cells that would still be present and indicate that the treatment has resulted in benefit, but not yet complete eradication of those cells, at least at the level that we can test.

I'm personally very excited on how this test allows us to better understand the implications of our treatment. And I think it's becoming very clear that this is an early indicator of long-term benefit for patients. So I think as our audience thinks about this, you're going to see that term more and more being applied to the interpretation of clinical trials.

Jenny: Okay, great. So maybe you can share with us why MRD testing is so important and what it's trying to teach us.

Dr. Fonseca: I'm happy to. The testing that we do in myeloma has evolved through various phases. like other cancers, there's a number of markers that can be used to gauge how much of the tumor you've been able to eradicate. In the beginning, we used to do testing through the protein analysis of the blood and mostly through what's called the protein electrophoresis.

Then the technique was refined and there's new sets of dyes that could be used for immunofixation. And about 25 years ago, we started doing what everyone knows now as the serum-free light chain. So those are measurements of those proteins that are present in the blood that indirectly tell us about what's happening in the bone marrow.

So we're very fortunate that the myeloma cells produce these proteins and that they go into circulation so we don't have to be going into the bone marrow and poking patients trying to find out what level of response they have. I use the analogy that measuring these proteins in the blood, it's a little bit like, you you walk past the building and you see smoke coming out of the windows. And so first you make a diagnosis, there's a fire inside the building. But as the firefighters start their work, you see fire go down, the smoke go down. And that's an indicator that the fire is becoming better controlled.

So that's how we have used proteins. But there's a limitation in this measurement in that you can only reach a certain level. And beyond that, you can't really tell what else is going on in the bone marrow. So people ask the question, is there another way by which directly going into the bone marrow we can query to greater depths? And that's exactly what MRD testing is.

MRD testing is something that can be done, and we'll talk a little bit more about this, through two techniques. One of them is called flow cytometry, which is an automated high throughput way by which we put some stains on cells and then try to count how many of the remaining cells in the bone marrow may be abnormal. And the second most common one is done through DNA testing, DNA sequencing. The audience will hear the term next-generation sequencing. The most common assay is called ClonoSEQ (by Adaptive).

And how that works is that the myeloma cells, before they became myeloma cells, they were a normal B cell. And part of becoming a normal B cell is being able to produce the antibodies I mentioned. Now, when you're going to produce antibodies, the cells gain some changes in their DNA that allows us to identify what I would call a DNA fingerprint or a DNA signature.

And it is because those cells have a very unique DNA sequence that is not present in any other cell of the body, that down the line we can go in and run the same genetic test and find out if there's detectable cells in that bone marrow sample.

The first technique in general is said to go to about one cell per 100,000, although some groups can take it to one cell in a million. And the second technique, the sequencing one, is routinely testing cells at the sensitivity of one in a million. So that's kind of in a nutshell what MRD is.

But I would say without describing the techniques, it's just simply a better test to look at the depth of the response. one of my hopes today is to demystify, if you may, MRD. I don't think it's anything particularly different. It's just a better way by which we can measure the depth of response that we're able to obtain when we establish treatment.

Jenny: And the two you mentioned are bone marrow biopsy tests, right?

Dr. Fonseca: As of now, they are bone marrow biopsy tests. The reason for that is that the myeloma cells don't like to go out of the bone marrow for the most part. Sometimes they do. And there are some variants of myeloma like plasma cell leukemia or extramedullary disease where the cells are okay being out of the bone marrow. But for the majority of myeloma patients, the plasma cells stay inside the bone marrow. That's where they live.

And we cannot measure the cells very well in the blood if we do standard blood tests - you normally don't see myeloma cells in those blood tests. So that's why we have to go into the bone marrow to perform the MRD test.

Jenny: Okay, it makes sense. So this is just a more sensitive way of detecting how much myeloma you have after you've been treated. So for that one test you talked about, you get a baseline because it's looking for the DNA and then the flow, you might not need a baseline. But this is a way that you will test after you've been treated how little or much disease you have if it's not detectable from the test that you mentioned.

How does MRD testing influence different care strategies? How do you use this information as a clinician?

Dr. Fonseca: Sure. I would say there's three ways by which MRD should be thought as being influencing what happens in the clinic.

The first one is a direct one, and that is understanding the medical literature and understanding the efficacy of treatments in 2025 is best done when we get reports that include MRD testing. And we'll talk more about that when it comes down to regulatory perspectives. MRD testing is a very good indicator of how profound the effect of a treatment might be.

The second way by which MRD can inform clinicians, and oftentimes people say, well, what would I do different? What we do different is we inform patients. So having that conversation with a patient where you can report where they are with regards to their MRD.

And why not when the results are very good, share the excitement of that result. I think it's one of the most important aspects of my clinical practice. And I would argue quite a joyful one to be able to tell someone that, you know, all of your efforts and getting through that treatment have now led to the situation where your MRD is negative. So that's, that's an obviously a very rewarding conversation.

Lastly, we can use MRD to establish a better monitoring at these low levels.

And based on that, we have clinical decisions that would follow. If a person is on a good track but perhaps remains MRD positive, a good argument can be made to continue on the same therapy. Or if the results are not going in the right direction, perhaps even consider a different therapy. We can also monitor for MRD negativity over time and if a person achieves that, I think that becomes one bit of information that potentially would allow for someone to consider this continuation of therapy. And lastly, this is a great way to monitor for those patients that have great responses, because if the patient were to experience a relapse, and hopefully not for a long time, but if they did, then early intervention might be warranted. And I'm not saying that immediately just because an MRD becomes positive, you always will propose the starting of treatment, but it is a foreshadowing of what's coming.

And then the clinician working with the patient will have to decide when is the appropriate time to start therapy. So as you can see, there's a very broad range of situations where MRD can be useful.

I think one of the most important things for our audience to know is that MRD should not be considered an exceptional test or as the sole decider of what we do. This is an argument I often repeat, and that is it is just one more bit of information that makes your situation be more informed for you and for your physician.

Jenny: And I know traditionally MRD testing was done kind of in the research scenario, but it's expanding its use in regular clinical practice. Would you share how you're seeing that change?

Dr. Fonseca: I consider MRD testing a standard part of our clinical practice. At the beginning, there were some comments that it's emerging, evolving, promising. There were even some conversations some time ago about, it quote unquote “ready for prime time?” We need standardization.

Well, the good news is all of that has been solved. We have tests that are approved by the FDA, that are covered by the insurance companies and that have a body of knowledge behind their use that is really quite extensive at the moment.

So I think we have moved well beyond the point of considering this something experimental. Now, I will recognize that not all centers have yet been primed or not ready to start using MRD, but that's mostly an administrative hurdle. It's not really a scientific or a medical one.

If you do the testing, for instance, if you do the testing with the DNA sequence that I mentioned, it can easily be done through a reference laboratory. It requires no local sophistication. You collect the sample. The sample is shipped. And a week later, the results will come back. So this notion of standardization and approval, that's all being solved. So I think the important part is to know how to use MRD in your clinical practice.

Jenny:  And there are different levels of MRD testing, right? Do you want to explain 10 to the minus five and 10 to the minus six, to be these, some of these basic concepts?

Dr. Fonseca: Sure. So when we do testing for MRD, what I mentioned before is we're just using tools that would allow you to seek for abnormal cells at a greater depth. At the beginning, when we did bone marrow, what the pathologists would do is they would count 500 cells and then they would tell us, there's 1% cells, 2% cells, which was important.

But today is woefully insufficient to get a report like that because there could be 1% normal cells or 1% abnormal cells. We just don't know. In fact, when I see those pathology reports, I always get a grin because I go, yeah, thank you, but I really want to know what the MRD testing is.

And then what we did is then people started adding things like dyes, and then we went on to flow cytometry in the next generation of sequencing. And that is what has determined the so-called level of sensitivity.

So the test is geared to answer the following question. If you were to take 100,000 cells or a million cells, can you detect any residual cells? So this is many more, of course, than the 500 that the pathologists originally counted. The most commonly used thresholds today are 10 to the minus 5, which is a more routine one used with flow cytometry. Again, some people can take that to the threshold of 10 to the minus 6. So 10 to the minus 5, it's one cell out of 100,000.

No, if you get a negative result on a test that has a sensitivity of 1 to 10 to the minus 5, what you can say is, at the current level of 1 to 10 to the minus 5, we were not able to detect cells. Because we're trying to prove whether cells exist there or not, one could think of this as trying to prove a negative. And you cannot prove a negative. You can never prove a negative.

So you can't say, well, just because your test is negative, I can assure you that there's no myeloma cells that remain in your body. That's simply an inaccurate statement. What we can say is to the level of testing that we did, we didn't find those cells. Could there be cells elsewhere? Yes. And we know that because even patients who have this negativity at 10 to the minus six, so one cell in a million, will experience a relapse. Not always, and we don't know yet what the significance is of being 10 to the minus six in the very long term.

But what we know is there are some patients that even when they're negative at 10 to the minus 6, they can experience a relapse.

A way that I learned from Dr. Ben Derman from the University of Chicago to think about this is as follows. Let's say you're in a pond or in a lake or in a pool and you throw some coins. And then you have a diver and you send the diver and say, can you tell me if there's coins that remain in the pool? Now the diver will have different abilities to go to different depths.

But even the best diver, as of now, goes to that depth of 1 to 10 to the minus 6. Now, if the diver doesn't reach any further, which is what happens because we cannot test the whole body of the person, we can say, at least with what we know from the diver, it seems like there's no coins remaining in that pool. But could there be? Yes, of course there could be. Now, the good news is if the diver comes back and finds no coins, we can say, hey, based on what we know, this is the best response possible.

This is very good sign and an early indicator that the treatment will have a longer effect.

Jenny: I think it's very exciting to get a result where you're MRD negative, speaking from personal experience. So it's fantastic when you say that.

Dr. Fonseca: You know, I've taken it as a personal practice that I currently, since we do the next generation sequencing, the results come to my inbox in my email. So very quickly into my phone, I can open the result and I'll share with you. I always open it with a little bit of trepidation. Just wanting to see good results, right? There's some anxiety there as you're doing that. And when I get those great results, I call patients at home right away. And because I know as a patient, that's one thing you're waiting for, right?

Jenny: Yes.

Dr. Fonseca: Maybe Saturday, 9.30 at night, I'll take the risk and I'll give you the phone call and say, hey, guess what? They came back at zero. I think that's going to make the rest of your weekend so much better.

Jenny: Yes, completely. To me, this type of testing is really amazing. It's kind of an evolution, part of an evolution that I watched in the field of multiple myeloma. Back when I was diagnosed, I went to a family educational event for multiple myeloma and somebody asked the question, you know, how many patients know what their genetic markers were? And maybe only about 10% of patients raised their hand and said they knew.

And some of the doctors were saying, well, we don't know how we would change treatment differently if we knew the markers, so maybe we shouldn't get the genetic testing up front. But that's completely evolved, and many people do genetic testing now.

I see MRD testing is being somewhat similar. If you're not doing the testing, you don't have the data to know what to do with it later. But if you have the data, that's going to inform many other things in the future.

So you're probably better off to be getting the MRD test at baseline and then after you get treated and then over time because that body of knowledge is going to continue to grow and become more informative. Would you say that's helpful?

Dr. Fonseca: Absolutely. And for those in the audience who may be hearing and say, I wish I had MRD at baseline, we have ways by which we can measure this down the line, even if it was not done. the flow cytometry test does not require a baseline sample. And when we want to do the sequencing one, oftentimes what we do is we will call the laboratory that did the first bone marrow. And we request they send us the glass slide. Usually when they do a bone marrow, they put some of those cells in glass slides that are stored.

We can actually scrape off those cells from those slides and send them to the company where they actually can run the test. I think people have seen that through science documentaries and movies, you can get DNA long after there was a live cell there. So actually we can we can tell what the sequence was. So this can be done after the fact. So the short answer to your question is, of course, you know, I think it's it's important for it to be done.

And I think of a few things here that I like to use as analogies or metaphors for why I think this is important. The first one would be the free light chain. The free light chain has dramatically changed how we manage myeloma. I don't think there's any doctor anywhere that would say, well, I just don't need the free light chain and my clinical practice is fine without it.

We understand how important it is for renal function, for measuring disease, how the disease can transform. Sometimes I only produce a light chain. Amyloidosis patients need to know what their light chains are. So it's really a standard test. We do that every cycle of therapy. And the free light chain never went through the scrutiny that the MRD testing was subjected at the beginning. People didn't say, we need clinical trials to understand the free light chain or it's not ready for prime time. It was understood as it should have been understood. This is just another marker. So that would be, think, point number one.

The second one is I went to my colleagues in radiology and if you had a CAT scan that would give you better resolution, would you ever say, no, I want to go to an old CAT scan?

And the answer is no, of course, we would always want to have the better resolution and the MRD testing is the best resolution we have right now to know exactly what's going on. And the last point is a bit more towards the clinicians, know, when hospitals, when doctors are rounding in the hospital and you're outside of a patient room, what we call rounds, oftentimes like the interns and the residents and the fellows present cases, right?

And so when I go to meetings, medical meetings now, and I see that they present all this data, CR, PR, VGPR, the classic response criteria. And then the next slide tells us about the MRD. My first thought is, why did you waste our time? Just let's go to the MRD.

And the analogy I use with rounds is like you're doing rounds in the hospital and you have a resident that speaks for about 15 minutes about all the findings on the x-ray only to tell you next, and by the way, we have a CAT scan of the chest.

So you've lost that time. With the point being is that we have better precision tools that allow you to make a better assessment of where you are. Now, you don't have to do it all the time. It would be like doing a CAT scan all the time. If you have a patient who still has a sizable amount of proteins that is detected in the blood, that wouldn't be a circumstance where we would use MRD. But as the patients get very close to this appearance of the abnormal proteins, that's where MRD expands the range of what we can measure.

Jenny: Okay, I just think it's like what you said, a more efficient way to do this. Now let's talk about patterns. You referred to them before, treatment patterns, and you're saying that care, it's this one additional point of data that you're using to make treatment decisions. For your practice, how are you looking at the utility of MRD testing? Like how many follow-ups do you do? And then if you're seeing patients be MRD positive or MRD negative, how do you think about changing their care or not changing their care?

Dr. Fonseca: Sure. So there's three main scenarios where we're using MRD right now. There are many more, but there probably are more nuances or new ways in which we're thinking about it. But the first one, probably the most important one, is that in patients who complete initial therapy and go through a stem cell transplant. And we oftentimes will obtain an MRD after they complete the stem cell transplant to assess the rate of the response.

Because we're an academic center, we also obtained that before. We want to know what the contribution of transplant may have been to that MRD change. And then based on that, we monitor patients. If a patient remains MRD positive, oftentimes we'll provide additional treatment. Nowadays, that's becoming more common because people are using consolidation treatment more often, but it didn't used to be the case. And I would argue it's important to document and hopefully see the change towards MRD negative.

In that same patient, as time goes by, we might do this once a year. And the reason is to monitor the continued response of the person. One practical and easy way to think about this is in patients who are on maintenance, for instance, with a medication like lenalidomide, or Revlimid, many in the audience know this is not an easy drug.

We used to think of this as an easy drug, but it causes fatigue, cloudy thinking, and in some patients unfortunately it can cause diarrhea.

So if a person had the opportunity to come off of the Revlimid, that would be welcome. So you have a patient who's been two and three years on maintenance, and the person remains MRD negative 10 to the minus six. I think if they have symptoms, one might be perhaps more inclined to persuade that, yes, we can discontinue therapy because of the symptoms and because we are reassured by the MRD negativity.

On the other hand, someone who's maybe still evolving but is tolerating a treatment, well, one might say, yeah, let's stay on treatment. Let's stay on track. It is impossible in my law, and in medicine for any condition, to make blanket recommendations about what needs to be done. Everything has to be individualized. But this would be two examples where we use it. The second one would be in patients who don't get transplant but also are receiving some of this very effective new therapies. Patients who are transplanting eligible.

If you were to ask me five years ago or two years ago, know, MRD is that important for a patient of advanced age? I probably would have been somewhat lukewarm. And today I understand it's very, very important. Some of the best treatments give us results of MRD negativity that are quite impressive, as high as 50% of patients, even without transplant.

And again, if you have a conversation with a patient like that, you can tell them, listen, based on what we know and knowing that you're now MRD negative, the likelihood that you will need a new treatment is X, Y, or Z. So that's important. And it will come into play also as we think about duration of therapy.

And lastly, and probably very excitingly, I would say with the advent of new therapies that target our immune system with the bispecifics and with CAR Ts, we're seeing that patients, even in later lines of therapy, can become MRD negative. And that can be very profound and very durable.

So having the ability to see that kind of response is quite remarkable.

Jenny: And what about standard risk versus high risk patients? How do you look at MRD testing in those types of patients?

Dr. Fonseca: I would say that given what we know, two statements probably can be said. One is if your standard risk and your MRD negative, your prognosis is absolutely excellent because of what we are seeing with the current treatments. If you look at the clinical trial per se, that has been much talked about in the past few months, if you just look at patients who get the quads and have standard risk disease, their prognosis is excellent. This is over 90% and four and a half years.

Now, if on top of that, you put a layer that you're also MRD negative, which could be up to 75% of those patients, then you say it's looking really, really good. If you have high risk, what we have learned is that if you achieve MRD negativity, you dampen or you significantly lessen the impact of those negative genetic factors. Some series suggests that it becomes the same as standard risk. think probably high risk always will have a little bit of a handicap.

But it certainly looks much better than it used to be. And what we know is if you have a better treatment that is able to make patients who are high risk MRD negative, sometimes what we see is patients who are high risk that become MRD negative do better than patients who have standard risk and remain MRD positive.

So when I see a patient now with high risk, I make sure that we don't think of this as binomial -  you have high risk and then the situation is desperate and there's no hope. No, it's a more difficult team, but we can still win the game. So I say, I keep that in mind and I'm particularly keen on making sure that whatever the decisions we make, that we try to make that patient MRD negative.

Jenny: This is one more reason why I think patients need to consult with experts like you because you're looking at all these different data points and you're not just looking at one, you're using every tool in the toolbox to make these assessments. As I think about it, you cannot do shared decision-making with your doctor without data. So you need to have this data in place.

Dr. Rafael Fonseca: Yes, absolutely.

Jenny: So what do you suggest to patients who maybe come to you later or as you're speaking, whose doctor maybe hasn't brought up MRD testing or isn't suggesting that a patient get tested?

Dr. Rafael Fonseca: I tend to be pretty clear and frank with patients, very respectful. I tell them, I do believe that MRD testing, if that's the case for that particular situation, would be helpful.

I understand maybe your doctor didn't think about it or was not keen on doing that, but here are the reasons why I would think that would be important. I can tell you, I've seen a few patients over the last several months or a couple of years whose reason for referral was to talk about their MRD status.

And myeloma patients, and of course, thanks to efforts of groups like yours, are probably some of the most informed patients. So many patients come with a very deep level of knowledge of what MRD means, and they inquire, they ask, they propose things based on how they understand how the level they have, be that zero or positive, may be related to the treatment decisions they need to make.

Jenny: Okay, now when you're thinking about choosing a variety of drugs to use or increasing the duration of treatment, do you try to get patients into that MRD negative status? Like will you keep adding treatment to their protocols until they reach that? I think there's a debate about that.

Dr. Rafael Fonseca: Yes, I personally do. And this may change, and I'll get to that in a second, but I personally do. So historically, what we were doing is if a patient completed stem cell transplant and they were MRD positive, we would have the following situation:

If they were standard risk, I would offer additional treatment. And most often, it was in the form of a combination of a C38 antibody like daratumumab and Revlimid. If they were high risk, I would insist they get more treatment.

Of course, the patient always has a final decision, but I would insist they get more treatment. One of the reasons for that is that historically what we have done is we do four cycles of therapy before transplant, and then we do transplant. And then I would ask ourselves, why do we do four? I mean, is there something magical only about four?

And the answer is no, it's just a historic legacy because in the old days when we use chemotherapy combinations like that, it would be very difficult for a patient to go for more than four cycles. Now, why do I say this? We have seen recently, both with the PERSEUS as well as the MIDAS clinical trial, that if a patient is responding to a four-drop combination, why not go to six or eight cycles or sometimes even beyond that? And what we have seen, if you do that, you can increase the percentage of patients that become MRD negative.

So there's nothing magical about saying all four cycles came from the sacred place in the mountain, that that's what we're going to do for induction for myeloma. It's just what we have done historically. And that's why we offer that consolidation after the fact. Now I say it's temporary because many of the clinical trials that are coming forward propose the idea of both consolidation and maintenance. We saw that again with PERSEUS. We saw that with the AURIGA clinical trial that looks at maintenance post-temp cell transplant with the dartumumab.

And for instance, with AURIGA, what we saw is a combination of Dara and Len greatly increases the likelihood that you will become negative. And not only that, but we know from other studies that it doesn't matter when you become negative, whether that's immediately after transplant or even a year later, that that negativization or negativity, if you may, becomes a powerful indicator of good prognosis down the line.

Jenny: Well, let's talk about clinical trials because these trials that you mentioned are starting to incorporate MRD testing inside of the trial design. And do you want to share how that's changing? Because that didn't used to happen. It was very infrequently used and I'm seeing it more and more in all these different trial designs.

Dr. Rafael Fonseca: Yes. Well, let me start with a short answer and walk us a little bit through history. As we know, in April of last year, the FDA convened an Oncologic Drugs Advisory Committee (ODAC) meeting to see whether MRD could be used for regulatory purposes. And by unanimous vote, it was decided that, yes, this was a good way by which we could start predicting the long-term outcomes for patients. Parallel to that, we've seen a number of clinical trials now that their primary endpoint is attainment of MRD negativity.

Now, for our audience, I'm just going to mention, sometimes they might hear, well, you don't want to pursue MRD negativity blindly. Hey, we agree with that. I wouldn't want to do things that are very toxic to a person just for the sake of MRD negativity. But if we can do safe things and things that are tolerable, not with enduring toxicity that would allow us to reach that negativity, I would say it makes sense. Let's do that.

I think that's why it's so important we'll see more clinical trials measuring MRD as their primary endpoint. Now, historically, what we did is we use things like overall survival. And overall survival is considered the gold standard, but that can only be done when you have situations that are critical and short duration of therapy and projected survival that is not so good. In myeloma, if you wanted to run a clinical trial that measured overall survival today,

It would take many, many years, probably decades if we wanted to show that because the improvements and outcome are so good.

Jenny: It would take forever.

Dr. Rafael Fonseca: So, initially we went to PFS (Progression Free Survival) and there's some people that fret at this and they go like, you can't use PFS. It doesn't always correlate with overall survival. And yes, there are exceptions, but by and large, if you look at all the clinical trials and you say, if there was a benefit in PFS with additional time of follow-up, we usually see that improvement in overall survival. It's a logical thing.

Better and deeper responses result in more durable responses. But PFS is going to take a long time. The PERSEUS trial, again, it's not known what the median PFS is going to be. And in fact, some analysis suggests that it could be in the excess of perhaps 12 years, 15 years. Who knows? So are we going to be able to measure a median PFS? No, of course not. That's going to take a long time. And that's where MRD comes into play. Because as we think about

drug development and patients having early access to some of these treatments, to me, as long as a drug, and this is drug agnostic, or a combination of drugs, a strategy, a self-product, has a good track record for safety, then we can early on start thinking about MRD as a way that we think for how to introduce this in our clinical practice.

Jenny: And PFS is Progression Free Survival is the time you're spending in remission, right, before you relapse?

Dr. Rafael Fonseca: I should have mentioned that. Yes, progression free survival.

For the audience, that is, if you take 100 patients, at which period of time about 50 of them would have required a different therapy, have shown some evidence of disease progression. And again, I think it's very important that you always say this. It's not like a set clock that you go, you have a PFS of three years. That means that three years is over. For some people, unfortunately, they will require treatment before those three years, but half of the patients have not required a change in three years, so it's very important to recognize that.

Jenny: So it's a timing issue. If you want to wait for these standard measurements like PFS or progression free survival or overall survival, like you said, you're going to wait decades. So MRD testing, you could get this earlier indication that it (a new drug) might be just as effective. And you're trying to correlate now MRD results to progression free survival results. And you're seeing a correlation there, right?

Dr. Rafael Fonseca: Absolutely. So the correlation is that if you are able to achieve MRD negativity, that usually is an early indicator of better PFS and better overall survival.

Also for the audience, let me add another comment since we talked about overall survival. Sometimes people will say, this clinical trial improved progression-free survival, which was a primary endpoint for the trial. But if the trial was not designed with a statistical power, the numbers and the duration of follow-up that's needed to make observations about overall survival, then no observations can be made.

And the reason I say this is probably one of most common mistakes I see on social media.

People say, well, this improved progression of free survival, but not overall survival. But they state the last part as if it was a fact, when in fact we're just talking about a deficiency of data. We cannot make statements about overall survival. A good example of this would be recent clinical trials for stem cell transplant.

And I think you've seen this, you probably talk to patients that go like, well, it improves progression-free survival, but not overall survival. The reality is if the clinical trial is not designed to address overall survival, which as I mentioned, is very challenging today, then you cannot say it doesn't improve overall survival. You can say it hasn't been shown yet to improve overall survival, but you cannot say it doesn't. In other words, the absence of evidence is not evidence of absence.

Jenny:  Totally makes sense. And overall, survival is getting harder and harder.  Many patients have gotten so many different types of therapies, trying to collect that data al is almost impossible.

Dr. Rafael Fonseca: Yes, absolutely.

And sometimes even, you know, the overall survival, people will say, well, if they had used a different comparison R, maybe the results would have been different. But I think it's important to remember the following. When I started in myeloma 25 years ago, the projected overall survival barely exceeded two years. If you look at multiple series now, institutional series, you look at data from the clinical trials, myeloma patients who are newly diagnosed should expect to live greater than 10 years, and oftentimes we're seeing 15 and 20 years survivals and beyond that.

And you would say, OK, well, let's take all the clinical trials that have been published and aggregate the number of months that are shown in improvement in overall survival. You wouldn't come close to that. So what gives? And the reality is that the overall survival is there, but it just has to be demonstrated with very long duration of follow up.

The real world analysis are showing overall survival improvements. One of the frequent slides I use has three large series, one from MD Anderson, one from Emory, and one from the Canadian group, all of which had patients treated with VRD mostly, stem cell transplant and maintenance with lenalidomide, where they show this median survival is 150 months. So the survival is there, and it's not that the hematologists are smarter, it's just that we have better tools.

Jenny: Yes, it’s incredible. It's getting harder to run clinical trials, in my opinion.

Dr. Rafael Fonseca: Very hard.

Jenny: That's a great problem to have, but your trial design has to be so careful. It's very challenging. So the FDA committee that you were talking about, you had 12 people on this committee that all voted in favor of using MRD testing. I think the FDA has to come out and vote. Have they come out and voted yet on implementing?

Dr. Rafael Fonseca: I haven't seen the final determinations and I eagerly awaiting that.

I think they've been slow walking this but hopefully they become ultimately convinced that this is the way to go. And for people who are keen on finding a faster way for drug development and perhaps even the economics, if we have faster drug development, then there's more competition. And that would help as well too.

And you know what's surprising to me? People in other fields are puzzled by the attitudes of some within the myeloma community saying, you know, it's so self-evident.

What the lawyers say “prima facie” is just like self-evident that MRD is the way to go. And for instance, in ALL (acute lymphoblastic leukemia), it's clearly the standard of care. And they know that achieving that negativity becomes critically important.

Jenny: So we talked about when patients should get an MRD test, and you talked about not needing necessarily to get a test at baseline, and then the frequency, but is there any other frequency that you think? So you were talking about the stem cell post and stem cell transplant standard risk patient might get it once a year, or how do you determine that?

Dr. Rafael Fonseca: I don't know that we have set guidelines or commonly agreed protocols, not even in our center, not even in my mind of what I, you know, this is how it should be done.

But I would say for most patients, it can be done once a year. Sometimes we do it twice a year in some special circumstances. And I can think of many anecdotes of how I think it has been informative in my clinical practice, but it all has to be individualized. Now we recognize that one of the challenges is that it does require a bone marrow biopsy.

Now, I would say, you know, bone marrow biopsies can be done much better than the old way. So not to toot our horn, but at Mayo Clinic, we do all bone marrow biopsies with sedation and we use a power device which uses a smaller bore needle. So it's easier on patients as opposed to just, you know, doing them in the usual way. So I think that helps us as we propose to do bone marrows, but still it's a procedure.

We would like to be able to do things that would be similar to MRD through the peripheral blood. As of today, and we and others have looked at the data, the use of the same tools doesn't really reach the sensitivity that we can reach with going directly into the bone marrow. And that is just a reflection, not of technology, it's just a reflection of those cells just liking to live inside that bone marrow space. So that precludes us from using blood.

Now there's other ways that are coming forward, including ultra sensitive methods to measure abnormal proteins in the blood that may complement, I don't think they will replace and we can talk more about that, but I think they will complement our evaluation of patients with very deep responses.

Jenny: Is there anything that can predict who will achieve MRD negativity or who won't?

Dr. Rafael Fonseca: Not as of yet. What we know is that MRD negativity is probably a little bit harder to attain in groups of patients with high-risk markers. There's not a lot of information.

We even looked at our own database and looked at patients by genetic markers. We couldn't find much difference, but patients who have very high risk or ultra high risk, like two genetic markers of high-risk disease or bi-allelic P53.

We saw that in the ISKIA trial (44;20?), the MASTER trial, those patients have a slightly lower rate of MRD negativity.

Interestingly, I've learned recently, and this is perhaps a topic for another day, that the same may be true for patients with 11;14, which traditionally have been thought to have better prognosis, and I still think it's a more favorable form of myeloma.

But it just may reflect that the current treatments don't carry the punch for 11;14. As I said, that's probably a topic for another day. So I think we have an opportunity there to make them better with the use of some of those BCL-2 inhibitors.

Jenny: What do you think is the future of MRD testing in myeloma?

Dr. Rafael Fonseca: My hope, well, let's say the data becomes true. Let's say that the statistical projections become true, that you have a projected PFS of 220 months. So my hope is that as we incorporate MRD testing and we apply these filters to data sets like that, that we will be able to tell a patient, okay, if you have standard risk and you have three years of consecutive MRD negativity, two things will happen.

First, you will be able to stop therapy. But second is we can reassure you that you will have a 90% chance of not relapsing ever. So I think that's where the field is going.

As you started with your introduction to this particular session, we're not done yet. We still need to make things better for more shorter duration of therapy, less toxic. But yes, we've moved in grades from you know, D therapy to C therapy. Now we're kind of flirting with the A's, but it needs to be A plus plus. At the recent American Society of Hematology meeting in December, two groups presented data with introduction of immunotherapy as part of either induction therapy or consolidation after transplant. And in those two studies, which I will say are very limited because of the small numbers, 20 patients here and there, but they had 100% MRD negativity.

Jenny: Incredible.

Dr. Rafael Fonseca: If that expands, I think my prediction is not going to be far-fetched. I think it's going to be unfair. I wouldn't bet against that.

Jenny: That's just incredible. Okay, well we had a lot of write-in questions, so if you don't mind taking some of those, that would be great.

Well, Kathy was asking (you already answered this question) is a bone marrow biopsy better than a blood test? But her follow-up question is do they ever do both to see if they agree? I thought that was kind of an interesting question that she had.

Dr. Rafael Fonseca: Happy to.

We have done a study and others as well too, and they agree when they're positive, but what you can find is the bone marrow is positive and the blood is negative when you use traditional methods. Now to expand a little bit on the answer, I just mentioned this peripherally. We're using ultra sensitive methods now to detect proteins. Mass spec is a term that people will hear about more and more.

Jenny: Yes, will you explain that?

Dr. Rafael Fonseca: Sure. So mass spec is a very sensitive way by which we can actually look for proteins in the blood. Traditionally, people took a blood sample and then they ran it in what we call a gel. It's literally a gel. So you only have so much space. And then it's visual inspection of that gel. And that tells you if you have an M-spike or not. And then it's run through a computer.

With mass spec, what you do is those are tools that can just spread out your proteins over very long distance. So then you can actually define the different peaks of the different proteins that are present in the serum. And what it does, it gives us such higher level of precision of measuring what's happening in the blood.

Now, I think this tool, because it can go to somewhere between 10, 100, perhaps even 1,000-fold more sensitive than the current methods of protein analysis, would allow us to monitor patients. Now, what's happening is we actually are doing this routinely at Mayo Clinic.

We no longer do protein electrophoresis. Every single protein analysis we do is through mass spec because of this. Which, by the way, I always say we do it because it's more accurate, it's faster, and surprisingly, it's cheaper. So you got the three aspects right there, right? The only challenge with mass spec is that we have learned that antibodies, and that's a protein, of course, we monitor in myeloma.

Jenny: All around better. You've got the trifecta.

Dr. Rafael Fonseca: The lower the concentration in the blood, the longer the half-life. And that has to do with how our body kind of processes antibodies. There's some recirculation through cell membranes. So that on the way down, you can have abnormal proteins remain, even if the cells are completely gone. Going back to my analogy of the building on fire, this is like you put out the fire, but you still see the smoke floating around. That's kind of the protein. That's how that works.

So I think on the way down, at least from what we understand with mass spec, it probably won't be as useful to tell short term what's happening with MRD status. Where I think it's going to be very useful is if someone has been on the way down and becomes negative by mass spec and then starts staying as mass spec negative, years down the line, this would be a very good tool to look for recurrence.

And also would be agnostic to where you do the bone marrow because you can say, well, I did a bone marrow here, but what if there cells elsewhere? Well, the mass spec would be able to tell the difference between those two. So that's how we're using it. And you're going to hear more and more about this multiple groups are interested in mass spec. And I think we'll be standard clinical practice.

Jenny: Well, it sounds like it's one more very important data point.

Dr. Rafael Fonseca: It is. And we're very fortunate. I tell people myeloma, because of the biology, is the cancer that has the best biomarkers hands down. I was once at the scientific meeting with all tumor types organized by one of the most prominent scientific organizations. It was all about biomarkers. And no one was talking about myeloma. They were talking about PSA for prostate cancer and this other thing. So I raised my hand. said, isn't it ironic? We have the tumor that has the best biomarkers hands down multiple genetic proteins, we've done it.

And I think it can serve as a model for other diseases and how you incorporate biomarkers to assess response and monitor patients.

Jenny: It's extraordinary because even in all of your clinical trial research you can use that as markers and there are diseases like ALS for example that have zero biomarkers so the only way you can tell somebody has ALS is by just decline in function. yeah comparing that to myeloma is incredible.

Dr. Rafael Fonseca: Exactly.

You know, I tell my my myeloma colleagues, imagine if we were like the solid tumor guys that are competing to do PET scans all the time. I mean, if I had to monitor my patient with PET scan, I would feel like I'm driving in the dark. I can tell me a few things and a PET scan is important for myeloma, but it's completely insufficient.

Jenny: Doris is asking, if you have a small protein, is there any value in getting an MRD test?

Dr. Rafael Fonseca: For most patients who have a measurable, clear evidence of abnormal protein, the MRD doesn't add much. And then you would say, why do the bone marrow one? We know we can monitor that. But there are some patients where the protein is small enough that I think can be helpful.

And going back to the mass spec, one of the things I've learned is once your M-spike is at 0.6 or below, it is very difficult to tell what the real concentration of that protein is. And unfortunately, sometimes to know whether the protein is even still there. So this is something we're learning because of the use of mass spec. This has nothing to do with the training or the quality of the pathologist. It's simply a limitation of the technology. So in those circumstances, I think it could be helpful. But if you have measurable disease, then it's not going to be very helpful.

Jenny: And I think there's an unusual situation like post-CAR T. I had this happen to me where there was, I was MRD negative, but I still had an M-protein for some reason. And it like took a while, took like six months for the protein to disappear, which I didn't understand at all..

Dr. Rafael Fonseca: That relates to this whole thing that I was saying, the smoke remains after the fire. Let me give you an example of how dramatic that can be. There's a study that was published by my colleagues in Rochester where they use mass spec. And if I were to give you a dose of the dartumumab and nothing more, and I came back a year later and measured the mass spec, I may still detect the dartumumab. And that is because the elimination of that protein is not a linear thing. It's just the lower it gets, the longer it takes to get clear.

So it's not surprising. So that's why I see patients now post-Car T with the same situation, that they still have a protein and they're worried, man, is this bad? And I say, don't worry, the bone marrow is now negative. In all likelihood, this is the time your body's taking to clear that abnormal protein.

Jenny: Well Beth is asking about MRD specifically post-Car T. She just said, can you discuss MRD negative findings after CAR T? It seems not quite as valid in that scenario. So I'm not sure exactly what she means by that, you can expand.

Dr. Rafael Fonseca: Beth, you can be reassured. think it's valid in any scenario. So we're seeing that as we look at bispecifics, we look at CAR T, patients who have deep responses tend to have better outcomes. Now, there's one tricky part with CAR T's, and I'll tell you what we went through.

When we started doing CAR T's, we were measuring the bone marrow one month after. And then what we realized is the CAR T's are still doing their job. Those little Pacmans there are still working. So it was too early.

So what we do now is we do it like with a stem cell transplant. So we wait for three months, which is the time of greatest activity of those CAR T's to do the bone marrow. And even when we looked at our data, at one month, it was less clear what the effect might be. At three months, it's very clear that becoming negative becomes a positive prognosis.

Jenny: Fascinating. Jan is wondering, besides a bone marrow biopsy, is there another way we should follow up after a transplant or a year of maintenance? But that's probably just go get an MRD test.

Dr. Rafael Fonseca: And, you know, I would say we do the MRD, we do the protein testing. I mentioned we're doing the mass spec. And of course, there's the whole part of what people call the survivorship plan.

Make sure you have the right preventative medicines, you know, later on vaccinations. All of that is very important, but it's just part of the context of 3D Mildome.

Jenny: Jay has a very common question that a lot of patients have. This goes back to asking your doctor about MRD testing. He said, “I've been told MRD testing is not relevant because there's no real manner in which to remediate an MRD positivity issue. I've been in remission for 30 months. Should I pursue MRD testing?” We get this all the time. Questions from patients like my doctor just says, what am going to do with that result? So they don't give a test, but it doesn't make sense to me.

Dr. Rafael Fonseca: Sure. Well, you know, let me say, first of all, 30 months remission. Excellent. I'm so happy. And one could say, if you're not going to do anything different, if you were curious, you could do it and get it to that point. The reality, there's two realities that I think come into play here. One is a lot of people, and when you're dealing with your doctors, and I know the same would be true for me, particularly when you're in community centers, you have to deal with everything. So it's impossible to stay abreast of everything.

And I think that goes back to your point, Jenny, at some point it makes sense to bring someone who has expertise in myeloma into your team. Fortunately, I think there's myeloma now centers across the nation, multiple places, so people don't have to travel very far. I can think of many states where I can say, hey, you can just go see, you know, Jill or Jay, and you're going to be in excellent hands.

The second one is I think doctors tend to be very doctor-centric. That probably comes from the old doctrine of medicine where it was kind of hierarchical and then you will do what I say.

And the doctors ask themselves, what am I going to do differently? And I think a lot of patients that are hearing this that know the information know that, you know, if you finish a transplant, let me give an example, a very clear example.

Many doctors would treat patients still with three drugs before transplant, let's say VRD and the patient goes to transplant. I would not do that, but many patients do that. Then you finish the transplant. If you're MRD positive and you were placed on the lenalidomide alone, you're in no likelihood 57:30? of going to experience a relapse in less than the five years that followed the transplant, probably sooner.

And if you said, well, my doctor now read the AURIGA clinical trial, and that AURIGA clinical trial demonstrated that if you used daratumumab plus lenalidomide post-transplant, you increase the rate of negativity and you delay progression.

There you're doing something. So there's multiple scenarios where they can do that.

I think it's only human, right?. We don't want to be challenged and there's such a wealth of medical information that I can see someone saying, it's not ready for prime time. I don't know what I would do differently. And I think I've given multiple examples of things that we would all do.

Jenny: Yes, absolutely. Darlene is asking, at what point in time should MRD testing be done if you have a complete hematologic response and your treatments are a bispecific antibody? And do your recommendations change if you have both myeloma and amyloidosis?

Dr. Rafael Fonseca: Two questions, a great question. So the bi-specific, it's incredible. Those drugs are fascinating. Bi-specifics are pretty binomial. And what I mean by that is when we give it to patients, if they respond well, they can respond dramatically well. So if someone has an okay response, we unfortunately don't think of that as a very durable response. And oftentimes we have to change something else.

But if you respond well, the results can be astounding as good, if not better sometimes than CAR T.

There are patients who are getting bispecifics and if they get a complete response - so I'm going to go back in time, I'm going to call it complete response instead of saying MRD. You know, some of these patients can have that response be lasting out two and three years in about 80% of patients, some clinical trials. It's just remarkable. I would want to know that. And that's what I would want to know what my MRD status is.

The second thing is, the bispecifics being such great drugs, obviously, also carry some consequences with regards to toxicity. And some of the clinical trials with bispecifics, like the one for cevostamab, ask the question, can we use time-limited bispecifics?

I think people know that that is probably a trajectory that some of us are going, spacing them out, maybe even stopping them in time to see if patients can recover some of the normal immune function and so forth.

And if you tell me, you know, I've been on a bispecifics, it's been three years, I'm doing great. Can I stop because I'm MRD negative? I might say yes. No one has clinical trials. There's never going to be enough clinical trials to address all the questions. But I think it would be a reasonable clinical decision.

Jenny: We have a lot of questions you've answered already, so I'm not going to re-ask those, but there's someone from the UK has an interesting question. Some people, despite being MRD positive, can have very long remission times or progression-free survivals. How do you look at that? Are there early indications about who they might be and what's different about those patients?

Dr. Rafael Fonseca: Yes, happy to address this. That is true. And in fact, when I talk about MRD, I always tell the audience, you know, we all are going to think about those patients that we have in our clinical practice that have small monoclonal protein and still do very well. But the one thing that is very important, that is a retrospective observation. That is something you know in time. That is something you know 10 years later.

When you start, when you're at the start line, you have to say, I'm going to try to do everything and anything that I can do safely and with the patient agreement to get them to be MRD negative.

So Jenny, let me finish with some quick thoughts. First of all, we're talking about MRD only because we need to talk about MRD, which reflects the betterment of treatments. So that's the greatest piece of news.

The second one is, let me just say that there's a story that I found about the very first use of MRD ever in oncology that I'm aware of, and I'll share with our audience.

Back in the first days of chemotherapy, at the NCI, was Ming-Ching Liu, who was a physician there, who was treating patients with choriocarcinoma. And those patients produced the same hormone that we detect for pregnancy, HCG. And what they found is the patients were often responding well, but then they would relapse. And what he decided is, no, I'm going to treat patients until that HCG test, the marker, becomes negative.

Now he was called a maverick and he was fired from the NCI. So he went to Memorial Sloan Kettering. Turns out in time, the patients that were cured were those that became HCG negative. I think it's a remarkable story. And the last point that's, could be that five years from now, you and I talking about MRD, we might say we no longer need it because it was a bridge therapy. Because it could be that there is a point that the myeloma therapies are so good that we don't even measure risk.

Jenny: That's a great story.

Dr. Rafael Fonseca: If there's a standard treatment five years or 10 years from now where patients get four drugs and we can assume that a high percentage of them will be cured, then why even measure MRD? my hope is that at some point in the future, MRD will be useless.

Jenny: I love that sentiment and I hope that happens soon. We love it. Thank you so much just for everything you do in myeloma. You are just this incredible leader in the field and I think your title as Chief Innovation Officer is very representative of you as an individual because you are constantly innovating and thinking of different ways.

But you're so patient centric and you explain things in such amazing ways. So just thank you for everything you're doing for patients.

Dr. Rafael Fonseca: Thank you, Jenny. And I couldn't do well without returning the favor for all of your efforts and everything you do for patients. We're so fortunate to have such an empowered community because of the leadership of people like you that really make the difference. And HealthTree, the information, I often get comments like, yeah, we got to know you a little bit before this appointment because we went to the Health Tree University. So thank you again and keep up the good work. OK.

Jenny: Good. I love seeing that.

Dr. Rafael Fonsec: Thank you.

Jenny: Well, thank you to our listeners for listening to the HealthTree Podcast for Multiple Myeloma. Join us next time to learn more about what's happening in myeloma research and what it means for you.