MRD testing is coming of age in both clinical trials and in the myeloma clinic. Ben Derman, MD of the University of Chicago shares MRD basics, how MRD testing is being evaluated by the FDA as a new clinical trial end point, and clinical trials that are using MRD testing.  It is too soon to tell, but over time, perhaps in the future MRD testing can inform patients about how well they may do on treatment, and when to start or stop therapy based on the results. 

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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. We’d like to thank our episode sponsor, Menarini Silicon Biosystems, for their support of this program.

Now, before we get started with today's show, I'd like to share a little bit about HealthTree Cure Hub. This is a revolutionary way that you can find help navigating your myeloma, and a remarkable way that you can help accelerate myeloma research. In HealthTree Cure Hub, you can connect your medical records to track your labs, find personalized treatment options and find open myeloma clinical trials. At the same time, you can help accelerate research for myeloma investigators who can benefit from studying real-world evidence from thousands of myeloma patients. As always, personal information is kept private and survey results are aggregated and anonymized.

To give you some examples, we're using HealthTree Cure Hub to help Urvi Shah, MD at MSKCC on a study to understand how diet impacts myeloma progression. We're also helping Craig Hofmeister, MD at Emory University to better understand how patients use opioids and cannabis for pain management with myeloma. We performed a survey with you about MRD testing to understand your perceptions and knowledge about it. Each time we do this, we save these investigators, on average, $150,000 and a year and a half to facilitate their research.

Why does that happen? If a researcher has an idea, they need to get funding, get IRB approval to run the survey. If they don't have enough patients at their particular center, they have to sign cross-center agreements for data sharing. That all takes significant time and money. Thanks to your support and your participation, our average time to complete a survey is four to six weeks with hundreds of you responding, and we provide the data back to the investigators for free. I just want to say thank you to all who have participated in HealthTree Cure Hub because in the past, researchers couldn't do this type of work because it was just too expensive and time-consuming. We're opening up completely new methods of real-world evidence for researchers by helping them help us as patients, and the possibilities for this type of research are really endless. If you haven't already, please create a HealthTree Cure Hub account at HealthTree Cure Hub.

Now onto our show today. MRD testing, as we all know, has become a hot topic in myeloma, and we welcome Dr. Benjamin Derman from the University of Chicago to join us today to discuss how MRD testing is and will change myeloma treatment and FDA approvals potentially. Dr. Derman, welcome to the program.

Dr. Derman: Thanks so much for having me.

Jenny: Well, we so appreciate you joining. Let me give an introduction for you before we get started. Dr. Benjamin Derman completed his education at Northwestern University with his postgraduate training at Rush University and the University of Chicago. He's Assistant Professor of Medicine and now Director of the Multiple Myeloma Clinic and Tumor Board at the University of Chicago. He's a member of the University of Chicago Comprehensive Cancer Center Clinical Trial Review Committee to review new trials. His awards include Resident Teacher of the Year Award, Chief Resident and Chief Fellow in Hematology, and a Postgraduate Teaching Award at the University of Chicago. He's the Principal Investigator on the MRD2STOP study and is Principal Investigator on a large number of BCMA and CAR-T studies. He serves on the editorial board for Blood Advances and is a peer reviewer on many publications, including Journal of Clinical Oncology, Blood Advances, and BMT. He's an expert on MRD testing, and we just look forward to learning more about that particular topic today.

With that, let's get started on some MRD testing basics. I think, Dr. Derman, we might want to start by just going over, what is MRD testing, and why should patients really care about this?

Dr. Derman: That's a great way to start, and thank you so much for that lovely introduction. Yes, MRD is really at the heart of everything that I do with patients, both on the research side and in clinics. What the heck are we talking about? MRD used to refer to something as minimal residual disease, and now the name has slightly changed. You might notice the nomenclature changing to measurable residual disease. One doc who does MRD work in leukemia has said there's nothing minimal about minimal residual disease, so we should change the name. MRD in myeloma refers to low levels of myeloma cells that are detectable really only using advanced diagnostics.

The way I like to describe it to patients is, think about it like this, imagine a diver is getting ready to dive into a pool whose depth increases along its length, four feet on one side,12 feet on another let's say. The deepest end of the pool is just beyond this diver's skills to reach, and it remains inaccessible to them. Now I've made it more challenging because I'm going to say that they've been tasked with finding a small coin that may or may not have been cast somewhere into the pool. They don't know if it was actually thrown in there or not. If they're lucky, the coin is going to be found at the shallow end of the pool, and it won't require much effort to detect. That might be like our conventional MRD tests that we use to look for disease, either in the blood work with light chains or the M-spike, or even just looking at the bone marrow biopsy using our standard methods.

More challenging would be if the coin is found in the lower depths of the pool, but still within their capacity to obtain. They could still reach the bottom maybe at six or eight feet, and that's really our MRD testing. These are more sensitive techniques that allow us to dive deeper to look for disease. It's still possible that that coin could be in the deepest end of the pool that we cannot reach, and more frustrating is it may be not in the pool at all. How could we know? That's really where we talk about the limits of MRD testing which we can get into. That's how I like to think about it, is that we have these different techniques that allow us to zoom in more and more and more to find where the disease may be, but there still may be disease beyond what we can detect, or there may be nothing at all.

Jenny: That's a great explanation. I love that analogy. There are also different types of MRD testing now, some blood-based, and this is all one type of test, right?

Dr. Derman: Correct. Traditionally we've relied on bone marrow biopsy and aspiration, which is the liquid part that we take from the bone marrow. Any patients who are listening know very well what that's about. Traditionally we've used bone marrow testing to look for MRD. There are two very popular techniques that are used. One is called flow cytometry, and one is called Next-Generation Sequencing. You may hear me refer to flow and NGS to refer to those both. Flow cytometry looks at the markers on the surface of the myeloma cell. The technology has improved over the years such that now, if you are able to take 10 million cells out of the bone marrow, you can find a cluster of 20 of them, and that gives us a one in a million type of sensitivity, as we say. When we say one in a million, that refers to 10^-6. We're looking at trying to find one abnormal myeloma cell out of a million total cells that we've analyzed.

Now next-generation sequencing can actually do the same, but with a fewer number of cells. You only need about 2 million cells in order to pick out a single abnormal cell per million. Those techniques still have that deepest sensitivity, what we call 10^-6, is still relatively new overall. Some centers may not have it offered or may not have it, especially flow cytometry, while you can take a fresh specimen and analyze it, and you don't need to have what's called a baseline tumor sample with a high amount of disease. All you need is that fresh sample, and you have to run it. The issue is that it requires specialty pathology to really be able to do it at that 10^-6 level. NGS can be done centrally.

Adaptive Biotechnologies has an assay called clonoSEQ that's FDA-cleared. We can send samples off to them to run a sample. The nice thing about that is it's really standardized and centralized, so it's done all by one place. Of course, that comes with additional cost, and the biggest thing is you need a baseline sample from time ago, potentially, where somebody had more disease, to be able to pick up the myeloma fingerprint, so to speak.

Now we've moved not just from doing bone marrow biopsies to now doing other things. The PET scan is one thing. That's an imaging test. MRIs as well. What we're looking at is, looking at disease outside of the bone marrow, what's referred to as extramedullary disease. Extramedullary disease is not something that we're going to be able to pick up on a bone marrow biopsy, so that can be helpful, but recent studies have shown that PET scans are relatively insensitive to picking up MRD when the bone marrow hasn't been able to – in other words, it's very rare to see the PET scan pick something up when the bone marrow hasn't. That's led some interest into the holy grail of MRD testing in myeloma which is the peripheral blood, the blood test. Wouldn't it be amazing if we had a blood test that we could do that would tell us if there's disease present or not, and be able to circumvent having to do a bone marrow? That sounds great.

Jenny: That would be great.

Dr. Derman: Every patient's dream is every physician's dream too. The issue is that myeloma really likes to stay in the bone marrow, and it doesn't really like to circulate in the blood. On average, we see that the blood is about one to two times less sensitive, we call it, logs less sensitive, than the bone marrow. In other words, if I looked at a million cells in the bone marrow and I saw one cell per million in the bone marrow, you would need to have ten to 100 cells per million in the blood in order for us to be able to detect it. The blood is less sensitive. Maybe with newer technologies we'll get there, but so far that's been a consistent scene.

Now, there's this newer idea that instead of looking for the myeloma cells themselves, let's look for the proteins that myeloma makes, and that's called mass spectrometry. If we want to get into that a little bit more, I'm happy to do that. Basically, mass spectrometry is this ultra-sensitive technique to look for the protein. Think of it like the M-spike that we look at on the serum protein electrophoresis, but kicked up multiple notches here. It is a very sensitive test. There's a very sensitive test and that, so far, has shown the greatest promise in terms of potentially complementing the bone marrow. There are still cases where the bone marrow picks something up, and the blood doesn't; and the blood picks something up, and the bone marrow doesn't, in these cases. Right now, I would say that's really leading the front in terms of a peripheral blood test that really has the potential to be used as an MRD test.

Jenny: Okay. Well, it'll be interesting to watch the progress as that moves forward. Maybe you can go over some basics, too, like how, when and why is MRD testing used for care after a myeloma treatment?

Dr. Derman: I think there are really three reasons that we, as a field, are interested in using MRD. The first is for prognostication in order to help patients understand how long will their disease remain in a response before it progresses, and potentially, how long will their survival be in the long run. The second thing would be to use it as what's called a surrogate endpoint for clinical trials. I think we'll get to that later. The third thing is to guide decision-making in the clinic. Now, right now, the strongest evidence for MRD is really only with that first point, which is prognostication. It's not profound to say that having less disease is better than having more disease. Being MRD negative, meaning not having evidence of disease, is better than if you had evidence of disease, being MRD positive. 

Now we have several trials. In fact, there was a study done that analyzed 44 different trials, we call it a meta-analysis, on 44 different trials. They found that MRD negativity leads to better overall survival. Time to death, of course, how long people are living, and the time to progression as well, when you look at, doesn't matter what is the sensitivity of the test, the type of test, the risk of the disease, high risk or standard risk, the setting in which you do it, newly diagnosed versus the relapsed refractory setting; all of those things in all of those situations, MRD negativity is associated with better outcomes.

Many of the patients in my clinic, and myself too, are very interested to know if patients are MRD negative, because I can tell them, hey, I think you're likely to do quite well, and I think your prognosis is very good. It's like a checkpoint along the road where we can say, are you likely to enjoy a long response or not?

There are opponents, I guess I would say, of MRD that say, it doesn't change what you're doing, so why would you measure it? If you're not going to change what you do, if you're going to continue lenalidomide maintenance forever, then why are you doing this? I think those people have a point. I would argue that I think MRD is already being shown that it's possible to use this in clinical decision-making.

Maybe we can touch on that in a little bit, but one of the things that I really like to do is set up a trend. One result is not necessarily going to change my mind on what we do, but setting up a trend to understand what is happening with the disease is super important. There was a trial that was done that looked at conventional responses.

Many of you may be familiar with what is a very good partial response or a complete response. A VGPR refers to a 90% reduction in the protein. A complete response or a stringent complete response essentially refers to no evidence of disease by bone marrow or blood testing with conventional means, not MRD testing, just the conventional tests that we use.

This study showed that it didn't matter what your response was by conventional means. If you were MRD positive, your outcomes looked pretty much the same. It was only the patients that were MRD negative that had the better outcome. We used to be very excited when we saw a complete response. It's becoming increasingly common, and yet some of those patients still progress.

We have to move the goalposts a little bit in my opinion, to say, I think MRD negativity is a very worthy goal. To set up a trend, you can see, does MRD negativity, are you able to sustain it? Are you able to keep the disease away at this very deep level? Then that's when we can start to potentially pull off treatment. I think that's where I'm really interested in, and we're leading a study precisely to look at that. I can touch on some studies that have done that as well, but I think that's really, right now, in terms of the on-treatment or post-treatment, especially after transplant, that's where I'm really interested in.

The slippery slope is, what do you do if patients never get to MRD negativity or turn back to MRD positivity? What does that mean? Is that something worth going after? Is it worth chasing after?

Jenny: Yes, it's a tricky situation because I have some friends who have been MRD positive for a very long time. They have this low level of disease, and they are on maybe one particular therapy and have been for years. I know what you're saying is absolutely true that the general trend is if you're MRD positive, it's worse typically than being MRD negative, but there are some patients that have this low level and they just keep going on for a decade or more. So interesting.

Dr. Derman: Well, there's this concept of an MGUS-like phenotype, meaning, these patients have residual disease, but it's almost like you’ve reverted it back to its earliest stages, earliest precursor stages that make it very unlikely to progress into myeloma again. Identifying who those patients are is extremely important. The Spanish group does a lot of work on flow cytometry. They are the flow wizards of the world in myeloma, if such a thing exists. They have identified the MGUS-like phenotype. In other words, we can identify this profile that identifies patients who still have residual disease but don't progress. It's still a rare percentage. It's a small percentage of patients, somewhere in the ten to 15% range probably. I think it was actually under 10% in this small study. I mean, those patients exist. I'm not saying they don't exist, but they're like unicorns, in my opinion. They're out there, but hard to find. I think that's a key thing to remember here.

We did a survey, actually, of clinicians, and we asked them in this first iteration of the survey, hey, are you making decisions based on MRD? About 35%, 37% actually, to be exact, of respondents, the clinicians, said that they were making decisions based on MRD. We didn't go any further into it, and I felt a lot of regret about that. We did the survey again, and we got even more people to respond. We tried to get more community providers as well.

This time, we didn't just ask, are you making decisions based on MRD, but we gave common clinical scenarios and gave them disease characteristics. We asked, are they MRD positive or negative in these situations, and asked them to comment on what they would do. Then we would ask them what they would do if the MRD result was the opposite. When we did that, we found that actually 60% of clinicians were making decisions based on MRD testing.

I think what people say and what people do might be different things. In part because, once you know that answer, you can't really ignore it. It's out there. It's just this very subtle influence, I think, on our decision-making. Now, I just saw another survey that was done of patients, finding out what their perspectives are on MRD testing. I think something that you might have been touching on is MRD negative results of course make patients feel happy because that's the best result that you can have, but MRD positive results do have a negative psychological impact on patients. I'm very acutely aware of that.

I think any time we give MRD results or if you're a patient receiving MRD results, you have to put that into context. Somebody who has two cells per million, that could be a great result if you were at 500 a year ago. You have to always put these things into context for patients. Otherwise, what are we doing? It doesn't make any sense.

Jenny: Right. Plus, what you're saying, the trend is so important. You're watching it over time, and you don't want to take somebody off treatment too early if they're not stabilized. Yes, I understand the psychology of that.

Dr. Derman: We call it multiple myeloma, but some people refer to it as the multiple myelomas because of the different ways that myeloma presents and behaves. Patients who might have high risk disease characteristics, even if they're MRD negative, that may not be enough to really tip the scales. Whereas, somebody who has standard risk disease and their disease should behave more politely, so to speak, those might be the patients who potentially we might even be curing. MRD negativity serves as a way to define the absence of disease in order to actually identify who might be cured. Again, context is very important here.

Jenny: And it seems like another tool to more personalize care, in my opinion.

Dr. Derman: Absolutely. Absolutely.

Jenny: Like what you're saying, the standard risk versus the high-risk patient.

Dr. Derman:  Yes, and actually in that survey I mentioned where we asked clinicians what they do, we also included high risk and standard risk to see how that changed. That had more of an impact on decision-making than MRD, but I think those right now are the two critical pieces that affect patient care in myeloma is, what is the disease risk, and that you can know up front, but then as far as MRD testing, that's that checkpoint in the middle that helps us modify things as well.

Jenny: Fantastic. Well, it's so fascinating to hear that they are using MRD testing in that decision-making process. Interesting. That's very interesting. Let's talk about something else also that could be meaningful for the continuation of innovation in myeloma, which is potentially using MRD testing as a clinical trial endpoint. I think we need to go back to basics and have you explain, what is a clinical trial endpoint? Let's start with that.

Dr. Derman: The age-old saying is that we want to adopt a new treatment or a new treatment regimen if it does one of two things. It improves overall survival, how long people live, and/or it improves a patient's quality of life over the existing standard of care. Those are the two things that probably matter most, not that probably, that matter most to patients.

In myeloma, the overall survival in the early 2000s was measured in two to three years. Now, we don't even know because it's increasing too quickly to know, but it's at least a decade for most patients. When you do a clinical trial and we have a regimen of interest, are we going to wait ten years to see that signal and then adopt that treatment? By that time, we have new treatments that are coming down the pipe that we're more interested in. This led to what's called a surrogate endpoint called progression-free survival.

Surrogate endpoint, the idea is that you find something that happens sooner in this case but is used as a prediction of overall survival in this case.

Progression-free survival is this idea that it's the time not just to death but to progression. If a patient is on a treatment for five years and then progresses, that counts the same as a patient who never progresses but dies after four years from something else. The reason for the death doesn't matter. The reason for the progression doesn't matter. They're counted the same.

Progression-free survival is typically shorter, well it should always be shorter, than overall survival. That has been used in many different cancers, myeloma included. The FDA, who reviews the data for large trials and is in charge of approving these drugs, accepts progression-free survival as a surrogate endpoint.

Now PFS, progression-free survival I'll refer to, PFS still takes a long time, especially in newly diagnosed myeloma, which is what we're focusing on a little bit here. That could take five or six years, which is still considered to be too long. If you're a drug company and you want to get your drug out there sooner, that's too long. If you're a patient and you want access to novel drugs sooner, that's too long.

MRD negativity has become very attractive as a clinical trial endpoint because the thought is, I just told you, it's been associated with improved progression-free survival. It's been associated with improved overall survival. Why should it not be used as a surrogate endpoint? The FDA has yet to accept it. In part it's because, we can get into the nitty-gritty, but the idea here is that to be accepted as a surrogate endpoint, you can't just take a bunch of trials and show that it's associated with PFS or OS or overall survival.

What you have to do is show what's called trial-level surrogacy, which means the intervention that you did to improve the rates of MRD negativity was also associated with an improved overall survival. That takes randomized phase 3 trials, many of them, and it requires measuring with the similar techniques, with a similar depth and at similar time points so that you can put that all together. MRD, up until now, has been the Wild West. We were using 10^-4, one in 10,000 cells, 10^-5, one in 100,000, and 10^-6, one in a million. We've been using flow cytometry or NGS. We've been using different techniques. There is this effort being put together by industry, by independent statisticians and by myeloma research groups called the I-Squared team, which is looking to generate the data for this trial-level surrogacy, but it's not there yet.

The FDA in particular has drawn their line in the sand that they're really going to need to see this data in order for them to accept MRD negativity. Part of the reason for that is that there have been trials where patients have had higher rates of MRD negativity from newer drugs, and yet they had worse overall survival. More patients died. How did that happen? Well, the drug was too toxic. It caused too many side effects.

In particular, this drug was Venetoclax. It caused too many infections. Even though the MRD negativity rate was higher, the overall survival was lower. These are the pitfalls of MRD testing. It can fool you, it's still not as good as something like overall survival. I think that's really the struggle right now with using MRD as what we call a surrogate endpoint.

Jenny: That's so fascinating. The Venetoclax was one they ran that trial for all patients, not just 11;14 patients, right?

Dr. Derman: Exactly. If they would have run the trial specifically in 11;14 and the subset analysis showed this, those patients did great. They were really driving all of the benefits. I think it's instructive of the way that – I mean, this could happen with any other drug that you're studying, that there may be a certain subset that really benefits, that's driving the difference in responses, and driving the differences in progression-free survival. Then when you look at overall survival, there's either no difference, or it could potentially be worse. A lot of it comes down to designing the right trial.

Now some have looked at what's called sustained MRD negativity as a more important endpoint. Sustained MRD negativity means two MRD negative results that are separated by at least a year. The thought is that if you can show sustained MRD negativity, you're, in some ways, accounting for patients who've been able to live long enough to get to another endpoint, another result, but also you're showing that the disease is continually suppressed. That's probably what we need to see in order to make any decisions about using it as an endpoint or even for clinical decision-making, that we probably need to see a sustained MRD negativity rather than just a single time point

Jenny: That makes a lot of sense. Can I ask you a question about overall survival in today's landscape with myeloma? It just seems to me that, let's say, you're newly diagnosed, and you join a clinical trial. You're doing quad therapy or something as your induction, and that's your trial. Then you relapse, and you start other therapy. You have five lines of therapy. You live for 15 years and then you die. How in the world do you determine what of those ten therapies that you had contributed to your overall survival? I think that's my mental challenge about using overall survival as the best endpoint because patients keep getting treated over and over again. I don't get it.

Dr. Derman: I think this question is most relevant for patients who are earlier on in their journey, when you're talking about newly diagnosed or early relapse. If somebody is doing one of these CAR-T trials in the late settings, in five, six prior lines of therapy, actually, overall survival is probably a great endpoint to look at because the differences are going to be pretty significant.

I'm with you. I'm with you, though. I'm not a purist in the sense where I think that overall survival has its disadvantages in the sense that there's constant innovation. Now, an OS purist, so to speak, would say, well, hold on, what does it matter what the order of the drugs or the sequence of the drugs that you get is? If you're living the same amount of time, why does it matter? A patient doesn't necessarily experience progression-free survival. If you progress but you live the same amount of time, does it really matter? Now, that's what some people would say.

I would argue that there's definitely a psychological impact, from my own experience, from progressing and having to start a new therapy, and I would like to always try to get as much time out of a single line of treatment rather than without, rather than to sequence things out in a different way. You take quadruplet therapy, for instance, combining four drugs as induction treatment, which seems prime to show a progression-free survival benefit.

We don't know if the overall survival is going to be different in the long run. It may not be. If you add a CD38 monoclonal antibody, which is what's been added to the regimen to make it four drugs, if you were to hold off on that and add it later, your outcomes may be the same after two lines of therapy. It might all equal out in the wash. We see now with transplants, when you don't do a transplant upfront, but you do it later, it might all equal out.

Now, you have to account for what's called attrition. Some people die because of progression or something else in between each line of therapy. There's not a guarantee that a patient will make it to the next line of therapy. For that reason, we might want to maximize the treatments that we have available at each level. That's how I actually do like to approach it. While I like to give everybody listening here a sense of both opinions and make maybe a decision on their own, but I agree with you. I think overall survival is actually really challenging to look at in the newly diagnosed setting or even early relapsed setting because of what you've just mentioned, the constant innovation and the changes in therapy, such that it makes it hard to really understand the impact of our regimen.

Jenny: It's tricky, because you look at stem cell transplant like the example that you used, and yes, there was no overall survival benefit. If you can get more years in remission, then you could more likely jump to something else in that window of time, to a newly developed therapy, to a bispecific or to a CAR T or something like that, in that time. I don't know, I feel like as patients, we're playing chess with our lives. Every move counts. To me, sometimes I look at it strategically like that. Okay, maybe not on the overall survival, but will it give me enough time for something new to be developed, and then I can jump to something else? It's not the purist research perspective, that's for sure.

Dr. Derman: Yes, but I think that's important, if it's important to patients. Who am I to say what's important to patients? You guys are the ones that know. I feel like that's the piece that's a little bit of an unknown. When I ask most patients, I think they would agree with you that they would like to maximize their treatments at each stage. What really gets interesting is with CAR-T therapy. We've seen two CAR-T therapies, FDA-approved, and now we have two phase three trials showing that when you use it even a little bit earlier than the initial approval from the FDA, we're seeing that it's better than the other options out there. Not just that, but instead of having to come in weekly or even more in some cases for treatment, these patients are off of treatment.

They still may be dealing with side effects from the CAR-T therapy, but they could potentially be off of treatment, in some cases as long as three years or more, if you look at the data with Carvykti, for instance. Now you have a situation where quality of life in the long run could be significantly better with a drug where overall survival is not. Because if somebody gets a CAR T later, maybe it'll make up the difference. My argument is here we might see a significant improvement in quality of life. That's why I'm so bullish on CAR T for patients, especially even earlier in relapse, is that the tolerability in the long run and the home time that patients get back in the long run is very significant.

Jenny: Wonderful. Okay. Well, time goes by fast, and we have some more things to talk about. Let's talk about clinical trials that are using MRD testing in the trial. When I did a search on clinicaltrials.gov, I found 141, but you outlined about five that we might want to talk about. Why don't we start with your MRD2STOP study and just talk about how these are being used in trials today?

Dr. Derman: I could talk about this study for the rest of the time, but I'll keep it short. Actually, let me back up. Why don't we talk about the studies that have already been published that actually have used it because sometimes people don't realize that MRD has been used in clinical trials to guide decision-making?

I would say there are two big ones that we should talk about. The MASTER trial was a trial that looked at patients who got quadruple therapy called Dara-KRd, and then they got a transplant. They had MRD testing basically after each stage of therapy. Basically, what the idea was, is that any patient that had two consecutive MRD negative results using NGS with the clonoSEQ assay could then discontinue treatment altogether. If you were MRD negative after four cycles and a transplant, you're done. If you weren't, then you would keep going with additional cycles of Dara-KRd and potentially even lenalidomide maintenance. Once you had two consecutive MRD negative tests, you'd stop treatment completely. This is a very aggressive de-escalation study.

They had some patients who had standard risk disease, and they had a lot of patients who had high risk disease. What they've shown is that a large percentage of patients remained free of disease progression and free of MRD resurgence, meaning converting to MRD positivity, at several years out. Now, the patients who did not do well in this study were the ones who had two or more high-risk mutations, high-risk abnormalities by cytogenetics. Those patients, only about 50% of them, remained off of treatment and without progression or death even two years out. That's probably not the population we want to be doing this for, but it was a great group of concepts that you could use MRD testing to guide.

Now, I told you that sustained MRD negativity is one year apart. These were not. These were not sustained MRD negativity. It makes me wonder what would have happened if patients actually were on therapy long enough to show sustained MRD negativity before stopping.

Would the outcomes have been even better? Now, we were involved in an investigator-initiated phase three study between the United States and Poland called the ATLAS trial that was published earlier this year. The ATLAS trial looked at patients who had finished induction and a transplant and were now going on to maintenance therapy, and the standard of care for a while now has been lenalidomide maintenance. We investigated whether adding carfilzomib to the maintenance therapy would improve outcomes. In particular, we were looking at progression-free survival.

What we did, though, is we allowed, so patients would do three years of this KRD or lenalidomide. It was a randomization. What we did in this study is that patients who are on KRD with the carfilzomib, if they were MRD negative after six cycles, they could stop the carfilzomib and as long as they had standard risk disease and go on to just lenalidomide alone. This is a de-escalation approach in a different way, not stopping treatment completely, but dropping this proteasome inhibitor carfilzomib. What we found so far is that on the whole, patients who got KRD had better progression-free survival than patients who were getting lenalidomide alone, but also the patients who stopped earlier did just as well as the ones who continued on for three years. In other words, MRD negativity could be used potentially to guide de-escalation for patients in whom we use that strategy.

Those are the two existing trials that are really out there that already show what we can do. We were involved in a study. We ran a study, a small study with erlotuzumab and KRD, and we did the same thing. Patients who had MRD negativity could drop carfilzomib in that study as well, and we did not see any difference in outcomes. Okay, fine. MRD2STOP though is more like the master trial where we're actually stopping treatment completely for patients who are on maintenance therapy for at least a year and have shown that they are MRD negative by the deepest levels of MRD testing that we can do, which is 10^-6, one in a million, by next-generation sequencing.

The study is still ongoing, but what we reported back in December is that 84% of patients, after one year from stopping treatment, didn't even have any evidence of disease by MRD testing one year out. Eighty-four percent of patients were free of death, no one died in the study, fortunately, of progression and MRD resurgence, meaning converting to MRD positivity.

We're following patients for three years on this study, and then off-study, we hope to follow them even further. We're also collecting quality of life data, performing peripheral blood tests, doing everything that we can to figure out, how can we identify the patients that are able to safely discontinue treatment?

Now, you remember this pool analogy that I mentioned at the beginning, that there's a part of the pool that we cannot reach. Let's call that analyzing 10 million cells in the bone marrow. What we try to do in MRD2STOP is allow us to access the deepest part of the pool. We can actually take 10 million cells from the bone marrow. That's not the hard part. The hard part is analyzing that number of cells to be able to tell if there's one in 10 million. We devised this technique in order to be able to filter down just the cells of interest from the 10 million cells that we took to be able to tell if there's any disease when we look at that sample.

Oddly enough, well, I wouldn't say oddly enough, our hypothesis so far has been confirmed that you can detect disease when you do this technique, even when it wasn't detectable by the regular assay, the 10^-6 assay. Not only that, but those patients are the ones who seem to be progressing later on down the line. If you use a deeper method, you could detect the disease and potentially figure out who shouldn't be discontinuing treatment in those circumstances. That's what we're hoping to show after three years of follow-up as well.

Jenny: Well, that would be just so huge because having patients take a break in therapy is mentally, psychologically, just even with your immune system, to be able to stop for a season so that you can have some of that recovery would be very helpful to patients, if possible, and the cost too.

Dr. Derman: Absolutely.

Jenny: In lots of ways that would be fantastic if that's possible to identify them without impairing their outcomes. That's an important thing.

Dr. Derman: That’s a great point. There's a similar trial going on at Sloan Kettering, and they've published their initial, or they’ve presented their initial quality of life data. What they showed with the quality of life data is that actually it wasn't better since stopping lenalidomide particularly, which is a little bit surprising. I can say that we've held off on analyzing our quality of life outcomes, our quality life data until we have more long-term follow-up, but we hope to be able to share that soon. That was interesting and a bit surprising. I can certainly tell you from my own experience that patients definitely enjoy having time off of therapy. I think it really makes a huge difference. Even among the patients who have progressed, we've been able to actually very quickly get their disease into a deep response, in some cases, getting back to MRD negativity. There's something about their disease that allows it to be very sensitive to treatment.

Now, there are two other studies I wanted to mention that are using MRD to guide decision-making. One is called the DRAMMATIC study, which is a cooperative group study. It's a very large study. It starts out actually randomizing patients after transplant to either get lenalidomide or lenalidomide and daratumumab to see which one might be better. Then there is actually the second randomization later down the line, where patients in both arms who are MRD negative after two years will be randomized to either continue their treatment or stop altogether. Then we'll follow and see what happens.

We're going to get a lot of data from this trial. One is, what is the impact of daratumumab in addition to lenalidomide? Also, what is the impact of stopping after two years of therapy? I think that's going to be super, super helpful. I will be much older and have even less hair than I do now when we'll get that answer. That's why we're hoping that MRD2RTOP will be helpful, but I certainly think this is going to reap a lot of benefits in the long term.

There's another cooperative group study called the EQUATE study which takes newly diagnosed patients to get daratumumab, lenalidomide, and dexamethasone. If they have not achieved MRD negativity with that regimen, then bortezomib or Velcade is added to it. It's like an add-on trial to try to escalate therapy to see if you can get them to MRD negativity. That's another one that I think is a really interesting question that could be very clinically applicable to us in the near future.

Jenny: Yes, so fascinating. So many different strategies, but all great for patients to come to these conclusions. These are such important questions you're asking in these trials, and so helpful for patients. We are okay on time, I think. I'm wondering, you had mentioned the Adaptive test, is there a best test that's being used in these clinical trials? You mentioned earlier that the level of sensitivity wasn't standardized and the type of test wasn't standardized. Do you ever run multiple types of tests for MRD testing in these clinical trials? You can do head-to-head comparison with the tests or the outcomes?

Dr. Derman: That’s a great question.

Jenny: That might be difficult if you have to do a bone marrow pull. That has to be high quality, right?

Dr. Derman: Right. The first pull, meaning the first sample, the first few milliliters that you take from the bone marrow aspirate, that's the best stuff. That's the goal. That's what you want. The stuff that comes after that tends to become more diluted. If you take 20 milliliters from the aspirate, some of that stuff is not going to be very good. Ideally, what you would do is do two separate pokes, which any patient listening is probably cringing.

Jenny: Yes.

Dr. Derman: The first pull of the aspirate is always the best. Now, there was a study called the FORTE trial that actually did both flow cytometry and NGS and found that when you use the same sensitivity for those tests, they correspond very closely. There's not a lot of difference in the test. I think the bigger issue is not the test that you use, but the depth that you use. In my opinion, 10^-6 is the best. If you were 10^-6  you have better outcomes if you're negative at that level than if you're only negative at 10^-5.

In this French study called the IFM 2009 trial, patients got one year of lenalidomide maintenance, had MRD testing, and regardless of their MRD result, they were followed off of treatment. These are people who were actually off of treatment by design because they couldn't get lenalidomide paid for indefinitely, like was done in the United States trial. What they found is that if you were negative at 10^-6 just on one occasion, after one year of maintenance, you had a 75% chance of being free of progression or death after three years. Whereas, if you were only negative at 10^-5, it was something on the order of 45%. That tells me that being negative at  10^-6 is much more important than 10^-5. 

Now here's what's crazy to me, and maybe I'm the only one that thinks this, but the FDA has issued guidance. They said, hey, if you're going to do a MASTER trial and you're going to do an MRD2STOP study, and you're going to do an ATLAS trial or whatever it is, and you're going to make decisions based on the MRD test; we don't recommend using 10^-6 as your limit because not everyone is going to have a result at 10^-6 because of dilution of the specimen, or it's hard to get it.

Also, in particular, the assay accuracy tends to not be as good at the very limits of that test. They say you should really use 10^-5 as the threshold because you can be very confident about that result. In my opinion, if you're talking about stopping treatment in patients who you know have disease, that seems wrong to me. That seems inappropriate.

The MASTER trial and many others have used 10^-5 as the cutoff, including this DRAMMATIC trial that I mentioned, but in MRD2STOP, we thought about this very carefully and decided that we were only going to use 10^-6 because we couldn't, in good conscience, in our opinion, stop treatment in patients who we knew had some disease at a level that has been validated at that 10^-6 level. You asked me, what's the best test? It's 10^-6, and I think that's really what we should be focusing on, is not 110^-5.  You'll see a lot of reporting at 10^-5 because that's what the guidelines have stated previously, and that's what the FDA accepts, and that's what is most feasible for most patients. People run a lot of treatments especially after transplant or something like that. It's hard to get 2 million cells to look at, to even give you a result at 10^-6, but if I'm a patient, if I'm a physician, if I'm taking care of somebody with myeloma, that's what I want. I want 10^-6 negativity.

Jenny: That makes sense. It seems much more meaningful as a result then you really know when you're making decisions with greater confidence rather than let's just hope for the best and hope that was good enough. If you already know that, that would make sense to me as a patient.

Okay. Well, I want to open it up for caller questions, and we had one emailed question. If you have a question for Dr. Derman, please dial 347-637-2631 and press 1 on your keypad. While we're waiting, Deborah emailed in a question, and she said, “Do you recommend that a non-secretory patient have MRD testing done before and/or after getting a stem cell transplant?”

Dr. Derman: Yes, but I would say that for a secretory patient as well. Just so everybody's aware, non-secretory refers to patients whose myeloma does not produce a protein that's detectable in the blood, or not at a very high level, so it's very hard to monitor disease response in these patients. You have to do more frequent bone marrow biopsies or PET scans to be able to detect any residual disease. That's the beauty of MRD testing in the bone marrow with NGS or flow cytometry. You don't have to rely on the protein product. Mass spectrometry, that could be a little bit more challenging because you do, but as far as bone marrow biopsy tests that we have, I absolutely would, yeah. I would do that for secretory patients too, by the way.

Jenny: Good to know. I know non-secretory patients are very difficult, but you're doing a bone marrow, so that's how you measure it with those patients and not necessarily the blood. Okay, we have two more questions. Go ahead with your question.

Caller: Hi. Can you hear me?

Jenny: Yes.

Caller: I have plasma cell leukemia. I was diagnosed in November. I've been treated for about six months now. I'm just off treatment because I'm getting my stem cells harvested soon.I was on Dara, dexamethasone, Velcade and something.Now I've then changed to dara, methylprednisolone because I had trouble with the dexamethasone, KYPROLIS. I'm just wondering, because it's plasma cell leukemia, I'm just getting such mixed messages. Is plasma cell leukemia always high risk? I am MRD negative now via bone marrow biopsy. I'm trying to find out, as you're speaking, if it's 10^-6 testing. I'm just wondering, can you clear up for me, plasma cell leukemia, if I'm responding, am I positive now? Or am I still wary that because it's plasma cell leukemia, it's going to come back, and it's going to come back quickly? Is that always a given?

Dr. Derman: First of all, that's awesome. I am so happy to hear that. It sounds like you've been through a lot, and it's great to hear that at least by some measure, you're MRD negative. To answer your question, plasma cell leukemia typically does behave aggressively, but one of the things that we notice is that it does respond well initially to therapy. One of the challenges is actually not about whether it goes into a response, but can you sustain it?

You've heard me talk about sustained MRD negativity a couple of times now, and I think that would be the really important piece. What I would say is, if you think about myeloma like people who have different personalities and give off a first impression, the first impression of yours would have been a very shady one, not somebody you want to be friends with. After time, maybe you've gotten to know them, and you think, okay, well, I can get along. What really matters now is to see, this is the true test of friendship, so to speak, can you sustain that MRD negativity, whether it's with a transplant or whatever else is being done, and keep it there? Because if so, then that is probably what matters more than anything else. Maybe our first impression was wrong. Does that help clarify a little bit?

Caller: Yeah, it does. I do have the 11;14 translocation, and I am on Venetoclax. Revlimid and Venetoclax are the ones that I forgot. Yeah, that's what I keep trying to ask my doctors, and I have good doctors. I won't mention their names, but they're specialists. They just keep navigating to not answering, was I high risk, and now that I'm responding so well, am I lower risk?

Dr. Derman: I don’t know that you would ever go with the low risk. You have to really be more aggressive with plasma cell leukemia because there's still always a risk of earlier relapse, even if you've had a good response. This is one of the perils of MRD testing, where one result is not all that we go on. We have to see sustained MRD negativity. If you were to show that, I would feel really good about where you are. I would think that, to some extent, you've neutralized some of that high-risk nature.

Caller: Excellent. Thank you so much.

Jenny: Great question. Very tricky situation and great question. Okay, next caller. We'll try to do two more. I know we'll be over time, so let's try to be short, I guess. Go ahead with your question.

Caller: Yes. I've had a couple of clonoSEQ tests completed. I've had myeloma for five years. Actually, right after the first initial treatment, my doctor requested that test, and it came back as 17 cells in a million. So they kept me on Revlimid for five years. Just in the fall, in September, they ran the test again. This was the clonoSEQ test. It was seven cells. Then in March, ran it again, I had a new physician, and it was zero, MRD negative.

I'm off of Revlimid. I've had a history of breast cancer plus some multiple myeloma. I was very concerned about another cancer because of Revlimid, and the Revlimid, I was such at a low level, but it just kept me at a low level. It didn't do much, so they took me off of it and are monitoring it. My question is probably more a technical one, that when the report came back from clonoSEQ, it has, specimen, use blood. The marrow was sent in, and some blood. I actually called them just because I was curious. I said, is this a blood-based test? They said, it's the same. It's the same as bone marrow. I don't know if you can shed any light on that. I'm not worried, but it just seems kind of odd.

Dr. Derman: Someone can send blood tests and do clonoSEQ. Actually, clonoSEQ is approved for ALL and CLL as well. Oftentimes the MRD tests there are done on the blood, and they show very similar results to the bone marrow. That's because those cells like to live in the blood, and myeloma, as I mentioned, does not. It's certainly good to be zero in the blood, but I would not give it the same weight as a zero, so to speak, in the bone marrow. Bone marrow is by far the best. Bone marrow testing with clonoSEQ is really going to be the best way.

Just to give you a sense, if you look at some of the data, people who are on lenalidomide maintenance, within the first year, depends on the study that you look, but somewhere between 12 and 40%, it's a pretty wide range, but 12 to 40% of patients will convert to MRD negativity within the first year. About half of that will convert in the second year. Beyond that, we don't really know. In general, what I advise patients is I would be very pleasantly surprised if you were to convert to MRD negativity now, but it's very unlikely that I would see conversion to MRD negativity after two years of maintenance therapy. Not to say it can't happen, but I rarely, rarely do, and the data doesn't seem to suggest it. That's where we stand with it right now.

Caller: Okay, so they could probably, next time, just request the bone marrow. It was a new transition. I think he was like blood, and I think actually the lab –

Dr. Derman: I personally don't do blood testing clonoSEQ. Although I know that they'll offer it, and some physicians do it. We are doing some research on that to understand it, but in general, you have to know that it's not as sensitive as the bone marrow. A positive result can be helpful. It could spare you a bone marrow test, but a negative result does not mean that your bone marrow is negative.

Caller: Okay. Okay. All right. Well, thank you very much.

Jenny: Great question. Thank you. Dr. Derman, I know we're over time. Do you have time for one more question, or do you need to go?

Dr. Derman: Of course. Let's do one more.

Jenny: Okay, caller, go ahead with your question.

Caller: Well, thank you, Dr. Derman, for making the time. You so elegantly noted how MRD's role in reaching clinical decision-making is beginning to take shape. My question is really, are there specific points in the disease’s course where you see it taking shape sooner? For instance, in my own family's case, we have someone who completed quadruplet therapy. They've done their stem cell transplant. They're entering maintenance. They're standard risk. There's a divide right now in the field, it seems, between single agent-led maintenance or those who follow the GRIFFIN trial to a T and look to add dara as well. Do you see MRD, or do you use in your own practice, all else being equal with patient factors, to help inform or tip the decision-making process one way or the other?

Dr. Derman: This is a great question.

Jenny: It is a great question.

Dr. Derman: I'm going to do my best to answer it in the best way in a brief manner. Let me tell you what we don't know. I don't know that if we do MRD testing after four cycles or six cycles of induction therapy that that's really enough to determine, should somebody go for a transplant, for instance, or not? Because if somebody's MRD positive at a low level, I don't know, that still means the treatment worked really well. Maybe they just need more treatment, and it doesn't mean a transplant in order to be able to drive it down. I told you it could take two years before people get to MRD negativity in some cases.

Now post-transplant is interesting because that's usually the first time that I'll use the deepest techniques after transplant because I feel like, number one, it starts the trend. That's the time point where I start to see what is the impact of all of our interventions.

If someone's not going to transplant, it might be after eight cycles or something like that, to mirror what's been done in clinical trials. Eight cycles or after a transplant, that's the first peak. Now, I don't necessarily make a decision on that result in and of itself. Again, somebody who's MRD positive alone, they still might be doing really well. That's still a good response. I've seen plenty of patients who convert to MRD negativity a year later. It's helpful for me to know what the trajectory is. If I wait to do MRD testing until a year after their transplant or after eight cycles of induction, I have no idea where they were, where they started from. I really like to have the trend.

I use more high risk versus standard risk to determine if I'm going to do len maintenance versus something more than that. Then I'll use MRD testing right after transplant and then a year later to figure out, hey, that high risk patient that I put on carfilzomib or bortezomib or daratumumab, if they are MRD negative before and after, or they converted to MRD negativity, hey, maybe I could pull off that proteasome inhibitor, give them a little bit of time away from the clinic now.

Maybe I could pull off that daratumumab, give them a little bit less therapy. That's one way that I do it. For the people who are maybe just on lenalidomide, and I say just, but obviously it's still a drug, if they can show sustained MRD negativity, then that's when they start to have the conversation of, hey, you're interested in our MRD2STOP trial? Or, hey, here's the data from MRD2STOP. Do you want to stop therapy at some point? Is that a goal for you? I like to create that trend. I hope that answers the question, but basically, that's how I'm using it right now.

Jenny: Great answer and great question. Thank you so much. Dr. Derman, thank you so much. We appreciate you. This has been a fantastic discussion. Your explanations are so clear, and it's just wonderful. We really, really appreciate it and are grateful for you doing the work on all of this, so we can come to these important conclusions for patients. Because if we can get off treatment and still have the same outcome, we would love to do that.

Dr. Derman: I agree with you. Jenny, thank you so much for creating this forum for really informed patients to be able to ask such excellent questions, and you always come so prepared. I guess I want to give one caveat as we finish, which is to say, you're talking to an MRD evangelist, so to speak, who very much believes in this technology, but your own physician, you'll see a lot of difference of opinions on this. It's important to recognize that. I recognize that, too. There's not one way to do this thing, so it's really important to have these conversations and ask the tough questions to your physicians, to your clinicians who are part of your team.

Jenny: I agree. Sometimes you do need to ask the clinicians and even to run the initial test to get your baseline so you can have sequential results. The more you learn as a patient, the more you can ask those questions of your care team, and understand their rationale for doing it or not doing it. That's always important, to become an educated and well-prepared patient as you go into doing, especially your bone biopsies. Because you're doing them anyway, so why not, in my opinion.

Dr. Derman: Amen.

Jenny: Well, thank you so much. We're so grateful to our listeners for listening to HeathTree podcast. Join us next time to learn more about what's happening in myeloma research and what it means for you.