(Guest Lecture) February 2023 - Is MRD Negativity the End Goal?

Now, today's topic is, is MRD negativity the end goal? And we're really going to focus on understanding when and why it's important. There's a lot of buzz in myeloma about minimal residual disease testing and MRD, and quite frankly a long way to go before we have a lot of the answers to the questions that we hear frequently. Many of you are familiar with the basic concept of MRD, but it might be the first time that hearing this term and you're joining because you want to learn more about it. Some of you might feel guilty or pressured that you're not getting to this MRD negative status, which has kind of been glorified. And we're going to talk about why that doesn't need to be hanging over you. I don't want to, I couldn't give the presentation, but I don't want to give it. So I'll just move on by saying that's why it's the topic tonight, because we know how important it is to all of you. It is now my pleasure to introduce Dr. Brownstein to you. And he had a quote on his website that I really loved. And so I wanted to share it with you so that you guys can get to know him a little bit more. It says, every patient that comes to me has a unique story and individual experience. I enjoy getting to know each person and providing personalized care and treatment options that suit his or her needs. I treat people with various types of malignant and benign hematologic conditions with an emphasis on hematologic cancers, which multiple myeloma is one. I have a specialty focus on plasma cell disorders, particularly multiple myeloma. I also see patients who have iron deficiency, bleeding and clotting disorders and cancers involving the bone marrow and lymph nodes, such as lymphomas. He has been interested in a young age in science and has applied this passion to his role as a myeloma specialist. Dr. Brownstein, we're privileged to have you tonight and we're grateful to hear from you. The time is now yours. Thank you so much, Audrey. Let me go ahead and share my screen. Can you see the slides? Yes, that looks great. Perfect. Yeah. Well, thank you again for that wonderful introduction. It's really a pleasure to be back here speaking with the Health Tree community. I really love speaking to this group because I think they're a pretty savvy group and we already have questions in the Q&A section. And just looking at them, I think we're going to actually answer some of them in the talk, which is good. So I'm here this evening in Eastern New York to talk about minimal residual disease, which is somewhat of a controversial topic. Not so much from the point of view that we don't appreciate its importance in myeloma, but we still need more studies to help guide how to use it. So let's go ahead. These are my disclosures. So these are our objectives tonight. I want to make sure everybody understands the concept of minimal residual disease, or MRD. We're going to discuss the process of testing for it and some of the pros and cons of testing for it. We'll describe the evolving role of MRD in managing myeloma and we'll discuss what the future holds for MRD in myeloma. So let's start with an introduction. Some of you may already know a lot about MRD testing, but let's do some basics. So I think you're all familiar with the schematic of the course of multiple myeloma, from its asymptomatic precursor states of MGUS and smoldering myeloma to symptomatic myeloma with all its ups and downs of remission and subsequent relapses. Now the goal, whether we're talking about transplant, maintenance, MRD testing, the goal is always the same, and that's to extend remissions and prolong survival. But in the process of that, we want to avoid complications of the disease, such as kidney problems or bone disease, et cetera, and avoid complications of the treatment as well. So if you're on maintenance therapy, we want to avoid complications from the maintenance phase and so forth. And overall improve quality of life so that individuals going through their myeloma journey can do the things that they enjoy ideally. And fortunately, we're doing pretty well in terms of the trend of survival. So if you had this disease in the 1970s, the five-year survival was expected to be about 25 percent, and we've more than doubled that since then. And you can see the curve is nicely kind of uptrending as an inflection point here and continuing to uptrend. And I think we're going to continue to see increase in the five-year relative survival, which is based on the past decade, about 58 percent. And I think we're going to continue to see that. And that's largely due to advances in therapy from the inclusion of autologous stem cell transplants in the 1980s to novel anti-myeloma therapies like proteasome inhibitors like Bortezomib or IMIDS like lenalidomide to novel monoclonal antibodies like daratumumab, for example. And now we have even novel agents that aren't even captured in the survival curve, such or bispecific antibodies or cell mods. And so the future is definitely bright. And the longer patients are living with this disease, the more therapies that are likely to come out and extend survival. So if we're going to talk about remission, we have to appreciate that in multiple myeloma, remission is a spectrum, right? When you think of somebody with a solid tumor, let's say lung cancer, and they get a scan, it doesn't show cancer, that's it. They're considered to be in remission. But with multiple myeloma, remission is a spectrum. That means you could be in a partial remission where you've reduced the disease or the M spike by about 50 percent. You could be in a very good partial remission where you've reduced the disease down to 10 percent or complete remission where as far as you can tell based on looking at the cells under the microscope and the myeloma markers, you have no remaining disease. And just like a diver, the deeper the diver goes, the longer it takes the diver to come up, the deeper you drive the disease into a remission, the longer it takes to relapse. And that's kind of a paradigm that we have to appreciate in multiple myeloma. But patients will inevitably relapse for the majority. And so the question is, are we really going to the bottom of the depth of remission? And that's where minimal residual disease testing comes in, as I'll explain on a future slide. The importance of how we assess remission is that the better we can detect residual disease, the more we can try to actually achieve a cure by eradicating as much myeloma as possible. On the flip side, it also could potentially allow us to detect relapse earlier before complications happen or before there's disease resistance. So what is minimal residual disease? So MRD, sometimes it's called measurable residual disease as well. And it means using our most sensitive techniques to determine whether any multiple myeloma cells are detectable. And the deepest remission possible, as far as we can assess at the current state, is called absence of MRD or MRD negative. That means there's no detectable minimal residual disease. So sometimes I liken this to looking up at the stars. If you use a less sensitive technique, just looking at the cells from a bone marrow biopsy into the microscope, it's like looking at the universe from Earth with a basic telescope. You say, well, there's nothing really out there. And then you have more sensitive telescopes. You say, well, actually, there's a lot more than we thought. And then you develop maybe the most sensitive telescope we have, the James Webb Telescope. Neil deGrasse Tyson would be proud of me for this slide. We have the most sensitive telescope here. And now we see, well, there's actually a ton more than we thought there was. The more sensitive our techniques to measure whether something remains inside the bone marrow from myeloma, the more we can detect minimal residual disease. So because minimal residual disease, for the purpose of this talk, is generally assessed from bone marrow biopsies, I want to actually talk about what goes on when you have a bone marrow biopsy done. We're not going to talk so much about imaging techniques used for MRD assessment. We're really going to focus on the bone marrow. So the techniques used to assess MRD status generally come from obtaining a bone marrow biopsy. And as you know, this is done in the hip, because that's where the active bone marrow is in the adult. And when we take out a sample, even though we call it a biopsy, there are two parts to it. One is the liquid part of the bone marrow, which kind of looks just like blood. And then there's the biopsy, which is actually the solid part that includes the bone and a piece of the bone marrow. So what happens from there? So the liquid part can go into tubes. And it can also be smeared on a slide that the pathologist can do different stains on. And the bone biopsy goes into a preservative. And they can kind of piece that up into small slices and look at it as well under the microscope. And this gives us different information. For example, flow cytometry on the liquid part, the aspirate, can tell us if there's the presence of any abnormal cells. But it doesn't give us the actual morphology that you would get from a smear or the biopsy. It's the bone biopsy itself. Another liquid tube goes for cytogenetics. These are the genetic studies we use to determine if a patient is standard risk or as high risk features that will drive the disease forward or make it resistant to treatment. The smears are used to define the percent of plasma cells that distinguishes people with MGOS or smoldering myeloma or multiple myeloma based on the percentage of plasma cells. The bone biopsy is used for special stains, such as looking for amyloid. But what about MRD? Well, that's generally assessed from the aspirate. But it can be also assessed on unstained slides from the bone biopsy if you have archival historical slides that you're going to use to compare to a future slide if you don't have the original sample in hand. And we'll talk about why that's important. So the two most common techniques that are used to assess for MRD status on bone marrow samples are either flow cytometry or next generation sequencing. And they're completely different techniques. So next generation flow cytometry or NGF basically takes the aspirate, the liquid part of the bone marrow, and passes it through a machine that uses a laser to detect different kind of barcodes on the plasma cells. Now, I mentioned flow cytometry in the last slide. This is a more sophisticated type of flow cytometry. It's sort of like GPS where you have like three satellites to determine where you are. Instead of three satellites, this is like using eight satellites to figure out exactly where you are. So it's much more sensitive to detect if there's any myeloma plasma cells there. That's different from next generation sequencing. And there's an assay called the Clonoseq assay from Adaptive that's approved for MRD testing in myeloma. And this is completely different. This doesn't look at the cells. This looks at the DNA from plasma cells. And the assay can detect how many pieces of the myeloma are there, and that correlates with the number of cells. So there are some differences here. Let's compare them. So first of all, we talked about how the tests work. What's the resolution? How many parts of myeloma can we detect in a crowd of cells? So they both generally can detect up to one in a million parts of myeloma, although the next generation flow on the left typically goes up to one in a hundred thousand, whereas the next-gen sequencing can go a little bit deeper. Although some next generation flow cytometry tests, depending on how many of those sort of satellite analogies, depending on how many signals they can detect, can go up to one in a million. But there are some differences. So the next generation flow is not necessarily standardized, and so the resolution can vary. As I mentioned, the KonoSeq assay is standardized and FDA approved to test for myeloma. And so that tends to be used a little bit more in clinical trials when they're looking for a consistent test. So the next generation flow, because it's not standardized in one lab, there may be different sources of where you send that sample to in terms of labs that can actually do that test. For the next generation sequencing, on the other hand, it comes in a kit from the company that makes the KonoSeq assay. So you have to have the kits on hand. For next generation flow, it has to be processed within 48 hours, because if the sample degrades, then you really can't pass the cells properly through that machine. Whereas next generation sequencing can be done in archive samples, but you do need a baseline sample. If you didn't, if your myeloma team didn't do the original sample, you can try to obtain the original one from where it was done if they have unstained slides. But it does require a baseline sample, and that's different from next generation flow, which you can do on any bone marrow sample, and you don't need a comparative sample from baseline. So the next generation flow has a little bit of a faster turnaround time, but in general, these aren't decisions that need to be made in a day or two. We can wait a week or more to make decisions based on the result. And studies have shown that these two assays have about an 80 to 90% concordance, which is good, which means that whichever test we do, we're probably getting an accurate result. So what's the importance of MRD? You may have seen these survival curves in the past. The top shows that when patients start on their journey and then some patients progress over time, and the higher the curve, the fewer patients progress. So patients who are MRD, and we're going to go through this in a lot more detail, but patients who are MRD negative, those patients tend to have longer duration of remission and longer overall survival than those who are MRD positive. And that's really the main use of MRD right now is as a surrogate endpoint, meaning it's something that we can measure that correlates with something in the future, meaning survival. But if you look at MRD, going back to that diver who's swimming down and we're looking at the depth of remission, you can see that there are limits of our conventional testing, meaning doing an SPEP, a UPEP, the rest of the blood work and looking at the cells under the microscope. Those are the limits. Using those two tests I mentioned in the last slide, the next generation flow or next sequencing for MRD testing on the bone marrow, you can detect further residual disease. And that's what minimal residual disease is essentially. It's saying that there's more out there in space in the universe with these more sensitive techniques. So again, using MRD can improve our assessment of what we're actually calling the deepest remission and it can be used to detect early signs of relapse. For example, if someone is considered to be MRD negative and then they convert to MRD positive, and we're going to talk about what that means down the line in this talk. So let's just go back to survival curves. Sometimes these are called Kaplan-Meier curves. I'm sure other other individuals have shown these at prior talks to this group. And but basically the way it works and this is the way we view results of survival, either progression free survival, meaning the time in remission or overall survival, meaning life or death. And so basically everybody starts at the in the study at the top and then one group does better than the other. And in general, if you were doing a randomized study, let's say the Maya study, which was Daratumumab lenalidomide arevlamide and dexamethasone versus lenalidomide dexamethasone alone for newly diagnosed myeloma. In general, the three drug group did better. And so the survival curve was higher and the investigational regimen, the three drug, did better than the control, which was the two drug over time. Now, follow me with this because this is interesting. Now, when you separate those curves further into the investigational three drug group and the control group, which was the two drugs by their MRD status, it's sort of intuitive that the folks who got the investigational drug and were MRD negative, meaning the deepest remission, did the best. Right. Because those are the groups that got the what turned out to be the better regimen and who were MRD negative. Whereas the ones who got the control and were MRD positive, who really didn't respond well and didn't get into the deepest remission, did the worst. But when you when you separate out them further, this is where it gets kind of interesting, is that what we often find, and this is a generalization, but what we often find is that even the control group who got the two drug regimen, when they're MRD negative, they do almost as well as the folks in the investigational group who got the three drug regimen. And that means that it may not matter so much what the regimen you use is if you can get them the patient to MRD negativity. However, we don't know exactly how to match that regimen to the individual patient to get them into an MRD negative state. And it's worth noting, too, that more patients who got the investigational drug end up in MRD negativity than even the control group who's MRD negative. So the bottom line is that patients who achieve MRD negativity generally have better outcomes regardless of the treatment. However, more patients in general tend to be MRD positive in studies than negative. And this is a real world example. So some of you may have been treated with this regimen of daratumumab, lenalidomide, dexamethasone. And this is a study called the Maya study that was published in New England Journal and updated in Lancet Oncology in 2021. It's a randomized study of transplant ineligible, generally older patients who received either DRD or RD. And the primary endpoint was progression free survival, meaning how much time before people relapse. And the overall responses were superior in the blue group for the patients who got the three drug DRD regimen. But when they separated the curves by MRD negative, again, you can see that the control group in the blue who were MRD negative did pretty close to the group who got the three drug regimen who were also MRD negative. So MRD negativity does matter. And it's worth noting again, though, that the majority of patients were MRD positive here because only 31 percent in the three drug group and 10 percent in two drug group became MRD negative. So, again, it's still better to get the three drug arm of the study because there were more patients in that group who got who achieved MRD negativity. But overall, the majority did not achieve MRD negativity. So just we're going to talk a little bit more about what that means, but just the summary of the section. So, you know, it's a paradigm of multiple myeloma that depth of remission predicts the duration of the remission, the deeper you are, meaning this complete remission versus a partial remission. The complete remission generally has the longer remission than the partial remission. MRD is an important tool that correlates with long term outcomes like progression for your overall survival. And increasingly, clinical trials are using MRD as an endpoint. And there are some advantages of that. And you can see from this kind of pie chart, from a kind of a review paper where they looked at current trials from 2020 that were using MRD as either the primary endpoint of the study or just a secondary endpoint. But they were increasingly using this as a tool to assess patients because the value of MRD in a clinical trial is that you can assess it any time you do a bone marrow. You don't necessarily have to wait years until somebody has a progression event. So you can assess it very early and it correlates as a surrogate endpoint. It correlates with that progression event. So what are the implications of MRD? And the way I broke this section down is by questions that I think people in this audience have and that I often get asked when I talk about this with patients. I'm also part of the transplant team at NYU and patients often ask questions related to how this ties into transplant. Should we be measuring this? Can I stop therapy if I'm MRD negative? So we're going to break all these questions down one by one. And the punch line is we don't really have the answers to all of these questions, but where data exists, I will show you. So first question, I'm not MRD negative. Should I be concerned? And the answer in general is no. Survival is improving, as I showed you on that curve, and it's largely based on our conventional response measures, whether you had a CR or VGPR, not based on whether you are MRD positive or negative. And I would I would posit that maintenance of remission, meaning how long you stayed in remission, let's say after your transplant, is more important than one time point saying I'm MRD negative. In other words, the biology of the disease on an individual patient level is revealed essentially by how well they respond to treatment and how long they stay in remission. And so that maintenance of remission to me is more important than one time point that says somebody is MRD negative. And that's also why we tend to get sequential MRD tests to see if people are remaining MRD negative or if they're just remaining in a complete remission. The other thing is that many patients, as I mentioned before, will not achieve MRD negativity yet still have a favorable survival. So in the MIA study, we saw that only 31 percent of patients became MRD negative, yet 68 percent survived nearly five years before progressing. In the Griffin study, which is for transplant eligible patients who received, you know, that's a little bit of a typo. There are two D's there, but daratumumab, lenalidomide, bortezomib dexamethasone, the four drug regimen, 51, more patients, 51 percent achieved MRD negativity, which is impressive, yet 96 percent were progression free at two years as far as the study has been read out to date. So even if you're MRD positive, still there were favorable outcomes. Now, when it comes to high risk patients, these are patients who have high risk features such as multiple lytic lesions and diagnosis or high risk cytogenetics. These patients are, you could potentially argue that outcomes are improved if you're MRD negative, but it's unclear in the long term yet if that really mitigates the risk of earlier progression in the high risk setting. So the current practice, and it may vary in your with your care team, but the current practice in general is not to necessarily intensify treatment if you're in a complete remission and you're MRD positive just to get your MRD negative. Now, that might change in certain scenarios if you're a high risk patient or if you've had a discussion with your care team. But in general, that's the practices lacking any data to support it is not to intensify treatment on maintenance, for example, to get from negative from MRD positive to negative. And one of the reasons for that is that on maintenance therapy, patients may convert over time to MRD negative if they were MRD positive without intensifying treatment. So this is a review paper that looked at several studies of individuals on lenalidomide maintenance and what they found that at a median time of about 18 months, 34% of the patients who were originally MRD positive when starting maintenance eventually converted to MRD negative without having to intensify treatment. Let's move on to the next question. Am I MRD negative after induction? Fantastic. Do I need a stem cell transplant if I'm stem cell stem cell transplant eligible? And this is certainly a fair question and one that I think we struggle with a little bit because it remains debatable. There are a number of questions that are being asked about this. And I think that's a good point. And I think that's a good point. And I think that's a good point. And I think that's a good point. And I think that's a good point. And I think that's a good point. I think we struggle with a little bit because it remains debatable. There are no randomized studies that have said if you are MRD negative before transplant, we're going to randomize some to transplant, some to not transplant and see what happens. We do have phase three randomized studies that have randomized patients to transplant or no transplant, but it wasn't based on whether they were MRD positive or negative. So two of those studies you may be familiar with that were recently published in the past the French IFM study, which randomized patients to transplant or no transplant after induction with RVD, a three drug regimen. And then they got maintenance for one year. And then the determination study, which was done in the US, which was very similar, except that they got replamid maintenance until progression. And what they found was that patients had a longer time to progression with the transplant compared to no transplant after initial therapy and more patients, as you can see in the table, were MRD negative if they got transplanted. But to date, there hasn't been a change in overall survival, meaning who lived and who did not. But there was a delay in progression to the next line of therapy. Now, it's worth noting in both of those studies, crossover was allowed. In other words, if you were randomized to the no transplant arm, you could get a transplant in the next line of therapy. So that might have diminished the differences in survival between the two groups. But again, neither of those studies determined whether or not you could use MRD status to guide whether or not to get transplant. They just said that the likelihood of getting into an MRD negative state was higher if you got the transplant. There are two ongoing studies, though, to answer this exact question. One is called the Master II, where you get that four drug regimen they used in the Griffin study of DARA-RVD. And then patients are randomized to transplant or no transplant, depending on whether they're MRD negative or not. And the MITA study is looking very similar with a similar regimen, esotexumab KRD, and then transplant or no transplant, depending on their MRD status after initial therapy. Another question that comes up, can I stop maintenance if I am MRD negative? And the answer is perhaps, because there are emerging data sets that suggest that we don't do harm by stopping maintenance in that setting. So a while back, I came to talk to this group about Revlimid and Revlimid maintenance. But there really is not a clear consensus about what the optimal maintenance regimen is either after transplant or without transplant, although lenalidomide or Revlimid is the most commonly used regimen for maintenance. So there are two ongoing studies that are exploring using MRD negativity as a way to deescalate therapy, including stopping maintenance. And I'm going to go through one of these called the master study. It's a phase two study, which means there's no randomization, there's no comparator group. But what they did is they gave newly diagnosed patients a four drug regimen of DARA-KRD, and then used and then transplant. And then if the patients had two consecutive MRD tests, they allowed them to stop maintenance therapy. And this is what the it's a little bit of a busy slide, but this is what the study did. So patients got four cycles of DARA-KRD, and they got an MRD test then. Doesn't matter if it's positive or negative, they went into transplant. Then if they were negative a second time, though, they were allowed to come off of consolidation. If they were MRD positive, they went on to four cycles of consolidation. If they were MRD negative after that, again, they came off of the study and so forth. Including in the maintenance phase, they came off the study, off of treatment entirely, if they were MRD negative. Now the study, again, did not have a comparator group. And they didn't necessarily look at progression free or overall survival. But what they looked at is when they subgroup the patients by whether they had high risk cytogenetic abnormalities or HRCA, the patients with one or no high risk cytogenetic abnormalities did about the same. And what that means is that you can potentially de-escalate therapy without causing much harm to patients with higher risk features. In other words, they did the same despite stopping therapy. So next question. What are the implications if I convert from MRD negative, so you were in that deepest remission, to an MRD positive state? The answer is that it's probably a warning sign that relapse is on the horizon in the next three, six, or 12 months. In absence of any biochemical evidence on the labs or on the bone marrow that there are detectable cells or detectable M-spikes to suggest that relapse is imminent, it's unclear whether we should be jumping on this conversion from negative to positive. Because there are no prospective studies to guide management in this setting. There is an ongoing study called the remnant study in which MRD negative patients after induction therapy, the initial therapy, are randomized to start treatment at the time they convert to MRD positive versus just at the time of progressive disease by conventional international myeloma working group criteria, meaning they had a 25% increase in their M-spike and the usual conventional testing for relapse. There was a retrospective study of about 568 myeloma patients post-transplants, and they were just looking to characterize the rate of conversion. So about 39% of those patients converted to MRD positive at a median of 6.3 years. And what the study found when they looked at the subgroups in this retrospective study is that those who converted from MRD negative to positive after three years following transplant generally did better than those who converted within three years of the transplant. So is it wrong if my doctor didn't check my MRD status? Do I need a new doctor and a little tongue in cheek? But the answer is no. MRD testing is still evolving. If you're listening to this talk and said, my gosh, my doctor never even spoke to me about MRD and never even tested it, that's not necessarily wrong. There's a saying in med school that we learned that we only order a test if the results will impact our management plan. And as you can tell from the previous slides, we don't have all the answers about how to use MRD testing or what to do with the results. But I would say that it's becoming increasingly relevant and certainly clear that it's a predictive marker of outcomes. Yet questions do remain how to use it. So for one thing, MRD has some logistical barriers, costs. It requires a bone marrow biopsy, and patients may not want to go through a bone marrow biopsy every six or 12 months. And if you're sending the next generation sequencing, the Clonocic test, you have to have the kits on hand. You have to have a comparator sample. I've had patients who were diagnosed outside this country and we can never obtain the original sample to compare to. Whereas the next generation flow, again, requires a specialized lab that can actually do that test. And the reality is that MRD testing is not a perfect science. For example, the bone marrow, the myeloma is not necessarily evenly distributed in the bone marrow. So if you had a watermelon with seeds in it and you stuck a corer into it and there were no seeds in it, you'd say, well, it's a seedless watermelon, but maybe you just didn't hit the part where the seeds were. So if you didn't hit the part where the myeloma was, then you might say you're MRD negative, but there is myeloma there. You just didn't get it in your sample and that's a false negative. Sensitivity can be variable. So how much of the universe are we capturing? One in a hundred thousand myeloma parts, one in a million? What about one in a billion? We may get more sensitive techniques to truly say that someone is actually MRD negative. And if you are having MRD testing, you want to ask your team, are you assessing it in one in a hundred thousand or one in a million? Because one in a million is what's typically used to say that someone is truly MRD negative. Interestingly, you can have measurable disease, meaning you can have an M spike and still be MRD negative. And that's sort of a paradox, right? Because if you're telling me I'm MRD negative, I shouldn't have any detectable myeloma by any other means. But there are some theories of why that can potentially happen. For example, the M spike is M protein can linger in the blood, even though there's no residual disease in the bone marrow. But the reality is that most patients are tested for MRD when all their other markers are negative. So we may be missing patients who are actually MRD negative, even if they have an M protein in their blood. Overtreating patients to get them to MRD negativity can potentially lead to harm due to overtreating them to try to just pound the myeloma down and in the process cause undue harm to the patient. And as I showed you before, some patients may convert during their maintenance anyway to MRD negativity. And of course, all the testing we've been talking about doesn't account for disease outside the bone marrow, such as plasma satomas detected by imaging. So that argues to do multiple tests, not just the bone marrow biopsy, but also imaging to look for MRD negativity. So the bottom line is talk to your care team about what their opinion is, what your opinion is on it, whether you want to have it done as part of your testing. And I think it's an individual case by case basis. So how often should we assess MRD status? The answer is whenever a bone marrow biopsy is planned, if you are tracking MRD, you can send for MRD testing. The IMWG recommends serial sampling rather than relying on a single time point to make decisions. And PET imaging should be included as part of the MRD surveillance, again, because it may capture disease outside of the bone marrow. So there are various scenarios how MRD could be used to guide management in the future as more data are revealed in terms of how to use MRD testing. So if someone remains MRD positive, you continue on your consolidation and maintenance, whereas if they convert to MRD negative, maybe that's an opportunity to have a discussion on deescalating treatment. So just rounding out the talk now, how about the future of MRD? So there are other techniques that are being examined that can be used to assess for MRD other than the two we've discussed. And I think the reality is that we'll likely be using combination approaches to be able to truly assess whether someone has zero residual disease. So the future goals are one, to improve sensitivity, a better telescope, maybe looking for the deepest possible remissions, and also ease the procurement of samples. And that might entail getting what we call liquid biopsy, meaning getting samples from blood to assess for MRD. And one technique to do that, which I'll touch on, is called mass spectrometry. Another way could potentially be using circulating tumor DNA. Now myeloma tends not to circulate and tends to stay put in the bone marrow or in a plasma seytoma. But circulating tumor DNA is being used in other cancer types, such as colon cancer, to monitor patients for relapse. And then, of course, imaging. Not going to necessarily touch on this, but Dr. Ola Langren is going to be talking in April about immunopet to this group. So I'll leave that to him. So let's just touch on mass spectrometry. So when we do an SPAP, or immunofixation, to measure the end protein in blood, that's not the most sensitive techniques. I mean, these are techniques we've been using for decades. Basically, those use, they pull the blood through like Jell-O, basically, through a gel. And it says whether there are some proteins there that are abnormal. Mass spectrometry uses kind of like a magnet and a laser to break up all the proteins in the blood and then very finely detect each one by their size and charge. And so this can detect with much higher resolution whether there's any residual end protein in the blood, much lower than an SPAP can. Certain institutions are actually using this routinely, although it's not yet FDA approved to monitor disease in myeloma, but it is accepted as a valid technique by the International Myeloma Working Group. And there's a small study of 41 patients that looked at what the concordance is with conventional MRD testing. And in general, there is relatively good concordance in the study between conventional MRD testing and using mass spectrometry. And the last slide, just about PET imaging. You can see here that PET imaging is very sensitive, although kind of the dark spots in the bones for looking at either plasma cytomas or lytic bone lesions. And we can use that to track response to treatment. And that actually correlates with better outcomes if you convert from PET positive to PET negative. And there are some ongoing studies of using more sophisticated PET imaging. For example, using antibodies which have a radio tag on them. And those antibodies are specific for binding plasma cells. So that would be more specific for myeloma. So let's talk about some conclusions. So the National Comprehensive Cancer Network, or NCCN, are the guidelines that are generally referenced for how we manage myeloma patients from a general standpoint. And what they advise is they don't settle on one particular technique that they recommend for MRD testing, but they do recommend serial testing to truly confirm. And they say one year apart to truly confirm that someone is MRD negative. So to get back to our question, is MRD the end goal? Well, MRD testing is clearly a powerful tool to assess for depth of remission. And achieving MRD negativity does predict longer remission and survival. And clinical trials are increasingly using MRD as a measure of the effectiveness of the trial agents. So emerging data suggests that MRD can be used to potentially de-escalate treatment, particularly on maintenance therapy. But nevertheless, challenges do exist, and we need additional studies to answer some of the questions that we went through. So I do believe, though, in the future, we'll be using more than just one test to assess for MRD. But when it comes to the end goal, the goals are still the same. Extend remission, prolong survival, using tailored therapy to the individual patient to avoid complications, and overall improve quality of life. And overall improve quality of life. With that, I will thank my colleagues, my fellows and staff, and of course, our patients and their caregivers, who are just a pleasure to work with. And thank you for listening. I'll take any questions. Wonderful. Thank you, Dr. Brownstein. We're really grateful for your presentation. I love that you went through commonly asked questions, because that answered quite a few questions that we have here in the chat. As you know, this audience has amazing questions, highly well educated, and I'm excited to get to them. Several questions were asking about the bone marrow biopsy itself. Is it smart to alternate between hips or maybe even find a different location once in a while to test from? Great question. So the bone marrow can be patchy. And one way to potentially guide where to actually place the needle is based on the PET scan. So if I have a newly diagnosed patient and the PET scan shows that there's a lesion on one hip and not the other, I'll generally try to do the biopsy where the lesion was in that hip on that side. Originally, when we were first kind of proceeding to bone marrow biopsies earlier before the modern age of myeloma, it was recommended to do two bone marrow biopsies at the same time on different hips to get a more accurate capturing of whether a patient had myeloma in their bone marrow. That's not really the convention these days, and I think it would be more painful. So you could consider alternating sites when you do serial bone marrows, but I think using a PET scan to guide whether there's a lesion there would probably be more accurate. Awesome. Thank you. Excellent answer. A quick question about the... There's a lot of awesome questions. I'll just preface that. But one of the questions was considering the timing of that mass spectrometry and other liquid biopsy options. I know patients are really hungry for MRD testing that does not involve their bone marrow. Any insight on that? As are we as clinicians. I mean, what I always tell patients is we want to go from the least invasive testing to the more invasive testing. And so I don't necessarily do a bone marrow biopsy on someone who appears to have MGUS unless they have certain concerning features. And so whatever tests we can do short of doing an invasive test are preferable, and that involves the conventional testing on the blood, the M-spike, the light chains, and imaging studies. So mass spectrometry is not certainly ready for primetime. It's not used conventionally. There's no standardized test that's been FDA approved. Although some institutions are trying to use it more in routine practice before it's actually approved. And so the mass spectrometry would be done similar to your typical blood work when you take blood to get the M-spike or the light chains and anything else. That's certainly the convenience of it. And you can imagine how wonderful it would be to be able to use a more sensitive test than the SPAP and the light chains to look potentially even for MRD at a monthly basis rather than doing a bone marrow once or twice a year. I think we'll be using that much more at a much more frequent pace than our current MRD tests using a bone marrow biopsy. Yeah, I do too. I'm hopeful. We had Dr. Faith Davies come speak. She's amazing, huh? And she estimated within about five years and then somebody who actually works on mass spectrometry in Europe piped up and said, yeah, that's about when we can start thinking about it. So I wish we could say tomorrow, but it's probably going to be longer than that just because of approvals and things like that. That's important too because you don't want to have false results either. You want standardized tests accurate. Exactly. A couple more questions regarding testing. So Marjorie was wondering with those trials that you shared the data from, is it standardized which MRD tests they use? Do they use the flow cytometry or do they use the next generation sequencing? Yeah, great question, Marjorie. The only approved test is the next generation sequencing, the Clonoseq test, and there are kits available and it's sort of all packaged. But it comes with the inconvenience of having to compare it to a baseline sample, whereas the next generation flow, you don't need to compare it or sample. You can do it in real time anytime you get a bone marrow out, even if you don't have the original sample or didn't send the next generation sequencing on the original sample. But it's less standardized. So in modern clinical trials, most of them are using the next generation sequencing. In modern clinical trials, most of them are using the next generation sequencing and I think that's also because the FDA prefers that as a standardized test. Thank you. One more question about NGS. Why does it require a baseline sample? Great question. Yeah. Because that's a DNA-based test, it's actually individualized for each individual patient by comparing the DNA of their myeloma cells at baseline to the DNA at the follow-up sample. So it's sort of like a fish hook that's specific for only one type of fish. And so it's specific for your individual myeloma. So they need to use the original sample that was likely enriched with plasma cells of diagnosis to get the exact sense of what to look for when they do the follow-up sample. They need to compare that baseline to know what to look for down the line because it's DNA-based. Yeah. Thank you. A good question here about frequency of MRD testing. How often do you recommend that your patients who are in complete response have MRD testing? Yeah. This is a good question. And if you ask five myeloma doctors, you'll get 10 answers. You'll get five. You'll get 10 answers by the end of the day of the week. So the greatest challenge for me is the fact that I have to do a bone marrow biopsy and not all patients want to undergo that. If I have a patient who says, I'll undergo however many you want. I just want to know about my MRD status. Then I would say it's probably not relevant to do it more than every three months and probably not even more than every six months because not that much is going to change in a three to six month period. That's probably how often many of you are seeing your doctor on maintenance treatment anyway. So I would say no more than every six months in general. Thank you. There was some confusion. So Patty had a good question. Can you get to MRD negative if you have a Kappa light chain higher than 38? So Patty, thank you for your question. So I think the Kappa light chain, I think what you're saying is that can you get to MRD negativity if you have some measurable M protein or myeloma protein in the blood? And there are instances, as I had mentioned, that a patient is MRD negative by the testing we discussed, yet they have some residual immunoglobulin or M protein in their blood. And so most of the time that we test for MRD or when they test in a clinical trial is when someone is in a complete remission, meaning they don't have the Kappa light chain in the blood or they don't have the M spike in their blood. But it is possible to be MRD negative and still have some residual myeloma proteins in the blood. So that's a reason to potentially even test for MRD if you're having a bone marrow done, even if you do have some Kappa light chains circulating in the blood. Interesting. That's fascinating. A question here relating to that, how often you get false negatives in MRD testing? Yeah, that's a great question. And a false negative would be if the test said that you're MRD negative, but you're not. And I would say that that probably happens up to 10% of the time. And so that is the reason to do serial testing, because if you just capture one time point, it's going to be less accurate than if you do multiple testing to really confirm that you're MRD negative. Yeah. Annabelle asks a great question that I think is shared by many others. When do you stop worrying? I mean, when do you stop trying to achieve the MRD negativity if after consolidation, for example, you don't get it? When is your time point where you're like, we're just not going to worry about this anymore? That's a really, really good question, because sometimes watching weight is watching worry. And anxiety can impact quality of life just as much as a painful bone lesion. And so addressing the anxiety of surveillance for myeloma is very important. And so for me, it's more about what the trend is in monitoring patients, whether there's any signs of a relapse by conventional testing and changing their blood counts, things like that. And I think you sort of as a clinician, you never stop seeing the patient because there is always a risk of relapse. And we can try to stratify patients by high risk or standard risk features to determine who's more at risk for progression. But I think that we go by the data. And if someone is in standard risk and they're post-transplant and they're in a complete remission or stringent complete remission or even MRD negative, the likelihood of them relapsing within the next few years is extremely low. So we can take a sigh of relief there. But we always want to continue to monitor for any signs of relapse as early as possible. Yeah. Similar question. Gretchen has very low MRD positivity. So should they be concerned if their disease is stable but a low MRD positivity? And maybe we talk about that difference. MRD positive is a hard term because you could have high evidence of disease and positive and very low. Yeah. That's a really sophisticated question. So when you look at the result of the ClonaSeq assay, it actually gives you a trend line to see by what percentage you're MRD negative and what depth of MRD negativity. So are you one in 10,000? Are you one in 100,000? Or one in a million, which is the most sensitive depth of remission we can detect. And so if you are less than one in a million, that's what we would call truly MRD negative. If you're one in 100,000 sort of MRD negative but more than one in a million MRD negative, then there's no data to say, well, we have to get to one in a million from one in 100,000 to one in a million to get to absolute depth of MRD negativity. So there's really no good data to guide what to do in that situation. But what I would say is that if you are in a stringent complete remission or a complete remission by conventional testing and you've gotten close to that one in 100,000 or less, that's good enough for me to say you're practically MRD negative. And again, the trend is important because let's say you were one in 100,000 and then it became one in 10,000 down the road, maybe you're converting from negative to positive at that point and that can predict a possible relapse down the road. So the trends are more important than the absolute value. Completely agree. Thank you. Okay, let's kind of talk about high risk. You touched on this briefly in your talk, but does MRD negative mean the same thing for high risk myeloma patients that it does for standard risk? Does it have the same implications and outcomes? Sure, good question. So what we saw from the master study was that patients with higher risk disease did practically just as well as those with no standard risk disease when they stopped treatment based on MRD negativity. I think for high risk patients, MRD is a powerful tool to monitor them and potentially aim to achieve because they have a higher risk for earlier progression and in general, MRD negativity predicts a longer time to progression. But it's not clear yet whether MRD negativity completely obviates the high risk features of having high risk disease and the earlier progression. So we still need more studies to address whether we should really be aiming for MRD negativity and actually escalating treatment in the high risk patients who are MRD positive. Right, because that's one of the questions here. Do you keep them on multiple maintenance drug regimen just because they were known as high risk or do you just slowly bring it away? It's a difficult question. Yeah, in a way, it's almost easier to address the question if someone converts MRD positive to negative than if they stay MRD positive. A lot of the maintenance studies have shown that in general, if you use two drugs versus one drug as maintenance, you can achieve higher rates of MRD negativity. But again, the goal is still to avoid adverse events due to maintenance treatment. And so it's unclear what the best maintenance regimen is. And again, Revlimid is still the convention. But with some of the newer regimens, we're using two or three drug combinations like daratumumab, lenalidomidaz maintenance. And those studies have yet to be read out in terms of whether you can convert someone from MRD positive to negative. Yeah. A good question here. Does amyloidosis change any of what we've talked about tonight? That's a really interesting question. As far as the practice status is in 2023, where MRD might be relevant is using mass spectrometry to assess for amyloid proteins, even in the blood. Because mass spectrometry is a very powerful tool to subtype amyloid. And we use it conventionally now on bone marrow samples to look for amyloid. But the markers that are used in the setting of amyloid are conventional blood tests like a troponins or a test called the pro-BNP. And those are done routinely in a regular lab that runs the same things as your blood counts. So right now, MRD is not really used often in clinical trials for amyloidosis, unless somebody has concurrent multiple myeloma. Thank you. Great answer. Awesome questions tonight. We'll answer a couple more, and then we'll finish up for tonight. This is a great question. Can you speak about patients who are MRD positive but still have achieved very long remissions? Are there some patients whose immune systems are just that adapt or used to myeloma? Great question. And this is one of the controversies about how we use MRD because the actual course of the disease reveals the biology of it. Even if someone is MRD positive, right, they could still be in a stringent complete remission by our typical response measures. And that doesn't necessarily mean that they're going to have bad outcomes. It just means that someone who's in a complete remission and MRD positive is expected to have slightly shorter remission than someone who's MRD positive, but doesn't mean that they're going to have a poor period of remission or short remission overall. And that's where there are some controversies about someone who's in complete remission and MRD positive should we try to actually convert them into negative. When again, they may naturally convert to MRD negativity during their maintenance phase, as I showed in the talk. So questions still remain. Thank you. Trying to type some answers to people who have duplicate questions or things like that. So make sure to keep an eye on those answered questions to see if I've responded. Let's see, there was one that I wanted to ask here. It's related. Does the depth of MRD negativity determine the length of time to progression? In general, yes. So the deeper the remission in general for myeloma, the longer the remission. Now, whether there's a nuanced difference between being MRD negative at a rate of one in a hundred thousand versus one in a million is probably not that substantial. But for someone who's MRD positive versus MRD negative, those who are MRD negative are expected to have a longer time in remission. Thank you. And then from your knowledge, do insurances and Medicare pay for MRD testing? Yes, for the next generation sequencing tests because it's FDA approved and it's in the guidelines. So in general, yes. Thank you. Have you ever seen clonocic tests done with people who've had hip replacements? Yes, because the hip replacement generally doesn't impact how we do the bone marrow biopsy. Awesome. Thank you. Well, with that being said, Dr. Brownstein, I'll give you a minute to give any closing statements that you'd like, or if you want to quickly look through the Q&A and see if there's any leftover that you'd like to answer. Well, just thank you again, Audrey, and then the health community again for the opportunity to talk to you. Again, these are really amazing questions and I wish I had the answers to all of them, but we still await the studies to reveal the answers. And yeah, I'm happy to come back and talk about other topics because things are improving and evolving so quickly in the field and it's a great time to be practicing in this field and to get to talk to folks like in this community. I totally agree. Thank you so much for being here tonight. To our audience, I do apologize we didn't get to all of the questions, but thank you for your awesome questions that provided for an excellent discussion. Dr. Brownstein, have a good night and thank you again for joining us. To our audience, as Dr. Brownstein mentioned, in two months since this chapter meets every other month, we have the privilege of hearing from Dr. Ola Landgren, who's coming to talk about immunopet technology. Now, if you don't know Dr. Landgren, he is one of the top myeloma specialists in the world. So having him come to speak to us is a huge, huge privilege. It's going to be April 26th at 1 p.m. Eastern. It's an open clinical trial, so he's going to tell us about how this immunopet can be a companion to MRD testing that we've talked about today to get a more accurate picture of what myeloma is residing in your body. And he's also going to promote his clinical trial that's open so that if you want to join it and help accelerate myeloma research, you can. So please mark your calendars. Make sure to join us April 26th at 1 p.m. Eastern. You might be interested in other community events that we have upcoming. Tuesday the 28th is our Florida regional chapter. We're going to be having a group discussion on discussing myeloma with your family and keeping the conversation up with your family about myeloma. The second is our health tree moves for myeloma chapter. We're going to be hearing from Dr. Keith Guernsey. Keith was scheduled earlier in this year to speak to us and was unable to. He's since recovered and is excited to speak to us again. That night is our southeast chapter, so if you're located anywhere from Delaware all the way to Georgia, you're welcome to join us as we also talk about how to talk to your friends and family about your diagnosis. So those are regional, which is why you see them repeating, but they'll be talking about those topics. Another thank you to our sponsors, Bristol Myers Squibb, GSK, Genentech, Abbey, and Amgen. And thank you to each of you for helping us build this myeloma community. I'm so grateful for you. Hope you have a great rest of your night. Thank you everyone. Take care. Bye-bye.