(Guest Lecture): September 2022 - What to Do with Your MRD Results: Starting or Changing Treatment

Today's topic is going to be what to do with your MRD results, starting or changing treatment, and minimal residual disease testing for myeloma is gaining traction and popularity, but the verdict on what to do with these results is still uncertain and varies depending on who you're talking to. There's so many specialists out there who have really good opinions, but they differ from one another, and that makes it difficult to truly understand minimal residual disease testing. There's different types of testing, and then what do you do with those results? So Dr. Costa has done different clinical trials to test this theory, and he's going to be talking about some of the results and also just about this question in general and how you can tackle it. Dr. Costa, I'm going to introduce you just briefly and then turn the time over to you. He serves as the Associate Director for Clinical Research at the O'Neill Comprehensive Center at UAB, and his primary research focus is the development of new therapies for plasma cell malignancies. Dr. Costa leads several multi-institutional and international projects exploring new cellular and immunotherapies and minimal residual disease in myeloma. He's regarded as an international leader in the field with more than 200 peer-reviewed abstracts and publications in high-impact journals such as Blood, Leukemia, the Journal of Clinical Oncology, and the New England Journal of Medicine. He is well respected by his colleagues and loved by his patients. Whenever he is referenced in other events, there is always a string of We Love Dr. Costa comments, which I'm sure we'll get today. I look forward to hearing from him today on this important subject, and with that being said, the time is now yours. Thank you, Dr. Costa. Thank you very much for the kind introduction. Um, I want to make sure that everybody can see me and more importantly can see the screen that I'm projecting. Is that visible? No, try one more time because I had my screen up, so. Okay, so let me see here. What about now? Perfect. Great, great. Well, thank you. Thank you again for a kind introduction. It's always a pleasure to speak to this audience. We always get more interesting and quite honestly more relevant questions when it comes from patients and families than sometimes when it comes from our own peers. And I'm going to spend the first 20 minutes talking a little bit about MRD in general. I try to convey some of the concepts and some of the current status of the knowledge and the research questions in this area to a way that everybody can relate to. So let's talk about, you know, minimal or measurable residual disease. I think we need to think of this as being nothing else but a quantification of how much cancer there is beyond what can be provided with protein-based tests like seroprotein metapheresis, even a fixation and so forth. Okay, so why is this a new thing? Why we're talking about this now not 10 or 15 years ago? Part of that is because the technology has evolved and those tests are now can be performed quite routinely. But more important is because in the past we didn't need that MRD. You know, when the responses were uncommon and incomplete, when just about everybody had plenty of myeloma left behind beyond therapy that you could measure with the protein metapheresis and complete responses were uncommon, you really didn't need a microscope to look at an elephant so to speak. Now in 2022, sorry I need to update that slide, I would say this is important because most patients with newly diagnosed myeloma receiving state-of-the-art therapy will achieve complete response. So that means their myeloma would not be detectable by seroprotein metapheresis, by seroprotein metapheresis, immunofixation or free light chain. Or if you do a bone marrow test, you're not going to find an increase in plasma cell numbers. So you either, you know, stay on the dark knowing that disease is low but you don't know how much or you need a better tool to measure disease and that too is provided by some of the assays that I'm going to discuss with you. However, we still have a lot of open questions, you know, what's the best method, how feasible it is to do in a large scale, can it predict clinically meaningful outcomes and most important, can it be deployed as an endpoint in clinical trials for at least for regulatory purpose. So essentially we have two methods for the most part to measure MRD in the bone marrow. One of those methods is flow cytometry. You know, flow cytometry is not new, has been around for several decades and just about every time somebody does a bone marrow test in a patient who is suspected of having multiple myeloma or who is known to have multiple myeloma, flow cytometry test is performed. However, flow cytometry is not, not ever flow cytometry test is an MRD flow cytometry. Let me explain that to you. So this test is actually quite intriguing. You take cells for the bone marrow, you wash those cells, you resuspend the cells and then we use tiny antibodies that are marked with a different color. For example, if you want to detect CID38, you have, you put a fluorochrome, an antibody that is bound to, so to a substance that emits green light, for example, that is, and that is, that is targeted CID38. If you want to know if the cell expressed kappa light chain, you get, for example, an antibody anti-kappa that is marked with a red fluorochrome, you know, and so forth and so on. So you can actually have up to eight markers against eight different things in each of those cells. And then a very complicated piece of equipment called a flow cytometer make those cells pass one by one through a nozzle and face a laser and the laser diffuses light in different frequencies. So that machine captures the size and complexity of that cell and what color is that cell marked with. And if you know what color means, what protein in the surface of the cell, you have a near complete characterization of the proteins on the surface of that cell. So that's flow cytometry. Okay. And that allows you to identify clonal plasma cell versus normal plasma cell and allows you to quantify those plasma cells. Another methodology that's called next generation sequencing is a bit distinct. And to explain that to you, I'll just tell that every plasma cell, normal or otherwise, undergo a process early on that's called rearrangement of the heavy and light chain gene. So those are genes that code for the antibody protein that the cell eventually produces. And each cell, each plasma cell or B cell undergoes a rearrangement. So only one type of sequence is produced. Now, when you do a bone marrow test in somebody with newly diagnosed myeloma, you have like 50% plasma cells or 20% or 80%. Right? So you have those abnormal plasma cells that are a clone. So they are identical to one another. So whatever genetic rearrangement the first cell had, all the other cells will share. And I simplify here as being a yellow dot. Okay. But on the background, you have other plasma cells that are by standards. I mean, they're just there because they belong there. They're not malignant. And of those cells, you're going to have one or two of each, but not thousands, millions, not 50% of the bone marrow. So if you now take that bone marrow sample and sequence the heavy and light chain of every single cell in that bone marrow, you're going to see that there is one sequence that repeats over and over and over and over again, because that's present in those 20, 50 or 80% cells that are from the myeloma cells. And then you say, ha ha, since this one is appearing over and over and over and over, that must be from that clone that I'm tracking. So you write down that sequence. Okay. That's a clonogenic sequence. Then the patient goes on to treatment. And then, you know, months down the road, if the patient achieved a remission, and you now want to quantify minimal amount of that cancer left behind. So how do you do that? Same thing. You repeat the bone marrow and you do a sequencing of every cell in that bone marrow. Now that sequence that is from the cancer is not going to be predominant anymore, hopefully, because you had a good result for therapy. But you can, doing very powerful computer analysis, you know, bioinformatic analysis, you can search this other sequence that's you can search this other sequence that's still out of that process. And for that one that is unique to that person's myeloma, and by identifying that and, and seeing how often that sequence pops up, you can quantify how many cells are left behind. So that allows you to calculate the burden of myeloma at a very, very low levels. So essentially, we have three technologies that, you know, first generation flow that just about every laboratory has the next generation flow that is a very specialized protocol that is only available in a few laboratory, and next generation sequencing thing. They have advantages and disadvantages. For example, the next generation sequencing requires you to have a sample at the time of diagnose that can be used to calibrate the machine. The flow does not. Conversely, you need money more cells to have a highly sensitive readout on flow. For example, here in this case is, you know, 20 million cells versus versus only three million cells on the next generation sequence, which amounts to a smaller sample that is obtained from the patient. In terms of sensitivity, Clonocic, which is the commercially available in FDA endorsed platform for MRD, has a higher sensitivity that can detect really less than one cell in a million, as opposed to flow that the limit of detection is about two cells per one million. Okay, now that we understood a little bit about methodologies for MRD, why does that matter? So instead of trying to focus on MRD, let's think about response in general. Why is it important to know that I had, you know, patient had a complete response versus a very good partial response versus a partial response? Well, intuitively, you would answer, and I would agree that, well, you know, the deeper the response, the better. If I have, you know, a complete response, I'm probably better off than had a very good partial response, right? But when you look at even a modern trials like this Spanish trial with, you know, hundreds of patients with long-term follow-up, you see this very interesting pattern. If you look at progression free survival or overall survival, you see that partial response, complete response, very good partial response, they kind of go together. The group that really does better is the group that had a complete response, but MRD less than 10 to minus five or less than one cell in a hundred cells. Okay. So if you're not looking at the MRD, those patients are going to look like they had a complete response, which they did. And we'll make the complete response overall look better. So in other words, what gives complete response a good name is that embedded on those among those patients are patients who have achieved MRD negativity. Once you take them out, you separate them out. The ones who are left with complete response and are MRD positive, they do just as well as patients with partial response or very good partial response. Okay. So I like to challenge ourselves to say, if I'm going to go through the length of trouble of doing a bone marrow to see if my patient is in complete response, should be no reason why not to do MRD, right? Because there's no point of doing a bone marrow to see if the patient is here or here. If I can do a test that tells me if the patient is here or here. Does that make sense? So I think that's the easiest thing to agree on on MRD is a very powerful prognosticator. And despite all the caveats that we have with different methodology, different levels of threshold, different reports, when you put it all together with something we call math analysis, what Dr. Mushi did in this publication a couple years ago, you see that MRD negativity predicts progression for survival and overall survival. And that, of course, the deepest the levels, so the lower the threshold for positive and negative that you define, the more precise that too is in separating patients are going to do well versus patients who are not going to do too well. And that applies even for high risk patients, applies for both high risk and standard risk patients. So let me show you some examples. For example, this is a Spanish trial where patients receive bortezomibase therapy, autologous transplant, and some maintenance therapy. And you can see here that patients who had high risk disease, but who became MRD negative have an excellent prognosis compared to those who are MRD negative who are standard risk. But among the patients who stay MRD positives, the ones with high risk disease do far worse than the one with standard risk. So, you know, as a patient, I would rather be high risk and achieve MRD negativity than to be standard risk and remain MRD positive. So that is, you know, very important. So if for those who say, well, why bother doing MRD is only prognostic, I would answer to that. Why bother doing fluorescence in cytohybridization in the bone marrow to look at your chromosomes is only prognostic. There is no study that prospectively demonstrates the value of adapting therapy to the risk determined by fish, the same way that there isn't for MRD, right? So if you are looking at one, you probably should look at the other. Now, let's look at this other study that I think many of you have heard about before, is the IFM 2009. That's the study where everybody got DRD, which is a regimen that very popular nowadays with Bortez-Velcade, Revlimid, and dexamethasone. And patients receive an early transplant in one arm or transplant was safe for recurrence in the other arm. And long story short, the arm that did transplant did better. But here again, you look, those are patients who achieve MRD negativity. The ones who got transplant did a little bit better than those who did, even though they are all MRD negative. But look again, those patients still do far better than the patients who remain MRD positive. And after seven years of follow-up, the patients stop therapy after one year by trial design. They were not on maintenance here. The majority of those patients are still alive and progression free seven years later. So the problem we have here is myeloma trials have always been designed like I catch all the patients, I randomize them to treatment A or treatment B, and I describe the median outcome. And you learn some variable lessons on doing so. The problem is that does not, that covers the average patient, but doesn't allow you to look at the nuances. And if we're going to think about, well, not all my myeloma patients need to get the same treatment, we got to personalize the treatment, we got to adapt the treatment to one's needs. I can think of a better tool to do so than MRD, because you can now recognize those patients here and say, hey, maybe they are good candidates to not receive any further therapy. But you can look at those patients here and say, hey, they're not going to do well. They're good candidates to try something new or to stay on longer therapy. The same way that many of us feel comfortable doing, for example, for the presence of high-risk chromosome abnormalities. And I will show you a more modern example. This is the Casio-Pia trial. So this is a trial done mostly outside the United States that is the first trial to test the value of the monoclonal antibody daratumumab in patients with newly diagnosed myeloma who were to receive an autologous transplant. And the bottom line of this trial is half the patients got Velcade, Thalidomide, and dexamethasone with transplant and have got the same treatment plus daratumumab. And after that therapy, there was a second randomization and half the patients received daratumumab maintenance. The other half received no maintenance. And we found the daratumumab did not make a difference for those who received daratumumab early on. But the bottom line is, you can see here, those patients who achieve MRD negativity and maintain that for one year, even though they haven't received any further treatment, over 90% of those who received daratumumab and are MRD negative do not have a progression even after three years of follow-up. We tried to, we did that in, I think, I believe was the first study that took this prognostic information and used that to tailor therapy. We did that on the master trial. So it's another quadruplet. We used daratumumab with chyprolis, Revlimid, and dexamethasone. So proteasome inhibitors, I'm going to go into body, and Revlimid for four cycles, transplant, and then up to 80 up to eight more cycles. But we test MRD at each one of those cassettes of therapy, each one of those blocks of therapies. And patients who had two negative MRDs, they stopped therapy and went to a phase we call MRD sure, which is treatment-free observation with MRD surveillance. If they did not reach such milestone, they went on on Revlimid maintenance. And what we have learned is, patients with no high-risk chromosome abnormality or with one high-risk abnormality or two or more that we call ultra-high-risk disease, they all had a very good chance of achieving MRD negativity throughout, about 80%. However, when you look at their, how they do long-term, you know, the patients with no high-risk abnormality or with one high-risk abnormality, they do very well. But the patients with two or more high-risk or some abnormality, they have a lot of early progressions, even though they're receiving quadruple therapy or progression shortly after disease therapy. So we used to think of myeloma as being standard risk and high risk. And I would challenge you to think of this now as being more like, you know, ultra-high risk versus the others, because those two groups are going very close together with excellent results. So where do we go from here? So we need to do trials where we identify early, not after they progress, patients who are not going to do well based on MRD achievement or lack, negativity achievement or lack thereof. And one of those trials is done, is being done in France. It's called the MEDES study. They use six cycles of quadruple therapy. Patients who are MRD negative, they're randomized to transplant versus more of that quadruple therapy for six cycles. So trying to see if we can omit transplant in those early achievers of MRD negativity. But for the patients who remain MRD positive, they're asking the question whether two transplants would be superior than one. What we're planning on doing, hopefully very soon, is what we'll call the Master II trial, which builds on what we learned with Master I, but uses a longer induction for six cycles. And similar to what the French are doing, we also asking whether we can omit transplant on those patients without compromising their likelihood of achieving and sustaining MRD negativity. But for the patients who remain MRD positive, despite six cycles of more intense therapy, we're asking whether a transplant followed by DARA and Revlimid is sufficient, or they can be, those results can be further improved by introducing a novel type of therapy, which is a T-cell engager, or often called BITE, called Teclistamab, for a limited duration of therapy. And regardless of what arm patients who have sustained MRD negativity for one year, they go on to treatment cessation and observation. Now, I'm going to go very quickly here. One problem that is not current, but I think is upcoming, is if you assume that many patients will achieve MRD negativity, and they can be followed longitudinally, it is inevitable that some of those patients are going to have a resurgence of MRD. The MRD reappears, the cancer starts reappearing at the molecular level without the patient having any M-spike or any myeloma symptoms. And currently, we don't know what to do with that. We learn to treat myeloma once it becomes symptomatic or has a biochemical progression. But now we're looking at things at a much deeper level. So there are trials trying to address that very question. The limited data that is available suggests that patients who have loss of MRD negativity, they have a much higher risk of progression, even that those patients who remain positive all throughout. So essentially, if you go from negative to positive, if you have an increase in the burden of myeloma, even at the microscopic level, that tells you have disease that is growing despite ongoing therapy. And those patients seem to be destined to relapse. So in the future, I think we're going to be learning to identify those patients and intervene early versus later. So if I were to give you some message, well, let me skip in terms of time, let me skip to this. So it all comes down to this. So now in 2022, should we, and in what circumstance should we adapt therapy based on MRD? And there is no clear guidance, because there's limited perspective data. But that'll give you my perspective. One place where it's very tempting to use is post-transplant, post-induction, to decide whether or not patients should undergo transplant. And I would warn us to be careful about this. I think this is an area where it needs to be studied prospectively. Because with therapies, particularly with VRD, that's still the most popular regimen in the United States, few patients, less than 20%, we would achieve MRD negative before transplant. And as you saw, the impact of the foreign transplant of those patients is currently being studied. Now, what about post-transplant? Most patients who become MRD negative, they do so after transplant. Transplant is very powerful in driving down disease burden and converting patients to MRD negativity. And I think at that point, we should consider more therapy, consolidation or intensification, if possible by introducing a new agent or a new class of agents for patients who remain MRD positive, particularly if they have high-risk disease. Because we saw, we already know, those patients don't do well, high-risk disease with MRD positivity. Another scenario that comes very often is patients who have been on maintenance therapy for years, and they were tempted to just continue maintenance therapy. And the point I always make is, no, we do not have data to answer us exactly what the impact is of continue or stopping maintenance of somebody who say is MRD negative, you know, four years down the road on Revlimid. What we do have, however, is data from the IFM 2009 that tell you the risk of progression on patients who are MRD negative and stop therapy, because that's what happened in this study, by design patients stop therapy here, right? So if you are now a patient trying to balance the risk of the risk of benefit of continuing Revlimid or stopping Revlimid, you are based on your gut feeling or how the side effects or the cost of the Revlimid have, but wouldn't be nice to have that information. Say, what is my risk? Should I stop therapy? And the MRD gives you that risk, gives you that information, because now you can tell, okay, here's my risk. Should I stop therapy? Should I be MRD negative? And this is my risk. Should I be MRD positive? So it gives you a very different type of information that you might want to factor in before you make a decision with your doctor whether or not to stop Revlimid. And the last is for patients who are in observation of therapy and we're considering resuming therapy because MRD turned positive. And that is completely unknown, in part because the therapies up to recently have been, you stay on treatment until progression, so we don't have a large cohort of patients who are observation with monitoring of MRD to learn the natural history of that MRD resurgence. And with that, I'd like to conclude. I hope I didn't make things more complicated. They already are. And I'll be delighted to spend the rest of the hour with you trying to address some of the questions you might have. Thank you so much. That was such an excellent presentation. I feel like you gave very simple explanations to complicated topics and made it very patient-friendly language. So I do appreciate your explanations of those things. Some of the questions that I had and that others shared, you've already answered, especially concerning, for example, what you just talked about when an MRD negative person begins to, when should we begin treating them after they turn MRD positive? And in fact, this is one of the things that Health Tree Foundation founder Jenny Alstrom struggled with was when those numbers started to turn and the question was, when do I begin treatment when it's showing on my labs but it's not expressing in other ways? It just shows the complications of it and the need for more data. So thank you for hitting that point. One of the questions that I had, we talked about maintenance therapy, perhaps using MRD results as a determining factor in deciding whether or not to continue. Do you have a, not necessarily like a clinical trial result, but you as a physician, how long do you usually wait for your patients to sustain MRD negativity before you consider removing the maintenance therapy? That's a great question and it's not, it's never one factor, right? So I don't necessarily need to see a number of consecutive values to give that guidance. How that, most of what we, you know, we all, and I agree, we all appreciate the value of sustained MRD negativity, no doubt about it. However, we also have to acknowledge that a lot of what we know about MRD is based on a single point, right? For example, the data I showed for Navium-109 is a single point, right? So if you have a patient who is like four years into maintenance and like, I don't know, I have diarrhea, I feel so tired, the week I'm off, I feel better, but then I have to go back on and I don't have much energy. And, you know, I have diarrhea that I have to take some Imodium every time I want to go out of the house, but I'm afraid if I stop, my cancer might come back faster. So, you know, in those circumstances, a single point in MRD is very health, right? The issue of sustainability is, you know, of course, at some point you have to have a compromise because, you know, one year of sustained MRD negativity is better than a single point in MRD negativity. Of course, two years is going to be better than one and three years is going to be better than two. At some point, it becomes a self-fulfilling prophecy, okay? And if tomorrow I came back to you with data saying, hey, look, I've proven to you by this clinical trial that if you are MRD negative for 10 years, then you are low risk and then you can stop treatment. I guess I will thank you. After 10 years, I know I'm low risk, right? So, you know, the more demanding you become, the higher the bar we put for that MRD to be able to act on it, the less able we're going to be to identify early because the secret is to identify early. You know, after, you know, you know, I'm trying to use a good sport analogy here. I can think of a soccer, right? You know, like 90 minutes and one team is, you know, 10 to one. I know you, I can tell you who's going to win, right? The key is to be able to predict early so we can intervene early. Intervene for some, maybe try something new to control that ugly clone that is resistant to the existing therapy. But for many others is to, you know, stop that therapy at some point so you're not exposed unnecessarily for years of drugs that can make you feel unwell, cost a lot of money, give side effect and increase the risk of other cancers. Yeah, yeah. Multi-factorial then. That makes sense. One question here is 10 to the negative five in next generation sequencing, the same as 10 to the negative five in the flow cytometry? Yes. As far as you can tell, yes. Most of the data that we have is, most of the trials, most of the studies published is either one or the other. When you look at that meta-analysis from Dr. Munch, you see if you're giving a certain threshold 10 to minus five, if you look at that by flow and if you look at that by NGS, the discriminatory power is very similar. And there are a few studies where both are done simultaneously showing a great level of concordance. So for our practical purpose, you can assume them to be the same. Now, keep in mind, not every lab that calls MRD is really doing an MRD assay because there's not regulated, right? I can do my flow and call MRD without going through the hurdles of demonstrating that level of sensitivity. So for you as a patient, if you're presenting with a flow cytometry result, say here's your MRD, it's negative, try to look a little bit further. Is that a next generation flow? And there's a set of validation, there's only a few specialized labs that can do next generation flow. Okay. Thank you. I see several questions on here that are talking about what does being MRD positive mean? And I think this is a pertinent question because A, there's different MRD testing out there. So sometimes when somebody is MRD negative, when they're testing one in 10,000 cells, they become MRD positive when they test one in a million. Do you know with those trials that you shared what tests were used and to what sensitivity? Yeah. So mostly what I, you know, there is some attempt to homogenize that or harmonize that. I had the privilege of leading an effort in 2020 to come up with an international consensus on how we should perform and report MRD in myeloma trials. So this document is out, it's published. And I think people are pretty good at following that. Even before that, the International Myeloma Working Group came up with the recommendation that for the time being, we agree around 10 to minus five. So when people say MRD negativity and don't qualify any further, for all the contemporary or recent trials, we talk about 10 to minus five. Okay. And then when it comes to being MRD positive, I mean, it seems to me that three in one million is going to be less of a risk than those who have 300 in one. Exactly right. Yeah. So that's one problem with MRD, right? We got used to saying positive and negative, but there are positives and positives. And as you pointed out, they mean different. The other thing is MRD means different things in different contexts, right? Most of what we know about MRD is in the context of patients with newly diagnosed disease treated more intensively. Now there's data that also on the MRD is prognostic in patients with non-transplant eligible newly diagnosed myeloma, usually older patients, is prognostic also in the relapse, for example, but it's certainly very context dependent. Yeah. Because if you have somebody that has been through multiple lines of therapy and tests MRD negative, that doesn't necessarily mean long sustainability. That's correct. I mean, most of what we know is for newly diagnosed and being negative, all it means is whatever cancer there is, it's so little now that is below the threshold, right? What it doesn't tell you is the behavior of that cancer, right? So usually when you get to, that has come up quite a bit in CAR T therapy where patients can be MRD negative two months after treatment, but then they have progression eight months, six months later. And that doesn't mean the MRD was wrong. It doesn't mean MRD is meaningless. It means there's disease there that went down big time, but then also came up big time because that the myeloma over multiple lines of therapy have become more aggressive and fast growing. Dang it. It's such an unfortunately smart disease. It's frustrating. It can be. Yeah. But thank you for all you're doing to help. One question here is based on trends. A lot of people are wondering when to worry when they get their MRD test results back. Is a jump from three to 10 something to worry about? Is it jumped from three to 300 something to worry about? When do you start to say it looks like something's changing? Yeah, that's a great question. That's a great question. And we don't, honestly, we don't know that, you know, perspectively. We know, however, you know, when you get your result, if we talk about clonosec, which is usually those numbers are assigned, you see there's a number, there's a confidence interval, right? You say, wow, your number is 20. But look, that could be 11 to 35. Okay. So that tells you, you know, you're going to have if that means you have, if you keep doing an MRD on you every day, 95% of the time is going to be within that range. So the truth is somewhere between 11 and 35. Right. So that is important, because we should not be too upset if we have some changes up or down. Okay. Of course, the bigger the change, more meaningful it's likely to be. And we don't have much data. I consider one log change to be an eye opener. Now, if you go from three to 30, or if you go from, you know, you know, 15 to 150, 10 time increase, that's usually means something that is that things are going in the wrong direction. Now, there are a bunch of caveats that can affect this as well. You know, it's important that, you know, when we do a bone marrow based MRD, you know, when we aspirate a bone marrow, the first few mls are pure bone marrow. If you keep aspirating, you get what's called hemo contamination, you got more blood mixed with it. So you're going to have more blood cells and fewer bone marrow cells. So if I do, you know, now and I send the first sample, the first two cc's to analysis, or if I send or if I draw a test for everything else and then send the last two cc's, they're going to come up with very different results. So it's important that the first pool of the bone marrow, the first pool is the one sent for for MRD. By the time you, I consider this a little bit, maybe a little bit controversial, but by the time you know you have myeloma, you know what type of myeloma you had, you receive treatment, and I'm doing a marrow for the sole purpose of assessing disease response, the most important information you can get is MRD, and that for should be the first pool. Everything else is secondary. Interesting. Okay. Let's talk about when you get a patient that has jumped from 50 or to, you know, 25 to 125. What are your personal next steps? Do you order PET scans? You order CT scans to see if there's any involvement going on outside the body? What is your next step with that patient? Very good question, right? So it depends on the patient. I mean, some myelomas cause bone disease, some don't. If that patient's a patient who never had bone disease and it's unlikely that's going to be the case. Yeah, but you're right. I mean, if I see this, I'll look for any other thing that corroborates the suspected disease is increasing in burden, right? And of course, if now you have a new bone lesion, then bingo, you don't have to wait for anything else. But in absence of anything else, I would at the very minimal repeat that MRD, not in a year, but maybe in a few months, six months. And also depends on what the patient is on, right? If it's a patient that I have been observing without any therapy, then it becomes easier to put the patient back on some treatment because I say, Hey, the standard here for if I didn't have the MRD, I'll be giving everybody Reblimid maintenance, right? And if I have omitted Reblimid because of confirmed MRD negativity, now that it turned positive, the minimum I can do is reinstate the Reblimid. So to me, that's an easier call. What is much harder than the patient is already on Reblimid, or is already on some therapy and you see a climbing rate. And I don't have any data, nobody has any data to take to the bank. But if I see a patient who has two consecutive assessments that are going up, and you have gone up by more than a log, I'll definitely change therapy. Because to me, it's a clear as it gets that you have disease underneath that is growing despite the ongoing therapy. It's just a matter of time before it becomes a biochemical progression or even a clinical progression. Yeah. All right. Thank you. We talked about some patients have bone involvement, other patients have renal insufficiencies and involvement. How does all of this discussion affect MRD negative patients with renal insufficiency? Do the same rules apply? Yeah. So that's interesting. Most of the times when we talk about multiple myeloma with renal insufficiency or myeloma causing renal insufficiency, it's caused the mechanism of how the myeloma causes insufficiencies through a process called Cas-Nephropathy. Essentially, you have a large amount of free light chains present that gets filtrated through the kidney and precipitated in the tubuli. Using very simple terms, it floods the kidney. So in other words, if it's unlikely that you're going to have recurrence of that problem or worsening of that problem, unless your free light chains go up again. So now you're talking about going from MRD negative to MRD positive. Well, that's not sufficient to plug the kidney because if you're seeing now light chain elevation, then it's no longer an MRD question anymore. It's already progression. So I think those patients whose myeloma is capable of causing kidney problems, they always give us more concern. We always follow those patients closely, but I wouldn't interpret MRD in any different way than I would interpret a patient whose myeloma does not cause kidney disease. Nobody's going to go from MRD positive to kidney failure without having elevation of light chains. Thank you. In kind of addition to that, one of the patients was wondering where relapse was most likely to show up first, let's say MRD negative show, you know, turns positive. Would they find it in physical symptoms, light chain ratio? I'm guessing it depends on the patient because our friend myeloma is very unique depending on- Unfortunately, I'm sorry that my answer seems to be it depends, but in this case, it depends. In general, I say myeloma likes to repeat itself. So if the first manifestation was bone disease, likely you're going to produce light disease again. If at first the myeloma produce an M spike, likely you're going to have an M spike again. If you have, you know, just was a light chain myeloma, you saw the elevation free light chain, that's what we're going to see again. Now, if we just watch those patients, the time between the MRD turning positive and having a full blown relapse varies tremendously. Some series is about three years, but of course it depends a lot. Depends on the, you know, on the pace of that one particular person's myeloma, depends on what the patient, how secretory the myeloma is, how much protein the myeloma makes, and ultimately what the patient is on. You know, sometimes the treatment the patient is on is going to cause that increase to be slower in some and much faster in others. Yeah, definitely. Okay, a couple more questions. Does everyone need to get to MRD negativity? I mean, I see this question all the time. MRD positive, should I continue intense treatment until I get MRD negative? What's your opinion on that? My opinion, so I'll tell you this. So the answer to that is we don't know, right? You know, it's easier to show that MRD negative patients do better. It's much harder to come to prove that taking patients with MRD positive and converting them to MRD negative, you make their behaviors the same that they once were MRD negative with the prior therapy, you know? So that remains to be seen. Now, does everybody need to be MRD negative? No. I mean, the majority of patients with current standard therapy do not achieve MRD negativity. The majority of patients do very well. So I think the MRD negativity signal would allow us to start picking up among the patients, those who are doing extremely well, who might be candidates for treatment de-escalation. So I like to tell patients in this day and age, think of the MRD negative being the exception because it's easy for, it's not easy, it's natural for patients to feel let down, to feel disappointed when, oh, my MRD is too positive. Well, you know, just assume that is going to be the case because that is often the majority of the case. The MRD negativity is the honor roll, so to speak, is the exception. It doesn't mean you're not going to go to college because you didn't make two on a roll. You know, that is exceptionally good, but it doesn't mean the MRD positive are a bad thing. There are patients who remain MRD positive with minimal therapy for years, sometimes decades, and that is very well described on patients with hyperdeployed myeloma, which is one of the most common types of myeloma. Now, I think the situation where I would, and I think, you know, my approach, and that is highly controversial, is very individualized. I think if you talk to other myeloma doctors, you're probably going to get a very different impression from each one of them, is I pursue that. I adapt therapy to try to achieve MRD negative up to a certain extent, right? It doesn't mean I'm going to keep, you know, pulling things from the hat until the patient, you know, either kills the MRD or the patient drops that. That's not how it goes. I think there's within the boundaries of what is acceptable ways to do standard treatment, I tend to modulate that using MRD information. So, for example, you know, if a patient is, you know, MRD negative post-transplant, and then I do consolidation, patient's MRD negative again, particularly if the patient is not an ultra-high-risk patient, I say, well, I think I have data to show that you're going to do very well without any therapy. Here's an option. Let's just monitor you, including MRD, and not do any maintenance therapy. Conversely, if I have a patient who, let's say, has high-risk disease, receive, you know, VRD and transplant and still MRD positive, we know those patients don't do well. So, those are patients I'm more likely to recommend, you know, consolidation therapy and introduction of a new agent, in this case, a monoclonal antibody. So, there are circumstances where I think you can, you know, use the whole scope of what is considered acceptable therapy to pursue that to a certain extent. But I don't go, it's not like I'm going to start, you know, coming up with regimen after regimen to pursue MRD negative. I think there has to be some balance there. Yeah. Yeah. The last question that I see repeated throughout is, you know, what about the location of the biopsy? I mean, there are patients that can get MRD negative in their left hip and then MRD positive in their... Yeah. So, that is often brought up as a caveat for MRD. And I agree with that. It's a disease that is not homogenous throughout the bone marrow, and it can even have extra medullar sites. But I think part of that is because we have this dream that the MRD is going to be the one test that tells it all. And there is not such test in myeloma or any other cancer, right? So, you know, the same way I have, there are patients with high risk chromosomes that do extremely well. And some of the hardest patients to treat in terms of disease refractors that I have had are patients who had standard risk myeloma, right? So, there is not one test in myeloma that perfectly separates people who are going to do well, people who are going to do unwell. One of the limitations of MRD is that you're sampling the bone marrow in that particular place, and the disease can be different in other sites. And you can have extra medullar sites of disease, like, you know, like a tumor in the liver, for example. That's not measured there. And all those things probably help to explain why MRD is not perfect, and why patients with MRD negative still often relapse. That being said, the mitigating factors, if you will, are the following. One is extra medullar disease is uncommon or less common in the newly diagnosed setting. And if you're looking at patients who had five, six, seven lines of therapy, that becomes more common. That's why MRD is not as clear cut when you look at, for example, CAR-T data or bispecific data. The other thing is that, you know, we make a lot of that heterogeneity. Say, oh, you know, look, I did a bone marrow on this side was 5%. I did it on the other side was 12%. But, you know, that seems like a big difference. But we are in the same ballpark when you look at the logarithmic scale, right? Now we're talking about going from one in a million to one in a thousand. That's like a thousand times more. Talk about big difference, right? So what we see is those nuances that exist on marrow infiltration, they're usually not a log high. It's not like this side of the marrow is 5%, the other side is 50, you know, or more. So those are, and the other argument is very pragmatic. You know, I show you the data. I mean, you got one point MRD, and that is what tells us that's the big separation that it makes in prognosis. So with all those limitations, with all those limitations, is still the best prognostic information that we have for people who have received prior therapy for myeloma. Yeah, you would say it's an accurate assessment of the overall myeloma burden in the body? It's the most accurate that we have. That we have. I like that. Okay, sorry, I said there's just there's so many great questions in coming in. So I'm just going to finish with this one. How often do you recommend that your patients get tested? Standard versus high risk? Does that change? I feel bad because my answers have been it depends or I don't know. And this is both, it depends and I don't know. So, you know, if we had a good blood-based MRD test, for example, we didn't talk about today, but something that's being actively pursued, then it would be great. We could do that every month, but we don't. It's bone marrow and it's expensive and it's painful to the patients. And there's a point of diminished return, right? There's a point where you're not learning more by doing it more often. So patients who are on maintenance therapy or patients who I observe without any therapy, I do try to do once a year. You say, well, you know, if you're high risk, should we do more often? We don't know that, you know, because at the end of the day, if you achieve MRD negativity already, you might be very close to the standard risk. You know, at that point, it may not matter that much. And conversely, maybe somebody with a disease that is so aggressive that I can do MRD, you know, every three months when the myeloma comes back, it's going to come back in between anyways. So the optimal frequency of MRD testing on those patients is unknown. What we tend to do for those who we're observing without therapy and monitoring for the need to reinstate therapy is once a year. Awesome. Thank you so much. Absolutely. The compliments are coming in and they say, as always, you make it even the most complicated concept easy for us to understand. Thanks again, outstanding presentation and Q&A, Dr. Costa for M.M. Hall of Fame. That's to kind of you all. And I'm sorry that I couldn't spend more time with you, more help. This is a very complicated field, rapidly evolving. But I hope that the spending is out with you help at least you feel better that it's not like you don't know the answers. We don't know the answers either. But we're in this together trying to find some of those answers. Okay. Yes, we're in this together. Well, thank you so much for preparing. Absolutely. My pleasure. You guys have a great week. You too. I'm going to finish up with just a couple of outro announcements for the audience. So remember, as you're leaving the session today to take two to three minutes to participate in that survey. It means a lot to us to get your feedback and understand your experience during today's event. You can join us for next in two months as we meet every other month. So we'll be meeting in November to be talking about methodologies and interpretation of MRD results. So we kind of talked a little bit today, actually a lot of it today, thanks to Dr. Costa about the different MRD tests that are out there. And each of them have different results. So where are they the same? Where are they different? And how can we really understand the different methodologies of MRD testing? Upcoming events you may be interested in tomorrow, we have two events, the morning event or afternoon event, depending on where you are, is our cell and XR chapter, we're going to be meeting with Dr. Craig Cole about a cell and XR clinical trial. That's also known as ExpoVIO. And then that night is our Northeast Myeloma Community Chapter. So if you live anywhere from Maine to Pennsylvania, come join us. Nutrition advice is what we're going to be discussing with a registered dietitian. September 13th at 1pm is our nutrition and wellness for myeloma chapter. We're going to be talking about how to combat anemia, fatigue and GI side effects through diet. Is it possible? And what is another registered dietitian's advice? Going to sign up for those events and even more events I haven't mentioned is found at the bottom of that slide and will be included in our follow up email. Another thank you to our sponsors, Mr. Mya Squibb, GS Cage, and NTech, Janssen Oncology and Abbey. And a big thank you to all of you for helping us build this Myeloma Community. Your questions are amazing and the education that you allow to happen because of your excellent questions and thoughts just really mean a lot to me. And I'm grateful for you taking the time out of your evening to spend it with me. Have a great night everybody and thank you so much for joining us. Take care.