(Guest Lecture):April 2024 - Diagnosed with High-Risk Myeloma: What Now?

high-risk myeloma, what now? We chose this topic because it's a highly requested one, and we want to know the difference between high-risk myeloma and standard risk myeloma, the treatment differences, and the hope for the future of high-risk myeloma. So we have a very special guest here. I'll introduce her. Her name is Ana Idima. I hope I'm pronouncing it the right way. She's a third-year hematology oncology fellow at Clinica Clinic with clinical interest in plasma cell dyscrasias, maybe, including multiple myeloma and light chain amyloidosis and CAR-T cell therapies. She completed her medical education at the University of Athens in Greece and her internal medicine residency at Tufts Medical Center in Boston. So we are really happy to have her here, and I'll turn the time over to you. Awesome. Hi. Give me one moment because I can hear my voice echoing. We can hear you. Okay. Perfect. All right. Give me one moment to share my slides. Can everybody see okay there? That's perfect. Awesome. Fantastic. Okay. Hi, everyone. It's very nice to be here today. Thank you so much, Marisol, for having me here to speak about newly diagnosed high-risk multiple myeloma. And as you said, yes, this is a very hot topic these days. There are a lot of advances over the past few years and a lot of more awareness. So I'm really glad to talk about that. I'm a third-year fellow at Cleveland Clinic, and soon I will start my job as an attending physician at the University of Washington in Seattle. So I just put a slide here, my first slide. I just wanted to show how the survival of multiple myeloma has changed over the years. Ten and 20 years ago, the only drug we had was melphalan steroids. But since then, we see here we have so many advancements and so many new drugs that we can use. And all these drugs make people live longer, give us longer remissions, and also people have better quality of life. Over the past couple of years, we've seen the introduction of car T cell therapies and by specific antibodies into the treatment paradigm of relapsed refractory multiple myeloma. And a couple of days ago, actually, with all these car T cell therapies being approved for earlier lines. So the hope is that within a few, hopefully, couple of years that we're going to have these therapies available for newly diagnosed multiple myeloma. And I think it's going to be very important, especially for the subset of patients with high-risk disease. So let's start a little bit with the basics. I'm not really sure because I know most of myeloma patients, they know their diagnosis very well. They do a lot of reading online and they know their labs better than their doctors sometimes. I just wanted to start a little bit from the basics and just give an overview of the diagnostic workup of myeloma. So when a patient comes to my office, the first things that we're going to do just to monitor their myeloma are just some simple blood tests. And these include just blood counts and some chemistries including kidney function and some other markers of proliferation of the myeloma cells, which are the LDH, the better to microglobulin. And then we'll do all the specific myeloma labs, which are the SPEP, the immunofixation, and we'll do those in the urine as well. We want to see what the immunoglobulins look like and then the free light chains. Imaging is also important because some patients do present with a lot of bone disease. Therefore, we try based on the patient's history to get comprehensive imaging, I would say maybe once per year or if like more often if we worry about relapse or patient is more symptomatic and we worry about something else. So we can do a PET scan, we can do a low dose whole body CAT scan and also whole body MRI, which I haven't been really doing because it's really hard to get a whole body MRI and insurance is not easily approves that. So I either go with PET scan or a low dose whole body CT scan. And then of course, the bone marrow biopsy, we do the aspiration core biopsy when somebody's diagnosed because we want to see how many plasma cells they have in their bone marrow because that's kind of important. And then the most important thing that we want is the cancer genetics. We want to see how the cytogenetics look like. And sometimes that as we're going to talk about in a few minutes, will inform us whether a patient has tenor risk disease or high risk disease or even ultra high risk disease. So moving along, I just put here the myeloma defining events. So basically when a patient is diagnosed with myeloma, there are different criteria that they can meet. First of all, we look at the bone marrow plasma cells. If somebody has more than 60% of plasma cells, even in the absence of any other symptom, they're diagnosed with multiple myeloma. And this is the same for another blood test, which free light chains. So if the ratio of involved to uninvolved free light chains is more than a hundred, again, this is considered myeloma and patient most likely will need therapy initiation. And as we talk about imaging, patients can have what we call plasma cytomas, which can be like formation of tumors outside of the bone marrow or close to the bone marrow. And if a patient has one, then we don't think otherwise there's no other symptoms and their marrow is clean. That's not myeloma. We can radiate that. If somebody has two or more of those and the size of each one of those are more than five millimeters, that's also myeloma. And then of course we have the classic CRB criteria. So if a patient comes in, they have some plasma cells in the bone marrow, no matter what the percentage is, if they have high calcium renal failure, anemia and lytic lesions, which we can see in even simple x-rays, then that is considered myeloma and patients need therapy. We have a lot of staging systems that have evolved through the years. I think the most simple one we have is the ISS, International Staging System. And I think that was established back in 2005. And it only based on two simple blood tests, the albumin, which is a general marker of, I would say, wellness of the patient. And then another lab that's called Beta-2 microglobulin. And that kind of shows us how quickly the plasma cells are growing. So patients with stage one were considered to be low risk disease and patients with three were considered to be high risk disease. But over the years we figured out that's not enough. This is a very simple kind of scoring system. So we most likely have to include more factors just in an effort to make more accurate predictions. Therefore, we have the revised version of the ISS scoring system that also included the cytogenetics, which basically are just genetic alterations in the chromosomes of the plasma cells that are growing fast, like the cancer plasma cells. I have a lot of patients that ask me, oh my God, is this something that I can pass to my children? Is this something that I had when I was born? And I say, no, these are just mutations that are in the plasma cells that are malignant nowhere else. So it's important to know what kind of mutations we have because that might again show us how quickly the tumor can grow or if the tumor can be more resistant to therapies. So we have three high risk cytogenetic abnormalities that are incorporated in that system. And these are the translocation 414, translocation 416, and deletion 17P. So after the development of that system, we kind of figured out that there are more, that the other cytogenetic abnormalities that are of high risk. So then there was a second revision of that scoring system where they also incorporated the gain or the amplification of 1q. So, and then the last parameter that is incorporated into the RISS is also the LDH. So based on what patient has, we again categorize patients in three categories, one, two, and three. And sometimes not uncommonly patients can have more than one high risk cytogenetic lesion. Moving forward, so let's define like what is high risk multiple myeloma. So basically the most important thing that kind of shows us the biology of the myeloma is the cytogenetics as we talked about. And I have here put what are the most important mutations that are considered high risk at this moment. Again, the translocations between chromosomes 414, 416, 1420, gain amplification of 1q, deletion of 1p, and also deletion and mutations of a specific gene, the TP53 gene. When somebody has two or more of those high risk features, we call them ultra high risk myeloma, because there have been some studies that are showing that these patients doing a little bit worse than patients with just one high risk feature. But sometimes patients might not have any of these mutations or chromosomal abnormalities, but still we might consider them high risk because they have high risk clinical features this time. And what are these? First is extramedullary disease. And extramedullary disease means just tumors of plasma cells that grow outside of the bone marrow. And the more research we've done over the years, we've understood that sometimes these tumors can be adjacent to the bone. And at that, in that circumstances, we call them paraskeletal disease. That's not that much different from the bone marrow disease, but tumors of plasma cells that grow, for example, in your liver, or I had a patient who had like a plural plasma cytoma like close to their lung, or maybe in the soft tissues. These are considered to be high risk. Large lytic lesions, sometimes patients present with very large lytic lesions. We take these patients like very seriously. And sometimes we like worry that might relapse sooner than patients with standard risk cytogenetics. And then the last thing that I wanted to say is when we see circulating plasma cells in the blood. So most of the times, plasma cells are not like, when we say leukemia cells are not in the blood, they stick in the bone marrow. We rarely see them in the blood. So when we do see them, we worry because that's a high risk feature. So in the past, we would define plasma cell leukemia as having more than 10% of plasma cells in your blood. But now we've realized that even less of that is significant. So even if we see three to five percent, we still need to take that seriously and make sure that we monitor the patient and we give them the most aggressive, at least frontline therapy to make sure that they get into remission. So patients with high risk disease, they represent about 15 to 20% of all patients with multiple myeloma. The rest, 80% are just patients with standard risk disease. And this is a barrier to these patients enrolling in clinical trials because we see most of the clinical trials, the majority of the patients are standard risk disease. It's very, even if they do recruit high risk patients, the numbers are not high enough to make meaningful conclusions. And there is a paucity of trials just dedicated to high risk patients. And for sure, this is an unmet medical need and we need more trials dedicated to high risk patients because that's going to help us tailor therapy for this patient population. So even if somebody meets criteria, what we talked about for high risk disease, these scoring systems are not perfect. And sometimes they don't really predict well the future. And this is why I want to talk to you about, I'm going to return to these slides in a moment, about functional high risk multiple myeloma. So functional high risk multiple myeloma, it is considered a high risk disease, but most commonly it happens to patients who have standard risk cytogenetics. So this is really unexpected because you go to your doctor, the doctor tells you, okay, your bone marrow, I mean, you have myeloma, but you know what, you don't have high risk cytogenetics, so we're good. But guess what, you start therapy and then you relapse soon after the initiation. And soon, like early relapse means 18 months after initiation of induction therapy for patients who don't plan to go to transplant or within 12 months from transplant. So that's considered an early relapse. And patients who have early relapses, we know that by definition, they're high risk patients, even in the absence of high risk cytogenetics. There are several groups that I have tried to predict who might relapse earlier. And we have several scoring systems, I've listed them here, like the CIBMTR, the EBMT, which is the European, like physicians are there, but they all have conflicting results. They don't agree with each other. And the most important is that these systems, they just evaluate the patient's disease or diagnosis. But by definition, functional high risk multiple myeloma, it's something that happens over time. It's basically a dynamic term. And it's just really hard to predict something by just evaluating the patient at one moment, the moment of diagnosis. So we for sure need to have better tools that will allow us to not only evaluate patients at diagnosis, but also throughout their treatment. Because that might give us very important information about how their myeloma might behave. So these patients with functional high risk myeloma are usually misclassified. And for example, they might not get as intensifying, I'm saying maybe maintenance therapy, or sometimes now, and we're going to talk about that a little bit later, sometimes physicians might stop maintenance therapy, if somebody's MRD negative for some time. And these patients will relapse shortly thereafter. That's why we need to be very careful with those decisions. Genetic factors and tumor microenvironment are felt to play a role in the development of functional high risk multiple myeloma. But we don't really know much about it. And we don't really actually know how to predict who's going to have that. So it's just very hard for physicians to know from the get go, like from diagnosis, what patient might have a functional high risk multiple myeloma. And of course, when you're diagnosed with that, let's say patient relapsed six months after transplant with standard risk cytogenetics, then you kind of physician realizes, okay, that myeloma behaves aggressively. So now maybe we should be more aggressive and try to achieve complete response stage with more aggressive therapies, or sometimes try to do more imaging, so as to catch some relapse early, instead of waiting for too long, and patient comes in pretty bad clinical relapse. And of course, there are two trials now, CAR-T trials that are enrolling patients with early relapse. And they're studying IDA cell and CILTA cell for patients with early relapse. So that's really encouraging because I personally think CAR-T will have significant role in these patients, because these patients need better therapies. So now I'm just going to go back a few slides, and I am going to talk about a little bit ultra high risk multiple myeloma. So ultra high risk, as I previously said, is when you have two or more of these high risk cytogenetic abnormalities. And what we've seen so far is that patients with ultra high risk myeloma do worse than other patients. So here I'm showing some curves. So the patients with ultra high risk myeloma are the ones with the green line. And they did not as good with triplet induction therapies as the rest of the patients. So they have shorter remissions than the rest of the patients. And then a group of physicians did a meta analysis of 14 clinical trials. And meta analysis are very important for high risk myeloma, because as I said before, because as I said before, it's just really hard to have a trial just dedicated to these patients because they're the minority within the myeloma population. So it's really important to combine patients from different studies and just trying to see what happens with these patients at the end. It's not a perfect method, but it's okay. It's very, very acceptable. And what that showed is exactly the same thing, that patients who had two or more of these aberrations did behave worse, like their myeloma behaved worse than the rest of the patients. Here's the Forte trial. And I just put it there because it contained a high risk, like a large number of patients with high risk multiple myeloma. So what did they do there? So they randomize the patients in three different groups. The one group received carfilzomib, cyclophosphamide, and dexamethasone with transplant as induction therapy. The second group, instead of cyclophosphamide, they received linalytomide and then transplant. And then the last group just received chemotherapy with no transplant. And the interesting thing is that here, just see the three top graphs. Regardless of the regiment that these patients received, the ultra high risk patients did worse with each one of the regimens. And then they just saw within these high risk patients, was any of these regimens better than the other. And they figured that the carfilzomib, linalytomide, dexamethasone regimen with transplant, and then with consolidation and enhanced maintenance therapy, did better than the rest of the groups. So that's something to keep in mind. So these patients, the hallmark of the trial is that they received very intensive maintenance therapy. They received a carfilzomib and linalytomide maintenance. And as long as they received that therapy, they remained in depremission. But when they stopped the carfilzomib and they deescalated the maintenance to just linalytomide, which is the common maintenance therapy we give to patients, then the disease came back pretty quickly. So as long as they received both the drugs, disease was under control. But the moment that they deescalated, the disease came back pretty quickly, which again, it's very confirmatory that these patients behave differently than the rest of the patients. So, but what does high risk myeloma actually mean? I mean, we talk about all these like shorter remissions and more aggressive disease, but what does that actually mean? So basically, when patients have high risk disease, we know that they have more proliferative disease. And the treatment, and they will require, I'm sorry, more treatment than patients with standard risk disease. They might relapse more quickly to a therapy, and it's most likely that they're going to become resistant to a therapy more quickly than patients with standard risk disease. Sometimes what we've seen is that there is a shorter time between the biochemical relapse and the clinical relapse. So when we detect the biochemical relapse in patients with high risk disease, we need to act quickly. We can't just let it go and say, okay, it's just a little bit of rising in your numbers. Let's just see what happens. No, when we see a trend, even in the absence of clinical symptoms, we have to do something because we know that the patient will do something because if we don't, symptoms can come back very quickly, which is not the case with patients with standard risk. I've seen patients with standard risk disease, we didn't really treat them for a couple months, two, three, four months, and then the fourth month, we're like, okay, let's just change the therapy. But we can do the same thing in patients with high risk disease. We need to be very vigilant with these patients. And continuous therapy in patients with high risk disease is very important. We need to give aggressive therapy in the beginning and make sure we bring them into deep remissions. So I like when my patients with high risk disease achieve a complete response. I want them to achieve a complete response. In a patient with standard risk disease, I might say, okay, a very good partial response might be okay. But no, with high risk disease, I want them to go in complete response and then give them therapy to keep that there because it's important to control the disease with ongoing therapy for like a long time. So high risk disease means difficult to treat myeloma, like an easy term. Low risk disease means just myeloma that's easier to treat. There are studies that they say that patients with high risk disease, they have shorter overall survival. But honestly, I would not really worry about that because I've seen it myself in clinical practice, all these predictions about how long patients live, they are never accurate. So I just wanted to say that out there, like I literally saw a patient last week in clinic who had one high risk disease feature. And after transplant, and she's now like eight years post transplant on like a minimal and a little my dose. So for me, that's what breaks the rule. Like this patient was not supposed to do that well, and then she did fantastic. So all these systems that we have, and all these predictions, they're never like, 100% accurate, not even half of the times, I would say. So let's now discuss about treatment selection. So what how do we choose therapy for this patient? So a few things that we need to keep in mind. First, how many drugs we want to give for induction therapy? We want to give four or three. And then if is the patient transplant eligible? Do they have any end organ damage? For example, does the patient have kidney failure, or liver failure, or some very bad side effects? So we need to make sure we tailor the therapy based on that. And then another important question is what maintenance therapy we should use. I'm just having here a few criteria about transplant eligibility. The one thing that I wanted to say to the group is that age is not a like a factor. As long as patients are fit and they have a good organ function, we even took patients to transplant like we had an 80 year old in our floor a couple of weeks ago that had transplant. So age is not a cutoff. There's no cutoff in age. So let's talk about the induction therapy. So most of the patients who are going to go to transplant are going to get a four regimen induction therapy for most of the times four to six cycles, then we'll go to transplant. In three months after transplant, we will start maintenance therapy. For patients who don't go to transplant, we can choose how many cycles and what kind of regimen we want to give. We can do most of the times like six to eight cycles and then deescalate to maintenance therapy. And here I want to say that we have two types of patients who don't go to transplant. So we have patients who are not eligible for transplant because they have a lot of comorbidities. However, there are other patients who they don't want transplant. They're like really fit, they're in good shape, but they're not ready for it. So for these patients, I tend to use quadruplet therapy. I don't use like the lighter schemas that I use for ineligible patients, but I always advise them and I say to them, let's just collect your stem cells because you never know. You might want to do transplant like a few months into like down the road, or maybe you want to do transplant a second line of therapy, but it's always good for these patients to collect their stem cells because at that time, they're the most healthy they'll be and their stem cells are fit, like are good stem cells. So always urge your patients to collect stem cells even if they don't want up front transplant. So here the frontline regimen that we use, deratumum, bortezomib, lenalidomide, dexamethasone, and that was based on the data that we got from the Griffin trial and from the PERSUSE trial, two trials, and why deratumumab is important because in the past we used to do bortezomib, lenalidomide, dexamethasone only. Now we added the deratumumab. So deratumumab leads to deeper responses and faster. So even within one cycle, after one cycle, patients achieve like CR and that's really important because that improves their symptoms like their bone pain and their neuropathy, or if they have renal failure, it helps a lot reverse their renal failure. And deratumumab also shows that it keeps patients in deeper and longer remissions. And we had less early relapses when we gave deratumumab up front. And of course, we have more quick achievement of MRD negativity that has proven to be prognostic for multiple myeloma. So here I'm just going to briefly talk about the Griffin trial that kind of changed the practice and led physicians to use deratumumab up front. So it was faced to a randomized trial. So patients received dera or no dera. And then in the maintenance space, they received dera revlimid versus revlimid. And as I mentioned here, only 15% of patients in this trial were high risk. So not really many patients. So we saw very, very high overall response rates above 90% and really fast. And the complete response or better rates after the transplant and overall were really impressive as well. So responses were fantastic. The most important thing though is that patients with high risk disease, they did better with dera and that these two figures here show that. So patients that had one high risk cytogenetic abnormality had better rates of MRD negativity and PFAS. However, patients with two or more, they achieved MRD negativity in very good rates, but their progression free survival, which means the time that they stayed in remission was kind of the same as the VRD. So it didn't really improve outcomes as much in patients who are ultra high risk, but it did certainly improved outcomes a lot in patients with only one high risk aberration, which is very important. And then here is a similar trial, which is the Perseus trial. They did exactly the same thing. They gave dera or no dera upfront. And the different thing that they did here is instead of just giving their tumor blend a little might in the maintenance space, they kind of followed an MRD guided decision-making, which means for the patients who receive dera upfront, if they were positive, they will continue the two drugs. If they were negative, they would, patients would be able to just deescalate to just lenalidomide. And that we're hoping to give us more information about how to use MRD as a tool to deescalate therapy in the future, hopefully in the near future. Other, I'm just going to go a little bit quickly here because I've seen, I've been talking for a long time and I want to have questions, time for questions. I'm sorry, I'm really chatty. But other than that drug combination, which is considered the standard of care today, the deratumumab, bortezomib, lenalidomide, dexamethasone, other combinations have also been used. For example, one of them is deratumumab, carfilzomib, lenalidomide, and dexamethasone. So instead of bortezomib, we added carfilzomib, which is a second generation proteasome inhibitor, like a stronger drug. And this, this trial is very important for patients with high risk cytogenetics. Why? Because it included many patients with high risk cytogenetics. And the investigators here, Dr. Costa, what he did was he gave a lot of induction chemotherapy with his four drugs. Then the patients went to transplant. And then we checked MRD. And if they were MRD positive, they continued in therapy. But if they were MRD negative in two time points, like in two consecutive measurements, then patients could stop chemotherapy. And what happened in the patients with high risk disease and ultra high risk disease? So the patients with just high risk disease, again, which means one cytogenetic abnormality, they did okay, actually. However, the patients with ultra high risk disease, they, when they stopped therapy, they relapsed faster and their survival was poor. So what that trial taught us is that with this intensified combination, yes, you can achieve very good MRD negativity rates, even in ultra high risk patients. But when you deescalate and you stop, then the myeloma comes back very quickly. So we should not stop maintenance therapy in patients with ultra high risk myeloma. That's what this trial kind of told us. Some other combinations that have been used instead of veratumumab, here they've used isatuximab, which is a similar drug. It's just not approved as first line therapy in the US right now. And a little bit of future directions, there is the Cartitude VI trial that will take place in Europe. Unfortunately, the FDA did not really like it. So we're not going to have it in the United States, but this trial, what we'll do is that it will compare transplant versus carthesyl therapy in patients who have received induction therapy with four drugs. So the bottom line of this, in my clinic, if I see a young patient with high, high risk disease and ultra high risk disease, I'm going to advise them to take veratumumab, pertussomab, and lanolidomide, and dexamethasone for six, four to six cycles. And then I will recommend transplant. And as I said before, if somebody does not want transplant as the first line, but they're fit enough, I will at least advise them to collect the stem cells. And then after the transplant, three months after the transplant, we start maintenance therapy, which in high risk patients, it should be doublet. It should be pertussomab and lanolidomide. Of course, there are sometimes there are patients with neuropathy and some other side effects. So we're limited with regards to what we can use, but in general, that's what I would do. And why is transplant important in patients with high risk disease? So this trial, it's called the determination trial. It's a very large phase three randomized trial that randomized basically patients to transplant or no transplant, followed by lanolidomide maintenance, and show that patients with high risk disease did better with transplant. Overall, for the entire population, the trial showed benefit with transplant in with regards to progression free survival. So patients remained in the longer remissions. However, it did not show us any overall survival benefit, neither in the high risk or in the standard risk patients. For patients who are not eligible for transplant, and they're kind of frail, I would still use deratumumab as frontline, but now I would not really use the pertussomab, but I would just use the Maya trial regimen, which is just deratumumab, lanolidomide, and dexamethasone. And you can do that for eight cycles and then just deescalate the lanolidomide maintenance. So this trial showed that the patients, again, deratumumab led to really good responses pretty fast. And the patients who had sustained MRD negativity, they actually stayed in remission for a longer time. So that was really, really good. And it's the only trial within this population that has also shown an overall survival benefit. Just the progression free survival for this trial in this frail patients is more than five years, which again, for me, it's really impressive. So that's my to go regimen in transplant in eligible patients, um, and show that these good results were maintained in patients with older age, younger age, and in patients who were frail versus not frail. So did pretty good across all subgroups. Here we have another regimen sometimes we're using in transplant in eligible, which we call VRD light. If the patient has neuropathy, we can consider this regimen, but I think deratumumab should be, you know, the preferred regimen for some reason, patient has no access or some other issue with insurance, this is an alternative patients frail patients can use. Um, so I just talked about that, that my preference is that there are RD for the transplant in eligible patients. A few things about maintenance therapy. I promise I'm going to be done in five minutes. Uh, we have plenty of time. You can ask me whatever you want. Uh, I have rather in a rush. So maintenance therapy, um, what is maintenance therapy? So maintenance therapy is basically a milder version of induction. And the general idea is that some maintenance is better than none. So they did the very big meta analysis of patients, um, um, that received maintenance or no maintenance therapy. And we saw that patients who are on continuous linoleumide maintenance, they had longer remissions and better survival. So it's our approach that we always have to give a maintenance therapy to the patient, at least for the beginning. Um, stopping maintenance therapy based on MRD status is involving a controversial topic. And based on the results of the master trial that I talked about before, I don't think we should deescalate maintenance therapy or stopping basically maintenance therapy in ultra high risk patients for patients with one high risk abnormality or standard risk cytogenetics. It's a different story. And I think there are a lot of trials now trying to answer this question, but I think for ultra high risk patients, we should continue therapy. It's very important. Um, so for standard risk patients, we just give Revlimid and we start at lower doses that we do at induction therapy. So 10 to 15 milligrams, three weeks on, three, one week off. However, for high risk patients, we tend to choose doublet maintenance therapy with bortezomib and linoleumide. Um, sometimes patients have neuropathy and they cannot tolerate long term bortezomib. So in these patients, I would give them DeraTumumab maybe along with Revlimid, even though we have no data that Dera actually helps. Uh, but I think it's important to, to give these patients like more intense therapy. Uh, there was a recent, um, big retrospective analysis from CIBMTR that showed that just bortezomib alone is not any better than Revlimid alone in high risk patients. Um, so we don't really use bortezomib by itself unless there is a contraindication or an issue with insurance about Revlimid, which is not uncommon these days. Um, there are no randomized data, um, to compare Revlimid versus, uh, Revlimid and Velcade in high risk patients. Uh, however, there are some good, um, retrospective data and that's where we, uh, base this decision. And, uh, now there are very interesting, um, studies in the space of maintenance therapy that are basically assessing DeraTumumab lenalidomide based on what the MRD shows. And we're hoping that this will give us more information regarding, first of all, the efficacy of DeraTumumab in the maintenance space and also if we can deescalate therapy based on MRD. And the one thing that my friend, Dr. Rahul Banerjee says, please do not give dexamethasone to patients in the maintenance setting. Dexamethasone is not good if it, if it's given continues and should not be given. Um, so we kind of talked about all this and this is the dramatic study that is basically assessing, um, like the doublet of DeraTumumab and lenalidomide based on, uh, what the MRD shows. It's called the dramatic study and it's enrolling more than a thousand patients. So we are very excited to see what it's going to show. And I'm really excited because the primary endpoint is overall survival, which should be when we're studying, uh, maintenance therapy. Um, future directions. There is also a CAR-T trial here that will compare, um, lenalidomide maintenance to CAR-T cell therapy, actually in patients who, uh, do not intend to undergo transplant. So I, I'm personally really, um, eager to see what this will show. Uh, and some, uh, just to finish some key takeaways. Um, what I want you guys to remember from today's session is that the number of cytogenetic abnormalities are important in high-risk multiple myeloma. However, we should always keep in mind that some patients are going to be high-risk without high-risk cytogenetics. And these are the patients with functional high-risk multiple myeloma. And unfortunately, this is an entity that we can only, um, recognize and diagnose after some type of therapy. Um, there are no randomized trial in the high-risk newly diagnosed multiple myeloma showing survival benefit. From what we have right now, it seems that DERA, pertussomy, lenalidomide, and dexamethasone, uh, benefit patients, all patients, including high-risk patients. However, the benefit is less in those who have two or more high-risk cytogenetic lesions. However, this should be our preferred regimen in these patients. Um, early transplant, like first-line transplant, we always recommend at high-risk patients, uh, based on the results of the determination study, because it showed a good DFS benefit in high-risk patients. Um, so there are, um, some other studies that they have assessed for filzomib, uh, in the front-line setting, but there's no study that has actually compared DERA-2-MUMAB-VRD with carfilzomib-based, uh, therapy. So we don't really know if carfilzomib is, is better than DERA and Velcade. We're not really sure about that. That's something that we need to figure out in the future. Um, what else? Um, we need to remember that in transplant in eligible patients, DERA-2-MUMAB is also important with lenalidomide and dexamethasone because it has showed overall survival benefit and that should be our first-line regimen. Um, lenalidomide is standard of care in the maintenance space. However, in high-risk patients, we prefer to do doublets, most commonly bortezomib-lenalidomide, but there's no randomized data to support that. Um, and there are, uh, a few exciting ongoing trials, um, that will help us understand the role of MRT-guided decision making in the maintenance space, whether we can discontinue or not in patients with standard or maybe one, uh, high-risk feature and also inform us regarding the utility of DERA-2-MUMAB in the maintenance space, which is another important thing. And I think I am done. Thank you so much. It was a very interesting presentation. So thank you. I had a couple of questions, but I think you, um, answered that without me asking. No, we can go, yeah, we can go through everything. The one you said, the things you said about age, like the age not related to the treatment and transplant, because we do have to ask like frequently if they are candidates for a transplant of their age. So yeah, that was an important point. Um, we have a couple of questions here, so I'll just read them. Is it possible to lose some of the high-risk genetics after stem cell transplant or other treatments? That's a fantastic question. That's a very good question. So I would say once you have a high-risk feature and it was diagnosed at some point throughout your disease, I would consider you as a high-risk patient. Sometimes what we do with therapy is that we give you very high amounts of chemotherapy or, or new, newer targeted therapies. And we basically kill all the cancer cells in the bone marrow, especially after transplant, like transplant, literally the high dose melphalan kills 99.9 of all cells in your bone marrow. So when we do an aspiration after the transplant, we're not going to see any myeloma cells and we're not going to see any high-risk cytogenetics, but simply because there are no myeloma cells there. When the myeloma cells come back, we will see the high-risk cytogenetics. So once you have a high-risk feature, you have it, you cannot lose it. But patients with standard risk disease, sometimes we see patients having standard risk cytogenetics when they're diagnosed. And after multiple relapses, they might acquire a high-risk feature. So you can go from standard risk to high risk, but you can never go from high risk to standard risk, basically. Okay. That's very interesting. I didn't know. Yeah. Thank you. Let me read the other ones we have. Absolutely. I think they are all related because they were in the same person. So I'll just read them. What is the current PFS rate for someone with four high-risk factors? Four high-risk. I think it depends on what factors you have. It's really hard to tell because for example, I've seen patients with high-risk disease. What I would consider, and I've seen clinical practice, let's say you have two or four, and when you say high-risk factors, I'm assuming it's maybe cytogenetics or maybe some clinical factors. So I would say transplant with maintenance therapy can give a good PFS to people, maybe around two years. And with the addition of maintenance therapy, we've seen patients extending that to even three and four years. So for me, that would be a success. I've seen patients with high-risk collisions, more than one, being able to achieve that, like four years out of their transplant with maintenance therapy. But we don't stop maintenance therapy. We give you a doublet and we're hoping for the best. Sometimes it's hard to tell. As I previously said, sometimes patients with high-risk features, they tend to relapse sooner, but that's not the case with everybody. What I would say is make sure you follow your doctor's advice, make sure you don't stop the therapy. Of course, if there's any side effects that reduce the quality of life, there's always a discussion about some other regimens that we can introduce in the maintenance setting in the presence of toxicities. For example, I had a patient who was on linoleumide. They have a really bad rash. We ended up giving them pomalidomide as maintenance. But I would say if you're able to get four years out of your transplant, that would be really good. That's perfect. Hopefully, that's going to be even better with CAR-T. I'm really hopeful that CAR-T in the setting of maintenance therapy after transplant, we will see really good outcomes there. That's great. We had an event about CAR-T a few weeks ago. I'll just video in the follow-up email so you can learn more about CAR-T. The other two questions he had were related. What did the studies show about lifeline and research? I think you just answered both of those questions. We have a new one. How would you approach someone with ultra high risk multiple myeloma differently than those with just double high risk? Double high risk means ultra high risk. When we have two or more cytogenetic aberrations, that's by definition ultra high risk. What I would do for these patients is that I would make sure I will bring them in a deep remission with frontline therapy. I will start DERA-TUMUM-VRD, and I would make sure that they go in a deep remission. Then I would recommend transplant as I would recommend to my standard risk patients. But if the patient was skeptical, I would be more persistent and say, hey, you need the transplant. We have to do this, especially if my patient is really fit. Then what I would do differently than the standard risk patients, I would keep the patient on double maintenance therapy. Sometimes patients after transplant, they come to the clinic and they say, can I just stop it for a few months? Maybe we can do a bone marrow biopsy. If I'm MRD negative, just please give me a break. If the patient's ultra high risk, I would say, we can't do that. We have to keep going and make sure we maintain this deep response. For high risk patients, it's so important not only to respond, but to have a deep response, a complete response. When you get the complete response, keep it there. Don't de-escalate the regimens unless, again, if there's toxicities, we can play around with drugs. We can see how we can best help patients. But if there's no major toxicities, these patients need to keep going. Do you have any reservations giving DERA during maintenance for high risk, or do you prefer to save it for relapse? I would say when it comes to induction therapy, I would give DERA because patients are just exposed to it. They're not usually refractory. As we saw in the Griffin trial, patients who received DERA had more than 90% overall response rate. It's interesting. I am not sure if DERA will be effective in the maintenance space. I think that's why it's very important. The dramatic study and the Perseus trial, they will both show us if there's an overall survival benefit with DERA to UMUMAB. For me to incorporate the drug in the maintenance setting, I need to see an overall survival. PFS is not good enough for maintenance. If there is a trial that proves to me DERA helps prolong your life, I would totally put DERA in the maintenance setting. Why? I don't want my patient to relapse. Every time my patient relapses, then the remission of the next line of therapy is shorter. It's very important for myeloma if we respond to first line therapy, keep the response as much as we can do. Again, we don't have good data right now that they say DERA is effective in the maintenance space. That's why I don't give it. The only reasons why I might give DERA in the maintenance setting is let's say it's a high-risk patient that cannot tolerate bortezomib because they have pretty bad neuropathy. I would consider adding it. Or if I had a very old patient, maybe 85, 90, because we have all these patients sometimes in clinic and they cannot tolerate their lenalidomide because they take lenalidomide and they're out of it. In this patient, because I want to give something, I would give them DERA, but not in a patient who I have other options. Not yet, I would say. Okay, that's interesting. We have a question about dexamethasone because you mentioned it at the end. It says, doctor recommends not using dexamethasone continuously for maintenance therapy. If so, that concerns me because I've been on it for two years. Oof. Okay, there are different... Sometimes we might give dexamethasone as a pre-medication with other drugs. For example, if my patient is on carfilizomib, I always give them some dexamethasone with it. It's just because it helps with nausea. But I would never give dexamethasone for first-line maintenance ongoing. I can't think of a time when I've done it. What I basically do with dexamethasone is that I give the full dose in the beginning, the first two maybe cycles, because dexamethasone kills myeloma cells and it makes you feel better and improves your pain. I wanted to give it in the beginning. After the first two cycles, I would just start going down, and then stop after a few more cycles. I won't give it in the maintenance setting. I'm not really sure. Again, myeloma patients are very complicated and I'm not very sure what's going on. But I would say just discuss it with your doctor. Maybe again, some patients are on another drug and they just need it as pre-medication maybe once per week. That's okay. But I would not give it more than that. Even at that time, I would just give maybe eight milligrams like a baby dose. Okay. That's interesting. I've never heard about that. That got me thinking. We have another one. It's for the bone marrow biopsy just preceding transplant. Is there a certain percent of infiltration that a patient needs to be under in order to continue to transplant? That's a very good question. We don't transplant patients right now for myeloma who have disease progression. We always want to give some type of therapy to bring the myeloma in under control. Now, there are some studies that have shown that the least amount of plasma cells are the best response you have pre-transplant, the better the outcomes might be after transplant. But always keep in mind, some patients are very hard to manage, especially in the past when we did not have DERA. It was not easy to bring them to a very good or complete partial response. If I had such a patient and I could only achieve a partial response and that was the best I could do, I would move forward with transplant. There's no good or bad. It's just from my perspective, is the least amount of cells we can have or the better the response we can have prior to transplant, the better it is. But as long as the patient has some response, it's okay. It's not acceptable to just do a transplant with progressive disease. No. Or if a patient has refractory disease, no. But if you achieve some type of response, it has been shown it's okay to do transplant. Now, with the DERA to myeloma, I really think people will achieve depremations pre-transplant. That's why it's important to incorporate DERA to myeloma upfront because it really, really helps bringing these plasma cells down even after the first cycle. In the past, when we're just giving bortezomib, lenalidomide, and dexamethasone, we might even have to give this regimen for four cycles to even see a partial response after four cycles. Now with DERA, we see complete response after a cycle, which is a huge, huge, huge difference. I think that's why also the outcomes, I mean, in general, they're so much better after transplant and even without transplant. We have a question about the transplant here as well. So I'll add it to this one. It says, I have PCL, but was very healthy on induction, normal, and in between lesion 3.5, main symptom anemia. So she collected the stem cells, but she's holding off on SCT. So what are your thoughts until relapse? I would say if you're in a good shape and your myeloma, your plasma cell leukemia is under control now, do the transplant now because you never know what happens in the future. Sometimes when some patients are high risk, they might get into depremission, but then for some reason, because by definition, high-risk disease means, which includes plasma cell leukemia, it just means it might come back faster. And we don't have a lot of time from just detection of your biomarkers and symptoms. And when that time is not enough, we might not have enough time if you relapse to get transplant. So I always to my plasma cell leukemia patients, I say, if you're in a good shape, if you're a young patient, we have a great response with first line therapy, please get the transplant now. Yeah. Okay. Perfect. Yeah. And that might change in the future because we talked about CAR T. CAR T might be another option, but for now, I think transplant gives the best chance of remission. Yeah. I know some centers, they do tandem transplants, which means two transplants in a row for high-risk disease. We don't do that here because of some trials, like the Stamina trial didn't really show any benefit with that. And I know there are other centers that they do like some crazy regimens for plasma cell leukemia and ultra high-risk myeloma, like very, very cytotoxic regimens. But I think if a patient with plasma cell leukemia, they're able to get a very good response with their VRD, just go ahead and get the transplant. Usually transplant for myeloma has risks, but it's relatively safe compared to, for example, to patients with leukemia when they get allo-transplants. Like I've been to the BMT service for three years now on and off a few months per year. And I can say whenever we have a new myeloma transplant, I'm really happy because I know they're just going to chill at the hospital, get really bored and then just go home. So I mean, transplant can make you feel really fatigued for three months after transplant, but it doesn't have long-term complications. For example, like you don't get somebody else's cells, so we don't have what we call graft-versus-host disease with that type of transplant. And after three months, patients come back to their baseline. Like I haven't really seen somebody with autologous transplant having long-term side effects from the transplant itself. Okay, perfect. Yeah. We have time for a couple more questions. Yeah, yeah. Sure. So we have one. Are there any studies being done of nilural for any risk levels of multiple myeloma? Yeah, nilural is a really, like I don't really want to... So nilural, there are a lot of opinions about it. Right now it's not approved as first line. It's approved in the relapse setting. I would say nilural to me, like in a simple words, it's just an oral version of Velcade, of Bertezomib. So where I sometimes use it is if a patient can get Velcade, like because some patients, they're old, they're sick, they have no family members, and they don't want to come to the hospital to get therapy. Like they're like, I can't even come even once. Like Velcade is once per week or once per two weeks in the maintenance setting. Sometimes patients don't want to do that. And they're like, I just want pills. So that's when I'm going to use nilural most of the times. When I can't really give Velcade, I need to give something oral, curfewl, so maybe it's another proteasome inhibitor. It's again IV. I don't really use that drug very often, to be honest. I'm not saying it's not a useful drug. It is because a lot of patients, they need their oral option. It's really important to have pills, like chemo pills. It just helps some people a lot. But if somebody can get IV or subcutaneous drugs, I don't really use that. Like there's just these special circumstances where I'll just pick to use it. But otherwise, I'll just go with Velcade because it's first line. And in the relapse setting, I usually don't do Velcade or nilural because I think they're just the same. I'm going to do something stronger. Okay. Perfect. Thank you. We have another question. It's a good one, so I'll just read it. It says, great presentation. I have heard that 1Q gain is less risky than amplification. And that's the 17 PD lesion, maybe lower risk if the percent of a plasma cell is less. And if there is no P53 mutation, so I'm wondering if there is more non-syn determining ultra high risk. Is this something an NGS test could tell me? Yeah. So the NGS test, okay. So there are a few. So yes, there are some data that suggest that just having one extra copy of 1Q is less bad than having two or three or four copies, which is amplification. It's just in the scoring system because remember, patients with high risk myeloma, not many. So we don't have a lot of information from trials because it's trial, most of the trials, the max that they recruit is 15%, 20% patients with high risk myeloma. We don't have that many information to be able to tell exactly what the risk of one copy, two copies, three copies, but there are some data, not like extremely strong data, but some data out there suggesting that the more copies you have, the worse it is. Then it's the same thing with, as the patient said, with other high risk cytogenetics. When it comes to NGS, there are several types of NGS. So when we send an NGS in the clinic, it's usually a myeloid NGS. So the plasma cells come from the lymphoid cells, not the myeloid cells. They're just like a different type of white cells basically. So it's really hard. We don't really do NGS for myeloma routinely. I might do NGS when a patient with myeloma has anemia and I worry, oh, maybe there's something wrong with other types of cells in the bone marrow other than plasma cells. There are a few studies that big centers have done when they look at cytogenetics. They look at the genetics of the myeloma cells and they do whole exome sequencing, which means they take the malignant plasma cells and they analyze the DNA of these cells. This is different than the myeloid NGS. That can only be done in a lab. So people have found certain genes that might be associated with higher risk of progression and higher risk disease overall. And we call this genetic signatures. However, when we analyze the whole exome of a plasma cell, we might find so many mutations, but we don't really know what these mean in clinical practice because a very part of the DNA is silent DNA. Even in our body, there is just a small part of our DNA that's expressed into proteins and they end up to just being like the phenotype us. There's a lot of the part of the DNA that doesn't do anything, just sits there. And a lot of times when we see these mutations, we don't really know, are they clinically significant or no. And I think there's a lot of work that has to be done there. There has been some start, but I think what we know so far is not good enough to be able to tell based on these mutations, what these mutations mean and how they can change the disease trajectory or therapy. I think if you had a myeloid NGS on the other hand, these are mutations in the myeloid cells. These are different from the plasma cells. And these cells mostly have to do with myelodysplastic syndrome, leukemia. And I think more and more physicians, like myeloma physicians, sometimes they get that if their patients are anemic or they have low blood cell, white blood cells, just because the myeloma patients live so long and they are on chemo for so long. And chemo itself has secondary risk of causing other blood cancers, not from plasma cells, from myeloid cells. So patients who are on therapy forever might have increased risk for therapy related AML, like acute myeloid leukemia or myelodysplastic syndrome. And I think sometimes we obtain that because we just want to see what's going on in the bone marrow is something that we're missing. Because if a patient, I recently had a patient who was diagnosed with MDS and I had to stop the lenalidomide, because if somebody has MDS and their own long-term lenalidomide, that's not good. So I had to put this patient on DERA, but this is just what happens when patients live so long. So we have to make sure we're not missing anything, especially second blood cancer. I think that's why physicians, they get myeloid NGS sometimes in patients with myeloma. That's very interesting. The other part of the question was, do you think high risk, ultra risk could consider doing CAR-T earlier? Correct. Yes, that's a fantastic question. So now we have all these CAR-Ts approved for first and second line therapy. But CAR-Ts, I love CAR-T cell therapy, but I have to be honest with you. I've seen some side effects, especially with CARVIC-T, some long-term neurotoxicities and nerve pulses that have made me very skeptical in using these drugs as first or second line of therapy. I would say I would use CAR-T cell therapy for high and ultra high risk multiple myeloma if they had primary refractory disease, which means you don't achieve a response to the deratumumab VRD. So you don't achieve not even a PR. Then I think that's a patient that might benefit from CAR-T. Or patients who have suboptimal responses to transplant or to induction therapy. That's another subset of patients that might be a good candidate for CAR-T or patients with early relapse who, let's say, they start induction and they relapse within less than 18 months. Yes, I think CAR-T will help eventually ultra high risk patients, but it's just we need to make sure that we implement CAR-T in a safe way because the big CAR-T, like CARVIC-T trial, not the CAR-T one, the one that compared CARVIC-T to standard of care therapies, there were 10% of patients that got nerve pulses. 10% is a high number. In these pulses, sometimes you don't go, like it just stays there and we don't know how to treat it. Sometimes after a few months patients might go back to their baseline. But I saw a few days ago a guy who I gave him CAR-T, CARVIC-T, the guy was totally fine prior to CARVIC-T, very healthy. He was on carfilzomab for like a year or two doing great. And I was thinking with my mentor, let's just give him CARVIC-T so he has a break from chemotherapy. And he got nerve palsy, cranial nerve palsy. He lost his vision for quite, and his vision was really blurry. And he got a sanding rubber. I think he's now wheelchair bound. And we're What did we do with this guy? So we have to be really careful. Yes, I think we will use CAR-T more in ultra high risk patients earlier with the hopes that that will help us, as I said, bring the disease down quickly and keep that deep remission. We just have to be very picky who are these patients because we want to avoid neurotoxicities. We do because these are really hard to deal with. And 10% for me, it was like a high number. 10% is not 5 or 1%. It's 10%. So we have to be careful. Yeah, yeah, for sure. We have another one here. Is there a difference between T14-16 and other translocations? Or should we just focus on that we are high risk or not worry about the specifics of the translocation? Yes, exactly. I would do that. I wouldn't really worry about which one you have. I would say how many you have matters most. So if you have, let's say, one, two, or you have 414, it's like your doctor. And I think your management is just going to depend on you just having high risk disease, not which one specifically you have. But the number matters. So if you have two of them, it matters. Two of them, your disease might be more difficult to treat than having one of them. Okay. And the follow-up question is, do you do any consolidation after stem cell transplant before maintenance? No, I would not do that. No. So in most of the times, no, because we don't really have to, because there are two of them that works really, really well. I think the only space where I might think of doing some consolidation is, let's say, we have a very ultra high risk patient, a plasma cell leukemia that we take to transplant. And then after transplant, the response is not as great, which means that they have some response. They're not refractory. They have, let's say, a partial response. But I want them a little bit deeper. I might consider doing a couple of cycles of consolidation, but I don't routinely do that. No, this is like a pattern we're doing in trials, but in real life, my Loma doctors don't really do consolidation very often. It has to be an accepted, a specific scenario. But for me, ultra high risk or plasma cell leukemia with suboptimal response to bone marrow transplant after a very powerful induction, that might be a reason why I would consider consolidation. Okay, perfect. We have another one. What are the best markers during induction therapy to see if the myeloma is getting under control? What would the term in four versus six cycles? Oh, good question. So there are different ways of assessing the myeloma. I think the ones that we use routinely in clinic is just your myeloma labs. For example, we just see how your light chains are doing and your M-spike. And if everything disappears and we cannot see anything in your blood, that means you're good and you don't really need four cycles. Like you don't really need six cycles. If I see everything going down like really quickly, I would just do four cycles and take you to transplant. Of course, pre-transplant, you're going to have a bone marrow biopsy. Now we can send an MRD positive and see if it's positive or negative. And that would be the most, most sensitive marker, whether there's any myeloma in your bone marrow or no, but that would not change the decision whether to go to transplant or no. If your plasma cells are down, if there's nothing there, or if it's a little bit there, we would take the patient to transplant. I would just say just your markers, like your blood markers. And for me, the earlier I can take a patient to transplant, the better it is. Because with now with one or two cycles, patients go in complete remission with DERA. I don't want to expose them to too much DERA with no reason. I would just do the minimal four cycles. If you had a complete response, I would take you to transplant. Some patients might need a few more cycles, just depends how aggressive their myeloma is. And the physician might just say, okay, let's do six if the response is not as good. But I think that was mostly with the Velcade, when a little might maintenance because with that regimen, we saw a response, not a complete response, just an initial response after four cycles, three, four cycles. So patients usually needed a couple of more cycles to go in complete remission and then go to transplant. But with DERA, it's sooner. And the least amount of DERA exposure, I think it's for the best for relapses. So we can use this drug at relapse with minimal exposure in the frontline setting. Okay, perfect. Thank you. I'll just take the last question we have, we're running out of time. So no, don't worry. On data maintenance for years post post-tum cell transplant in different had an allergic reaction to Reblimid. I'm concerned about my NK cells and overall immune system being affected, being negatively affected because his doctor won't discuss long term effects of DERA. Okay, I would say, as long as DERA works for you and you're in complete remission, stay on the DERA. Don't get off the DERA. DERA has minimal side effects, minimal side effects. It doesn't, it doesn't, it might cause a little bit of immunosuppression, but when you take DERA in the maintenance setting, remember you just take it once a month. You don't take it every week. It's minimal. It's minimal the effect of DERA in your immune system. And I would say myeloma, the greatest fear is for the myeloma to come back. That's what's going to really impact your immune system. Cause when our cancer is active, then our immune system is really low. So as long as you're in complete remission, you're doing DERA and your doctor was very reasonable. I would have done the same thing. If somebody had an allergic reaction to Reblimid and for some other reason, quality of life, they don't want to go on Velocated because there's neuropathy. I would have done the same thing. Just give them DERA once a month in the maintenance setting, really low risk drug. Does not really have many side effects. When we give it to patients more often, you might be in increased risk for infections, but with the once a month regimen, I think it just, it just has minimal side effects. I think it's, this is probably the light therapy, like the light, lightest chemotherapy that you would require throughout your course. So as long that works, just keep it on because if you stop and then your myeloma relapses, then your immune system is going to be down and you're going to require more toxic therapy, which is going to have a higher impact on your immune system. And of course, your doctor can check your immunoglobulins and if they're low, you can get some IVID just to boost your immune system. Especially if you, especially in the winter when patients sometimes tend to get some cold, colds and like some pneumonia or infections, that's an option, but otherwise keep doing what you're doing. I would strongly suggest. Okay, perfect. I'll take just the last one. Yes. It says I've been in deep response on the GlistaMAP. I did have three other lines of treatment. What is typically the line of treatment when you already, when you are already at BiSpecifix? So now we do BiSpecifix after four prior lines of therapy, four prior lines of therapy. And they have proven to be really good. Right now we do study BiSpecifix in earlier lines and even in the maintenance setting after transplant. There's going to be a trial assessing one of the BiSpecifix, which is similar to the GlistaMAP. It's called Elrenatumab after stem cell transplant, just to see if that drug will give us a longer overall survival. But yeah, for CAR-T, actually no. CAR-T a couple of days ago, it was approved for first and second line of therapy. But let's say a month ago CAR-T was approved for only patients that had four or more prior lines of therapy. It's the same thing with BiSpecifix antibodies right now. Okay. Yeah. We did post an article about that, that Jenny wrote. So interesting. You can find it in the newsletter. So thank you so much. This is an interesting presentation. We got a lot of- My pleasure. My pleasure. It's always so nice to talk to patients and high-risk myeloma is a very challenging diagnosis, but there's so many new drugs moved up earlier in lines. There's a lot of hope and already patient outcomes are so much better than they used to be. So there's a lot of hope in that field. And hopefully there are going to be soon dedicated trials to patients with high-risk myeloma and novel agents, because that's what our community, our myeloma community really needs. Yeah. Yeah. Hopefully we, I just want to make this quick mention, but we have this new, what do you call it? The Healthful Foundation that it's called the Research Hub. So- Oh, nice. They come here and do their own research with the information our patients provide. So I know we, I know not everyone is eligible for clinical trials, but these are different types of research. So I'll send you the link so you can- Yes, please. Please. I know my colleague, Dr. Banerjee has told me so many things about health theory. He absolutely loves talking to patients and getting involved. So I'll work with him next year. So I'm sure I'll get a good sense of all the good things you guys do. And thank you so much for supporting our patients. That's very important. And awareness in myeloma is so, so, so important. And I would say we have the smartest patients. You see patients with lymphoma leukemia, they don't know anything. You see the myeloma patients, they already know their disease better than you do. So you always have to be ready. Yeah. They're very well informed patients. Yes. Well, thank you for your time. I'll- Thank you. Again, that you're free to leave. Thank you for your time. I know it's late there. So- No, no, that's okay. Don't worry at all. Thank you. I really enjoyed it. Thanks so much. Thank you. Bye-bye. Thanks. Bye, everyone. Thank you. Oh, for everyone here, as I mentioned, the way we can help doctors do their research, we just mentioned, is participating in our surveys or cure hub. I'll link everything in the follow up email. Our next meeting will be in September. We don't have the specific date yet, but it will be around that month. And we will talk about dexamethasone that I know we had a lot of questions about that. So we'll tackle that. We have three upcoming events. One is an in-person event, the Black Myeloma. The first Black Myeloma in-person event will have a mingle and learn session on Saturday, the April 20th at 1130 Central Time. Then we have our M. gosmoldering myeloma event. And we'll talk about what we know and where we're going. It will be on April 22nd at 5 p.m. Eastern. And then we'll have our regular Black Myeloma meeting at 2 p.m. Eastern on the 25th. And we will talk about talking to your healthcare team. So the link to sign up for these events and some more we have coming up soon as roundtables are linked to are in the bottom of this screen. And you can just go there and register for the event you are interested in. Another thank you to our sponsors, Regeneron, Sanofi, BMS, and Johnson & Johnson. And thank you all for being here and being part of this community. Thank you so much. Bye bye.