Tremendous progress has been made in improved survival and quality of life for multiple myeloma patients. Continued advancements in effective treatment options has changed the outlook for patients and physicians.
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Introduction Newly Diagnosed Multiple Myeloma, Transplant Eligible Phase 3 Trials for Relapsed/Refractory MM Moving Beyond the 3 Core Drug Classes Therapies for Triple Class Refractory Multiple Myeloma Immune Therapies in Multiple Myeloma Targeting Approach Incidence and Management of Cytokine Release Syndrome BCMA-Directed CAR T-Cell Therapy for Patients with Early Relapse Common Treatment-Emergent Adverse Events Fixed-Duration Therapy with Bispecific Cevostamab MEK Inhibitor Repurposed for Multiple Myeloma Triple Mark Inhibition in a V600E BRAF Mutated Multiple Myeloma Patient Future Strategies Hello everybody. Welcome to grand rounds on this Monday afternoon. Delighted to welcome our uh our special guest, Doctor Joshua Rector, um who, as you may know is an associate professor of medicine and hematology and Oncology in the Myeloma Division at the TIS Cancer Institute at the Icahn School of Medicine at Mount Sinai, and the director of Myeloma at the Blavatnik Family Chelsea Medical Center at Mount Sinai. Uh He has a particular interest in immunotherapy multifunctional antibodies and precision medicine. And we're excited to have him talk to us about myeloma today. Doctor Richter. Take it away. All right. Oops, before I already messing some things up, thank you guys so much for having me. Um So yes. Uh the title of the talk today, a little bit of a play on some Charles Dickens. It's a myeloma, Carol, the story of the past, present and future of myeloma. Um Don't worry there will be, you know, a ghost of past, present, future. Um But uh I was reached out to by your chief president to talk about uh you know, the future of myeloma. And it's kind of one of those like lessons we all learn in a P history, you have to know where you are from, to know where you're going. So let's uh let's kick things off and, you know, understanding that malignancies, uh some malignancies are a repercussion of modern day life things that we eat, drink smoke encounter. Um Myeloma is an ancient disease and it's actually been documented uh on some imaging of Sarco guy from some of the great kings of Egypt that were known uh to actually have died from myeloma. So this disease does date back quite a bit of time. But you know, our first understanding of this is a disease really didn't come to the 18 forties. And this is really, you know, where things all got started. It was a letter from Doctor William mcintyre to uh Henry Bench Jones. And uh for those of you who kind of know a little bit about myeloma Bench Jones protein is really what we call uh the myeloma protein in the urine. And this really all started uh when he sent the letter saying dear Doctor Jones, no, not uh Indiana Jones. Although I do hear they're working on yet another movie. Um You know, he was looking at the urine of a patient of his and he kind of divulges into this. It contains urine of spec high specific specific gravity, it boils, it becomes opaque. It eves heat liquefies it. What is it? And this uh uh correspondence that was published. Uh um You know, over 100 and 50 years ago, really started our understanding of what this disease is. Now. The first person to ever be officially diagnosed with myeloma was a young woman by the name of Sarah Newberry. Uh Now Sarah was in her late thirties. She was diagnosed in the 18 forties and therapy back then, was much, much different than it is today. Um You know, nowadays we talk about uh revlimid and diab and antibodies and carts. Uh Her induction therapy was rhubarb and orange peel. Uh Now it may not be a shock that rhubarb and orange peel didn't really do too much for her. She went on to her second line therapy which was steel and quiNINE. Uh also didn't really do a whole lot. Uh And in her final days on this earth, uh she was actually given the latest and greatest of her day. Uh And in the late 18 forties, the greatest medical advent was leeches and bloodletting. And I try to imagine an end stage myeloma patient who probably already had a hemoglobin of six or seven was then given leeches. And it really was, you know, a horrible thing. And one day, I'm hoping we look back to what we do today, even with our successes and laugh at it. Now, uh it took a long time until we actually had real clinical studies, real medical evidence based medicine of how to approach myeloma. And the first uh randomized placebo controlled study in myeloma was published in blood uh, in the 18 sixties, sorry, the 19 sixties. So I wrote this down 1966 to be exact. And this was a head to head study of urethane. Yes. Urethane. The stuff that's underneath your floors, uh, compared against a, um, a syrupy uh, placebo drink, which was pretty much like flat Coca Cola. Uh, and this was a legitimate study. It's published in blood head to head and yes, coca-cola or Flat Coke did slightly outperform uh urethane, um you know, wood solvent. So, uh you know, again, as silly as this is, this was the path that we took to start understanding that in medicine, you can't just give something, you have to reestablish a standard of care. We compare against the standard of care and we slowly improve upon that. Um So how do we kind of progress from Cola to cure? Um You know, we look at the progress that we made and the see your website is really great at giving us a hint into where we've come and where we're going. And if you look back to the 19 seventies and the 19 seventies, the entire journey from diagnosis to death for myeloma patient was two years. Doesn't matter if you're old, young, fit, frail rich, poor two years was the median overall survival. And now we're looking at five year survival rates uh of almost 60% and newly diagnosed patients with standard risk disease diagnosed in 2023 are gonna live over a decade, if not decades. So we really come very far away from the 19 seventies. So we only have to look at what our most recent data is for what we talk about with newly diagnosed patients. And again, nowadays, you know, we still talk about stem cell transplant, autologous stem cell transplant. But uh you know whether or not you're doing that or not, the outcomes are still amazing. So here's our recent data about what we do in transplant eligible patients. And we're talking about overall response rates that are budding up against 100% with progression free survivals that we're measuring in 345 and six years, not as a total journey, but our progression free survival for our first line therapy. So young and fit patients with the latest and greatest in the US are probably getting on hold about 5 to 7 years average from the upfront therapy. Um Even if you're not eligible for transplant, if you're not eligible, you're older and frailer, we still have regimens that are getting us up to 93% response rate from the Maya study. And Maya study is a combination of Daratumumab A T D 38 monoclonal antibody and lenalidomide, a derivative of thalidomide. If we give that to the transplant ineligible people, people, the medium progression free survival. And we're not even at there yet. We haven't reached, it is greater than 60 months. Meaning in the 19 seventies, if you were duly newly diagnosed, healthy fit, no medical problems, the entire journey from diagnosis to death was two years. Now, if you're in your eighties or nineties, your first line therapy is going to get you more than 5 to 6 years. A real far cry from how far we were uh back in the seventies. Now again, stem cell transplant is still part of our core approach in younger fitter patients. And if you look at the Griffin data and this is really established as the new standard in multiple myeloma, this is your average patient that we diagnose. We give a four drug or a quad combination of daratumumab, the CD 38 antibody dexamethasone, the steroid Leidy, which is the derivative of thalidomide and bortezomib or Velcade, a proteasome inhibitor, we are getting 100% response rates. So again, sitting down with a newly diagnosed cancer patient and saying what we're going to do next works 100% of the time is an amazing achievement and a a pleasure to be able to provide in the clinic. And if you look at um you know, on the left, sorry, on the right, if you look at some of these uh response rates and survival rates, you know, they're unbelievable and people that those are pretty flat curves. Now at four year overall survival rates with a quad combination of 93%. So really newly diagnosed patients are doing absolutely amazing on the whole and we expect their survive survival not to be measured in months or even years, but some of them even decades. Now, what happens when the disease relapses? Because unfortunately, we see more and more relapsed and, you know, uh to really sit down and go through the hundreds of trials is not going to be helpful. But I really just kind of want to lay the landscape of where we're at at the moment when the disease comes back. Uh And when the disease comes back for the most part, in the early setting, we're using variations on a theme. Instead of giving one thalidomide analog like revlimid, we may use palmy instead of using one proteasome inhibitor like Velcade, we may use Carys aid instead of one CD 38 like diab we use is Touma. And these studies here are for the most part, just 2nd and 3rd generation drugs of the same class of agents. And we see progression free survival rates here ranging from around 11 months, all the way up to around 30 to 40 months. If you look all the way to the right, those not reached, I apologize. This has been updated at, at uh recent meetings and when you combine Carys, which is a second generation proteome inhibitor with an anti CD 38 antibody, our our responses are really measured in the 30 plus month rate. So again, you take about a 5 to 7 year upfront, you add around a three year second remission. And again, patients can get multiple lines of therapy. And pretty soon you have your decade of response for most patients. But again, there are still people relapsing after that and there are people with high risk disease that aren't even doing that well, that we need to look for the next generation. So where we've been in the last 5 to 10 years has been staunchly in the three core classes of drugs for myeloma, the Holy Trinity of, of Myeloma therapy, which has been thalidomide analogs, thalidomide, Leny Liam and palm uh proteome inhibitors, Tez Carib Sazi and CD 38 monoclonal antibodies, Daraa and Touma. And for the most part, our front line gives some of these, our second line gives others and third line gives what's left left. And that's been the core of our approach for the last decade. But we're now we're moving beyond that because number one that, that cures almost nobody. Uh and everyone relapses and some people relapse very quickly. So we're starting to understand the new agents that we're really looking for towards the future. Now, some of these are already approved drugs like Cellex or uh a selective inhibitor of nuclear export that's already approved in people who've gone beyond these three. Um and drugs like Veneta claques can be used. But really what we're looking towards in the next generation is the T cell redirection therapy. Uh take basically doing something to take your T cells that are fighting off bacteria, viruses and not enough of them are fighting the cancer and taking them and redirecting them towards attacking the cancer. And this is mostly coming in the realm of cart therapies and by specific specific antibodies and coming up down along with that is the kind of next generation of thalidomide analogs that are even more potent Ibert amide and Zam, which we'll talk about as well. So what do we do when you become refractory to those three classes, images or derivatives of thalidomide proteome inhibitors and monoclonal antibodies. How are we doing right now? Not. Well at all, if you look at the progression free survival here, the second to the bottom row, when you get beyond those three drugs, the medium progression free survivals are measured in a handful of months with overall survivals barely eking out a year for most patients. So, so this is a huge unmet need that we're starting to chip away at. But again, uh to quote, staying, we're starting up a brand new day and this is where T cell redirection is going to lead the pathway for extremely long durations for some and for some people, probably a cure. So, what are we thinking of when we're thinking of T cell redirection? Well, well, basically what we're talking about is using our own immune system, harnessing our effector cells to attack the myeloma in the day gone by, we used to use allogeneic transplant. Noticing that in a normal state of things, our immune system fights off the cancer. But when the cancer gets too big, if you bring in somebody else's immune system that can fight off the cancer, the problem is allogeneic transplant and myeloma carries with it a minimum of a 10 to 20% mortality rate which is not quite acceptable. So the new gestalt is saying what if we can harness the patient's own immune system to work better and we can harness N K cells, T cells, macrophages. And we have a litany of targets both on the cancer cells and on the effector cells and trying to find the right combinations to get them together. Now, we're going about this in a large number of ways. Now, we can go about this in the standard antibody approach, you generate an antibody that attacks something that's on the cancer cell and antigen and you try to kill it directly that way or you can bring two cells together or we talk a lot about in cancer about immune checkpoint blockade. Essentially, our body makes T cells and immune cells all the time and has a natural checkpoint on it. Because if you let that system go wild, that's what autoimmune disease is. But sometimes in cancer, you, you want the porridge, not just right, you want it a little bit hotter and the way to do that is to remove that immune checkpoint or a better way of thinking about it. If you're on the highway, driving a car and I tell you to go faster, the answer is not step on the gas. It's easier, foot off the brake and maybe trying to find a better sweet spot where our immune system doesn't go full blast into autoimmunity, but settles a little bit higher level to fight off the cancer. So, you know, really, what's the archetype of this is car T cells, chimeric antigen receptor T cells. And this has been uh an amazing technology which is already FDA approved in Leukemia lymphoma. And now we have two FDA approved car T cells in myeloma. Now, although this has been fairly recent, the concept of carts dates back almost 30 years uh to the original generations of this concept, the notion that we can re off someone's T cells, we can engineer them in the lab to all attack a specific antigen. In the case of myeloma. Right now, we're all targeting them to attack BC MA or B cell maturation antigen. And then we can give them back to the patient to fight off the cancer. And here's a little concept of how it works. We take the T cells, we use viral DNA insertion that now expresses the antigen receptor and then it goes and attacks the tumor cells. And this is really uh almost the revolutionary way of attacking cancer. And although this is approved in these three fields, uh We are now evaluating this in solid tumors as well. Now, really the data from this comes originally from the Karma study. Now, this is pretty much what we talked about. We leuco or collect these T cells. Uh We give you bridging therapy basically to hold the myeloma under control while we manufacture the T cells because right now it takes standardly about 4 to 8 weeks to manufacture the T cells. Now, we can't just infuse them into you because that would be a voice among the crowd. We need to create immunologic space. How do we do that with lympho depleting chemotherapy? So right now, even if we re off your T cells and engineer them, you still have a diverse T cell repertoire. So you want to create that space, you basically turn the patient into an aids patient. You give them fludarabine and cyclo fos to clear out their endogenous T cells and then we infuse the engineered T cells as the dominant force to attack the myeloma. Um Now, in a space where as you saw previously, the patients who were factory to the three prior lines had a median response rate of around 20 to 30%. A median progression free survival of around 3 to 6 months and a median overall survival of less than a year. Here we start to see IO which at cellular doses of 4 50 is giving us an 82% response rate. And when we look at responders, if you don't get a good response, a partial emission or worse, which means only 50% reduction of the myeloma, you do dismally. But for those who achieve a complete response, your medium progression free survival is up around 20 months. A far cry from the 3 to 6 months of our standard therapies. Now, what happens about side effects? Well, if you're infusing a T cell, the first thing it's going to do is start to engage that antigen and recruit other T cells and expand and it releases cytokines I 01 I 06 T N F alpha T G F beta I L 10 IOL eight, they all go up through the roof and you can develop cytokine release syndrome, which is the main toxicity of any T cell redirecting therapy. C R S is uh associated with high fevers, tachycardia, hypoxia hypertension and can look very much like an infection. So we have to kind of figure out from a clinical standpoint and timing standpoint. You know, if you have a cancer patient who shows up in the er hypotensive tachycardic febrile. The answer here is not seine in vac or as Mount Sinai calls it vaca. The answer is therapy to lower the cytokine levels to quiet down the C R S in general. Our first approach is to give tocilizumab an anti six antibody. Now, what happens when those activated T cells cross the blood brain barrier. Well, you can get something called icons, immune effector cell neurotoxicity syndrome. And those activated T cells can actually go up into the brain and cause anything from a little bit of headache and confusion to coma, seizure and even progress to things like Parkinson's disease. Uh And this is another modality we need to watch out for when altering our T cells. The carti tude, one study looked at a slightly different constructive cart same scenario, patients who would progress beyond those three prior lines, but this was a slightly different engineer product. And again, these were patients who had six prior lines of therapy that refractory to everything. But here we saw a 97.9% response rate when we gave this, the median time to first response is a month. So again, we're having patients respond very quickly, which is crucial because if you're refractory to that many drugs, your disease may be blasting off. We need something that's gonna work very quickly. The median duration of response to this therapy is two years, medium progression free survival of 24 months. We're really getting amazing responses in a heavily refractor group of patients. And again, some of our overall survival metrics are not even reached. So in a heavily relapsed patient, we are changing the paradigm of what we can do for them. Now, this is a more effective product, at least on the surface. Now, there are some differences in the trial components between this and the previous one. There were fewer patients that maintained disease control during that bridging time and there was more extra medullary disease disease outside the marrow in the karma study, which is why some of those response rates are lower. But the toxicity here does seem to be a little more pronounced, higher levels of C R S, higher levels of icons and what we call M N T S, these motor neuron issues that can cause a parkinsonism like disease. Now what happens when we start to actually compare what happens to a patient directly, at least the matched adjusted indirect comparison between patients and later stage myeloma who get standard therapy versus car T and slide. After slide, you're gonna do way better in the heavily relapsed setting. If we get a car T as opposed to a standard therapy, how much better? Well, the overall response rate in the real world analytics is showing about a 32% response rate, 76% if you get a car t medium progression free survival. Again here, this is real world data 3.5 months versus 11.3 months. But we're starting to figure out ways to optimize carts even better to improve that even more. Now, what we're starting to say is, you know, any time you give any therapy in myeloma, the later on you give it the worse the response the earlier on you give it the better response. So what happens when we take car T cell therapy and moving it up to an early relapse, not a relate relapse. And this data was recently presented. Again, this is Ilta cell also called Carvi giving the patients with early relapse. It has a 100% response rate and again, the data is early. But so far, these remissions are extremely durable. So, uh you know, I think what we're starting to understand is that manipulating the immune system in this way, when you start to use it towards the end, you may be dealing with an exhausted T cell. Remember that we're trying to collect T cells and engineer them. But what does A T cell look like after you've had 10 lines of therapy? It looks like me after being on call over a weekend, it, it doesn't want to do as much. But you know what if you take a well rested Saturday morning or Monday morning T cell? And that's the idea of early collection of T cells that you may collect a more fit and aggressive T cell that you can then engineer and then get a better response on the back end. So what are we doing to improve this? Well, so far we have the two approved car T cells and they're doing amazing. Um Now, what about alternate manufacturing? So alternate manufacturing. Well, what if you are able to manufacture right now instead of 4 to 8 weeks. There's the fast car out of China that gets manufactured in 24 to 36 hours. Again, if you have a patient whose disease is taking off and you can give him this therapy in a week. As opposed to two months, you may get better outcomes. What about adjusting the target, the antigen, the engaging the epitope, all of this may lead to better responses. What about allo cars? So the A 07 15 trial is saying, well, auto cars are great but they still need to be manufactured. What if you had an allo car ready to go in your cellular infusion lab? That you can literally say, oh, you're progressing today, you get lympho depletion tomorrow and then you get the car t that may be the next generation. What about different targets on myeloma cells? Right now, BC MA has been the main target. But when you attack BC MA, you don't just kill myeloma cells, you kill everything else that BC MA is expressed on BC MA is expressed on early B cells, some mature B cells. So now we're looking towards newer targets like G PR C five D, which is more selectively expressed on plasma cells or really malignant plasma cells so that we may get fewer off target effects. And when you don't kill those off, when you don't kill the other B cells, you may have lower rates of infections and other complications. But to me, some of the big areas of interest are really going to be bi specifics. And by specifics again, right now, they have two arms, one grabs onto a target on the myeloma cell. The other grabs onto a target uh called CD three, which is located on T cells. To me, this is the wave of the future and this has to do with practice patterns of myeloma in the United States in the United States. The average hemo doc your average doctor somewhere in the midwest sees 0 to 10 cases of myeloma per year. I'm insane and I see 60 to 100 a week. However, there are way more of them than there are of me. And about 80% of all my alone in the United States is treating the community, the community is not able to give carts, they don't have cellular infusion, they don't have the expertise. It's something that is not going to make it there so quickly. If you think about auto transplants, despite the fact that it's a standard in the US. Only 30% of transplant eligible patients get a transplant in the US for a lot of reasons including lack of access to a transplant center. Car keys are more complicated. So how can we bring immune therapy to the masses and make sure that if you're in, you know, New York, you can take a rock and you can hit a major medical center. There are places in the country, you have to drive 3 to 6 hours to get to one. What about bringing immunotherapy to your average he Monk doc or two person practice down the block? And that's where bispecificity coming. And there's a number of targets that are really coming in as being major ones. BC MA G PR C five D and F C R H five. So right now BC MA bi specifics have been the real windfall and so far we already have one approved. It's Alisa, the BC MA CD three by specific was approved by the FDA. This past year. It is available in the clinic. El Reata was filed for FDA approval a week and a half ago and we're hoping to see that within the next six months and these other therapies are also available. And again, response rates for most of the bispecificity in heavily pretreated patients are a ranging from 60 to 80%. So Talisa was the first of these and it was approved at the end of last year based off of the majestic one study. And here is the data for that. And again, this is a diagram in the middle of the drug. The bispecificity engages the myeloma cell, it engages and activates the CD three positive T cell and leads to local cell kill. Um an extremely effective drug response rates of around 63%. And as you can see with the swimmer's plot on the left, most of these, if you look right now, about 70% of patients in the original trial are well beyond a year, still in remission with their progression free survival much better than our standard therapies. Now, Reata is a similarly constructed BC MA by specific, again, this was filed for FDA approval about a week and a half ago, same concept. And again, we're also seeing response rates here of around 64% and patients staying in remission well over a year now, because these drugs can also induce cytokine relief syndrome. The way that we mitigate it is by doing step up dosing, you give it a little bit of the drug and a week later, you give a little bit more of the drug. Uh And right now, Talisa involves patients being admitted to the hospital for 7 to 10 days during the step up period. And management of C R S A reata is shorting it, shortening it to about five days and doesn't even need a step up dose. But again, here we see patients on the Kaplan Myer curve for magnetism, one median duration of remission of 17 months. So, whereas car T is a one and done, you get your car t and you're off therapy after that by specifics at the moment, you continue them as long as you tolerate it. And as long as it stays in remission. And again, we can treat people here so far in magnetism, one meaning duration of response, 17 months and again, it's same types of toxicities. We see uh hematologic side effects. We see a number of uh C R S and icons events. The other big issue is infections. So when we're treating patients, remember one of the consequences of redirecting T cells is that now nobody's minding the shock your T cells that were ready to fight off viruses. Bacteria fungus are now over here fighting the myeloma. So it has become a major issue is we're able to control people with these drugs very well. But we're starting to have a lot of later complications of viral bacterial and fungal infections and are seeking ways to better offset this risk. Much of this is coming in the way of giving supplemental intravenous immune globulin. And the other thing that's back on the rise is Pneumocystis pneumonia in the old days when the only thing we had to treat myeloma was dexamethasone. Most patients were treated with what we call pulse, 40 mg of dexamethasone, four days on four days off, four days, on four days off, et cetera. Once we started having our newer agents, we stopped doing that and the rates of PC P dropped now that we're redirecting T cells again, making patients functional aids, patients P JP rates are back on the rise and we're starting to have to prophylaxis patients all over again. Now what happens is when we start combining these bispecificity where we take Talisa, they already approve BC MA bispecificity and start combining it with drugs like Lena and Diatom. Well, now your overall response rate is jumping up to 93% with over 90% of patients getting a V G pr or better. That means a 90% reduction in their myeloma or more. Again, the problem is now you're knocking out any cell with BC MA, you're knocking out any cell that expresses CD 38 infection rates are through the roof. So as our response rates are climbing higher and higher, we need to continue to find ways to optimize patients from an infectious prophylaxis standpoint. How do you sequence all of this? There's so much to do. Can you sequence these therapies? Most of the studies didn't allow a lot of prior T cell redirection, but some of them did. And we note that although you still can't eke out responses, your responses are muted when you sequence BC MA therapies, for example, in reata, the overall response rate was 54% with a prior BC MA. If we look at some of our internal data, this is still better than any other therapy. So if you have a patient that's refractory to everything, the best thing to do is to give them a T cell redirection. If they progress beyond that, if you give them another T cell redirection, they're not gonna be as good as that first one, but it's still better than anything else we have to offer at the moment? What about the non BC MA targeted by specifics? Well, there are three main ones and one of them is a bit far behind the first one is Takuma. Now Zuma was also filed for FDA approval uh at the end of last year and we're expecting Talma to be approved in either quarter two or quarter three of this year. This is A G PR C five D CD three by specific for him to make is an earlier phase G PR C. Uh by specific specific, it's a bit farther behind only in phase one data. The other target uh is F C R H five. Another ubiquitously expressed antigen on plasma cells. This drug is a little further behind uh than Thuma, but we're likely to see approval in 2024 or 2025. The benefit here is that BC MA as a target, it is a problematic issue from an infectious standpoint. So trying to find a more specific target to minimize other immune cell killing is to our advantage. So Taima and the sentinel work was actually done here at Sinai with the New England Journal of Medicine article published by Doctor Raja Chari is the first author uh was really leading the way in the non BC MA targeting by specifics. Again, response rates here were extremely high, 70 even 80% in some of the cohorts. And again, infectious rates are a bit lower. The one complication is G PR C five D. Although not expressed in a lot of other immune cells has other expression. It's expressed on the squamous epithelium of the hands and feet, salivary glands and lining of the G I tract. So, the main toxicity of this drug besides cytopenias and some infections is a risk of dyschezia, weight loss and a declamation, hand and foot rash. The monumental one study is what is really leading to the FDA approval. And here is some of the data looking at what happens in patients who already had T cell redirection. Again, as opposed to 70 80% you're still eking out a 63% response rate um and significant durability so far. So really looking for sequential T cell redirection, potentially with alternating targets as the next generation of myeloma therapy where you give ABC MA, then a G PR C five D and an F C R H five may be in different orders. Now, again, mechanisms of resistance are not solely related to antigen loss. Meaning when you progress on ABC MA by specific specific, it's not necessarily that you no longer express BC MA. Uh it's that T cells may becoming exhausted and we may need to reinvigorate them. Uh So a lot of great work being done there. Sosa is our F C R H five CD three by specific which we are doing a lot of the work here. Again, F C R H five is ubiquitously expressed on myeloma cells a little bit on nor normal B cells but not a whole lot. Now, one of the things that we noted is that C R S rates with these therapies can be quite high, 70 80 90%. This is what's requiring us to admit patients to the hospital. And part of the reason why although at Mount Sinai and our system, we are well equipped to admit patients to deal with this but not in the community admitting patients for a week to 10 days, not so easy giving patients a drug that has a 70 to 90% chance of cytokine release if they're older and frailer is not gonna be ideal. So what can we do to mitigate this? What about giving prophylactic Touma? So prophylactic Aisle six blockade and what we saw in this study is we saw a reduction in the C R S rates uh dropping from around 91% to 38.7%. Now, two things come to mind if you're blocking aisle six. Number one, are you blocking some of the efficacy? And the short answer is no, even in this small study, those patients that had prophylactic Tosa actually had a higher response rate probably because they were able to stay on course with their drug a little better, but it still remains to be seen is do you have an increased rate of infections because aisle six is part of the prodrome of inflammation that helps fight off infection. And when you blunt that you may put yourself at risk for further infection. Again, it's a one time dose of the drug. So it may not be a big concern, but we're still trying to tease that out. The other issue is at the moment, we are giving our bis specifics continuously. You stay on it and you're on it, so you don't tolerate it or progress for Talisa, the FDA approved by specific, the drug is given once a week every week, no break by the FDA label. That's a harsh thing for patients to literally come in once a week. What if there was a way to rationally stop these drugs and mitigate a risk of relapse? Now, the Saouma trials are designed to give 17 cycles and since the drug is given every three weeks, that pretty much amounts to one year of therapy and then we stop and observe and if you relapse, you can restart the drug. Now, we have some data that we presented at Ash and we're gonna present at the upcoming Comey meeting showing that we have a large number of patients that were able to maintain their response. What's really interesting is that anyone who had a string and complete remission or deeper has not relapsed yet. So maybe we're starting to enter a realm of biologically driven response mechanisms by which we can alter our course of therapy meaning just like in the carts. If you had a deep response, you did well, if you didn't, you did not do as well here. If we're able to deepen your response so much that you achieve a stringent and complete remission, maybe that's enough to stop our bios specifics and not only get you off therapy but give your T cells a break and a chance to not be completely exhausted, take a couple of breaths and only reengage them when they need to be engaged so that a therapy works better and b they can go back to mining the shop to prevent other infections. So the wave of the future of bispecificity is going to be fixed duration and probably driven by depth of response. Now switching gears to some of our other therapies. Uh The new derivatives of thalidomide also called cell mods. Now, cellmo is a marketing term, these are all derivatives of thalidomide. So thalidomide, Leny Pym and now the 4th and 5th generation Ibert amide and Mazy Amide. These studies have, these studies are ongoing. We are running them here at Sinai. Uh And originally, we're seeing Ibert amide uh here given at different cohort levels uh as a dose expansion alone with dexamethasone here, this is showing us pretty much what we're seeing uh with our standard therapies and late therapies, a response rate of around 26% with disease control rates that are not tremendous. Uh And again, when you combine them. Yeah, your medium progression free survival here is 13 months, which is pretty good. But what is more important is the future of these therapies is likely to be given in concert with carts because at the moment, we're not curing with carts and one of the drawbacks and one of the reasons that people progress after carts is T cell exhaustion. Well, what do thalidomide analogs? Do they upregulated M K T cells? So maybe you give a cart to knock people down and you maintain N K T cell activity by giving them a pill like I betide, those studies are ongoing. Now, we're starting to notice that these drugs are overall well tolerated and Ibert amide has actually less myelo toxicity than reveled our standard drug. So there's a push to start moving Ibert amide into every place that menotomy exists because it seems to have a more potent efficacy and less in the way of lower blood counts. Now, what happens? Of course, we're gonna combine this with other therapies in the big phase 12 studies are combining Ibert amide with daratumumab and Borte. And now we're starting to see response rates get a little bit higher, 40% 60%. So again, it's really about inventing a drug and then optimizing its use later on. Um what is looking at the next generation beyond Ibert amide is Mazy also called C C 924 80. This data was just presented at ash a few months ago by Paul Richardson. Again, these are pills. So when we talk about health related quality of life, giving these big carts or immune effector cells. Wonderful. But if there's a way to maintain the response with the patient at home, taking a pill a day, that's a lot more optimal. And again, now the pill alone is showing response rates of 40 to 50% including patients who had prior BC MA therapy. So again, this is what happens when we look at the drug towards the end, what happens when we move it further up or what happens when we take a patient who's not progressing but in remission from their myeloma, either with a T cell redirecting bispecificity or a T cell redirecting cart. And instead of continuing to pummel the T cells with more redirection, we just up regulate the whole thing with an uh a cell model. And on the last two minutes, I kind of want to talk about a few other approaches that are really changing the way we approach myeloma. Now, there may be people on the call who remember the days where we used to give Interferon for everything. Hopefully, a lot of you are young enough not to have to live through these days. But there was a point in time where for C M L myeloma HEP C, we were giving Interferon. Now, one of the main issues with Interferon is that it gives you, depression like symptoms, suicidal ideation and makes you feel generally awful. However, what happens when you approach this great cell kill from the standpoint of an antibody drug conjugate. And that's what Moda alpha is. You take a CD 38 bispecificity. It links on to the CD 38 myeloma cell and injects the interferon. This data was recently presented by Dan Fogel uh at the 2022 ash meeting. Now, the response rates here were around 43% with uh a bunch of responses in patients with heavily pretreated uh disease. Now, this may not be as fancy as some of the T cell redirection but the average myeloma patient in the US is 70 years of age with multiple comorbidities. Not everyone is going to be either have access to or be a candidate for T cell redirection. So this is gonna be a nice alternative for some of our patients in the community who don't have the access to some of those more aggressive therapies because this is not associated with any T cell activation, no C R S, no icons. The other thing is the concept of repurposing of uh some of our clinic, some of our other drugs. So it turns out that myeloma uh the way we approach it is not from a genomic standpoint, we give the combinations we give because these are highly active therapies. Well, it turns out that myeloma has when we do deep sequencing or next generation sequencing, we can find a number of what we call actionable mutations. And as we can see here, this is a list of some of the more common mutations, things like K ras N R F G F R three B R F P I three K. And the reality is many of these genomic aberrations already have drugs that are FDA approved and other cancers. Many of these ras mutations are seen in lung and G I malignancies. B raf mutations are seen in over 90% of melanomas. F G F R three is seen in G U malignancies, et cetera. So what happens if we do deep sequencing and we can identify these mutations in a myeloma patient? Well, we can use these drugs that are already approved for other diseases but use them in the myeloma space. And here's one of our patients who responded amazingly well to this type of therapy. Um We're actually doing this from a clinical trial standpoint with the my drug protocol which is being led by the M M R F. We take patients with what we call functional high risk disease or what does that mean? Well, when we first evaluate a myeloma patient, we look for genetic abnormalities, things like P 53 mutations, p 53 being the big bad proto oncogene and we call them genomic high risk. What a functional high risk is is if the standard response to treatment upfront is 5 to 6 years and you relapse in a year. It doesn't matter what your genetics show you are functionally high risk. You're behaving poorly. We deep sequence these patients, we give them a backbone of a steroid, an image and a proteome inhibitor. But add on 1/4 drug which specifically targets the actionable mutation in that individual. You get a ras mutation, raft mutation I DH CD K to provide a personalized approach. The concept of personalized medicine has been the brass ring of myeloma for generations and we're starting to do this in the clinic. So this is uh a patient of ours that we took this approach. This is a patient who had many, many, many relapses and there was nothing left available. We did a deep sequence off of the study and found that they had what we call a canonical V 600 E B raf mutation. We took a combination of three drugs, the NIB which is a B raf inhibitor trei, which is a mec inhibitor and regain. Now the reason you have to use multiple drugs is if you remember these pathways back to your first year of medical school, you know the ras raft mec er pathway. If you block one of these, the disease will find an escape pathway around it. So you have to use multilevel blockade to get around the cancer, finding escape pathways. But again, in a patient that had no other options, this was a driver mutation of their malignancy. And as you can see, after three months, they were in a complete remission. So, really leading to personal therapy. So in kind of closing, this is the natural history of my alone, right? We diagnose patients, we decide to treat them. Uh we go through real admission, relapse, remission, relapse. Eventually we get to refractory to our main classes of drugs. And then our general outcomes are dismal. A study called the Mammoth study. Looked at what happens when you're refractory to our main five drugs, reveled polis Velcade cars. When you become refractory to those five, the so-called pento refractory, your median overall survival is 5.6 months is absolutely horrible. What does the next generation look like in the next 10 to 20 years? A completely different concept? We've gone through the three epochs of myeloma from the classical chemo days after world war two to the novel agents in the late nineties and early two thousands. And now to the realm of true immunotherapy with T cell redirection. Our upfront therapies are able to give us a 100% response rate. When we redirect T cells in the first relapse, we can get 100% response rate. What if we sequence this properly to get everyone into not only a deeper mission but an extremely deep emission, what we call M R D negative, minimal residual disease negative. That means on bone marrow aspirin, we do not find one cancer cell in 1 to 10 million cells analyzed. Maybe right now, we're treating everyone to progression or intolerability that we don't need to. Maybe if you can get them down deep enough, you can stop. And if they have a relapse, you can come in with another T cell redirection with a reinvigorated T cell group. Combining the concepts of bispecificity. T cell engages car T therapies, antibody drug conjugates and some of the newer constructs like tris specifics which engage a myeloma cell A T cell and also have a checkpoint inhibitor to take that break off to make sure we maximize the T cell efficacy. Those drugs are in trial here at Sinai as well. So we're really looking towards a new realm where when I started doing myeloma, I said, I'm sorry, we don't cure myeloma. It's an incurable disease. When patients come in today, I say we're curing a small number of patients by accident. We give an 80 year old, these combat nations and they die at 90 of a heart attack and never relapse. They were functionally cured. But the future of myeloma is intentionally curing everyone through manipulation of the immune system in a very intentional way. And with that, I, I think we're actually coming into a new realm where myeloma in the coming decades will be a cure of malignancy. And with that, I will thank you for listening to me and take any and all questions. Uh Thank you so much, Doctor Richard. What an incredible, uh, talk. Such a fascinating topic. Uh, thank you for, for giving this, uh, uh, this great, great lecture. Now, I'd like to open it up for questions. I think you already got some chats about halfway through, uh, from Doctor Parsa. If I could bring them up here, I could read them out to you. Uh, hi, Doctor Rich. You're sending this question for the end of the talk. Is there work being done on figuring out whether we should stop therapy for patients who have been on a bios specific, specific for X number of months with no detectable disease. Do you think we should give prophylactic I V I G for the bio or sorry for the uh specific patients or treat a decided upon number looks like he started to address some of the question while he was typing. Yeah. So, um you know, there's a few things, one is the depth of the response that M R D negative or not. The other is the genetic phenotype. Do you have high risk disease or low risk? And we're starting to understand from some of our trials that good risk disease that gets undetectable, you can probably stop so far any time we try to stop in high risk disease, it comes back more aggressive. And the doctor par comment. Yes. One of the big toxicities of all of these therapies is hypogamma globule anemia. Now, which we can fix with I V I G. The big question is, should we give primary prophylaxis or secondary prophylaxis? Primary being we just give you the I V I G when your immunoglobins are low, even if you have no infections, secondary is you have an infection. And now we're playing catch up in general, we mostly give secondary except now we're starting to give primary and T cell redirection. So everyone who gets a car, T gets I V I G until their munos are recovered. And we're starting to have conversations about doing something similar with the bispecificity. Excellent. OK. Any questions from the audience for Doctor Richter? Yeah, I got a question. Sure. Sure. Would I come up? Sure. Yeah. Doctor, it's Eddie, I think uh I was in your service uh uh a number of months ago, but uh just a quick question. Um Thank you so much for a great, great talk. Um So, so it seems like the biggest problem uh kind of like a big, big picture is the relapse. Uh At least uh it's one of the biggest problems. And is there a way for us to actually be able to tell uh if a patient is more likely to relapse than another patient and if there is anything else that we can do really to kind of get ahead of that? Um And uh maybe like uh using other car T cells or uh another therapy. Uh Another one of the newer approaches to kind of uh make sure that uh we can extend that uh progression uh or uh extend that uh uh time uh point until they relapse. So I'll answer this in two parts and it's a phenomenal question. One is the therapeutic, the other is the diagnostic therapeutic that trial is on is starting, which is right now, the standard is induction and transplant. But we have a study saying that if we go through all of that and we still have any detectable disease, we have a trial to come in at that point with the car t to make sure we do everything we can to prevent a relapse because we've shown the deeper the emission, the more durable. So if we get you from up here, down to there and there's still a little bit left, maybe that's the best time to come with a cart that trial is underway. Now, the other question of a diagnostic one is being done by the Italian group under the helm of Bruno Piva. Now, we all know that people can have an MGUS and you can be diagnosed with an MGUS that never progresses. And part of the rationale is, well, there's kind of a two part to that. Why does it not progress? It doesn't progress because the disease itself is not aggressive and the person's immune system holds it at bay. What happens if after all of our treatment, there's still some disease but it has an MGUS like phenotype, meaning even though it's still there, it's benign stuff that's left and the immune system is recovered to hold it under, under control. Bruno is doing this great work to identify these patients that we will never eradicate their disease, but we actually convert them from myeloma to angus. And now if you're a 75 year old with a low grade angus, that's never gonna progress, maybe the answer for you is not to keep pummeling this because we'll knock down your good immune system. But maybe your disease is good enough and your immune system is good enough where it's not gonna go anywhere. So that's part of the next diagnostic dilemma is maybe you don't need to kill it all, but you just need to kill the bad stuff and let the rest of the immune system recover. Oh, thank you. All right. Great questions so far. Let's see. I think we have another chat. Oh, just a thank you from Doctor Rupani. Ok. Any other questions from the audience for Doctor Richter? Nothing from in person audience and looks like no chats here. So, Doctor Richard, thank you so much for your time. Wonderful lecture. Uh Welcome back. Any time we love to again in the future. Thank you so much for having me and I wish everyone a great rest of your day. Thank you.