(Guest Lecture): March 2024 - Real-World CAR-T Data Update

So the topic today is real-world CAR T data update. And we chose this topic because myeloma patients and their loved ones have been learning a lot about this novel CAR T therapy. And it's improving significantly our myeloma care. So a lot of the information we have come from clinical trials. And we are learning a lot of new information. So we want to have a specialist so he can explain more about this. So I will introduce him. He's a medical oncologist specializing in the care of people with multiple myeloma and related plasma cell disorders. With his colleagues at Memorial Sloan Kettering Cancer Center, he's focused on identifying optimal treatment strategies for people with these disorders. His research focused on the development of novel immune and cellular therapies, including humeric and T-gen receptor CAR T cell therapies. We all know that term, right? For patients with myeloma. He also serves as the clinical director of the cellular therapy service at the research director of MSK. So I will turn the time over to Dr. Myelin Kody. Oh, we thank you. Thank you so much. And thanks everybody for joining. I have a few slides that I can share very quickly. Okay, so we're going to try to cover in the next 25 or so minutes some of the highlights of CAR T cells, what they are, where are we using them currently, why are we using them, and then I'll open it up for questions. These are my disclosures. So we're going to talk about clinical data for particularly CAR T cells, but I have a few details for bispecific antibodies, which is a closely related treatment that we use in the same setting. I'm going to talk about using them where we are currently, which is for patients with advanced multiple myeloma, but also the potential use of these CAR T cells for patients with earlier lines of treatments for patients that have not received as many lines of treatment as in the initial approval of these products. Then talk a little bit about what is happening in the research side for these CAR T cells, new targets, different CAR T cells that are being developed. Talk a little bit about this approach called Allergenic or off the shelf, and we'll come to why that's important and why do patients not respond to these treatments when they don't respond and what can we do about it going forward. So this is just an overview of some of the available myeloma treatments over the last three decades. So actually over the last six decades, but most of the activity is here to the right in the last 25 or so years. So we've, as many of you, all of you probably know, there's been a substantial amount of progress in drug development for multiple myeloma in the last 25 years with the introduction of multiple new drugs and treatments. For instance, immunomodulatory drugs. These are drugs like thalidomide, lenalidomide, pomalidomide, proteosome inhibitors. These are drugs like Bortezomib, curfulsomib, exasomib, antibodies like daratumumab, esatuximab. And in the last five to 10 years, the development of these immune treatments called CAR T cells and by specific antibodies. And many of these treatments are now FDA approved and these treatments have led to patients with multiple myeloma living longer and living better due to improvements in outcomes related to the development of these different treatments. Specifically, the focus of this talk is these two T cell redirecting therapies or immune therapies. On the left is what a typical CAR T cell looks like. So this purple here is a myeloma cell. The green is a T cell. T cells are all immune cells. We all have them in our body. They're part of our immune, our defense system. Now, what we do in CAR T cells is take these T cells out and genetically engineer it to insert what is called as a chimeric antigen receptor. That is this whole domain here that's called a chimeric antigen receptor. And the reason to do that is to help the T cells recognize a protein that's specifically present in myeloma cells. So this red here is the protein that's present in the myeloma cells. This purple bar can go and bind itself to this specific protein. In the case of myeloma, typically that protein is a protein called BCMA or B cell maturation antigen. This antigen is primarily present in myeloma cells, very little to no expression in any of the other normal tissue. So we re-engineer these T cells to recognize and go after cells that have BCMA in them and thereafter get rid of it. Not only do they recognize and bind to it, but also get rid of these T cells. So that's the essential idea. Take the T cells out, engineer it so that it's able to recognize tumor cells, wherever it is, and then get rid of the tumor cells. And it's called a chimeric receptor because this receptor is not a naturally occurring receptor. It's a chimeric. It's a hybrid of different parts. It has a part that recognizes the antigen and it has these two parts here that allows the T cells to attack the cells that have this antigen and get rid of it. So that's essentially what a CAR T cell is. Now to the right is a bispecific antibody. The reason I have it here is they're somewhat complementary to CAR T cells. So bispecific antibodies are drugs. These are not engineered T cells, but these are drugs. But they do something similar to the CAR T cells. On the one hand, they bind to a protein present in the tumor cells, say for instance, BCMA or B cell maturation antigen. On the other hand, they bind to a protein that's present on the T cells, say for instance CD3, which is a protein that's present in T cells. And by doing this, they bring the T cells in close proximity to the myeloma cells and again help the T cells attack and get rid of myeloma cells. So both of these treatments use our own T cells, the patient's own T cells, to redirect and attack and get rid of myeloma cells. So that's essentially the two approaches. In one case, we have to take the T cells out, genetically modify, engineer, put the cells back in. In the other case, we give a drug. So therefore, there's not this process of taking cells, engineering, putting them back in. We just give a drug similar to many other drugs that patients get for treatment of multiple myeloma. And as the next few slides will go through, both of these have shown promising results in terms of efficacy in treatment of multiple myeloma. So I guess one more slide of what practically happens when somebody, when a patient is getting current T cells. Like I said, we have this multi-step process. We have to start with this first step called leukophoresis. This means collecting the patient's T cells from their blood, as shown here, using an either a peripheral IV or a central line, which helps us collect the T cells from the patient. This process is relatively simple, takes about three to four hours, one single day. There's no additional medications needed prior to collection, et cetera. And so that's the first step. Once the cells are collected, the cells get sent to the pharmaceutical company or the laboratory that makes the engineers the CAR T cells, where they use viral vectors. These are inactive viruses that help deliver the chimeric receptor into the T cell. So we insert these viral vectors with the T cells into the T cells that makes the CAR T cells. Once this is made, they then expand the number of T cells so that we have the adequate required dose to put back into the patient's body. Once all of that is done, and this whole step from leukophoresis all the way to the completion of manufacturing can take anywhere from three to six to eight weeks. There's also quality check and other other steps involved here. But essentially that whole process can take somewhere between three to eight weeks at this point. Once all of that is done, now we have CAR T cells that are ready, customized, made specifically for the patient. The company or the lab that's making these T cells will send the cells back to the doctors or the hospital where the patient is being treated. Before the cells are put back into the patient's body, there's yet another step where we give some chemotherapy called lymphodepletion that's listed here. And the purpose of giving this chemotherapy is to try and reduce the number of the patient's only immune cells so that these new engineered T cells can go in with minimal resistance. So once the T cells are ready, we do this chemotherapy. It's usually three days. It can be done as an outpatient. Usually involves two drugs. One is called floderabine. The other one is called cyclophosphamide. The doses and intensity of treatments are much, much lower than, let's say, a toll on the stem cell transplantation, for instance. And they're, like I said, can be done outpatient. Once the three days of chemotherapy is done, we then put these engineered T cells back into the patient's body. They go in quite easily. It's like giving blood transfusion or stem cells. It's a single day process. It takes about 35, 40 minutes to infuse the cells typically. And once the cells are administered, there's then a period of monitoring both for side effects, but also hopefully for efficacy of these treatments as well. So that's the logistics. And as you can imagine, this is quite different from many of the other treatments we have in myeloma in that we have to collect cells, manufacture, wait for six to three to eight weeks, then put the cells back in. So it's a multi-step process. There's a lot of logistics involved in this in addition to the clinical management of patients who receive CAR T cells. So the next few slides are going to look at some of the CAR T cells and bispecific antibodies that we currently have available for our patients. These are all approved products. While I have listed them here side to side, these are not head to head comparisons. There has not been a head to head comparison between different CAR T cells or bispecific antibodies to date. So the numbers may be different, but that doesn't necessarily indicate that one product is better than the other. But these are listed here because all of these four treatments, IDA cell or ABACMA, CILTA cell or CARVIC-T, TECLISTA-MAB or TECWAL-E and L-RENATAMAB are all BCMA targeting treatments. Two of them are CAR T cells, that's IDA cell and CILTA cell, and two of them are bispecific antibodies, TECLISTA-MAB and L-RENATAMAB. All four are currently approved for patients who have multiple myeloma that is relapsed and refractory, which means the disease has stopped responding to multiple previous treatments. And for patients who have received at least four lines of treatment, so that means that their disease has been treated with four different courses or lines of treatment and includes most of the standard treatments that are already available for myeloma like VELKE, UPPERTESAMAB, LAMBOLITAMIDE, CARFULTAMB. So many, most patients have received all of these treatments. These treatments were approved based on single arm studies. So like I said, there's no comparison between other treatments or between themselves. They were approved because in this setting, in patients who have had four or five plus lines of treatments, we have limited treatment choices, which is why the FDA approved these treatments over the last three years based on single arm studies. This first slide looks at the kinds of patients that were treated on this study. So as you can see, the average age on these treatments were some 60 to 68 years and with the bispecifics maybe a little bit older than with the CAR T cells. Many of these patients had high risk features, for instance, extra medullary disease. This means that myeloma is not only in the bone and bone marrow, but outside of the bone and bone marrow, which typically tends to be a more challenging form of myeloma to treat. And on this study, somewhere between 13 to 40 percent of patients had a high extra medullary disease. Psychogenetics that, again, many of you are familiar with. These are genetic changes in myeloma cells, some of which may be associated with high risk of progression. And so in this study, again, about 25 to 35 percent of patients had high risk psychogenetics. As shown here, these patients had many different treatments, in some cases all the way up to 10, 12, 15 treatments. But on average, at least five to six different treatments prior to getting to the other treatments, these specific treatments itself. And the majority of patients were what's called a triple refractory, which means that they had already received and had progressed on a proteasome inhibitor, immunomodulatory drug and CD38 antibody, the three main classes of treatments we have available for myeloma. So I think the summary of this slide is these are very heavily pretreated patients, multiple treatments already received and very limited treatment choices at the time that they were going on these trials. So what happened that they did have side effects and there are two major side effects we worry about with CAR T cells and by specific antibodies. The number one is called CRS or cytokine release syndrome, which is basically inflammation. So when these T cells attack the myeloma cells, they do so by setting up an inflammatory process or inflammation and that inflammation can spill over. And so many patients can have symptoms like fevers, sometimes low oxygen, low blood pressure, occasionally affect the liver, kidney, et cetera. And so as shown here, about 75 to 95 percent of patients had CRS. So it was quite common with all four treatments, but reassuringly high grade, that means severe forms of CRS was less common, less than five percent. So not zero percent, but not as high as one might be worried. And over the last 10 years, we've gotten much better at managing CRS. So we have good treatments available for treating CRS and these symptoms tend to develop pretty quickly after treatments within the first seven to 10 days, which is why the first week or two after CAR T cells, especially the first or maybe even first four weeks after CAR T cells are the critical time point for monitoring and surveilling patients after these treatments. The second group of symptoms are neurologic. So about 20 to 25 percent of patients can develop neurologic symptoms, again, usually within that first seven to 10 day period. And this is in the form of confusion, sometimes difficulty with writing, speech in more severe forms, insomniacal and non responsiveness seizures. And again, very severe forms of these neurotoxicity are much less common, usually in the order of about 0 to 3 percent, with the exception here with silta cells, likely higher percentage of neurologic toxicity. So these are the two major classes of side effects that are true for all of these treatments, CAR T cells and by specific antibodies, those that are targeting BCMA, but also those that target other proteins, as we'll come to in a few minutes. So those are side effects, largely manageable, although they are serious and they require very close monitoring and they're available mostly in specialized centers for these reasons. But once you pass that one month mark, typically there are fewer and less intense side effects with the CAR T cells. What about efficacy? How well do these treatments work? So a majority of patients who get these treatments have a response. So somewhere between 60 to 98 percent of patients respond. That means that their M spike or their light chains or the lesions or the number of myeloma cells in the bone marrow goes down by 50 percent or more. That happens in a high proportion of patients. In many patients, they have what is called as a complete response. And keep in mind, again, these are very heavily pretreated patients. So we don't with conventional treatments, we don't really expect to see complete responses in this setting. But with these CAR T cells and by specific, somewhere between 30 to 80 percent of patients have a complete response. And those responses can go on for weeks, months, in some cases more than one to two years. And again, considering this is all in patients with pretty advanced, heavily pretreated patients, these are very encouraging results and numbers, which is why all of these treatments are now available. For patients with advanced multiple myeloma. So this is what we call as a Kaplan-Meier curve, which means at every time point we're seeing these the X axis here is the number of months that the patients are in follow up. And the Y axis is the probability that the disease has not progressed and they're still alive and well. And as you can see, with time, more patients progress. But even after 20, 22 months, there are some patients, more so here than here, there are some patients who have not progressed. So that means that there are patients who have received one single treatment with these CAR T cells who are out one year, 18, 20 months without any progression of disease, which again is very, very encouraging for this treatment. So one more slide, I think that summarizes some of the logistical challenges with getting CAR T cells and why as patients and as doctors, we ought to be discussing this early on because the planning can take quite some time and the actual process is very, very long. And the actual receipt of treatments can take some time as well. So what happens when a patient comes to see me for CAR T cells when I see them first, one, I have to determine if they're eligible, if this is the right treatment for them. We do that together, the patient and doctor discussing their clinical situation, the available treatment options, side effect profiles. And let's say we decided this was the right treatment for the patient. Then we have to make sure there's a slot available. What does a slot available mean? We have to collect these T cells and send it to the company. The company should have the resources to manufacture the T cells. So there's limited number of slots. So we have to decide, do we have a slot this week or next week or four weeks from now? So that can take some time. Once we know there's a slot available, we have to arrange for logistics. We need a donor room where the T cells can be collected. We may need to put a catheter in, as I mentioned, to collect the T cells. So that can take some time as well. And typically we want patients to be off of treatment for at least one to two weeks before collecting. So we have to figure out if they're already on some treatments, can we hold those treatments for a couple of weeks to collect their T cells? So this whole process can take two to four weeks. So let's say we did all of this and then we collect the T cells. Once the T cells are collected, they get shipped over to the laboratory or the company to make the T cells. Now, as I said, that process can take another four to eight weeks. What do we do then? Maybe the disease is progressing more quickly. Can we wait eight weeks without any treatment? Many patients in this setting may not be able to wait six to eight weeks. So we end up giving chemotherapy options, other standard treatments, deratumum, afcar, fulsomeb, cytoxin, some other treatments to help control the disease. Not necessarily to get rid of the disease, but at least to prevent it from progressing and affecting liver, kidney, et cetera. So that's called bridging therapy. And about two thirds to three quarters of patients receive some bridging therapy. Once this is all done, the cells have come back to us and we go ahead and now are ready to give the CAR T cells to patients. And when we are at that stage, we go ahead and infuse the CAR T cells and then obviously monitor for side effects like CRS, neurologic toxicities, low blood counts, infections, et cetera. And then hopefully at the other side of this, we see a very good and durable response to patients. One of the key challenges, because this takes up to eight to 12 weeks from deciding a patient should get a CAR T cell to them actually receiving a CAR T cell. There are a group of patients who are rapidly progressing, who do not have very good options for breathing, et cetera, for whom maybe the CAR T cells is not the right treatment, or at least not immediately the right treatment options. So settings we use these by specific antibodies, which are also effective, but do not need that long wait time to be able to get the treatments. So that's one of the ways in which we may decide which patients benefit the most from CAR T cells and which ones benefit more from maybe going ahead with a by specific antibody. So that's where we are with CAR T cells currently in patients with four or more treatments previously. Can we use them earlier? So actually there are two different clinical trials that have both shown promising results with using them earlier. The top panel here looks at the study called CARMA 3, which is a randomized study. That means that some patients got CAR T cells or IDA cell, and the others got a standard treatment, say for instance, teratoma map, palmitidomidexamethasone, or any one of the listed options here. These patients had previously received two to four lines, so not the four plus lines, but two to four lines, and everybody had received teratoma map previously. And if the patients got the second group and their disease came back, they were allowed to go ahead and go to crossover to the other side and get IDA cell. The second study listed in the bottom here is called CAR T 4. This was even earlier, not two to four lines, but one to three lines. And many patients had not even gotten teratoma map on this study, which is a very standard treatment, so much earlier line. And these patients were what we would consider as lenalidomide refractory. And again, patients received either CAR T cells or a standard treatment, one of these two choices, teratoma map, palmitidomidexamethasone, or teratoma map, wildcade, dexamethasone. And this trial, unlike the other one, did not allow for crossover. So if you were in this side, you remained on this side. If you were on this side, you remain on this side. There was no crossing over after the fact. Both studies showed that compared to standard treatments, the CAR T cells had better progression-free survival. That means more people did not have disease progression or did not die compared to the standard treatment. This was true whether you looked at the IDA cell study or with the CILTA cell study. Again, because the IDA cell study was in the more advanced patient population, the numbers are here. And for CILTA cell, the median progression-free survival, that means the time at which more than 50 percent of patients had progressed had not yet been reached for the CAR T cell. Again, suggesting that even when you move these CAR T cells earlier and compare it to standard available treatments, the CAR T cells tended to perform better. This is not quite yet approved by the FDA, although there was a big meeting at the FDA last week to review these results. It is expected that in the next few weeks, the FDA will make a final decision on whether ABACMA and CAR VCT, IDA cell and CILTA cell, can be used and approved for patients with earlier lines of treatment. If it is approved for patients with earlier lines of treatment, that would mean many more patients will now have access to these treatments at an earlier time point before their disease has progressed through multiple lines of treatment. A couple of other thoughts. I guess these treatments are very effective, but unfortunately they don't appear to cure the high proportion of patients. Eventually, one year, two years, three years later, the disease does tend to come back. So our group and others have been interested in developing other treatments similar to these. So one of the ones that we have been working on is developing a different CAR T cell targeting a protein called GPRC5D. So similar to BCMA that's listed here, GPRC5D is also present in myeloma cells. It's not really seen in most other normal tissue, making GPRC5D a pretty good target to go after in multiple myeloma. I'll skip these slides, but these slides essentially show that it's present in myeloma, but not present really in much of the normal tissue, liver, kidney, heart, etc. And I'll skip through these as well. These are studies that were done in mice to show that GPRC5D CAR T cells can be helpful, even in the setting of mice that were treated with BCMA CAR T cells. But then come to this slide here, which was a clinical trial we conducted a couple of years back for patients with fairly advanced multiple myeloma. About half of the patients on this study had already received a BCMA CAR T cell and had stopped responding to those treatments. And we treated them with our GPRC5D CAR T cells. There were a total of 17 patients treated. And because this was a very early study, we treated patients at different doses. What we saw was that there were side effects similar to the CAR T cells, the CRS and neurologic side effects. CRS, these are neurologic. And then we did see some other side effects. Again, in the interest of time, I'm going to skip those here. But we saw good responses. Two thirds of patients had responded. This included even patients who had had a previous CAR T cell. So even in patients whose myeloma had not stopped responding to a BCMA CAR T cell, we were able to give them another CAR T cell targeting a different protein and still get very robust responses and in some cases, very durable responses. One of our earliest patients is at this point about three and a half years out from getting this CAR T cell and continues to be doing well. So again, highlighting the promise with CAR T cells, not only those that target BCMA, but perhaps targeting other proteins in the myeloma cells as well. So this is just an example of one of the patients we treated. If you're familiar with looking at a PET scan, these brightly lit areas are all areas of active myeloma. These are extra medullary sites, lesions outside of the bone and the bone marrow. And this patient, who was actually the very first patient we treated with the GPRC5D CAR T cell here, actually maybe anywhere in the world. He had a lot of these lesions. These are just two examples. He had multiple of these lit up areas of myeloma across his PET scan. We gave him the CAR T cell, the lowest dose, 25 million, and then when we checked the PET scan four weeks later, those lesions had all disappeared. And when we did the bone marrow biopsy, his bone marrow had completely cleared as well. And his blood work showed his M-spike and light chains had gone down quite dramatically at one month. Now, this patient did quite well for many months, but unfortunately, eventually his disease started to come back again and he needed to go on to other treatments. Again, highlighting some of the promise with these treatments, but also what that we still need to do in terms of trying to understand why does the disease stop responding and what can we do to help it perform better. In the interest of time, I'm happy to take questions about it, but I'm going to skip the Allergen A CAR T cells just because I want to leave enough time for questions. And then just spend a couple of minutes on the question that I just posed, which is when these treatments stop working, why do they stop working? We, our group here and others are looking into this question. So one possibility is that the protein that the CAR T cells target, maybe the myeloma cells don't express them anymore. And if there's no protein in the myeloma cells, the CAR T cells cannot get rid of them. So that's one possibility. The second possibility is that the T cells we use to manufacture, maybe they're tired and beat up and exhausted. These T cells have seen a lot of chemotherapy before. Maybe that's why we can't really reinvigorate them, remanufacture them and help them attack myeloma. And then lastly, as I mentioned, there may be something about where these myeloma cells reside. For instance, patients who have extramedullary disease, like I said, myeloma typically, you see them in the blood, you see them in the bone marrow, you see them in the bones. You don't really see them in liver, kidney, other organs, but rarely we do. And that's called extramedullary myeloma. Maybe these extramedullary myelomas are particularly resistant to T cell directed therapies and we need different approaches to do this. We have shown that in a handful of patients, at least with both PCMA CAR T cells and GPRC5D CAR T cells, there are genetic changes in these myeloma cells that make it so that these cells no longer express the protein. And that's one of the ways in which the CAR T cells can become resistant to treatment. So what can we do about it? This is again experiments in mice, which I don't have time to go through in great detail, but suffice it to say that my colleagues in the lab have shown that targeting BCMA and GPRC5D at the same time, instead of one after the other, could be more effective, could be a more effective treatment strategy. And that has led to this clinical trial that we are currently, unfortunately we've completed the study, a study where we're giving patients two different CAR T cells. So not BCMA, not GPRC5D one after the other, but both of them at the same time. The hope and idea is that by giving both of them together, perhaps we can get rid of more myeloma cells and keep those myeloma cells at bay for a longer period of time than giving either CAR T cell by itself. So that's one approach. Another approach, which is also a clinical trial we currently have available open at MSKCC is for patients who get IDA cell. Let's say these are patients who have four plus lines of treatment and they got IDA cell. We then say don't wait for the relapse to come. Why don't we go ahead and give them consolidation with Talquidamab, which is, which we have no time to cover here, but is a vespasmic antibody that targets the other protein GPRC5D. So the idea here is again, targeting both BCMA and GPRC5D at the same time, but instead of using two different CAR T cells, we are using a combination of CAR T cells and a vespasmic antibody. So this is again a study that's currently actively open and we're enrolling patients and our hope is that by combined targeting of these two proteins, we can get better responses than either treatment by itself. I'll skip this as well in the interest of time. And so to summarize my talk, I would say we have now two CAR T cells that are targeting BCMA that are approved. We also have two vespasmic antibodies targeting BCMA that's approved. These treatments have very high responses and in many cases very promising duration of responses, but they're not yet necessarily curative treatments, which is why we need other treatments. And one of which that's emerging is GPRC5D targeted treatments. We have both CAR T cells and vespasmic antibodies. As I mentioned, relapses are common, but we don't currently know exactly why many patients relapse and what if anything could we do to overcome the challenge of relapse. And then as some of the data that I alluded to and showed you some preliminary evidence for, we do think that combining these treatments, either targeting both antigens at the same time or combining it with other myeloma treatments, may be one way to provide more responses, more durable responses. And the other is to try and use these treatments earlier on, so not wait for patients to be four or five lines in, but maybe earlier. And as promising as these treatments are, I think one of the key challenges for the next few years is also going to be how do we ensure that everybody who needs these treatments gets it? That's both in terms of access, geographic locations where patients live and how close they are to different hospitals that have these treatments available and how can we make it easier, as well as cost of these treatments, which are obviously quite expensive. And if we need to use more than one of these treatments sequentially, can we make sure that everybody who needs these treatments within the United States and outside can continue to access these treatments at the time that they need them? Thank you so much. Happy to take questions. Thank you. It was a great presentation. It cleared up some of my questions. So I'll start with the ones we have in the chat. We have, what are your feelings on CAR-T getting approved by the FDA and in what line of treatment? Will having or not a prior ACT factor at all? So I think the first question asks, would we feel like the FDA will do whether or not the treatments will be approved? I think obviously ultimately the FDA will decide. But based on the data that we just looked at, it's quite possible that the FDA will approve it for patients with earlier lines of treatment. So either one to three lines or two to four lines, which means it's available for more patients. And again, I think if the FDA does approve it will match what the trials did, which is for silted cell one to three lines and for IDA cell two to four lines, whether or not that will mean transplant is acquired or not. Again, I don't know what the FDA will decide, but I don't know that they will benchmark it to previous transplants. So it's possible that they would not have a specification on whether a transplant is acquired or not. Great. Then we have what would cause a low CAR expression as a result not being able to continue with a CAR-T? I don't know if I understood this question. There are some patients in whom we can't manufacture CAR-T cells, so I don't know if that's referring to that. So even though about five to ten percent of patients, we may not be able to manufacture it despite our best intent. And why that happens is varied reasons. Some of it could be because patients have received so many treatments and they have very few T cells that we can collect. Some of it could be manufacturing issues that we can sometimes not overcome. We can try to recollect and remanufacture a second time and we are sometimes successful doing that. Again, if that's not feasible, we have the option of doing by specific antibodies which don't need the manufacturing part of it. So obviously everybody in principle is able to get a specific antibody. Yeah, I think that's what she meant. Perfect. Thank you. Then we have does length of time on Darselex preclude patients from being a candidate for CAR-T therapy? No, it does not. I mean, as you all know, deratumumab is quite commonly used in multiple stages of multiple myeloma. So it's quite common for our patients who are getting CAR-T cells who have received deratumumab in the past. The amount of time they're on deratumumab or their response to deratumumab does not really affect it. We like to keep about a two week break from deratumumab before we collect the T cells whenever possible. And so that's one consideration. But otherwise, deratumumab should have no major impact on the ability to get CAR-T cells. Perfect. Then I see, could you comment on the new dual targeting CAR-T therapy GCO-1-2F that targets both BCMA and CD19? I know it's new and the study only included 22 patients. How long this type of treatment might be available? And will patients who have already been on by specific targeting BCMA be candidates for this type of treatment? Yeah, so that's a good question. So I think this is referring to a CAR-T cell that is targeting two different proteins. One is BCMA, the other one is CD19. CD19 is not really a target we use in myeloma very often. But the belief is that maybe some of the myeloma precursors, the very early stages of myeloma express this protein. Regardless, initial data mostly from China looks very promising with a high proportion of patients responding and responding for a long period of time. This product is expected to be developed here in the U.S. in clinical trials as well. Whether the trials allow prior BCMA therapies or not and what restrictions will depend on the specific design of the study. But my hope and expectation would be they would allow patients who have been treated by specific antibodies in the past. Again, it adds to the number of effective treatments that target BCMA we now have available and hopefully continues to become available for patients. Perfect. I see if the FDA approves CAR-T for earlier patients, won't this make manufacturing problems increase? What is being done to improve this? Yeah, you know, the manufacturing is done by the two companies that have developed these CAR-T cells and they are hopefully will continue to improve on manufacturing processes. Learning from lymphoma and leukemia where these CAR-T cells, similar CAR-T cells were approved even earlier. After the first few years, the companies are able to ramp up manufacturing. So hopefully they'll not only keep up but improve on the manufacturing capabilities such that again, everybody who needs these treatments will get them at the time that they need them. But they're probably whoever asked this question is probably somewhat right in that there may be a lag in a few months when we're scrambling. But eventually, hopefully this year, next year, the year after the supply will continue to improve and therefore more patients will get these treatments. Thank you. I see we have. What do we know about long term remission? If a patient gets CAR-T and is progression free for 12 or 14, I mean for 12 or 24 months, is the risk of relapse lower than at the beginning of the treatment? That's a very tough question to answer. At this point, we do worry that eventually the majority of patients may have a relapse. Even if they're obviously the longer you go without any relapse, that's better. That's true for any treatments. But I don't know that we're at a point yet where we say if it's three years or five years or six years without relapse, can we say some of these patients may not ever relapse? It's a little too soon. The earliest CAR-T cell treatment for myeloma is only about 10 years back. So we're talking that this is anywhere in the world. The very first patient to get CAR-T cells was in 2014. So we're less than 10 years from when the very first patients were treated. So we don't have a lot of patients who have been followed for three, five plus years. But obviously, the longer you go without the disease coming back, the more reassuring it is. Great. I see a good one here. Do you see any difference in response in CAR-T between patients who have had stem cell transplant versus no transplant? I don't know that it's been systematically studied, but my own experience and those of the data we've looked at, I would say there's no major difference. Okay. Patients who have had a transplant or not had a transplant both have good responses and similarly good responses. Okay. You see we have, I had a CAR-T cell six months ago. I am now MRT negative. But two months after the therapy, I developed debilitating neuropathy. Have you heard of other patients with this side effect? How should I be treated? And then it says it was it was silto-sil. Okay. So I mean, this is a slightly tougher question. I will say we do have some patients who develop nerve damage or neuropathy after CAR-T cells, both peripheral neuropathy, which is hands and feet or legs and hands, and cranial neuropathy, which is facial nerve palsy, other things. I don't want to make a specific treatment recommendation without knowing all of the details, but Gambapendin certainly is a reasonable treatment option in some settings, depending on the timing of this and how it developed and other factors. Steroids may have a role to play as well. So at a minimum, it's reasonable to talk if it's a very debilitating and affecting quality of life. It's a reasonable discussion to have with the treating doctor to say, do you think something like a steroid might be helpful in this setting? But I think it would need a little more details on like the timing and the nature of the neuropathy before being more more definitive about the management of this. But it is a known side effect. Okay. Do you see this as being an outpatient procedure in the near future? We actually do outpatient CAR-T cells at our site. We have an out robust outpatient team. So we are doing outpatient. I mean, the caveat is outpatient doesn't necessarily mean you get to stay at home. Although if your home happens to be very close to our site, you can stay at home. But we do require people to be within 30 to 60 minutes of our site, come in every day to see us. If you have done transplants as an outpatient, which is a similar kind of logistical thing. So, yes, I mean, that's not all of the CAR-T cells we do, but our center, others as well similarly have the ability to do some of these caring, the select patients and select situations to CAR-T cells outpatient. So we hope that that number will continue to improve. That's perfect. I didn't know you could do it. Outpatient. So are new lymphodepletion drugs being examined that will have less impact on TC health? And if you don't have any stem cells available for post CAR-T cytopenia support, can you collect them at some point prior to CAR-T before, after T cell selection? So the answer to the first question, are we looking at different lymphodepletions? We ought to, but I don't know that we are necessarily because there's so many questions with myeloma, CAR-T cells and treatments. I think that people have not really focused as much on alternate lymphodepletion. There's a period of time in the last couple of years when we were at significant shortage of fluid aerobene when we used Benda-Mustin. I would say the data is somewhat mixed, so I don't know that we would necessarily go back to using Benda-Mustin unless it's really the only choice we have available. So yes, we should be studying more about them for depletion, but that's not necessarily happening or happened as much as we would like. To the answer to the second question, ideally, I would feel better if patients had stem cells collected. So if there's the ability to collect prior to CAR-T cells, which again, not everybody has the ability to, would be reasonable, at least to discuss with the doctor whether it's necessary to collect stem cells prior to going with CAR-T cells. So it's certainly not a standard, and in many patients, it might not be feasible to go ahead and collect stem cells. But yes, cytopenia after CAR-T cells, that is low blood counts after CAR-T cells, is a challenge for say about 10, 15 percent of patients. Mostly we're able to do manage that without stem cell boost, but if you had stem cells, that provides an additional option to manage these very low blood counts that some patients are susceptible for after CAR-T cells. Okay, great. We have one. Is there any data that reviews those cases that have both multiple myeloma and AL? AL amyloidosis, I think is. Yeah, so when the trials were developed for these CAR-T cells, unfortunately patients with AL amyloidosis were excluded, so therefore there's no trial data. But since the approval of patients who have concurrent myeloma and AL amyloidosis at our center, others, we've treated patients like that, and they've responded very nicely. I see no reason to exclude patients who have AL amyloidosis that's well controlled from hopefully trials, but certainly from access to these treatments now that they're approved. Perfect. We have this question, availability of CAR-T or by specific antibody treatment within Europe, particularly Eastern Europe. CAR-T does not seem to be available. Is it easier to access by specific antibodies? So I don't know the answer. I mean, each country in Europe, I guess, makes its own determinations based on cost effectiveness, approval by EMA, etc. I can't say that I know very well which ones. I've heard that CAR-T cells are less available by specific antibodies, again, are quite expensive, so I'm not sure some of the many of these countries have yet reached an agreement with different manufacturers. I certainly hope that it becomes more available, but I don't know the answer to the question. It says, do high-risk patients respond equally well? Like the ones they have plus 1q? Yeah, so I would say, you know, I think there's two parts to this answer. Part one is for patients who have high-risk myeloma, I still think that T cell-reducted immune therapies, CAR-T cells and by specific are still the best available treatments in this setting in patients who have advanced multiple myeloma. That said, it does appear that the duration of response and the proportions of patients who respond to these treatments are somewhat lower in patients of high-risk cytogenetics like DELICION-17 or 1q amplification, others similarly. So yes, these are best available treatments, but like other drugs and treatments, there is a challenge with high-risk myeloma that we can't fully overcome with CAR-T cells or by specific antibodies. Perfect. We have post-CAR-T relapse. Can the CAR-T treatment be administered again? Giving the exact same CAR-T cell a second time around does not seem to work. So in other words, if you had a patient who had IDA cell, they did well for two years, the disease came back, giving them another dose of IDA cell does not seem to work very well. The same is true for CELTA cell as well. But could you give a different CAR-T cell? Sure. As we showed, I guess you could go BCMA to GPRC5D CAR-T cell, but re-treatment with the exact same CAR-T cell does not seem to provide any good efficacy or response in that setting. So that's typically not done. What maintenance therapies are involved in these treatments? So this time there's no approved or standard maintenance for patients who get CAR-T cells. And at our site, we don't typically do maintenance for most patients, again, because there's not a good option for maintenance in this setting. There are, however, clinical trials looking at maintenance with immunomodulatory drugs like lenalidomide, pomalidomide, mesigdomide, iberidomide. As I mentioned, I guess that's not quite maintenance, but you could also use a by specific antibody as consolidation or maintenance afterwards for six months or 12 months. So there are several clinical trials exploring how best to use these drugs as maintenance or consolidation, but there's not a single approved strategy at this point to help maintain the responses. That's perfect. Are you familiar with the phase? I think it says LLB study of selenextor in combination with carfilzomib, diatomomab, or pomalidomide. What's your opinion in terms of efficacy in this treatment versus CAR-T cell? I have not specifically that kind of, I don't know the specific study, but I am aware that selenextor is being studied in combination with these other treatments. They're not CAR-T cell necessarily. I guess these are traditional myeloma treatments and they have their role. Whether you would use that over a CAR-T cell or before or after, I guess, is very much dependent on the specific patient and what's available and how quickly you can get these treatments. But certainly, selenextor-based combinations have efficacy in myeloma and are a reasonable consideration for patients who have myeloma. Thank you. We had a lot of questions similar to this one, so I'll just ask one. What are your thoughts on CAR-T for older patients, 75 and older, who are not well represented in the trials? What's your experience being in this patient and does it matter if they are not responding well to their second line therapy or their fourth if they are 70 plus years? Yeah, so I mean, I think we think of age more as functional. If there's a 75 year old who's otherwise well, there's absolutely no reason for them not to get the treatments like CAR-T cells and bispecifics. We have given people both on the trials we've done here as well as since the approval of patients in their 70s, 80s even with CAR-T cells and successfully done this. This is all a matter of what is their organ function like? Are they functional? What other treatments have they received? Absolutely, I don't see a reason to have a hard cut off in age for these treatments. They should be available for patients across different ages as long as they're adequately evaluated and there are no other major limiting factors. We see good efficacy in this setting as well. Arguably, CAR-T cells can be a one-time treatment that provides a long period off of treatments for people in their 70s and that would be a valuable thing for people in their 70s and 80s. So I see no reason to exclude them. Perfect. It says, can you speak about T cell exhaustion and how that informs the strategy for how to stage CAR-T versus bispecific? Yeah, so I mean, it's a very good question, but I don't know that I have the answer. So I guess what this alludes to is the, I think I presented a little bit to say that T cells can be exhausted, which means that our own T cells, the patients own T cells that have already received melphalan and other chemotherapies may be, quote unquote, tired because of all the treatments and therefore may be not very functional. There are a few challenges with this. One is we don't have a good testing to say what's exhausted versus what's not. There are different markers, but there's not a real well accepted threshold for what would be defined as exhausted versus not. The second is in patients in whom we think the T cells are exhausted based on whatever testing we have available, we then give them CAR-T cells. Some of them may do very, very well. So it's not all or none that if you have exhausted T cells, you don't respond to CARs or bispecifics. And so for both of those reasons, we don't currently have a way in which we can look at exhaustion and say, this is a patient who should get CAR-T cells. This is a patient who should get bispecific antibodies. So the hope is with the kinds of studies we're doing, other people are doing, we may come in the future at a time where we can make an informed choice and say patient A would benefit from getting a CAR-T cell because their T cell health is XYZ, but patient B should be getting a bispecific antibody because their T cell health is different. But we're not anywhere close to doing that. Thank you. Recently there has been reporting of a high prevalence of secondary tumors in patients receiving CELTA cells. Do you know whether this is a realistic concern or is this an incidental finding due, for example, to the fact that many of these patients are already more susceptible to secondary cancers? So I think there's two kind of stories with secondary cancers with CAR-T cells. The first one, which is the most straightforward one, which I'll address, is that when we genetically engineer T cells, we may introduce changes into the T cells that make it so that these T cells become malignant. So instead of just making them a CAR-T cell, we can transform them into a cancer. So these are called T cell malignancies that are related to the actual genetic manipulation we do. Those are very, very infrequent. The FDA is aware, I believe, as of their last reporting of about 22 cases of these T cell malignancies across all of the different CAR-T cells in myeloma, leukemia, lymphoma, etc. So it appears to be a very low risk, at least for now, and a rare event, one in several thousand patients. And that's obviously pretty bad for the patients who develop. But I think considering we're using these treatments for patients with active advanced multiple myeloma, that very low risk would not probably deter me from giving these very effective treatments to patients. The second group is general secondary cancers. So not because of the genetic manipulation, but our patients who get CAR-T cells more at risk of leukemia or lymphoma or MDS or other cancers. And part of the concern is because the original CILTA cell study that was done in the first 97 or so patients who get CILTA cell, about 10 to 15 percent of those patients developed a secondary cancer. Now, as was alluded to, many of these patients, all of these patients had had previous treatments with melphalan, lenalidomide, other drugs that can cause secondary cancers. So for now, I do believe that that that signal that was seen was more related to patients receive their prior treatments they received rather than the CAR-T cells itself. But obviously, we're closely following that number in other trials and other randomized studies to see if there's a true risk. But for now, it appears that that risk is largely related to the previous treatments and not necessarily a direct effect with the CAR-T cells. OK, OK, perfect. So we have so many questions, but I'll take your I'll take just one or two more so we can finish on time. So are there any clinical trials including plasma cell leukemia patients reactions to novel therapies at MSK? So we don't have clinical trials of CAR-T cells for patients with active plasma cell leukemia. However, if they have made the FDA labeled indication for for the CAR-T cells and happen to have plasma cell leukemia, we would consider giving them the FDA approved CAR-T cells in those settings and and also FDA approved by specific antibodies in those settings. We have treated some patients who have had history of plasma cell leukemia, but now controlled through other treatments and the disease is coming back, but not necessarily as plasma cell leukemia. We have treated them on trials of specific antibodies and CAR-T cells with good effect. So, again, I think patients with plasma cell leukemia would benefit from these treatments. It's a challenge of how these trials are designed and treatments are administered where sometimes that's a limiting factor. Thank you. Will long term treatments such as daratumumab seven years plus deplete or diminish the body's natural T cells? We don't think so. We have had patients who have had many years. I don't know if I've had somebody who's had seven years of daratumumab, but certainly many years of daratumumab with good efficacy. So I don't know that it would have any long lasting effect on the T cells enough that we would be worried about its impact on the efficacy of CAR-T cells also by specific antibodies. OK, perfect. And this I see this question a lot. So can stem cells be turned into T cells? I think the answer is no, right? Not at this point. I mean, on a research scale, I think it's hypothetically possible to convert collected stem cells into T cells. But I don't think it's a point where we can do that on a clinical scale. So the answer is no. Yeah. Yeah. So one last question we have here. Have you changed your treatment recommendations in response to reports of T cell malignancies? Not really, no. For the reasons I alluded to earlier, it's a very uncommon. It's something I discuss with my patients, but I don't know that it changes for a patient who has four plus lines of treatment as myeloma has come back after four lines. I think the risk with myeloma is unfortunately much higher than the risk of developing a T cell malignancy. So I have not changed my thinking about the risk benefit in that setting. OK, that's perfect. Well, we're wrapping up here so you can leave and we can finish on time. I want to thank you for your time. It was an excellent event. And I want to know if you have any closing remarks or anything you want to share. I'm so sorry. I see there's so many questions that are open. I apologize for not getting through all of them. If there are any specific questions, if you send it to me, I'm happy to respond by email afterwards. I just feel badly that so many people have questions that we couldn't get through. But if there are questions that were not covered in the discussion, some of these questions seem to be overlapping with some way we've answered. But if there are specific questions that were not addressed, please feel free to send them to HealthFree. And if they send it over to me, I'll do a written response to those questions. But thank you so much for the interest. And I wish you all the very best in whatever phases of your treatments you or your loved ones are. And I'll only say that I'm very, very optimistic of what the future holds for our field. The new treatments are being developed every year, every other year. And there are so many more exciting treatments that we're all very excited about that are yet to come, that are either in very early stages in the lab or in in clinical trials that I'm very optimistic of what the future holds for patients who are diagnosed with multiple myeloma. Thank you. Thank you for all you do and thanks for your time. Thank you. Thank you. Why, I'll just share my screen again to give you some outro announcements. Our next meeting will be in August once Audrey is back because she just had a baby. So that's the reason she couldn't be here with us today. And we are talking about proper sequencing of immunotherapies. And these are our upcoming events. We have the non-secretary myeloma community event tomorrow on how to monitor non-secretary myeloma. Then on the 21st, we have our nutrition and wellness for myeloma events. And we're talking about how to optimize your health as a myeloma patient at 1 p.m. Eastern time. And on Thursday, the 28th, we will have our Black Myeloma Health Community event. And we will talk about CAR-T therapy as well for relapsed or fractured myeloma patients in the Black Myeloma community. So the link to join the link to register for these events and the other ones we're having, it's at the bottom of this slide that will be sent out on the follow up email. Another thank you to our sponsors Regeneron, Sanofi, Johnson & Johnson, GSK, and BMS. And thank you all for participating in this webinar. Have a great rest of your day. Bye bye.