(Guest Lecture): May 2022 - Learning about CAR-T Therapy with Dr. Noopur Raje

possible today. So before I move on with our announcements, I'd like to stop and take this time to hear from Ellen. Ellen, go ahead. Okay, hi everybody. My name is Ellen Reich and I live in Massachusetts. I was diagnosed with smoldering myeloma in 2011. And since they thought of putting any drugs in my body was the last thing I wanted to do on earth, I, it was a watch and wait at that point. And I was drinking green juices every morning before I went to work. I kept working, I was teaching high school English and it wasn't, I met Dr. Rajay during that time, but it wasn't until September of 2013 that I started therapy and went to her and my M-spike had gone up. And I reluctantly started the traditional RVD treatment because I did not want to put drugs in my body. Since then I experienced about seven lines of therapy, which as we all know, work for a while and then lose their effectiveness. My M-spike never went down to the point where I could even consider a stem cell transplant. And that also would have freaked me out. The amount of toxicity, I don't know what I would have done. That didn't happen, that didn't happen where I had to think about that. During 2018 and to 2020, I experienced nothing was working and Dr. Rajay would at regular intervals bring up the CAR T cell therapy. And at one point she organized a team and gave me a 38 page consent form I sent to my family. And they said, no way, you just could not do all that toxicity, not put all those drugs in your body. And so I was, since I was, she found out I was, had the genetic translocution 1411 and went on Venetoclex and that held for a while. And if something's working, then at that, for that particular trial, you weren't eligible for a CAR T. But that only worked for maybe a year and a half. And then in June of 2020, which is the middle of COVID, she called me and said, I have a slot for you and you really need to do this. And she was very reassuring. She said, we'll be with you 150% and I was strongly advised to make the plunge. And then it was, I had to be tested to see if I was eligible. So you can't be too weak or too strong. And she thought I was just at a point where I could do it. Again, I had never had a stem cell transplant and I really think people kind of think they're the same and they're very different. But from what I have read and studied, the CAR T has a lot less toxicity. Of course, the 38 page consent form has to say everything. So I was afraid, but once there was a lot of organizing to do once I passed the tests. And I had to have the T cells taken out. And then I had five weeks where I had bridge therapy and where they are re-engineering your T cells. And then I had to come back to Mass General and get chemotherapy and of course, a COVID test and a bone marrow biopsy. And then I was in the hospital. I had to get chemotherapy so that they could repress the T cells that were left in my body. So they wouldn't fight these new T cells that were coming in. And it was all very scary, but I was so busy organizing who is somebody has to stay with you before you're in the hospital to have the T cells put back in you. And then you're in this cancer ward for two weeks. And then afterwards, someone had to stay with me right across the street and I had to go in for checkups and they had to take my temperature person with me. So for a person that's completely freaked out by putting drugs in my body and my wish for life was to not have to, here I am two years later, I'm not on any therapy. And I still get bouts of fatigue. I'm trying to build my strength up and do exercise and I'm still very conscious of eating healthy and that. So if I could say it, the fears I had, it was not as bad as I thought. And they watch over you, take care of you like you wouldn't believe in At-Mass General. And I've got friends to volunteer to come with me in the beginning and during, nobody could come in, it was COVID, but right after where I had to be monitored, a friend stayed with me for two weeks. And so it's a real story of my reticence for any kind of therapy and then gratitude that I took the plunge and I would do it again and that it's working. So. That's beautiful, Ellen. I have a lot of more detail, but that's like basically. Yeah, and maybe, as Dr. Rajik is talking, we can come back to you and listen to more of your experience because I would love to hear more. But that was a perfect introduction and hopefully people got to know you a little bit more through that spotlight. So thank you, Ellen, for being willing to share with us in the beginning. If you haven't figured out by now, today we're talking about CAR T therapy. And I kind of want to know, and whether you write it in the chat or whether you answer it later in the meeting, you know, how familiar are you with CAR T therapy? There's two FDA approved CAR T therapies and we're learning about this promising therapy. Lots of patients are responding excellently to the therapy and what will that mean in the future in terms of a cure for myeloma patients? I'm not saying this is the cure, we found the cure, but what does it mean and what hope does it bring to the myeloma arsenal as we treat myeloma in search of a cure? So I'm really excited to talk today about these promising therapies. It's my pleasure to introduce Dr. Rajik to you and then I'll turn the time over to her. She's the director of the Center of Multiple Myeloma at Massachusetts General Hospital. She is also the associate professor of medicine at Harvard Medical School. Her primary focus is treating patients with multiple myeloma and related plasma cell disorders. Dr. Rajik leads a dedicated clinical team engaged in an investigator initiated multi-center national and international clinical trials, all aimed at developing new promising therapies for multiple myeloma. Her laboratory efforts are focused on identifying cellular signaling pathways that contribute to the survival and proliferation of myeloma cells in the bone environment for which targeting may result in improved therapeutic outcomes. Dr. Rajik is a genius and a caring physician and I'm really excited to hear from her today. I'll turn the time over to you now. Thank you, thanks so much Audrey and thank you so much for the invitation and thank you all for joining. We have a real big group of people and we're gonna make this very conversational. Ellen, that was fantastic. Thanks for sharing your story. And we'll see how this goes. I do have a few slides just to sort of get you focused on what we're gonna be talking about, but we can go back and forth as I'm going through some of this, Ellen, and feel free to jump in both Audrey as well as Ellen. These are just some conversation starters, so to speak. So it's really an honor and a pleasure to be here with all of you this evening. What I am gonna try and do, and we'll see if the Zoom world has taught me anything here, is try and share my screen. Just give me a minute. I think I, hold on. I think I have to make you a... Yeah, you have to allow me to share my screen. Yes, now you should be able to share. Let's see if I've learned anything about Zoom here. So I am sharing my screen, and I'm gonna get my slides up. All right. Perfect. Can you see my slides? Oh, yes. All right. So what I thought I'd do is just give you a little bit of a sense of what Cartes are all about, and really talk about some of the things which Ellen has so nicely mentioned in her opening, is who are the people that we think about for CAR T cells? And with myeloma, the good news is there's so much going on in myeloma. It's a really exciting time. There's not just CARs. There's a whole lot of other things available for patients as well. And how do we begin to think about what makes most sense for you as a patient? So we have the CARs, we have bispecifics, and really talk about what we think is gonna be the future with the care of myeloma patients with all of the new developments that we have. So before we talk about CARs, I think it's important to understand who are the folks who are actually eligible to get the CAR T cells? And Ellen has really nicely highlighted to you the fact that she's been through multiple lines of treatment, and whenever we start something novel, something new, we always tend to use it at the back end of myeloma. So most patients have been through multiple lines of treatment. Audrey has very nicely told us, at least for myeloma, we have two drug products which are approved. We have Idocele and Cilicele, and we'll talk about that a little bit. But as of right now, most patients who can get this type of therapy are patients who failed sort of conventional treatments. So you had to have had the typical IMID-based treatments or Revlimid, Carmelidomide. Most patients have had Velcade, have had Carfilzomib, and the majority of patients have had the CD38 monoclonal antibody also, either Derritumumab or Isatuximab. So obviously when you come in for CAR T cells, your disease, as Ellen said, has to be sort of progressed on those treatments that I've talked to you about. As of right now, the FDA wants you to have had at least more than four lines of treatment. I will say that the majority of CAR T cell patients that we are treating as of right now have had multiple lines of treatment, and Ellen has already told you, I think Ellen, you mentioned, was it seven lines of treatment that you had? Thanks, I counted that. So typically that's what we expect. So you have to be progressing on whatever treatment you've been on and typically have had the drugs that I've just mentioned. I do think it's really important to understand that we do not want the disease to be progressing too rapidly either. And the reason for that is, as Ellen has really nicely told you, we have to go through the process of taking out the cells, have to be able to manufacture the cells, and then have to be able to give you back the cells. So it does require a lot of sort of working closely with your treating oncologist, your treating team, and really trying to figure out what the best timing for this CAR T-cell therapy should be. I will argue and say that the majority of myeloma patients should be thinking of a strategy such as CAR T-cells. Right now it is approved after three or four lines of treatment, but we do have a lot of clinical trials. When something works, when you've failed everything, our obvious next step is to bring it up early. So most centers like ours have lots of different clinical trials where we're doing it early on as well. So having a discussion with your treating oncologist is really critical. And I think everybody at myeloma crowd, and Audrey will be the first one to say this, having, even if you're getting your care locally, wherever you are, closer to home, which we always recommend, but having access to a center of excellence, which does a lot of myeloma related work is actually critically important as well. I just wanted to give you all a sense of what CAR T-cells are, just so that you all understand. So as Ellen mentioned, we take the T-cells out, we engineer them. What CAR stands for is a chimeric antigen receptor. So we actually insert this receptor into your T-cells. So this, for example, is the surface of your T-cell. What we've done here then is inserted this CAR construct. Right now in the clinic is what we refer to as second generation CARs. And the reason that they're called second generation CARs is we've inserted this CAR construct on the outside of the T-cell, you have an area which this we refer to as the extracellular domain or the antibody domain. And this is what recognizes your myeloma cell. And as of right now, the CARs that we have in the clinic are recognizing a protein called BCMA. BCMA stands for B-cell maturation antigen. This is a protein which is present in all of your myeloma cells. And this is what takes your T-cells to your myeloma cells. This is what attaches to your myeloma cells. Now just attaching the T-cell to your myeloma cell is not enough. We need to kill those myeloma cells. And how does one go about doing that? And that's why we have these second generation CARs. The first generation CARs, all they did in the old days was activated the T-cells. But those activated T-cells don't live around. So what we have now is the T-cell activation domain. And we also have something which we call a post-imulatory domain. And once the T-cells get attached to your myeloma cells, they activate your T-cells. They cause proliferation of your T-cells. And then your T-cells do all of the killing which we want them to do and get rid of your myeloma, which is in essence what these T-cells do. So this is just showing you an example of what most patients have to go through. This is a patient with myeloma. We collect your lymphocytes. So this is a little bit different from your stem cells. When you do a blood stem cell transplant, peripheral blood stem cell transplant for myeloma, we still collect it carefully. But we're collecting stem cells. Here we are collecting your lymphocytes. Lymphocytes are what has your T-cells. Then they go off to get engineered. That engineering process, as Ellen has told you already, takes anywhere between the actual process doesn't take that long. It takes about 10 days. But for us, when we take out cells from your body, and we're going to be putting them back into your body, it's not a closed system. We want to make sure that when we take the cells out, they are in no way infected by any means. Then we do the process of the genetic manipulation. And before we send those T-cells back to you, we've got to be sure that when we've done this process of genetic manipulation, we haven't introduced any infections. So if you take all of that from the beginning, so taking it out of your body, getting it back into your system, it takes anywhere between three and four weeks. And a lot of it is to do with some of the infectious testing that we end up having to do. And that's why you have to have the four weeks in between, which is why I mentioned early on that you cannot have disease which is progressing very rapidly, because you may not have those three or four weeks. Instead of that, you need to control the myeloma a little bit better before you can go ahead and do this. So although I've told you that you have to be refractory to all of these lines of treatment, it's important to think early about CAR T-cells so that you can plan ahead, so that you can make this available and try and get this as a slot for you. Obviously, a lot of logistic considerations. And I think, Ellen, you've spoken to some of these, right? And I think this is where it is a commitment. It is not done at every hospital. It is done at a few places. So I think the big thing that you have to consider is how far is the closest treatment center. And I know Ellen, who lives a little bit away from Mass General. And for her to come in, it takes a little bit of time. For the patient to travel or remain close to the center. And we want you to stay close. And Ellen mentioned this. You have to make arrangements, Ellen, to stay close to Mass General for about four weeks after you were discharged. So two weeks after you were discharged, right? Two weeks you were in the hospital, and two weeks after you were discharged. And the reason for doing that is most of the anticipated proxies happen in those first four weeks or so. And we want you to be close to that center, because not everybody is used to taking care of those complications. And that's why we expect you to stay within sort of a 30 mile radius of our hospital. And we help with making those logistic arrangements of living close by. And really, we do a lot of times as of right now, we're doing this on clinical trials. But now that we have two drug products which are approved, we actually have the social workers work with you. We work through your insurance, because these are expensive treatments. And we do not want you to be stuck with the expenses of the treatments. We work very closely with our social worker, our financial folks at the hospital. And these are the folks who work with your insurance folks and make sure that the drug product is completely covered and that you are not set up to have to pay any of those big bills out here. And again, I think it's really important to figure out what is the best time to collect those lymphocytes that I've talked about so that we can really generate cars which are going to be effective. So we are relying on your own cells to do their job after genetically modifying. And there's enough data now to make sure that those T cells are not very unhealthy. We want some more healthy T cells so that we can manufacture them, we can genetically manipulate them, and then we can get them back to you. This is just giving you a sense of the patient journey. And I think this is really helpful for most of you. We identify who will need the CAR T cells, typically after you've had all the treatments that we've talked about. Then we refer you to the center. We look for eligibility. Ellen talked about getting the consent form. And then she had to go through a battery of tests. And the battery of tests had to ensure that kidneys were working well, the heart's working well, everything else is looking good so that we can actually go through the process of apheresis. We do the apheresis. After that, she talked about conditioning. And that is the chemotherapy that we give you. We started doing that as an outpatient. We've always done it. It's three days of chemotherapy. And that's, in general, given to get rid of some of those T cells which would have otherwise fought your CARs. So we want to try and mute them down a little bit and then infuse them back, infuse your CAR T cells into you as of right now, at least in the clinical trials. The infusion itself of the CAR product doesn't take a long time. It's almost anti-climactic. It literally takes five to 10 minutes for us to give you that. But then it's after that, when it starts doing its job of finding your myeloma cells, killing those myeloma cells, which can actually make you quite sick. And we'll talk about some of the things that can happen wherein you have those adverse events. We've typically kept you in the hospital for two weeks. That was on clinical trials. I can, Ellen, the last week that you were here with us, I'm sure you were bored and wanted to get out. But on the clinical protocol, we have to keep you in the hospital. But as these drug products now become commercially available, if the patient's doing fine, I do think we're going to be able to discharge. We're already doing that. And some CAR products in the future, we may also be able to do as an outpatient. Once you are out, the two weeks of being close to the hospital is something which is recommended. And then once you're discharged, over time we continue to follow you so that even today, Ellen, keeps coming back for our clinic visits so that we can make sure the blood counts are fine, that myeloma is still at bay. So I'm just going to pause here a little bit, Autri, if you guys have questions before I go on to the next. That sounds great. Let me tell them how they can raise their hand if they have any questions. Or you're welcome to put it in the chat that we've been using. If you want to click on reactions, if you're on a desktop or laptop computer, if you click on reactions, and then you could see the button that says raise hand if you have a question that you want to say out loud to Dr. Rajay. If you're on a tablet or a mobile phone, I believe that it's by clicking more, the three horizontal dots, clicking more, and then raise hand. So I see a couple of people that have already raised their hand if you're good to accept questions. Dr. Rajay, we'll have Bonnie go first. If you want to unmute yourself, Bonnie, and ask your question. OK, thank you. Can you hear me? Yes. Dr. Rajay, I love listening to your talks. I always make sure I catch them. So thank you once again. You're a great teacher. Can you please say, are we at the point where you talked about assessing the best time for collecting and the health of the T cells? Are we at the point where you could assess them and perhaps say, based on that, no, this patient, we should change the plan and switch to a bi-specific. They are not really a great candidate for CAR T. Bonnie, that's an awesome question. I don't think we have the answer to that. And in all honesty, the longer you're treated for your myeloma, we have looked at this. So we've looked at T cell fitness, for example. How fit are your T cells? Well, not just the CAR T cell part of it, but just for the bi-specifics as well. And the question is, the earlier you treat with some of these immune therapies that we believe, the better the outcome is going to be. Because your T cell health is better at that time. And these are all T cell mediated issues. I don't think we know as yet which patients would benefit from bi-specifics versus CARs. And I think it's almost a good news problem to me. Because if you look at CARs, the response rates are so high. So even when you've been through all your treatments, it's amazing to me that the majority of patients are actually responding to the CAR T cells. And when you look at responses between bi-specifics and CAR T cells, the response rates for CAR T cells are so much higher. And then once you get the CAR T cells, it's sort of a one and done, and you're not doing anything after. I think the big question is going to be, if everybody could get the CAR T cells, we would love that. The issue right now is we don't have that access, even though we have these two drug products approved. And so what can we do? And while you're waiting for the CARs, can you get a bi-specific before you get the CAR? We don't have data on that. We have the data in the reverse order. So we have a lot of trials at least at MGH where we've been able to get people CARs. And if the disease has gone, come back up again, we've given people BITES, and that the bi-specific T cell engages, and that seems to have worked. And if you just think about it, I think that sequence to me works. The sequence the other way, I think we need to test. And the reason I'm a little bit cautious about the other way around that is getting a bi-specific and then getting a CAR, because the way bi-specifics work, and we're gonna look at that, and I'll show that to you in a picture form, is the bi-specific, we're doing what a CAR does in your body, right? We are going in, we're engaging your T cells in the body, we are activating your T cells, and we're going and finding your myeloma cells. But we give bi-specifics on a weekly basis, right? Every week, once a week, forever. And what we are doing is constantly engaging your T cells and constantly activating them. So if we have to then take out these T cells, genetically modify them, I think that could be an issue. And my suggestion would be there has to be a gap between a bite followed by a CAR. Whereas CAR followed by a bite is easy, because once you've gotten the CAR, we are doing nothing. For example, Ellen has had her CAR T cells about two years back now, Ellen, and you've been on no treatment at all. So what's going on right now is just the endogenous T cells, which should be healthy and should be able to respond to bi-specifics. Did that answer your question, Bonnie? Oh my gosh, yes. And of course it generates a lot more, but I'll leave question time for others. Thank you. Thank you, Bonnie, for your excellent question. Yeah, we had several patients wondering about bi-specifics. So I'm glad to hear that you're gonna go into that a little bit later. A couple of other questions and a couple other raised hands. So one of the questions that I saw was what type of chemotherapy is used for conditioning? Yeah, again, a great question. So the chemotherapy we used is two, cytoxan. I think most of you are familiar with cytoxan, because around the time that you collect your stem cells, a lot of us use cytoxan. The dose of cytoxan is pretty low though. It's 300 milligrams, it's given over three days. So, you know, Monday, Tuesday, Wednesday, then two days of rest, and then you come in for your cars. We also give another chemotherapy called Fludarabine. And Fludarabine, most myeloma patients are not that familiar with it. It's a drug which we use for CLL. We've used it for years and years. And we have data to show that when you use a drug like Fludarabine, it's able to dumb down some of those T cells, which could otherwise work against your cars. So cytoxan, Fludarabine is what we're using currently. All of it done as an outpatient and in general, extremely well tolerated. It doesn't cause any hair loss. It doesn't cause the kind of toxicity that an autologous stem cell transplant can do. Interesting. And then Gail was wondering, in terms of kidney damage, can you still be eligible? And if so, is there a certain level? Yeah, this is why I love doing these because the questions that you guys asked are incredible. So kidney damage is a problem. And as of right now, at least on the clinical trials, we did not allow people who had kidney problems to get cars. I think that is gonna absolutely change, Gail. And the reason being, we know that kidney problems is a major issue with multiple myeloma and we are beginning to do cars. We are actually gonna be doing our first car in a patient who has kidney failure. I think the big concern with kidney failure is the issue around using Fludarabine. So cytoxan is a safe chemotherapy. You can give it with kidney damage, cars you can give, but the Fludarabine is cleared by your kidneys. And it can actually cause a lot of toxicity. We have some data to suggest that if you don't use Fludarabine with cytoxan, your cars don't take. And that's part of the reason why we didn't use it. But we are looking at protocols of trying to change the dosing of Fludarabine so that we can include people with kidney problems as well. But this would be a perfect place where I would think about using a bispecific T cell engager. If you really have kidney damage where you can't get to the Fludarabine, thinking about a bispecific is a great idea. And isn't it beautiful that we have these options? I mean, it's just so exciting to see these novel therapies, immunotherapies being used in the myeloma arsenal. I love it. Just hopeful. Tom is raising his hand, Tom Williams. If you wanna unmute and ask your question. Yeah, hi. Hi, I had a question about the chemotherapies leading up to the CAR-T. Do they cause the same sort of immune suppression that you get with a melatholin? The drug used for stem cell transplants where your immune system's pretty wiped out and your vaccinations are wiped out. Is it the same thing with CAR-T or not? Yeah, again, a great question, Tom. Thanks for that question. So not quite like melphalan, your immune system does get wiped out. And one of the drugs like the Fludarabine, we're giving it intentionally with the intent of getting rid of some of the immune cells. Having said that, most of the vaccinations, we allow you to get vaccinated three months out from your CAR-T cells. With transplant, we generally wait for at least six months. Your immune system is not 100% and that's part of the reason why we will keep you on certain medications. Like you stay on drugs like acyclovir, the antiviral. We keep you on prophylaxis for PJP with drugs like Bactrim that you're used to. And those are things that we continue in general in the majority of patients. But by three months, your immune system starts coming back quite normally. One other thing to think about, Tom, is we are using CARs against this protein which I mentioned to you, it's BCMA. So BCMA is a protein which is present on not just your myeloma plasma cells, but your normal plasma cells also. And because it's targeting BCMA, it actually suppresses your plasma cells. So the one thing we do see and we do need to do for patients is give intravenous immunoglobulin. And that puts you at a slight risk for infection. So we actually supplement you with what we call IVIG and that's given intermittently on patients who've had CAR-T cells. Thanks. Yeah, that was a great question. And actually one that I shared, you hear about this 100 days of recovery after stem cell transplant where you need to be extremely careful to prevent infections. And I was wondering if it was that same type of thing that doctors recommend, but it sounds like it's a little bit easier on the immune system than a total wipeout from L-Flam. Great. Did you wanna keep going, Dr. Rajay, or did you wanna keep fielding questions? So we can keep going quickly. And then, I'm happy to take questions along the way as well. So I do wanna talk a little bit about the process and what you, these are more sort of practical insights into CAR-T cells, but feel free to stop me whenever you guys have questions. So this is sort of just the overview. We've gone over it a little bit. We've talked about the apheresis, which is the collection. We've talked about the pre-CAR thing. Then we've talked about the manufacturing process. We've talked about the lymphatic bleeding chemotherapy, which some of you asked really great questions and then infusion, and then more monitoring people sort of long-term. For the apheresis procedure, the reason you are wanting to do this is to collect your T cells. And there's a few things, you know, with myeloma, we've really not worried too much about what, so remember when you get your stem cells collected, we used to give you growth factor. We give neupogen for a few days ahead of collecting. We use a stem cell booster for collecting the leukoporesis product or for collecting your CAR product. You don't need anything. We just want to make sure that you have enough lymphocytes and our threshold is really quite low. So as long as you have an absolute lymphocyte count of a little over 100, we are good. So most times we're able to collect drug T cells to create a drug product quite effectively. The one thing we have done though is prior to your collection, we generally would stop treatment of whatever you're on for about two weeks before the actual collection. Several other things to think about, you know, we prefer that you not get very key cytotoxic chemotherapy. Drugs like bendermustine, drugs like a whole lot of Cytoxan, Melphalan, just prior to collecting is something which is not advisable. So we try and make sure that you've been away from those kinds of drugs because they do affect one, they affect your counts and they do also affect your T cell function. Outside of that, if it's a monoclonal antibody that you're on like deritumumab, for example, certainly two weeks off from deritumumab, preferably three weeks off because that's sort of the cycling time for deritumumab. Bridging therapy, I think that's something we all think about and talk about. And I think hopefully it's gonna become less of a problem as we start moving these treatments earlier on in the course of the disease. And the bridging therapy is basically to try and control disease during, when we've taken out your T cells and we're working on manufacturing them, we still wanna control your myeloma and trying to get to your CAR T cells and as good a condition is probably the best way of doing it. So controlling your disease is a good idea. And once we've collected your T cells, we can use any of those phenotherapies that I've talked about. So bridging therapy is important. We generally try and get rid of the bridging therapy at least a couple of weeks before we admit you to get your CAR T cells. And the reason for doing that is we wanna make sure we've sort of washed out whatever toxicity you have from the bridging therapy so that you can tolerate your CAR T cells better. So that's as much as I had on sort of CAR T cells. And then I was just gonna briefly talk to you about by specific T cell engagers, because I think like Bonnie just asked us, how do you decide one versus the other? And it's not a straightforward decision. So just to give you all a sense, what is the question? Can I, sorry, can I interrupt you really fast and ask a couple of questions? The bridging therapies, do we see things like X-fobio or selenaxor as bridging therapies? What are things that you have found successful to be bridging therapy since so many people are refractory to so many things at this point? Yeah, that's again a great question Audrey. And drugs like selenaxor, we have used as bridging therapy. They've worked out quite well. When we were doing CARs as part of the clinical trials, we were very restricted and we were restricted by the FDA and we could only use what a patient had already seen before. That was a struggle for us because what the FDA wanted to make sure and see was that we were not getting the effect of the drugs being recycled and it was truly a CAR effect. Now that these drug products are approved, it gives us a lot more flexibility so we can use other things. So Ellen mentioned 11, 14 translocation. People who have 11, 14 translocation for bridging, I've tended to use venetoclax, that's not the majority. Drugs like selenaxor I've used. I tend to use Cytoxan a lot with either Velcade or with Carpalumet and that's helped some in patients. We have rarely, and that's very rare, one patient that I've used Belant, Mammapodotin also in the mass. But generally we've stayed away from sort of BCMA-directed approaches in that bridging timeframe. Awesome, awesome. Couple other questions. Someone was wondering, since it's such a successful therapy, if it would be, I don't mean to laugh at the question, but I just, myeloma therapy is so complex. When we think of getting deeper and deeper remissions when it comes to minimal residual disease, is CAR-T therapy something that in theory could be applied to a patient that's in remission and then therefore get a deeper response? Yeah, no, listen, again, fantastic question. And that's exactly what we're doing. And before we started doing this, the concern was, you know, these, when we give you back these cells, the way these cells work is they have to engage with the tumor, right? And you have to have some level of antigen out there for those T cells to start growing and expanding. We don't believe that you need too much. I don't know if you need to be MRD negative, but prior to MRD negative, we have done it in the upfront setting where we've given people a little bit of chemotherapy, chemotherapy is RED or KRD or one of those combinations and then gone in and done with the CAR-T cells. And I do think if you do it in the setting of disease burden, which is low, you're gonna end up seeing less toxicity. Same time those T cells are expanding, they are doing their job and they are controlling the disease. Now the early data, and we have data both with either cell and with CILTA cells in trials, which are early on, it's too, you know, the data is still fairly early data. It's not mature, but so far we have this good disease control, but absolutely if you are able to get to a deep molecular remission and stay that way, that's the goal. And that's part of the reason why bringing it upfront is what we're doing. Yeah, yeah. And what kind of timeline do you think we're looking at in terms of bringing CAR-T to upfront therapy? And do you think that it will become standard for patients to receive CAR-T therapy or does the manufacturing make it too difficult to assume that? No, yeah, but you know, I think the goal is to bring it upfront, right? And we're already doing clinical trials. Right. For example, there's a clinical trial with CILTA cells, which is comparing it to autologous transplant. There is a trial with iris cell, which is using it right in those patients who've gotten a stem cell transplant and are still MRD positive, can we give them CAR-T cells? So that's already happening in the newly diagnosed space. You know, I think as, I think access to these, because it's not off the shelf and it requires this process of manufacturing, it's a very personalized way of treating and therefore having planning and having more, the ability to create more drug product is gonna be what's gonna change the landscape. I think the fact that we've been able to get two drug products approved through a pandemic is a testament to not just the investigators, the companies, but I will say to patients, Ellen told you that she went through this during COVID. That was not easy, you know, because we did not allow a single visitor because we kept trials like CAR-T cells open at our center because we know that they have such an impact, but it's not easy to remain isolated for two weeks without a visitor in the hospital and not, you know, getting COVID tested. Every time she came, we will always have to do that COVID testing. We're to you. Poor Ellen. Right? Ellen can speak to that. Ellen, you're on mute. The fact that we have two drug products through a pandemic is really a true testament to people willing to do this and everybody rallying behind this. So, you know, we've had challenges with creating drug product. Part of the challenge is I showed you when we create the CAR-T cell, you need a viral vector to put a gene into your T cell. And we are reliant for that viral vector on certain production. That there's a supply chain issue with everything happening right from food. It's happening in the CAR-T cell world as well, where we do not have enough vector and that's where the limitation is. Our hope is that as we do more, there's gonna be more access, there's gonna be more production, and it's what we're doing. Yeah, wonderful. Steve, I saw that you had your hand up and then Karen, I don't know if Steve's still here. Yeah. Okay, we'll have Steve go first and then Karen. Yeah, shall I speak now? Yes, please, yeah. Sorry if I wasn't clear. Yes. Oh, okay, great, thank you. Yeah, hi, thank you so much. Steve Morris here from National. My question is sort of a simple one. I was diagnosed at the age of 79. I was in perfect health. I also liked the speaker and became a marathon runner. Eat only healthy stuff, great diet, great weight, everything, perfect health. Going for a checkup and they tell me I have multiple myeloma and plasma cell leukemia and the only way to save me was to ingest poisons. So my question is a simple one. I had to overcome that same thoughts that the speaker has had. I was assured that the side effects from the chemo were manageable and rare. I was assured that it was better to do that than not be treated. My question is I became eligible because I went right into remission and I was eligible for stem cell transplant. My question is this. I was told that the quicker I get my stem cell transplant and I assume the T cell, T-cell one, the longer will be the remission. It'll never go away completely because of my disease. So my question is, is that true? I ended up having the transplant, the stem cell transplant, no reaction. It's terrific, I'm six months out, I'm in MRD remission, I'm going for my bone marrow at the end of the month. Is that true? All of the experts advised me to get my transplant as long as I was eligible in perfect health as quickly as possible and I did. Knowing that eventually my disease will come back but not as fast as if I didn't have it. That's my question. Steve, congratulations, you are doing fantastic and I'm so happy for you. That's wonderful, but you're absolutely right. I think what your oncologists have told you, it's true. The stem cell transplant does control the disease for a longer period of time. It does not cure your disease and even with a stem cell transplant, unfortunately the disease can come back again. But that's part of the reason why we're talking about some of these other therapies which are not transplants and some of the immunotherapies that we're talking about is unlike the transplant. And if and when, nobody's good at predicting as to when the disease will come back, Steve. And that's where I think having all of these options available to you is critical. And that's why I think the timing of when you're diagnosed, how you're diagnosed, what's accessible makes such a big difference in the care of myeloma patients. Thank you, thank you both. Karen, if you want to unmute yourself and ask your question. Okay, I don't know if you can see me or not, can you? I'm not sure, I can hear you though. Can you? Ask your question. All right, well, my question is this. So I am on cellmod now, IDA cell, and I am starting to have my numbers go up. I have extramedulary disease, it's in my liver. And so I've been through, you know, isotuzumab and all the different treatments obviously to have gotten me on the IDA cell trial. I'm on 11 years, and I'm wondering if CAR T is my next step versus bispecifics given that it's in my liver. And, you know, I just like your opinion on that, Dr. Rajay. Yeah, no, thank you for that question, Karen. And really, you know, it depends on what you have access to and what your general health otherwise is. And if you're able to, between bispecifics and CAR T cells, right now we do not have a bispecific which is FDA approved as yet. We're working very hard on getting them FDA approved. My feeling is that they're gonna be FDA approved by, I wanna say not the end of the year, but sometime in the spring of 2023. So until that time, a bispecific is something you're gonna be able to access on a clinical trial. If there is a good clinical trial where at a center close to you or your treating oncologist has access to and thinks that you are eligible and fit for, I think you're gonna do well with a bispecific. If you have access to CAR T cells, I think that would also be wonderful because what CAR T cells do is, you know, you are able to get the CAR T cells, it's done and you can always get the bispecific after as well. So end of the day, it really depends on what is available. And I would look at both. Both CARS and bispecifics have high response rates. The difference is one is on a trial, one is standard of care. So it depends on what is available to you out there. Awesome, thank you so much. A question that I think leads well into talking about specific antibodies. Is there any treatment after CAR T or is it the last resort? In other words, if it is what can be done or all else fails? So with that question, if you wanna kind of continue the presentation and talk about different therapies. Yeah, we'll talk about, listen, we're all talking about life after CAR T cells. So there is life after CAR T cells. It is not, and it should not be the last resort. And that's part of the reason why we are having this conversation even today, right? We wanna think about doing this early. We wanna plan ahead so that we can get the best possible response ever. And then even when the disease comes back, the one thing I will tell you is we do see a resetting of your immune system. So there are drugs which you had been on before, post-CAR T cells, if your disease comes back again, you can respond to some of them. And then we've done things like the bispecific T cell engagers. And I'm just gonna show you what we mean by a bispecific T cell engager. So this is just an antibody. And this is like your deritumum app, for example. This is naked antibody. It recognizes, this is the part which recognizes an epitope on your tumor cell. And what deritumum app does is recognizes CD38. So it goes and attaches onto your myeloma cell and it kills your myeloma cell by a process which we refer to as antibody drug conjugate cytotoxicity, ADCC, okay? Now what are antibody drug conjugates? These are ADCs. So they have the same antibody. That antibody recognizes a protein on the tumor cell, but to that antibody, we actually attach a toxin, okay? Now this is the toxin which does the killing. And this is what you have with Belamath, for example, Blend Rep. Blandtomabapidotin is an antibody drug conjugate. It recognizes BCMA. So the same target that's recognized by the bispecifics as well as by the CARs, but what it has is MMFA. It's a toxin. It's a tubulin toxin. So this antibody goes and attaches to the tumor cell and it's this part of the antibody which actually causes killing of your tumor cell. So that's one way of working. And then you have the bispecifics. Now what are bispecifics? Bispecifics are this antibody. This is your antibody complex here. It has essentially two arms. One arm targets your T cells. The other arm targets your myeloma cell, okay? And the target antigen in myeloma is essentially BCMA. So it attaches to the tumor cell. It also, the other arm of it goes and attaches to your T cell, brings your T cell to the myeloma cell. So in essence, it's doing what CAR T cells does and then causes killing. And this is just an example, the same thing out here, right? This is your antibody. The green part is recognizing the tumor. The red part is recognizing your myeloma cell. By activating the T cells, it's killing your myeloma cells. And we have a whole range of bispecific T cell engagers, which are in clinical trials right now. The majority of them, two of them, one is called Toclystumab. The other is called Elranitumab. Both of them are pretty much along the way in their development. Our sense is that they will get FDA approved sometime next year. We do have other bispecific T cell engagers, not targeting BCMA, but targeting other proteins. And that's a very relevant question to what you just asked, Audrey. What about life after CAR T cells? Well, all of the CAR T cells that we have are against BCMA right now. So using antibody drug conjugates against, we have two other proteins that we are targeting. One is called GPCR5D. The other is FCRH5. We have one antibody bispecific called Talcfetumab. The other one is called, blanking on the name of that, Talc and Cevostumab. Cevostumab is against the FCRH5. All of them work against your myeloma. And that's the big question, right? What's next? And what's next is we are working very hard in the laboratory. Some of the questions that all of you have asked is, is it all T cell related when the CAR T cells stop working? And it's not all T cell. T cell intrinsic problems are one part of why T cells don't work. And we are studying the function of these T cells, but it could be myeloma specific also that your myeloma stops responding. And those are studies we are doing. And to try and overcome this, we are looking at other targets. I've mentioned two of these. And finally, in myeloma, we've done a lot of work around your bone marrow micro environment in the laboratory. And we know that there are certain factors that are secreted by both your T cells and your myeloma cells, which make all of these immune strategies less impactful. And so in the future, what we're already beginning to do is not just CAR T cells alone, but CAR T cells in combination with some of these other factors, which could down regulate things on your tumor cell or within the micro environment. So for the future, I think what we are already working on in the, not just in the lab, but actually in people where we are doing things like dual targeted CAR T cells, for example. So we have a clinical trial here at MGH, where if you fail BCMA CAR T cells, then you go on to what we refer to as a CAR T cell called TRIPRIL. TRIPRIL targets two completely different proteins. So this is a dual targeted CAR T cell targeting TASSY and APRIL. So targeting two proteins on your myeloma cells. We are also working on tandem bispecifics and those bispecifics can also target a whole bunch of different proteins. And I think Karen, you mentioned that you're on some of these cell mods. We do have Iberdomycin and CC480, which are the next generation of drugs. So they come after, we started in the old days and I'm old enough to remember we first used Thalidomide with myeloma. Then we went to Linalidomide, now we have Humididomide. And now we have the super imides, which are called cell mods, which is Iberdomycin and CC480. And all of these actually work in people who failed everything else as well. So we're doing a bunch of combination studies with some of these, both with bytes as well as with CAR T cells. So there's a lot of excitement, post CAR T cells also, and how can we begin to combine? How can we begin to sequence? And how can we put all of this together so that you can get the best possible response for the longest possible time? So I think what we have learned really is that our immune system is really important in myeloma. It is a real powerful tool and we're beginning to be able to really modulate this immune system with all of those different things that I've talked about. We know that BCMA is a great target, but we have moved beyond BCMA as well, where we have a bunch of different targets. And in the future, we're beginning to try and understand how best to combine these, how best to sequence this, and how best to improve the efficacy of all of this. So that's all I had for all of you. I do, I have this wonderful team at MGH, which has helped take care of Ellen. And we couldn't do it without the entire team, our research nurses, our nurses, our clinical research coordinators. And ultimately it's you all who completely have complete trust in us and sign up to do, sign up that 38 page consent form, Ellen, and agree to do the trials. So a lot of progress has been made because of your willingness to participate in these trials. So again, I'm happy to take questions now, Audrey. Perfect, thank you. And thank you for your sacrifice as well. I know this takes several hours, I mean, so many hours of your time and just your willingness to participate in this research and truly save lives and care about those lives you're saving is really evident, so thank you. A couple of questions and feel free again to raise your hand. I see we have a couple of raised hands. One of the questions is, have you seen CAR-T to be effective on a genetic abnormalities within patients? Yeah, so again, great questions as always. Myeloma patients are really, you're part of the reason why we have to keep doing better. Fantastic question, when we started out, so remember we talked about all of these immunotherapies agnostic of your genetic risk. And whether you have the P53 deletion, whether you have deletion 17P, whether you have 414 translocation, most time these CAR-T cells do work, but what we've seen over the course of studying this, that high-risk signature still seems to remain a high-risk signature. So they are the ones where the disease can come back sooner. So that's the patient population where we would really advocate for combining things. So not just doing CAR-T cells, but maybe considering doing some form of maintenance in the very high-risk patient population. Yeah, have you seen it successful in any non-secretory patients, for example? Very effective in people with plasmacytomas, for example, extramedullary disease, non-secretory disease. Part of the problem with the clinical trials was we weren't allowed to include those patients. Now that we have the CAR products which are approved, we can actually treat those patients. We had just one trial here at MGH. It comes from the company Arcelex, and we did actually specifically allow for extramedullary non-secretory patients, and we followed them using PET scans. I love that. And I can tell you, my longest, he got the treatment now two and a half years back. He would not have made it on any other clinical trial except for Arcelex, and he is doing fantastic. He had all of this extramedullary disease. Nothing worked, but he's been in remission without being on any treatment, which is really great. Fascinating, wow. For those that aren't aware, because I see some questions, non-secretory is, in layman's terms, when you don't have an M-spike, and it's not the same. You're not able to monitor it in the same way as you would a normal myeloma patient. Fred, how about you unmute yourself and ask your question? Fred, please. Okay. This may not be a short answer. I suspect it's not. But we talk all of these strategies about killing myeloma cells, and I really wonder, as we all expect our disease to come back at some point, what are we doing to understand why our body produces bad plasma cells and how to stop the production of myeloma cells as opposed to just killing the ones that are produced? Again, amazing question. Thank you for that. So obviously, we're doing a lot of work around that as well. And that goes, you know, the interesting thing, Fred, is we have a disease where it's a model disease which has a precursor disease state, right? Most myeloma patients, before they become myeloma, have MGUS or have small ring myeloma. And yet not all MGUS patients turn on to become myeloma. And what is it about those patients which is different? And what is it that's keeping that myeloma in check? So we've studied the genetics of the tumor cell quite extensively. And I will tell you, when you look at the genetics of anybody with MGUS versus as far down as plasma cell leukemia, the genetics of the plasma cell itself is not that very different. What we do believe is the surrounding cells, the microenvironment is what keeps the disease under control. And we are beginning to understand what are the breaks that come off, which results in the development of this uncontrolled proliferation of plasma cells. We have some ideas now on the immune signature. And really, when you think about controlling the myeloma clone, you have to control it at that MGUS or the small ring myeloma stage. And we're working on ways of better risk stratifying patients, doing interventions. In my lab, for example, we do a lot of work around, it's not just the immune cells, the bone cells, but the path cells, which live in the bone marrow, which feed the myeloma cells. And understanding those signals is really gonna be critical in getting rid of these plasma cells, as you said, and not just kill the ones which have already developed. An excellent question, Fred, and excellent answer. Dr. Rajay, thank you so much. Another, a couple other questions. We talked earlier about how CAR-T slows down the process because you have to go get it manufactured and then test for infection, et cetera. Are buy specifics considered off the shelf? Like, will they be created ready to go? Oh, they are ready to go. They are off the shelf. Having said that, as of right now, we are still, most of the trials will, we're doing what we call a step up dosing for buy specifics. We are hospitalizing people for the first week of the buy specific. And the reason for that is you're gonna get the same kind of toxicity. And we didn't talk much about the toxicity. The big toxicity that we worry about with all of these immune therapies is twofold. One is something known as cytokine release syndrome, or CRS. And that's something which is an on target toxicity. We expect to see it. And what happens is your T cells come, kill your myeloma cells. And when the myeloma cells die, there's a whole bunch of cytokines which are released by your myeloma cells. And those cytokines can make you quite sick. Now, the same thing applies for the buy specific T cell engagers as well. How does one manifest? How do you present with the CRS? You can get fevers. You can get, your blood pressure can go down. You can get very sick very quickly if we are not able to take care of you. And that's part of the reason why you have to stay in the hospital. So even with the buy specifics, the incidence of CRS is a little bit lower than with CAR T cells. And the rate of CRS is a little bit lower, but it still exists. We have good treatments for this. And one of the drugs that we use is a block of some of these cytokines called Rosalucimab. And it's not readily available at community hospitals. So the first dose of the buy specific we're giving as a step up dosing. So two doses over a week. Most of our patients are hospitalized for that first week. After that first week, it is off the shelf and it's given weekly. And it's easy because most buy specifics are given as shots now. It's not an infusion. It's given as a shot. There's one or two which I am still in infusion for. That's fascinating. Thank you. So fun to learn about these new therapies. April is wondering if an autoimmune disease would make a patient ineligible for CAR T. Good question, April. I don't think so. So we will allow people with autoimmune disease also to get CAR T cells. Autoimmune disease becomes more of an issue when you're using things like checkpoint blockers, PD-1, PD-L1 inhibitors. We don't use those in myeloma as much. So I think a CAR T cell should be allowed. You have to check in though with your oncologist and make sure that whatever the autoimmune disease is under some sort of control. And the other big thing is with autoimmune disease, you tend to be on steroids for the autoimmune disease. So while collecting your T cells, you wanna make sure that you're not on those steroids. Things like that need to be considered. Great points, thank you. Gail wanted to re-clarify just to make sure you do need to get re-vaccinated after a CAR T just like the stem cell. Correct. And we allow that three months out, yeah. Awesome. Bonnie, would you like to ask another question? Yeah, except brain fart. Oh, I know what it was. You were talking about the microenvironment, and that's what causes the, is a big factor in allowing the myeloma cells to proliferate from MGUS. Do you believe there is a myeloma, an actual myeloma stem cell? So again, great question, Bonnie. So I don't know if there is a myeloma stem cell and the reason I say that is this has worked from years ago now, right? And some of the data which came out of Johns Hopkins has not panned out specifically when they targeted CD20 with the rituximab because we've not seen any responses. The reason I'm a little skeptical about the whole stem cell theory is plasma cells are very differentiated cells. They've already promulgated the T cells they've already prom these cells matured and form plasma cells. But I do believe, and there's data and there's data from my lab as well, where we think that, why does myeloma get better? And why does it keep coming back? And the reason it keeps coming back is there's some inherent myeloma left behind which then gives rise to myeloma again. And what that is referred to as dormant tumor cells. So they get into a dormant stage and then there are certain factors within the microenvironment which wake them up. And if we can make that microenvironment unfriendly so that they do not wake up, that would be something that I would think would result in sort of long-term disease control. So whether it's dormant tumor cells or whether you wanna call them stem cells, I think those are semantics. Thank you. Very, very helpful, thank you. You have lots of patients singing your praises in the chat, Dr. Rajay. They think you're the goat, the greatest of all time. So another question, speaking of longevity, Anka was wondering, how long have you seen patients have a durable remission without treatment? You hear of those outliers, have you seen any yourself? Yes, I've been doing this long enough and I'm old enough and gray enough. So no, we've had people out 20 years and we've always said this, right? We never, we always hesitate to say that we've cured myeloma. And the reason we hesitate is, you know, we still have patients for dying of myeloma and that is a problem, right? But I will tell you that we have a lot of long-term survivors going 15, 20 years on baby doses of something. Those are the patients where I will tell them, let's try stopping your treatment, but they are so averse to stopping treatment at that time because you're so used to being on that treatment that you don't wanna stop it. But I do think that we're curing a fraction of people already. We already, in my opinion, we're curing about, I wanna say about 40 or 50%, what we wanna do is cure the majority and we're not quite there. And it's mostly the high-risk disease that we need to really focus on. Yeah, I would agree from what I've been learning. My last question for you, Dr. Rajesh, why myeloma? Why did you turn your life passion to treating myeloma and researching? No, that's a great question. So, you know, I didn't wake up and say, I wanna do myeloma, I wanted to do oncology. So that was, and the reason to want to do oncology was, you know, oncology is not, like you're not just doing the heart or the GI tract, oncology encompasses everything, right? You have to know infection. I used to love internal medicine and that's why specializing in oncology made the most sense. Why myeloma? I think that was an opportunity. I got a fantastic opportunity working with Ken Anderson and with Ray Pauls in the UK. And as I started to learn more about myeloma, it was just one of the most fascinating diseases. And I sort of feel spoiled because, you know, I feel like I've been, like I started doing my research in myeloma in the late, early 2000s, late 1990s. And that was the beginning of Velcade, PS341. That was the beginning of Revlimid. That was the beginning of, you know, I remember writing my first editorial on thalidomide. We were using thalidomide in myeloma. So it's been such an exciting journey for me that when I look back, I've actually worked with these drugs in the lab. I've pipetted with them and now I see that they're all FDA approved and they've made such an impact on our patients. So to me, it's just been such a joy. Wonderful. Well, thank you. We can feel that joy and really appreciate you sharing this time with us. Thank you so much also for the excellent questions and participation. It's an awesome chapter to be a part of. Thank you everyone. And thank you for your time, Dr. Raji. We're gonna close with just a couple of outro announcements. So please join us next month. We're gonna be hearing from a team at Dana Farber who will lead us in a presentation about the PROMIS and P crowd studies. Their purpose is to study myeloma as a possible genetic disease passing on through family or genetics in that sense of the word and understanding risk factors for what, as Dr. Raji was mentioning earlier, what leads that MGUS patient to become smoldering? What leads that smoldering patient to become active myeloma patient? Your family can participate in this study as well in order to further myeloma research. So it's an exciting way to get more people involved in searching for a cure. So don't miss it. That's gonna be on June 9th at 6.30 PM Eastern. Another thing I wanted to mention is in June, we're gonna have a Northeast Myeloma Moves Challenge. So the goal is to be mindful and increasing physical activity as a chapter throughout the month. So hopefully this is something that really brings us together, something that's exciting for our community. How we're gonna do it is we'll track our activity on the Health Tree Moves Fitness app. You can get that in the Apple Store or on the Android Google Play Store. And it really is whatever counts as movement for you. So whether that's walking, swimming, hiking, gardening, yoga, biking, strength training, water aerobics, anything that gets you moving. I had a lady go up and down the stairs of her condo because that was what moved her. But it's whatever gets you moving. We're going for 20 minutes of activity a day and that's gonna be through the month of June. So mark your calendars. I'll be sending out reminders if you want to participate with us. All participants who are active for at least 120 minutes throughout the month are gonna receive a special Northeast Myeloma merch. We're thinking either socks or a shirt or a hat, but special merch for the Northeast Fitness Journey that we're gonna be on together. And we'll also have raffle prizes for qualifying participants such as maybe an Apple Watch, a $100 Amazon gift card, other fun, bigger prizes like that for those who participate 25 out of the 30 days of moving for at least 20 minutes. So I'm looking forward to that and wanted to on your radar as we move forward. You may be interested in other community events coming up. On the 17th is our non-secretory Myeloma community chapter. We're gonna be hearing from Dr. Sasha Tuchman as he talks about clinical trials for the non-secretory Myeloma patient. Dr. Rajay was mentioning earlier that because they don't have an M-spike, they're not usually admitted into clinical trials, but it's exciting to hear that through PET scans and other means, they are including more non-secretory Myeloma patients in trials such as that. Wednesday, May 18th is our Mountain West regional chapter. So that's a different regional chapter, but you're always welcome to jump regional chapters and join and visit them. It's gonna be a Q&A with Dr. Manny Mohunin. So he's gonna tell you the great news that we have about Myeloma, and he's also gonna tell you the not so great news that we have about Myeloma research that's being done. He wants to get the full picture. And then on the 24th at 1 p.m. is the immunotherapy treatment chapter. We're gonna be talking a little bit more about antibody drug conjugates with Dr. Jesus Bredeja. The link to sign up for any of those events and even more events I did not mention is found at the bottom of this slide and will be sent out in a follow-up email within 48 business hours of this event's conclusion. Another thank you to our sponsors, Bristol Myers Squibb, GSK, Genentech, Janssen Oncology, and Abbby. And again, thank you to each of you for helping me build this Northeast Myeloma community. Couldn't do it without you. I really appreciate you and hope that you have a great rest of your evening. Thank you, Ellen, for sharing your story as well. Thank you all for being here tonight and taking the time. Have a good night, everyone. And go.