(Guest Lecture): November 2022 - Immunotherapy 101 for Multiple Myeloma Patients

So today's topic, as you know, is immunotherapy 101 for multiple myeloma patients. I feel like no matter where you are on your myeloma journey, this is a great topic because even if you're advanced down the line relapsed myeloma or maybe in complete response, maybe newly diagnosed, learning about immunotherapy and where it falls and how it compares to chemotherapy and what constitutes as immunotherapy, what makes it different. It's just such an important part of understanding what myeloma treatment is, what the future of myeloma treatment is, and we can all learn and benefit from this topic today. So as you can tell, I'm really excited to talk about it today. Dr. Holk-Herns is back due to popular demand. This time she's going to share with us this crash course in immunotherapy. What makes immunotherapy different? What even is it? Is it going to take over chemotherapy? These are kind of the things that we're going to be discussing today throughout the Q&A and her presentation. So I'm really looking forward to it. It's my pleasure to introduce her. Dr. Holk-Herns is a board certified hematologist who specializes in the treatment of multiple myeloma and other related plasma cell disorders. She is focused on further optimizing treatment strategies for people with multiple myeloma and offers a variety of modern treatments, including clinical trials and novel immunotherapies. She is also working on measures to continue to improve patients' quality of life while receiving treatment for multiple myeloma. In 2015, Dr. Holk-Herns received the Research Fellow Award from the Multiple Myeloma Research Foundation and the International Postdoc Award from the Swedish Research Council. Dr. Holk-Herns is fluent in Swedish and English, and I am just so excited to hear from you today, Dr. Holk-Herns. It's your time now. Thank you. Thank you so much. Thank you for that very kind introduction and thank you for having me back. I'm also as excited as I'll do to be here. So let's get started. There. So what we're going to talk about today is we are going to talk about multiple myeloma and this is Immunotherapy 101. So let me see here. Multiple myeloma and immunotherapy. We're going to touch briefly on what is the immune system, what is immunotherapy, the different types of immunotherapy, and then the future strategies and how this fits into where we are with treatment. So what is the immune system? If you look at the National Cancer Institute, the immune system and kind of the textbooks is a complex network of cells, tissues, organs, and the substances they make that helps the body fight infections and other diseases, that meaning cancer included. The immune system include white blood cells and organs and tissues of the lymph nodes, such as the spleen, lymph nodes, and the bone marrow. Let me see if I can move here. So continuing on the immune system, some of our immune finders, they are the lymphocytes. We have different types of lymphocytes. We have B and T lymphocytes. We have the natural killer cells. We have the cytotoxic T cells. We have the B cells. These are the ones that make the antibodies and these are the ones that normally they mature also into the plasma cells. We have regulatory T cells and we have the CD4 helper T cells. We're going to focus on a few of these during this presentation. So during the tumor immunology, what we see or what we want to see is that all these different types of lymphocytes, they help fight the tumor. But what we also do see in multiple myeloma and a lot of different other types of cancers is that there is a T cell dysfunction and eventually in T cell exhaustion. So due to the chronic stimulation, these end up get tired and they get exhausted and they don't work as well. So their effect goes down. They don't proliferate, so they don't divide as effectively and really they don't work as effectively to fight the cancer cells. We're seeing starting this, we're seeing that this starts already actually in the MGUS phase. So what happens is that the malignant plasma cells, the myeloma cells, they escape, they evade the immune system. So they find ways of hiding and also due to this T cell exhaustion, it's an interplay here with the exhausted T cells that don't recognize the myeloma cells and the myeloma cells also kind of then they kind of like this T cell exhaustion as well. So they have ways of maintaining this as well. So they do want to hide. But the good thing is that these T cells, they can still be stimulated to effectively fight multiple myeloma and we're going to see that later. So what is immunotherapy? The American Cancer Society says that the immunotherapy is treatment that uses a person's own immune system to fight cancer. This can be done in several ways. Immunotherapy can boost or change how the immune system works so it can fight and attack cancer cells. So it can work smarter or harder to fight the cancer cells. So it can be helped by making substances in the lab that are just like immune system components and by using them, we can help restore or improve how the immune system works to fight the cancer cells. So how is this different from chemotherapy? Chemotherapy really goes in and this is again the traditional chemotherapy that we sometimes use for multiple myeloma as well, but these are really the traditional ones that were invented many, many years ago. So these really go into the cell and they interfere with different types of cell functions. So they can inhibit DNA synthesis, they can damage the DNA, they can interfere with cell function and they can interfere with cell division. So they really come from the outside, they go in and they interfere, they damage things in the cell so it can't divide and it can't function and then it dies. So immunotherapy on the other hand, it really works with the immune system. So it does work, it uses the immune system in different ways to, as mentioned before, help to fight the cancer cells in different ways. So the different types of immunotherapy that we have, they're monoclonal antibodies, immunomodulatory drugs, antibody drug congugans, we have the chimeric antigen receptor T cells or the CAR-T cells, we have the bispecific antibodies, we have checkpoint inhibitors and then we have cancer vaccines. So we're going to go through all of these. So for the monoclonal antibodies, these have been around for some time now. These are the first type, they're what we call naked antibodies. So they have, they're an antibody that looks like a Y and they have, they bind to the myeloma cell. So this is daratumumab, it binds to CD30H which is a protein on the myeloma cell and it does have both indirect and direct effects. So it can have a cross-linking effect leading to a direct killing and the indirect effects are that it recruits the immune system and in different ways uses different cells to recruit them and then to kill the myeloma cell. The ones that we use are daratumumab, isotoxumab and elotuzumab. Sorry. The immunomodulatory drugs, these have different types of effects. These are the image, these are the ones that we use a lot, also formal myeloma, the linalidomide, formalidomide and thalidomide. And then the new version, which has a slightly different or slightly enhanced effect, we think, and also has maybe a little bit more of the immunomodulatory effects of the cell mods. So these work through a protein called cereblon. They get into the cell and one of the main effects is that it helps to degrade. So it helps to, it targets different proteins in the cells and then these get degraded and the myeloma cells, they can't function out without these proteins. So when these are essential to the myeloma cell and without them, then the myeloma cell dies. The other thing is that it also does, these, they also do have immunomodulatory effects, so they can activate T cells, they can activate NK cells, they can affect the building of blood vessels and so on. So they have a number of other effects on the immune system as well. Next class is the antibody drug conjugates. The one that we have here that's FDA approved is Bdentumab mephidotin or Blenrep. This one targets BCMA or B cell maturation antigen on the myeloma cells. So what this is, this is a kind of a combination of an immunotherapy and a chemo. So it is an antibody that does bind to the myeloma cells. So you see this here. And it does also affect the, it also does recruit the immune system. But these little things here on the side of the antibody, these are small chemo agents. So what it does is that it delivers, it binds to the myeloma cell, gets taken into the myeloma cell, then it releases these chemo agents and this has an effective killing of the myeloma cells. And so they are targeted in of chemo delivery as well. The overall response rate here is around 32%. And these are also, this study was done in patients that have gone through several lines of therapy, so four or more lines of therapy. The medium progression free survival was 11 months. The main side effects here are eye side effects, so ocular side effects, up to 70% of patients in this study experienced that. These can be dry eye or blurry vision. We also see some thermocytopenia, so low platelets. So with these eye side effects, the way that this drug is approved is that you need to see an eye doctor before each dose. And by doing that, we can actually manage these eye side effects pretty effectively. So if we see that there are small changes or we see that there is no changes or small changes, we can continue with the dosing. And if there's a higher grade of these changes, we can reduce the dose or we can delay the dose. So we can manage this pretty effectively. The next class, and we're going to spend a little bit more time on this, these are the chimeric antigen receptor T cells, so the CAR T cells. These are human T cells that have been modified and then grown in the laboratory and then given back to the patient to target the tumor. So how this works is that first we collect or harvest the T cells from the patient. We take them into the lab. We give them a new gene to code for this new receptor. And this receptor is called the chimeric antigen receptor. So that's the CAR. So we give them this new receptor and then we grow them and then we give them back to the patient. So they're small, you know, missile cells that then come back into the patient and very effectively kill these cancer cells. This is considered a one time treatment. So it's kind of a one and done. We see very durable responses also after these treatments. The one thing is that this also, this whole process, it can take up to six, eight weeks. So often we have to give something, some treatment maybe before, sometimes in between as well to bridge that time from the when we harvest the T cells until we can give them back. So the different targets, so different proteins on the myeloma cells that we can target with these cells. So the main one is BCMA, again B cell maturation antigen. Here we have two different CAR T cells that have been approved. One is a Beckma or IDA cell. Second one is CAR-VCT or a CELTA cell. The third one that we have also at MSK is something called ORVA cell. But there are a number of different BCMA targeted CAR T cells. Another one, another target is GPRC5D and a colleague of mine, Dr. Melancholi, just published this in the New England Journal of Medicine. So we see very high, we have very good results also with this target and it's a different target. So even those that have gone through a BCMA targeted treatment, they can actually respond to CAR T with BCMA, but they can also respond. It might be more attractive sometimes to give a treatment for a different, targeting a different target. And the GPRC5D is very appealing as well. The third type here or another different type is what we call allogeneic. So these are CAR T cells from someone else, not from the patient itself. So these are, we can use them, they're called off the shelf. So we can, we're kind of almost ready to use. Most of them are targeting BCMA as well. And this, the advantage here is that we don't have to go through that six to eight week of the production process. So this is, I'm going to show quickly results for one of the CAR T cells. This is for CAR-VCT or CILTA cell. These are really high results rates. So the overall response rate, that means that this is a group, this groups everyone that has a partial response or better. And partial response means that the M-spike goes down by 50% or more. So depending on which CAR T cell it is and which patient group, almost more the patient group, you know, how many lines of therapy, how refractory they are, then this is effective in around 70 up to almost 100% of patients. For this one, this is the CILTA cell trial. For this CILTA cell trial, we see that the overall response rate was 98%. 80% of patients went into or had a complete response, meaning that the M-spike or the light chains go back to normal. M-spike goes back to zero. Almost 95% had a very good partial response. And that means that the M-spike goes down by 90% or more. So these are really good results. We also see that there's a very durable responses. This trial, after two years, the majority of patients were still in remission without any maintenance therapy. So very exciting. The one thing, though, with all of these CAR T cells, IdaCell, CILTA cell and the ones that are approved, is that there is an issue with availability. So there are some production. Unfortunately, they can't produce unlimited number of cells for an unlimited number of patients. So we have to, at this point, we have to prioritize a little bit who needs it most. And that's a very tricky process. But going forward, hopefully the production will go up and we will have these. We will have a lot more availability. The CAR T side effects. These are cytokine release syndrome. And this means that the body kind of sets off. It's kind of like a bit of a cytokine almost storm. So this can cause fever, can cause shortness of breath, low oxygen, headache, elevated heart rate, low blood pressure, rash. And this is seen in any grade up to almost 80% of patients. We treat this with fluids, with steroids, with IL-6 blocking agents. So we kind of try to manage and decrease this release and this kind of cytokine storm. And due to this, most of the trials or most of the time we have the patient admitted. So we go through this time period when you're in the hospital. The other thing that can happen is something called ICANs or immune effector cell associated neurotoxicity. This can affect aphasia. So talking, it can affect the mental status. You can be confused compared to cognition. So thinking the higher function can lead to weakness and seizures. This is not as common and most of these are reversible. Thank you. Thankfully. So there's a lot of interest in also developing these different CAR T cells. So we have a lot more new different CAR T cell constructs that help. And the main goal of this is to have the CAR T cells work better or work longer. So stay around longer. One thing that we have at MSK is something called a dual CAR T cell trial. So we're giving now the BCMA targeted and the GPRC5D targeted at the same time. We're just about to start this trial to see if that has an even better and even longer effect. Next topic is the bispecific antibodies. And there's been a lot of interest in this, especially now that the first one has been FDA approved. So the way that these work, these are antibodies. And compared to the naked antibody, which I showed you before, these are the these are or that have the two arms that are targeted to the same kind of molecule. These have two arms that are targeted towards different things. One binds to the myeloma cell and the other one binds to the T cell. And what it really does is that it tells the immune system, it tells the T cell that this is the myeloma cell. This is the one that you should attack. And it brings them in very close proximity. So there are different types of these bispecific antibodies. So some of the first ones that are developed are these bytes. So this is a trademark from one of the companies. And this takes the one part of the top part of this antibody here and the top part of the tumor directed antibody here and go together. And then it brings these in close proximity. Most of the bispecific antibodies that we'll talk about are something called a dual body. So it has the full antibody and it has one arm that is directed to the T cell and the other one that is directed to the plasma cell. So the targets here are similar to those of the CAR T cells. Most of them are BCMA targeted. Teclistomab was the one that was just recently approved. Elranantumab also gotten very far in in the trials. We have we have one from Teneo bioavvi and then one from Regeneron. We have the GPRC5D targeted and then we have one also that is targeted towards FCRH5. And all of these are proteins molecules that are on the surface of the myeloma cells. These are given intravenously or subcutaneously as a shot. They're given every week or up to every four weeks depending on which antibody it is and what the dosing schedule is. The overall response rates here are between 60 and 70 percent. This is also super exciting because these trials also start the first trials that are usually done in in any kind of cancer treatment is that you start out with those that have gone through the standards. So these trials are for patients that have gone through four lines of treatments. So they've been through and unfortunately relapsed, but then still can have a very good response from these specific antibodies. I'm going to go through a little bit just of tick list in my just because this is the one that is approved. So the overall response rate in this trial, this is the phase two trial, was 63 percent. VGPR or better, almost 60 percent. Remember that was the response where the m spike goes down by 90 percent or more. CER, almost 40 percent, so complete response. MRD negative, meaning that we can't see it in the blood and we can't detect it in the bone marrow either, was almost 27 percent. So really good. Median time to response, meaning how quickly a response is almost after after a bit over a month. So very quick responses and very durable responses. So in this trial, the duration of response had not been reached yet. So people continue to do to respond. The side effects from the specific antibodies. There is the same risk of or the similar side effects with the cytokine release syndrome and icons as with CAR T cells, but they are lighter. They're not as severe and they're not as severe grading. So that's why the way that tick list is approved and the way that all the studies are done is that for there's a step up dosing where we give a smaller kind of test dose first. And then a few days later, we give a bit higher dose. And then a few days later, we give eventually up to the full dose. So we do that inpatient to monitor and to be able to treat the cytokine release syndrome. And then after you get through that step up dosing phase, then everything else can be done as outpatient. So you can come then to get your either IV or you can get your shot every week or every two weeks, every three weeks, every four weeks, depending on which antibody it is and what which dosing schedule it is. The other side effects that we have to, that we've seen with the by specific antibodies is immunosuppression and infections. So they not only have a very good effect in treating the myeloma cells, it does also suppress some of the B and T cells. So we do see quite a bit of infections here. So we're really closely monitoring for infections and we're giving prophylactic treatments for to prevent these infections as well. So the studies that are ongoing with the specific antibodies, the single agent studies, they're ongoing or almost have been completed for many of these different these different drugs. Now we have also a lot of the combination studies. So for multiple myeloma, there is, as probably many of you know, we do a lot of combination treatments. So we do treat myeloma when you kind of get at the myeloma cell from different from different ways. So we we attack it with different mechanisms of actions. So we're now combining these by specific antibodies with the imid, solenalidomide, promalidomide with proteasome inhibitors, bortezomib, greifelsomib, daratumumab. So we are combining different by specific antibodies and then also checkpoint inhibitors, which I'll get to in a second. Actually here. So the checkpoint inhibitors, this is a different type of drug. So the definition here is that this is an immunotherapy drug called immune checkpoint inhibitors, and they work by blocking the checkpoint proteins from binding to their partner proteins. So this prevents the off signal from being sent, allowing the T cells to kill the cancer cells. So then this is what happens under under under when under normal or when the tumor cell tries to hide here from the immune system. So you have these different bindings here with the PD one and PD one. So this is a signal that the tumor cell shows to the T cell and it says, Hi, I'm a normal cell. Don't kill me. So the T cell does not recognize the tumor cell, but any kind of the tumor cell can go on with, you know, go on with this day. What happens when you have this type of checkpoint inhibitor is you block this link here. So the T cell is then allowed to see that the tumor cell is an abnormal cell and should not be there and then activates the killing of this tumor cell. So this is a very smart, smart mechanism and this the person who invented this, he won the Nobel Prize for this a few years ago. This works very well for many different cancers, among them melanoma and lung cancer. So checkpoint inhibitors and myeloma has not, we haven't seen, unfortunately, the same really good effect. So it's been tried for monotherapy. So just by itself, it's been tried with imides, specifically lanolidomide, and these didn't really have a good effect. Unfortunately, now we are testing it with bispecific antibodies, and we have a trial open also at Memorial Sloan Kettering. So we're hoping that these two together will work well. Cancer vaccines, I'll touch briefly on. And these are a form of immunotherapy where you help and you educate the immune system what the cancer cell looks like so it can recognize it and then eliminates it. So it's similar to when you have a vaccine towards, you know, any kind of virus or bacteria. So, and you can make these actually personal so you can take the body, the person's specific tumor, and you can make a tumor vaccine with the specific antigen. So with the specific things that are shown on the tumor cell surface, and you give it back, and then you then you help the immune system educate the immune system. This is what the tumor looks like and this is what you should attack. And then the immune system should recognize this and then cause the myeloma cells to die. And this has, we're still kind of, there's a lot of studies ongoing with this and they've been studying both in in early precursor or with this mold ring and then also after transplant. We're still waiting on a big breakthrough for this but there's still a lot ongoing here. So, in summary, we do have a lot of different new drugs and a lot of different ways of using the immune system and we can, as I said in the beginning, we can still wake up the immune system and educate and help the T cells to recognize and then effectively kill the myeloma cells. The ones that we're mostly excited about are the CAR T cells and the bispecific antibodies. So, this is a general approach of what we do now in multiple myeloma. We have the induction you have a produce some inhibitor of alkydocarpicemab, you have an image so usually lanolidomide, and then usually combined with anti CD8, so anti CD8 antibodies so diatomumab or isotexamab. So, you have your induction, and you have a transplant and then you have the maintenance. And then in early relapse, you're going to use some of the similar drugs or different combinations or different drugs but kind of within the same drug class and usually these work still very well. And then in later relapses, if the disease still comes back, that's where we have the trials and the approvals now for the bispecific antibodies, the CAR T cells and other different types of therapies. So what's going to happen in the next couple of years or next five, 10 years is that we're likely going to see induction therapies that include bispecific antibodies. We may not, we may do CAR T cells instead of transplant here. And there are actually studies starting to compare these two different treatments already now. So, in linkedinase, we can use different bispecific antibodies, we can have targeted therapies, is this where we're going to use the cell mods. And then for when we use all these very effective drugs up front, the relapses will hopefully, if they come, will hopefully come much later, if maybe at all. So what are we going to do at that point? That's still a very open question, but I think we're going to see a lot more deeper responses and longer responses when we move these treatments up in earlier lines. So in summary, immunotherapy for multiple myeloma is highly effective. And one of the most exciting things are the CAR T cells and the bispecific antibodies. And as I mentioned, this will be used more and more and in earlier lines of therapy. With that, thank you very much. I'm really excited to be back here and I'm happy to take any questions and thank you again for inviting me back. Thank you. That was such an excellent presentation. I think you went through a lot of complicated things in a really efficient manner. So thank you. That is your strong point and that's why you were invited back. So thank you. Well, that's one of the reasons you're invited back. There's lots of great questions in the box already. I'm going to go through and let's start actually with this question. Have you ever seen immunotherapy reaching high risk smoldering myeloma patients? Or is that something in the works of clinical trials or is it more of the wait and watch kind of thing? Right, just a second. That's fine. I think that's a really good question and that's some of the things that we are really discussing at the moment. High risk smoldering, I think, should be treated in the setting of clinical trials. But I do think that we should be exploring a lot of clinical trials in the high risk smoldering because it really is a questionable kind of how long you can stay in that stage. Should you call it early myeloma and start treatment or should you kind of wait and watch? That discussion we usually have with each and every patient and a lot of patients are asking this question. Should we not treat earlier and kind of have a better response or potentially better response? I think, as I said, high risk smoldering, I think should be treated in the clinical trial setting. We don't really treat that much smoldering outside of the clinical trial setting, so it's much better to study it and see kind of what are we doing and what should we be doing? I certainly think that in a couple of years we're going to see the bispecific antibodies already in smoldering. We're actually discussing a few of those concepts as well. So that is something that is in the works. How exciting. Do you see vaccines being used in precursor myeloma? It has been studied. I think it's a really interesting concept. We haven't really seen a big kind of breakthrough in that just yet. I think theoretically, I think it's a great idea. And I think it's a really interesting, but we still have to make it work a bit better. Yeah, we have to watch and wait. Exactly. Okay, wonderful. Let's talk more about moving from precursor to newly diagnosed frontline therapy. We have Darzalex that is now the standard of care, combining DERA with RVD is now the new standard of care, although it's not being used in oncology settings in the local clinics, which I feel like that's one of my missions of 2023 is to help get that out there. So that newly diagnosed patients can have better frontline therapy. But let's talk about CAR-T, bispecifics. Do you ever see these becoming frontline therapy for newly diagnosed? And if so, Absolutely. I think that in in. So first of all, I 100% agree with you. I think that I think that DERA VRD is an excellent frontline therapy. I also don't think that we should should forget about CAR-T or even for some high risk even think about DERA CAR-T. But I think that certainly we should be moving to more effective therapies than than VRD. I 100% agree with you on that and happy to discuss that with anyone who has questions. So, the way that that cancer drugs and myeloma drugs are developed, we usually, so all the studies that they usually start in those that have gone through the standard therapies. So usually now the ways that the trials are written is that you have to, or a lot of these these trials for the relapse refractory and also the approvals the FDA approvals in the label they have you say that you have to have gone through four lines of therapy before you can have this. This is also something that we want to kind of discuss because that traditional four lines of therapy that would include that you would have, you know, the different combinations of the three. Different combinations of the produce of inhibitors and then there are selects and then, you know, so now if you if you have the say around the five different drugs that we use a lot or if you take the drug classes of the produce of inhibitors the image and the CD anti CD 38 antibodies if you use them in different combinations. Now you're going to do that in two lines instead of if we use four of them up front. So by two lines you've, you've almost gotten to that point where you would want to have something new so. So this is also something that's being discussed how we design the different trials. Going forward I think that these are just the way that carfilzomib or that daratumumab or lanilumab all of these were, you know, first tried out in the relapse setting. And then when we see that they work and they're safe, we move them up to earlier and earlier lines and then also we move them to the smoldering setting. So, as we get more data on these and as we see that they work and they're safe, which I hope we don't, I mean, everything has side effects but but this is what we're expecting to see that we can move them up earlier and we can use the more effective drugs in earlier and earlier lines. But of course we have to, we have to do this because we don't really want to jump through any of these stages either. We want to, you really need to go through the different stages of the trial. So you have to do the phase one, you have to do the phase two and then the FDA approval, if it shows efficacy and safety, then it gets approved somewhere after phase two or phase three. So you really have to do, go through those both to see that they're effective and also to look at all the safety signals. We don't want to, even though we have very high hopes, we don't really want to jump over any of these steps because we want to make sure that everything is safe. So, but as we do this, what we expect is that we'll see all of these being used in much earlier and I think that transplant I think is a very good treatment for multiple myeloma but it is going to be challenged with the CAR-T. Yeah, let's talk about that a little more because there's questions about that. Do you see personally right because every myeloma specialist seems to have an opinion on this. But do you see CAR-T as replacing stem cell therapy, being in tandem with stem cell therapy and then there was another question about if stem cell or if cells are harvested in the same way for stem cell transplant as CAR-T. So if we want to hit on that a little bit. So, I think it's certainly going to be challenged and I think we do have already, these are two very good treatments so I don't think the transplant is going to go away. And we really as I said with the safety and efficacy we really have to do the trial and see which one is best. And it having one that may be better than the other doesn't mean that the other one is going to go away. As you said you can use them in tandem and we have actually trials, where we do in the relapse setting where we do a stem cell, usually, that means there's usually a second transplant leading into the CAR-T. Yeah. So, and in that setting, we sometimes we have the possibility of harvesting the, at the same time. Right now, it is very hard to, it's very hard to harvest the T cells and just store them, because there are a number both practical and then kind of storage issues. I mean, but even if we would overcome the storage issues and kind of all the practical logistical things about that. The T cells. They work better if they're fresh when we start, when we start kind of working with them. So, we don't know if they're going to work, maybe not as well if you have them stored for or frozen, and then try to use them again so so we really want the fresh T cells, the way we do it right now. This is also might hopefully change it but but this is really how we do it now so we, for practical reasons and for kind of the effect and the outcome we do want the fresh cells. Yeah, and is it through aphoresis like stem cell, or is it? It is. It's a little it's a one day procedure for the for the CAR T. So, it's slightly easier it's the same thing you need to have the line usually, and then it's an aphoresis, but it's not, it doesn't take as much time, so it's usually one day just only. Yeah. Okay, let's keep talking about CAR T if that's okay. We talked about the delay that's significantly impacting the availability. Do you see that this ever resolves it I mean, that seems like a silly question right. Do you see it resolving itself, and do you see aloe as, I mean we talked a little bit about aloe maybe being the solution to this. Give me a little bit more of your thoughts on that. So, I think this can be. There are lots of things about how we can overcome this and part of it is now is that the production is done in the central lab through the companies, on the commercial side. On the research side, at least at Murensone Kettering we do like the cells are produced at Murensone Kettering so you don't have to go, it's quicker. It still takes a few weeks, not six to eight weeks but it still takes a few weeks that whole process. And so I think for, and there is kind of discussions on should every hospital or the bigger hospital kind of have a CAR T cell lab on site. How do we make sure that the quality is good, how do we make sure it's the same product and that everyone gets And there are a lot of practical issues that I don't think are really resolved yet but that might be one of the things that you can have a local lab in one in every area. And then that is approved and that is you know FDA inspected and all of those things to make sure that it is the same quality everywhere. These things are yet to be resolved. But the way that it's done right now. I think we can get cut down a little bit on it but I think it's going to, it's going to be harder to, harder to do less than four weeks or so. Yeah. And what do we know about aloe carty is it as effective in our graph versus host disease a problem with aloe carty. Well, these are excellent questions. So for the. It's, as I said, it's kind of off the shelf shelf so you can you can you can use them directly. They seem to be as effective they're not the, it's still the reports are still from very early trials there we haven't done as many or as big trials as for for the other countries. I see a little bit more infection so I think it might have a bit more effect on the immune system. The graph versus host. A lot of these are actually modified so the so they're kind of manipulated not give very much reference as host but, but it seems that they might have a bit more infection so so it's, it's a bit more foreign than, than your own Carty. Yeah. Let's talk about infection because that's the one cat. I'm using very broad statements here. I feel like it's one of the biggest caveats of immunotherapy is, wow, now we're at higher risk for infection which is the leading cause of death in multiple patients. You know it seems like it's, it's a risk because it's the exact opposite of what we want and yet it's helping kill the myeloma so what do you advise your patients like is it the older frail ones that you watch for and say you know maybe this isn't for you, or are there things being done to not kill those B and T cells, you know what I mean like what's being done when it comes to this. So, unfortunately we don't really have a way of saying oh well we'll just target these ones and kind of have the healthy or normal and and so on. That would be a great solution to. So what we're doing now is really monitoring for each patient that are on trials. What, as much as the immune system is very hard to measure because the immune system is so complex and there's so many cells and so many different molecules and antibodies and so on involved. So, what we can do is to, we can measure the different B and T cells and we can measure the subsets and we can get an idea of what is the immune suppression is there immune suppression and kind of how much in every, in each and every patient. We can start giving immune the prophylactic so we can give prophylaxis towards different viruses and that that's one of the signals that we've seen. We have seen some viral infections with in some of these patients so we can give prophylactic medications also against pneumocystis, pneumonia. So there are a number of these that some of the infections that we tend to see in immunocompromised patients. There are a lot of them that we can prevent and we can monitor and prevent that's kind of the strategy that we have right now. That's encouraging I think because I know it's a big worry of people going into it. One of the questions here I thought was really intriguing. Mike's wondering if diet and nutrition play a complementary role with immunotherapy? Yes, and I would encourage you to, I think Dr. Lusokin who had the gut microbiome therapy as well. So I didn't touch very much on that but it does for sure play and it does for sure have an interplay for sure. So, and there's a lot of a colleague of mine, Dr. Shaw, she's doing also some nutritional studies and early disease and we do see that it can affect these are still very early studies so there's a lot more that we want to know. But we know that the gut microbiota so the different bacteria that you have in the gut, everyone has a lot of bacteria in the stomach so which type and the diversity there really impacts also how it can affect in other diseases that has been studied for or left versus host disease, for instance, and it can even impact kind of how you respond or how it so there's a lot more there that we want to know. And what you eat affect which bacteria you have so yes indirectly what you eat affects your metabolism, it affects, of course, if you have any deficiencies that can affect the blood counts. But, and then also with the, with the gut microbiota the different types of bacteria you have and that affects also in the end point how you respond and that might be a little bit of every statement but it can affect kind of how you do on therapies and especially especially graph versus host but look at Alex's doctor. Yeah, yeah, I'll make sure to send that out. Dr. Lashokan gave a microbiome 101 so lots of one on one crash courses. So, on a very basic level I would say that eating healthy and and participating in active fitness active movement lowers comorbidities and lowers risks which qualifies you for more immunotherapy. Right. And so, even to that very basic extent of you are doing yourself a favor by a qualifying for the treatment and be having a better response to the treatment, possibly because you put in all this work and don't have hypertension and don't have diabetes, type two and things like that. So, yep. And that I don't think we can emphasize enough for all different stages from m goes to small drink newly diagnosed relapse. How you eat, if you can healthy nutritional diet lots of fruits, vegetables and fibers and exercise both affect how you're doing in your physical body and your mental status as well. So, this is really one of the big things that we want to encourage everyone to do to get your diet and look at your exercise and then sleeping patterns as well but that tends to come as a secondary effect as well. Yeah. And also difficult on those next days. Wonderful. Okay. Lots of other great questions. The one that I want to hit next is from Tobias and he's asks why is my own was so difficult to treat. I'll expand on that just a little bit. This is so smart. Unfortunately it's such a smart disease and it makes me mad that it's, it's able to trick these natural, you know, killing cells. So, you know, let's talk a little bit more about why with Dr. Jim the Allison's in checkpoint inhibitors. It works well in tumors but myeloma, because it's with the blood because it's with the bone marrow. I mean, that's, that's essentially why it's not working as well so why is myeloma so difficult to treat. Yes, I would wish I would have a great answer to do that. But it is really a disease that is, as you said it is pretty smart unfortunately and it has both. It is an immune cell so it kind of knows also how to obey the immune system and knows how to hide and it knows how to send out signals that signals to the immune system and say like hey don't, don't look at me don't I'm not here kind of thing. And then also said it affects the teeth regulatory cells and it affects the, the, like on the tea cell as a whole. It, they become exhausted in a way so they don't recognize the, the other angus or smoldering or myeloma cells. So the myeloma cells has a way of kind of creating this little micro environment around itself where it kind of hides and gets away evades from from the immune system so that's one thing. The other thing is that it has ways of like inside of the cell, there's an ongoing evolution of the mutations. So in the myeloma diagnosis we know that there are a number of different cell clones, it's not only one disease. So, if you treat, you might treat safe. I think there's an average eight to 10 clones or something. If you treat, and it has a very good effect it kills eight clones but then you have the two clones that are a little bit more resistant and those are the ones that are going to grow out and then if the disease comes back it's going to have higher, higher percentage of those that are those cells that are a little bit more resistant. So, as you treat it's going to get more and more kind of resistant to the therapies that you give. But one other thing is that there is has been shown to have these like clonal tights so these clones they like come and go a little bit so that's why we can also reuse these treatments. So if you have one treatment and then the disease goes down and then it starts coming up, you want to change treatment and give it something else. But then if it comes back again you can sort of use if you had a good response in the beginning you can use those drugs again. So there it's a little it's different, the percentage of these different clones vary a little bit when at the different times that it tends to come back so that's one thing the other thing is that there are other ways of getting away from the immune system is, or from the cell surface is that some of these things that we have on the cell surface, the myeloma cells can find ways of getting rid of them. So if you have something that targets the CMA or so that there is actually a little enzyme on just there that cuts off BCMA from the cell surface. So if you have a drug that targets the CMA drugs are not going to use that they're not going to work as well. So there are actually studies ongoing and we have one at MSK where you combine a BCMA targeted drug with an inhibitor of that specific enzyme. And if you have a inhibitor of that specific enzyme that cuts off the CMA you're going to have more BCMA on the cell surface so the BCMA drugs can work better. So, yes, the tumor cells are very smart and very different ways. But we're catching up that's why I'm thinking as well. Wait, I think you're on mute. I was just going to say I think that's the mirror. The miracle I'll use that word of myeloma right now. The myeloma field is yes this disease is super smart but the amazing research that's being done. Thank you Dr. Holkrans thank you to your team, because there's so much hope in the myeloma field right now I mean we just spent an hour talking about these immunotherapies that are having amazing results in very refractory myeloma. I mean, yes, it's smart but I really believe that you and myeloma scientists are smarter, and we are finding ways to treat it it's highly treatable, maybe not curable right now but I'm confident I mean, in the amazing research that's been done. The amazing products that we have now to treat myeloma. I mean it is incredibly difficult to treat but thank you for all you're doing. And how exciting it is that it is highly treatable right now and continues to improve literally every day in the myeloma field to just even hearing about those clinical trials that you and your team are working on is just so hopeful. And so, thank you. Thank you so much for what you're doing. Well thank you for all you're doing and kind of educating everyone as well. This is a super important task and I do 100% agree that these are very exciting times. So, I think we're going to, with these new drugs and with all the different types of new drugs with different combinations and different ways we can use them and use them in sequence. I think we're going to see very different a much better outcomes from each and every And also kind of over time so I think we're going to see a lot of improvement over over the next year so thank you to everyone I think it's great that there's so many people are here and to wanting to to be educated about this and to wanting to engage. I do encourage everyone clinical trials we have a lot of clinical trials clinical trials are very good and that's the way that it's, it is really a resource to get access to new drugs and also to to help all of these things move forward so so if you have a chance and, and if you're offered I would certainly consider that. Yeah, yeah, thank you so much I really appreciate you Dr. Holt Kranz and thank you to our audience for taking the time today I know there were many questions we didn't get to but I really do appreciate the questions asked in the participation here it just brings me so much joy. Thank you Dr. Holt Kranz. Thank you. So, to our audience as you leave this session today we would appreciate you taking two to three minutes to fill out a brief survey about your experience what did you like today what can we do better and what are your future topics suggestions as I love to hear from you what you want to learn about. And then you can join us in January as we're going to go more in depth about CAR T, discuss what's available for whom and what the future might bring when it comes to CAR T. You can also participate in our upcoming events. Tonight at 630pm is our Florida chapter. We're going to be discussing side effects when they need a second look and how to manage them. The 16th at 1pm Mountain is our Mountain West regional chapter we're going to be discussing how fitness affects the Mountain West myeloma community. And then the 17th at 2pm Eastern is our Black myeloma health chapter. We're going to be discussing how to give and receive care when on the myeloma journey. Another thank you to our sponsors Bristol Maris Squibb GSK, Genentech, Avvy and Amgen, and thank you to each of you again for taking the time to be here and helping us build the strong myeloma community. I really appreciate you hope you have a great rest of your day. Thank you everyone. Bye bye.