(Guest Lecture) June 2022 - The Role of Allogenic Transplants in Myeloma with Dr. Matthew Fero, UNM

How is that? Yeah, that looks great. Okay. So I thought I would I haven't done a zoom poll before so this little experiment. I thought I'd answer some questions, and this is not really like a test of right and wrong answers it's more like a survey of what people's experiences are and opinions, and I thought I'd like to see that and then and then also check some of these things afterwards to see if any things, any opinions have changed, for example. So the first question is what your personal experiences if you're a patient or if you're a relative or caregiver. What, what is the experience that you've had. So, have you had an allogeneic transplant a B, are you considering it in the future. See, have you, you know, thought about it but decided against it, or for some reason it's not you know not possible. So, whether if it doesn't really apply you can answer D. So, how this works do I know they're gonna have to answer all four, and then submit it before we see the results so if you want to go through all four and then we can look at results together. And I think you all have the poll there so I will change my slide. So the second is kind of like what your knowledge base is if you feel like you are familiar with this topic or not so a is not at all I don't have don't even know what this is all about. So we have some basics information about it. See is you're fairly well informed on both the process and the pros and cons. And D, you feel like you are a specialist or you're really, you know, you've really mean maybe through personal experience or what have you, you're really well informed. Awesome. So we'll give a couple more moments for them to answer those questions. Okay, I have two more questions. This is overkill. No, it's good. And then this is more about your opinion. So, what do you think about an allergenic transplant for myeloma. A, it's highly effective treatment for many patients. B, it's only good for young and healthy patients. See, it's, it's very limited in benefit. So maybe only for special cases. And finally D, this is something you should avoid. Again, there's no right answers here but interesting to see what people say. Yeah. So, as far as challenges with transplant, what would you say that you know these may all be true but what would you say is the biggest challenge of these so a it's very dangerous or lots of side effects. D, doesn't work very well. See, the treatment is expensive, you know, or there's, you know, lack of insurance coverage, so finance barriers, and D, it's just really technically difficult and that's in terms of time travel, you know, treatments you need caregiver support and all that. So those are my four questions. I'll try to touch on some of those. And we'll see what people's opinions are later on. Okay. Do you want to read initial results or do you want to do it all. Oh yeah sure yeah okay. Okay. Well, okay so we still have some people voting but it's pretty it's a pretty mixed bag so we have 25% that have had an allogeneic transplant. 50% are considering an allogeneic transplant in the future. And 25% said it's not currently applicable. So, the knowledgeable people are 8% are unaware of what it is at all, 42% have only some basic information. 33% feel fairly well informed on the process and then 17% are highly informed in terms of their current opinions. And then for number four the chief challenges. 67% voted that the treatment is dangerous with lots of side effects. 8% voted that the treatment does not work very well. 8% voted that the treatment is expensive, and then 17 voted about technical difficulties the time need to travel caregivers etc. So, thank you. That's good. That's interesting. Yeah. And again I you know especially on that last question I think you know they're all true to a certain extent and some of it is a matter of your perspective right. And I can see from a patient's perspective the risk is a major consideration. Yeah, definitely. But they're all they're all issues so that's interesting. Okay, so I'll move, then, and try to give some background here. I. My poll is in the way so I'm going to move that way. Okay, so first of all, what is my alarm I you know I think this crowd knows a lot about what it is but it's basically a disease of plasma cells that have become malignant and plasma cells are part of the normal immune system but when you have gene mutations in them, you can get a tumor in that cell just like any other cell of your body. But in this case it's, you get plasma site Thomas as a result. And there's various consequences. And so we call that the you know the diagnosis and usually you had to buy up to see it to know that they have the diagnosis. We also stage myeloma and that means where is it at or how much is there. And we and that's oftentimes it requires imaging. And then, as far as how much there is, it's nice and myeloma that we have these blood markers so one aspect of a plasma cell and of and of a myeloma is it makes they make antibodies. That's their normal function, and you can, you can distinguish the abnormal myeloma antibody on blood tests and measure it in the blood so it's kind of unique and that there's a very easy blood test to monitor the status of the, of the disease. And in some, in some patients have her that my own protein is is actually harmful, it can come up the kidneys, for example, and cause some problems with kidney function. So, again, myeloma is a tumor of plasma cells and they normally live in the bone marrow. Are you. Be careful with my mouse, are you able to see my cursor moving around the little arrow. It's so let me know. Sorry say that again, my cursor the little arrow Are you able to see that. Yes, yes, yes. Okay. All right, thank you. So, what happens in the bone marrow normally well that's where blood cells are made and these little trees kind of represent the development of blood cells from a stem cell through these different pathways and to make red blood cells, which carry oxygen platelets, which are important to stop bleeding white blood cells that fight infection. And there's actually two major arms of white blood cells. And myeloma comes out of the lymphocyte lineage, and it specifically the B lymphocytes, when they're activated. They become these big protein antibody making factories, and that's called the plasma cell that the antibodies are designated by these little wise here. And so that's part of the humoral arm of the immune response which means humoral means like liquid, it is the plasma protein contains these antibodies, and they go on to like bacteria and things and help your immune system clean clean it out. That is that distinguishes plasma cells and B lymphocytes from another arm of the immune system that is the T cells, and they also provide an immune response but they do cellular survey surveillance so they will actually go along directly contact other cells in the body and sense whether they are infected with a virus, for example, and kill the cell if it is and so that's kind of interesting because that T cell is actually therapeutic. And so, the purpose of this slide isn't just to show you what happens in normal cell development or myeloma, but also we can use these cells for therapy. And so, in the case of both an allogeneic transplants on one hand and more modern car T therapies that T lymphocyte is a key player because if it can be trained to attack the myeloma cell then that can be of therapeutic benefit. And then over here on the right, you can see the plasma cells make antibodies and if you get a gene mutation, the cells look a little different but for the most part there's just more plasma cells and a more of a particular antibody that you can pick up on blood test. So, it's important to acknowledge that not all myeloma cases are the same, not everybody's disease is the same. And so, part of our job was is to figure out how that is for an individual person. And so, for example, sometimes it's very diffuse and spread out I kind of colored this bone orange to show it spread out, and you may not see holes on an x ray for example. However, it can fill up that whole bone marrow space, cause the blood counts to drop. You become anemic, cause the platelets to drop. This would have to be very advanced because you basically would have to almost fill up all the bone marrow for these things to happen, or it can chew up the bone so much that the calcium level goes up and so those are all symptoms of myeloma. Now, in other patients, it's very patchy or clumpy and it forms these plasma cytomas, and that can eat away through the bone and cause a hole in the bone and the bone can break you can get a pathological fracture meaning it breaks without any trauma, or you can get compressions of the vertebral spine that's very common, which is kind of similar to if you have osteoporosis, and that of course is painful. And then in many cases it's kind of a combination of the two something intermediate so there will be a diffuse component that you might see on a bone marrow biopsy. Sorry. And there's a kind of a spotty component you'll see on x rays. And then finally, they generally will all make a monoclonal protein that protein can vary somewhat in different patients, the amount can vary. But in some cases that protein is toxic to the kids. So that's kind of the basics of the disease and it's kind of what it does when we treat myeloma, we have various goals. One is to take away those symptoms if they're already a problem. And then we can put the disease in remission and to postpone the development of those symptoms again, as long as possible. And to improve the, the life expectancy of the patient. And ultimately we'd like to cure the disease but I think as most people know, there is no treatment that has a well established track record for curing myeloma. In other words, even diseases that work treatments that work very well to treat the disease. If you look over time it looks like there's this continual risk of it coming back. And, and, of course, that's a goal of our newer therapies. And this is the timeline of treatments for myeloma and so one of the earliest. In fact, I think maybe the earliest treatment were corticosteroids, you know, like dexamethasone and it's still added into everything we do for myeloma. But Melphalan, a chemotherapy drug, was discovered early on, and it took a while to kind of figure out how to use it effectively. But ultimately it was used in high doses and became the basis for the conditioning or the preparative regimen for autologous transplants so that really relies heavily on the chemotherapy. Around that time, allogeneic or transplants from a donor were also being developed. But around these times it was still very risky and a lot of side effects, and it never really took off very much in that format. In other words, with high dose of chemotherapy and then a bone marrow transplant. A lot of things have changed in allogeneic transplant and bone marrow transplant in general since then. So we don't always, we seldom get bone marrow directly out of the donor's bones. We usually get them from the bloodstream. So that's called peripheral blood stem cell transplant, but the process is similar. And the treatment has become safer for patients as well. And I'll talk a little bit more about that, how that is. So also showed on that last graph was a timeline of some of the newer treatments, and you can kind of classify the types of myeloma therapy in a couple other ways. One is all these small molecules, so basically drugs that you can infuse, and then immune therapies. And immune therapies either come like as large molecules, in other words, antibodies. So again, where myeloma makes antibodies, but these are therapeutic antibodies you can infuse into a patient, because they've been designed to target the plasma cell, and you activate the immune system to take it out. That's the cheap way that things like their Tumumab work or Elatuzumab. I don't know why I didn't put the engine number on here. But they basically just rely on your immune system to do it, and they just provide a tag and then stick on to the cell. So the antibodies are somewhat limited that way because maybe the immune system isn't very strongly activated. And so there is another approach in cancer medicine where you'll take the antibody and use it as a tag, and then you'll put basically a chemotherapy or a toxin molecule chemically bonded to that, and the antibody will take it to the right place. And that has many side effects in other organs. And Bilanthamab mapodotin is an example of that. It's an antibody that's conjugated to a toxin. And so that's a very promising therapy, because it can provide increased activity in a very specific way. Now this is, again, quite different than an allo transplant or a CAR T therapy, because these are cell therapies. Again, you're giving whole cells to the patient to treat the disease. It's not just a protein molecule that's floating around. And in fact, an allogeneic transplant, it is the immune cells in there that provide a lot of the benefit. So as opposed to an autologous transplant, which is mostly just about giving a lot of this melphalan chemotherapy, for an autologous transplant, the purpose of the cell infusion is just to recover the bone marrow more quickly afterwards, because melphalan is toxic to the bone marrow, the healthy cells as well as the disease cells. And so with an allogeneic transplant, if you use high dose chemotherapy, then the cells provide that benefit also. They help the blood recover. But they also provide a new immune system. If your donor is not an identical twin, there's going to be antigens that are different that will be recognized by those T cells that will cause an inflammatory reaction. Now that inflammatory reaction has both pros and cons. The pro is that it goes against the myeloma cells. So that's graft versus myeloma. And there is data to support that that is a real thing in myeloma treatment. I'm sorry I didn't make a slide on that. But basically the evidence that the immune system is active after an allogeneic transplant against myeloma comes from several studies that show that patients who get an allogeneic transplant and have some of that immune reaction side effect called called graft versus host disease. If they have some of those symptoms, they statistically are much lower likely to have their disease relapse or it will relapse later. And so that's a good sense that that immune reaction, although it's not specific, it causes both side effects and benefit. You know, it is providing some therapeutic effect. And so with that in mind, one of the developments that's happened in cell therapy for myeloma is that transplants have been designed that focus more on that immune side of the treatment than on the chemotherapy side. And so what that means is essentially that you can do an allogeneic transplant with lower levels of chemotherapy. Those are called non-myeloblative or mini transplants. Just a little bit of chemotherapy to let the stem cells go in and then graft. And then you are relying on that immune response to go after the myeloma. And so I'll talk a little bit more about the results from those kinds of interventions. And then finally, CAR T cell therapy is an immune therapy too. And here you're not just giving a whole bunch of lymphocytes from a donor that might react non-specifically. Typically you're taking, it's autologous, you're taking your own lymphocytes out. They don't have the capability of reacting against your self molecules and antigens. So they are genetically engineered in the laboratory to specifically attack plasma cells. And that's the base of CAR T therapy. I won't talk too much about that, but just to kind of contrast that to transplant. So I mentioned this a little bit. Currently for more than 90% of allogeneic transplants, the source of the stem cells is no longer obtained from the bone marrow itself, but they're obtained from the peripheral blood of the donor. That's a lot easier on donors for sure. They do have to, they, normally there's not too many stem cells in the blood. So the donor does get a growth factor shot for several days ahead of time. And then the percentage of stem cells in the blood is enough where you can run your blood through a machine and you collect the white blood cells basically by differential centrifugation. They're less dense and they're lighter and they'll just collect a little blood bag up there. Finally, I won't talk about it today, but there is umbilical cord blood transplant, which is another source of cells. So there's a small but appreciable number of stem cells in placenta and umbilical cords after the birth of a baby. And so that's normally discarded, but if you get the blood out of it, that can be used for a transplant. Okay, so I did talk about these different kinds of cell therapies. Again, there's auto transplant and allotransplant. Those are usually, you know, what you would typically call a bone marrow transplant because you're replacing all the bone marrow. And that's different from an autologous or allogeneic CAR-T therapy where you're really, it's only the lymphocytes that you're using for the therapy. And then finally, there have been a combination of auto, a combination of transplants and those are called tandems. So a tandem transplant literally just means two transplants in a row. And that could be two autologous transplants in a row or an auto transplant, followed by a mini allotransplant. So again, I mentioned that one development is that you can do a donor or allogeneic transplant with a very low dose of chemotherapy. You're not going to get much benefit from the chemotherapy that way, but you will get the immune response. And so the idea was you can make this safer if you do a myeloablata allogeneic transplant, in other words, a donor transplant with lots of chemotherapy. One of the problems that we'll see is that there was just a lot of toxicity and a lot of people, frankly, died from complications early after the treatment. I think we have gotten better at doing transplants and we could do it safer now, but that was one of the reasons early on where people moved away from traditional transplants for myeloma in particular. And the one idea to get the benefit of both the chemo and the immune reaction was to separate them. So first do an auto transplant because that's all about chemo. Then the patient recover and then go on and do a non-ablative allotransplant where they'll get the immune benefit. And so by separating those treatments in time, not having it all happen at once, it did turn out to be relatively safer. Okay, so this is me being a little bit pedantic or professorial. A little bit of basic information about clinical trials and these so-called Kaplan-Meier plots, this kind of statistics, I call this Statistics 101, because I'm going to show some of these plots. And I think a little bit of explanation makes them a lot easier to understand. And then some terminology. So to the right of the graph here, you have what is called a Kaplan-Meier plot. And basically these are all, it's a plot of all the people who have enrolled in the clinical trial at the start. So it starts off at 100%. And then over time, the curves will drop. And there's two general kinds of curves. One is, are the people alive or not? So that's their survival. And obviously that's an important thing to keep track of and to compare with different studies. Another kind of curve is, it's called an event-free survival or progression-free or relapse-free survival. They're all similar kinds of endpoints. And you're looking at the time to the event of something happening, something that you don't want to happen, like the disease relapsing or them getting sick or something like that. And so that could also be plotted over time. And in myeloma, that's particularly important because the longer you remain in remission, the longer you're not going to have the problems with the disease. And so both of those are important goals. And then for allogeneic transplant, there's another term which is kind of important. I'm not going to get into it too much, but we track this also. And that's called non-relapse mortality. If you have a treatment that is risky and you are not dying of the disease, but you're dying of disease complications like infections or graft-versus-host disease, it's important to keep track of that too. And so overall, survival would be a combination or any kind of fatality you have would be a combination of either the disease relapsing or something else that's not from the disease relapsing. Now on the right, there's a few more other little minor points I might point out here. So you start up at 100%. Every time there's an event, it'll drop. And so a little drop in the curve means that there was an event. And that's depending on how many people are in the study, that may be a little step or a big step. If there's a lot of people in the study, say 100, and there's one event, then that only drops 1%. But if there's few people in the study, like 10 people, and one person drops out, then that would be a 10% drop. And so the accuracy of these curves is very much dependent on how many people are in the study. And one challenge in myeloma and in transplant is to get enough patients to have statistical significance. Another little feature that you'll see are sometimes these little hash marks, that vertical line that I've added in there, those are called censored points. And that's because this is not a lab study with a bunch of lab mice. These are people who enrolled in the study over time. And the results might have been published before all of them had completed the same amount of time on the study. So some people enrolled earlier, they might have been followed for five years, some people might have enrolled recently, they've only been followed for one year. And so just to indicate that they've only been followed for a year and you don't know what's going to happen after that, they will put a little vertical hash mark on it. Finally, what is often missing on clinical trials, which I think is kind of a shame, and that is kind of these extra gray shading that you see here, that represents the confidence intervals of the data. So if you have a lot of people early on in the study, the confidence intervals are tight. You can really tell if there's a small change. But later on, as there's fewer people on the study, these confident intervals get wider and wider, and you have to take caution in that. You have to take caution at interpreting results that are happening at that part, at that time point, because there's more and more error and uncertainty in the results, meaning you could repeat the thing and it could show up anywhere, anywhere else in this curve. And so you need to have a lot of participants to get accurate information. And that's why it really is important for people to participate in clinical trials if at all possible. A little bit more background. So this is a big question patients have, so I thought I should talk about this. When you compare two different therapies, or compare no therapy to no therapy, you might see a change in one of these Kaplan-Meier plots. And if you see like the curve shift to the right, what you're seeing there is that the average life expectancy is improving, or the average time that the disease stays in remission has improved. And that's often measured by at this 50th, 50th percent mark, 50% of the patients have had their disease stay in remission longer, for example. So that will be an increase in overall survival or event presurvival. Now that's quite different than this kind of shift. And this kind of shift, it didn't shift to the right, but it shifted up. And what that means is that you have improved survival at some late time point. And when you see a curve flatten out like that, that's kind of the holy grail in cancer treatment, because that means these people seem to no longer be at risk of their disease coming back or dying from the disease. And so in other words, they're cured. And so that is sometimes what you see with alginate transplants for things like acute leukemia. But to be honest, with most therapies for myeloma, what you see is a shift to the right. So you get improvement and you get the disease in remission, but you don't see this subset of patients where the disease is not coming back again. Unfortunately, in larger studies with almost all therapies, that's what you see is kind of this continual risk, but it can be improved with treatment. Okay, so we talked about these different types of benefits from transplants. Auto transplants is all about chemotherapy, and the cells just bring back your healthy blood cells. So you get a mini aloe transplant, doesn't use much chemotherapy, but you get this immune reaction. And it gives you graft versus host disease, a side effect. And then if you combine the two with a conventional high dose chemotherapy and aloe transplant, then you really have both going on, both benefits and both side effects. And it's happening at the same time. So that's how it was first done. In the beginning, all alginate transplants used what are called myeloblative regimens, so high dose of chemotherapy, and it was thought, you know, we need to get rid of this tumor and this disease, so we need a lot of chemotherapy. And this was some of the very early data that was reported in 1992 from the Seattle group, and what it shows is that there was a large number of patients who developed fatal complications in the first year. So if you take a look at this, this is one year, half of the patients have died, and that's probably not from the myeloma, that's probably mostly from disease complications. Now, there was some promising long term results because if you made it through that, there were these people that were living much longer. And so this was kind of an impetus to look at to study this more often, I mean to study it more detail, and also to try to find ways to do it more safely. Now, in retrospect, there's a caveat. So if I wanted to be a skeptic, I would say, well, statistically, this could be an artifact. In other words, there's several reasons for that. Number one, these hash marks, there's only four patients who really got out to this point. And as I said before, you have very little accuracy when you get out to the, when you have small numbers and you get out to those late time points. Number two, there's two competing risks that are happening here. So this is kind of a, kind of a nuance, but there's this early risk of the treatment causing problems, and then there's the late risk of the disease causing problems and the kinetics of that are different. So you might get this artificial flattening of the curve that is a little bit misleading. So, one way to make it safer, as I said, was to separate the chemo and high dose chemotherapy from the stem cell transplant and the immune reaction. And, and so the development of these mini or non-oblative transplants was people got that idea that you could first do an auto transplant, get a lot of chemotherapy, knock down the disease, and then do a mini allo transplant and that immune reaction hopefully could mop up all the stragglers. And perhaps it might work better for that, those little small amounts of residual disease than it would for the large amount of maybe more rapidly growing disease. So there was very good scientific rationale for that. And there also was other tandem transplants that were done. So if you hear tandem, you don't know which it is. And then you could do two autologous transplants. And that also had been done early in the course of transplant developments and was shown to be beneficial, but most of the benefit came for people who had only a partial response and so it's, it's not as often done these days. Typically you would do one and maybe say stem cells for a second auto for later on. So this is some, this was a study that created quite a lot of excitement in the New England Journal of Medicine back in 2007 from the Italian groups and they had done this approach. So they had done an autologous transplants, followed by a mini allo transplant. But to really know if you're providing, you know, you could do that and find, see what the outcomes are like, but are you really provide, how much benefit are you really providing from that approach? In, in clinical trials, you have, it's best if you have some kind of randomized comparison. And it's hard to get people to sign up, hey, do you want to do this, this approach or, you know, or do nothing. So you can't do a placebo controlled study. So they came up with a clever idea that they would compare two auto transplants, that kind of tandem to an auto allo transplant. So the two different approaches. And to make it less biased, like if you just say, oh, I think you should do this and you should do that, you might have your own opinions bias kind of swaying the results. So what they did is they HLA type the patients for donor transplant, you have to do the so-called HLA typing and see if you're, if you're a match or not. And so if they were fully matched with a, with a sibling, a brother or sister, they said, okay, you go on and you'll do an auto followed by the mini allo. If you didn't have an HLA identical sibling, which is kind of a random thing, then you would go on and do two autos in a row. And the excitement came because in this report, the patients got who got the auto followed by the allo graft seem to do much better, both in terms of their overall survival and the time that the disease stayed in remission. Now, again, this was not statistically significant. This seemed to be, but as I mentioned before, the errors bars are not being shown here that shaded parts not being shown. So these are pretty, there's not a lot of certainty that that that's, you know, that that's definitely better, but it certainly was promising and especially this kind of flattening of the curve, you know, the Holy Grail of it, of it not coming back again. Now, unfortunately, larger studies that were done in follow up in this country didn't really show that same kind of benefit. So this was a very similar approach that was taken. I don't know if they did that biologic randomization of HLA or not HLA, but it was a larger study with a lot more mature data. And in this case, the auto and the allo actually did not do better at all. So I think they're a little worse, but these are so close that it's not really statistically significant. So based on this, I think the field generally moved away from this as a standard recommendation that a lot of insurance companies wouldn't pay for it. I think the proper interpretation of this. So in retrospect, looking at it all is that doing two autos in a row is probably just as good or better as doing an auto followed by an allo. And as I mentioned earlier, we've kind of moved away from doing two autos in a row, because it's not much better than just one. And it's better mostly in people who have a lot of disease and it takes the two autos to get it into remission. So, I don't know if there's been chats or comments or questions, so please interrupt me if there has been anything. No, you're explaining amazingly. Keep going. Okay, I feel like I'm getting too wonky sometimes, so I'll try to not get too deep into this. That's great. Now, so folks have gone back to the drawing board and tried to see, well, can we make this better? Because again, there's pretty good data that there's this graft versus tumor benefit that's happening. And so you could think about, well, how can we make it stronger or how can we make it so it's not so risky? This is actually pretty recent studies, only two years old, but it took a long time to do this study. I was in Seattle 10 years ago and they were enrolling people on this study. And so if you kind of think about this compared to that early ablative stuff, remember how in the first year, half the patients had died from complications. That was pretty harsh. What they've done here is they're trying to get that same benefit that you might get from high dose chemotherapy, but get it from a radiation therapy instead. And so provide more treatment than you would with just a little mini transplant. You would get the immune response, yes, but you also would get this radiation benefit. And this radiation isn't just like the whole body or the whole bone marrow. They've tagged an antibody, anti-CD45, which goes and attaches to all white blood cells with this short-acting radioactive isotope so they can inject it. They can give a lot of radiation to the bone marrow without a lot of radiation to the rest of the body. And they actually did some dose symmetry. So they gave a test dose and measured and did calculations. And they gave a dose which was going to be very favorable in the bone marrow and not so much in the liver or organs that might have toxicity to radiation. And so it's kind of similar to those old things. It has promising long-term results, but again, there's like only four or five patients who've been out. But this is quite a long time. This is five years, six years. Some patients have had their disease not come back. And compared to those early studies with ablative chemotherapy, there are fatalities happening, but it's not nearly as bad as the other one. And so I think it is an improvement. Unfortunately, this took so long to accrue. Technically, it's challenging. I checked clinicaltrials.gov and the study is not open anymore. So I think the field has kind of moved on from a lot of these things. So it's a little bit frustrating. The main place where the field has moved to in cell therapy is, of course, CAR-T therapy. And there's a lot of excitement with that. There are two CAR-T therapies which are approved. One of them is shown here, cell-to-cell. This is a Janssen product, and it's also known as CAR-VICT. Again, this is using a T cell to attack the tumor, but it's the patient's own T cell and it's been genetically engineered to be very specifically attacked plasma cells. And that's by fusing an antibody gene sequence for BCMA, which is on plasma cells, to the T cell receptor, which activates T cells, and then those T cells from the patient will go and attack their myeloma. Now, this looks very promising. And of course, these patients have had many other therapies. They had a minimum of four lines of prior therapies which have failed, and most of them had autologous transplants. And compared to our other known treatments, these people usually will stay intermission for only about six months, and their disease will get gallop out of control shortly thereafter. So the fact that they're surviving this long and so many have been intermission is quite encouraging. But look at this timeline. This is only two years, right? We don't have a large background knowledge on this, and this is a different time scale than some of those other studies I've shown you. The last one was a six-year follow-up. So if you would shrink this graph down, this would look like a more steep curve in comparison. So I think you do have to take things with a grain of salt. We need to follow up. We need to know how things will work in the long run. But that, I think, is where most of the field has gone with cell therapies. The other issues I'm just going to mention here to acknowledge them. Since a lot of these studies have taken place over decades, it's really hard to know the risk-benefit ratio of allogeneic transplant in the modern era. So we have gotten better with allogeneic transplants, mostly through our discoveries in patients with acute leukemias. We've been able to make them safer and more widely available. We can do transplants using half-match-related donors, and we can do transplants with mismatch-unrelated, so it used to be very dangerous from all the graft-versus-host disease. But we've gotten so much better at controlling that and preventing that transplants have gotten a lot safer. And yet we don't really know in myeloma, because it hasn't been studied as much. Like, okay, would we, is the story change for myeloma? And we don't know, because a lot of those studies are at least 10 or 15 years old. There are finance challenges. Medicare does cover myeloma, allogeneic transplant for myeloma, but only in a clinical trial. And the number of clinical trials is becoming more limited, so it's harder to get access to that. It is expensive, but it's maybe half the price of a CAR-T therapy, so I guess that's all a matter of perspective. And then there is the logistics, and it's very significant. So typically there's a four-month stay at a transplant center. You need a caregiver with you there the whole time. And then you're not done. You still have, on average, two to three years of immune-suppressive therapy that you need to be on, and then you gradually taper off over time. And so that's a lot to ask for patients to go through. So I looked to do a quick study. My impression was there wasn't so many allotransplant clinical trials, but I just did a quick check. And this is a little bit of an overestimate. I found 31 studies, and they fall into kinds of different categories. The ones which are really doing something new and different in allotransplant are actually much more limited. I only saw about eight or nine that seemed to fit in that category. And one of them is to make transplant safer, like I said. This PTCY, post-transplant cyclophosphamide, it's just a way to make the graft-versus-host disease early on, the acute GVHD, much more minimal and much safer. And so that's been widely developed in the last decade. So that's been studied in myeloma. And then there are some attempts to make it more efficacious or to make it work better. One approach is to combine the transplant with other myeloma therapies, like giving Belcade or a proteasome inhibitor, if the patient hasn't had all those options yet. If you can kind of knock the disease down better, then maybe that immune response will be able to keep it under control longer. Another approach I saw was a checkpoint inhibitor, ipilimumab, rolls up a tongue, and it is an activator of the immune system. It takes away breaks on the T cell, and it could be, I wouldn't necessarily want to do this in someone with graft-versus-host disease, but if you don't have that, maybe you haven't gotten all the benefit. We know patients who get GVHD symptoms have a lower rate of their myeloma revapsing, so it makes sense to add that in to try to stimulate some of that. Another approach that has been done in the past is to do what's called a donor lymphocyte infusion, where you will take the lymphocytes from the donor and give it to somebody if they have never had any GVHD and their disease is not in remission, you might be able to knock it down into remission by giving them more lymphocytes from the donor after a transplant. And then finally, with CAR-T therapy, I found 37 trials in the US, including alginic CAR-T. And so that's not really the same thing as an alginic fomorad transplant, but it is a way to try to improve on our CAR-T therapy. One of the challenges with CAR-T therapy is that it's a custom-made product that has to be made for every individual patient. You have to get that patient's lymphocytes, collect them on a machine, take them to a large company that can manufacture the CAR-T cells. And so that takes two or three weeks. The patient may be very sick during that time period. It's been very hard to scale it up. All the companies have shortages trying to manufacture enough of these things because it's not just like bottles of a drug on the shelf. So using alginic donors, where they would have a pool like from the National Marrow Donor Program, a pool of patients who could donate cells, maybe they could donate enough for multiple transplants, it could shorten the timeline. But it is still this biological manufacturing process that's somewhat elaborate, so it will have challenges as well. I just wanted to give a few conclusions here and then we'll get back to people's opinions. So my general conclusion is that the alginic transplantation does provide benefit from graft-versus-myeloma immune response, number one. And auto and allotandums have been a way to make the treatment more safe. But randomized studies really didn't show a whole lot of benefit of combining those two things in that way over just auto-transplants alone. And so it really has not taken off as a therapeutic option. The overall trend in cell therapy seems to be away from alginic transplantation towards CAR-T and other novel approaches, but there still are ongoing clinical trials. That seek to capitalize on the developments in alginic transplant and see if they can be transferred to myeloma as well. So that was my summary. Thank you. Awesome. Thank you, Dr. Farrow. I came to learn and you made that happen. I am pretty impressed by the amount of information you shared and just the ability. You're a great teacher. I've learned a lot today. Do you want to do the post survey now or do you want to do questions and then post survey? We should do a survey. Why don't we do the questions now while it's fresh in people's minds? Perfect. Okay. So I skipped the first one. Just what is your background with this since that shouldn't have changed. But as far as your opinion about what you know about transplants, how knowledgeable do you feel about it? I don't know what it is. You know some basics. You're kind of well informed about the pros and cons or you are highly informed and experienced. I'll give you a minute on that one. The next question is your opinion about transplant. It would be interesting to see if this has changed. It's a highly effective treatment for many myeloma patients. It would be only good for young and healthy patients. I didn't touch on the age thing so much there. C, it is very limited for special cases, limited benefit for special cases or D, it should generally be avoided. The next question is about the challenges of transplant. Is the main challenge that it's very dangerous and risky or a lot of side effects? Or B, it doesn't work very well. C, it's expensive and there's finance barriers. D, it's technically difficult. There's time travel, caregiver support and medical requirements that make it very challenging. I added one more question on here. That's this one, question five. This was just kind of your general sense for like has your opinion changed as far as whether you think it in a positive way or negatively. So after this presentation on allogenic transplantation, A, I have a more favorable opinion of the treatment. My opinion has not really changed. B, C, I'm less inclined towards the treatment or D, I am totally confused and overwhelmed. Awesome. Okay, just a couple more minutes. They're submitting right now. Let me ask you one question while people finish. Do you, okay, maybe I should wait to announce the results here. I don't want to skew anybody's answers. Do you feel like there's an ideal, no, it's not that big a deal. I just don't want to distract them. Is there an ideal candidate for an allotransplant? I'm thinking identical twin. Let's say an identical twin comes to you, has cancer. Is your first thought, let's just do the allotransplant since they're so genetically similar, or do you still go for the auto or the auto allo? Like what, do you know what I'm trying to say? Is there a... I do, yeah. Yeah, I think of it a little differently. So if you have an identical twin, there's another term for that. That's a syngenaic transplant. And so it is in terms of the process and the benefit and the risk, it's virtually identical to an autologous transplant because you don't get that problem or the benefit of the immune reaction because the identical twin cells won't really cause an autologous transplant. You know, cells won't really cause an inflammatory response in your body. It has been looked at in comparison to autotransplants since it's very similar to that. And there seems to be a lower relapse rate. And so it wasn't until I saw that data that I thought, wow, it really is important for an autotransplant that you get someone in remission when you collect their stem cells, because the stem cells you get from an identical twin, they don't have any myeloma. And so you won't be getting any there. I always was of the opinion that when you relapse after an auto, it's mostly because you didn't eradicate it with the chemo in their body to begin with. And that mostly is the case. But since twin transplants do better, I would do the twin transplant. There's no point in doing an auto in that case. They usually can give you enough stem cells as you need, and you could do that multiple times. And it would theoretically have lower relapse rates than an auto would. Your question, though, about when would you when would I recommend an allotransplant? To be honest, I seldom recommend it now because we have so many other treatments available. The auto allotandum really didn't pan out in the largest studies. I think, though, in in almost all cases, people run out of options at some point. So I would think about it in a in a younger patient. And especially if they can get onto a clinical trial where I was excited about their approach and they thought they were doing something new and different. So I didn't mention this, but for most transplant centers, they will have an age limit to their allotransplants. For you know, some it may be that depending on the on the center, but oftentimes it's for patients under age 65, for example, you can do non ablative the mini transplants and older people. And so that's one of the benefits of it. But again, I would try to look for something maybe a little more intense because it because the the relapse rates were still very high with the mini transplants. Awesome. Thank you so much. Let's share. Yeah, yeah, let's do that. And so 25% still said, you know, only some basic information about allot 67% said they were fairly well informed on the process. And then one 8% said they were highly informed or experienced. So it looks like most of them moved from knowing only basic information and being fairly well informed. So that's great news. Opinion on allogeneic 25% said it was a highly effective treatment for myeloma patients. 8% said only good for young healthy patients 67% with the very limited benefit for special cases and nobody said it should generally be avoided. The chief challenges 33% thought the treatment is dangerous 8% said it might not work very well. 17% said it was expensive or lack of insurance coverage which I was surprised to see that Medicare statistic that it was only covered in clinical trials. And then 42% is technical difficulty time needed to travel, etc. And then after this presentation 25% said they had a more favorable opinion of the treatment. 42% said their opinion is unchanged. 25 said they were less inclined and 8% said they were a little bit confused have information overload or need to process the info more so anyway last one's my fault and I apologize for that. I know that's the risk. You know what, I think it's myeloma. There's not it's not an easy topic and so that's why I wanted to kind of share information but it's easy to kind of get lost in it. And, and certainly didn't even cover everything. Maybe the fact that people have some have have a more favorable and some have less maybe that means this was fair and balanced. I think it was good. Yeah, I think you I think you gave the information and then people get to decide for themselves. Yeah, and people are all coming with different experiences and an opinion so I think it's interesting. Yeah, I would say I had a pretty negative. I didn't think of it very highly or see see the need for it and very well understand it so I was, I was interested to learn about the many aloes that they're not full on allogenic. That's something that I learned. And also just learning about the financial costs and the success of it in general and how it's been studied throughout the years I thought it was a great presentation and I'm excited to watch it again as the recording. So there's several patients that have questions so I want to kind of go over those if you have some time. So Jen is saying she had an aloe transplant in 2014 from an unrelated donor relapsed in 2018 currently on treatment is having an aloe transplant keeper from participating in future clinical trials. Well, it's a good question and I don't know the answer I think you every clinical trial has a long list of inclusion and exclusion criteria so you would have to look at each trial. I think theoretically just thinking about it, certain kinds of. Well I mean for like most drug trials that probably would not exclude you. You wouldn't be able to do an autologous transplant, because you're autologous, you don't have autologous cells. And I don't know about other therapies like a car tea therapy I think that might be a problem. Well, you know, maybe, maybe not. I think that you could get lymphocytes and genetically engineer them but I, I would not be surprised if it's on the exclusion criteria because they're so selective on clinical trials sometimes they want a very uniform group of people to get clear results. Yeah, I wonder if it would be a good. I wonder if in the. What am I trying to say, I wonder if an allergenic stem cell transplant receiver would be a good candidate for aligenic car T. Do you, do you know. I think it should not really matter so I didn't talk about that much because I didn't want to go off topic or, you know, go over time, but with an algenic car T so you're getting you're getting a donor, it's not, it doesn't even need to be related or anything because you're not trying to use that immune system for the benefit you're going to engineer that cell anyways. One of the downsides with that is that your own immune system is going to recognize that cell is foreign you're not on immune suppression and you're going to reject it. So they're not as long lasting unless there's some tricks that are done to make them longer lasting. When you do your own autologous car T that that cell is alive it can grow and stay in your body keep fighting the myeloma for a long time. So it's similar to an aloe transplant those cells stay around also for an aloe car T, your immune system is going to attack it, it'll provide some benefit but then it's going to be short lived. Now if you've had a bone marrow transplant, you know, in the past I don't see how that's really pertinent at all you're still good you know it's still going to be the same thing. Okay, thank you. Cindy is wondering your studies even the recent ones still show 50% of multiple myeloma patients die from 18 to 40 months regardless of treatment so why would somebody pick auto slash aloe. I kind of missed the statistics on that the 40% of patients die in what timeframe. No, sorry so 50% she was saying according to those graphs, you were showing that 50% of myeloma patients die within 18 to 40 months. Is that true. 18 to 40 months so it's a year and a half to three and a half years. Yes, I think it's the, the, there was relapse in that time period but I don't think there was fatalities in that time period so you do want the disease to stay in remission and that's one goal but you want to be alive too. So, I do think that I could go back to the slides and look at it. I think it was a little better than that, but the point is, is important why would you want to do this. So, what, what is the benefit, what is the real demonstration of benefit. Some of the early studies you saw there were some long term survivors. I mean so there are there is some benefit happening there but really the question is it better than alternative therapies. And one of the alternatives they've looked at is just like doing two autos and it's not really strong evidence that better than just doing another auto and certainly less, it's certainly more complicated than doing another auto. Yeah. So I had a question with that you know I've heard of some doctors recommending an auto transplant to people that have failed their auto stem cell transplant or not really having any results to an auto. Is that something that you would do or why can you give us an understanding of why doctors would recommend an aloe after a failed auto. If you have an auto and you do a second auto, you can get benefit from the second one but it won't be as long lasting. If you did an auto and you relapse in in less than a year, then why would you do another one it's going to be even less long lasting so then I think it might make sense to try to get it under control and do an aloe or or car T or something you know something novel. Could they do, do. Okay, sorry I'm trying to think of how I want to word this. Would it be an aloe if they don't qualify for car T because I mean with the promising results that we're seeing from car T. Obviously I'm not a myelin specialist but I would advocate for myself to be to receive car T versus aloe, unless I didn't qualify for car T. Well that's what I recommend for my patients to so I try to get them treated. One of the problems with car T therapy right now is that sometimes you can't get it especially like patients in New Mexico, I would say the majority of them tried to get it and couldn't. It's just not available there's, there's waitlist, we, we now try to be very proactive and think ahead of time. Okay. Maybe you should do a consultation somewhere sooner rather than later. We've been trying for two years to get car T here at UNM and they won't even put us on the list, you know, provided because they can't provide enough they can't keep up with the demand. And there are, you know, there are financial burdens too. And there are, there are logistical challenges you don't have to go out and stay quite as long for car T therapy but you need, you need to go spend several months at the center typically. What was the quote, what was the rest of that question. I had my own question and I was just wondering about. Wait, I don't remember now. I'm sorry. I'm like, we have a patient where they had very high risk disease. The person is on this call I don't know. We who had progressed on standard therapies, very limited responsive risk had progressed on standard therapies, everything we finally got them in remission with old fashioned VTD pace chemotherapy and auto transplant. And we've been trying to get them to car T as soon as possible and that worked really well that's been like your four years down they've stayed in remission. So I think an auto car T tandem. That's a thing might make more sense sometimes than an auto allot and yeah yeah that makes sense. Okay Marcia saying that she has plasma cell leukemia and had an auto transplant but cells showed signs of beginning, mds which I think is the precursor to aml, if I'm not mistaken. So the only option would be then an aloe transplant. So would a mini aloe take care of the mds or would it have to be the whole thing, you know, like the whole. That's a good question. So that's kind of a unique circumstance because there's two disease that you're that you're treating. So I think first of all that that is a known risk with auto transplants. And it's kind of interesting because it's usually not the chemo chemotherapy can cause mds it's it's another thing that you know chemotherapy can damage cells the bone marrow cells when they're damaged can cause mds or acute leukemias. And you see a higher rate of mds after some auto transplants. So that's probably not the chemotherapy for the chance because remember when you collected those stem cells that's before they got the chemo, they might have gotten revelment or something like that. But then you give it back and they got mds well they didn't have mds before. Well probably there was a clone of mds there and it, unfortunately, it grew more than the healthy cells group but so by taking them out of putting them back to kind of gave this opportunity for the mds the bad cells to grow. And so it is seen I have a patient right now who that happened to last year. So to answer the question why would you do an aloe transplant. Well, number one, it is a treatment for myeloma but number two is the only way to cure mds, mds can be managed sometimes if it's not such a severe case with more conservative things, but if it's not well controlled then then an allergenic transplant is necessary. So you could lower a full. So can you do a mini aloe. Well, that's a good question. There is more efficacy for higher dose therapy with mds. And so if you can tolerate it now. I showed those early studies where there was a very high fatality rate with high dose chemotherapy and transplant but in a way that was so long ago that was 2030 years ago we've gotten much better. And also I kind of call I just made it sound like there's minis and there's a blade it's well now there's a whole range of things in the middle to called reduced intensity. And so that might be the best way to go is to something that's safer than those old regimens, but will provide more benefit against the mds and the myeloma to. And then what's the more time we didn't talk a lot about GV HD. What's the mortality rate regarding allogeneic transplants. Many and full, I don't I don't know what to call them. So the ablative my lobe and the mini transplants. So, historically, things have changed but historically, the ablative transplants had like a 40% non relapse or treatment related mortality in the first year. That was just too much even in the old days. And so then with the mini or non ablative transplants, then there was about a 25% treatment related or non relapse related mortality. And again that was offset by the benefit but the overall risk and benefit wasn't really better than an auto. So, the alginic transplant is a dynamic field so you have to remember those studies are all kind of old now and things have changed so we can do transplants with much less graph versus host disease. And we don't have drugs that really discriminate. We do have ways to eliminate the early versus the late. I mentioned that as a study that's ongoing post transplant cycle boss might by giving a little bit of cycle boss might be a good way to eliminate the early versus the late. I mentioned that as a study that's ongoing post transplant cycle boss might by giving a little bit of cycle boss my chemo right after the transplant you get rid of all the early stuff. And you still can get benefit or side effects from the later chronic crap versus disease. And so I think it'd be early to do be interesting to see if that would, you know, shift the risk benefit ratio significantly. Yeah, thank you. Penelope has three young healthy siblings generally speaking what's the probability that a sibling would be a match. Statistically speaking and each sibling is about 25%. So you have to kind of do the do the math there. 25% for the first one and then you have three and you know, I can't I can't add it up right now. You have a pretty good chance that there's a match. Now, you have an even higher Matt chance that you'll they'll be haploid identical haploid identical is when you inherit one of the blocks of HLA genes and from from a parent and about half your siblings are haploid identical. And by necessity your parents and your children, your biological children are automatically haploid identical because they you know you get one of these things from each parent. And it's now very feasible with that same chemotherapy strategy I just mentioned to get rid of GVHD you can do haploid identical transplants. That was not a thing. Back when those studies were being done, but it's very common now and there's really not much of terrible GVHD like there used to be even in the old days with half match transplants. And so, you, you generally can find suitable donors nowadays. That's fascinating. Thank you. We have a patient saying the clinical trial in which they're participating things. I'll only works as a frontline therapy before you even. Obviously, yeah, you know what frontline therapy. They feel they're not worth the risk other. Otherwise, what are your thoughts on that. I think transplants work better early on. That's a that's a true statement for every treatment I've ever seen. And but, but that doesn't really answer your question as to how you would use this treatment most effectively, you know if it's. There's a lot of reasons why you don't want to do something early on if it's risky, you might not want to do that early on. And then, you know, if it's a positive you might want to, you know, postpone that that concept applies to other treatments so an aloe transplants and auto transplant car teeth. This is kind of just an interesting aside on the economics there it's a big chunk of money that has to be paid like all upfront and then there's some ongoing expenses that are not as intense. That's different than some of our other myeloma therapies like rebel mid maintenance that drug is is freakishly expensive. Yeah, and if you're on maintenance you stay on it and you stay in the longer, the better it works the longer you stay on it so that's great for a drug company that's like the perfect drug. But transplant and car t aren't like that there's this big expense up front so it kind of makes sense from an economic standpoint, that you would do those kinds of treatments up front where you get the most benefit from it and you don't have an ongoing expense and save the ones that have this ongoing expense for later on in your treatment. Now nobody asked my opinion on this you know in Medicare or something like that, but financially that it makes sense to do expensive things early or things that have a one time expense. Yeah, that's an interesting perspective I don't know if I've thought of that. I have one more. We're well over time so forgive me but one of my questions is why does it work so well and other cancers, and not so well. That's a real, that's a real dilemma I have to say I was kind of disappointed when those larger auto allo tandem studies came out, especially after the initial Italian studies look promising. And I don't know the answer to that so I can speculate. So, so myeloma cells the individual cells don't grow as fast as leukemia cells do leukemia cells, you give them chemotherapy and boom they know they'll oftentimes melt away. And then there's a range of range of leukemias as well. But, and then that that somehow that those residual myeloma cells can escape the graph versus leukemia effect right so somehow they're doing it pretty consistently and so until we can figure that out. You know it's, that's going to be an ongoing problem. Yeah. Yeah. Okay, three more questions and then we can finish. Steve's wondering if you get turned down from a clinical trial from one hospital can you apply for the same trial from a different institution. Well yeah you always could. Technically, if you have a, you know, a red line exclusion criteria, you're not going to qualify no matter where you where you do it. To a certain extent there's some things which are a judgment I guess you know like, does the doctor think you're too sick to be able to tolerate it. So that's kind of a difference. I've had patients where, you know, there were there were social factors that were a hurdle and then one for one institution was a bigger problem than for another institution. Okay, thank you. Cindy's wondering, you know, just back to the very first question that we touched on. So, and to having an allergenic stem cell transplant could affect your options in the future, possibly car T not being qualified for that, and things like that. Yeah, I'm sorry I don't know the answer to that, whether the current car T trials exclude that I honestly don't know. I haven't seen that it's the case but but I haven't had a haven't had that situation. It's great for us there. I don't know if anybody's looked at has encountered that. Yeah. Okay, and then the last one, we have a patient who's scheduled for an aloe transplant next month as a fully matched brother who will be donating his stem cells. It's 100% match. So does this mean that the transplant will be more effective or less effective because of the 100%. It's generally safer. I think that's the main benefit. I think there's historically when you've looked at mismatched transplants or unrelated donors or, you know, there was more graph versus host disease more side effects and more risk. And as I said, that's something that's changed very dramatically recently so like you can do haploid identical half match related donors with almost the same risk. So, it's, yeah, it's not the same, same story anymore. How sooner, like how what a kind of a timeline is that how recent is that that these half don't half match donors. It's, it's, it's kind of, it's kind of embarrassing how long that technology has been around before. Giving, we 20 years ago or and more we gave methotrexate chemotherapy after transplants to reduce GV HD. I don't know why we didn't give cycle possible because it works way better. I knew about it 15 years ago, or more, when there was just sort of animal studies being done and I didn't believe it I just thought there's no way that can work. It took a long time for the field to really come around. But in the last five. You know it's been it's been well established for about 10 years in the last five years it's just taken off. Well thank you Dr. Farrow for sharing this time with us and your awesome presentation I like I said I learned so much and I'm excited to share this knowledge with others so thank you. Thanks for having me. Yeah. You can join us next month. As we talk about the true cost of stem cell transplant, what you need to know financially going into the procedure resources to help you etc. and the date of this event should be announced shortly. And then on the 14th, we're going to have the newly diagnosed myeloma patients chapter talking about risk status and multiple myeloma on the 15th. And then on the 14th, we're going to have the newly diagnosed myeloma patients chapter talking about risk status and multiple myeloma on the 15th. On the 15th, 1pm Mountain is our Mountain West regional chapter we're going to be talking about equity diversion, diversity, excuse me, and inclusion at myeloma for myeloma at the Huntsman Cancer Institute. Link to sign up for any of those events even Mormons I haven't mentioned this down at the bottom of the slide and will be included in that follow up email. Another thank you to our sponsors crystal Myers quibb GSK Jen and tech dance and oncology and happy. And a big thank you to each of you for taking the time out of your day to be with us. We appreciate you and hope you have a great rest of your night. Thank you everyone. Take care.