(Guest Lecture) A 2023 Update on CAR-T Therapy in Myeloma With Dr. Craig Hofmeister

This topic is a 2023 update on CAR T therapy in myeloma. And as I mentioned, we have the privilege of hearing from Dr. Craig Hofmeister, who is a multiple myeloma specialist. And he will give us an update on the role of CAR T therapy in multiple myeloma. We'll talk about things such as what products are currently FDA approved and what new products are being developed. And we also all have this question of, will CAR T become more widely available or will it continue to be delayed as, well, I don't wanna get into too much. He will go into it. But how widely available is this product going to be for multiple myeloma patients? And will it ever become frontline therapy? These are some of the things that we'll discuss either in the presentation or the Q&A. And we're looking forward to learning with you. It is now my pleasure to introduce Dr. Hofmeister. Dr. Craig C. Hofmeister is a professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine. Board certified in internal medicine and hematology. Dr. Hofmeister's practice focuses on plasma cell cancers, including plasma cytomas, multiple myeloma, AL amyloidosis, smoldering myeloma, and monoclonal gammopathies of renal significance. He started practicing with Emory Healthcare in 2018. Dr. Hofmeister focuses on empowering his patients with knowledge so they can receive the best treatment and care. Dr. Hofmeister, with that being said, the time is now yours and we look forward to your presentation. Excellent, thanks so much for the introduction. Let's see if I can get to it and not screw it up. Okay, please somebody shout out. It looks great. Huh? Yeah, it looks great. Oh, great, hot diggity. All right, so welcome, welcome. I'm here to talk about CAR-T updates and in general, most of my talks that I give to patients generally have a quick introduction section so that if this is your first time at a support group, at a webinar, et cetera, I give you the tools to understand what I'm talking about. We're gonna talk about CAR-T's, what is it, what are the first generation of CAR-T's like, and what's wrong with them and where could they be improved? Little bit about basically myeloma in general. You can see the myeloma cell on the left-hand side. It makes a monoclonal protein most of the time, which often causes kidney damage and the myeloma growth in the bone marrow. And you can see lots of myeloma cells here that can fill up the bone marrow with cancer cells and chew at the outer portion of the bones. The inner portion is a soft marrow. The outer portion is a structural part leading to fractures and basically chewing that bits of bone that then gets sucked up by the blood. And we see that bone bits of calcium come back into the blood causing high calcium levels and myeloma cells in the bone marrow can fill it up, making it difficult to make red cells causing anemia or infections. So fractures, anemia and kidney failure. Most of the time patients will often present with bony pain here on the left-hand side. You can see a side view, a cartoon of a compression fracture. This is what it looks like on an MRI. And this is where oftentimes where patients, where doctors will put a needle into this. And then the cells are put out on the slide. And as you can see on the right-hand side, these are all big plasma cells here. And that's a problem. And that's really looking for a plasma cell disorder. That's the definition of myeloma in most patients. Myeloma doesn't come out of the blue. In general, you have a precancerous or precursor states that are poorly named. The second worst name is MGOS, monoclonal gammopathy of undetermined significance, which means that there's abnormal antibodies in the blood and smoldering myeloma, which means basically there's simply more abnormal plasma cells. These are precursor conditions that put you at risk of developing the blood and bone marrow cancer multiple myeloma. And the line is oftentimes, but not precisely, developing the criteria of high calcium in your blood, kidney failure, anemia, and holes in your bones that can cause spontaneous fractures. The different plasma cell disorders are shown here with a lot of the details that I'm not gonna go over all that much here. MGOS and smoldering myeloma are precancerous conditions, multiple myeloma and its sister disorder, AL amyloidosis are conditions that require anti-plasma cell treatment. In essence, they need cancer treatment and oftentimes very similar treatment to be effective, but not always overlapping. There's a little bit of a busy slide and I apologize for this, but I'm gonna use these terms a lot in this talk. And if I don't go over it at least a little bit, it's gonna be relatively confusing. So when we talk about how patients are responding, we often think about getting blood tests for patients with measurable myeloma prior to a treatment, you give them treatment and then you assess their response. And we use these terms again and again and again, and we write them in our notes and you can probably read them in your physician's charts. And so you'll see the standard response that we're looking for is a partial response or better, which includes a partial response, very good partial response, a complete response or a stringent complete response. So you're looking from going partial response or up in this chart. And a partial response usually means there's a 50% improvement in either the monoclonal protein or an improvement in the difference between the involved and uninvolved free light chains. And if that sounds crazy to you, then you're just beginning some of the challenges with myeloma in understanding the status of the disease. And usually patients will have a monoclonal protein or a light chain that is an accurate representation of the status of the myeloma. So if you have a partial response, that's an okay response. A very good partial response is a 90% or more reduction and usually either the monoclonal protein or the involved light chain. A complete response means that there's nothing in the blood, there's nothing in the urine and a bone marrow biopsy was done and it showed less than 5% plasma cells. And a stringent CR means that it means everything the CR was. So no, nothing in the blood, nothing in the urine, bone marrow biopsy had less than 5% plasma cells. And even if it was less than 5%, there was no evidence that there were any clonal or so-called cancerous plasma cells and the patient had a normal free light chain ratio. This is often the highest response that you can get as the first step. Actually, we've gone above and beyond these response categories now. These are just the blood, bone marrow and urine, but then there's additional response categories looking at whether there are this plus, are they PET negative or this, are they also MRD negative? So there's additional levels or ways to think about depth of response. Okay, so that was the introduction, you survived. So let's keep on going. We're talking about CAR T cells and here everything in this slide deck, there's a bunch of cartoons. I love cartoons because it helps me understand the world. So myeloma cells here and then myeloma cells are being interacted with. They have a little protein on the cell surface here. This is often thought to be an indirect representation of a tumor antigen or a target. Oftentimes we'll talk about BCMAs like BCMA is a tumor target, GPRC5D, FCRH5, all these proteins on the cell surface of the myeloma cell. Then you'll have this targeting region and what this is looking for a particular tumor antigen and this targeting region also makes the CAR T cell visible and this is the CAR T cell here. It has a hinge domain, a portion that goes through the cell surface and then the internal portion here. This is the intracellular domain, the part inside the CAR T cell and this overall activates the T cell and that's what makes CAR T cells so cool is that you infuse a relatively small number of T cells into the patient that are genetically modified and then they get excited to see all the myeloma and start reproducing. It's a drug that almost makes itself inside the patient and becomes powerful. So this same idea of these cartoons, you can see how there was a first generation, we're kind of in the second generation now, third and fourth generation are coming up and these are getting more and more complicated. This is a relatively older slide, but this is what we have now and you can see that you have the tumor targeting portion up here, the part that goes over across the cell wall and then the internal stimulatory domains that if the outer portion binds to the target, the inner portion sends a message to the internal part of the cell saying, get active and kill. Now we have two CAR T products here, one called CARVICTI and one called ABEKMA and we're gonna talk in detail about both of those. You can see as just going across here, how this internal domain gets kind of more complicated as we go increase in generation and also the outer portion gets also more complicated. This is often looking for one target and third, fourth, fifth and sixth generations are looking at multiple targets. Okay, so what is a CAR T and how does it work? The first thing that you do is you need to get normal T cells out of the patient and you want to do something to them. So you schedule a patient to undergo a procedure to pull these cells out and you ship these cells off to a laboratory and at that time in that laboratory, they infect these T cells so that they are forced to create a target on their cell surface that hones these CAR T cells to myeloma cells. These abnormal T cells, they're still your T cells but they've been genetically modified to target towards a particular focus on a myeloma cell are then expanded and then re-infused back to the patient four to six weeks later. And what happens inside the patient is that these chimeric antigen T cells meet up with the myeloma cells and they get excited whenever they find a myeloma cell and they end up killing most myeloma cells that they meet. So how does this work in the trenches? On your day to day, how do you go from one step to the other? Well, the first thing is that you have to go to a, in general, a center that does CAR T cells for myeloma patients and then be seen by a physician or a team there that will assess, look at the status of your myeloma, go through if you are fit for the procedure and then schedule for recess. We then get the cells, we manufacture the cells at an offsite location. Once they come back, we ask them, hey, we'd like to have these cells back as soon as you can. Usually that's a four to six week delay with this first generation of CAR T cells. And then patients are set up for what's called lympho depleting chemotherapy or chemotherapy that is to make space for the CAR T cells in the patient. So during this time, it's usually two drugs that are given over about a five day, over a three day period, but oftentimes five days in total. Often done as an outpatient, you come in once a day for three days, get this chemotherapy, and then this causes your counts to fall, but also allows you to take in these CAR T cells and allows them to expand better. Oftentimes patients at our center are admitted to actually receive the CAR T cell and are monitored for approximately seven to 10 days for side effects of the CAR T infusion. And we're gonna go over this a lot in detail. The infusion actually at our center is pretty quick. It's very anticlimactic. People often have, you know, this is my birthday, this is a big day, you're expecting fireworks to go off and that really is not what happens. Usually you sleep through it because patients get a bunch of Benadryl just prior to it. And then afterwards, we look for side effects, we look for side effects, we look for response. And then oftentimes patients are kind of stuck to us at our center for the first two to eight weeks after this CAR T cell infusion. We usually like them to be within two hours of us for at least four weeks. There is some documentation and requests about driving for eight weeks, which makes not as much sense in the myeloma world, but the goal is to be able to monitor patients appropriately for unusual side effects. Now, you're gonna often hear along the way, salvage therapy and bridging therapy. So salvage therapy is often what happens because of the timing of all this is that patients are usually identified as, oh, this is be a great CAR T patient. And then once we get a spot from a commercial spot, sometimes this is a month or even two months away from identification for a patient that's ready to go. So now we know, okay, between now and eight weeks from now, I'm trying to get their myeloma as well in control as possible. This is called salvage therapy. This goes on up until about a week prior to sending the cells out to get genetically modified. So that's a one week washout period from salvage therapy to the time of collection or pharesis to get these T cells. Then after we obtain the T cells, then we have another four to six weeks to play with where we call it bridging therapy, treatment to reduce tumor burden, make life better, but as best as we can stabilize the disease without giving the patients really toxic treatment prior to CAR T infusion. This usually has to stop two weeks prior to giving the CAR T and then there's five days before the CAR T where they receive lympho depleting chemotherapy. At many centers, this can be done inpatient and at many centers it's done outpatient. It all depends on what's available to both the patient and the center. So if they're inpatient, usually we admit patients for seven to 10 days based on the product. They stay within reach basically for four weeks. Usually there's a suggestion to not drive for up to eight weeks, which doesn't make a ton of sense in the myeloma world and I think four weeks is quite enough. And then we monitor patients for safety. If this is done outpatient, well then patient definitely needs to live close. They're oftentimes seen numerous times at the center for labs and review of side effects. And so they can get admitted 24 seven should they have either fever or confusion. Okay, now we're gonna go through a bunch of CAR T products in myeloma, some of which are FDA approved. The two FDA approved ones are IdaCell and CiltaCell. And then we're gonna go over ones that I thought were interesting and that have been presented at one point or another. So IdaCell, no one can say this whole long two words. So we just say IdaCell, cause it's a whole lot easier. This is made by BMS and there's a series of so-called karma trials that review, that study CAR T in relapsed myeloma patients. And this was a single arm phase two trial looking at numerous dose levels. You can see 150 million, 300 million, 450 million of CAR T cells. And this is for patients who've been extensively pretreated and who weren't being controlled with their most recent treatment. And then this is where the response comes in that we talked earlier. Remember that boring slide where we talked about, did you have a complete response, partial response, et cetera? So ORR is the overall response. And you can see the overall response was lower if they had received 150 million CAR T cells, 70% if you had 300 million cell and 82% if you had 450 million cells. So you had a better response, the more CAR T cells you had, which makes sense. The larger your army, the more effective it likely is and the more likely it is to win, not every time, but certainly all other things being equal. So I want you to take away from this slide that if a patient gets a CAR T cell, that they have a very good chance of response, 82%. So overall response is 82% of patients. I want you also to take away from this slide, one other thing is that the N of 158 is not the N that actually received the cells. So for these trials, these patients are relapsed, refractory, they've been through a number of therapies, their myeloid is very active. So sometimes we could consent them for the trial. Sometimes they were stable enough for pharesis and sometimes they weren't stable enough to actually undergo the CAR T cell. So there was often a fall off between the time of consent and then we lost patients between pharesis and for infusion. And that's all about timing and that's important because there's a nationwide shortage of slots to get CAR T. And so for both IDA cell and CILTA cell, and we currently in Atlanta, we often get one, two, three slots per month for CILTA cell or IDA cell. And we often know about them a month or two in advance. So we have an internal lottery to try to figure out which patient and which physician's patient gets that particular pharesis spot. And then it's left to each physician to try to find a patient that can both make it to that pharesis spot and then also make it to the infusion. Even though there's 158 patients that were consented, probably only about 100 of them is what we're talking about for overall response. The second thing I want you to come away with from the slide is the median duration of response. So overall, this was 11 months and that was pretty darn good because in all of these patients, that was 11 more months than they had as they had exhausted every other prior regimen. Okay, this is a complex slide and I found this challenging to think about. So the question is, does IDA cell work after exposure to other BCMA-directed treatments? So if you look on the right-hand side, which is what I looked at first, the overall response to prior BCMA-directed targeted therapy, that's what TT stands for. So out of 48 patients, 36 of them had an antibody drug conjugate. This is a drug called BlendRep that was BCMA-directed. A bi-specific is a type of antibody that acts a little bit like a CAR T cell and that it brings together the target and a T cell right together to cause an explosion basically or a prior CAR T. And so for those who had a prior antibody drug conjugate, ADC, their response at that time, relatively low number of patients had a response. They didn't ever respond to the bi-specific and they had 80% had a response to the CAR T. Then on the left-hand side, you can say, okay, if you've had a prior antibody drug conjugate on the left-hand side, what's your likelihood of response to the CAR T cell? What's your likelihood response to the bi-specific or to the CAR T? It was pretty good. Just because you got it prior doesn't always mean it's not gonna work. But I think this talks about sequencing of CAR T's and that's something I wanted to discuss very briefly in that when a patient receives a CAR T cell, these CAR T's expand in the first day, 24 hours to seven days in the patient. You're literally teeming with CAR T's in your peripheral blood, but this has a sharp fall off over the next weeks and months. So there's often very difficult to find these CAR T's six and 12 months after infusion. Now that means that this CAR T is going to be very active at controlling the myeloma clone for six to 12 months. Afterwards, there is oftentimes, cats away, the mouse will play. So the myeloma is gonna be active again after the CAR T becomes exhausted and falls out of circulation of the blood. A bispecific, here in the middle, these bispecific antibodies, these bispecific antibodies are often given weekly. So it's a constant treatment. So if you have a bispecific that's targeted to BCMA and you respond it and then became resistant to that bispecific, well, usually that means your myeloma is resistant to BCMA targeted treatment. So it's unlikely that a CAR T will work, but it has worked in the past for any number of reasons. Sometimes these bispecifics and CAR T's look for different parts of BCMA and sometimes they're different targets altogether. So in general, sequencing treatments, doing a BCMA directed CAR T and then a BCMA directed bispecific, that bispecific has a good chance of working because oftentimes the CAR T's have been exhausted. But the other way around, if you're getting a BCMA directed bispecific and then try to move to a CAR T, your response is likely to be much lower. Okay, so there's two FDA approved CAR T's. There's one from BMS called IdaCell. The other one is called Cilticell. And this is from Janssen. It's a CAR-titude series of trials. And this looked at patients who've been extensively pretreated and they always look at these nice cartoon domains. This is the outer portion, the transmembrane portion, the intracellular portion of the CAR T cell. And this binds to BCMA in two spots. And we don't know if that's significant, but it might mean that it's better binding. The response was 97% over this population. So you saw a lot less of that dose response in this patient population. And the takeaway from this is that the median duration of response was about twice as long. And I'm not sure whether it means it's twice as good as IdaCell, but in these very particular patients who hadn't, many of them received any other BCMA treatment, and all of them, many of them had a good dose here, the response rates were better with CAR-victi or Cilticell than they were with the Beckma or IdaCell. And take it what you will, it's a small number of patients. The Poseidon trial. This, I didn't get to modify the slide very much, but this is what's called, instead of using a viral vector, oftentimes we use lentiviruses to infect these T cells. These are called transposons, which is a very temporary way to cause T cells to put the receptor on their cell surface, target the myeloma cell, and then these CAR-T cells often don't retain their anti-myeloma activity for terribly long. They have a prime trial here that I'll go over in a slide here. And you can see that if you look at this overall responses, you can see at the bottom, the mean dose, so this is millions of cells, and the higher the cell dose, the better the response on average, obviously between 847 million and over 11 million, there weren't, I'm sorry, 1.1 billion cells. There wasn't much of an improvement, but you can see that the response seems to overall depend on the number of cells infused. And what we don't have here is how long did they keep that response? So if you have an overall response of 70 to 80%, that's in the same kind of school district as IdaCell and CiltaCell, what we don't know is how long are they gonna retain this response? And that data was not reported, not surprisingly, because the median follow-up in days is relatively short. So we don't know that yet, and we're looking forward to seeing where these kind of temporary genetic modifications of these T cells will bear fruit. Another way to think about this is, hey, well, let's not try to get the patient's own T cells and genetically modify them and then infuse them back. That takes a lot of arrangement at the local center, and then you have to, it takes six to eight, four to six weeks to genetically modify the cells and ship them back. A lot of things can happen during this time with these patients who have very aggressive disease. Well, what about trying to get an off-the-shelf solution, trying to get a donor CAR T cell? And so what this is, it's called Allogeneic, that's a donor CAR T, anti-BCMA, that's the target, and we're doing a T cell product, and this is the T cell. Basically, all this excitatory domain goes through, and it's marked against BCMA, but they've added lots of complexity to it. There's a spot that you can basically turn it off by giving retoxin. You have to knock out a whole bunch of other proteins so that these T cells don't just attack your normal cells, they're just going to attack BCMA-expressing cells. So there's a lot more science to this that is done to try to make it safe to infuse somebody else's T cells into you. And they had the universal trial here, and this looked at a bunch of different doses of chemotherapy prior to, that's what all these rows are, and then different amounts of chemotherapy, or different amounts of CAR T cells that were actually infused into the patient. So this is the first group that actually tried to change the chemotherapy prior to the CAR T cells to see if they could increase the effectiveness of these donor cells. And what they found overall, you can see it in this first row, the overall response, you'll see 64%, 80%, 67%, all of these overall look pretty good in these different dosing of lympho-depleting chemotherapy. And then the median duration of response in months is not terribly long. So three months, eight months, et cetera. So not really a huge improvement over IDA cell and CILTA cell from my point of view. We're gonna talk about these common side effects, cytokine release syndrome and neurotoxicity, but we see this at about the same percentages in this donor CAR T cells as we do autologous, we're using your own T cells. This is a different, so this is a CAR T trial, the MCAR trial, and this is targeting GPRC5D. Now GPRC5D is just a different tumor antigen, and this is the internal excitatory domain, this involves standard viruses that modify or genetically modify these T cells. And in general, they get the standard lympho-depletion, get the standard CAR T, nothing unusual here in terms of the dosing or lympho-depleting. The only thing that's different is this, these are patients who are using their own T cells, so it's not a donor T cells, these are using the patient's autologous T cells. And the second thing is the target, the target's all different, it's GPRC5D. This is in general, BCMA is primarily expressed on T cells and plasma cells, they've seen it in the basal ganglia in your brain, and this GPRC5D is located in hair follicles and on your nail beds, but also predominantly on myeloma cells. And so for this trial, again, they looked at different doses of CAR T cells, 25 million to 450 million, and you look at the overall responses, and I tend to see PR better is an overall response, and you see that some, as you increase, their responses got better, but it's overall a very small number of patients. So it certainly lends credence to the idea that if you change the target, this way of treating relapsed myeloma will still work pretty well. So I think it's proof of concept, and we'll look to see more patients studied. And you certainly can see how, hey, listen, we need more targets, because somebody who has a BCMA targeted treatment and that doesn't work, well, then you can switch the target. Does that mean a different target will always work? Well, no, because there's a couple things that could go wrong there. One of them is that the relapsed myeloma cell may not have this target on its cell surface. Maybe when they became resistant to a BCMA-directed treatment, they down-regulated GPRC5D at the same time. The other possibility, and often more likely, is that the supportive cells around the myeloma, when they became resistant to CAR T cells pushing for BCMA, they also became resistant to other CAR T cells that have the same capabilities, no matter what the target. So myeloma is oftentimes when you have a single treatment and your single treatment is not targeted toward necessarily a single myeloma cell. It's gang warfare. You're really targeting that myeloma cell as well as all of its friends in the supportive tumor microenvironment. So it's a significant foe. So let's talk side effects. Toxicities are side effects, and the things we're gonna talk about in detail are cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome. This rolls off the tongue, doesn't it? So this is called ICANS, or neurotoxicity, or neurotox. We often say CRS instead of saying cytokine release syndrome, and we often use the word ICANS. Cytokine release syndrome, we'll talk about ICANS, is confusion, cytopenias, or low counts. And oftentimes it's a sequence of low white cells, low red cells, low platelets. Delayed side effects include hypo-gamaglobulinemia. Again, rolls off the tongue. This is when you get a very, very effective CAR T therapy that kills most of your plasma cells, kills the cancerous plasma cells, kills the normal plasma cells. So your normal plasma cells can't make the normal antibodies that should float in your blood, your normal IgG, IgA, IgM. What does that do? That increases your risk for primarily bacterial infections, but antibodies have a large number of things that they do, but the big thing is trying to keep you free of infection. Prolonged cytopenias are low counts, and late infections driven by both the cytopenias and the hypo-gamaglobulinemia are a big deal in CAR T. So cytokine release syndrome, I left this figure on the right. I thought this figure was so great, but it's way above what I wanna talk about in general. It's super complex, but it tells you a lot of ways that these CAR T cells here, they're targeting CD19 in this cartoon, causes a number of the supportive cells in the tumor microenvironment to get all excited, and they make these inflammatory chemicals here, one of which is known as interleukin-6, but there's any number of them here, which cause all sorts of troubles for the patient. How does this play out for the patient? Well, this means that after, when these cells, CAR T cells are infused and they expand, they develop fever, and they can develop hypoxemia or low oxygen concentration in their blood and low blood pressure. So it's fever plus or minus low oxygen level and low blood pressure. You can follow this by looking at your C reactive protein or your CRP and ferritin. These are blood tests that generally go along with the expansion of these CAR T cells. And you can imagine fever and low blood pressure, that sounds a lot like sepsis. In fact, it absolutely looks like sepsis, plays like sepsis, and it's just as dangerous as sepsis. So we interfering early in cytokine release syndrome is very appealing. So for Cilta cell and Ida cell, Cilta cell has this median duration of CRS, usually within the first 24, 48 hours, even though it can go on for seven days to show up, most of it occurs early on. Cilta cell on the other hand, can wait for a while for the CRS to occur and sometimes wait up to a week before it can actually start. And the risk factors for severe cytokine release syndrome are usually pretty obvious. It's just anyone who has really bad myeloma has a big risk of having a bad cytokine release syndrome reaction. How bad is bad? Well, we often grade things because we like to quantitate and we think about the American Society for Transplantation Cellular Therapy grades these. Grade one is basically a fever. Grade two is a fever with either a low blood pressure, low blood pressure, not requiring medications and or some evidence of low oxygen concentration. Grade three is a fever. And now you need to keep life sustaining medications in there to keep a blood pressure that's measurable. So this is a very sick patient. And generally anyone with grade three or grade four CRS is in the ICU. And grade four CRS is multiple medications to keep their blood pressure reasonable. And these patients are often being ventilated with a mechanical ventilator to breathe. So all of a sudden, something is just a fever. These patients can be significantly more sick, but once you're grade three, four, these patients are often monitored and treated in the ICU to keep them alive. ICANs, this Immune Infectious Cell Associated Neurotoxicity or neurotox. This in general doesn't occur in myeloma unless you have CRS. So you don't usually get confused just by itself. You usually have fever first and then confusion, or if you do happen to have confusion first, you should wonder is it really ICANs because either a fever is just on its way or you have another source of your confusion. Sometimes it can be headaches, tremors, mild movement disorders. This can get worse and develop into focal paralysis and seizures. We don't see this a ton. We see very minor neurotoxics, usually in patients who've had fevers first, they're getting treatment for their CRS and then they also develop some confusion. We grade the confusion as well. Again, it's the Society for Transplantation Cellular Therapy. Grade one is minor changes in their so-called ICE score. These are questions that we give patients at least oftentimes three times a day, but this goes from grade one, which is I'm confused about where I am, to grade four, which is patient is barely arousable. So this is a huge breadth of patient sickness here and even this often leads us to treat patients. Although some of the guidelines suggest that grade one patients can only be monitored, it's very upsetting when you start missing some questions on orientation. The ICE score, these are the questions. It's orientation, naming, following commands, handwriting and attention. You can imagine if you're getting these darn questions every eight hours, you get sick of this. And if somebody wakes you up at two in the morning to check on your writing, it may not be perfect. So sometimes you can lose a point on your ICE score and it means nothing, but this is the grading system here for these ICE score impairments and it certainly gets you when somebody loses their orientation. So CRS again, fever, low blood pressure, high heart rate, low oxygen content, that's all common. The downstream consequences, well, in myeloma where the median age of diagnosis is 70, these can cause, you have a situation looks like sepsis, they can develop heart failure, kidney failure, respiratory failure. In general, you see CRS come first as the CAR T cells expand in the blood. These neurologic events can occur most of the time, right at the time of CRS or for any number of days afterward. And usually this is when you're teeming with CAR T cells. These can be, the neurotoxicity again is confusion and then gets worse and can cause seizures. We see this a lot less often now than we did when we didn't give patients treatment for CRS or neurotoxicity as early as we do. The incidence for IDA cell, this is the BMS compound, cytokine release syndrome happens in the majority of patients. It happens relatively early and if they do have ICANS, they all have CRS. Cilta cell, again, the majority of patients, it happens later and again, neurotoxicity is associated with CRS but generally does not occur alone. The management in general, we get all sorts of blood tests, we give anti-seizure medications if they have confusion because it may decrease the incidence of seizures. CRS is usually treated by tocilizumab, which is an IL-6 antibody. And usually if that's ineffective, we add on dexamethasone. For neurotoxicity alone, we usually don't give tocilizumab and generally give dexamethasone because it's a steroid that crosses the blood-brain barrier. And in general, again, grade one for us in myeloma, we often will give tocilizumab whereas lymphoma, CAR T's, we'll often observe these patients. For neurotoxicity in myeloma, we often give dexamethasone again because even though in myeloma, in myeloma, we give dexamethasone early for confusion and dexamethasone and tocilizumab, you'll see over and over again for the sometimes overlap between CRS and neurotoxicity. Lastly is that there's a high incidence of prolonged cytopenia after CAR T's for lymphoma, leukemia, and myeloma. And I wanted to go over this because this is oftentimes not talked about. People talk about CRS, they talk about confusion, but they don't talk about the fact that there's a proportion of patients, usually again, patients who had their myeloma not well controlled, who have difficult to treat disease, they can have severe thrombocytopenia. Look at this, really more than half patients have severe anemia and thrombocytopenia. There's a difference and they define it being protracted is somebody who has a neutropenia, thrombocytopenia, et cetera, for the first 30 days or so, and then prolonged happens after that. And you can see that at the bottom, greater than 21 days, the majority of patients can have some significant neutropenia. And these, this off, I have a patient right now who's getting, coming into the center three times a week to test for need for red cell transfusions, need for platelet transfusions, and getting as much supportive care as we can possibly do to decrease his need for transfusions. This is also associated with infections. So there's no small thing to have prolonged cytopenias after CAR T and it's one of the less well-talked about side effects. Certainly patients along with this can have hypogammaglobulinemia, which I talked about in the beginning. That's when you have relatively few normal antibodies, but you can see that low counts and few antibodies can be a recipe for disaster for patients that can develop severe life-threatening infections, 15 to a hundred days out from CAR T. So it often requires good communication about how to keep patients safe after CAR T. I think I'll stop there and look forward to getting into the Q&A. Wonderful, thank you, Dr. Hofmeister. I especially appreciate you walking through some of the definitions and acronyms in the beginning because I know that's really helpful for patients even if they've been diagnosed a long time. There's a lot of excellent questions. So we'll start with Marla's, which is can you do more than one CAR T? In general, you can't. It's too complicated and it's very unlikely that you have two of them that are FDA approved from two different companies, but we do have CAR Ts that have dual targets. They'll look for right now, you've seen what's published is CAR Ts that are focusing on CD19 and BCMA. That's been published and done in China, I think, just now, and there's a US trial ongoing and seems very effective, but waiting to see longer follow-up and more patients. Interesting, thank you. Greg's wondering, once a CAR T cell destroys a myeloma cell, does that CAR T cell die or does it go on to attack other myeloma cells? You touched on this a little bit, but let's reiterate. Great question, I wish I knew. We don't have a lot of, what would need to happen to get that answer is that we'd actually have to have a patient with a microscope inserted into their bone marrow at the time of infusion. You can imagine that these patients don't appreciate that. They're remarkably invasive. And so we have some animal studies, but they often don't go on to what happens after an individual T cell. So these are great questions. I'm not sure if we have all the tools necessary to gather answers to that, but great question, I don't know. Thank you. Tom's wondering if Dara-Tumamab is considered to be a BCMA targeting therapy. Dara-Tumamab is a naked antibody targeting CD38. So CD38, like CD38 is a different protein. Like BCMA is a protein, CD38 is a protein. It's expressed on the cell surface of myeloma cells. It's also expressed on many normal white cells. And Dara-Tumamab and Isotuximab are both naked CD38 antibodies. So by naked, I mean that they just glom on to CD38 and they wait for the immune system to come by and clean them up. It's different than a bispecific. A bispecific antibody binds to BCMA or CD38 or whatever it's supposed to bind to, but it also has something waving out in the bloodstream waiting for a T cell to walk by. It grabs the T cell, usually CD3, and then has an activated T cell right next to a myeloma cell, bringing about the myeloma cell's death. Oftentimes bispecific antibodies have a little less effective but very similar response rates to CAR-Ts, but obviously they're more toxic and they're just recently FDA approved. Tecvally or Teclistumab was just FDA approved in October, 2022. This is a BCMA directed bispecific. So more to come with naked antibodies, bispecific antibodies, and trispecific antibodies are certainly in research testing and clinical trials. It's absolutely amazing. I mean, when we're thinking, when we really think about what's happening at such a small molecular level, it's fascinating. So thank you for sharing that. Another great question here. What are some important questions to ask when considering a CAR-T trial? The biggest thing is trying to make sure that the physician that's at the CAR-T center is familiar with myeloma and you feel like you can navigate the time between talking about the CAR-T, getting workup for the CAR-T, undergoing pharesis for the normal T cells to get taken away. And then you have a plan to keep your myeloma stable for four to six weeks before you actually get the CAR-T cells. Having somebody to plan the process, to make sure that you're likely to be stable enough for doing that is very appealing. And oftentimes we think of CAR-Ts for patients who are coming from far away. They're not close to a myeloma center, but they have in their mind, yeah, a one and done treatment would be much better and I can plan a way to make this happen without significant injury. Whereas oftentimes for us, we're pushing patients towards Ticvali, the BCMA-directed biospecific, who have no plan, their disease is totally uncontrolled and it's this or nothing. And those patients, especially if they live close, they can handle the weekly treatment and follow-up. Very good points, thank you. Let's hit a little bit on this one and done that you referred to. Jackie's wondering what role, if any, does maintenance therapy play after a CAR-T? Maintenance therapy may be a big thing. There may be things that we can do to prolong the effectiveness and overall lifespan of CAR-T cells. There may be treatments that we can do to enhance their effectiveness, even if they're circulating only a little bit in patients. Those questions are certainly ongoing. Of course, we're gonna combine CAR-T cells with IMIDs and other myeloma treatments. But to my knowledge, we haven't found a clear path forward. We're also combining CAR-Ts with things to increase the expression of the tumor cell, tumor antigen. So for instance, BCMA, there's a gamma secretase inhibitor that you can give along with the CAR-T to try to get the myeloma cells to put up that target on their cell surface and then give them the CAR-T cells to attack it. Again, data for that, not clear, not a clear win yet, but we've got a long way to go to get answers. Fascinating, thank you. Several people are asking if there's an age limit to qualify for CAR-T. Not to my knowledge. So I think that there... I'm not aware of a clear age limit for these patients, and we try to assess functional status at the time of these initial consents, but we as doctors are not great at functional status. So it's something we need to do better. Would you feel comfortable putting an 80-year-old who was relatively fit through a CAR-T? We've done that, and we've done patients older than 80, and like all things, the devil's in the details. We've put patients through CAR-T, through bispecific, and sometimes it's been a great decision, and then other times we look back on it and wonder if that's not the right decision. So very individual. Yeah. Jeff's wondering how many CAR-T centers are there in the US? I don't know. So I would like to know that information. I'd like to have that on the tip of my tongue, Jeff, and I don't. I will try to look it up and send it out because that's a good question. I know lots of people share that question. All right, let's talk a little bit about non-secretory patients or non-secretory, depending on where you live. You pronounce it different. These are patients that don't have an M-spike available through their myeloma routine blood work. Have you seen the CAR-T be successful for non-secretory patients, if any? Yes, we've had a number of non-secretory patients have good responses to both CAR-Ts and bispecifics. Everyone's myeloma generally becomes less secretory on average with time with each relapse, but that's not always the case. And so, and some of them are non-secretory at diagnosis. So the secretory status has not been reliably linked to a whole lot. Thank you. Doug's wondering if we can tell us a little bit more about the allogeneic CAR-Ts. It's absolutely fascinating. Do they look to be effective? And are there any, is there any like graft versus host or anything weird happening in terms of adverse events? Right, allogeneic CAR-Ts, especially from this company called Allogene seems to show some clear activity and patient responses in multiple myeloma. What they're trying to do is tweak their lympho-depleting chemotherapy, improve on all the things that they do to maximize the activity and maximize the survival of those CAR-Ts cells. To my knowledge, they haven't had any graft versus host disease or GVHD. Thank you. Jackie's wondering if the chemo, what's that word? Before this CAR-T is similar to that before stem cell transplant. Great question. People often confuse the two. So the chemotherapy prior to autologous transplant is called melphalan. It's an old time chemotherapy and there you're trying, and it gives you the highest value for patients who have easier to treat myeloma because that one and done philosophy can often give patients years of disease control. That's melphalan, it's given over 30 minutes and it causes a ton of nausea, diarrhea and fatigue about a week later and complete hair loss. So that's melphalan. Luderabine and cyclophosphamide are just small little doses. They're kind of making space for the CAR-T cells. Yes, it causes low counts. Yes, it causes some gastrointestinal nausea and diarrhea, but not very much and nothing like melphalan. So in general, you should think of the Luderabine and cyclophosphamide as a walk in the park compared to melphalan. Well said, thank you. Several people are wondering if there's a way to evaluate T cell fitness or efficacy. Right, is there something we can do to assess whether myeloma patients T cells are gonna be up and at them? Are they gonna do well? Yeah, their vitality. Are they going to survive? Are they gonna be able to expand? That's a great question. The other question we have is, hey, why don't we just grab T cells at the beginning? Freeze them. When patients are relatively newly diagnosed or just after first line therapy, then maybe that would make them a lot more effective and much more able to undergo genetic modification, expansion and reinfusion. All those questions are unknown. Great questions. Like to get those answers, but we don't have them yet. Definitely. I see several questions about BCMA sequencing, and I just want everybody to know that our next immunotherapy session will be exactly that. We'll be talking about what we know and what we still need to know. So if we don't get to your question, just know that we will continue to have those kind of talks. One of the questions that is asked here as well, I'll summarize, but do you personally see CAR-T becoming frontline therapy or ever replacing a stem cell transplant in terms of standard of care? Great question. So on average, there are certainly trials looking at incorporating CAR-T as part of upfront therapy, as the sole part of upfront therapy in high-risk patients. And certainly you'll see that CAR-T is there. You'll see bispecifics in that same field in a research setting. And before it becomes standard, it has to really be vetted and show some positive data in patients who have difficult-to-treat disease, who are not being well-served with how myeloma patients are treated now. If it makes it through that, then there'll be more of a randomized setting and for a larger, more standard risk patient population. And then, what do I see in my Walmart purchase crystal ball in the future? Well, in general, I see that most likely the incorporation of bispecifics or CAR-Ts makes good sense in the high-risk patient population. And I think we're still going to see autologous transplant with high-dose melphalan be primarily used for patients who have low-risk myeloma, as you just can't beat the value of an autologous transplant in a low-risk patient. Thank you, I appreciate that answer. Bev's wondering, we'll ask two more questions. I know we're approaching the end of our session. So Bev is wondering how kidney-affected patients fit into this treatment. Do they qualify for CAR-Ts and is it successful? In general, it's more challenging because the dosing for fluid arabin has to be significantly reduced in patients with renal insufficiency. That's part of the lympho-depleting chemotherapy prior to CAR-T. And no one knows anything about how to reduce cyclophosphamides as pharmacokinetics are known only to somebody who's never come forth. So it's just challenging to dose those lympho-depleting chemotherapy with renal insufficiency. That said, myeloma and renal insufficiency are like peanut butter and jelly, they just go together. So it hasn't stopped us necessarily with significant renal insufficiency. And I don't know about patients on dialysis who have renal failure going forward with CAR-T yet. And I see those patients being preferentially shunted towards bispecifics. Awesome, thank you. Our final question, Cindy is asking, myeloma free years to be gained from CAR-T. And I'll just add to that. Why does CAR-T and other immunotherapies give you hope in the treatment of multiple myeloma? Right, so all of my patients are either going to be suffered through complications or eventually gonna have untreatable disease. We hate that. We wanna have new methods to treat and new success with those methods. So CAR-T could be part of the process and this is just the first generation of CAR-Ts looking at just a single target, looking at just targeting the myeloma. And I expect that CAR-Ts as we move forward, we'll look at multiple targets at once, will improve in terms of their survival and these CAR-Ts won't die off so quickly. And I expect that we'll be giving CAR-Ts that ideally will work against that supportive tumor microenvironment, the friends of the myeloma cell in the bone marrow that causes myeloma to currently be incurable. I expect and I hope for somewhat the same thing with BiSpecifix, even though it's going to be hard to have multiple targets with BiSpecifix, but BiSpecifix does have the option to bring together any number of normal immune cells, such as T cells and NK cells altogether. So there's a chance that some of the, even when the targeting may not work, they're bringing more of the immune system to bear on that portion of the cancerous tumor microenvironment might be more effective. So I am not at all hopeful that these first batch of BiSpecifix and CAR-Ts will lead to cure. But what keeps me excited is that we're just getting started and I'm excited to see the next generation and see how well it will be effective. Very well said, thank you so much and thank you for your time. I apologize to our audiences, there's several unanswered questions, but we do appreciate your participation and your attendance today. We're going to finish up with just a couple of outro announcements. Thank you again, Dr. Hofmeister for being here and taking the time. If you would like to join us next month, we're going to be, excuse me, in April. This chapter is going to be every other month throughout the year of 2023. On April 11th at 1 p.m. Eastern, we're going to be discussing the question that many of you guys have, sequencing BCMA therapies. So for example, I saw questions about, is there BiSpecifix trials that are open after CAR-T therapy, things like that. And this is going to be discussed in April with Dr. Joshua Richter. So you will be notified when that event is ready to register for on April 11th. Other events you may be interested in tonight, if you live anywhere from Delaware to Georgia, we're having our Southeast event. This will not be recorded and we're going to be talking about survivorship and creating survivorship plans and optimizing wellness. The seventh is our Myeloma financial chapter. We're going to be discussing federal, private and prescription legislative changes that you need to know on that same day at 6 p.m. Pacific. And that's because it's a regional chapter. So Cal, our Southern California Myeloma community chapter is meeting, we're going to be discussing the science and art of creating your personalized Myeloma treatment strategy with Dr. Jona Karam from City of Hope. The link to sign up for any of those events and even more events I didn't mention is found at the bottom of the slide and will be included in our follow-up email. Another thank you to our sponsors, Bristol Myers Squibb, GSK Genentech, Avie and Amgen. And thank you to each of you for attending today and participating. We're happy to have you. Have a great rest of your day, everyone. Take care.