how we can ask our questions in an organized manner. Today's topic will be Noir Myeloma Immunotherapy, antibody drug conjugates. During a part of this immunotherapy treatment chapter, one of my goals is to really dive deep into the immunotherapies that are out there and better understand them because these are things that are either entering your body, your loved one's body, affecting your life with their side effect profile, et cetera, hopefully increasing the quality of your life as well as the longevity of your life. And so today we're gathered to learn about antibody drug conjugates that can help fight myeloma. And we're hearing from the expertise of Dr. Jesus Berdeka who I'll introduce formally in just a moment. We're gonna be talking about what's the mechanism of action, what types of antibody drug conjugates are FDA approved and are there any on the horizon? And what is the future of ADCs in myeloma and what might their side effect profile be as well? It's now my pleasure to introduce Dr. Berdeka to you. He received his undergraduate degree from Stanford University and medical degree from Harvard University. So he's very intelligent, completed his internship and residency in the Department of Internal Medicine at the University of California in San Francisco and fellowships in medical oncology and hematology Johns Hopkins University School of Medicine in Baltimore. Prior to joining the staff at the Sarah Cannon Research Institute in Tennessee oncology, Dr. Berdeka held appointments in the stem cell and bone marrow transplant program and in the division of hematology and oncology at Loma Linda University in Loma Linda, California. Dr. Berdeka has been certified a diplomat in internal medicine, medical oncology and hematology by the board of internal medicine. Additionally, he is an active member of several professional organizations, including the International Myeloma Society, American Society of Clinical Oncology, the American Society of Hematology, International Myeloma Working Group, Clinical Trials Myeloma Intergroup Committee and the Center for International Blood and Mero Transplant Research Plasma Cell Working Group. An active researcher, Dr. Berdeka has been the principal investigator on a number of funded clinical trials in the field of multiple myeloma. And he has published extensively in peer reviewed literature and is a frequent invited lecturer. We are extremely grateful and privileged to have Dr. Berdeka with us today to talk about antibody drug conjugates, better understand the role that this immunotherapy can play in myeloma treatment. With that being said, I'll turn the time over to you, Dr. Berdeka and thank you for being here today. My pleasure as always. And thank you for showing that picture. You remind me what it used to look like. But let me share my screen here. All right, but thank you again for inviting me. I always enjoy these talks and I hope that you get as much of it as I do from them. And I'm sorry that I can't see you all out there, but I know that some of you are watching me. So thank you for attending. So I'll get right into it. So today we're gonna talk about the antibody drug conjugates. So let's start with a little bit sort of introduction. So when you talk about immunotherapy, we're looking at several things. So one are the monoclonal antibodies and these you know very well, they're things like Dx and Lisa and for example, and these directly target the myeloma cells. You also have ways to overcome immune suppression and that includes the inmates and the checkpoint inhibitors. You can also boost certain cells in your body to help fight myeloma and that an example of that is the CAR T cells. And of course you can also activate your immune system to try and fight myeloma, which is sort of the idea behind vaccines not to be similar from how vaccines work in the infectious disease world. So today we're gonna talk about antibodies and there's three particular types of antibodies. So the first type is what we call the monoclonal antibody. This is just an antibody that is, has nothing else attached to it. It binds to a cell of, for example, myeloma cell and then it waits for the immune system to come and recognize that down antibody and kill the myeloma cells. Antibody-to-drogue conjugates, we'll talk about a lot more. And then you can also, we now also have bispecific antibodies and the idea here as you can see in the cartoon there is that you have two full antibodies and you can have two full antibodies together or just pieces of those antibodies and that recognize two different sites. And one side is the myeloma cell and the other side is CD3 on a T cell for example. And so these redirect the T cells to kill the myeloma cells and they're called bispecific antibodies, which I'm sure somebody will be talking about at some point in the future. Actually, concentration antibody-to-drogue conjugates. So what this means is you take an antibody and this antibody is now bound to a payload and it's usually, this is usually a drug or it could also be radiation, for example. So the idea here is that the target, the antibody binds to the target and then it is internalized and it kills the myeloma cells by delivering this. The target that you all probably know very well at this point is BCMA. And so BCMA now, there's a lot of immunotherapies developed against BCMA. So why is BCMA such a great target? So you can see here, we have sort of the natural sort of progression of how a plasma cell is a plasma cell from the lymphocyte and eventually becomes malignant to myeloma. And BCMA is expressed as the cell sort of kind of matures and its expression actually increases in the plasma cells and it actually increases further as the cell becomes malignant and it's expressed much more avidly in myeloma cells. And so that makes it an excellent target for myeloma cells. The other thing is that it has really no expression other normal tissues. So technically, if you can sort of kill the cells that have BCMA expressed, you won't affect any of the cells in the body and that will help with the side effect profiles. BCMA actually is a very important molecule for the plasma cell. And so because of that, it has a key role in B-cell maturation differentiation and allows the cells to survive. And so because of that, the cells will express it. And so it should be incredibly rare that a cell will not express BCMA. So we'll start with the most sort of dominant in this class. The first, antiviral conjugate. And so here in this cartoon, you see on the left, I don't know if you will see my arrow or not, but I'm using it just to... And you see here on the left, you have the actual conjugate and that's the... In gray is the antibody and then those little sort of orange circles around the antibody is the toxin, the chemotherapy. And so if you go to the middle picture, you see the green is the myeloma cell. And then you have in purple here, the BCMA protein sitting on top of the cell. And so now you have your antiviral conjugate that combine the cell. And so its main mechanism of action is to then this whole complex is internalized into the cell. And so once it's internalized, it gets cleaved and the chemotherapy gets released and kills the myeloma cell from within. Another mechanism of action for this is that this antibody actually still functions as an antibody. So if you go to the right here, you see that the antibody is bound to BCMA and it still has this FC receptor. And the FC receptor is what allows your own immune system, so cells like your T cells to recognize the bound antibody and to kill the myeloma cell via that process that we call ADCC, very similar to how Darcelex and implicitly would work. So the Lanthema mafidotin was first studied in the DREAM-1 study. And that was the Phase 1 study that established that Bellemath was safe and effective. The dose that was determined there was 3.4 milligrams intravenously every three weeks. The DREAM-2 study then was the pivotal study that kind of looked at that dose, but also tested a different dose of 2.7 milligrams every three weeks. The reason that was done is because as we started to see more patients on the treatment, started seeing that there were some particular toxicities that we could talk about that they hoped they would be able to sort of mitigate by looking at a lower dose and seeing how efficacious it was. Here I have just a summary of the DREAM-1 and DREAM-2 studies. So the DREAM-1 study is in the first row, and that's the patients who had myeloma after they've had a proteasome inhibitor and an imid and transplant, but did not require C38 therapy. And so 35 patients were approved, and the response rate at the time was 60% with the medium progression pre-survival. So that was the original studies, and that's amazing. So when we looked further into that study, however, this study was accrued mostly in Canada, and in Canada at the time, DERA-2-MAM or no anti-CD38 antibody was approved for use. And so a lot of these patients actually were naive to anti-CD38. So in the DREAM-2 study, which is the second row, you see that the patients now were required to have relapsed refractive myeloma after an imid, after a PI, and also an anti-CD38 antibody. And so when you look at that, the overall response rates are lower and more of what sort of we expect with sort of the single agents in these late line of therapies in the much heavily-protruded population with overall response rates of about 31, 34%. And you can see that it was very similar for both the 2.5 milligram per kilogram and the 3.4 milligram per kilogram dose. The medium PFS was short, three to four to five months, which we see in this sort of kind of late, heavily-protruded population. But there was an update of the DREAM-2 study presented at ASCII in 2020 that looked just specifically at the 2.5 milligram dose. And what we saw that is in those patients that did have a response, the response was actually quite durable and lasted for 11 months with the median overall survival of 13.7 months. So quite impressive in terms of sort of how long lasting these responses can be. What about the side effects? So if we look at the side effect profile, pink orange box, you see that this is a profile for just a 2.5 milligram per kilogram dose. So if you look at that, you see at the top that the main toxicity that was seen was this thing called keratopsis, which was toxicity to the cornea, and that was seen in most of the patients. And this was- Sorry to interrupt you. Yes. Something's strange with your audio that it's going in and out. I'm not really sure what's happening. Do you have a microphone or? I do. Can you hear me now? Yeah, we can. It would just go like in and out and in and out. So I wanted to- I'm gonna get the microphone much closer to me. Is that better? Uh-huh, I think so, yeah. I'll let you know if that happens again, but I think we're good now. Thank you. Sorry, I apologize to everybody, but so we'll try and continue, and hopefully my audio is better. So just to backtrack a little bit, so here we're seeing the side effect profile of the Lantham and Maffodotin at the 2.5 milligram per kilogram dose. And so the main toxicity that we see with this that's different from pretty much every other drug in myeloma is this thing called keratopathy, which is toxicity to the cornea. And that was seen in 72% of the patients, and this often was picked up by an eye exam by an ophthalmologist with the patient potentially being completely asymptomatic. But if people were gonna have symptoms, it was usually blurred vision, seen in 22% dry eyes and 14%, and there were some patients that reported decreased vision. I'm sorry for the typos there, but that's basically what that says. There were also infusion reactions, which are pretty mild only in 20% of patients, so much less than the monoclonal antibodies. And then other toxicities included low platelets in about 35% of patients, but these were pretty transient and usually with the first second cycles of therapy. And otherwise there were minimal other side effects. So when we look at the actual toxicities to the eye, it is very important that patients who receive this drug have an exam by an ophthalmologist or optometrist to sort of have a baseline exam. The symptoms once you're on treatment can include dry eyes, blurred vision, changes in vision, or you may have no symptoms at all. And so it is important sort of that people kind of get eye exams, and the FDA actually mandates eye exams before each dose of therapy to try and catch this before it becomes a problem. So as noted before, 72% of patients did have keratopathy and examination, and about 50% of patients on sort of clinical trials, sort of not just DREAM2, but other trials have reported significant worsening in their vision. So it is an important side effects. The good news, it is generally reversible. So in terms of management, it is important to identify it. And as soon as it gets to a grade of concern or symptoms of concern, then the drug is usually held or stopped or dose reduced. And with that, usually the symptoms resolve. So because of that, it is very important that an ophthalmologist or an ophthalmologist follows along with the oncologist and the FDA mandates an exam before each dose is given. Most patients who do develop eye classes, we are able to continue on the treatment, which is the good news. And then in terms of sort of kind of treatment for this, there's really not much other than just supportive care. Lubricating eye drops are important. They help with the symptoms. Steroid drops don't usually help. So based on this data, belatum and methadone became BlendRep, and it was FDA approved in August of 2020. The dose is 2.5 milligrams per kilogram, intravenously every three weeks. It is approved for adults with previously treated multiple myeloma. And patients must have had at least four prior lines of therapy that include an IMID, which for example, is a double metapomalist, a prism inhibitor, either Velcade, Caprolis, or Munaro, and an anti-CD38 monoclonal antibody, so darsal exorceraclism. So in terms of sort of where we're going with this drug, there are combination studies that are being looked at in the relapse refractory patients, and these are combinations with standard of care drugs. So for example, Dream6 and Dream7 are combinations with Bortezomib or Velcade, or with linalytomide, otherwise known as Revlimid. And there's early data with that combination showing the excellent activity. The Dream8 study is a combination with pomalidomide and dexamethasone, and that was actually recently presented by Dr. Trudel, Ash 2020 meeting, and Ash shows very promising results with excellent toxicity. And I'll talk a little bit more about that study in a second. And then other combinations are ongoing as well that haven't reported clinical data yet. There is also a potential, I told you that this is not just an antibody drug conjugate that delivers chemotherapy, but also can mediate sort of antibody type responses. And so the question becomes, can you use this in combination with other immunotherapies trying to boost the immune system's response to this treatment? And that's what the Dream5 study is trying to do. And there was early data in combination with this agent called Icos, which is an agonist basically stimulating an immune response to myeloma, against myeloma. And that was presented this year at Ash in December. There are also combination studies being looked at in the newly diagnosed patient. And so Dream9 was presented as well, and that's Belomath with Bortezumab, Lumbidomide, dexamethasone, or VRD, which is a very common combination. And this is in transplant in eligible newly diagnosed patients. And basically the early results show that this is feasible and that it's tolerable. So more to come with these combinations, but that's sort of where this development is heading for the lentiment map of dole. In terms of the dosing, the truth is we actually don't know the optimal dosage schedule, and that's still being investigated. And so the goal here is to improve or maintain the efficacy. So what we're seeing is that, and while reducing the toxicity, and what we're seeing is that patients who do get some of that eye toxicity have to be held. And usually during the whole patients do well. And then you often either resume the dose or continue at a lower dose and the response continues. And so because of that, it appears that maybe we don't have to be as aggressive with the dosing, with the frequency. And so actually doses as low as 1.9 milligram per kilogram are being investigated. And the schedules that is currently every three weeks in terms of dosing has been investigated every four weeks. So we're seeing that there is a lot of different combinations of doses, and that's been up to eight weeks instead of every three weeks. There is also arms looking at whether the dose needs to be split given over two days instead of one day. And so a lot of these schedules are being investigated in all these different combination trials that I discussed a little bit earlier. But again, I think the important thing to note here is that the patients are able to maintain their response during a treatment hold and can continue to respond even with those reductions or less frequent dosing. So it's important that if you are experiencing some of this that you talk to your doctor about those changes and even schedule changes. So I'm briefly gonna talk about Medi-2228, which is another antibody drug conjugate. And this illustrates a couple of points. So the antibody goes against BCMA just like BlendRef. But in this case, instead of MMAF, the actual chemotherapy is this really huge picture here, it's called PBD. And PBD has very different side effect profiles as you will note. But basically the idea here is that the antibody drug conjugate binds to BCMA, it gets internalized and it releases the chemotherapy just like the BlendRef is just a different type of chemotherapy. But interestingly with this antibody, they actually remove the FC portion, which is what usually allows it to be a monoclonal antibody as well. And so this does not have the monoclonal antibody effects like BlendRef. So data was presented at ASH 2020 by Dr. Kumar and the dose escalated and so here in blue, you see what was considered sort of the optimal dose that they were gonna carry further at 0.14 milligrams per kilogram. And so 41 patients, they saw an overall response of 65%, which is quite impressive, and even including VGPRs and CRs. When they looked at the toxicity, the toxicity profile is very different from what we saw with BlendRef. And so here you still get some eye issues, but this is photophobia. And so this is very different from corneal toxicity, which was not seen with this drug. Here, patients basically had pain when exposed to light, similar to when some people get migraines and you kind of get that photophobia. And that was very common, it was seen in 58% of patients. And that was the most common cause for dose emissions or discontinuation. RASH was also seen in 32% of patients. And then when you look in the other column here, you see low platelets in about 30% of patients, but you also see pleural effusions, which means there's fluid around the covering of the lung. And that was seen in 24% of patients. And there are other ADC conjugates and other diseases that use the same chemotherapy. And photophobia, RASH, and pleural effusions are not uncommon with those ADCs. So we know that these toxicities are coming from the actual chemotherapy that is bound to the intubot. And so that's important as you kind of see the different ADCs. So you can see that there's a lot of information about what they're binding, but also what their payload or toxin of choice is that will potentially result in the toxicity profile. Unfortunately, despite this looking promising, it is unclear if Medi-228 will be developed further. And part of that has to do with just how crowded this is, perhaps the toxicity they felt would not be something that they wanted to continue to develop. But it's possible that someone might pick it up and perhaps try different schedules, just like we're doing with BlendRep, and try and mitigate some of those toxicities. But it's a good proof of concept with ADCs. So stay tuned from that standpoint. But as it stands right now, BlendRep, our valentum and methadone, is still the only FDA approved ADC against myeloma. And so we have some unanswered questions for ADCs. And then after this, I'll stop and then discuss sort of more of this in your questions. But so the antibody-drug conjugates, so how do they compare to the naked antibodies, such as Darsalox? You know, with BlendRep, it was difficult to know whether it was the actual chemotherapy delivery that was leading to the responses, or was it the actual antibody. I think Medi228 showed us that even if you don't have the antibody, that the delivery of the toxin can be effective. And so now you have, you know, the, so now you have two different mechanisms of action, which may make it preferable to a mountain coronal antibody. And so you can deliver both the toxin and function-mike in antibody. And so that's potentially a plus from a standpoint of activity. And just like we saw with Darsalox, the initial responses are similar, and as you move it in combination, it becomes much, much more active, which is what we're hoping to see with the ADC. The problem, of course, is when you do add the toxin to this, is you may increase the activity, but then you also will increase the toxicity. And so as we've seen, the toxicity is very particular to the payload that is being used with BlendRep, and specifically the NMAF, we know and seen with other ADCs and other diseases that use NMAF that this coronal toxicity is being driven likely by the toxin, although it's not 100% clear. And the question is whether this toxicity will limit its combination potential. Because if it does, then that could become a problem, because then you will have to use it just as a single agent as it is approved now. The other thing is, you know, in myeloma, even though most of us don't like it, essentially you don't like it, is the treatments are given long-term, right? So the patients usually stay on treatment, especially in the relapsed refractory setting until intolerance or progression. And so with these types of toxicities, is this a type of drug that can be given long-term? And the answer is we don't know. We still don't know the optimal dose or schedule to minimize the toxicity, so that stay tuned. Unfortunately, in myeloma, we do have several similar examples, recall Kyprolis or Charyfizumab, where the dose that was originally FDA approved was very different from the doses that we're using now, and that includes the schedule. And so it's not unusual for us to have to do this sort of later on after the FDA approval. The other drug that comes to mind is Selenexor. So Selenexor also was approved at a certain dose and schedule. And then as the drugs are to be combined, it was seen that you can use that same dose and schedule to mitigate toxicities, the doses have been changed, as is the schedule. So the same thing is happening with BlendRev, so kind of stay tuned as to what will become the optimal dose and schedule. And it may actually be patient-specific. So how do the ADCs compare to other BCMA-directed therapies? So obviously, as you all know, or will hear, or have heard, there are these things called bispecifics. There are CAR-T cells that go against BCMA. And so these are looking very powerful, very effective. The truth is we actually don't know exactly if someone's had a BCMA-directed therapy, whether they will respond to another BCMA therapy. Most of the early studies of CAR-Ts and bispecifics and even Belantimath excluded patients who had prior BCMA therapies. The good news is as we learn more about why people may stop responding to these treatments, it does not look like people or people's myeloma cells are losing the BCMA. And so it is very possible that mechanisms of resistance are very different for the different drugs. And now there's emerging data that having had one prior BCMA therapy doesn't necessarily affect the ability for another one to work. There actually are some studies ongoing with some of the CAR-Ts and bispecifics looking specifically at patients who have had prior BCMA therapies, which will help us answer that question as to whether we can kind of give these one after the other. And so for now we sort of are left with, this is where we are, but can they be sequenced? The answer is yes. Is that optimal? We don't know. And so actually with that, I will stop and I will, happy to answer questions and have a discussion. Awesome. Thank you, Dr. Rodeja. I really appreciate your preparation for this. And I'm excited to get into the questions and answers as well after an awesome presentation. I guess one of my first questions would be, who is your ideal candidate for ABCs in myeloma? Who do you recommend out of your patient population for ADCs? Yeah, I think when we look at sort of the BCMA-directed therapies, and again, like I said, there's no good data to know how to best sort of sequence or whether we can sequence these, meaning we can give one after the other. So if I have a patient in front of me and I have a CAR, right now the only FDA-approved BCMA therapies are BlendRep, which is an ADC, or you have two CAR-T cells, right? You have IDA cell and SILT cell. And so the therapies are very different. So the CAR-Ts are much more likely to give a response and to maybe give a deeper response and potentially last longer than the ADC. The problem with the CAR-Ts is that you have to wait for it. So the patient that is best for a CAR-T, for example, is someone that is able to collect, you have to collect your cells, and then your disease has to sort of be controlled to be able to deliver the CAR-T. There are some patients that unfortunately can't wait that long and may need something right away. And so that's a patient that I may kind of go with the off-the-shelf treatment like BlendRep. On the sort of the opposite side of that is also, CAR-Ts do have some toxicities that can make it difficult for more frail patients. And so oftentimes a frail patient may be a better candidate for something like BlendRep, but really the main toxicity is the sort of protein deposited in the cornea, which oftentimes is asymptomatic and is reversible. And so in my experience, it is otherwise very well tolerated. And so oftentimes that's the patient that I may choose the ADC versus the CAR-T. Excellent, thank you. Let's talk a little bit more about the eye toxicity, the keratopathy, how do you say it? Keratopathy. Yeah, after how many patients do eye issues tend to appear? It can actually be just after one. And so that's why the current FDA REMS program mandates that if you're gonna start a BlendRep that you get an ophthalmologic exam, and it can be an optometrist, not an ophthalmologist as a baseline. And then before each subsequent treatment, that exam has to be reviewed by your oncologist to make sure that you can proceed with the next dose or if it has to be helped, or if it has to be adjusted. And so then usually what happens, let's say, after two doses, you develop great keratopathy, which usually mandates that you hold until it reduces to a grade one or better, meaning a much lower level of, or even complete results, then usually the drug is held until that happens. And then you start, again, depending on the grade, on the same dose, and oftentimes you don't get the same problem, or the mandate is to reduce the dose. And so there are very specific guidelines set that your oncologist will follow based on the results of the exam. But yeah, it can be as early as after the first dose. Interesting, and you said some patients are asymptomatic. Would you say more than not, or would you say most of the patients experience significant current keratopathy? I would say about half the patients are asymptomatic. Okay. And again, part of that is because I think most will become symptomatic if you just let it go. But that's because we're looking very closely and it's more about what you're seeing on the eye exam that mandates what you do than more about the patient's symptoms. Now, actually there is a way to sort of, there is a test looking at sort of symptoms being really, really, really good about sort of kind of assessing symptoms from the patient standpoint that may predict who's gonna develop keratopathy and so forth without waiting for the exam. But at least at this point, the symptoms can be so subtle that people just don't report them. Right, yeah. It's important to report any symptoms very quickly, but at the same time to also realize that it is important to get that test. I know it's an inconvenience to have to go to two different doctor appointments, but it is a very important part of making this a safe therapy. Awesome, thank you. Joseph's wondering if, oh, that's my next question before we ask that. Is BlendRap known to cause any problems with tasting? It is not actually. There's definitely other drugs that can't, but this at least has not been reported in many cases. Just realize that some, and when you look at studies, as some patients may be getting BlendRapid combination with other drugs, and so then the symptom side effect profile might be very different once you start combining. But with a single agent, that hasn't been reported. Interesting, okay. Lots of great questions about BCMA coming up. So Joseph's wondering, can a myeloma cell survive without BCMA? Unfortunately, it can. So BCMA is very important in the normal development of plasma cells. But as we know, once these plasma cells become malignant and become myeloma cells, sometimes they do take sort of superpowers, I guess, in that they develop other ways of surviving. And so unfortunately the answer is yes. And we know that because there are patients that have had CAR-T, for example, that have lost sort of the gene that actually makes BCMA. And so their cells do not produce BCMA any further, but they're still alive. So yes, unfortunately they can develop other ways to survive. Interesting and unfortunate how smart these myeloma cells are. So is BCMA expressed then on other non-cancer normal cells? The short answer is no. And that's what makes this a great target. Obviously, there's a lot of other drugs. And as you know, there is a CAR-T. Well, actually there's two CAR-Ts that are FDA approved against BCMA. And one in particular, we're starting seeing this sort of late neurotoxicity, which we can't really explain. But then there was a report that was done. One of the patients that developed this, and unfortunately did not, eventually ended up dying from myeloma or the toxicity. And so at autopsy, this person was found to have a loss of the basal ganglia cells that sort of kind of were shown to express BCMA. And so it's possible that there is a cell in the nervous system that can express it. But again, that is a very unusual toxicity. We haven't seen it with any of the other BCMA drugs. And it's possible that it's just like the super, super like sensitive drugs that may sort of be able to detect that little tiny detection that's outside of the plasma cells. But that's really it. Whereas with other drugs, usually you see, or with other targets, usually expression in other cell lines and other skin cells and BCMA, it's really just the plasma cells, so the late B cells. Yeah, that's fascinating. Where are the side effects coming from then? As you were just mentioning, sometimes certain drugs attacked other cells because they're similar to the genetic makeup of myeloma cells. So where are the side effects coming from in BCMA targeted therapies? Just in general, BCMA targeted therapies. So I think the- I know, it's a big question. We've left one. I think the toxicities are specific to the mechanisms of action. So the good news is at least the actual target itself is probably, again, is expressed the most direct on the plasma cells with very little other expression. And so that's why we've seen a lot of drugs against BCMA. But it often is not from the cell that is targeted, but often by the mechanisms of action. So with Blender, for example, we talked about sort of the mechanism being the actual payload. And so the keratopathy is actually the drug, right? The NMAF, just like with Medi2228, the different toxin led to different toxicities. With the bispecifics and with the CAR-Ts, most of the toxicity is coming from actually the incredible stimulation of the immune system that is actually being to the toxicities. And so usually you think of cytokine release syndrome and neurotoxicity, and those are things that are being created by the activation of your T cells and the release of all these cytokines. And so it's actually, it has nothing to do with BCMA at all. It has to do more with sort of kind of what your drug is doing. And so here with Blunrep, this is not considered a T cell redirecting therapy, so we don't see cytokine release or neurotoxicity as you would with the bispecifics or CAR-Ts. That's an excellent answer to the question. Thank you, that makes a lot of sense. How long does the toxin stay in the body? So the toxin enters the body, how long does it stay? It actually gets excreted pretty quickly. And there's very little toxin that is actually dissociated from the antibody. So it really should only be going directly into the myeloma cell, very little circulating toxin. And that's why you can deliver it at much higher doses. It'd be very different because this drug potentially could be given just like chemotherapy, but through the vein, but then you would have to give a much lower dose and it'd be likely to be less effective because of that. So what makes it special here is that because it's down to the antibody and it's released inside the cell itself, you can give a much more potent dose from that standpoint. But the half-life itself should, I actually don't know the exact answer to the half-life, but it should be pretty quick, but it really should be no circulating detectable drug. Yeah. Okay, I have a couple of things that are still a little confused about how BlendRap is affecting, how can it affect other cells that don't express BCMA? So can you explain one more time how specifically BlendRap leads to keratopathy? Yeah, so the short answer is we don't know for sure, but having other drug conjugates that use this particular toxin or chemotherapy called MMAF, it appears to be a toxin-specific toxicity. And so BlendRap is an antibody and it's bound to the toxin, right? So when the antibody binds BCMA, that's its target, that's bound on the plasma cells themselves, it attaches to the BCMA. The plasma cell or the myeloma cell now internalizes the whole antibody drug conjugate or the whole complex is internalized, kind of like a Trojan horse. So as it gets internalized, the antibody is cleaved away from the chemotherapy, the chemotherapy is released, and then the myeloma cell is killed. So the chemotherapy then obviously has to, because once the cell lies, the chemotherapy does get released on, of course. And so it's the chemotherapy itself that likely is leading to the toxicity. Now, the interesting part is that you don't really see significant levels in the blood, and so that's why we can't say for sure exactly how the chemotherapy is doing that, or perhaps the antibody itself, perhaps maybe if you have the antibody and you're doing ADCC and the antibody drug conjugate is not internalized, perhaps then the chemotherapy is being released outside of the actual plasma cell and leading to the toxicity. But the truth is nobody really knows the exact mechanism of action. Interesting, thank you. So one patient is wondering, your treatment with deritumumab has been successful, but then the efficacy of the deritumumab has kind of slowed down. Would you recommend an antibody drug conjugate as a next step? Yeah, so that's a difficult question to answer. So just remember that we have a lot of myeloma therapies, and so a lot of the treatments and what is the best option for you depends on how well they worked and also how many you've had. So for example, BlendRip right now is only FDA approved after a patient has had four prior lines of therapy, which is actually pretty late in the game. So if you're on Darcelex, that's your second line or even in your front line, and then you're starting to progress, BlendRip would actually not be an option for you, unless it's on a clinical trial looking at earlier dosing, which is here's where I get to plug clinical trials. And that's why they're so important. Not only do we get answers, not only do we then get to hopefully figure out the best way to use the drugs, but it also gives access to patients much earlier. And so for example, I have patients who had a CAR T probably now six or seven years ago. So it's just so you know, so and that'd be a clinical trial of course. So again, I would encourage you that if you are progressing or if you're starting, your doctor's looking at your next line of therapy, if a clinical trial is available to you to consider that. And so again, that question would be, it's difficult to answer specifically for the person that has to, but definitely this would be an option for someone who is refractory or progressing after an anti-CV38 antibody as LCTAR select. Great, thank you. After the four lines of prior therapy, is there a minimum percentage of myeloma cells required before starting VNREF? So the short answer is no. So as soon as you and your doctor have determined that your myeloma is progressing, then no particular degree of disease is required to be treated as a standard of care. Now, clinical trial is a little bit different. And so unfortunately, clinical trials have to prove that their growth works, right? So we need to be able to measure your disease. And so usually that's done by the M protein in your blood or urine that determines whether you considered measurable disease, the free-like chains. So anyway, so yes, so on the cold trial, you would need a certain amount of disease that is measurable, but a standard of care, the answer is no. Awesome, thank you. Joseph's wondering in the spirit of clinical trials, there are many trials going on to, well, there are some trials going on to enhance the presence of BCMA. Is there, what are your thoughts on these trials and is there any hope? Yeah, no, I think that's great. So actually it turns out that BCMA can be downregulated after you start treating with BCMA, just and that BCMA therapy is just like with any other target, right? The cell is very smart, it tries to kind of decrease. So you can actually increase the expression of BCMA in myeloma cells with this thing called GSI. And that's being tested right now. It's been looked at both with CAR-Ts and with the vice specific antibodies, but also, and I mentioned the DREAM-5 study, that's one of the arms that is being looked at is actually using GSI to increase expression of BCMA and see if it actually potentiates the efficacy of something like LUNREN. So great question, more to come, stay tuned. That's fascinating. Our patient population is so educated, I love their questions. It's amazing, I tell you, these questions are way more sophisticated than the ones I get at panels that like, BMW or anything like that. That's great, that's awesome. Thank you for helping me prepare for those. Yes, exactly. Another question that they have, and again, this is on par with how educated the population is, but let's talk about the efficacy of antibody drug conjugates versus BITES and how, and if you could briefly explain BITES for those in the audience who might not be familiar. And then the follow-up question is, how will those be available commercially? Yeah, so it's an excellent question. So the BITES or BITES specifics are basically an antibody that has two targets, is the easiest way to put it. So unlike the monoclonal antibody like Darcelex that just binds to CD38 and then waits for the immune system to come and to see it bound, and then let's say waits for the T cell to come and see it bound and actually kill the myeloma cell. The bias specific of the BITES have two targets. One target is the myeloma cell and the other target is CD3, which is usually found on T cells. And so by binding the T cell, it activates the T cell, it basically activates the T cell, the T cell that turns around sees the bound antibody, and then basically you're basically lassoing and forcing the T cells to go after the bound antibody on the myeloma cell. So we call those T cell redirecting therapies. There is no chemotherapy, nothing. It's purely immune activating therapy. And actually I will put the bias specifics and BITES sort of at par with the CAR T cells, because we're doing the same thing with CAR T cells, but the difference here is that we're actually putting the antibody on the T cell itself. So the antibody now or the CAR T now can identify myeloma cells even without an antibody. But you're also redirecting those T cells to go fight myeloma. And so those are the kind of responses we're seeing. So I sort of separate them a little bit from the ADCs. I think the bias specific BITES and CAR T's are giving us much higher response rates and are looking much more sort of powerful in that sense. Whereas the ADC is more like the, like Darcellex and other monoclonal antibodies with the added potential of having sort of this directed toxin. And so they're very different compare. And just like the first question you asked me earlier about, it's gonna be about patient selection and what makes sense. Now the added benefit of the bias specifics against the CAR T's is that these will be off the shelf. And so they will be more available, similar to the ADC for someone who needs treatment right away and can't wait for a CAR T to be manufactured. Having said that, the bias specifics also will have the potential toxicities that we see with CAR T's, which include the cytokine release syndrome and neurotoxicity. And so someone, a patient is more frail, may not be able to withstand the intensity of that therapy and may still be preferable to go on the ADC. So right now there are no bias specifics that are approved, but the question is, when do I expect one? Actually, most likely the first one we'll see approved will be Toclistamin and that is a BCMA CD3 bias specific. And that probably will be coming in about a year or less. Actually, Telquetamab is not too far away from that and maybe add another six months to that one. And that is actually a different target. That's not even BCMA, that's GPRC5P. So there's lots of excitement and lots of new things coming your way, which again, all of these are available on clinical trials. You don't have to wait for them to be actually approved if you have access to clinical trials. That's exactly what I was gonna say. Thank you for putting that plug in. Yeah, and so exciting. You and I were talking about earlier before we even started the meeting, just what hope there is in the multitude of myeloma treatments that have been approved recently and are even being tested right now. I mean, you were saying even four years ago, we didn't have this on the horizon. So it's very exciting. Couple more questions and then we'll finish up here. There's a question about, do ADCs lead to secondary cancers? Yeah, no, that's an excellent question. Not that we're aware of, at least at this point. Now, realize that there's no sort of long-term data with these, at least in myeloma. There is longer-term data with other diseases like lymphomas, even Hodgkin's where they are used there. The problem is that it is always hard to know if somebody does develop a secondary malignancy, whether it's from that particular drug or something that was given prior, anything with CAR T. So we know that some people are getting secondary malignancies after CAR T, but the truth is most likely it is related to the prior rebumet, the prior transplant chemotherapy that was given. And so you have this cumulative sort of continuous, I guess, sort of kind of hits that can increase your risk as you get sort of more relapsed refractories. So, but by itself, there's no, there's no obvious, there is a potential for sure, because it is a chemotherapy, but there's no obvious data to suggest that that's the case. Are there any age limitations? The stem cell transplant occasionally with varying doctors have an age limitation. Do you see age limitations? You mentioned frail patients, but is there any age limitations for ADC's CAR T or bispecifics? There is actually no particular age limitation. Now, some studies do limit age. Most don't. It's really more about organ function and performance tests. And so as long as you meet criteria for kidney function and heart function and all those different things, the age by itself should not be excluding. There actually, we did, we actually looked at the IDA cell, for example, which is a CAR T, looking at those patients, because there were patients enrolled up to 79, but there was no cutoff. That was just the oldest patient. Looking at the patients who are 70 or older, and there's really no difference in the toxicity or efficacy of the drug in the older patients versus the younger patients. And so again, it's really gonna be sort of you and your doctor determining whether you are strong enough for some of these therapies, but not necessarily because of age. Awesome, thank you. And I don't know how to say this without, just if you don't feel comfortable with what your doctor has said, and you can also seek a second opinion. If you feel strong enough, if you feel healthy enough, if it's relatively something that you are strongly passionate about and interested in, and you don't feel comfortable, always seek a second opinion, and then you know for sure whether or not that's true. I agree, I think that's always an important thing. No doctor should be impossible when you want to get a second opinion. There's some nuances that may not be familiar with a particular therapy and they actually don't know the answer. And so it's not wrong to seek a second opinion at any point that you feel that you wanna know more. Awesome, thank you. One last question here. What would you recommend? And this is more of a personally based question. So just if you could give a general answer to a personal question. What would you recommend for someone who's 11 years out with extravigilary disease, has been through four different clinical trials, including SAR and Selmod 480, which is failing after 10 months. Often, if I could just make a comment here, often patients feel like there's no other steps and it's very anxious and undesirable feeling. What feedback do you have for this specific patient? Well, I mean, I think, again, it's always hard to give specific advice, not knowing the entire clinical record and you actually don't want them to. You don't want them to, but I don't have all of the facts in front of me. So that's why it is important to listen to your doctor, but then maybe get a second opinion to just make sure that everything coincides. And also we all have different clinical trials. So just because there may be, you're sort of exhausting your options that are standard of care, doesn't mean that there is not something that's being looked at that may be effective. I was talking earlier before we started that I have a patient that actually has gone through now four lines of therapy on different immunotherapies in the last five years. And at that time we thought we had exhausted all standard of care options. So again, just because something is not FDA approved or an option right now doesn't mean that there's not something that's looking fairly active that is in clinical trial. So that's what for this particular person, that sounds like they've gone through several clinical trials already or exhausted, and you may have exhausted clinical trials at your site. Remember, we all have different trials. We can't all have the same trials because then we wouldn't be able to sort of kind of really push everything forward as much as we can because not every patient will go to one site. So make sure you, with the help of Malma crowd to find if there's based on your prior therapies, whether you would be eligible for some other clinical trials. Because there are trials looking at even patients who failed some of these things we're talking about, looking at mechanisms of resistance and why are they failing and allowing patients who had prior therapies. But for example, there's a trial right now ongoing that for patients who have failed prior BCMA therapies, even failed prior GPRC5D therapies, looking at combinations to try and overcome the new resistance to that and see if we can gain function. So again, and then there's new targets a bit all the time, of course, as well. So I would encourage you to seek out some of those therapies if you're still feel like more therapy is needed. Awesome, thank you. And thank you for the plug. I was going to mention as well, the Malma crowd by health treatment has personalized clinical trial options for you through health tree care hub, which is something that I will be including more information about in our follow up email that we'll send. Thank you so much, Dr. Bardejo for your time, for your presentation, for your question, I mean, answers to the questions. I truly appreciate you and thank you so much for being here today. You're welcome, thank you for having me. Yeah, we'll close with just a couple of outro announcements and then we'll finish. You can join us next month. We're going to be continuing discussion on bispecific antibodies. What role do they play in myeloma? How soon can we expect them to be FDA approved? We talked about that a little today, but we'll just, as I said, continue deep in the discussion next month. We're still working on a potential speaker to find a date and time with them, but we will add more details about this event and let you know via email when it's ready to register for. You may be interested in other myeloma crowd community events we have upcoming tomorrow at 1 p.m. Actually, that has been changed. It's going to be at 12 p.m. That was just recently changed, so that's why it's not reflected here in the slides. It's going to be one hour earlier at 12 p.m. Eastern. That's going to be our relapse refractory myeloma treatment chapter. And Dr. Benjamin Dermen is going to be sharing about infection prevention for multiple myeloma patients because as we know, we're working so hard to fight against myeloma, we don't want to die from anything else or get sick due to anything else. That's the reality of it. Thursday, May 26th, African-American myeloma community chapter is meeting to talk about changing your diet while keeping your culture. M. Gus patient Will Wright is going to talk about a clinical trial that he took part in that completely changed his life, reduced his comorbidities, and has potentially slowed down the progression of his M. Gus Dismoldering Myeloma, which is extremely exciting. And then on the 26th at 2 p.m. Eastern is our newly diagnosed myeloma patients chapter. We're going to be talking about clinical trials for newly diagnosed patients with John Rosengard. He's going to be sharing as a newly diagnosed patient the Griffin trial that he participated in, what that looks like, how many years that lasted, and how he's doing now. Often we think of clinical trials for something in the relapsed or refractory setting, but it can even be for newly diagnosed patients. And as Dr. Rodejo was saying, it's such an excellent way to further myeloma research. A special thank you to our sponsors, Bristol Mary Squibb, GSK, Genentech, Janssen Oncology, and Abbe. And thank you to each of you for taking time out of your day to be with us and to learn together. Hope that you have a great rest of your day. Thank you, everyone.