(Guest Lecture): June 2022 - Know Your Myeloma Immunotherapy: Bispecific Antibodies with Dr. Cesar Rodriguez

know your myeloma immunotherapy by specific antibodies. So if you've been a part of the immunotherapy treatment chapter for a while, you'll know that we have highlighted different immunotherapies throughout this chapter. We've been trying to get to know them a little bit more. And this month is by specific antibodies. They have the potential to really change myeloma treatment. And there are so many different by specific antibodies being treated or being tested, excuse me, right now in clinical trials and awaiting FDA approval. It's hard to keep track of all of them. So that's why I kind of wanted to do a review today by specific antibodies. I want to learn, you know, what are their mechanisms of action? How do they differ from one another? How do they differ from other immunotherapies that are already out there? And what is their potential in treating myeloma? So as I mentioned, I'm really excited for today's presentation. And it's my pleasure to introduce Dr. Cesar Rodriguez to you. He joined recently the faculty of Mount Sinai Hospital and is the clinical and operations director of the myeloma program for the system. He previously was associate professor of hematology and oncology at the Wake Forest School of Medicine and led the myeloma program there for six years. His focus is early phase clinical trials, translational medicine using 3D culture models and immunotherapies. So we're glad he's here to talk to us today. He's led a number of first in human studies with myeloma therapies and has opened the first trispecific therapy for myeloma targeting and case cells. And he'll highlight that in his presentation. He is one of three winners of the second myeloma crowd research initiative competition. And his project uses a three dimensional organoid tumor modeling platform, which allows the testing of multiple treatment combinations against a specific tumor to identify treatments that will work best for each individual's type of myeloma. This personalized approach may help doctors to help find useful drug combinations that will have the most impact and avoid treatments that will be ineffective. Dr. Rodriguez earned his MD at the Escuela de Medicina Ignacio Santos, Instituto Tecnológico y de Estudios Emporios de Monterrey, Mexico. And he completed his residency at Texas Tech University Health Sciences Center in El Paso and a fellowship at the University of Louisville. So you can tell he's very accredited and more than the perfect speaker to speak to us today on the topic. So Dr. Rodriguez, with that being said, the time is now yours. Dr. Rodriguez- Thank you so much, Audrey. And excellent Spanish, by the way, in your accent. I today I want to talk about immunotherapy and specifically by specific therapy, and I'm going to share, I'm going to use some slides and share my screen if I am able to do that. Audrey, is it possible to share my screen so I can share the slides? Dr. Audrey- Yeah, are you not able to? Dr. Rodriguez- It doesn't give me the option. Audrey- I wonder why. Dr. Rodriguez- Okay, there we go. Audrey- Okay. Dr. Rodriguez- Okay, so I'm going to try to make the talk, the slides portion of the talk brief and concise so that we can actually have a better discussion afterwards. But I want to just talk about by specific antibody therapy and myeloma or T cell engagers. But just to give you an idea of T cell redirecting therapy or immunotherapy, we use the term immunotherapy to describe different types of therapies and medications from lenalidomide and pomalidomide, which is some of the early versions of immunotherapy to what we now call T cell redirecting therapies, which include CAR T therapy, by specifics and vaccines. So we're going to focus just on the by specific antibodies at the moment. These are my disclosures. And just briefly in case people don't know what antibodies are and how they work, I want you guys to picture your blood and your immune system. So our blood has platelets to help heal wounds, red blood cells to help carry oxygen and white blood cells to help fight infections. And out of the white cells, there's different subgroups of white cells. One of those subgroups is called plasma cells, which is where myeloma originates from. But a healthy plasma cell, the function of that cell is to produce a protein called antibody or immunoglobulin that is released into the blood. And that antibody is going to be swimming and trying to attach to or trying to recognize through its little hands here, the binding sites, in any foreign object, whether it be a virus, bacteria or something that should not be part of the body. And when it attaches to it, it signals the immune system that there's something foreign that it needs to be attacked and that activates the immune system. So we're taking advantage of how antibodies work in identifying surface proteins of things that are whether it be viruses, bacteria or foreign objects in our body and using it to try to identify our own cells, specifically cancer cells. And we take advantage of the proteins that are in the surface of the cancer cell and to design antibodies, whether they be monoclonal antibodies like their tumor map and elotusumab and insetuxumab or by specific antibodies like what we're going to talk about so that then it can signal the immune system to go ahead and destroy it. But you guys might be familiar with the DaraTumorMap and elotusumab and insetuxumab. These are called monoclonal antibodies. They just attach to the surface of the cell and try to signal the immune system and try to wave at it so that if it sees the antibody, it comes and binds to the antibody and then destroys the cell. But the problem is that the myeloma cells are very, very sneaky and they have the ability to actually camouflage themselves. So we need extra help. And the plasma cell surface has many different proteins. Some of them you might be familiar with CD38, the targets there are tumor map, SLAMF7, the elotusumab targets that. Then we have others like PCMA, GPRC5D, FCRH5, CD19. And there's many more proteins that are on the surface of the myeloma cell. And some of these are very unique and particularly found only in myeloma cells that seem to be good targets that we can potentially use for a by specific therapy or to design immunotherapy. But you must probably already know that there's many clinical trials using by specifics. And I want to say that even though you might think that it's the same by specific or the same structure, they all have very different forms, structures, and binding sites in the target protein that they're going to use. Now, BCMA is one of the most common ones. And here I just want to show you four different types of BCMA by specifics and how they're very different from each other. And that helps it's affinity or how effective it is or whether it can attach to one part of the protein or another. But by specifics, as opposed to Dara and Isa and Elo, it's going to not just bind to the myeloma cell, but it's going to have another arm that's going to actually bind to the immune cells, specifically the T cells. And that way it's dragging both. And once it has both in its hands, then it's going to activate the T cells so it can destroy the myeloma cell better. So that way, we're trying, it's almost like a seeing eye doc that's guiding the immune cells to the myeloma cell and therefore overcoming that camouflage that the myeloma cell likes to have. Now, let's talk about BCMA, which is the most common by specific therapy that we have available right now. BCMA is actually a surface protein that stands for B-cell maturation antigen, and it serves to promote cell survival and proliferation. And it is heavily expressed in myeloma cells, but it is also expressed in other B cells and plasma cells. But it doesn't seem to be expressed significantly in other body parts or in other types of cells. So this makes it such a very interesting and appealing target for by specific therapy. And there's been a lot of agents that have been developed by many drug companies. These are just an example of some of the by specific targets that are available right now. Teplistimab, Herlanatinab, ABBV383, which was before known as TNB383B, Regeneron 5458, AMG701, CC93269. But the original ones, the original BCMA was called Abite, which was from Amgen, and it was called AMG420. Unfortunately, that did not survive because it wasn't that effective. It was very tedious, but it was the beginning of the start of this by specifics. And now I want to show you this table, which is extremely busy, but it's going to help guide a little bit as to give you some better insight of the by specifics that target BCMA. So we have here are the most advanced studies that we have so far developed AMG701, CC93269, Herlanatinab, Regeneron 5458, Teplistimab, and TNB383B or ABBV383. And I wanted to show this table, even though it's very busy, and even though there are different studies, to show the differences that each one has. When you see this table, I don't want you to be comparing results between one study and the other because that's not how we should do it. The criteria and the patients that are enrolled in each study are very unique and different, so we can't be comparing apples to oranges. But I do want to show how some of these are given IV, like the AMG701, CC93269, Regeneron 5458, and ABB383. But some of them are given subcutaneously, like Teplistimab and Herlanatinab. And there is a push for some of the drugs that are being given IV at the moment to transition to subcutaneous administration as well for convenience of patients. Some of these are given on a weekly basis. Some of them are actually being studied on every other week as well, like Herlanatinab and Teplistimab. And some, like the TMB383B or ABBV383, is given every three weeks. The majority of antibody, of specific antibody therapies, is given in a step-by-step approach. You start with a small dose to try to reduce the side effects and toxicities and let the body assimilate, assimilate this drug, and then the full dose is given later on. Some of them require just one step-up dosing. Others require two step-up dosing. And there's only one study at the moment that does not have any step-up dosing, which is the ABBV383. Now, the number of patients that have participated in this study is still small compared to CAR-T therapies. That has been in the myeloma realm a little bit longer than bispecifics, but we still have very relevant data from all of these studies. And one thing to keep in mind is that all of these studies have been tested or trialed in patients who have been heavily pretreated, on average five to six prior lines of therapy. And this is very important for you guys to keep, I want you guys to keep this in mind because normally when we start thinking about myeloma and how it tends to relapse, after the three or four lines of therapy, we don't expect a significant response to the treatment. We might see 20% response, 30% response, if we're lucky. If you guys remember when Selenectazir and Melfloufen were approved a few years ago, initial response rates were 30%. The same thing with the tumor of a single agent, the response rates was 30%. And here we're seeing that patients who received five to six prior lines of therapy and get therapy with a bispecific that targets PCMA, the response rates are between 60 and 80%, which is very, very significant and something that we haven't seen outside of CAR T therapy. Now, we see a lot of responses. We're very excited that people who are refractory to the current therapies are responding beautifully to this treatment. As you can see as well, the majority of these patients have been exposed to immunohistamides, whether it be lenalidomide or pomalidomide, to a proteosome inhibitor, whether it be bortesamide, carfilostomide or exasamide, into an anti-CD38 agent, whether it be daratumumab or isotuximab. Here are examples of the frequency of each one. Majestic or texistumab is being given on a weekly basis. And this one was started IV. It's now given subcutaneously. And right now it's weekly until progression of disease. This is the one that has the most patients enrolled to date and the more mature of all of the studies. ABVV383 is given every three weeks. There is no step-up dosing unlike the other ones. It is given IV. Regeneron 5458 is given on a weekly base. And then after 16 weeks, it gets based out to every other week until a disease progression. And it does have step-up dosing. The CC93269 follows a schema similar to daratumumab that's given weekly for the first few months, then is spaced out to every other week for the following months, and then eventually transitions to a monthly dosing. So that's just to give you a sense of what to expect in terms of the variability between the different bispecifics. Toxicities is something that I want to talk about as well, because even though it's very exciting to see that there's a great response in patients that have been heavily pretreated, and we are very interested to see as we advance this drug earlier, if the responses are going to be better, we cannot ignore the toxicities. And the most common toxicity is ERS or cytokine release syndrome, which tends to be an overactivity of the immune system. So when the immune system gets activated, I want you guys to think of when you get the flu. And if you get the flu, you're going to have fever, you're going to have warmth, you're going to have flushing, you're going to have some chills at times. Your blood pressure could potentially drop if a lot of the fluid that's inside of your veins gets out of your veins and causes generalized edema. And that is a similar response that we sometimes see in immunotherapy, whether it be criteria or bispecifics. And we call that CRS or cytokine release syndrome. There is also a drop in the white cells, drop in platelets, drop in the hemoglobin, this could be just transitional, the risk of infections that happens with this disease, with this treatment, sorry, and neurotoxicity, which is rare, but we have seen cases of neurotoxicity that can be manifested as headaches or confusion, or sometimes forgetfulness, or tremors. And all of these neurotoxicities that have been seen in bispecifics have all been reversible and are not sustained or not permanent. But just to give you a better idea using a comparison of three studies that have a large number of patients. When we talk about CRS, almost everybody is developing CRS to some degree. We actually expect it to happen because we're activating the immune system, but we don't want to over activate it and cause the patient to blood pressure drop too much and become hypertensive, or require oxygen, or end up in the ICU with medications to maintain the blood pressure at an adequate level, or to be on the ventilator temporarily to maintain oxygenation. So whenever we talk about CRS and immunotherapy, we want to keep the CRS to low grades, which are grade one and grade two, where we don't need to do much intervention, other than just give Tylenol or some hydration. Grade three and four requires a little bit more aggressive hydration, or sometimes even medications to help maintain the blood pressure, or to control chills, or fevers, or even oxygen supplementation. So as you can see here, the degree of grade three and four CRS is pretty low compared to the overall CRS the patients are getting. And in terms of neurotoxicity, this is also pretty low across the board. Now, we're seeing these amazing results. We're seeing that patients have response rates between 16 and 80 percent, or 85 percent in heavily pre-treated patients who are refractory to IMIDs and proteasome inhibitors and to monoclonal antibodies, but relapse is still ongoing. We haven't been able to cure the majority of the patients with this therapy. And it's still a little bit early to see if there's a small percentage of patients that are being actually cured with this treatment, because we do have some patients that stay in remission for a prolonged period of time. And these studies are not that old, so we really don't know how far out these patients are going to stay, but the bulk of the patients do relapse, and we cannot ignore that. So we are looking at ways of trying to improve this. And how can we improve it without doing any combination with other drugs to see if we can make it more effective, similar to what DeraTumorMap did when it got approved that it only had a 30 percent response rate as a single agent, but when we combined it with lenalidomide or pomalidomide or bortesomib or perfilsomib, we saw that response rates really jumped to the 80s and 90s percentile. So combination therapy is one thing to use different targets that are not BCMA to optimize the design of the antibody that we're engineering, or to give earlier in treatment and not wait until people are heavily pretreated. So those are things that we're considering. And in terms of combination therapy, we have actually tried different drugs. There's been studies specifically with the Clistomap combining it with DeraTumorMap, and it's also been combined with pomalidomide. Elronatinap has been combined with lenalidomide, pomalidomide, and DeraTumorMap. And we are seeing that there is a slight improvement in the responses, as you can see here in the Clistomap, it only got 78 percent, but it also does increase some of the toxicities. So will this improvement be higher than the toxicities? It seems like the toxicities that are increased are not as high compared to the response that we're seeing, but we still need more data to analyze what's the right combination, how much of that drug to give in combination with the bispecific, and at what point are we okay increasing the toxicity so that we can achieve a cure or a better response. But we're also looking at other immunotherapies or bispecifics using a different target that are not BCMA. And there are some proteins in the surface of the myeloma cells that are unique of myeloma that we don't see in other cells, particularly GPRC5D and NFC-RH5. We really don't know the mechanism of what these do in a lot of detail, but we do see that they're highly expressed in myeloma cells and very rarely expressed in other tissues. GPRC5D in particular does have an expression in the nail beds and in the tongue, so that some of the toxicities can be seen there, but FCRH5 we have not seen it expressed in other cells significantly. We're also looking at other targets that are not necessarily the T cells. CD3 is the common target that is where the bispecific binds to the T cell and drags it to the myeloma cell and activates it, but we are looking at other targets like CD16, CD16 and NKG2D, and these are more commonly seen in NK cells, but other targets include albumin as well, and I'll talk about those in a little bit. So let's focus a little bit on bispecifics with non-BCMA targets, which means proteins that are not BCMA that we see primarily in myeloma. And GPRC5D or telcedema is an agent that actually has been studied as a single agent in a combination with diatomimab and in combination with diatomimab and pomalidomide to try to see if we're seeing more efficacy by adding a combination with other drugs. And as you can see, the response rates with this new agent that targets a non-BCMA surface protein is very good, and if we add the diatomimab, we are seeing a bump in the response rates. We're also seeing a bump in the toxicities a little bit, especially infection, and that's something that we cannot ignore, especially right now with the pandemic. Now, fortunately, GPRC5D is not causing an increased risk of complications with COVID or increased risk of infections as much as what we're seeing with BCMAs. Other BCMA bispecifics are having an increased risk of infections up to 30%, and people who do get COVID with therapy using BCMA or BCMA with their telomimab are at higher risk of having severe complications from COVID and not doing very well. So those are things that we're also keeping an eye on. Now, when we also talk about non-BCMA targets, aside from GPRC5D, which is, I would say, the second most studied target for bispecifics and other types of immunotherapy, we also have FCRH5, and FCRH5 actually doesn't have a lot of toxicities, and it's shown to be safe in humans and in myeloma patients, and the response rates that we're seeing are actually good. It's a little bit lower than other studies, and I don't want you guys to think, oh, this is not a good bispecific. Keep in mind, the patients that each study has are very unique, and the patients that were part of this study included a lot of BCMA-treated patients or patients that had received GPRC5D. So it is showing that even though somebody has had a prior BCMA, they're still having a response, and this 37% that you're seeing, a lot of it is including patients that were receiving treatment doses that were subtherapeutic because we were still trying to find the target dose for this agent. So we have other options that are not BCMA. So if somebody has received BCMA, whether it be a bispecific or a CAR-T therapy or an antibody drug conjugate like belentimum amafodotin, and they're progressing, we could offer them another non-BCMA bispecific, like atolketamab or serbastamab. Now, one thing I do want to talk about before moving forward with this is that in BCMA, like I mentioned in the first slide, there's different structures and designs. So being resistant to one BCMA doesn't necessarily mean that you're going to be resistant to another BCMA before you jump into this GPRC5D or FCRH5 receptors. We have done studies where people who have received either CAR-T or belentimab or prior bispecifics, when they relapse, they get treated with a different bispecific that is BCMA, and we're seeing responses that range between 38 and 45%, which suggests that there is still a potential benefit of another BCMA that could be a bridge to the next therapy. The responses are not as great as you could see, and the duration of the responses is not as long as if you were getting a BCMA for the first time, but it could help as a bridge to the next therapy. Now, in terms of these non-BCMA targets, I did want to just show, for example, the telketamab dosing. It's been studied on a weekly basis. It's been studied every two weeks, and this was initially started IV, and now it's being done subcutaneously. Cevostimab is being given every three weeks intravenously, and it does have two step-ups, week one, week two, and then the full dose week three. The telketamab is also using two step-ups, and it's all given within three days of step-up. So you get a dose, and then you get a step-up three days later, and then you get the full dose three days after that. So because of these step-ups, patients at the moment have to be hospitalized to monitor for toxicities, specifically CRS. Now, there are other modalities that are not your typical BCMA by specific, and your alternative targets like cevostimab and telketamab. We have now what we call trispecific T cell engagers, or trispecific immunotherapy, I should say. The reason why I say that is there's one trispecific that is BCMA-directed, so it'll bind to BCMA on the myeloma cell. It'll bind to the T cell at the CD3 protein, but it will also bind to albumin, and by binding to albumin, it hopefully is increasing the half-life of this by specific, so that you don't have to be getting it so frequently, and hopefully space out the doses, that frequency of the dosing. The other trispecific that we have, this BCMA CD16 NK G2D, it's actually not targeting T cells, it targets NK cells. And the rationale for this is NK cells are a little bit cleaner in the work that they do, so it causes less spillage of toxins, and it causes less CRS. And currently, there are a couple of NK trispecific agents that are being studied, which we will be getting some information in the next year. At the moment, I'm not deliberately to discuss the data, because it just opened late last year, but we are at the moment evaluating patients and trying to find the right dose for these agents. So an example of the trispecific that is binding to albumin, the design is still trying to incorporate what's the right dose, what's the right frequency, at the moment it's given IV, but very likely in the near future it's going to be tested as a subcutaneous study. Interestingly, this trispecific that binds to albumin is providing some toxicities that we haven't seen in other myeloma by specific agents, or CAR T, and that's an increase in liver incense. And this is just transient, it only happens with the first dose, and there is no complications after that. Now, in terms of toxicities, before I finish this talk, we do see some other unique toxicities with some of these by-specifics. So I mentioned that BCMA tends to increase infections in 30% of patients with some of these by-specifics. It does increase the risk of COVID complications. And then when we talk about TelketaMAP, which targets GPRC5D, it doesn't cause so much high risk of infections or increase the risk of COVID complications, but it does cause some changes in the nail beds, causes the nails to chip and flake and fall off, and then they will regrow. And it also causes changes in taste. So this is a unique side effect that we're seeing with TelketaMAP. And then with semostimap, we're not seeing these types of toxicities, but we are seeing drops in platelets. So in summary, by-specific antibody therapy really is changing our expectations of therapy in heavily pretreated patients. And the response rates that we're seeing that range between 60 and 85% and those who have received five or more lines of therapy, it's just never heard of outside of CAR T therapy. It's a very viable form of immunotherapy. It has unique qualities over CAR T because this you can start right off the bat. You don't have to be manufacturing your T cells and waiting four to six weeks and then finding out if the cells were viable or not, and you can get it. But it also has some disadvantages where you have to be getting it more frequently, whereas CAR T, you just get it once and you're done. There are multiple targets for by-specifics BCMA, T-PRC5D, FZRIH5, and there are some other ones that are being evaluated at the moment. The dosing schema, there's some that are given weekly, some that are given every other week, some that are given every three weeks, and there's push to try to space out the frequency to make it less frequent, especially after a certain amount of cycles. That's a transition to maintenance therapy so that patients don't have to be attached to therapy and clinic visits for infusions so frequently, especially if they have achieved their admission. But the thing that we do need to keep in mind is that all by-specifics are still in clinical trials. Some of them we're still finding the dose, others we have the dose, but we need more patients so that we can find enough data for safety and toxicities. So none of them have been NIFT data approved, but we do expect to have the first one approved later this year, hopefully. If it's not in August, it'll be early September, so stay tuned for that. And with that, I want to finish the slide presentation and open it up for questions. Great, that was amazing. Thank you so much for that presentation. Again, that's exactly what I was looking for when I asked if you could speak today, so it's really great to hear and really great to learn, I think, for me, especially understanding the differences between all of them, why there's a need for so many of them, and how they're going to be useful in the future of myeloma. It's exciting. I'd like to remind our participants that they're welcome to write their questions into the questions and answer section. It says Q&A. It's a little icon at the bottom. If you click on that and then type in your question, we will be able to see them and moderate them. I'm going to start with a couple questions of my own as we continue to get questions in, Dr. Rodriguez. One of my first questions is, who is your ideal candidate for bispecifics? Who is the patient that walks into your office and you say, you know what, I think you would be a great candidate for this clinical trial because? That's actually an excellent question and everybody keeps asking, criteria or bispecific? Which one should we get? And it's different populations. I would say, first of all, bispecifics have to be in a clinical trial because none of them are approved yet. Hopefully we'll get one later this year. But the nice thing about bispecifics is that it's readily available. We don't need to wait the four to six weeks to get the CAR-T generated. So somebody who has myeloma that's progressing pretty quickly and cannot wait those four to six weeks, I think bispecifics would be great. Another population of patients that I think would benefit from bispecifics is somebody who cannot take a two-month break to get the CAR-T and recover from that and then go back to work or their daily lives, but can afford to go to the infusion every other week or every three weeks, then that would be a perfect case for a bispecific. So they can continue doing their job or family responsibilities or whatever their life priorities are. I think that's a are at the moment. Great. Thank you so much. Another question. It's more readily available, but it's also almost a forever treatment until the disease progresses. What risks do you see with that or what? I mean, obviously it might be an inconvenience compared to the one and done CAR-T, but are there any risks? I mean, so that's, for example, for BCMA bispecifics, we are a bit concerned about immune suppression and the risk of infections. And if we give it continuously forever, will we be seeing infections that we were not seeing before? And we are seeing some viral reactivations like CMV reactivation or EBV, which we had not been seeing with other therapies for myeloma. We would normally associate it with people getting an allergenic transplant. And because of things like this, and also the fact that we don't want to have a patient tied up on a weekly basis until for the rest of their lives or every other week for the rest of their lives, we want them to, if they achieve a remission, to enjoy life and not think that, not be attached to an infusion center. We are currently doing studies and trying to set up a finite period of therapy. And there are some studies that are doing two year and stop there. We are proposing some to the drug companies to do studies that are going to give a finite period of time, whether it be two years, three years, or if you achieve remission, continue for a certain amount of time and then stop. But that's something that we're aware that the drugs all have side effects, all have long-term potential complications, and we don't know them yet because these drugs are so new to us. But we are trying to be ahead of the game and trying to see if we can, if it's safe to stop it at some point when we've achieved the desired response and have the patient continue to be off therapy with the potential of giving the therapy again, if we see that the disease comes back in the future. Right. Because as you were saying before, just because they have even one BCMA by specific doesn't mean they can't receive another one. Is that true? That's correct. So a lot of the clinical trials right now do not allow a prior BCMA by specific, if you're going to get a BCMA by specific, but there are some that do. And we actually have used it in some patients and we are seeing that there are responding to it. And we actually, so that opens the door to say, okay, if you fail one, we can try to switch it to a different one if we don't have any other options. But it also opens the door to, okay, if we stop the treatments now because you've achieved a remission and four years later, you relapse, we could possibly give you either the same by specific or a different by specific, or just a completely different therapy altogether if you don't want to use the same therapy. Yeah, yeah, that's fascinating, isn't it? I don't know. It's just leagues ahead of where we were just a short time ago. Yes. In terms of treatment. A little bit more about BCMA fatigue, you know, I understand that they might be successful with a different BCMA treatment, but after targeting BCMA so many times, I imagine maybe there's fatigue on those cells. I don't know. Does, let's, I know you can't talk about specifics of the trial, but generally, do you see that NK targeting cells would, you know, switching to a different cell target would help this? So this BCMA fatigue is a concern and something that's discussed a lot when we're giving BCMA by specifics or CAR T's because we think that with time, the myeloma cells are no longer going to express PCMA and therefore they're not going to be responsive anymore to either the CAR T's or to the by specifics. But we're, we are seeing that when we switched into a different by specific BCMA, there's some response up to 40%. It's not this impressive 60 to 80%, but there's some response. Well, that's even more than 30%, which is what FDA has done anyway. So there is some component there, but I would say it's not as horrible as we were initially thinking. We still need to learn that. Now, in terms of the NK cells, the idea of the NK cells is not so much for the BCMA fatigue, but it's more to make, to reduce the side effects, especially the CRS. The idea we expect that with NK cell therapy, we're not going to have any CRS, or if there is any CRS, it's going to be very minimal. And that's the rationale for using NK cells rather than T cells, because we're still going to be using the BCMA. Well, some of the studies that we have are targeting BCMA, so we could still have the same problems with, that we're seeing with the current by specifics. Yeah, thank you. One of the other questions that I see in here, and also one question that I shared, do you see by specifics as becoming eventual induction therapies, or even moving forward into smoldering myeloma in clinical trials? That's a big question. Yes. We are doing studies right now in patients with one to three parlance of therapy, and we actually just made some proposals for newly diagnosed patients that are transplant ineligible, or patients who don't respond properly to transplant. So I think immunotherapy in general will probably move up front, because the immune cells are healthier, so it would make more sense that the by specifics are going to be more effective. We don't know yet. So this is speculation. But we are doing studies doing it earlier on. Obviously, the FDA has us to wait in a step-by-step approach. They don't want us to jump the gun and give them a newly diagnosed without first making sure that it's safe in the relapse setting. But yes, I do think that we're going to see it. And there is a very strong probability that we might also see it in high-risk smoldering myeloma patients. Yes. Interesting. Again, just exciting to see the hope that is in the myeloma treatment field. Okay, we had an attendee ask, why are the labeling systems so complicated? Why can't all the antigens on cancer cells and all antibodies be labeled in ways that immediately reveal a common function? I wish I knew the answer to that. But the same way we like to use weird names for that, we have drug companies like to use weird names for the by specifics and other drugs. So that I don't know how to, I don't have an answer for that. If we could only all get along and understand each other. Jackie is wondering if a by specific could be used as a bridge therapy for Garty while they're waiting for that four to six week period. That is an excellent question. And we were actually just discussing that a couple of weeks ago. So we had the international myeloma working group meeting in Vienna a few weeks ago, and we were precisely talking about that. Carty therapy is showing to be very effective as well as a good option for immunotherapy, but it has its setbacks at the moment in terms of having to wait four to six weeks and have to give some bridging therapy during that time if the disease is out of control. And there are occasions where after those four to six weeks, the we come up with an answer and say, Oh, the car tease did not work. So we can't give them to you. So we have thought of using a by specific as a bridging therapy. And if for some reason the set the currenty cells don't pan out to be functional, and we cannot use them, then we can just continue that by specifics. But that's something that we're just discussing. There are no studies right now doing that. But we are planning on trying to use them as a potential study in the near future. Interesting. A couple patients have questions regarding MRD results of people that were in those clinical trials. To your knowledge, was MRD tested or used or in, you know, used as an indicator in any way during those trials? Yes, MRD was used. There's different MRD tests. There's MRD by flow and there's MRD by next generation sequencing. And there's different sensitivities of the MRD 10 to the minus five and 10 to the minus six. And all of the by specific clinical trials are evaluating MRD. And we are seeing that a good number of the patients who do achieve a complete response are also achieving MRD negativity. And they're sustaining the ones that sustain MRD negativity are the ones that tend to do the best. So that's, hopefully we'll be hearing specific data of some of these studies at ASH or at the IMS meeting later this year. And to your knowledge, was that NGS, next generation sequencing? It's next generation sequencing what we're using for them for these by specific studies. That's great. And for those who don't know, that is, to my knowledge, the most sensitive one at the moment that we have. Is that true, Dr. Rodriguez? Yes, it's the most, I would say it's the FDA approved. Awesome. Okay. And then one other question as a follow-up to that, even if they are MRD negative, are they still observed once the trial has ended? Or is it kind of like, you're on your own now, have fun with your oncologist. No, you're on your own. No, that's never going to be the case in the study. So even if you finish treatment, and I just want to emphasize that the majority of the studies right now are treatment until progression or treatment until you don't tolerate it anymore. But the ones that do have a finite time point of treatment, they will continue to monitor the patients after they finish treatment to look for toxicities, look for relapse and other potential side effects long term. Great. Are you aware of the trials accepting patients out of the ordinary extramedullary disease, non-secretory, PCL patients? Right now, I do not think there's any study that's taking plasma cell leukemias. We actually did discuss that last month, and there is a study that we're trying to generate to focus on plasma cell leukemias and more aggressive patients. In terms of extramedullary disease, the majority, all of the studies do accept extramedullary disease. If you have a measurable disease, either in the blood or in the urine, whether it be by M-SPAC or free light chains, there's only a very small amount of studies that are allowing non-secretory, which is the biggest show. It is, yeah. We actually have a non-secretory chapter where a group of people meet monthly. But there are a couple of life specifics that do allow non-secretory, so I don't want you guys to feel disappointed. We're hopeful. Okay. Jeff was wondering, one of the non-BCMA targets was Kappa-LC. He said he has IGGA, Kappa-Light Chain Myeloma, so please explain how Kappa-LC is a target. So we are, like I mentioned, right now there's so many bi-specifics that are targeting BCMA, and all the drug companies are trying to fight to see which one's the best and which one works, and which one works, because we're seeing such good responses. But it's so saturated, and we're seeing that it's not curative, so we're looking at other targets. GPSC5D, Taukema, is the next most common target. S-URIH5 or Sevastomab is the third most common. And then we're looking at other different surface proteins. And one, so CD19, SLAMF7, things like that. Light chains, unfortunately, are not on the surface of the myeloma cell. They tend to be inside of the cell, inside of the cytoplasm. But we are still trying to find ways of using that as a target to direct therapy. It just gets a little bit trickier on how to get it to, for us to be able to identify it, attach to it, or bind to it. But it is something that is being evaluated. Well, even as you were speaking, you know, I'm trying to think of how tiny a cell is, and then how does one go about creating an antibody? It's just fascinating. The technology and science that goes on, and I appreciate the sacrifice and time that you and your team are dedicating to this. It's so exciting and so hopeful. It is. It's so interesting to see how we are trying to use the same body function and mimic it outside and taking it to our advantage to help fight myeloma cells and other cancers. I think that's a very astute way of taking advantage of the biology of the body. Yeah, definitely. Bonnie has a question. She said, I understand you can go from CAR T to bispecifics without loss of BCMA expression, but not in reverse. Can you explain why there's not as much loss of BCMA expression with CARs as they expand? So that question is a little bit misleading because we have had patients who have received CAR T and then got in a bispecific, and the opposite as well. We have had patients who have received bispecific and now are getting CAR T. It's on the clinical trial, and we're trying to see, we're trying to answer a lot of questions that we don't know. One of them is, is getting a bispecific prior to a CAR T going to make the CAR T less functional down the line? Is there a washout period that we need to have between a bispecific and a CAR T and vice versa? So these are questions that we're still trying to identify, and the study about could we use a bispecific as a bridge to CAR T is also going to help us answer that question. But we have used it in both senses for both ways. It's a hopeful future, but still a lot to learn. That's what I've got. Okay, and last question here, and then I have one more question for you. What bispecifics are not associated significantly with taste problems? So taste, the one that's associated with changes with taste, or we call it dyskusea, is talcetumab, because that GPRC5D is found in the base of the tongue and thought to be also possibly in saliva glands. So we have noticed that patients who are receiving this therapy do have some change in taste, and as we space out the drug or reduce the drug, we do see some improvement in the symptoms. We don't see these taste changes with the other ones as much, but a lot of you who have had a transplant or who have had a lot of chemotherapy might be very aware that your mouths are a little bit drier and some things don't taste as well. And that just has to do with the fact that all chemotherapy tends to destroy cells that divide fast, and saliva glands tend to be a bystander at times, especially with a transplant, and that can affect taste to some degree, and it can also lead to being more prone to cavities or change of items. So it's always important to see a dentist twice a year and get fluoride at least once a year. That's a little plug. I love it. Okay, my question, well kind of statement slash question. I mean, we talked about this, that normal approvals usually are sitting at 30% success rate when the FDA says, sure, that's great, you know, let's pass it on. We're sitting here at like 80%, I was seeing, and that's such a hopeful place to be. I know I've said that so many times during this meeting, but to see the progress that's being made in the myeloma field is amazing to me. You who have been in the myeloma field much longer than I have, how hopeful are you for the future? And what makes you excited about the future of myeloma treatment? Well, I'm excited that what I learned when I was in training is no longer the case, and it's all obsolete. It is very impressive to see this degree of responses. It has us all very excited. And it's also making us a little bit more greedy in terms of new drugs, we're expecting better results, which is always good for patients. We do need to keep an eye on side effects and toxicities, especially because we're seeing that these new agents are actually controlling the disease for a longer period of time, patients are living for a much longer period of time. So now we do need to pay attention to those side effects. Before, people were not living long enough to see the side effects and toxicities of drugs. But now that people are living this long, we are seeing complications from other therapies that we used in the past and from current therapies. So we need to be very mindful that the drugs that we're using, we're using the right dose, the right frequency and the right duration. And the government right now is actually doing a very interesting initiative called Project Optimus, which is, it's a headache, I have to say, but at the same time, it's looking at the patient's best interest. And every time we're submitting a new drug for FDA approval, they're coming back to us and saying, is that the lowest dose you can give that therapeutic? Is that the best lowest dose? And if not, what try a lower dose? And they're asking us to try, even though we're submitting information at the certain dose, they're asking us to try, okay, now give me data at a lower dose to see if it's as effective and it's safer. So those are things that I think we need to look at in the future, safety, toxicity, duration of therapy, so that to make sure that we're not treating patients forever and ever and ever. But I also, even though I'm very excited about immunotherapy and how effective this is, I don't want us to just get siloed with immunotherapy and ignore all of the other types of therapies because they are also effective. And we will, at some point, maybe need to combine certain drugs or use drugs whenever the disease comes back. So we have so much, still so much to try. I feel like currently the current CAR-Ts and the bispecifics that we have in clinical trials that I currently approved are just like the early generations, like when the IMITs started to be used in myeloma and we had the linoleumide and we all went crazy for it. Well, I was not even doing this yet, but the linoleumide was the roar because it was having such good responses in myeloma, but it had a lot of toxicities. And now then we had linoleumide and then we have pomalidomide and now we have the celamides. So I feel like the same thing is going to happen with bispecifics and CAR-Ts and other immunotherapies. We're just seeing the beginning of it. How exciting. And I love that you mentioned too the things that we need to watch out for. I'm excited that we're at a point where it's becoming more chronic. Well, I'm not excited that it's a chronic disease. That's not what I'm trying to say, but I'm excited that we're able to shift our focus on quality of life instead of immediate survival. Does that make sense? Yeah, it's becoming a marathon. And I can say that we're having about 15% of patients that have this sustained remissions for life that we can say cure in those patients. So hopefully that percentage will increase. Yeah, definitely. Well, thank you so much, Dr. Rodriguez, for your preparation and your time tonight. I really appreciate just learning from you. Thank you for being here. It's been a pleasure. I'll finish with a couple of announcements. You can join us in September. We're going to be talking about myeloma and autoimmune diseases. So what percentage of myeloma patients have autoimmune diseases? What knowledge exists about these cases and whether these cases can be characterized at the cell level, prognosis, indicated therapies, etc. And the date and time to be announced will be announced shortly. You may be interested in other myeloma crowd community events we have upcoming on the 28th at 630 p.m. Eastern is our Florida myeloma community chapter. We're going to be talking about the mental journey of myeloma with Peter Riefke's Thursday, the 29th. It says 430 p.m. Eastern, but I think it's 630 p.m. Eastern. So I'll make sure to change that before we publish this. At 630 p.m. Eastern, time zones are super fun. Is our nutrition and wellness for myeloma chapter. It's a live screening of the Forks that Were Nice documentary. So we're going to watch that documentary together. And then we have a dietician and different medical professionals that are going to be speaking, going to be answering our questions after we've watched that documentary together. The link to sign up for those events and even more events I haven't mentioned today is found at the bottom of this slide and will be sent out in the follow-up email within 48 hours of the event's conclusion. Another thank you to our sponsors, Bitzel Meyers Squibb, GSK, Genentech, Janssen Oncology, and Avvy. And thank you so much for helping us build this myeloma community. I appreciate you. Hope you have a great rest of your day. Thanks, y'all. Have a good night.