I am just delighted to be here. Jenny, thank you so much for bringing us all together. I love doing this. I loved our last meeting and missed being in person, and I love learning from my brilliant colleagues. You are just so lucky to be here learning from the best, the best doctors that have just gone before me. And I just can't help but put a plug in for your website that you were just showing us and entering all your data. You know, we do not have favorite patients, but if you happen to bring all that data into one of your appointments, you would surely be a favorite patient. I mean, what a remarkable thing that you have done there, both for patients and for us who really want to make a difference in the world, and you're helping us do that. So thank you, Jenny. You have learned, we've kind of touched on so many different phases of myeloma. We had a really great breakout session talking about newly diagnosed myeloma, and it's just so important to get the ABCs done, right, before we get to the X, Ys and Zs. And we've kind of had a chance to learn so much already from Dr. Patel about CAR-T and some of the nuances and complexities of that. And I'm going to spend a little bit of time here talking about bispecifics, because there's been so much excitement about different new exciting treatments like CAR-T just to have another class of drugs become available. So bispecific antibodies, it's going to sound, you're going to hear some overlap with the CAR-Ts, but there are differences that are worthwhile understanding. Well, why do we need all these drugs? You know, I always talk to my patients to say, my goal is to kick the can down the road as long as I can, right? We hope that some point we are going to cure this thing, right? But in the meantime, let's figure out how we can keep a lid on it until the next newest and greatest comes out, because that's truly what has been happening that has allowed people with myeloma to just keep living. New drugs keep kicking the can down the road where patients are getting into remission, staying in remission, until the next new drug becomes available. And I love curves like this, graphs like this, which sometimes people start to glaze over, but I think the relevance of it is to say it's working. People are living longer because these drugs are so effective. And even this is still already, what, five years out of date. You can see that as that dotted line is the highest, the higher it goes, the longer people are living. And all these drugs are making a difference. The thing of it is that we have not gotten to that cure yet. And so here we go now to say, what is next? What is that next newest and greatest? And so CAR-T cells and bispecific antibodies both represent kind of two different drug classes that we call T cell redirectors. Just like Dr. Patel so nicely explained to you, we are asking the question to say, how can we take your immune system and fight your myeloma? Basic, that is it. Obviously there's like a kind of few logistics associated with it, and especially with CAR-T. Remember you heard from Dr. Patel, this requires a logistics of removing from your bloodstream your immune system cells, sending them off to a company where they can train them, re-engineer them, teach them how to fight those flags. I call them tags on the myeloma cells. That's a wonderful opportunity. Their treatments are fantastic. It is hard to come by. And reality is that sometimes patients cannot have access to them. Your local cancer center may not be designated as a cancer center that can deliver them. Your myeloma may be growing too quickly where we need to have something right now that we can treat you with. And bispecific antibodies may help us to kind of check some of those boxes. So bispecific antibodies are a medicine that your doctor, assuming they've kind of gone through some of the training with it, may be able to write the prescription for. And you could start tomorrow. Tomorrow insurance companies is what we're looking for. Tomorrow. And it's the same concept though as CAR-Ts are. I usually call them as a way that we have kind of a double-headed magnet, which is attaching to your T cell immune system, attaching the other end to your myeloma cell, and bringing them together to say, hey, this is the bad guy, get fighting. I heard handcuffs, is that yours, Dr. Patel? I like that. Handcuff the immune system, handcuff the myeloma, bring them together and say, you two are the partners that are supposed to fight this war. So bispecifics do the same thing as opposed to taking the T cells in and out, putting them in. Bispecific is a drug. It is a drug that basically connects the two together to say fight. And so it is a drug that is administered not unlike some of the other medicines you're on. You're getting daratumumab or Velcade, these medicines that you may have been receiving kind of on a schedule. Same idea with the bispecifics. So it's something that your doctor can write a prescription for. You continue to start taking, you take and continue to take as long as it's working. There are currently three different bispecifics that are approved in the US by the FDA. Two of them are fighting the same tag as the two CAR T cells that are available. That's that BCMA tag. The tags we're talking about just for clarification say, hey, this is me, I'm the bad guy. So if we can say that little tag is a way for the immune system to identify the bad guy, then it knows who to go fight. And so BCMA is one of those tags. The other tag is that GPRC5D, our alphabet soup, is the second tag that these bispecifics can say, all right, I'm gonna stick to that tag and stick to the immune system and bring those two together. So there's three that have been approved for bispecifics. And here are the tags, right? The goal when we're thinking about what the tags are, again, myeloma cell has these tags that identify it as the bad guy. When we look for these tags, we're looking for something in the myeloma cell that's maybe only on the myeloma cell. What we don't want is these drugs to go find the same tag somewhere else in your body and cause side effects by connecting to that one, for example, as best as we can. We're trying to identify those tags that are solely on the myeloma cell so that we can minimize side effects, maximize myeloma cell killing. And so these are three particular ones, the ones in red that have been identified as three great tags that we can look for as ways to start killing the myeloma cell. So we kind of talked about how this works with a handcuff. So literally it's the medicine is in the middle. You can see that it has a green side and a blue side. And so on the one hand, it attaches to that T cell, that's your immune system cell that does the fighting. And on the other hand, it attaches to the myeloma cell. And when it does that, it tells the T cells to get working, get to work, and they start releasing all these, let's call them chemicals, these cytokines we've talked about in different ways, different weapons that they can say immune system, rev up your engines, it's time to start fighting. And there's a couple of different ways we can do this. So we have on the blue there, you can see this is the tag, the antigen is the name we call tag, that is the cell surface tag, that is the antigen, what lives on the outside of the myeloma surface or the cell that then the drug can attach to. And you can see on the right-hand side there, this is such an important, exciting kind of time for the development of bispecifics. Everyone's kind of rushing to the finish line with these big pharmaceutical companies saying, I have the next newest and greatest. And BCMA was the one that was kind of the front runner in the beginning, and there are two that are approved for the FDA now and many more that are being evaluated, trying to see how they can improve upon those successes of what the two that have been approved already in terms of how can we improve the myeloma cell killing, how can we make it more convenient. Originally, a lot of the drugs were designed to be infusional, where you go, you get an IV put in, you'd get an infusion of it. Now we're looking at subcutaneous injections, which certainly makes it easier. Go in, get a shot, get out of there. Then looking to see, well, how often do we have to do it? The first one that was approved to Clistimab was designed to be given once per week, as long as it works. And we hope it works a long time, but that's a lot of weekly appointments, right? And so different approaches here, trying to see, how can we make these drugs be more effective, more convenient, and less toxic? And here they are, right? This is an example of some of these different things, looking at the BCMAs, looking at the different schedules. I only put this up here not to make you glaze over, but to say, there's a lot coming. We have three now that are available, but several more that are being evaluated in clinical trials now, ways that we can try and improve upon some of these successes. But I kind of point your attention to the top where you can see the ORR. So in fancy doctor language, this is our overall response rates, which basically means, for how what percentage of people does this work, right? What work means, means you have this much myeloma and it decreases. There are various ways that we can measure the decrease that occurs. As Dr. Patel was saying, our bar was very low once upon a time. The FDA would approve drugs if they worked 30% of the time, for 30% of people or 20% of people. Now you have CAR-Ts where they're working 80, 90, 100% of the time. So by specifics, kind of across the board, more or less work for about 60 to 70% of people. I mean that when you take all comers getting treated, you're gonna see improvements in 60 to 70%. There's some variations in that, but there's side effects that come with each of them. And with each tag comes different potential side effects that we'll touch on a little bit. But I think if the bar was 20 to 30%, we're talking 60 to 70%, we're feeling pretty darn good about these drugs and how effective they can be. They've all been studied in patients just like Dr. Patel said, was that they've been studying patients who have had many different treatments, maybe not many remaining options. And so this is a really interesting example of how the drug that we're talking about, the non-clinical trial, gives access, right? Gives access to new drugs that can be effective just to see that these patients with no other options are having really remarkable responses. So let's think a little bit about how we can make by specifics better, right? By specifics are so exciting because they work, but there are challenges that we still need to overcome with some of these things. As I mentioned, we'll go through a little bit about toxicity, which means side effects, right? By specifics are infections. And on a very simplistic level, if you think about how the drugs are killing off all the plasma cells, remember those are the cancerous myeloma cells, they're also compromising the innocent bystander, good plasma cells, so all of your immune system, forget your T cells, which are all going to work and fight the bad guy, all of your immune system cells are being suppressed or are busy doing other things. And for all those reasons, patients can develop quite a bit in the way of infection. We need to figure out how we can improve upon the risks, prevent those infections, and allow patients to continue to benefit from taking the treatment. There are a lot of logistics. You heard about for CAR-T, you have to go in the hospital for a few days, come out of the hospital for a few days, and we have to make sure we understand how to manage that cytokine release syndrome that we were hearing about. When that immune system starts revving its engines and it starts going to work to fight the bad guys, it can cause fevers, it can cause changes in your blood pressure, in your heart rate, and we want to make sure that we have an infrastructure, whether inpatient, in the hospital, or outpatient, to take care of you when that happens. And that can be hard for the hospital systems to set up and certainly inconvenient for you when we're trying to tell you to go to an emergency room in the middle of the night or whatever that may be. So a lot of the academic or big myeloma centers are still trying to figure out how to do it carefully and logistically, which means that a lot of our community oncologists are relying on us to still do these medications. And many of the local oncologists have not been in a position where they're able to administer these drugs, at least in the beginning. Other questions that come up is to say, well, you just told me you have three different drugs. Which one do I use first? Do I have CAR T or do I do Bi-Specific first? Lots of questions about what order to do these in. Is there a way that would make more sense scientifically? Is there a way that may be more logistically easier? And then what happens when they run out of juice? What do we do next? Why do they run out of juice? Why do they stop working? So we have lots of questions that we're still trying to look at to figure out how to answer. I don't wanna dwell on this too much because you've heard a lot about it a lot, but just like with CAR T, Bi-Specifics have two main side effects when you're beginning the treatment. It's important to recognize, just like CAR T, it's really in the first, let's say, seven days, maybe 10 days or so that you're at risk for having these particular side effects. So on the one hand, there's the cytokine release syndrome. Remember, this is where we said the immune system is going to battle. They are fighting those myeloma cells, and when they do that, it can manifest itself as a bit of a reaction in your body. That reaction can range from most commonly mild to much more rarely, but can happen to more severe. It can look like just a fever. Just a fever meaning it's a fever which can be uncomfortable, but we can manage it. But in more advanced stages or grades or severity of it, some patients need oxygen. Some people need to be hydrated because their blood pressure's low. This is why sometimes we do this in the hospital or at least need to have a plan to how to get people in the hospital if these reactions happen. When this happens, we have a whole kind of protocol in place to say if you have a fever, it's probably because of the treatment, but with your immune system presumably being weak, we can never rule out infections. So as part of a fever, we will do testing for infections, bloodstream infections, urinary tract infections, pneumonia, chest x-rays. We have a whole protocol in place to look for it. But probably it's the reaction to the medicine that you're doing. We tolerate a little bit of a reaction, but if it's persistent or it's progressing or getting more severe, as you heard, we have tocilizumab, which is a nice medicine to kind of just put a lid on it. Just say, hey, thanks for doing all this work. Can you slow it down a little bit without compromising the effectiveness of it? So that's cytokine release syndrome. The other side is ICANs. This is what I sometimes explain to patients to say this is almost like that same reaction that's happening, but as scary as it sounds in your brain, right? So what's happening, we don't really understand this. It's the same kind of allergic reaction. It can manifest itself in a variety of ways. It's as easy as a headache. This is a very kind of, let's say, less common complication or side effect of this, but also is limited to a specific duration. Again, CAR-T or bispecifics. We have ways where we can check on you. We can have you write. We can ask you a million times what day it is, what year is it, who's the president? Do all these questions basically assess how well you're thinking? And we have an antidote for that as well. So both of these things are temporary. Very, very rarely would you have any long-lasting kind of effects of this, but it's something that we all have to be aware of and be ready to intervene on. So when we're thinking about these three specific medications that are approved, there's two of them, as I mentioned, that are targeting BCMA as the tag. There's the third one that is targeting GPRC5D. They're all administered on slightly different schedules. Where in the beginning, we do baby dose at first, so we hope you have baby reaction, right? After the baby dose, a couple of days later, we'll give you maybe a medium dose and see maybe at that point, your body's like, yep, I've seen this, I know, not gonna react this time. I see what you're doing here. Before we get to the kind of main event, right? So little dose, medium dose, main dose is a way to kind of get your body used to it. And during that, what we call step-up schedule is a way that we can watch for those side effects that I just mentioned on, be prepared to intervene if we need to. But once you've gotten through this initial kind of week of the treatment, the likelihood of you developing those side effects moving forward is pretty darn low. Different drugs have different schedules. Some of them are given weekly. The FDA for Ticlistimab and for Telketimab both have weekly options. Elrinatumab starts off weekly and then can be changed to every two weeks. But if they all start off weekly, everyone, the next question everyone asks me is, do I have to stay on it weekly? So there's lots of interest now to say, let's start it off at every two weeks. Telketimab actually has an approval. You can say you can do it once a week or every two weeks and continue on that way for a while before you start spreading it out. Kind of like many of us are familiar with with daratumumab, right? It starts off once a week and then it goes to every two weeks and then eventually get to once a month and it feels like you're in cruise, kind of cruise control. So stay tuned for this. We know that this is how we'll start. We hope that we're gonna see that we're able to space things out so patients can stay on these treatments for the longer haul. Different ways to say, how can we prevent the rates of the reaction? So as you saw on the prior slides with some of the cytokine release syndrome and the ICANS, we have antidotes. We can stop it from happening. But why does it have to happen at all? Is there ways that maybe we can intervene and prevent it? And lots of different things out there saying, if we have these antidotes, why don't we just start with that and then give them medicines and see if we can prevent the CRS from happening at all. And so there's some initial treatments that are happening now and I think many of us are dabbling with it a little bit to say, let's give the antidote, then give the drug, make sure it doesn't compromise the effectiveness of the drug and prove what we think to be true is that we'll decrease the risk of you having reactions. And we're starting to see some of that. So that's certainly gonna make it easier for you to go through, to receive the medicine and have fewer side effects, for me to not have to figure out how to take care of you when you're at home and get you into the hospital for management of these treatments. So lots of exciting things here moving forward about how we're gonna help make the experience of getting these treatments easier. All right, so infections. We talked about CRS, we've talked about neurotoxicity. Let's talk about infections a little bit because we know that every patient with myeloma is at risk for getting infections. Why? Well, we can probably break it down into a couple of different groups. Let's talk about things that are related to the patient themselves. Age is just a number, but we do know as we age, maybe we're at more risk because we have other comorbidities or other issues. Maybe your kidneys don't work as well as they used to. Maybe you're on, who knows, whatever. Maybe you're just not as fit as you used to be. Your performance status that we talked about, these are factors that can contribute to your overall health. Well, let's talk about myeloma specific, right? Because we know that with a lot of myeloma, your body is not making all the immune system weapons that you need. It's too busy making myeloma and those don't work very well. So as your myeloma is there, present potentially growing, we know that your immune system levels are not at the same capacity that they normally are. And then, by the way, we're giving you treatments for your myeloma, which are suppressing all the bad guy myeloma cells, but take all the innocent bystander, good plasma cells with it. So we're suppressing your normal immunity just the same. So between all of these factors, you're in a kind of perfect storm of putting patients at risk for infections between their underlying health, the myeloma itself, and the treatment. Well, why is it more than specific to bispecifics? Why is the infection risk so great? Well, again, we know that with patient-related issues, for example, we know BCMA, more so than probably other tags, when we're trying to kill the myeloma that way, seems to be affecting the immune system more than others. And whether that's because it's wiping out more of the immune system cells or wiping out more of the good guy immune system cells, hard to say, but this is one of the treatment phenomenon we can see where it's then compromising in immune systems. And then again, you have your myeloma, which has been, let's hope a decade or more, being beat down, right? Your immune system has just been beat down just as we try to keep the myeloma in check. And as we've done that with the myeloma, we have compromised the normal immune system just the same. And then as I'm using treatments with bispecifics, I'm saying, hey, immune system, keep working, keep working. They get tired. As they're getting tired, they can't do as good of a job as they used to to help not only kill the myeloma, but to protect your body from the big bad world as well. So lots of different reasons why patients gets infections specifically with bispecifics, but across the board with myeloma. So it comes to beg to say, well, if we know that these bispecifics are putting patients at greater risk for infections, is there anything we can do to tailor the bispecific treatment? And one of the things that have come out is to say, maybe less drug allows for a stronger immune system, meaning that if I keep hammering the myeloma, I'm also putting so much pressure on the immune system to say, go fight the myeloma, that I'm not letting it kind of get some gas back in its system, right? You wanna give the immune system an opportunity to do all the jobs it's supposed to, but if I keep pushing it and pushing it to do one job, it never has an opportunity to grow and stay strong. So maybe instead of doing treatments once a week, which no one wants to do anyways, what if we space things out a little bit and it allows your immune system to kind of have a chance to take a deep breath, right? Have a chance to do the job that it's supposed to, both against the myeloma and against the, against for the bad guys in your immune system anyhow. But all things being equal, until we figure that part out of it, we have to think about how we can prevent these for you. How can we make and keep you safe? So it's important that anybody who's getting these bi-specific treatments that you and your doctor are aware of the risks of infections and do the best we can to prevent. And within prevention includes, sometimes you take some extra pills, probably many people are familiar with acyclovir or something like it to help prevent shingles. We always say, please get your shingles vaccination. It does still mean you have to take the acyclovir as an example, because we don't think it's 100% gonna prevent it, but vaccination and any kind of antibiotic or antiviral medicine that we have available to us, we will use in order to help protect your immune system. Other things sometimes is that we know that patients trying to identify who may need more antibiotics or who may be more at risk for more severe infections with like fungal infections and things, we need to be able to say, you're at risk, we need to give you extra medications or extra antibiotics as an example. Hypogammaglobulinemia is the biggest word I think we say. What it is is that means your IgG levels are low, right? If we've talked in our newly diagnosed breakout session about what IgG is and how important it is as a weapon, an antibody in your system to help protect you from infections, well, between myeloma, between the treatments you're getting, that IgG number just kind of plummets. And we've historically been able to use something called IVIG, which are basically human antibodies that have been donated and pooled together and given to you as an infusion to basically help boost your immune system. We've in the past reserved that for people who've had recurrence infections and say, okay, yes, those have been bad enough, you need to boost your immunity. Now with Bispecifics, we're saying, I think everybody needs this for prevention. So we've started being very much more proactive with giving IVIG or these IgG infusions sooner rather than later to try and prevent infections. So I think takeaway message is that we have different things that we can do to look for infections, prevent infections, but it's gonna take a kind of heightened awareness on all of our parts because we know this is such a great risk with the Bispecifics. I wanted to show off one of my patient's hands. He's like to be a hand model. He gave me permission to show you and it's probably just one example, but I wanted to show you that Telketomab is one of the new Bispecifics that's available and that tag GPRC5 is really nicely one of those myeloma tags, but this is one of the ones that is found on other parts of the body as well. And although this Telketomab seems to have lower infection risk, when you find the other tag, the immune system fights it and they know that it's on skin, it can be on nails, it can be on kind of your taste buds, let's say it, or your tongue, for example. And so we've seen that with patients that are getting Telketomab, we can see skin changes. Maybe not as clearly, but you can see his nails are kind of cracked, his skin can have little kind of abrasions to it. A lot of people will get peeling of their hands, the palms of their hands or the soles of their feet. We have different kind of techniques and strategies to just super moisturizing hands and trying different things to help with the taste, but I'd say that those are the two greatest side effects that we see with Telketomab, the GPRC5D Bispecific. And I think there's more that we can learn about how to prevent the taste changes because that's obviously very relevant to quality of life if you can't enjoy your chocolate or whatever it is. But it has definitely been a new drug with a new side effect that we're starting to learn about. And so as part of this in our remaining minutes, I wanna touch on just to say, all right, well, I've heard about CAR-T's, I've heard about Bispecifics, I've heard about lots of different Bispecifics. What is the best order to do this in and which one should I do first and which do I do last and can I do similar drugs back to back? And if you're asking these questions, you're asking all the right questions. We don't have a ton of answers yet, but we're starting to get there. And so brilliant minds like Dr. Patel and others are trying to look at these questions and trying to look back and say, what have other patients done in the past to help us get a sense of what may be helpful in the future? And some of the data that's looking out to say is, if you're trying to fight the same tag with successive treatments, it may not work as well as if it's the first time you've seen it. So as examples, if you had a Bispecific BCMA, fighting BCMA and then you went to CAR-T, that may not be just as good. You're kind of trying to hit the same thing at the same time and expect a different result, right? So if you've already taken that approach, you may wanna try a different approach. But maybe if we did it the opposite direction, you did CAR-T first and then do Bispecific second, maybe you've enjoyed a couple of years after your CAR-T without having a relapse and your immune system is back and ready to go and that tag is back and ready to be fought again. So there's a lot of interesting information coming out to help us understand which is the right sequence of how to attack these myeloma cells. And when we're thinking about, I'm gonna kind of skip through some of these, kind of, when we're thinking about real world life, I can stand up here and say, all right, this is what we think you should do. You should do CAR-T first, you should do a Bispecific next. The reality is this is not a realistic approach for a lot of people. We want to in an ideal state be able to say, do it like this, but there are many places that still cannot get a CAR-T. There are hospitals that do not have the capability of doing it, there are CAR-Ts that are taking too long to manufacture. We can only do two to four patients per month and lots of people are waiting for CAR-Ts. And so it becomes a very frustrating process for all of us and many other patients end up having to try alternative standards of care that may not be as strong. And when we're looking at patients who have undergone kind of one Bispecific and then going to another Bispecific, though it does work. It does work that you could do them back to back. So it offers us opportunities to say, let's try one Bispecific and use it for as long as it works, long as it lasts, but if it runs out of juice, can we go to the next Bispecific? And the answer looks like yes. It looks like it's still gonna work. Maybe not as perfectly as if you've never had a Bispecific before, but it does give us opportunities now to say we have all these drugs, let's use them back to back. Same thing here, these are just a handful of different studies. I'm gonna bore everybody after lunch with lots of tables. I think the answer to say here is that yes, we can do it. And so when we're thinking about this across the board, I think it's important to recognize now, Bispecifics are such a new, exciting part of our arsenal. We have enjoyed CAR-T, we've seen the successes of it over the last many years, and now we have a newcomer to the table that's showing us that it works. It's way surpassing the bar that we had ever known in terms of how effective it is, but with new drugs come new side effects and new issues that we're all kinda trying to work through. Questions that remain about, just as I've been talking about, is which one do I do next, which one's there? And a lot of times the answer may be based on what your doctor has to offer you at the time. If you have the ability, the luxury to kind of seek out other opinions or other hospitals and see what they have taken, please consider participating in clinical trials. That's where the magic is. That's where you can get access to things where you may not be able to have access to them ordinarily because they're not approved. So lots of work that we're doing and lots of exciting things to come. And I think at some point we're gonna call this an embarrassment of riches, but we're gonna enjoy it for the meantime. So thank you so much for your attention. Thank you. Thank you. Thank you. Good luck.