Myeloma Immunotherapy Explained: Monoclonal Antibodies, CAR T, Bispecifics & Trispecifics

Dr. Joe:
... even five years ago, it would've been a little bit challenging to think that we would have a whole session dedicated to immunotherapy and multiple myeloma. But the idea of this session, so now you're stuck with me twice, so if you need to get up, move around, get coffee, whatever, feel free. But we're going to do about a half an hour talking about these modern treatments. What do they mean? Tomorrow you're going to hear in much more detail from our guest speakers. There's going to be a breakout session for newly diagnosed relapsed myeloma. Some of this will be covered in relapse where they tell you more about the evidence behind it and when we would use these therapies. My focus today is going to be more just to help you understand what it means to try and make these complicated and challenging therapies a bit more comprehensible so that you can explain it to others so that you can understand it more.
We've said so many times at our patient meetings over the years that knowledge really is power. It gives you confidence in your ability to speak. I love the way how Susie Dury used to say it. We're not here so much to make you question your doctor, but to know the right questions to ask your doctor and to be able to have that conversation. So I'm going to try and make the complexity of immunotherapy somewhat simple. And in doing so, I'm going to discuss some of the concepts because I just want you to get some of the idea. I'm a nerd at heart and I'm a scientist and I love this stuff. It's really crazy to me to think of what we can do to employ the immune system to work in our favor.
And so I'm going to give you some sort of conceptual like things and then we're going to dive into some of the details of these really four primary ways of engaging your immune system. What we call monoclonal antibodies, what we call antibody drug conjugates, CAR T-cell therapy or chimeric antigen receptor T-cell therapy, and then these bispecifics and even trispecifics, even though we don't have trispecifics available yet, they're coming. And then I'll just give you a little hint and taste of what is yet to come because this is amazing, but what's coming is perhaps even more amazing. So this is not an episode of Star Trek or whatever, this is real, this is what we're doing, but I really want you to be amazed by it and hopefully gain some hope.
So you look at the slide and you're like, "What are you doing?" I give a talk, my favorite talk actually is called A Talk on a Talk, which is where I try to help our junior faculty learn how to give a talk. And I often say the worst thing you can do as a speaker is say, "I'm really sorry for this busy slide, but if you would just look at the corner," it's not a busy slide, it's a lazy slide because it means you didn't take the time to simplify it for your crowd. However, I do not think of this as a busy or lazy slide because it's purposeful. I want you to be a little... I have two slides that are kind of ridonculous, this one and the next one, that are designed to be a little bit overwhelming because I want you to get a sense of the magnitude of complexity of what we're talking about.
That being said, I am going to simplify this now 20 year old slide about how the immune system works. And I give you one simple statement and then I'm going to walk you through three parts of this slide. So the simple statement is, it is literally a miracle that all of us on this planet do not have multiple cancers. And the miracle, of course, is the immune system that protects us. Also, that same immune system would protect us from infections that are real. Some might tell you they're not so real, but let me tell you they're real and we need to protect ourselves. And thankfully our immune systems do a lot. That's not to say that hand washing and masks and all those things aren't really important.
Of course they are. They're an adjunct to it, but without the immune system, and we've learned this in particular in oncology and in parts of immunology where we take patients and literally take away their immune system, we know how at risk they are. But the specifics of how the immune system does this, I've always liked this model. One, because although it's complicated, I try to make it straightforward and it comes down to three words that all start with the letter E, as you may see here, elimination, equilibrium and escape. And just cut me a little slack here. The nerdy scientist wants to explain what this means.
Elimination. Your immune system right now is trying to eliminate the potential of cancer. If you were to grasp the number of not just chemical reactions, but really biological reactions that are going on in your body right now, how many cells are dividing, how many cells are sending messages to do this and to do that, it's in the trillions upon trillions. Even if you allow your immune system to say, "All right, you're allowed. What margin of error do you accept?" For those of you who may play a sport, so I had really never played pickleball to this last week and my wife's bestie said, "Dr. Joe, you're going to love this. We're going to play this." I actually end up really liking it.
What kind of percentage, if you say you're going to hit the same forehand 50 times, how many times do you expect to make it correct and incorrect? You say, "Well, probably at least 10 to 15% of the time I'm going to hit the net instead of going over it." If you allowed your immune system 10% error, thanks for coming out. You wouldn't be here today. The immune system's rate of error is in the minuscule of less than 0.00001%. There are all of these errors that could potentially happen, but your immune system is supervising these things. I think of it sometimes like the school teacher who is supervising the class and there's that one student, that Todd, and he's looking out the window. He can't wait till it's recess. He's not listening to the math lesson and the teacher's like, "Todd, please focus on the board. This calculus is riveting. You don't want to miss this."
What is that teacher doing? It's eliminating the tendency of that individual to turn away to come back in line. Your immune system is constantly doing that, protecting you. And this is why it's a miracle, as I say, with plasma cells who are constantly being called on to make different antibodies, it's a miracle that they don't go off the rails because it's easy for them to start multiplying out of control because they're constantly working. So the immune system helps by elimination. The immune system then can help by what's called equilibrium.
There are times when, unfortunately, a few cells are going to go a bit rogue and they're going to become cancerous. Well, the immune system says, "Okay, you know what? That's fine. We're going to find a balance. We're going to allow a few things to go wrong, but we're going to kind of sequester it." That is really what happens with MGUS, isn't it? That's what happens when you have a mole that has potential to become skin cancer but is not. And this can happen in multiple organs where there's that potential precancerous, but somehow the immune system keeps it in check.
Now to take this a step further, I can take you to the lab and I can put a really, really slow growing cancer in a mouse and it protects that mouse from getting the more aggressive cancer. It's a weird thought, isn't it? Sometimes a little bit of bad protects you from a big amount of bad, right? Sometimes eating a little bit of dessert saves you from going crazy at the dessert buffet, right? So sometimes the immune system finds a way to reach that equilibrium. We think that's what happens when patients get MGUS and smoldering myeloma, that there is some cancer there, but somehow the immune system kind of sequesters it or finds this balance. It can live with it. It can live with some amount of that dysfunction, but it doesn't tear down the whole organ or doesn't compromise the whole system.
And then lastly, sadly, the third E is escape. This is where the immune system just can't hold on anymore and too many of those cells have gone bad and the immune system escapes. Now, why have I given you all this boring science is to help you understand that as we work with the immune system, there are times we want to enhance its ability to eliminate and to reach equilibrium and we do everything we can to disallow that escape from happening where all of a sudden we just can't control that anymore. And this in many ways is the journey of a patient with multiple myeloma, right? Where often we're able to eliminate your disease, but there's that little bit that comes back, even that tiny little bit. We're talking about minimal residual disease.
One of the reasons why MRD is so important is as many of you heard me say before, typically the last soldier to be killed is Rambo, right? You don't want to leave that one Rambo cell left because it's going to multiply and have a whole army of Rambos, but those Rambos can come back. Sometimes paradoxically, we have myeloma patients that actually never get to MRD negativity. They still have a little bit disease left, but they do really well. You may be here today, you may be a five, 10, 15, 20 year survivor of myeloma, and you may always have a tiny little M spike. If you are, come talk to me at the break. I'm always interested in understanding that scenario better because it does happen.
I feel it's kind of like that equilibrium where sometimes there's just that little bit of disease left and somehow the immune system keeps it in check. That's why I always say, don't go to a conference like this and come back and say, "I have to get into MRD negativity." I have patients that come see me as an expert opinion and they're like, "Dr. Joe, you're going to get me to MRD negativity. We are going down this path together." They sort of feel like it's MRD negativity or bust. I gave a talk once entitled MRD, is it Rambo or is it Bambi? Sometimes it's Bambi and sometimes that little bit of disease is actually not going to hurt you. Let's not keep pouring chemotherapy and drugs and whatever into you to get that last little bit that may not be harmful.
And then of course escape, that's what happens when patients relapse. The immune system can't hold on anymore. It finds a way. And so I have colleagues of mine who dedicate their whole career to understanding escape. Why does someone with myeloma who's responded so well to their treatment, all of a sudden it becomes out of control? All right. The next ugly slide is this one and it's entitled... It's complicated, right? And the idea that I'm trying to convey with this slide is that the purple cells are myeloma. Everything else is the environment it lives in.
We sometimes think that cancer lives in its own little vacuum, right? Let's think about lung cancer or breast cancer. You think of a lump of tumor that's sitting in someone's lung or sitting in someone's breast and solid tumors tend to do that. They live that. They can, of course, spread sadly and metastasize elsewhere. Myeloma is a little bit more complicated because myeloma has learned not just to exist by itself, but to take control of its environment. The analogy I've sometimes used is to say, and I'm like the Canadian pacifist here, but imagine that the enemy goes and invades a building next to us here like the Sheraton. No, there's nothing wrong with Sheraton, but no, pretend that the enemy has gone into the Sheraton.
It's one thing to say, okay, the enemy lives in the Sheraton, but what if it's using all the resources of the Sheraton to its own benefit? It's now taking control of the wifi, of the water, of the power, of the employees there. So it's really become a stronger force than just using the Sheraton as a house. It's actually taking control of the house. This is what we see in multiple myeloma. It's not that these plasma cells just sit there all cancerous. One of the things that keeps them active and strong and difficult to get rid of is they marshal the resources and they just happen to live in one of the most resource rich parts of your body, the bone marrow.
Okay, I'm a hematologist. I confess. I'm a little bit biased, but I mean the blood is the coolest organ ever, right? I mean, really, honestly, what good is your heart if it doesn't have blood to pump? What good is your kidney if it can't filter blood, right? We need blood for every other organ, so blood is the coolest organ. So the bone marrow, the factory of the blood has all these other weird cells. Some of them you've probably never heard of before, like a stromal cell. Well, you have probably heard about a T cell because we've talked a lot about T cells. There are other cells like NK cells and these other kinds of... Which stands for natural killer cells. We have all these other things. And so as we study myeloma, we don't just study... It's not a tumor, right? It's not just the tumor that we study, we study the whole of its environment.
This is going to be important as now we get into the real stuff that we think about how we use that environment against the enemy. So if I want to take out the enemy and the Sheraton, there's no enemy in the Sheraton. Okay, please, I don't want any complaints later, but maybe I can't get to them because they're hiding somewhere on the fifth floor, but maybe I can take control of the resources. Maybe I can hack in and take control of the wifi. Maybe I can take control of the power, of the water, whatever else that allows me access. That's what we're doing with immunotherapy. We're not just going in and blowing up the building like we do with stem cell transplant. Still very effective, right? That's one way to get rid of the enemy, right? We're going to find them, we're going to snuff them out, we're going to get them. Let's just blow it up, right? That's one way of doing things.
There's a lot of collateral damage when you do that. But if I can be very precise and say, "You know what? I figured out that the enemy is on the third floor in this one room, why don't I just target that one room instead of taking out the whole building?" That is the modern way of treating cancer. Instead of saying, "Let's just give you this sort of general chemo," I give this lecture at Arizona State University on the history of chemotherapy. It's amazing. Hundreds, if not thousands of years ago, there was early ways in which we used to treat tumors. You don't want those ways anymore, right? But it's amazing now how much more sophisticated we can be.
So how do we do this? Well, we do it through these four different mechanisms that we're going to talk about, monoclonal antibodies, antibody drug conjugates, CAR T-cell therapy, and bispecifics. So what we're doing is we're using your own immune system to fight the cancer. It's ironic that myeloma happens to be a disease of plasma cells that make antibodies, and we actually use antibodies to fight myeloma. I mean, talk about fighting fire with fire, but that's what we do, and I've tried to show you in picture form what these are. This may be a bit more complicated and not clear to you, but I'll make it clear as we go.
So the first thing we've learned is that the outside of a myeloma cell is really a good place to target. Some of our treatments target the inside of a myeloma cell. When I shared with you earlier that new drug, ibertomide, that just got approved yesterday, remember Zen, that it works more so inside the cell, in the pathways of the cell, but these treatments I got to talk about right now are more focused on the outside of the cell. And so we have all these things that stick out of our cells. Sometimes we know what they do, sometimes we don't really know what they do, but if it's a way to grab onto the cell, to target it, again, going back to the illustration of the Sheraton, if I know with my device that I can scan the building and I know where the enemies are based on a heat signature or something, that then I know that's where the enemy is.
It's kind of what we're doing here. There's a signature. There's something on the outside of the cell that directs us to there. Well, how do they work? Well, we have historically used what we call monoclonal antibodies, which are very complicated, but in simple terms, they're that Y shaped, just like our remember antibodies I showed your Y shaped, the outside of the Y hooks on to the outside of the cell based on whatever target is. So if I have an antibody like Darzalex that targets CD38, it's going to go hook onto something that has CD38. Almost every myeloma cell has CD38 on the outside of it.
So it can do two things. It gets there and these drugs by themselves to some degree start to actually destroy the cell just by grabbing onto it. But secondly, with the back part of the Y, think of it as a little cord there, it makes a phone call to the immune system and says, "Okay, we have tagged the enemy, come get it." And so the rest of the immune system, we have all these different complexities, something called the complement system and antibody dependent system. We have all these different ways that the immune system is like multiple arms of the military will come in and help destroy the cell.
And so for years we've had monoclonal antibodies, they're called monoclonal because they have one target that they hook onto and they destroy cells. We've had this with daratumumab, with isetuximab, with elotuzumab and others that are still being developed. We're soon going to have another one that targets a different antigen. Sometimes that thing sticking out of the surface we call an antigen because an antibody hooks onto an antigen. Antibody, it hooks onto an antigen. We have one coming for a BCMA, which is just a single monoclonal antibody called belantamab, not belantamab mafodotin, but just belantamab.
Now, on the subject of belantamab mafodotin, we have what's now called an antibody drug conjugate. Same principle, monoclonal antibody, this time it's targeting BCMA, but attached to the Y, attached to the drug is what we call a drug conjugate, which just means something else that's hooked onto it that is toxic to the cell, the cell is not going to like. So it doesn't just hook on and make a phone call to the immune system. It does that as well. But thirdly now, it drops this toxin into the cell to destroy it. It's like a local bomb, right? It's a very targeted but local toxin that can help destroy the cell, and that's how belantamab mafodotin or Blenrep works.
CAR T-cell therapy is a totally different approach. CAR T-cell therapy is saying we have inherent soldier cells in our bodies called T cells. We actually have different kinds of white blood cells, lots of different white cells in the body. Often we break them into two big groups, what we call T cells and B cells, and that just happens to do with where they originated. T cells originate when you're very tiny in your thymus, which was a gland in your neck. B stands for bone marrow. Those are the ones that originate in the bone marrow. Don't have to worry too much about the origin of those cells, but these T cells have a unique feature that they're very good soldiers, but they're also very teachable soldiers.
We know that T cells can attack an antigen just like a monoclonal antibody can, but it can do so even more effectively. But you've got to make sure that this soldier is attacking the right thing, right? So the concept of CAR T-cell therapy is to say, let's train these soldiers to attack your multiple myeloma. How do we do that? Well, CAR stands for chimeric antigen receptor. That's the key word, the R, the receptor. So what I'm basically going to do is I'm going to take T cells out of my buddy Richard here and I'm going to say to these T cells, okay, I want you to fight Richard's myeloma. I'm going to help them fight Richard's myeloma by putting onto the surface of their T cells a CAR or a chimeric antigen, a receptor, kind of like a homing mechanism that is specific to the target on his myeloma cell, in this case, BCMA.
BCMA is another one of those antigens that sticks out of the myeloma cell. BCMA stands for B cell maturation antigen. It's almost universally expressed on all myeloma cells. And so now this T cell becomes a killer T cell, as it were, because the science behind it is pretty cool. What I do is I take these T cells out of the patient and then in the lab, I can actually create this receptor to go on the outside of that same T cell. Interestingly, the technology here is very similar to vaccine technology, which is why during the pandemic we had sort of a challenge of resources because we wanted to make vaccines, but we also wanted to make CAR T. That's why CAR T was very difficult to get for several months during the period of the pandemic. But nonetheless, I can then take these T cells and I give them back to the patient.
What's fascinating is I don't just give them back to the patient. When they get into the patient, the medical word we use is they expand or basically they multiply. So now I'm giving Rambo soldiers back to Richard, but Rambos are multiplying, so he has even more of them. Now, tomorrow we may talk about some of the side effects and so on. I don't have as much time today, but unfortunately, sometimes the expansion overexpands. We've learned that if we give too many T cells back to a patient or they produce too many T cells, it can cause some of the side effects because basically you've got all these amped up T cells ready to kill and they'll start trafficking to other places if there's not enough, if you will, myeloma to take down, right? And then they'll start going elsewhere. But then I give them back.
Now, before I give them back, I do have to give, and this will come later when I explain a different kind of CAR T-cell therapy, before I give these back to Richard, I need to tell Richard's current T cells and B cells to chill. I don't know if you use that word much. I never used that word when I was a teenager, but now my teenagers use it all the time. Oh no, dad, dad, I need to chill. No, you need to do the dishes. There's no need to chill here. But the idea here is you're telling his immune system, let's not get into some epic T cell battle, right? Let's calm them down. We sometimes call that lymphodepleting chemo, lymphocytes or white blood cells. We're depleting his white cells a little bit so that when these new ones come in, there isn't a battle.
Now, there's going to be a bit of a battle anyway, because the immune system's going to be like, "Hey, I don't recognize these T cells." And that's what triggers something called cytokine release syndrome, which I don't have time to get into right now, but that's part of the challenge of what we do, but we're getting better at managing it. So that's essentially how CAR T-cell works. We take T cells out of a patient. We do it very much like if you've ever had your stem cells collected for transplant. I assume that some people here have had their stem cells collected for... It's a similar process. You sit down, you lie down, that machine picks off your stem cells, gives the rest of your cells back to you. Same kind of thing. This time we just pick off the T cells instead of the stem cells.
We manufacture them. That takes somewhere between four to six weeks typically. We give you that lymphodepleting chemotherapy. We give you your T cells back. They expand and they take out your tumor. The real benefit here, of course, is that this is a one time infusion. Really, really quite remarkable. As I mentioned before, for time's sake, I'm not going to get into a lot of the detail of the side effects, but there are short-term side effects and they're long-term side effects, and we're getting much better at managing them. Looking to the future of CAR T-cell therapy, we have two that are currently approved. They both target BCMA, something called Abecma or ide-cel or Carvykti or cilta-cel, but we have others being developed.
Some have different targets. Some have what we call dual targets, where anything that makes sure that that T cell more carefully adheres to Richard's myeloma and nothing else, right? So the next generation of CAR T is being developed to ensure we want as precise a target as possible. We don't want those cells to traffic as it were anywhere else and to attack anything else. And so this binding of the myeloma cell becomes really important. As you can see here, there's something called dual binding, de-domain binding, other things.
The other remarkable feature looking to the future is something called in vivo CAR T. What I just explained to you with Richard, you don't mind, I use you as an example, brother, is what we call ex vivo, meaning I have taken his T cells out of his body, ex means out of, in of course means inside, and I have manufactured his T cells and give them back to him. In vivo CAR T, for which we have one incredible clinical trial where the first 18 patients treated on this trial all went into MRD negativity in the first month. In vivo means I actually just give a medication to a patient. It goes to their own T cells, converts them to CAR Ts, and they go and attack their myeloma. Marvelous, isn't it?
One, I don't have to collect the T cells. Two, I don't have to give the lymphodepleting chemotherapy, which comes with other side effects. And three, we've seen it very effective. And as I'll share with you tomorrow, I'm deeply committed to the issue with health disparities. We have it so good in the US. I have the privilege of going so often to the Third World and we see what was experienced in general health, let alone a multiple myeloma. I like taking pictures of the slums and the places that we don't ever really get to go to and show them to my daughters who live in Snotsdale and tell them, "This is how other people live. Next time your latte is not hot enough, don't complain."
And it's not just to be hyperbolic about it, but we have it so good in this country. But when I think of in vivo CAR T, I think of being able to bring this technology to larger groups of people because they don't need all the infrastructure of the apheresis and collecting the Ts. There are fewer side effects. It gives us their opportunity. And then lastly, I just got an email this morning about a study that I've had the privilege of submitting what we call an IND or an investigational new drug of an allo CAR T. Allo CAR T, so we had ex vivo CAR T, in vivo CAR T, allo CAR T is where actually we collect T cells from healthy individuals, create CARs from them, so make CAR T-cells, and then I can just infuse it in a patient like I would infuse a drug. We're at the early stages of doing that and doing those clinical trials, but that would make it even more available to the masses.
All right, time's going quickly, so I got to come to our last one here, which were the bispecific antibodies. Remember we said monoclonal antibodies have one target, bispecific antibodies have two targets, that's why they're called bi. So they're kind of shaped like two Ys together. One arm hooks onto the myeloma, much like the monoclonal antibody does, but amazingly, the other arm now reaches out and hooks onto a T cell or potentially other cells like natural killer cells. But let's focus on T cells for now. I don't then have to take T cells out of a patient and manufacture them and give them back. Now I'm just giving someone so-called off the shelf, meaning taken from our drug cabinet, we just give it directly to the patients.
This drug goes into their system, it finds their myeloma, it finds their T cells, and it activates or triggers that T cell to destroy the myeloma. We have several of these approved already. We have three that target BCMA, teclistamab, elranatamab, and linvoseltamab. We have one that targets a GPRC-5D called talquetamab, and this is not yet FDA approved, but we're working on one that has yet a different target called FCRH5, a drug called cevostamab. And so it's really amazing how these drugs bring together your own T-cells. You're not going to reject them, you're not going to dislike them. There's not going to be any epic T-cell battle here because these are your own T-cells and I'm engaging your own T-cells and we're still figuring out when is the best place and you're going to see really incredible data tomorrow about how bispecifics have so changed the way we treat relapse multiple myeloma.
And just as a commercial, because I know you're all already pre-registered, to go to our virtual webinar, which is coming up next week where I have the privilege of joining the Kennedys who are here with us today and another patient from New York, Terry Glassman. And we're going to talk about the latest data that has just come out in multiple myeloma and we're going to talk about some of these bispecific antibodies and the combinations that we're seeing. It is amazing. In one of them at three years, 85% of people are still in remission. It really is amazing what these drugs are doing. Looking to the future of bispecifics, amazing. As I mentioned, we have a new target. We have drugs that are now being given less frequently, once a month, right off the start. So now someone doesn't have to go to a specialized myeloma center, this can be given out in the community.
And then lastly, we have this development of trispecifics. So I've just opened a new clinical trial, for example, in Arizona where we have this trispecific. So I know I've been practicing my yoga here. So I have two arms and a leg. So it has three arms and basically two arms grab onto the myeloma. Remember I mentioned how important it is to have more precise binding? So it's binding the myeloma and then it's that third arm that engages the T cell to help destroy the myeloma. And what's fascinating about the trispecifics for me is that it's not only more enhanced binding, is they are designed to adhere more tightly to cells that express both of those antigens.
So if we take, let's say BCMA and GPRC5D, one of the reasons why we see side effects from these bispecifics is that some of your other cells express those antigens. Like you have BCMA on other good immune cells. You have GPRC5D on your taste buds. You have GPRC5D on your nails and your skin. For those of you who have had talquetamab, you may have experienced losing your nails or having some changes in your hair and your skin and your taste buds. But if we could develop a drug that preferentially only hits cells that have both BCMA and GPRC5D, do you know any cells like that?
Those are the plasma cells. It can more carefully... It's like saying you can drive with one hand on the wheel, but it's better to drive with two. These drugs are designed to hold onto the cells that have both of those antigens and they'll be even more effective. And the early results from these tri-specifics is really remarkable. So immunotherapy has really changed the way we treat myeloma. I think we're getting more effective and less toxicity all the time. And so I think the future of what we can do in immunotherapy is really, really remarkable.