CAR T therapy is a highly effective treatment for myeloma patients, even in highly relapsed multiple myeloma. We hear from Luciano Costa, MD of the University of Alabama at Birmingham who does a deep dive into CAR T therapy in multiple myeloma to discuss how CAR T availability is improving, how CAR T is being tested in earlier lines of therapy, side effects to consider, new CAR T targets, combo CAR Ts, maintenance therapy post-CAR T, open CAR T clinical trials and various new forms CAR T variants like NK CAR Ts. Listen to this important show on one of the most impressive therapies ever developed in myeloma! 

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Jenny: Welcome to today’s episode of the HealthTree Podcast for Multiple Myeloma, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. We’d like to thank our episode sponsor, Menarini Silicon Biosystems, for their support of this program.

Now, before our show this morning, I'd like to let you know about our recent HealthTree 2.0 announcement earlier this week on Monday. We will have two videos out shortly that will describe this event in detail. After 11 years of work supporting myeloma patients, we are ready to enter our next decade to help accelerate a myeloma cure.

HealthTree 2.0 defines three pillars of support for myeloma patients. The first is personalized, lifetime support important education. The second is meaningful patient-to-patient connections. The third is a powerful patient data portal called HealthTree Cure Hub. We are able to provide these three pillars with unique technology that includes 14 internally developed software programs that are all integrated together to support you.

Now, unusually, we can do this because we have an internal software development team that has helped us build these remarkable programs that are completely unique to HealthTree. HealthTree 2.0 is a laser focus on expanding two things that only HealthTree is uniquely positioned to do: increased reach and increased research. Our goal between now and the end of 2025 is to invite over 25,000 patients to participate in HealthTree Cure Hub and to raise $5 million towards myeloma research. HealthTree Cure Hub enables myeloma research to access anonymous myeloma patient data to accelerate their work. We can facilitate surveys or studies or other types of projects for the researchers. We provide this to researchers for free. So myeloma will be incurable until it isn't. Our collaborative participation can provide researchers with the data and the knowledge they need to cure us.

Now today, even a simple survey for a researcher to administer to myeloma patients can take about a year and a half and $150,000 in funding. We can do that for the researchers and reduce that time down to months and provide that help for free. What we're doing is saving money, time, and lives using HealthTree Cure Hub. Now, 100% of your donations go to research like this, and we invite you to join HealthTree Cure Hub today at healthtree.org/myeloma.

In 2024, we will be developing six regional communities and performing outreach across the United States. We will be inviting you to volunteer in these communities in a variety of ways. The development of a myeloma cure will move faster if we're all involved. Even if we have limited time or ability to volunteer, we are all needed. Watch for an email with two videos from our HealthTree 2.0 launch event, and watch the videos to learn more. Now on to our show.

CAR T is an exciting and expanding therapy in multiple myeloma, and the response rates for this immunotherapy are just remarkable, and significant work is being performed to learn how to make it more durable. We have with us today Dr. Luciano Costa, a fabulous myeloma specialist with significant CAR T experience.

Dr. Costa, thank you for joining the program.

Dr. Costa: Thank you very much, Jenny, for the opportunity to meet with you and your audience and discuss about this promise of challenging therapy.

Jenny: Yes, we're very excited for today's discussion. Let me give you an introduction before we get started.

Dr. Luciano Costa is Medical Director for the Blood and Marrow Transplantation and the Immune Effector Cellular Therapy Program and Professor of Medicine in the Division of Hematology, Oncology, and Transplantation at the University of Alabama at Birmingham. Dr. Costa received his medical degree and PhD in Brazil, his home country, and trained at the University of Colorado and Mayo Clinic in Rochester. Dr. Costa is Associate Editor of Advances in Cell and Gene Therapy and has published over hundreds of articles, books, and posters on stem cell transplant and cellular therapies in multiple myeloma. Dr. Costa's research interests include stem cell transplant, development of new therapies in multiple myeloma, and specifically cellular therapies and immunotherapies. We are so privileged to have you on the show today.

Maybe we want to just start with CAR T cell therapy generally. Can you speak to just this major innovation in myeloma care and a little bit about the history of its development?

Dr. Costa: Absolutely. I think if you go way back in time, this idea of using the person's own immune system to combat the cancer is actually quite old. If you think about it, our immune system is capable of quite a bit of surveillance. We actually suppress most cancers before they even become detectable by our immune system. I think kind of a very fruitful principle of that is that people who have chronic immunosuppression for whatever reason, people who get, for example, a heart transplant or a lung transplant, they are at increased risk of developing cancers of different forms.

So for decades now, people have tried to ramp up this and find smarter ways to redirect one's immune system against the cancer they already have. As you can imagine, that's not an easy task. If we develop cancer in the first place, it's because the immune system has failed on that immune surveillance task, and also cancer is essentially a corrupted normal cell, so it carries many of the characteristics of the normal organ and tissue from which it originates. It's hard to successfully harm the cancer without harming normal organs.

That being said, the tremendous progress has been made over the years. Perhaps the first biggest success of immunotherapy in cancer are the monoclonal antibodies, and we have those in myeloma as well, for example, daratumumab or Darzalex, isatuximab or Sarclisa, and elotuzumab or Empliciti, those are all monoclonal antibodies, antibodies that binds to a protein on the surface of the cell and tags the cell to be destroyed by the immune system. Those are, nevertheless, very important advances.

However, the cell that is the strongest part of our immune system in suppressing cancer and killing other cells are the so-called T-cells. T-cells are quite abundant. We have about 1,000 of those floating around at any given time, and they are trained over our lifetime to recognize and suppress different types of stimuli, particularly different types of infections. CAR T really comes from the pursuit of taking those T-cells and repurpose them from finding an infection, for example, to now being able to recognize and find the cancer.

The CAR T consists of harvesting those T-cells from the patient's own bloodstream and modifying those cells genetically to insert on those cells a gene that make them recognize something unique to the myeloma cell and then grow those cells into many copies in the laboratory. When it comes to treat the patient, we essentially infuse those cells that are capable of tracking themselves to the part of the body where the cancer is, multiplying themselves, so you have more cells that were given to the patient so you can tackle many other cancer cells Those T-cells should be able to, on the first encounter with the cancer, be activated and be able to kill the cancer. That's exactly what CAR T-cell therapy is. CAR T stands for chimeric antigen receptor. That means you have a receptor that was made up of different pieces via bioengineering. That chimeric antigen receptor is inserted in those T-cells, and those are the ones that treat the cancer, in this case, the myeloma.

Now CAR T did not start in myeloma. I think the first success was more than a decade ago in treating some leukemias, particularly pediatric acute lymphoblastic leukemia. But then later on was developing lymphoma, which is like a, you know, in the same kind of closer to myeloma than leukemia is, and of course, most recently in relevance for our discussion today, in multiple myeloma.

Jenny: That's a great history. Thank you very much. Now, we have two drugs that are FDA approved. One from Bristol Myers Squibb called Abecma, and one from Janssen Oncology called Carvykti. I think just to give a little bit of relevance, I mean, these are treatments that in relapsed, in heavily relapsed patients, even in those first clinical trials, they had anywhere between like 70% or 80% to almost high 90%, which is shocking. If you could help us understand the relevance between those types of responses and then other drugs that have been approved like daratumumab or Kyprolis, and those typical response rates, just so we can get a perspective of the difference.

Dr. Costa: Yes. I think that this is very important. I think it helps to understand why there's so much enthusiasm, so much hype about those therapies. Traditionally, I think many of people on the line understand this or have witnessed that firsthand. When you have a new treatment developed against any cancer, it goes through some development in the lab and some testing in a pre-human phase and then it goes into the clinic first, what's called Phase I trials. Those are trials meant to help understand how the drug works, what's the right dose, what the toxicity is going to be, and so forth. That is usually in patients who really don't have any more good options available. If we, on those settings, if we see a drug work, you know, 20%, 30% of the time, that is great news. That's considered a promising agent that people tend to invest in further development. A drug, for example, that was as transformational as daratumumab, for example, when it was first tested, it had about 20% response rate. Similar for isatuximab. Pomalyst, when it was first tested, it had something over 20% of patients responding, and nevertheless made and help on the evolution of myeloma therapy.

When CAR T first came about, are on the trials that you mentioned that led to ultimately the approval of Carvykti, the responses were in the high 70s, 80s, or even 90% range. This is like way, way above what we expect for a drug being introduced or a new therapy being introduced for the first time. That has to, however, be taken with a little bit of a grain of salt. As we start to understand, I mean, those therapies are quite complex. If I have a new drug that I'm testing and my patient is eligible today, I give that therapy a few days later and that patient counts.

For CAR T, what happens is, if I have a patient who is eligible and enrolling in those trials, the patient has to collect the cells, which sometimes take a week or two or more. Those cells go on to an outside laboratory. The production of the CAR T and the quality control can take several weeks. In the meantime, the patient is on my hands, and the disease might be progressing. I have to do what's called breathing therapy to try to suppress the disease and hope that at the end of those four or six weeks, the patient still meets eligibility. He still has a good heart function. He still has a good blood cell count. He still has a good renal function. He still has a good performance status, which is often but not always the case. That causes, if the patient for some reason does not make that criteria, the patient is not counted on those clinical trials. That automatically selects out patients who have a more aggressive disease and patients who couldn't wait, who are not even considered for the trial, or patients who are enrolled in the trial but do not make the four to six weeks. Nevertheless, it's highly encouraging to have therapies with that level of response in working settings where things are no longer active.

We had a chance a few years ago before there was CAR T to kind of collect somewhat the benchmark data, say how those people who have had 3, 4, 5 therapies, who have received a proteasome inhibitor like Velcade or Kyprolis, have received a proteasome immunomodulatory agent like Revlimid or Pomalyst and have received a CD38 monoclonal antibody like Darzalex or Sarclisa, how do they respond to the next thing you do, whatever that thing is? And the results are pretty dismal. Only about 25% to 30% response. We think the same population have a therapy that works more than 75% of the time is really transformational.

Jenny: Right, very exciting. I think when you first heard about CAR T, maybe even like 2015, 2016, I think everybody was thinking, oh, my gosh, this is going to be -- because it had been so effective in some lymphomas and things like that, leukemias, this might cure myeloma patients, but what we're finding is they're very high response rates and then you still have patients relapsing. Do you want to address that scenario?

Dr. Costa: Yes, yes, absolutely. In other settings like acute leukemia and lymphoma, a subset of the patients, actually an important subset of the patient seems to be cured. Essentially, you get the one-time treatment and the disease does not come back. Of course, it's not curable in everybody, but it's curable in a substantial number of patients. Now, for myeloma, that has not been the case yet. That might have to do with the very nature of myeloma that has a disease that comes back a lot more than lymphoma, for example, but also might have to do with a limitation of the therapies that we have had. There is certainly, those two products as wonderful as they are, there's certainly room for improvement in both of safety and efficacy but also the patient population, right? It's true for any cancer that your greatest chance of cure is with earlier lines of therapy.

I think there's still some substantial hope in the field that as we improve upon those therapies and we use those therapies in earlier lines, that we might have a fraction of the patients who might be cured from their myeloma. But at this point, that cannot be estimated yet.

Jenny: I love how you said "not yet," because you're learning so much. This is like, I think, every time new therapy comes out, you learn how to use it. You learn when to use it. You learn who it's most effective for. You kind of dial in with practice all the things that are not possible to figure out really in the clinical trial process. I just love that. Can we talk a little bit about -- because now that these are FDA approved and you talked about the process to collect the cells and so mostly this is done at an academic center, and before availability was sort of a problem, can you speak to how the availability is improving, if it is?

Dr. Costa: Yes, absolutely. What I usually explain to my patients is, if you have a new drug approved today, that means the company that makes has shelves filled up with drugs ready to be shipped out. In most cases, you can start using the drug the week after. That's how it works. Well, for CAR T, that's not the case because each treatment has to be individually produced for each patient. The therapy is made out of the patient's own T-cells. So the bottleneck, so to speak, is to be able to manufacture those cells, right? The sites have to collect the cells, send to central manufacturing facility that is going to produce those CAR T's and send back. So the manufacturing has been the bottleneck.

In the early days of approval for Abecma in 2021, that was the only product available, we all had a lot of patients in our practices that we thought would benefit from this therapy, and we all rushed into trying to get this as soon as possible. There was a lot of dilemma on matching the therapies to the patients, and it was a very steep learning curve for everybody. This has gotten a lot better in more recent months with the availability of Carvykti and increasing availability of Abecma. I would say it's not a gone problem. I mean, you cannot get either one or whatever you want, but it's far better than before. We also learn better how to use those agents, how to time that in relation to the patient's disease, and some of that demand that was suppressed before kind of has been taken care of in the past several months. We're a little bit of a more steady state situation right now.

Jenny: That's wonderful to hear that. I know that, well, I have a lot of questions, but maybe we want to talk first about, do we know who will and won't respond to some of these therapies? I know they were approved after fourth line, so some of my questions that I was thinking about, I think I might wait until, you know, what you mentioned at the beginning of the show, bringing them up into earlier lines of therapy. But for now, is there any way to predict who will and won't respond? And is there any way to predict who will and won't get some of the common side effects?

Dr. Costa: Now, that's a great question and certainly something that we all are interested in, but unfortunately at the present time, we really cannot predict who will, who will not respond. Part of that is because we're talking about therapies with 80 plus percent response rates, right? So now responding becomes sort of an exception. There are factors that are starting to come up that start telling us who will have a longer remission versus a shorter remission. That tends to be the usual suspects, right? Patients with a lot of disease by the presence of what we'll call extramedullary disease, I mean, disease outside the bone marrow. For example, not those in the liver or under the skin or in the lung, so in tissues other than the bone or the bone marrow, those patients tend to have a less likely the response or a shorter response. Patients with a high LDH, which we know is a prognostic mark in myeloma and so forth.

But the thing is, the things that make patients less likely to respond or less likely to have a long remission on those therapies are things that make patients less likely to respond and have a shorter remission with any therapy. As I like to say, we don't choose patients for our therapies. We choose therapies for our patients. In that sense, we have not been able to define a subset of patients who will not benefit at all, right? Now there are patients that we have learned that pursuing CAR T is not a good choice because sometimes we see the patient and the pace of the progression is so rapid that you can project there will be no way that patient will be kept safe for the four, six, sometimes eight weeks to take to manufacture the CAR T's. Unless you have an excellent bridging option on hand, you probably should be looking to a different direction on how to try to treat that patient.

The other part that is only partially understood is how our immune system plays a role into the persistence of the CAR T's and the response to therapy. You know, in a way, all the therapies that patients receive throughout life can damage the immune system one way or the other. If you're going to later lines of therapy, you're probably taking T-cells that are more incapable or less capable, let's put that away. But on the other hand, the process of manufacturing kind of overrides some of that, right? Because you are now inserting kind of superpowers in that T-cell that might be able to overcome whatever that exhaustion status that the T-cells have. But there are the other components of the immune system that we only partially understand how they affect one's likelihood of response.

Jenny: Okay, great. Do you want to review, just give a brief overview of the typical side effects that patients can anticipate for CAR T?

Dr. Costa: Absolutely. There are some side effects that are very, very unique to this therapy. The one that is most common and most relevant is something called cytokine release syndrome or CRS. For those who are listening to understand, cytokines are normally occurring substances that our body produces by different immune cells that are responsible for coordination of immune response. Our immune system is extremely complex and dynamic, and essentially one cell has to talk to another to kind of coordinate the operation, coordinate the attacks, so to speak. That communication is done through substance that we call cytokines. Well, when you take something like CAR T, when you overwrite this system and insert a large number of cells that have those superpowers, you essentially break through the body's mechanism of self-regulation and you have what is a very exacerbated immune reaction. It's sometimes called cytokine storm. That manifests in the patient with a fever. That's kind of the key finding. But in more advanced circumstances, that can produce low oxygenation, patient being short of breath, drops in blood pressure that in some occasions require stay in the intensive care unit with medications to keep the blood pressure up. In more advanced circumstances, it can cause more serious problems like kidney failure, liver failure, and even can be fatal.

Now, there are a few things that can predict that. The disease burden, how much cancer there is when the cells are infused, seems to at least loosely correlate with the severity of the CRS, which kind of makes intuitive sense, right? You have a lot of cancer. You have a lot of fuel for the fire, and you can have a more intense reaction. Now, fortunately, and that's true for both Carvykti and Ide-Cel. CRS is very common, more than 70% in both cases, but the serious type, the type that you have to be in the ICU, is too rare, way less than 10%. Also, over the years, and that's the type of knowledge that doesn't have to be myeloma specifically, we can learn that from the experience with lymphoma and leukemia we have better mitigating strategies for that reaction, particularly a drug that blocks one of the main cytokines that's called interleukin 6, and that helps to kind of cool down that reaction. There are other things that can be done like steroids and so forth.

Now, one other signature toxicity, as I like to say, is neurotoxicity. That has been called Immune Effector Cell Associated Neurotoxicity Syndrome or ICANS. This was primarily described and is more seriously more common in leukemia and lymphoma, but nevertheless can occur in myeloma. That's something that we still not fully understand. Some of that might be the cells actually making to the brain, but most likely it's the cytokines that the body produces in high quantity when you use those CAR T's making to the brain and affecting how the brain works. That can be a very disturbing experience for patients and families. It can be very subtle like you forget words, or you can't name objects. It can be like the person, the patient stops talking. So we call that aphasia. You know, you are there, you can understand, but you can't find your words.

One of the earliest and more specific findings is what we call dysgraphia, which is like your writing doesn't look quite right, okay? And more serious cases can be common. You know, it can be totally unresponsive. Fortunately, again, this reaction overall is uncommon, less than 10%. The serious type, the one that you want, you'll be kind of comatose, is kind of extremely, extremely rare. The good thing is that this is also amenable to therapy with usually corticosteroids like dexamethasone and so forth. They tend to be very short-lasting, a day or two, and usually during the time the patient is in the hospital setting or next to a hospital setting. Long term, the problems that bother us are particularly infections, so there are a few things that are usually done to help reduce the risk of infection. Sometimes the blood counts can stay low for a month or two, which often requires transfusion support. But those are side effects that we hematologists are very comfortable with and many of our patients are, in a way, comfortable with because they have faced that in some other therapies.

Jenny: Wonderful. As we mentioned earlier, these two drugs are approved for after fourth line of therapy, but I know that both companies have clinical trials in place that are testing these in the earlier lines of therapy. Do you want to speak to what you think the timeframe might look like to get these drugs approved or these treatments approved for patients who've had maybe one line of therapy or two lines of therapy?

Dr. Costa: Yes, absolutely. Both companies have conducted trials, and those were called phase three trials. Essentially, you compare this therapy with the existing available regimens in patients with earlier therapy. In the case of Abecma, there's a trial that we call KarMMa-3. We're fortunate enough to participate on that trial. I have patients with two to four prior therapies who have received all the three main classes of myeloma therapy. This drug, this therapy, CAR T, was compared with a conventional regimen. That study has been completed, has been published. It was a highly positive study with the CAR T having nearly more than 50% reduction in the risk of progression for those patients.

In the case of Carvykti, there was also a study. We're also happy to participate on it called CARTITUDE-4 that compared Carvykti with a conventional regimen in patients who had had one to three therapies and different from what we saw with Abecma, the patients here did not have to, even had receive a CD38 monoclonal antibody like daratumumab. They just had to be, the disease just had to be resistant to Revlimid, which is most time it is on patients with spectrum line or beyond. That trial was also very positive with more than 50% reduction in the risk of progression or death with Carvykti versus a conventional regimen. Now, this data is out. The regulatory authorities are looking at that, both for Abecma and Carvykti. I hear this can be as early as first quarter next year that one or more of those therapies might be available for patients earlier in their journey with myeloma.

Jenny: That's fantastic, because I think what you said at the beginning is true, that when you have a more resilient immune system, and for every therapy, everything works better when you're first diagnosed versus later. Well, let's talk a little bit about CAR T versus bispecific antibodies, because all these immunotherapies, CAR T was a little bit earlier, and now we like this flood of bispecific antibodies that are coming out, and talk about sequencing strategies. I know at the recent International Myeloma Society meeting in Greece, some of the data showed that if you can get it and if it's available, CAR T might be better in first and sequencing, but you still have the question, can you get it? And what you were saying earlier, like will your myeloma wait until you can get it? So that's still kind of open. But what's your opinion on the whole sequencing of these different drugs?

Dr. Costa: That is very interesting. For your audience, now that we talk about how we want to use T-cells to fight the cancer, CAR T is one way to do it. The other way to do is what Jenny has mentioned, bispecific T-cell engagers. Those are off-the-shelf therapies. They're antibodies, very much like Darzalex or Sarclisa or Empliciti are antibodies, but they bind two things. They bind something called CD3, which is on the T-cells, and they bind a target on the myeloma cell that can be either BCMA, like the CAR T, or it can be another protein called GPRC5D. What they do is they bring together, they force the T-cells to get in close contact with the cancer cell, and that is sufficient for activation of the T-cells and killing of the cancer cells. Those drugs don't require the patient to collect cells, don't require time to manufacturing. Essentially, once you think a patient needs it, you can give it in a couple days.

Those therapies are also extremely active. We talk about response rates in the neighborhood of 65% to 75%. It's natural that we cross-compare that with CAR T. Well, CAR T is better, 75% to 95%. We've got to keep in mind that those are very different patient populations. For example, somebody with a very aggressive disease, they get the bispecific, they can get therapy in a couple days. If it doesn't work, they count as a failure of the treatment, while if they had received CAR T, they would probably have not done well and never received the CAR T infusion because their health would have deteriorated, so they're not counted. There's always a 10% or so difference that favors the comparison to CAR T.

The other thing to keep in mind is CAR T has these advantages of "one-and-done." You get your therapy. You don't have to be on ongoing treatment and that is marvelous because there are patients that can enjoy sometimes months and months when they're well without being on treatment. They're going to trip. They are enjoying time. They love to have a break from seeing the doctors and nurses as often as they usually do. However, those CAR T's stick around for a few months and they're gone. Then, eventually, the myeloma kind of bounces back. The bispecific for being ongoing therapy, it's inconvenient because you're not really signing off from the treatment center, but that can be a double-edged sword because you continue the therapy that is engaging your immune system against the cancer. Some of those responses can be very, very long. I have patients, for example, approaching five years on a bispecific T-cell engager after having triple refractory myeloma.

It's not as simple as CAR T works more often than bispecific. Now, the challenge is, in a scenario where you have all those things available, how do we choose, right? And that is the question we don't have a good answer for. We're starting to learn how one therapy works after the other. If somebody has CAR T and it works and a year or years down the road the myeloma comes back, we can pretty much say the likelihood of responding to a bispecific, even with the same target, is very close to those patients who never had received a CAR T. The CAR T doesn't seem to burn any bridge in any meaningful way. The response is a little bit less but still very meaningful. So we know a little bit better about this path of CAR T followed by a bispecific.

The other way around is not very well known and a little bit of data that there is seems to not be very encouraging for somebody coming off of a bispecific with progression and jumping to a CAR T. Sometimes you can now manufacture the CAR T successfully and even when you do, oftentimes it doesn't work. We're only trying to understand why. Maybe because that continuous suppression of the myeloma selects out the cells that have lost the target. We still don't know, but that path seems to be a little bit less successful.

How do we make decisions when we have a patient in front of you? Very hard. I would say if you are somebody who, and that's how I counsel my patients, you are somebody who we think can safely do CAR T, can safely wait for the manufacturing, we have a slot available, go ahead, do the CAR T, the other option is still going to be there. What we have to be careful about is not losing an important therapy, which are the bipecifics, waiting to go from something that is excellent for something that we might perceive as being "better," which is the CAR T, and lose that option and lose the chance of receiving meaningful therapy.

There are also patients who, the other thing to take in consideration, and I discuss with the patients, the toxicity with the bispecific is certainly less and more controllable. As many of the audience might know, the bispecifics are given in a measured approach. You don't give the full dose on the first day. You do what's called step-up dose. They give intermediary doses, which gives you some control of the pace of that engagement and those reactions. With CAR T, you unleash the cells and all you can do is hope for the best and if a complication happens, you try to mitigate the treatment. You don't have much control of that reaction. If you have somebody who is older or have a more frail health that you think this person is, you know, will be unable to endure a severe CRS, that's sadly not a patient that you should pursue in CAR T. I have several patients on my practice who I have successfully treated with bispecifics for whom I would have never proposed a CAR T.

Jenny: Well, all these nuances are the exact reason why you need a myeloma specialist on your team, in my opinion. You think about all the things you just considered, and it's just so critical that people come to experts like you, especially for these newer and very nuanced therapies.

Dr. Costa: You know, I have to agree with you, Jenny. I think it's the -- I know we're a bit of a self-serving device, but I think the sooner you get a myeloma specialist on your team, the better. Even if the specialist is not the one you're seeing for your every month treatment, you have somebody closer to home with a general oncologist who is willing to work with that myeloma specialist is still important because there are a few things that, as you're sensing from our discussion, timing is very important, having a feel for one's disease, see how a patient tolerates this therapy versus that therapy. In CAR T, for example, with all the logistics involved in slot, insurance verification, collection, bridging, having somebody with firsthand experience that has been involved in your team from the very beginning is incredibly helpful.

Jenny: Wonderful. Well, do you want to talk about new approaches in CAR T? So we have these two approved drugs, and there are some new things coming out, like using two CAR T's together or using new targets like CS1 or GPRC5D or even having a facility develop their own CAR T. Do you want to review what, in your opinion, were the most promising looking approaches?

Dr. Costa: Absolutely. The two CAR T's that are currently approved, they target the same target called BCMA or B-cell maturation antigen.  Of course, they have been very successful. That's not the only target that is relevant in myeloma. We have, for example, GPRC5D, which is the target of talquetamab, for example, which is now an FDA-approved bispecific T-cell engager. There are CAR T's in development. Actually, our center has had a lot of experience with a GPRC5D-directed CAR T, again, very active and, if you ask me, quite safe. We spend, in my opinion, unnecessary energy arguing, is this going to be better or not better than the existing CAR T? But in reality, I truly believe it doesn't have to be better. It's just being different because of the different target that gives people another option. We have had several patients who have received two different CAR T's with two different mechanisms of action and derived incredibly disease response and longer emissions from both in sequence. In the future, people might benefit from CAR T in more than one point into the treatment trajectory.

The other approach that is only starting now is to design CAR T's that don't have one target but two. This is very intuitive, how two can do a better job than one. That's how you use chemotherapy, right? Many successful curative chemotherapies using cancer are using more than one drug, the hopes that a cell that is resistant to one is not resistant to the other. There is one in development that targets CD19, which is a very early marker in B cells as they transition to plasma cells in BCMA, and there are some down the road with BCMA and GPRC5D. That is certainly an exciting new development.

The other part that is exciting is, of course, the biggest challenge of CAR T is the time that it takes to collect the cells, manufacture the cells, get the cells back. So wouldn't it be wonderful if you could do the same thing with a product that's already on the shelf? You need to get it. That would only be possible with a universal donor CAR T or allogeneic CAR T. So far, the initiatives that have been taking in that direction have been hindered by the problem that if you get a cell that is not yours, you can reject the cell and the cell can reject you. What it takes to overcome that is some very strong immunosuppression that causes a lot of infections. But thanks to modern technology, now there are some initiatives of editing the DNA of that cell to essentially make that invisible to your immune system and make that incapable of attacking your normal organs, so you can have a cell that is super focused on finding and killing the cancer without causing any other trouble. So that would be ideal, right? You have an off-the-shelf product that is safe, and you don't have to go through apheresis collection and individual patient manufacturing. I think those are the things that if I have to highlight the three things that I'm most excited about future cell therapy, it will be those three.

Jenny: Wow, that's totally amazing. I have a few more questions for you, but I also want to leave a little bit of time for caller questions. So if you have a question for Dr. Costa, you can call 347-637-2631 and press 1 on your keypad. There's a caller that has a question, and then I'm going to jump back to my additional questions. Go ahead with your question.

Caller: Hi, I was most interested in the allogeneic CAR T. I appreciate the comment that was just made. Could the doctor speak a little bit more about the timeline on having that available to patients as an alternative to regular CAR T?

Dr. Costa: Thank you so much. That's a great question. The honest answer is we don't know. There are several that are in clinical trials. As a matter of fact, this morning I just had a meeting to activate one of those trials here at UAB. But from this phase where things are on trial to become approved, we're looking at least two or three years, if assuming those trials are successful. We still have a ways to go.

Jenny: Okay, perfect. Thank you. I want to finish up by asking some questions about maintenance therapy, if that's okay. Because you talked about CAR T being this one-and-done therapy, and most of the clinical trials have tested it like this. Do you see a maintenance therapy being added to CAR T cell therapy and when? How fast are your T-cells becoming normal again? So adding another drug that might kind of depress the immune system isn't going to do damage. I don't know. What's your opinion about what type of therapy or maintenance therapy? 

Dr. Costa: Jen, your question is great and your questions are our questions. Those are the things that we don't know, right? So you're absolutely right. I think the idea of maintenance therapy is very commonplace in myeloma because we have learned that from initial therapy, post-transplant therapy, the maintenance is beneficial. When you do CAR T one-and-done, you can't help but think about can I make this response better or longer lasting by using maintenance therapy? That, as you can imagine, is a very controversial and you can come up with a lot of reasons why that would be a good idea, and lots of reasons why it would be a bad idea.

Why would that be a bad idea? Well, you have, first of all, you jeopardize the one thing that is a great advantage, which is the one-and-done, and you can go travel without having to be coming to the doctor. You kind of jeopardize that if you have to be on ongoing therapy. The other reason is what you mentioned. There's already a degree of immunosuppression associated with the CAR T, low blood counts, and that can be made worse by adding yet another myeloma therapy. There are several reasons for skepticism.

On the flip side of that, you have therapies that can do perhaps, at least hypothetical, can do both. They can help suppress the myeloma and enhance the activity of those T-cells. We know, for example, cell mods, which are the evolution of the immunomodulatory agents like Revlimid and Pomalyst, the cell mods are iberdomide and now mezigdomide. They, at least in theory, can revitalize those T-cells and have a potent anti-myeloma effect. At least hypothetically, it could be optimal maintenance therapy, an oral drug that could make the response last longer.

Other things that are being pursued are combinations with CAR T's and a bispecific, perhaps even with a different target to try to clean up, or so to speak, the little disease that is left after CAR T and prevent a relapse. Of course, the timing of that is crucial. It's probably not something that is feasible. The week after you get your CAR T may be less feasible a few months later. All those things and a few more are being pursued, as we speak, in clinical trials. But at this point, none of which has been really presented, published, or fairly not established. At this point, the maintenance is yet not a feature of post-CAR T.

Jenny: Interesting. Okay, we have another caller question. Go ahead with your question.

Caller: Yes. My question, I just wanted to know if the doctor can review post-CAR T. Should the CAR T fail? You mentioned bispecifics. I just wanted a little more clarity on that. Thank you.

Dr. Costa: Absolutely. If you think about clinical trials that led to the approval of elranatamab, teclistamab, and talquetamab, those are the three bispecifics that we have approved. On the program for the development of those bispecifics, there were patients who had received prior CAR T, which gave us the opportunity to look at how the sequence happens. When you look at patients who had received a prior BCMA-directed CAR T and go on to receive teclistamab, which has the same target, BCMA, the response rate is still about 55%, which is not too far from the about 55% from patients without prior CAR T.

So now that those things are all available, it teaches us that patients who had a prior BCMA-directed CAR T and now is having a recurrence months later or years later, a BCMA-directed bispecific is still a good option. The same near identical results we're finding with the elranatamab program, so that is an option. I have now a couple of patients who have received prior BCMA-directed CAR T and the myeloma later progressed who are being successfully treated with a BCMA-directed bispecific. For talquetamab, it's a similar story. Patients being enrolled on the talquetamab trial, which was a monumental one, quite a good number, about 30 patients had received prior BCMA-directed CAR T. So now you're going from one target to another in the myeloma later progressed, and then the response rate was almost the same on those patients. I think it was over 70%, then it wasn't the general population and there was no different safety concerns. That tells us a bispecific after CAR T is safe and nearly as effective. But keep in mind, this is not planned sequence. It just happens that somebody got a CAR T, myeloma progressed, and they are still in good shape, they still meet the clinical trial eligibility, and they were known to receive a bispecific, right? None of those circumstances were an intended sequence. It's not like, okay, we're going to go on this plan and just send me that CAR T now and three months round the road to get a bispecific. It just happened to be that way.

Jenny: That makes a lot of sense. Okay, that's a great question. Dr. Costa, we are out of time. I think my last question would be, are there any CAR T clinical trials that you would like to mention that you are running or you are interested in to understand kind of the next level of CAR T understanding?

Dr. Costa: Without mentioning any particular program, because I don't want to place favorites here, but we are very fortunate that we are involved on all these initiatives that I mentioned with bispecific CAR T, with CAR T in combination with approaches such as maintenance therapy as well as allogeneic CAR T. I think it goes a plug, in general, and I think I suspect I'm a little bit preaching into the choir here, knowing how engaged your audience is. But clinical trial is always a good idea. Every time if you come to a crossroad and you need to make a treatment decision, be very proactive, inquire your doctor, and reach out to the center near you that is involved in myeloma research and look for clinical trials options, because it's ultimately how we advance the field, and ultimately how you as a patient can have early access to those therapies that are often transformational.

Jenny: Well, I would echo that because that's exactly what I did. Sometimes what you're saying is you need to talk to your doctor early to make those types of decisions because I joined a CAR T clinical trial, and now that these drugs are approved, I wouldn't qualify just because I hadn't had enough lines of therapy. I was able to get earlier access to that and it is a promising therapy. I love how you explained everything so clearly and easily. This is a very complicated topic and you did a fantastic job helping us understand CAR T and the status of it. So we just thank you so much for all this research work that you are doing. You're running these trials and discovering these insights for us as patients. So thank you for everything you do for myeloma patients.

Dr. Costa: Absolutely. Thank you, Jenny, for all the work you do. And thanks for all those who call in to listen and ask questions. Thank you so much. You guys have a wonderful weekend.

Jenny: Thank you so much. Thank you to our listeners for listening to the HealthTree Podcast for Multiple Myeloma. We invite you to join us next time to learn more about what's happening in myeloma research and what it means for you.