Bispecific antibodies are an exciting new therapy in multiple myeloma. Learn from Dr. Alfred Garfall and Dr. Bea Razzo about this new type of treatment that now has three approved drugs and more options in development. Drs. Garfall and Razzo talk about how the therapies work, the different targets, side effects that occur with bispecific antibodies and the strategies to limit the duration of bispecifics to lower side effects. Dr. Razzo shares this open clinical trial at UPENN testing teclistamab as fixed duration therapy for patients who have expericed stable disease after 6 months on teclistamab. 

Jenny: Welcome to today's episode of the Health Tree 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, Genentech, for their support of this program. We're very excited to begin the year with you on a new podcast format and for a variety of reasons, including technical capabilities, better tech consistency, sound quality, and doctor convenience, We'll be using this new podcast platform.

The show will be different and then you can email your questions prior to show time instead of asking questions as live callers. The shows will be posted on our website and all registrants will be alerted when they're available. We'll continue to share the shows on our Spotify, Google, and Apple channels. Today I'd like to welcome Dr. Alfred Garfall and Dr. Beatrice Razzo to talk about bispecific antibodies in myeloma, an important topic. We've now had three FDA approved bispecific antibodies for relapsed multiple myeloma. This is a brand new class of myeloma drugs.

Bispecific antibodies can be used for myeloma patients who have relapsed and offer new hope to these patients. We look forward to learning more about them in this show. Dr. Garfall and Dr. Razzo, welcome to the program.

Al Garfall: Thank you, Jenny.

Jenny: Let me give an introduction for you before we get started. Dr. Alfred Garfall is director of the autologous bone marrow transplant unit and Associate Professor of Medicine at the University of Pennsylvania. Dr. Garfall is a protocol committee co-chair for the Blood and Marrow Transplant Clinical Trials Network, is on the grant review panel for the LLS, and is on the National Cancer Institute R03 submission panel, and the Society of Immunotherapy of Cancer panel as an immunotherapy expert.

Jenny: Dr. Garfall has held many editorial positions for publications such as Nature Medicine, Lancet Hematology, Blood Advances, and Bone Marrow Transplantation, just to name a few. He serves on multiple UPENN academic committees and has significant teaching responsibilities at the University of Pennsylvania and is a regular speaker on CAR T and other immunotherapies. He graduated with honors from Princeton University and has received awards, including the Career Development Award from ASCO and Scholar in Clinical Research by the LLS.

He's a member of the International Myeloma Society as an advisor on CAR-T, as well as a member of ASCO and ASH. 

Dr. Razzo is a hematology oncology fellow at the University of Pennsylvania. She performed her internship and residency at NYU Langone in New York. She's a member of ASCO and ASH and recently received the ASH Minority Resident Hematology Award and an NIH Award to increase diversity in clinical trials.

So let's get started with our program today. Dr. Garfall, maybe you want to kick it off and give us a little background just generally on bispecific antibodies.

Al Garfall: Sure. So these are a very exciting new type of immunotherapy for multiple myeloma. We've been hearing about antibodies in multiple myeloma for a while. 

We've also been hearing about T cell immunotherapy in multiple myeloma for a while in the form of CAR T cell therapy. You can think of bispecific antibodies as bringing these two concepts together. We've had a couple different what we call monoclonal antibodies for myeloma approved for six or seven years now. We know these as very safe.

Easy to administer medications, daratumumab, elotuzumab, these have become mainstays of multiple myeloma therapy. We also have CAR T-cell therapy, which we've been hearing about for a while as this kind of, it seems kind of science fiction sometimes, the idea that we take T-cells out of a patient's body, genetically engineer them, and send them back into the patient's body to fight off the myeloma cells. 

That's a very complex therapy that involves genetic engineering and making a customized product for each patient. Bispecific antibodies kind of bring these two concepts together. They activate T cells against multiple myeloma in a way that's very similar to the way CAR T cells work, but they do it with the kind of simplicity that we think of with monoclonal antibody therapy, where you just kind of take the drug off the shelf and give it to the patient as a subcutaneous injection.

And so this makes it a lot easier to get that kind of T cell activation against the multiple myeloma that we know from CAR T cell therapy is a very potent way to treat myeloma, but does it with the simplicity that and convenience and accessibility that we've come to think of, uh, with that we've come to appreciate with, you know, monoclonal antibody therapies like, like daratumumab and elotuzumab.  

Al Garfall: And so I'll stop that there, but there's lots to talk about in terms of how these therapies work and how they differ from monoclonal antibodies. I'm happy to talk about those aspects if you'd like.

Jenny: Well, I think let's talk about targets because I know in CAR-T we have specific targets and in bispecific antibodies we have specific targets. Can you just talk about the targets, what they are, maybe the rationale for the approach, why they're good targets? I think that'd be helpful.

Al Garfall: Sure. So both conventional monoclonal antibodies and bispecific antibodies have to recognize multiple myeloma cells through a molecule that's on the surface of the multiple myeloma cells. And so the conventional monoclonal antibodies, isatuximab, daratumumab, elotuzumab, so isatuximab and daratumumab, they recognize CD38.

Elotuzumab recognizes a molecule called CS1. Bispecific antibodies that have been developed so far recognize a different set of molecules, and these are the ones also that CAR T cells recognize. So the first bispecific antibodies that have been developed for myeloma recognize BCMA, which many people know of as the target of the CAR T cells for multiple myeloma. There's a second bispecific antibody approved for multiple myeloma called talquetamab that targets GPRC5D. And then there's another one that's still in clinical trials that targets a third molecule called FCRH5. This sounds like an alphabet soup, I realize. I would say that because bispecific antibodies in CAR T cells are more potent therapies, we have to be a little bit more stringent with the type of targets we select.

We really want these targets to be as strictly confined as possible to the multiple myeloma cells and really not present on other cells in the body. Because if we unleash that T cell activity against normal tissues in the body, it can cause a lot more damage than it can cause with less potent immunotherapies like the conventional monoclonal antibodies. And so that's why there's a difference in the targets that have been selected for these T cell immunotherapies than there have been for the monoclonal antibodies. You know, another thing I'd say is that because the CAR T cells and the bispecific antibodies are more potent immunotherapies, you can direct them against targets that are present at low levels on the myeloma cells. For example, BCMA is sometimes present at relatively low levels on the multiple myeloma cell, but still bispecific antibodies in CAR T cells can work against those low levels of target.

That's a little bit different than CD38, which is what daratumumab, isatuximab recognize. CD38 is really highly expressed on multiple myeloma cells. So that's another factor for consideration when I'm thinking about the targets for these different therapies.

Jenny: I have a question, just a follow up question about that comment. Because I've never thought about this before. How much BCMA expression is present like for smoldering myeloma patients?

Al Garfall: It's not thought to vary that much between the different stages of myeloma, at least to my understanding, but in our experience, when we've looked at this in the research lab looking at different patients' myeloma, there is variation from patient to patient. And even within the same patient, you can see some cells that are kind of low for BCMA, others that are high for BCMA. There's a little bit more variation in that regard than there is maybe with another target like CD38.

Jenny: Interesting. And do you want to explain how they're different from the monoclonal antibodies like daratumumab and isatuximab? 

Al Garfall: Sure, sure. So the term bispecific means that the monoclonal antibody has two specificities. It recognizes two different molecules. So we've been talking mostly about the molecule on the multiple myeloma cell that the antibody recognizes. And with drugs like daratumumab and elotuzumab and isatuximab, they recognize just the molecule on the multiple myeloma cell, the CD38, the CS1. And then with those molecules, the antibody uses its tail end to engage the immune system. And so it binds on the head, the myeloma cell, and then the tail recruits immune system cells to the myeloma. And the type of immune system cells that a regular antibody recruits are cells like macrophages and natural killer cells, part of the innate immune system. And those cells can kill the myeloma cells, but it's not as potent as the killing you can get with T cells.

And so by specific antibodies, the goal is to engage T cells. And so in order to engage T cells, the folks that develop these drugs, they make the antibody recognize two different molecules at the same time. So one end of the molecule recognizes the myeloma cell by BCMA. And the other end of the molecule recognizes a T cell. And the way it recognizes a T cell is by recognizing a molecule called CD3, which is part of the T cell receptor complex on the surface of T cells. 

So the molecule really grabs a T cell with one arm, grabs a myeloma cell with the other arm and kind of pulls the T cell to the myeloma cell in the body while activating the T cell and forcing that T cell to recognize the myeloma cell. And that's how it generates the killing of the multiple myeloma cell. So it forms a bridge basically between the myeloma cell and the T cell and forces the T cell to recognize and kill the myeloma cell.

Jenny: Okay, perfect. That's a great explanation. Do you want to share which are FDA approved and which are in development?

Al Garfall: So there are a lot in development. It's hard to keep track of them all. So there are three that are FDA approved to target BCMA. So the first one that was FDA approved was teclistamab that targets BCMA that was approved back in October 2022. And then in the course of 2023, a second drug that also targets BCMA called elranatamab was approved. And then a very exciting one that targets a second cell surface target, GPRC5D, was approved and that one's called talquetamab. And what's exciting about having more than one target available is we've seen patients for whom one target works and stops working, you can switch to one against a different target and it might still work. And so it really does, you know, increase the treatment options for patients to have these drugs that can recognize different targets.

Jenny: Okay, perfect.

Al Garfall: And then there's many, many more in development. So there's many different ones that recognize BCMA in development, and they differ in subtle ways in their designs. I want to say there's at least half a dozen of them. And then there's some against other targets, like that one that targets FCRH5, which is exciting. And so it's possible over the next couple of years, we could have a handful of bispecific antibodies that recognize up to three different targets. And then to really kind of make things complicated,

Jenny: That's crazy.

Al Garfall: There’s something called a trispecific antibody that is in clinical trials right now. And that's a drug that recognizes two different targets on the multiple myeloma cell. So this is one that's being developed by Johnson & Johnson. It recognizes BCMA and GPRC5D while also grabbing a T cell along the way. And so this gets around one of the ways myeloma can kind of evade by specific antibodies, maybe by hiding the target on the surface. And so if we have a molecule that can recognize two different targets, that could be a winner in terms of combating some of the resistance mechanisms that we see.

Jenny: Yes, it's incredible. And I'm just curious about the boom because, you know, there are so many different players, there are so many different buy specifics that are in development. What do you attribute that to?

Al Garfall: Number one, I would say, what's great for multiple myeloma is that there are these safe targets. And so we know that we have a few different targets that are, that you could tell before you even get them into clinical trials, that they're likely to be safe because you can do these studies and show that these targets are present mostly on the myeloma cells and not really on too many other cells. 

We've been lucky with in blood cancers in general, especially in the B cell side of blood cancers, which is where multiple myeloma lives, you have these targets like CD19, CD20, BCMA. These molecules are expressed on some normal cells in the immune system, but they're cells that you can live without. Although as you know, a main thing that I hope we talk about today are some of the risks with these agents. And one of the major risks is infection.

And that comes because these cells do kill normal, or these antibodies do result in the death of normal cells in the immune system. And while you can live without those cells, which is what makes these drugs relatively safe, you do incur immune compromise because of that, which leads to some of the risks with these drugs. But the fact that there's not BCMA, the targets that we have for multiple for the most part are not expressed on other healthy tissues in the body. These drug companies, they can just start developing all these different drugs against these targets with different approaches like CAR T cells, by specific antibodies, regular antibodies, something called an antibody drug conjugate. When you have targets that are basically safe, you can go after. And so I think that's been probably the fuel for all this rapid development.

Jenny: Well, it's unbelievable. And I think it's a blessing of treasure. It's incredible. Well, it's a perfect segue because Dr. Razzo, I like to talk to you about side effects that patients need to be aware of when they're thinking about using a bispecific antibody.

Al Garfall: For sure, for sure.

Bea Razzo: Absolutely. And I think, you know, as Dr. Garfall talked a little bit about, because the specific antibodies work in a way that's activating the patient's own immune system, most of the immediate dangers from therapy actually relate to too much activation of the immune system.

And because of that, you can imagine that the side effects are actually similar to those seen with CAR T cell therapy, given that both involve these early on bursts of immune stimulation. And so I think the first major side effect to be aware of, and the first two I'll talk about, are the earlier side effects and then the last one that was alluded to was the infectious risk. 

But one of the first potential severe side effects of bispecific antibodies is called cytokine release syndrome or abbreviated CRS. Cytokines are proteins in our body that act as messengers between cells helping to regulate immune responses, inflammation and just general communication between different types of immune cells. 

And when both the CAR T cell or the bispecific antibodies is first introduced to the body, that can cause a surge in the cytokine levels that leads to a lot of inflammation in the body. And then the syndrome, that's a result of the kind of sudden release of a lot of cytokines, is something that ends up looking a little bit like sepsis or in severe cases like septic shock. In milder versions of cytokine release syndrome, that might look like just a short-lived fever for a patient. Actually 70% for teclistamab, the first bispecific antibody we've talked about and it's kind of the premise of the study. That occurs in about 70% of patients will have at least a fever. 

More severe versions of cytokine release syndrome can also occur, although that's rare for bispecific antibodies compared to CAR T cells. And the severe versions could include like low blood pressure, trouble breathing, and sometimes they have a need for admission to an intensive care unit. There are a few things that are done to decrease the risk of the side effect. One of them is giving the bispecific antibodies that all of the ones approved are given in some manner called step-up dosing. So a very low kind of first and second dose to kind of prime the body and prevent such a rapid increase in the cytokine levels. 

And then early studies actually with CAR-T but now widely used for CRS, when it occurs with specific antibodies, is an antidote medication we call, which is called tocilizumab. One of the cytokines that are released with CRS is called interleukin-6, and that drives a lot of the inflammation seen with it. And this antidote medication is essentially an antibody that suppresses some of the levels of of the cytokines that are driving the side effects.

Jenny: I think the story of the use of tocilizumab is fascinating from CAR T. Dr. Garfall, I don't know if you want to jump in and if you want to share just a brief version of that story and then we'll jump back to you, Dr. Razzo.

Al Garfall: So from what I understand of it, this was a story that started at our institution at PENN with one of the first pediatric patients with leukemia who was receiving anti-CD19 CAR T cells, the drug that later went on to become Kymriah, got the CAR T cells and the T cells started activating in the body and releasing this huge inflammatory wave that Dr. Razzo was mentioning about, resulting in the patient getting very sick with fevers, low blood pressure in the ICU, and everybody thought she was going to die. And they were doing whatever they could to analyze her blood in the lab to try and figure out what was going on. And they found that her body had really astronomical levels of this interleukin-6. 

So fortunately there was a drug that was already developed and approved that blocks the interleukin-6 receptor. It's used for different autoimmune diseases. And so they just really on like a wing and a prayer gave that drug a try. And I mean, it just shut off this inflammatory cascade, I think, over a matter of hours. And it's almost like the patient woke up and I think if it weren't for that discovery, in some ways this whole field would not have moved forward because these therapies would have been considered just too dangerous to try. And so it's a real, I would say triumph of translational science, very careful clinical investigation and just thinking about every patient that led to that breakthrough. And so fortunately with bispecific antibodies, we don't see quite as intense cytokine release syndrome as you can see with CAR T cells, but those lessons are still really important and it's an important part of managing the reactions to the bispecific antibodies.

Jenny: And I've heard some doctors saying they are giving tociluzumab prior to doses, even the step-up doses now. Do you think that's a regular practice? Is that just a few doctors doing that to just kind of ward off any potential cytokine release syndrome or CRS issue?

Al Garfall: So that's something that's been studied both with teclistamab and with elranatamab. I'm sorry, with teclistamab and with cevostamab. And there's been some presentation of small experiences with that. And so it's not an FDA approved usage of either the bispecific antibodies or teclistamab. It does seem to cut down on the low-grade cytokine release syndrome, but it doesn't completely eliminate it.

So I don't think it's a widespread practice right now. I think it would be more appealing if it just completely got rid of the possibility of cytokine release syndrome, but because it doesn't completely eradicate it. You still have to be quite careful and have, have measures in place to manage the CRS if it happens. And so it hasn’t taken off in widespread form yet.

Jenny: Interesting. Dr. Razzo, let's jump back to you and talk about neurological toxicities, which is probably what you're going to talk about next.

Bea Razzo: Correct, yes. So another of the kind of two most important immediate complications of both CAR-T and bispecific antibodies. So the neurotoxicity that we most often refer to in terms of those related to T-cell engaging therapies, it's called ICANs, which stands for immune cell, or Immune effector Cell Associated Neurotoxicity Syndrome.

Also a wide catch of symptoms, which most often may include confusion, delirium, but in more severe cases or life-threatening cases could include things such as seizures. For bispecific antibodies, the risk of these neurotoxicity events are lgenerally lower than with CAR-T.

And at least with some of the early studies with teclistomab occurred and mild versions occurred in just 3% of patients without any of the severe cases.

Jenny: And just a question about ICANs. So CRS is happening at these first doses, which is why they're doing step-up dosing and looking for mitigation strategies for that. 

When do ICANs usually hit - in the same timeframe during the step-up dosing process? I know some of the side effects like this can happen a month late after CAR T, or you see maybe some of the Parkinsonian symptoms or something like that, much later than the initial dose. Is that the same in bispecifics or do you typically see that in the first two weeks or how does that work?

Bea Razzo: I can give part of an answer. I don't know if Dr. Garfall will want to add. Interestingly with bispecific antibodies, both the CRS and the kind of classically defined to the first time, like the step-up doses and the first full dose. With neurotoxicity, there have been reports and then we also have seen in patients getting the commercial product. Not ICANN's neurotoxicity, but some other forms of toxicity, such as some movement to disorders happening later on, but generally the ones that the side effects we think that are more related to the direct surge in cytokines appear to happen exclusively early on.

Al Garfall: And I'm not aware so that the movement disorder, to my knowledge at least, has been reported mainly with the CAR T cells. I'm not aware of reports of the movement disorders with the bispecific antibodies. But it's something that we should be on the lookout for because if it is related to BCMA and T cell activation, it's possible it could emerge at some point. And it took a little while for it to become apparent with the CAR T cells too, because it's a very rare toxicity. So we should be on the lookout for it. Correct me if I'm missing something, but I haven't heard of any reports of like this Parkinsonism or the movement disorder happening with the bispecific antibodies. 

For listeners who may not be familiar, there are some reports very rarely after CAR T-cell therapy and it can happen kind of late even months or even years later where you where patients can develop this neurologic syndrome that looks a little bit like Parkinson's disease after the CAR T-cell therapies.

Jenny: Well, gladly something that's not that common and not that common in CAR T and not that even more rare in bispecifics. So that's a good thing. Well, let's talk about infections because you mentioned that earlier at the beginning of the show. I think that's a major concern for patients and providers.

Bea Razzo: Absolutely.

Jenny: Patients who have been on a lot of myeloma therapy anyway have dealt with this issue across multiple different kinds (of therapy) - stem cell transplant, you obviously deal with that, longer term use of some of the other drugs, you kind of deal with that as well. But maybe you just want to share what's specific to the bispecifics.

Bea Razzo: I think that's been the driver for a lot of the studies and the questioning about how to make these safer. I mean, they're so good that you can strive to make them safer as well, because even though, right, we're talking about some of the side effects being less severe or less common with specific antibodies, the risk of causing infections is kind of a steady risk throughout therapy. And so many of these patients doing very well on this medication can be on it for up to several years. The fact that it does seem to predispose to more infections, and I'll describe a little bit about what they are, and the fact that this risk is a continuous risk has really led to kind of the question of how to make this better. I think some of the preliminary early kind of information on this is that yes, patients with multiple myeloma in general as a cancer of the immune system are at risk for infections, but specifically with therapies, both T-cell engaging therapies and especially with the target being BCMA, do seem to be at a slightly higher risk even of getting infections. 

And actually all sorts of infections, common ones such as bacterial pneumonias, sinus infections, urinary tract infections do occur, but also some rare types of viral infections such as one called CMV or with a virus called JC virus, which can lead to a kind of a rare neurological complication called PML. And there at least in the initial study with teclistamab, seeing also more cases of a fungal infection called PJP, which did seem, common enough with teclistamab to the point where actually prophylaxis against this infection is recommended for all patients who are receiving treatment. 

I think we don't fully understand all the mechanisms that lead to this kind of array of multiple different types of infections. Certainly it has somewhat to do with the target itself and the fact that by giving treatment, you're not only depleting the myeloma cells that carry the BCMA, but other healthy lymphocytes as well, which produce the antibodies against several of these infections. So toward that end, another manner of decreasing the risk of infections is by giving back normal donor antibodies, intravenous.

Jenny: And some patients might know that as IVIG, they might have heard that term before, right?

Bea Razzo: Yes, but even with the prophylactic medications, so the PJP prophylaxis, the antiviral acyclovir, which many patients would have been on for other lines of treatment as well, and with getting IVIG, there still is this continuous risk of developing many times severe infections at any point throughout therapy.

Jenny: Okay, before we jump to the trial that I know we want to talk about, let's talk about response rates because to a patient, all that we talked about sounds a little bit scary. We need to know as a patient that this is worth it. Do you want to, both of you, address response rates as a single agent in highly relapsed patients? What are you seeing and why is this worth the risk, I guess, worth the trade off to to think about some of these other side effects that patients are kind of new to with CAR-T, but immunotherapies bring a whole new possibility and just other things to think about.

Al Garfall: So these drugs were first tested in patients who had really exhausted most of their available treatment options for multiple myeloma. And that's usually how new drugs are tested for the first time.

And so if we think about to teclistamab, for example, the first one to be FDA approved, the study that evaluated it first after finding the right dose, treated about 165 patients who were almost all what we call triple class refractory. So patients whose disease had become resistant to daratumumab and proteasome inhibitors like bortezomib and carfilzomib, and then IMiDs, lenalidomide and pomalidomide. So, patients who are really running out of options. And the response rates in that group of patients was 63%. 

And the response rate has been similar with the other ones as well, elranatamab and talquetamab. And so this is pretty remarkable as a single drug to have that kind of response rate in this group of patients whose myeloma had become resistant to so many therapies. 

What's also impressive and where we think actually gives us the window of opportunity maybe to give patients a break from treatment, this idea that we're testing in this ongoing clinical trial, is that the patients who do respond, almost all of them, and not everybody responds or some patients don't respond, but for the patients who do respond, almost all of them have, what we say, deep responses. So the myeloma tends to go down to either completely undetectable or barely detectable levels. And so that kind of response is really amazing for this more advanced patient population. So we've come to expect that maybe from CAR T cells, but we've never seen that kind of response in these types of patients with an antibody therapy. So it's really promising effectiveness.

Jenny: And you think about other drugs that have gotten improved in myeloma like Kyprolis or daratumumab or other drugs, a lot of them are in the 30-35% range. So comparatively as a single drug or a single treatment, it's pretty remarkable to have this whole new class of drugs that provides this kind of level of response rates for highly relapsed patients.

Al Garfall: Correct. For sure. And the responses are very durable as well. And that's also very important because a lot of those drugs that kind of gave 30% response rates, even the patients who responded, they would maybe get a few months of disease control from. We've seen, we have patients that our center at Penn and was very involved in the first teclistamab study. We have patients that we treated back in 2018 that are still on treatment.

Jenny: Okay.

Al Garfall: And if you look at the whole group of patients that have responded, we'll say the median duration of response has been around two years. And so that means that more than half of the or half of the patients are responding for longer than two years. And that's really remarkable from one drug, especially for patients who had some of these patients have had myeloma for seven, eight, nine years.

Jenny: It is. Totally.

Al Garfall: To have something that works so well. And it's the kind of responses that we've seen with CAR T cells. So really remarkable responses, really durable responses. I want to be careful because of course, there's still some people for whom these antibodies don't work and we need to keep working on new options for those patients. But for the patients that respond to these, they're really effective drugs. And especially with the BCMA target, once we worry about this infection risk, but while they're on the drug, they feel quite well actually. And patients will say that, you know, compared to the multi-age regimens that had dexamethasone in them and a lot of other side effects, they feel better on teclistamab than on any of the prior myeloma therapies that they'd been on in recent years.

Jenny: It makes sense. It's such an exciting opportunity, which is why so many options are coming in development and that we have three FDA approved in the same class. It's amazing. Okay, well, Dr. Garfall, do you want to cover sequencing strategies? Because I know as we talk about combination therapies, stem cell transplant, CAR T therapies, etc.

And when you look at it as a clinician, how are you determining which should come first? Do you do a GPRC5D bispecific and then go for a BCMA CAR T? Do you do a BCMA bispecific and do it in the opposite way? How do you think about that? That's a lot, that's a big question.

Al Garfall: It is. It's a complicated question and it's one that we're still learning our way through because all these drugs are new. They've only been on the market for less than a year, many of them. And we have limited experience from the clinical trials. While I always tell people this is where the art of medicine comes in, we try to make good decisions for individual patients because everybody's history and preferences are a little bit different. Our goal is to try and, because none of these therapies that what we have so far, even as effective as they are, none of them are curative.

And so we think we're going to get the best long-term outcomes if we can somehow make every one of these therapies available to all our patients. And that's the strategizing that has to happen for each patient is what for that particular patient is the best way to try and get access to all these therapies at some point in their, in their time with myeloma.

So I don't think of it as either or like, do I do bispecifics or CAR T cells? I think about it, what's the right order for an individual patient to do these things in? And so right now, all of these new drugs, the bispecifics and CAR T cells are really approved for patients in pretty late lines of therapy. So they have to have been through what we think of as the standard myeloma therapies before they can really have access to these medications, although it may change in the next couple of years as new trials come out. And so right now the situation we're confronted with are patients who are on three or four prior lines of therapy and they have a choice of maybe trying bispecific antibodies or CAR T cells. So first for CAR T cells, there's still an access problem in many parts of the country. And so some centers or some regions don't have access to a lot of CAR T cell slots.

Where we have pretty good access to CAR T cell manufacturing slots, there's still more patients who need these therapies than we have slots. And so if the patient's disease is progressing in a way that they need a therapy more quickly than we can get them CAR T cells, then we use bispecific antibodies. On the other hand, if the patient's disease is progressing in a way that we think we can control it with other therapies while we wait for a CAR T cell manufacturing slot, and while the CAR T cells get manufactured, which takes at least several weeks, sometimes a couple months, then we try CAR T cells for that patient. 

But even then, that's only if the patient wants CAR T cells because still some for CAR T cell therapy, the complexity of it is still daunting for some patients and they might prefer. And also we think of the risk of CAR T cells, while there's, you know, we think of it as manageable, but there's probably a little bit higher potential for severe toxicity, as Dr. Razzo was mentioning earlier with CAR T cells than by specific antibodies.

So some patients don't want to bear that extra risk and they prefer maybe bispecific antibodies. So it's a patient by patient decision, thinking about preferences, risks, and also how quickly they need a therapy. We are very comfortable. Considering the novelty of these therapies, there are some studies that have been published in which patients get bispecific antibodies after CAR T cells, and they seem to work almost as well.

if you've had prior CAR T cells than if you hadn't had CAR T cells before. So we're very comfortable with the idea of getting CAR T cells and then sometime later if the disease progresses, going on bispecific antibodies. We have a decent experience now where if you're on a BCMA targeted CAR T cell or bispecific antibody that you can move to a GPRC5D targeted bispecific antibody and have an excellent chance of response.

Jenny: That's great. That's terrific.

Al Garfall: We don't have quite as much experience with bispecific antibodies followed by CAR T cells. And you probably need to take a little bit of break from bispecific antibody therapy before you try CAR T cells. But I'm still optimistic actually that you can move from bispecifics to CAR T cells. You just probably need some kind of break with some other non-immunotherapy. But if you think about a bispecific antibody patient who maybe has been in remission for two or three years and starts to progress, that patient really could go back to some conventional myeloma therapies like daratumumab or pomalidomide that they haven't had in a long time and maybe get a little mileage out of therapies like that while they let the immune system reset a little bit before trying CAR T cells. And we're just starting to get to that point with some patients now and we'll have some more data on that experience, I think, in the next couple of years.

Jenny: That's fascinating. I think there's also a psychological component to this for some patients. Some patients, if they had good responses and did a one and done kind of therapy and then went for a long time not on therapy, they're more comfortable doing CAR-T. And for some friends that I have who have either maybe high risk myeloma or psychologically, their physician has said, you know, you need to stay on therapy. They kind of get nervous, I think.

So I think a bispecific antibody is a little more psychologically comforting that they're on something all the time, right? And you know, we know CAR-T's, we thought they were going to be this wonderful, fabulous cure and maybe they will be earlier lines of therapy or in other combinations or in other sequences and we were very hopeful because it's an amazing treatment. Do you see that with your patients? The psychology of it?

Al Garfall: Oh yes, patients are, I find that their preferences and anxieties about this are all over the map. You know, some people are very anxious about the toxicity.

Some people are very anxious about stopping therapy. Some people are very eager to stop therapy and think about these therapies as their chance, maybe to get out of the continuous therapy paradigm that they've often been living with for many years. So it's all over the map. And that's, like I said, our job is to personalize this for patients . I think patients' preferences and feelings about questions like this, risk tolerance and preference for duration of therapy are just as important as the medical and scientific factors in deciding which of these options to choose.

Jenny: So this is why we always encourage patients to see a specialist like yourselves because there are so many, well for one there are so many treatment options that are really nuanced can be personalized if you have an expert like you on board. So I just always suggest to patients that when you're making a decision about your therapy you go see a specialist and if you need to get a second opinion, get a second opinion.

Be very careful about when you're choosing your therapies because it's like a chess game in my opinion and you're mapping out your moves and you want to get the most mileage out of every move.

Al Garfall: No, it is a rapidly evolving area and those of us who specialize in multiple myeloma, we love working with patients’ oncologists who are close to home. So we recognize that this is a rapidly evolving field. And I know I couldn't keep track of everything going on in every different field of oncology. So we're happy to see patients, even if it's just to give some guidance about these decisions for patients to be able to get and maintain therapy with their oncologists that they've been comfortable with close to their home. And your organization, HealthTree, does such a wonderful job of connecting patients with.

information about myeloma specialist, the directory that you have online, and the coaching program that you have to share patients' experiences with other patients. It's a really wonderful resource for patients.

Jenny: Well, thank you. And we're proud of what we've done. You'll see us focus significantly on the research side (in the coming year). We'll continue to do all the education that we do. We'll continue to do all that community building. And in 2024, you're going to see us just expand significantly on the research side with our Health Tree Cure Health platform. So we hope that can be beneficial because we'll be running a three-year bi-specific study and we'll be running a three-year CAR-T study as well

Jenny: So we're excited and I think you'll be involved in that bispecific study with us, Dr. Garfall.

So Dr. Razzo, let's talk about clinical trials and the trial that you are working on to do fixed duration therapy and you can explain the rationale and the study design and all that.

Al Garfall: That's exciting.

Bea Razzo: Yes, absolutely. And I think two of the maybe three major drivers we've talked a little bit about, one being that there is such an excellent response to teclistamab, or to, in this case, I'm referring to teclistamab just because that is the specific drug that we're studying - patients getting teclistamab. But I think we should be able to extrapolate to other by specifics in general for this approach. 

But in general, there's this such a great response, but then, and one that can last for years and years and years, but patients are undergoing this continuous risk of getting infections. Half of most patients actually get infections and half of patients who get infections actually need some form of more intensive measure with whether it be IV antibiotics or admission to the hospital. 

One of the questions has been, okay, well, both bispecifics are approved as a continuous therapy until progression or death, but given such a remarkable and long-lived response, are there different ways or strategies of giving it that might maintain such an excellent response, but decrease either the severity or the frequency of these infections? 

And another observation that motivated some of the rationale or alternative means of giving bispecific antibodies is that some patients who needed to come off of a bispecific antibody and were in a good response actually did not progress for quite a while, even while being off of the drug.

And so this had led to the development of our study. And a lot of people are interested in this approach, whether it be through a trial or out of a trial. But is the idea of introducing treatment free intervals to therapy really as a means of decreasing infections, but with maintaining efficacy of the drug? And so this is the hypothesis of our study is that for patients who are, who do have a good response to therapy, that by introducing treatment-free intervals might not compromise efficacy of the drug and secondarily might ultimately lead to the decrease in infectious complications. And so those who are eligible. 

Jenny: Let's talk about the study design and then we, sorry to interrupt you about eligibility, but let's talk about who's eligible and who can join and all that.

Bea Razzo: Yes, absolutely. So, those who are eligible to join are patients who are getting to teclistamab and have been getting it for six to nine months with a good response. So, they're presently in a good response and have gotten it between six to nine months or more. And there are a few other eligibility criteria, but those are the main ones.

And pretty much when enrolled, they take a break from treatment and are monitored closely with blood work and with monthly calls from the research team. And as well as a close follow up with their primary oncology team, as well as an investigator of the study if the primary oncologist is not a member of the research team.

Jenny: And how long is the break?How long can they go?

Bea Razzo: In the study it's up until two years is how long we would monitor them if they remain in remission off teclistamab for up to two years. But if markers of multiple myeloma start going up, then they restart teclistamab.  And they remain on the study. This is not a reason to go off the study.

Bea Razzo: But rather the goal by restarting teclistamab is to see if those numbers stabilize or if they were significantly elevated, if they fall back into a range that we consider to be a response. And then in that case, they remain on teclistamab until its current indication, which is through progression or death. And only in the cases of progression, we come off study or if they choose to switch on to a different drug. But otherwise we continue to monitor and study.

Jenny: Well, it's great. You even saw this with some antibody drug conjugates - like you can space out dosing and you can reduce frequency, or you can reduce dose and space out frequency and take strategies like that because not every patient is going to be the same. I think that's what patients need to understand too. Their multiple myeloma is so different. So they need to understand the differences, some of those differences you're going to see.

Just in responses, how long you stay in remission, how fast your myeloma grows. Some of those differences are genetic and you need to know the genetics of your myeloma cells so you can make this kind of plan. But I love this approach because you're getting closer to personalized care for patients and you'll be able to separate out who's this best for in all your analysis. I love it.

Bea Razzo: Absolutely. The big reasons for doing this as a clinical trial, even though we've heard of many specialists who plan on doing similar approaches off of a study, we felt it was important to formally study this to be able to be a little bit more precise. And so it's not required of everybody, but we do offer the option of getting bone marrow samples at the time of enrollment and at the end of study to try to do some more advanced research techniques to answer some of these questions that might help us personalize therapy even further. 

And then we do also do a few extra research blood draws that definitely can allow us to do a little bit more immune studies to really try to understand who are the patients who do well for a long time, even after stopping teclistamab. What about changes to the immune system, either cause an increased risk or decreased risk of infectious complications? So a lot of kind of exciting secondary questions.

We hope to at least scratch the surface.

Jenny: This is the learning that happens. I mean,these new drugs get approved and then investigators like yourselves have to really understand the nuances and gain the experience of use. So you see that in your clinical practice and then it spurs these new ideas. Like, what if we had these pauses in between therapy? Can we do that?

You know the toll it takes on patients to be on continual therapy, it's tough. And it's great if it's working, you don't want to stop therapy. You'd rather have no myeloma and be on therapy than have myeloma and be off therapy. But ideally, it would be wonderful to segment these patients out into these different groups and really know who really needs to stay on and who can go off.

It's kind of an experiment that never really happened once maintenance therapy became a thing, it was like, oh, okay, everybody's on maintenance therapy and until progression or whatnot, instead of segmenting patients out to say who really needs it, who really doesn't. And so I love that you're thinking about these things.

Al Garfall: As I think myeloma patients know, there are so many day-to-day questions about myeloma therapy that we don't have answers to. You know, we have the big clinical trials about what drugs work and which ones don't and response rates, but some of the basic practical questions, you know, like for example, with maintenance therapy, you know, someone who's been in remission on maintenance therapy for a long time? Should I continue? Should I stop? Dose adjustments. We don't have good data for those questions, but every day, doctors and patients are making these decisions together, but we don't know what the outcomes are because a lot of these questions are not studied systematically. And so that's what we're trying to do with just a very small way with one question here. We know that there's an interest from patients in maybe stopping therapy when they're in a really, really good remission and they've been on therapy for a long time.

We know that physicians think that there might be, you know, a benefit to stopping therapy, but, you know, we want to try and study it properly as opposed to just kind of doing it. And so that's what we're trying to do with the study. Now, this is still gonna be a preliminary look at this question, you know, we're not randomizing patients to continuous therapy or interrupted therapy, but we think it's a first start to address this question just to get some basic information.

And there's some risk to that approach too. And that's one of the discussions we have with patients that there is some risk we think that if you stop therapy maybe you're going to compromise the control of the myeloma. But we also think that maybe that's not the case. And the only way to know is to study it.

Jenny: Well, it's fascinating. So this is a UPENN only trial or is it open at other centers? I think UPENN only, right?

Bea Razzo: It's presently open at Columbia as well.

Jenny: OK. I didn't know.

Bea Razzo: And we're working with opening at other partner centers, but definitely for folks in our greater area, we've really tried to make our protocol as accessible as possible. So allowing for remote enrollment, where patients can be referred, to PENN mostly for enrollment, but then continue the majority of their care with their local teams. So we've really tried to make it as streamlined and easy to access to our patients in the greater area.

Jenny: Well, here's something that I suggest, and this is why we're gonna be running the three-year bispecific antibody study, is you are able to do that kind of intervention. And through Health Tree Cure Hub, we're able to see what standard of care or what's happening in the real world. And we could compare those two arms together and provide that kind of data so that you would have a full understanding of what's happening when you're doing the intervention and then what's happening in the real world with patients that look similar. And that's the reason that we created Health Tree Cure Hub is to be able to facilitate that type of real world evidence research. So it would be really fun to dig into the same data set, same type of patient, and then use real world evidence as a comparator. I think that'd be amazing.

Al GarfalL: Yes, I agree. And real world evidence is one of these emerging areas. And there's all once these therapies get outside the clinical trial setting, it's really important to see how patients are doing in the real world, because there's a lot of differences between the regular practice of medicine and what happens on clinical trials.

But the challenge with real-world evidence is always the data. In clinical trials, data is gathered very carefully, whereas in the real world, it's a little bit more scattered. So efforts to try and organize real-world data are really important. And I agree that could be an interesting comparison for us to make in our group of patients who are going to have stopped teclistamab. We're going to make an initial comparison back to the clinical trial of patients who got teclistamab, but it would also be neat to compare it to a group of patients in the real world who have been getting continuous teclistamab. 

Jenny: It's exciting. Do you want to share any other clinical trial strategies that you're thinking about for bispecific antibodies or other clinical trials in the bispecific antibody space that you want to call out?

Al Garfall: That's a good question. There are a lot of clinical trials that are using by specific antibodies in earlier lines of therapy. And actually one that we're excited about is a trial that's going on in the European Myeloma Network that we're hoping to join with some other sites in the US that's testing teclistamab as a maintenance therapy after stem cell transplant.

And the exciting thing about this clinical trial is that in the trial, teclistamab is being given as a fixed duration, just like what we're trying to test in our trial. Whereas most of the trials with bispecific antibodies are giving them continuously until progression. This one as a maintenance therapy is, I believe it's a one-year fixed duration course.

Jenny: Interesting.

Al Garfall: And the focus of this trial is it's taking patients after stem cell transplant. And the three different treatments that you could be randomized to are the standard Revlimid maintenance, teclistamab maintenance, or the combination of teclistamab and Revlimid. And so it's offering maybe like a Revlimid free maintenance option. If that arm turns out to be the best, we could maybe, maybe we wouldn't have Revlimid as the standard maintenance after transplant, which is, which is a very effective maintenance therapy would also come with a lot of side effects. So, that’s a very exciting trial. 

And also just because of our interest in fixed duration therapy, cevostamab is a bispecific antibody that targets FCRH5. It's that one that isn't FDA approved yet. But all of the clinical trials, as I understand it with that drug, are giving it as a fixed duration therapy. So that's one that's being studied from the start as a fixed duration therapy. 

We even have preliminary data from ASH a couple years ago on that fixed duration approach with cevostamab. It's a very limited number of patients at that point who had stopped therapy and continued, most of them continued in response for many months after that. Hopefully we'll be hearing more about the results of that trial with longer follow-up and other clinical trials where cevostamab is used as a fixed duration therapy. And we're hoping if we show promising results with our fixed duration, one of the outcomes of that might be that other companies who are investing in trials that buy specific antibodies will start to design them from the beginning as fixed duration courses.

Jenny: Okay, fascinating. Well, we will be including a link to this open clinical trial in the transcript so patients can find that trial. And I just want to thank you both for participating in this show. It's incredible what you're working on. I think the UPENN program, it was so leading edge for CAR T in the beginning. It continues to be so leading edge in all of immunotherapy. So just thanks to both of you for everything you're doing in this space for myeloma patients, we appreciate it so much.

Al Garfall: Thank you, Jenny, for the opportunity to be here and for all you and HealthTree do for our patients also.

Jenny: Well, thank you.

Bea Razzo: Thank you for having us.

Jenny: Thanks for listening to the Health Tree Podcast for Multiple Myeloma. Join us next time to learn more about what's happening in myeloma research and what it means for you.