CAR T-cell Therapy: Multiple Myeloma
Tuesday, May 2, 2023
Presenter: Gunjan Shah MD, MS, Memorial Sloan Kettering Cancer Center
Presentation is 32 minutes long with 17 minutes of Q & A
Summary: CAR-T cell therapy is a promising new treatment for multiple myeloma. This presentation describes the versions of this therapy that are currently available, their potential complications and side effects, and the risk/benefit calculations in deciding when this treatment is appropriate.
- Treatments for multiple myeloma have expanded over several decades. Current treatments were only approved after 2000 and many clinical trials are exploring additional treatment options.
- There are two current CAR T-cell products for multiple myeloma. They require patients to have had at least four prior lines of therapy. However, current clinical trials are investigating whether these treatments could be used earlier in the disease process.
- Common side effects of CAR T-cell therapy are cytokine release syndrome and neurological toxicity, as well as infections.
(05:03): CAR T-cell treatment for multiple myeloma is now approved and approval for bispecific antibodies should be coming soon.
(08:39): CAR T-cell therapy uses the patient’s own T-cells that are removed, engineered to kill cancer cells, and returned to the patient’s body.
(09:20): Chemotherapy is used to make the patient’s body receptive to the CAR T-cells.
(11:00): CAR T-cells usually last at least a month in the patient’s body.
(17:48): In clinical trials, between 60% and 90% of patients with multiple myeloma have had some response to these treatments, and the treatments have worked for up to two years.
(19:51): The timing of side effects differs with each CAR T-cell product and must be monitored and treated accordingly.
(21:56): Patient-reported outcomes often describe fatigue, especially during the first month after CAR T-cell treatment, but it can last longer as well.
(23:40): CAR T-cell therapy is expensive but may be worth it because it works differently than all of the prior treatments patients typically receive.
(27:26): The possibility of using donor cells and its risks and benefits in CAR T-cell therapy is also being investigated.
(28:12): Two big concerns for patients interested in CAR T-cell treatments are insurance approval and timing.
Transcript of Presentation:
(00:00): [Lynne Spina]: Introduction. Welcome to the workshop, CAR T-Cell Therapy: Multiple Myeloma. My name is Lynne Spina and I will be your moderator for this workshop.
(00:08): It is my pleasure to introduce today's speaker, Dr. Gunjan Shah. Dr. Shah joined Memorial Sloan Kettering Cancer Center in 2016 and is part of the adult BMT service and the cellular therapy services. Her research has focused on improving access, tolerability and outcomes for patients with lymphoma and myeloma undergoing autologous and allogeneic stem cell transplant and CAR T-cell therapy. Dr. Shah is also, interested in the comparative and cost-effectiveness of treatments for hematologic malignancies. Please join me in welcoming Dr. Shah.
(00:57): [Dr. Gunjan Shah]: Overview of Talk: Thank you for inviting me. And I'm happy to give this talk and happy to answer any questions at the end.
(01:10): So, overall, what we're going to go through is that there are two commercially available, meaning FDA approved, CAR T-cell products for multiple myeloma. The timing of this therapy depends on treatments that people have had beforehand and the approvals by the FDA.
(01:30): There are two main side effects that are different than side effects we think about with transplants. One is called cytokine release syndrome and the other is immune effector cell neurotoxicity, otherwise known as ICANS. But there are also, a few other side effects and complications that are important. And overall, there are many options for therapy with multiple myeloma.
(01:58): What I want to go through today and think about is in the bigger spectrum of not just the care - we do a treatment and do you get into remission? How long does it last for? But there's a whole spectrum of when we look at whether a new treatment is helpful, worth it, beneficial, and part of that falls under this umbrella of value-based care.
(02:28): And so, there's, of course, the clinical outcomes that we think about in terms of responses and survival. There’s also the quality-of-life side of this. Even if it's the best treatment ever, if nobody can get it how is that helpful? If there are So, many side effects, are we really helping patients by giving them this treatment? And is it different between different populations in terms of responses? Things we need to think about.
(03:00): There’s also the healthcare system side. Can we physically in the buildings and, with the support systems and everything that we have, accommodate this new therapy? If we need X number of chairs to actually collect the cells for this process, are there enough places to actually give the cells back?
(03:24): And then There’s also the cost part of this. How much is the insurance covering? How much of it is being transferred back to the patient in terms of out-of-pocket costs? How long are you out of work for? And so, all of this, together, plays into the system of how we actually think about new treatments.
(03:43): Treatment options for multiple myeloma have greatly expanded over several decades. For multiple myeloma, we've been very fortunate. Over the last six decades, the landscape of treatment options has become very broad. And I give this example. If people that have seen the TV show "Call the Midwife", the first episode of the current season has a patient who has multiple myeloma in the '50s and '60s where that show is set. And all they were able to do at that time was give people steroids and pain medications and keep them comfortable.
(04:20): And that's very interesting to see, when we're now at a place where we have So, many more treatment options than that. Through the '70s and '80s we got more traditional chemotherapy and the availability to do transplants.
(04:36): Current treatments for multiple myeloma were only approved after 2000. And then really, after 2000, is where all of these, what we call sort of novel agents or newer therapy options. Everything that you actually get now was developed and approved after 2000. And so, we got treatments such as bortezomib and lenalidomide, and the next generations of carfilzomib, and pomalidomide, daratumumab, sort of the newer monoclonal antibodies.
(05:03): CAR T-cell therapy for multiple myeloma is now approved, and approval for bispecific antibodies should be coming soon. And then we come to the more recent approvals for the CAR T-cells. And hopefully soon to be approved - the one is approved now and then more coming - the bispecific antibodies. And so, we have made a lot of progress over this time.
(05:23): Lots of questions remain about how to use these new therapies for each individual patient. There's a philosophy of treatment, now, in terms of thinking about what order we use all of these different treatments in. And so, some of it is how effective are they? How quickly do they work? How likely is it going to work? And how long is it going to work for? Is this a one-time treatment? Is this you're on indefinitely for while it's working? If we pick one option now, does it prevent you from getting the rest of the options in the future?
(05:49): And then all of these treatments obviously have their own risks and benefits that go with them. And are there short-term risks and long-term risks? And how do we balance when you do which one, and when it's worth taking the extra risk for the benefit which could potentially be more or less?
(06:08): CAR T-cell therapy and bispecific antibody, or T-cell engagers, are two new treatments that work in slightly different ways. The first thing I want to think about are the two newer treatments: the CAR T-cell versus the bispecific antibody or T-cell engager.
(06:24): And so, the idea behind a CAR T-cell is really that we're taking your immune cell, the T-cell, which is always in your body, which is normally there to fight off viral infections and get rid of cells that are abnormal that shouldn't be there. And what was done was trying to figure out a way to soup up your own immune system.
(06:45): And you can see here where we have this receptor on the plasma cell, this little green thing hanging off on the left side of the plasma cell in the center. And the idea is that we want to bring the T-cell, whose job it is normally to kill off the cells that shouldn't be there and get it to purposely come to that particular plasma cell. And how do we get it to know that "Hey, this is what we want you to kill"?
(07:11): The way that's done is that this whole yellow piece, here, is added, which is the part that makes it the CAR, which is the chimeric antigen receptor. And so, there's a binding area which is going to connect to the receptor on the cell itself. So, you can think of it as sort of like we're putting a homing device on, and these two pieces have to match So, that it knows to pull this cell over here.
(07:32): And then in order to make this cell then work and do its job, we have to have these extra activation and co-stimulatory domains. And the differences in these are where you get different side effects between the different products. It’s also, why potentially we may eventually say one works better than another one. But this whole sort of yellow construct, here, is what we call the CAR T-cell, what's getting added.
(08:02): On the other side of this you'll see the bispecific T-cell engager. And in this, we still want the T-cell to do its job, but here what we're actually giving a patient is this sort of orange/red area where the drug, itself, binds to both, it binds to the T-cell and it binds to the plasma cell through that receptor. And so, the drug actually has two things, which is why it's called bispecific, and it binds on both sides. And so, the same idea, that you're bringing that T-cell to kill the plasma cell, but this time it's a drug that's connecting the two to each other.
(08:39): CAR T-cell therapy uses the patient’s own T-cells that are removed, engineered to kill cancer cells, and returned to the patient’s body. So, how do you actually get a CAR T-cell? So, what happens is the patient is connected to a leukapheresis machine, which is basically a machine that looks like a dialysis machine. So, the blood comes out one side, we take the cells that we want, and the rest of the blood goes back into the body.
(08:56): Those T-cells that we've taken out are sent either to a company for an approved product, or to whatever lab for the investigational products. And they add, as we said, that yellow protein to the outside. And then they grow it up and expand it and make many, many, many of them. And then they freeze it and they send it back to us.
(09:20): Chemotherapy is used to make the patient’s body receptive to the CAR T-cells. Once it comes back, we give what we call lymphodepleting chemotherapy and we'll talk more about that in a second. It's mostly the fludarabine and cyclophosphamide, and the idea behind that is that you're making space. So, we need to get rid of some of the current immune system So, that there's space for these T-cells to go and grow. So, you get the chemotherapy for a few days and then these cells are put in.
(09:46): The timeline of how this works is that right now it takes between four to eight weeks, or so, for the cells to actually be made. So, once it's decided that someone is going to get those cells, the apheresis part happens. That's the taking out of the cells and then that production happens. And in the meantime, we still have to do something to control the myeloma for six weeks, or so, until the cells are ready, and that's what's called bridging chemotherapy.
(10:14): [Bridging therapy] can be radiation, it can be some combination of drugs someone hasn't had yet. But basically the idea is if it controls the myeloma, that's great. If it gets us down to even really small amounts of myeloma, even better. But really, just So, [the myeloma] is not growing while we're waiting.
(10:31): Then you have the three days of the lymphodepletion chemotherapy and then on day zero you get your infusion.
(10:38): What then happens over the next couple days is there is some of that killing related to the chemotherapy itself. So, the blood counts are going to go down and then the blood counts are going to start coming back up about two weeks later. During that time the CAR T-cells are growing and expanding.
(11:00): CAR T-cells usually last at least a month in the patient’s body. We don't know exactly how long the CAR T-cells last, but we know that it's usually, at least, a time [when the CAR T cells are] expanding and then a time of those cells going away. So, the hope is that the longer they last, the more they're doing, but at least usually about a month or so.
(11:18): There's the risk of the cytokine release syndrome and the neurologic toxicities, which we'll talk about. And then the risk of infections which lasts longer as we wait for that immune recovery to happen.
(11:29): You'll see that there's this later box that I have over here for the same color of the risk of the neurologic toxicity, and we'll talk a little bit more about that later. But there is a risk on the myeloma side of some side effects that have been seen at later time points than just the early neurologic toxicities.
(11:52): CAR T-cell therapy has several side effects in addition to cytokine release syndrome. So, some of these main side effects that we think about, beyond the blood counts going down and coming back up due to the chemotherapy, can be the cytokine release syndrome, which we'll talk a little bit more about later on. But there can also, be things like fevers, your heart rate going up and down, your blood pressure going up and down, your oxygen level going up and down.
(12:13): Neurologic toxicity can also occur and can be mild or serious. The neurologic toxicity can be on a very mild level - word finding difficulties, trouble writing, getting tremors. And then on the more serious side it can be seizures. The other things that we can see during all of this, we can see some nausea and vomiting, some diarrhea. These are primarily more related to the chemotherapy.
(12:33): Inflammation and infections may also occur, especially when blood counts remain low. We can see more inflammatory things. So, this can be some fluid that's building up, the liver numbers going up, the kidney function worsening. And these can be related to inflammatory changes that are happening as the cells are attacking each other.
(12:47): And then, of course, the infections as we talked about, partly related to the blood counts being low and the overall immune system being low.
(12:56): In the first month after CAR T-cell treatment, bacterial and fungal infections are major risks potentially followed by respiratory viruses. So, during all of this, we know that there are these risks. And we can tell which infections people are more likely to be at risk for, and there's sort of this acute time, which is usually during that first month when the blood cell counts are low. Primarily during that time, we're much more worried about bacterial infections and fungal infections. So, you're on prevention medicines for those.
(13:27): As the white blood cell count recovers, your immune function can still be low. That's when we worry more about potentially respiratory viruses. Pneumocystis is another type of infection that you can get when your immune system is low. And then later on tends to be more pneumonias, upper respiratory infections, and depending on how long and how low the immune system is, it can still be shingles and other viral infections.
(14:03): There are many FDA approved CAR T-cells for leukemia and lymphoma. So, on this slide you'll see all of the FDA approved CAR T-cells, many of which are for lymphoma and leukemia. You'll see I've added in red on here as we get more and more indications and more and more timelines. So, on the lymphoma side, it used to be that patients had to have already had two lines of treatment and this was available for the third line of treatment.
(14:27): We've also, added other histologies, meaning other subtypes of lymphoma beyond the diffuse large B-cell, to follicular lymphoma and mantle cell lymphoma. And then, on the acute lymphoblastic leukemia side, there are products approved for that as well.
(14:44): There are two main CAR T-cell products for myeloma. Both require patients to have had at least four prior lines of therapy. On the myeloma side, the two products that we're going to spend more time talking about are idecabtagene (ide-cel) (Abecma®) and ciltacabtagene (cilta-cel) (Carvykti®). Currently, both of these require patients to have had at least four different treatments, or four lines of therapy, and so, that's where the biggest counting happens right now for whether someone is eligible for treatment or not.
(15:13): Both are made from your own cells. These are not made from donor cells. As we were thinking about in that original picture, which is repeated down here, that there are these different domains.
(15:32): So, the binding domain here, both of them are this anti-BCMA. This means that the protein that they are being attached to, or what they will connect to on the plasma cell, is called BCMA. There are other investigational CAR T-cells that are looking at two or three different other targets - other proteins that are on the outside of the myeloma cells - that these CAR T-cells could attach to.
(16:01): In these ones, the main difference in the co-stimulatory of these domains, basically what these tell us is that there are certain side effect profiles that can go along with that. In the lymphoma side, the different products have different of these domains. In the myeloma side, these are actually both similar and that they've used similar domains, So, that the type of side effects you're going to have are not necessarily different.
(16:29): The big difference, the only real difference that we see here, is that the cilta-cel, or Carvykti®, has two BCMA targeting sites. So, basically, it means that instead of there just being one area in that part that can connect to the plasma cell, there's actually two of them there. So, in theory, potentially you can connect double and maybe kill it a little bit more.
(16:57): As I said, both of these products require you to have had at least four lines of treatment prior.
(17:03): So, what do we know, So, far, from the clinical trials that have been done? And again, we actually can't compare these directly to each other because each of them comes from a separate clinical trial. And in each of these clinical trials they had their own eligibility criteria for patients that were included, So, you can't really compare them to each other directly.
(17:27): So, there are three columns that we have listed here,: the ide-cel (Abecma®), the cilta-cel (Carvykti®), and then teclistamab (Tecvayli®) - the bispecific antibody. So, what we know So, far, you can see that these have relatively short follow-ups, meaning that the patients on the clinical trial have been followed between a year and a year and a half, but this is what they saw.
(17:48): In clinical trials, between 60% and 90% of patients have some response to these treatments for multiple myeloma and the treatments worked for up to two years. And you can see that across all three that 60% to 90% of patients will have some response to treatment, which is great. Whether you have complete response, and the timeframe for how long that takes to get to it, is a little bit different potentially. And, again, this is where it's really hard, because you automatically want to sort of be like, "Well, 80% looks better than the 30%." But they're different patients. What they got beforehand is a little bit different and so, it's not directly comparable in that way.
(18:21): What we can see is that it was working for the patients that were on these clinical trials between one and two years, at least at that time. And the same for the progression-free survival - between nine months and about a little bit more than two years of was how long that these worked . [Numbers shown on the chart are median numbers - 50% of patients were above that number and 50% of patients were below that number.]
(18:54): So, now, the other side that we look at is the side effects. And so, when we look across all of these, we separate these out into any amount that was complained about, or seen, on a clinical trial and are the any grade [of severity]. The more severe ones are the grades three and four.
(19:13): Cytokine release syndrome with fevers were common side effects but they were mostly controllable and most patients did not need intensive care unit monitoring. And you can see, which is actually really great, that across all of these products the cytokine release syndrome, which again is the fevers and heart rate's up and down, and the blood pressure's up and down, So, that all of these products have a pretty good chance that you're going to have at least a fever in those early days. But that the chances that you're going to need to go to the intensive care unit for monitoring, that you're going to have to be on blood pressure support or breathing support are not very high. And mostly they're controllable. So, we can start treating early enough that we can prevent it from getting more serious.
(19:51): The timing of side effects differs with each CAR T-cell product and must be monitored and treated accordingly. You can see, though, that in the ide-cel and the teclistamab, these happen sooner rather than later, within a day or a couple days, and they may last for four or five days. And this is why we talk about doing these treatments, at least the first week of dosing for the teclistamab and the ide-cel, that you get the infusion in the hospital where you can be watched for those first couple days, because it's very likely to happen sooner rather than later.
(20:17): The cilta-cel tends to be where the side effects happen, but they tend to happen a little bit later. And so, if we automatically say someone needs to be in the hospital for the first seven days, but this doesn't start till seven days, then it's much more likely that you'd end up getting discharged from the hospital and then ending up having to come right back because you get a fever the next day.
(20:36): And so, the point of this really to say that we have to really look at the timing of when these side effects happen, So, that we can plan accurately for when people need to be monitored more closely or not.
(20:48): Neurologic toxicity may also occur, but high-grade reactions requiring intensive care monitoring are less common. The neurologic toxicity is kind of the same idea. These are much lower percentages than we see with the lymphoma CAR T-cells, and so, we have to have a different plan for monitoring and follow-up than we do for those products. And, again, you can see that the high-grade ones, which is more where you're getting seizures and having to be monitored in the intensive care unit, are much lower, which is good.
(21:11): Delayed neurotoxicity is very rare but may also occur. There has been seen with all of the products of the CAR T-cell, these ones and the investigational ones, this delayed neurotoxicity. It's very rare, there's only a few cases seen. But there can be this Parkinson's-like syndrome that happens even two months or three months after the CAR T-cells. And so, there's a lot of work that's gone on to try to figure out why? Can we predict who would have those side effects? It's such a small number of people right now that it's very difficult to know that or predict, and so, all we can really do is watch out for it and treat if that happens.
(21:56): Patient-reported outcomes often describe fatigue, especially during the first month after CAR T-cell treatment but it can last longer as well. The other big side effect, and the other thing that we want to look at that's important, are these patient- reported outcomes. So, this means that it's not when you go to the doctor's office and the doctor says, "How do you feel?" And you say, "I'm nauseous, I'm tired." These are more where you directly get to answer how nauseous or how tired you are.
(22:16): And most of the time these are done through survey questionnaires, either on paper or through an electronic porta, where you're being tracked over time to see are you getting better? Are you not getting better? Should we do something intervening? But you have much more control over how you're saying that these exist.
(22:36): And these are two of the figures that are there, one from each product's trials, where they kept track on these fatigue scales of what people were answering.
(22:47): I think the biggest thing to think about here is that over time it does take... Because of the treatment that you're having, people tend to be more fatigued especially in that first month. And then it sort of recovers towards baseline but it can take a long time, depending on what's going on, whether people relapse or don't relapse, and how long it's working for.
(23:14): But I think incorporating these allows patients to be more involved in their care. And so, you'll see that these are more and more being done and reported and being asked of people, even not in a clinical trial, but just ways that we can incorporate these into the standard practice So, that we can best coordinate care depending on what's going on.
(23:40): CAR T-cell therapy is expensive but may be worth it because it works differently than all of the prior treatments patients typically receive. So, there are a lot of discussions that you will see of how much do these treatments cost? And is it worth it? The cost comparisons that people have done So, far have really tried to compare different treatments with what's considered standard of the moment.
(24:01): And remember, the CAR T-cells right now are approved for people who've had at least four lines of treatment and so, they've probably had many of the approved therapies already. And so, when you compare to what you can potentially get if you've already had all of the approved treatments, that's where we really see a lot of the benefit, because the CAR T-cells work differently than all of the other treatments and we really do see these differences.
(24:27): Now the big thing with this, and you can see in this intervention cost, is that, automatically, the CAR T-cells cost at least $450,000. That's built into the product cost itself. And that's when we go to insurances and say, "We want to give our patient a CAR T-cell," this is what the insurance company is approving. We know that on top of that cost there is the actual cost of the infusion, of the monitoring in the hospital, the monitoring through that first month, and so, all of that gets incorporated into this total cost section.
(25:05): And then there' are a lot of assumptions in here of how well people did, how long they had to be in the hospital. But you can basically see that in these approximate calculations, it costs about, per month of extra survival, anywhere between $20,000 and $30,000 per month.
(25:30): And so, this is not to say that we shouldn't do this or everybody shouldn't do this, or anything like that, but it's more just to take into account that we have to balance the whole system. And so, what's the most appropriate in the order in which we do it, trying to maximize how likely are things to work, and in what order they're most likely to work in. And these are some of the factors that we look at.
(25:59): Current clinical trials are investigating whether CAR T-cell treatment can be used earlier in the disease process and how side effects can be more effectively managed. There are a lot of clinical trials ongoing with the two approved products. So, one of the big things to look at is can we use these treatments earlier? So, why wait until people have had four or more lines of treatment already? Can we do this when they've only had two or three lines of treatment? Can we do this in the beginning and this is the first treatment that they get? Do we do this instead of a transplant? What happens if you've had a transplant and the myeloma's still there? And people that are more high risk, can we use this as a way to prevent the myeloma from coming back?
(26:42): Oher clinical trials that are ongoing: we talked about how the cytokine release syndrome and the neurologic toxicities are really what limits people. And it's really why we keep people out of work for a month, it's why we keep everybody close by for that first month. And so, if you can prevent those from happening or you can treat them quicker, can that get people home sooner and not have to stay close by?
(27:06): If we get all of this to work better, if we get all of those response rates up at 100%, 90%... How do we make these better? And can we put more than one target? Instead of just the BCMA, can you have it be two different proteins that we're using at the same time, So, that you're more likely to attack the cells?
(27:26): The possibility of using donor cells and its risks and benefits in CAR T-cell therapy is also being investigated. And can we get the cells from a donor? There are some theories that when you've had four or more lines of treatment that the T-cells we get out to make into CAR T-cells are already very tired. They've seen a lot of treatments; they've seen the myeloma for a long time. And so, if you get a donor cell that's healthy, that's never seen any of these things, can they be made into better CAR T-cells that are going to last longer in the body, that are going to work more?
(27:52): But obviously, then, we have to sort of balance with the risks of using somebody else's cells that are not your own. And how do we do that without having the risks of graft-versus -host disease, that we can sometimes have on the allogeneic transplant side?
(28:12): The biggest concerns for the CAR T-cell treatments are the insurance approval and timing. As you know, it takes a little bit of time from when we decide that we want to give someone a CAR T-cell to actually be able to get approval from the insurance company. And so, if people need treatments in between because their myeloma's progressing very rapidly, how do we do that?
(28:34): Right now both of the commercially available products are giving centers a couple slots a month, meaning one or two, at most three or four. And so, how do you take into account everybody that qualifies for these treatments, everyone where we think it would benefit them, and how do you plan in order what happens when? What treatments we can use in between until then? Is a big part of what we do.
(29:01): As I said, the sort of logistics of this, of how do you have people stay close to a center? Staying one hour away in New York City doesn't mean you'll actually go that far, versus if you're in the suburbs and you're at a center not in the middle of a city staying one hour away, you might actually be really far away at that point. And so, that's very different.
(29:24): The access to these products, the approvals are different in every country. Even within the US they're only available at certain centers, most often bigger academic centers, places that already do transplants. Because of the risks and the potential risks that can get very significant, in terms of the side effects, being able to have good ICU level care and having the doctors around that focus on that, that understand how the CAR T-cells work and can work in conjunction with the CAR T-cell teams, is really important in terms of having that set up in advance.
(30:02): The challenge with CAR T-cell treatment is balancing the risks and benefits of different therapies at different times and in different sequences for each patient. And so, which treatment is right is not always the question. Often, we have to change the question to which treatment is right when? We know that transplants are very effective, melphalan is a great, very active drug for myeloma and has been for 40 years. It's not as expensive obviously, there's no manufacturing concerns, it's available everywhere. The risks of getting that type of transplant are very small in terms of infections. And we've been using it for 40 years, we know the safety of that.
(30:34): Versus with the CAR T-cells and the bispecific antibodies, the data is very early. We don't have people that are five and 10 years out from a CAR T-cell or a bispecific antibody even of the first clinical trials yet. And so, as we learn more from that, as we work out whether we can get more slots available. Can we get more and more people to be able to be treated in a shorter amount of time? Can we make it So, that people don't have to wait six weeks in between, and potentially have patients ' disease progress to the point that they can't even get to their treatment even though that we tried to get the cells out?
(31:11): And so, all of that are things that we take into account as we're planning the different treatments and the order. And so, that's why most likely along the case of time, from the time of diagnosis for a patient with myeloma, multiple of these will come up. And it's just a question of which order and how best to use each one to get the longest amount of time where we're able to control the disease.
(31:38): So, I'll stop there and I'm happy to take questions.
(31:45): [Lynne Spina]: Q & A. Thank you Dr. Shah for your excellent presentation. I'll now begin the question-and-answer session. The first question, Dr. Shah, is How long will my immune system be compromised following CAR T-cell therapy?
(32:14): [Dr. Gunjan Shah]: So, that's a very good question. There are a few different levels to that answer. So, there is that short term side, where when we look at the infections that are there, there's the very short-term part where when your blood counts are low, you're at much higher risk of certain infections. In the later infections we actually follow immune system markers, So, CD4 counts, CD19 count. With blood work we can measure how active and how many of those immune cells have come back.
(32:47): And so, there are some prevention medicines that people will be on for at least six to nine months, even 12 months. And it really depends. We check those numbers every couple months, usually every three months or so, once you've gotten past the first couple months, in order to be able to decide when it's okay to stop the prevention medicines and that that risk goes down.
(33:10): [Lynne Spina]: Thank you. Can you share the thresholds for each vital that I should be watching that are markers for immunosuppression?
(33:23): [Dr. Gunjan Shah]: So, the easiest way to sort of think about that is the first of these is the neutrophil count to come back up, So, that bacterial prevention usually stops once your neutrophil count is above one.
(33:36): The immune system numbers that we watch in the later one as I mentioned is the CD19 count. And so, that one we usually want the immune system or that CD19 count... sorry the CD4 count to be above 200 on at least two checks, So, meaning it's staying stably high enough. And that's when we would stop some of the other prevention medicines.
(34:02): [Lynne Spina]: Thank you. You mentioned two FDA approved CAR T for multiple myeloma. Are there more in clinical trials? And does insurance only cover those that are FDA approved?
(34:20): [Dr. Gunjan Shah]: So, there are many, many more in clinical trials, depending on where in the world you're looking at the trials. Even within the United States there are several others that are for both the same target of the BCMA, there are some for other targets, you'll see something about GPRC5D, So, just different proteins on the outside of the myeloma cells.
(34:43): The insurance covers completely for the product itself, the FDA approved CAR T-cells. For clinical trials it's really insurance specific, but most of the time what happens is that the product being investigated, itself, is covered by the clinical trial, as is any research blood work or procedures. But the standard of care things - the chemotherapy part, the taking care of you part - all of that is still covered by your insurance. And so, we still would have to get approval for everything except for the part that's actually being studied.
(35:22): [Lynne Spina]: Thank you. Is CAR T-cell therapy a second choice after an autologous stem cell transplant for patients with myeloma? Or perhaps the first? What would be the determining factor as to which would be better?
(35:40): [Dr. Gunjan Shah]: So, at the moment, because both products require patients to have had at least four lines of treatment, most patients will have, unless they're very old or have very significant comorbidities or things that prevented them, most people who are getting a CAR T-cell will have already had at least one autologous transplant. So, one time with melphalan before they're getting to a CAR T-cell.
(36:07): There are more and more clinical trials that are trying to move it up, to do it earlier in treatment. And so, we don't know yet whether we would do this instead of a transplant or before a transplant.
(36:19): I will say that melphalan is still excellent as a treatment for myeloma. And so, I think that most likely what will happen is even if the CAR T-cells move to very early lines of treatment, the transplant will end up just being later on at some point. Because right now even with the CAR T-cells we still don't have a way of saying that the myeloma won't come back and that people are cured.
(36:45): [Lynne Spina]: We have two questions that are relating to smoldering myeloma. Is CAR T-cell therapy for high-risk smoldering myeloma a viable option?
(36:57): [Dr. Gunjan Shah]: So, at the moment it's not. Right now, it's still being studied in much later lines of myeloma treatment.
(37:07): The big thing I would say to think about with smoldering myeloma is that smoldering myeloma, the goal there is partly to prevent it from becoming active myeloma. And so, if you are doing a treatment that has a higher risk of side effects and complications, then you do have the risk of transforming to full active myeloma that you would be treating.
Then it's very much a question of whether we're actually helping anybody by using that treatment earlier. A patient who was never going to need treatment, who would've been able to be monitored for several years but gets a really terrible infection and dies because we did a CAR T-cell early, that's where the balance is in deciding any treatments for smoldering myeloma. And so, I think right now we don't have any evidence to say that a CAR T-cell is the right treatment for smoldering myeloma.
(38:06): [Lynne Spina]: I am an 81-year-old female, I had CAR T infusion last November. At what point can I begin replacing my vaccines? And at what point can I begin assimilating back into my community?
(38:22): [Dr. Gunjan Shah]: So, I think there are two parts to that. One is, as we said, your doctors are probably monitoring your immune system. And it's great that you have all of that. Presumably you're doing well as you're on here and asking us questions. And that's great.
(38:38): I would say it partly depends. We're very careful in terms of infection. So, I think as long as you're being careful, the rates of COVID in your community are much lower, if you're inside places potentially still wearing a mask and trying to avoid people who are actively sick, you can probably start to integrate more into the society. I mean, I again would have to defer directly based on your numbers to your doctor. But that's where I would say.
(39:08): In terms of the vaccine part of it, we've mostly been repeating the COVID vaccines from about six months. Again, some of this can depend on how well you'll respond will depend on your B-cell count, So, the CD19 numbers, when they check your immune function. There are T-cell responses as well, So, again, it depends on how much of that CD4 count you do have.
(39:32): But the rest of the vaccines, in terms of pneumonia and polio and things like that, what we mostly do is actually check the titers of those vaccines, because you don't lose all of them the way that you do with a transplant. And so, what we would say is replace the ones that have gone down. Oftentimes that's going to be the pneumonia vaccines more than anything else.
(39:57): [Lynne Spina]: The next person says that he had a BCMA infusion late August in 2022 and heavy load at start. He responded well but it only lasted two months. He was non-secretory and then came back secretory. How does disease load play into response and duration?
(40:20): [Dr. Gunjan Shah]: That's a very good question and we don't really have the best answers right now. That's sort of where a lot of the research is, of trying to figure out... For how much disease you go in with, most people are already not responding to many other treatments. So, for us to just be like, "Oh, let's try to give something more before we start this," is often not really feasible or realistic.
(40:46): We do to a degree... It's always harder the more myeloma that's there. But that being said, there have been patients that respond really well. And how long it lasts for is the other part that's very difficult to predict beforehand. So, I think those are really active areas where people are trying to figure out those answers.
(41:13): [Lynne Spina]: This next person asks with BiTE, B-I-T-E, how is it fairly compared to CAR T therapy with efficacy, duration and remission?
(41:26): [Dr. Gunjan Shah]: So, let me see if I can go back to this. So, the currently approved BiTE is the teclistamab, which is also, for BCMA. Again, here it's also, still very hard to compare, because people have often had a CAR T-cell before they've had the teclistamab.
(41:48): What I would say is, mostly, the big differences here are that the CAR T-cells are sort of a one and done treatment, that you do them the one time it works or it doesn't work.
(42:04): The one approved bispecific, unfortunately, at the moment is mostly weekly, indefinitely, And so, that makes a big difference in terms of how much you're still having to be in the clinic.
(42:20): And obviously as long as things are working that's great, but there's some side effects to that as well. With the CAR T-cells, you expect your immune system to recover because you've had the treatment once and then it starts to eventually recover again. With the bispecifics it's a continuous thing where your immune system is low because of that.
(42:44): That being said, it's much easier in terms of slots and availability and things like that to get a bispecific, because you're not waiting for the manufacturing component. It's more of a drug that has to be given. And so, that's really the big difference right now, is the one and done versus continuous treatment.
(43:06): Response rates wise, they've actually been relatively similar So, far. And so, we think that all of these are appropriate and effective treatments. And a lot of it is which one can you get where you are.
(43:22): [Lynne Spina]: I have one more bag of my stem cells left from the initial collection from 2014. Can that bag of cells be used for the CAR T-cell therapy?
(43:36): [Dr. Gunjan Shah]: It's a very good question and the answer is, not directly. So, it's not like we could take those frozen cells, send them to a company and say, "Hey, here, we want CAR T-cells." Those cells that you have stored are stem cells, which are baby cells that can grow into your healthy blood and immune cells.
(43:53): And so, the way that you would be able to use those, there's sort of two ways. One, and we have a clinical trial where we're doing this right now, is that for people who have a lot of active myeloma, we do a second, third, whatever number auto transplant. We use those cells that you have stored from the beginning, and between three and six months afterwards you now have new T-cells that are not exhausted, that haven't seen all the treatments that people have seen in between. And those T-cells are then extracted and made into CAR T-cells that presumably - and this is what we're studying - because they're less exhausted, do they work better? So, that's one way you can do it.
(44:35): The other way that those cells that are in the freezer have been used is that sometimes after the CAR T-cell treatment, while we'd like and we have on the graphs and everything, where your blood counts go down and by a month they're coming back up, there are some times where we have longer times, weeks, months where the blood counts are still staying very low.
(44:55): And oftentimes what actually works for people that have myeloma, that for the people that lymphoma don't have this benefit, is because of having those extra cells in the freezer we don't give more chemotherapy but we can just put those cells in. And those baby cells will go and grow and help to recover the blood counts afterwards. So, there's still a benefit to having those extra cells in the freezer.
(45:19): [Lynne Spina]: Great comprehensive answer. Does the CAR T therapy that targets multiple myeloma differ much than a therapy like axi-cel for lymphomas?
(45:34): [Dr. Gunjan Shah]: The main difference is the target itself. The lymphoma CAR the target is the CD19, and in the myeloma the CAR the target is the BCMA.
(45:43): The logistics of how we make it into a CAR T-cell, how it gets infused, the side effects that we're looking for, the monitoring, all of that is pretty similar. The risk of the side effects, So, the rate of people that are going to have cytokine release syndrome and neurologic toxicities, those are a little bit different, but the actual process part is very similar.
(46:09): [Lynne Spina]: The next question is, you've touched upon it because they wanted to know about the expected side effects of CAR T. But they also, are asking Which drug has the best result or the fewest side effects? Would that come into play in your decision which drug to use?
(46:27): [Dr. Gunjan Shah]: So, we don't know at the moment, of the two approved CAR T-cells, which is better. We would love to have that answer, but we don't know. What we know is they both work and they both work well.
(46:42): And because of the manufacturing issues, the availability, and that certain sites are only approved for one versus the other, at the moment what we basically say is whichever one we can get and get in the right timeframe, that works for being able to treat someone that's the product that we use.
(47:13): [Lynne Spina]: And then my last question that I've got here is, I am a spouse of a person who is a candidate for CAR T-cell therapy for multiple myeloma. And I am wondering What are the differences or will be the differences in caring for somebody going through CAR T versus an autologous stem cell transplant?
(47:40): [Dr. Gunjan Shah]: So, that's a really good question too. There's are differences and a little bit of a long-term difference. So, the short-term difference is, part of it is very similar, the job of the caregiver is making sure the person is eating and drinking enough, making sure they're taking all of their medications. That if they get a fever, if they don't feel well, that you're calling and going back to the treatment center.
(48:14): The big difference here, especially early in those first couple weeks, is looking out for that cytokine release syndrome and neurologic toxicities. On the autologous transplant side, you're mostly looking for infections, but on this side, you're really looking for those other side effects. And so, if all of a sudden they have more of a headache, they have trouble speaking, they can't get their words out, that means something in this. And so, that's really the biggest difference in terms of being the caregiver, watching out for all of a sudden they don't make sense when they're talking to you.
(48:49): In the later time points, most of the time, because the chemotherapy is lighter here, that recovery in terms of energy and appetite and stamina and blood counts happens in a shorter timeframe than it does with the auto transplants. And so, we do expect people to have the potential to go back to work or the potential to do more activity usually even by that 30-day mark. Versus with the auto transplant, it may be two or three months before they really feel totally back to normal energy-wise. So, I think it's partly timing of fatigue and energy that's really a bigger difference later on.
(49:32): [Lynne Spina]: Closing. Thank you. And I'll be closing this session now, that was our last question. And on behalf of BMT InfoNet and our partners, I'd like to thank Dr. Shah for a very helpful presentation. And thank you, audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way. And enjoy the rest of the symposium.This article is in these categories: