(Guest Lecture): September 2023 - Making Revolutionary Treatments Mundane

Thank you. And thank you everybody for coming today. Great presentation so far, but we will now switch gears a little bit and talk about immunotherapy and the management of multiple myeloma. And I'll touch a little bit upon our work that we're doing in the precursor space here, as Dr. Gobriel has mentioned, but we will jump into some of the recent data that has led to a lot of these new approvals and kind of where they fit into the treatment paradigm. These are my disclosures. So Dr. Gobriel alluded to this previously in her talk, and as you can see, there's been tremendous progress in the field of multiple myeloma, particularly over the last, I would say, 10 years or so. So she kind of highlighted the initial discovery of thalidomide and dexamethasone. At that time, stem cell transplantation was the clear standard of care for patients that could receive it and can tolerate the high dose chemotherapy because that was leading to improvement in overall survival for patients. And then came the next generation immunomodulatory drugs, proteasome inhibitors like Revlimid and Velcade. And then you started to learn that if you combine these therapies together, you're seeing responses that were so much better than even what the stem cell transplant had brought in the previous era. So it really led to this excitement of not only having the disease under control with these really, really effective therapies, but also prolonging life and having patients kind of stay on some of these therapies for a long, long time. And then around 2015 came our first approval of monoclonal antibodies, and this includes drugs such as daratumumab that I'm sure many of you have received, elotuzumab, which is another monoclonal antibody. And then we started to basically add those monoclonal antibodies to what we had previously used in patients with multiple myeloma, such as Velcade and Revlimid and dexamethasone. So now when somebody walks through the door with newly diagnosed multiple myeloma, we're giving them four drugs at the same time. Back 20 years ago, you couldn't really imagine that because the four drugs we would have used back then would have had a lot more toxicity and certainly not the same level of efficacy. So because these drugs work so differently, you can actually combine them, and that usually, you know, with some adjustments of doses, as I'm sure you've all experienced, you can get many patients into these really, really deep responses with these quadruplet-type regimens, particularly in patients with newly diagnosed myeloma. Now we've entered a new era with these immunotherapies, so that's kind of where we were a short three, four years ago. At that time, we had no immunotherapies, and now we've really kind of moved on to... What's going on here? Is that me? Now we've really moved on to some of these new CAR T cells and biome specifics, and I would argue this is where, you know, we have the most potential right now because these therapies work so differently than anything that we had before, and now we have basically five of these approved to be used in patients, so two CAR T cell therapies and three biome specific antibodies. The problem is that these sit in patients that have had five lines of therapy, so as you can imagine, as I think it was alluded to earlier, you're not eligible for it in many circumstances, even though we think you should get it, but unfortunately we don't have control over that because of just where the FDA has approved it, at least as of today. So what we're trying to now do is move these earlier, and then also, you know, discover new combinations with some of these therapies, so that's kind of where the field has gone more recently, so I'll touch upon that throughout my talk. So what is BCMA? So BCMA is actually a protein on your myeloma cells or plasma cells, so this was a new discovery that led to a lot of these immunotherapies being approved, and then you had learned that you can actually target BCMA using so many different approaches. You have CAR T cells, you have these T cell antibody drugs, and I'll explain in a second, and then we actually previously had this drug called BALANTAMAB that some of you may have received or BLENDREP. That also targets BCMA, but it does it with a very different mechanism, so if you're sending T cells over to the myeloma cell using BCMA, it's actually just delivering this toxin that's in the drug that's attached to it, so even though it's BCMA, the mechanism is totally different, so a lot of times people get confused, if I've had one BCMA therapy, can I get the other? You know, which one of these will be better, et cetera, so just know that BCMA, all that means is that that's the target, and then what you do with the target is really depending on which medication or therapy or mode of therapy you're using. So CAR T cells, I'm not so sure how many of you are exactly familiar with how it works, so CAR T cells basically is taking your own T cells, which are part of your immune system, and then genetically modifying them by putting a code in there that is going to then express something on the edges of that cell that's going to then go attack the myeloma cell, so it's really creating an army of your own T cells that are modified to recognize BCMA on the myeloma cell, so that's basically what CAR T cell therapy is. And then the way it works is that once we identify that you're eligible for CAR T cell therapy, we will then do what's called a-phoresis, which is removing your T cells out of your body using a very similar machine to how you had your stem cells collected, for example, although it doesn't require the same injections, et cetera, you can just collect them in one day, and then they get shipped off to a manufacturing facility, and there's two current CAR T cells that are approved. It takes anywhere between four to six, sometimes eight, weeks for these cells to come back, and then when they come back, we usually give three days of low-dose chemotherapy. That's designed to sort of suppress your immune system just enough so that these CAR T cells can go in and expand, and that is what leads to the responses that we see. So as you can imagine, it's a pretty lengthy process. You have to know if somebody's eligible, whether advance, coordinate the a-phoresis, wait for the cells to be made, and then deliver the actual product. Where it's currently approved in fifth line, that can sometimes be a challenge, right? Because you don't have... Obviously, patients have had all these previous therapies, which is why they're eligible in the first place, so you have to then keep the disease under control in some way, shape, or form for a couple of months for the T cells to be made. So that's one of the challenges or nuances with CAR T cell therapy. So there's two CAR T cell products currently approved. One is called the Beckma, one is called CAR-VicTi. They are more similar than different. They both target BCMA. They're both CAR T cells product with the same exact a-phoresis and manufacturing, as I mentioned. The only difference is that the CAR-VicTi product has two BCMA binding domains. So when they make the CAR receptor that goes on to the edges of the T cells, it actually binds to the BCMA, I think a bit stronger than what we have seen with the Beckma, which was the first one that was approved. And I think that perhaps was leading to some of the better responses that we're seeing with that. But again, both of these have the same label, four prior lines of therapy, and you must have had the three classes of drugs, proteasome inhibitor, immunomodulatory drug, and a CD38 monoclonal antibody. So the first CAR T product, the Beckma, was approved based on this CARMA trial that we participated in here. Basically what this showed is that it was very active. So the higher doses were shown to have even more activity than the lower doses. This is how trials work, right? You kind of start low, and then you kind of see, escalate to a safe level, and then kind of come up with what you think is the best dose going forward. And in this case, it was 300 to 450 million cells was kind of where the FDA label currently sits. So at that dose level, we started to see results, patients getting approximately a year of remission time with this approach, and longer if you achieve a complete response or an MRD negative response. So this was very exciting, obviously, led to its approval. Then came CARVIC-D. So again, very similar, but what we started to see, in the first trial, you're seeing essentially about three quarters of patients, maybe slightly less respond to the Beckma product. Here you're close to 100 percent. So basically everybody that got this CARVIC-D product responded to therapy, which was very exciting, so it was clearly much, much higher. And the complete responses, where patients have complete disappearance of their M proteins and no disease in the bone marrow, were almost twice as high with this one compared to Beckma. So this clearly looked to be more active. And then this is what led to its approval. And over time, we've been waiting to get a sense of how long does that remission last with CARVIC-D, because we know it's approximately a year with the Beckma. And then more recently, just at the ASCO meeting this year in summer, the update was given after approximately a three-year follow-up that it is about three years. Actually, the median progression of resurveival was 35 months. And this is one-time therapy. So I know all of you, you know, that you ask me in clinic all the time, can I come off this therapy? Do I need to stay on maintenance, you know, et cetera? This is sort of one and done, at least as of now. If you can get to it and you respond to it and you get through some of the toxicities of CAR T cell therapy, this is the benefit. You can be off therapy potentially for three years, hopefully longer as we move this earlier in lines of therapy. So as you know, this has been, you know, both great options. Some of you probably got a Beckma, some of you may have gotten CAR-VICTi. Unfortunately, it's been out of our control because of the supply issue and how long it takes to kind of make some of these cells. So, you know, I'll kind of touch on that a little bit later. But essentially, they're both great therapies in my mind. They do have some differences. So as I mentioned, some of the response data is a bit different. How long it works for is a bit different. But also the toxicity is a bit different. So CRS or cytokine release syndrome, which means that you have activation of your immune system that leads to fevers. And sometimes patients can get pretty sick from that. That's the toxicity of these T-cell therapies. The median onset is about a week out for CAR-VICTi. And it's only one day for a Beckma. So when patients get a Beckma, they get usually a fever that night or the next day for the most part. Whereas in CAR-VICTi, it's not for a week. So what that's led to is us skiing, giving this therapy outpatient. So now when somebody comes into our center for, and they want to get CAR-VICTi, we are essentially treating them all outpatient. So they will get their cell infusion outpatient, and then we'll check in with them every single day. And then if they get a fever, or we think they need to be admitted, then they get admitted. So you're not sitting in the hospital for a whole week waiting for a fever, which is what's happened so far. So that's been actually really good. And then there's a risk of low blood counts. Some patients have had low blood counts for a while post-CAR T-cells, which we're still trying to grapple with a bit. And then there's this neurological signal. So not just confusion, et cetera, that can happen in the middle of when people are having fevers and are in the hospital, but there's also some reports of these delayed neurological toxicities that occur with these CAR products, perhaps a bit more with CAR-VICTi, where patients have had either some weakness and balance issues and Parkinson's-like syndrome, and then some cranial nerve palsies, like Bell's palsy, for example, that we see after CAR-VICTi. So these are some things, again, rare. Obviously, the benefit is far greater than the risk, in my opinion, for patients that are getting it, but it's something you need to know about because now you have options. You don't have to just choose this and take on the risks, because they're all a bit different. So what about bringing this early? Right now it's in fifth line, as I mentioned. So you can make a lot of arguments for using it early. So you have Fitter T-cells before. Right now you're collecting your T-cells after all this therapy over all these years. Your immune system is a lot healthier in the EMGA smoldering, early myeloma stage, than it is in patients that have had five lines of therapy. It may be safer. Many of you that have had CAR T-cell therapy will know that it's a bit of a, I don't want to say crisis, but it's very unsettling when your disease is active, you're trying to be on some chemotherapy that you know isn't working great, you're crossing your fingers a bit that the cells are going to come in on time. So we want to avoid that. We want to kind of do this when there is more predictability. You have slow rise in your M-spike, and you say, okay, you're now eligible, you have time to make the T-cells, and you're not in that situation. So I think bringing it early will hopefully allow that. It may be more cost effective. As we know, most myeloma therapies work better in earlier lines, but CAR T-cells have kind of like a fixed cost. So instead of being on maintenance with all these drugs for four or five years, perhaps a one and done would actually be better from an economy perspective. So those are some of the rationales for bringing it early. So what is the data? This is a CAR-titude IV study. So this was a very important study that was just reported this year. So what this is is actually using CAR-victi in one to three prior lines of therapy. So this is essentially bringing it to second line instead of waiting until fifth line. And it is being compared to some pretty standard regimens that we use in this space. So daratumumap, pomalidomidexamethasone, or pomalidomidevelkadexamethasone, some combination that we've used for patients historically in this setting, and it was all compared to CAR T-cell therapy. And what did it show? So basically it showed this. The standard of care therapy arm with the daratumumap type combinations led to approximately a year's worth of disease control. And the median still has not been reached with CAR-victi. So you can clearly see a big difference between the two in terms of how long it works for. So this is, I think, setting the stage, hopefully, for the labels to change for CAR-victi and bringing it earlier based on some of these bigger phase three trials. So more to come on this, but I do want you to know that this trial has already been reported, and it's being reviewed with the FDA I think early next year. So hopefully the label will reflect that. I wanted to highlight also some of the other studies that are ongoing. This is now the CAR-titude V trial, again, looking at CAR-victi. This is for patients that now have newly diagnosed multiple myeloma that are not heading to a stem cell transplant. And it's now being compared to RVD regimen, which is Revlimidvelkadexamethasone, that I'm sure many of you had, and comparing it essentially to CAR T-cell therapy. So no results yet on this, but again, setting the stage perhaps for using it even earlier in patients that have had newly diagnosed disease. And then similarly, the CAR-titude VI trial is now looking at CAR-victi and comparing it head-to-head to stem cell transplant. I think this is going to be a really important study, because as you know, transplant has had an evolving role over the last 10, 15 years. We've done a lot of studies to see if we still need to do it anymore. Some of those studies still keep coming back positive, because we still see the benefit of stem cell transplant, at least in terms of how long those remissions last. But I think all of us would like to move beyond it to not expose patients to high-dose chemotherapy if we can avoid it. Because as you know, it does have some deterioration of quality of life, at least for the short term, and it'll be nice to move away from that with some of these new therapies, but we have to prove it in some of these trials, which is what's ongoing now. So this is looking at the four-drug induction regimen of daratumumab RVD, and then either getting a transplant or getting CAR T-cell therapy with CAR-victi, and then having maintenance therapy with lenalidomide. So that's something that hopefully we'll have some answers for in the next few years. So this is all great, but in the end it all comes down to, can you get it? So it's not just the fifth line issue, it's also the supply issue. So we've had, since the approval of CAR T-cells, a huge challenge in myeloma to be able to deliver this therapy. Even today, we're getting about two, maybe three slots a month for CAR-victi. And as you can imagine, that's not enough for a center like ours, where we have so many patients that are interested in this therapy. So that's why I think at times over the last few years, at Beckman, CAR-victi, we kind of just said, well, this is what's available, we'll do what's there. Now a lot more patients want CAR-victi based on the data, right? But I'm seeing patients, I saw patients this week, and they're interested in this. Our next available slot is November, and that's when they'll get collected. I can't treat that patient until December or January, and their disease is super active, right? So these are like real scenarios that we come across, and I think that has to improve. I think it has to be moved early. We have to be able to, if for these patients, I would argue within two weeks of meeting them, for this to actually get to scale where we can actually treat patients in real time, you know, with these therapies, but we're just not quite there yet. So these are some of the limitations. And then come the bispecific antibodies. So this timing I think was great, because as we were struggling with some of these, you know, availability issues, we had Toclistimab approved last year, which is again a BCMA-directed T-cell therapy, but it's not CAR T-cells. It's taking your T-cells to the myeloma cells using just an injection, an antibody drug. So mechanism is actually quite similar, but it doesn't require the aphoresis and manufacturing and things like that. So this was approved based on this Majestic 1 trial, which showed about two-thirds of patients responded to Toclistimab. So it is a bit lower than what we saw with CAR-VICTE, but it does kind of seem similar to the results we saw with the BCMA actually. So this seems to be quite active. You still have the risk of CRS. You still have some of the risk of low blood counts, et cetera. But in general, they're a bit milder than we see with CAR T-cells. But on the contrary, these are continuous therapies. These are approved to be given weekly, once a week. So what this means is that you have to stay on it. And if you stay on it, there's significant suppression of your immune system. So what we see with this is a lot of infections. And now what we're trying to do is change some of the schedules and modify it based on how patients are doing to maybe not give it every single week, right? So these are some of the changes that are now occurring with CAR T-cells. So these are some of the changes that are now occurring where patients that have had a great response for let's say four or six months, we can then back off to maybe twice a month, et cetera. But this is an area that we still have to figure out. A lot of patients with T-clistomab are on IVIG to prevent infections and non-prophylectic measures that do our best to prevent it, but still, unfortunately, this remains an issue with these BCMA biopsy specifics. And now we had a second BCMA biopsy specific approved called L-dernatomab. And this was approved again based on this Magnetism 3 study looking at again a very similar overall response rate of about two-thirds of patients responding to therapy. So it looks relatively similar compared to T-clistomab, but we don't yet have kind of like the median progression free survival for these patients. So it's about a year, as what we've seen with T-clistomab. It could be a little bit longer with this. Again, they're smaller studies and you can't really compare them head to head. But with that being said, I think we may be getting a little bit of a longer duration of response signal with this, but we're just getting this up and running in our clinics. And as we treat more patients in the real world, we'll have a better sense of is it any better than T-clistomab? Are they kind of interchangeable? That's something I think we don't know yet, but it's nice to have another option in this space. And then we also had another biopsy specific antibody approved in the last month or so called Talquidimab. And this is now looking at a totally different target. So we're kind of moving beyond BCMA and targeting something called GPRC5D, which sounds like a Star Wars character, but it's actually just another protein or antigen on the myeloma cells. And this is nice to have again another target instead of just using T-cells to attack BCMA over and over again. Now you can actually take your T-cells and attack something different. And this is the Monumental 1 trial showing approximately three quarters of patients respond to this agent. So again, it's a biopsy specific antibody, so it has some of the similar toxicities. But you do see a slightly different signal. You do see a bit more taste changes, some nail bed changes, rash. So a little bit of a different toxicity profile. And I think we'll have to see how this plays out in the real world as we start treating patients, because some of those can have quality of life implications. So it's nice to have this option again approved in fifth line. All of these are. But we may be able to move from one to the other because we now have different targets. And what about combining the two? We have also the first data from this redirect one study that was presented at ASCO this year looking at basically combining these two by specifics. And you see a pretty impressive response rate. You're kind of now getting up to that 80, 90 percent response rate by combining these two. And again, the toxicities are there, but it's not like the toxicities doubled. So you still have the same CRS, you have the same kind of target specific toxicities, but it wasn't deemed to be like completely out of control when it comes to toxicities, which is always nice to see when you're combining these immunotherapies. So I think this is kind of the wave of the future is perhaps we can give them simultaneously like we've done before with myeloma therapies where you just essentially combine them to get even better results. So more to come on this, whether we're going to be doing this. And we're also participating in a CAR T cell trial looking at this GPRC5D target. So now it's actually doing basically what I said about CAR T cells and my specific antibodies with BCMA therapies. You may have a CAR T cell against GPRC5D and a my specific antibody. So it's nice to have these options. This is still in clinical trials. But I wanted to highlight this because this has been now presented this year that you're also seeing activity in people that have had prior BCMA therapy. So I think this is going to become kind of like our fourth class of drugs. And you have to kind of go beyond that in terms of what do you offer patients. So it's nice to have this kind of developing in the background as well. So more to come on this. What about small ring myeloma? I know they've kind of touched upon this a lot in the previous session. Again, as I mentioned, immunotherapy may make a lot more sense in this space because your immune system is completely robust and you haven't been exposed yet in many circumstances to therapy. So this will avoid perhaps some of the exposure to traditional therapies. And you can perhaps harness your own immune system to attack the disease and maybe even cure the disease before it even occurs. Right. So that's led to some of our trials that are currently enrolling at Dana Farber. This is the Immuno Prism trial looking at essentially to glist of another by specific antibodies and comparing them to let a little my index. So this is a randomized trial, two to one randomization to either to cluster map for now. And we're going to be adding more arms to this study and opening it at more centers. And we should have our first results presented at the meeting this year that we've submitted to. We have rolled approximately close to 30 patients already in this trial. And there's a lot of activity here. So some more to come on this. And similarly, we are the first center to study CAR T cell therapy and high risk small ring myeloma. So, again, these are not patients that have low risk disease or M. These are patients that are really showing signs that they're headed towards myeloma. And can you give them CAR T cells? And this is also ongoing now. We've treated a few patients so I can share that with you. It's a very slow enrollment because we have to make sure it's safe in this space. So basically one patient is being treated essentially two months apart right now per the FDA guidance. And once we get a few patients treated, we will then be able to share our results here. So this is something that, again, right now it's not obviously anywhere close to being standard of care, but I think it's going to inform us a lot about what happens when you give immunotherapy to patients with high risk small ring myeloma and maybe setting the stage to do this in patients with newly diagnosed myeloma because it's one step beyond that. So still at a research level, but a lot going on. So just to summarize, obviously I just kind of shared a lot of immunotherapy progress. But what is the best way to deliver these T cell therapies? They all have their pros and cons in my opinion. I think they're all great. They're all way better than anything that was available just a short few years ago. CAR T cells I think will have the highest response rates, but you've got to just be the right patient for it at the right time because there's a lot of coordination that needs to occur. Bi-specific antibodies you can give right away. So I think this is why we're seeing so many patients receive this recently. And now you have several of them. So you can actually choose between them and maybe go from one to the other. So I think patients that cannot wait for CAR T cells are essentially all getting these bi-specific antibodies. And then Bilanthomat was taken off the market because one of the phase three confirmatory trials and show the results that they were hoping for, but it wasn't taken off the market because of safety. So this does have some unique toxicities, particularly with the eyes for people that may have received it. But it was actually pretty active for people that responded to it. And there's a population out there that's not going to be able to tolerate bi-specifics and CAR T. So it's still under study in different combinations and maybe it'll make a comeback. But it'll be nice to have that option perhaps available in the future. Can you give one BCMA therapy after another? I think right now it's hard to know, but we are seeing responses in patients that have kind of gone in that sequence. It's a bit lower, but more to learn there about kind of exactly what the best approach is and what is the best sequence. Do you go bi-specific CAR T or do you go CAR T bi-specific? I think right now that's an open area. I think a lot of us feel like CAR T followed by bi-specifics may make more sense. So that way you're not having constant stimulation of your T cells and maybe not responding as well to another T cell therapy immediately after receiving continuous bi-specific antibodies. Maintenance after CAR T cells, we'll see. There's some trials ongoing in this space. And then how do you choose between the two BCMA bi-specifics? I think it's a little bit to be determined right now between efficacy, toxicity, convenience, cost. I think we'll get a sense over the next year or so how these are being used. Which line of therapy will be administering these BCMA therapies? Well, hopefully sooner than the fifth line of therapy that currently exists. Mainly because we're giving all these quadruplets and maintenance therapies with several agents now in the front line setting. Many patients have had exposure to all the drugs and would meet one of the indications for the CAR T cell therapy even today, but just haven't had five lines of therapy, which I think is kind of arbitrary. So hopefully that's going to change over time. And particularly with some of the trials that I've highlighted, more results there will tell us what the role of stem cell transplant will be. And I think overall there's limitations with each approach. I think we have to just acknowledge we need to understand better the mechanism of resistance, why patients progress on these therapies. There's even more targets that are currently under study, like FCRH5, which is another protein on the myeloma cell. There's a bi-specific for that that's currently in trials. And then combinations, can you combine this with some of our traditional agents? So a lot going on, but again, it's really great to see that we have these options available for patients because we're seeing, again, amazing results and now it's more about fine-tuning and putting the puzzle together even more. That was my last slide. Thank you.