(Guest Lecture): September 2023 - Personalizing Options for Relapse/Refractory Patients

It's not necessarily a bad thing, right, that all these car teasers are still here in a way, right, because you may still be on some very tolerable, relatively infrequent therapy for years and years and years before you have to even get to that point. And that wouldn't necessarily feel like you're missing out or something because you're stable on pomalidomide, for example, and with daratumumab, right, just to give you an idea. So you have to think about it just kind of as a big picture, you know, this is myeloma, this is what the roadmap may look like for me for the next several decades, hopefully. Right now at this point in my myeloma journey, I'm on this pill in a shot and then maybe in the future I'll have some T cell therapies, but don't just miss out on the fact that you're just kind of, you know, in that moment getting some stability out of some of these regimens because they're approved for a reason because they've been, you know, beneficial for a long, long time. So how is the field shifted? As I mentioned before, we're giving quadruplet therapies up front, so everybody's getting daratumumab, most of the time Velcade, Revlimid, and dexamethasone. Often with or without transplant, patients will then go on maintenance therapy. That's usually Revlimid, but nowadays we're usually giving something more than Revlimid in many circumstances. We might give daratumumab once a month with it. Sometimes we give Velcade twice a month, depending on neuropathy and some of the other issues that these drugs can cause, but frequently people may be on some of these therapies for five, six, seven years before you have to worry about the disease again. And then what happens now is since you've had these agents at diagnosis, and let's say you continue two of them for maintenance, when the disease then emerges, you're then refractory, which means that you're resistant to what you were just on. So Revlimid resistance is really common. Almost everybody's Revlimid resistant at the time of their first relapse now because of the way we treat myeloma on the front end. And now frequently people are also resistant to daratumumab because they're on it for years and we're just kind of venturing that now because we started doing front-line daratumumab like five-ish years ago for the most part. So some of the relapses that we're starting to see now are both Revlimid and daratumumab refractory. So you have to think about attacking the disease differently. You can't just continue those and tweak it, et cetera, like we used to because you have all these other options. So to me, one of the biggest determinants of what you get for relapsed myeloma is what you were just on because that tells us a lot about what you may respond to in the future. So frequently we try to switch the drugs around to confuse the myeloma and attack it a bit differently. So we may go to pomalidomide, which is a slightly different version of Revlimid, usually in combination. So carfilzomib or Kyprolis is an IV version of Velka that's a bit more potent. So that's frequently done as a relapsed regimen, that combination plus dexamethasone, which can always help these agents work a bit better and then we taper them down usually over time. And then beyond that, you still have several other approved drugs like elotuzumab. We have a drug called salinexor. We have Cytoxin, which is an older chemotherapy drug. And most of the time, you're kind of isotexamab that we touched upon before. So you kind of try to put a regimen together under individual circumstances and then hopefully get many years out of that regimen before you have to move on to something else. So that's where every situation is a bit unique. And we use some of the previous treatments you've had plus the side effects you've had plus your other medical history to make some of these choices before you move on to some of these T cell therapies. So that's kind of a general sense of how we think about management. So happy to answer any questions and love to hear. Yes. If you're refractory, they are a tumor man, and put a different treatment in between, can you then try Cytoxin? Yes, so absolutely. So this is something we've learned over time with myeloma is that because you're refractory to that class of drugs, for example, doesn't automatically mean you won't respond to a different version or in that same class. So the Revlimid and Pomelist is a perfect example of that. Same thing with Kyprolis and Velcade. That's how these drugs were approved. People that had previous therapies with these agents responded. Now, the response rates aren't as high as it would be if you were never exposed to that class, but that's what it is. We don't yet have that same data with Isotuximab and Daratumumab. If you just go back to back, we're not expecting to see that benefit. But to your point, if you had very long-term benefit with Daratumumab, which many people And you go on to, let's say, Carfold'somide, Pomelidomide, Dexamethasone, something like that, could you revisit that in the future in a different combination? Absolutely. That's something that we do, but the data is not quite there yet to solidify that as absolutely, we should be doing that. Thank you. Just a question about lines. Could you define what is a line of therapy? Yeah, it's very unfortunate, actually, how this all played out because before all these agents, we kind of went one at a time, essentially, so it kind of gave us a sense. So think about lines as the amount of relapses you've had that have required a change in therapy. So if you had one relapse, you're probably entering your second line of therapy, because you had your first line that stopped working. You had a relapse, then you had your second line therapy, and then you had another relapse, then you had your third line therapy. So it's kind of trying to define how many times do we have to switch things because your disease was starting to become active again. So that's a line. That's why when the question was asked previously, like, what about transplant? It's just part of your first line therapy. You haven't had a relapse yet. So we can't call that a new line of therapy. So that's how it's viewed. But I think that whole terminology is getting very dated because, like I said before, we have all these agents we give front line now, and we've called lines of therapy, but we also call them what we call triple class refractory. That means that you've had a CD38 antibody like daratumumab, you've had a proteasome inhibitor like Velcade, you've had Revlimid, which is an immunomodulatory drug. Frequently, you're having all of these at once. And if you stay on them, let's say for whatever reason, and you're having a relapse, you're technically resistant to all three classes. That's one of the requirements for bispecifics and CAR-T right now. But you're still in second line. So something doesn't add up, right? In one case, you're a refractory on one end, but you haven't had enough lines of therapy. So that's what's creating the challenge right now with the terminology there. Thank you. Yes. I had relapsed in May, but it was amazing to me how fast it happened. We could literally, in a month, see it in the blood. It literally went from being perfectly fine to sort of the Velcade and the Revlimid just stopped working. Yeah. And now I've started on the D-Tab and the pomalist and the steroids, and it's doing wonderful. Great. Yeah. It's amazing. We could see it in one month. Yeah. That's a good point because we see several different patterns of relapses, right? So there are some that we call biochemical progression, which means that your protein numbers are just starting to go up. Some people don't experience that five, six years after their first line therapy, and they may still go one to two years without having to really make any changes. All we've seen is that the protein has reemerged, but it's not causing any issue, right? So in that circumstance, sometimes we can observe patients for a while before we have to absolutely make that switch, and we have some internal criteria that we use for that just to make sure that we're not putting anybody in their harm's way. But that's one example. Conversely, you have somebody who had a great initial response but had a relapse pretty early. In that case, we don't wait because we know that their disease biology is different compared to the first person, that the same thing happened gradually over so long, right? So each of those scenarios we think about differently in terms of changing therapy, but that's why we check the protein numbers usually once a month, because a lot of patients will ask, well, I've been on Revlimid forever. Why do I have to still come in once a month or once every two months or whatever, right? This is why, because things can change, and you don't want to just assume that the behavior it's had all those years is going to continue for the next few years because you don't really know. Yes? Do we have to worry about being on these drugs for a long period of time? I've been on Daratumab plus Pondylus and Dent since April of 2017. Just completed my 72nd cycle this past Wednesday. And when they're on, you can clap. Yeah. When they're on these drugs for such a long time, do we have to worry about toxicity? Yeah, so this is a great question. When all these drugs were first coming out, I think everybody was obviously so happy and excited about all these approvals because it was leading to improvement in prognosis. Now we're starting to ask that question, like, do we need to continue forever? Can we stop therapy in certain patients? That's being studied in clinical trials right now. But what we have learned is as patients live longer and longer and longer, there are some downstream effects for some of the therapies we have done a long time ago. The best example of that is stem cell transplant. While it's great because it prolongs, it historically prolonged survival, now it still adds a few years of remission time for patients before they have to move on to their next slide of therapy. It does have some deleterious effects to the bone marrow because you're kind of wiping out the bone marrow with chemotherapy. And then when it regenerates, it's got different genetic mutations in it and things like that that may not necessarily turn into anything. But you've disrupted that environment, right? We have seen a certain pattern. People could develop leukemia and other bone marrow conditions a long, long time from now. That's one example. So every agent is different in terms of long-term risks. Dara-2-amab actually find to be one of the best drugs for long-term exposure because it doesn't have a lot of day-to-day side effects. Most people tolerate it well. It's relatively infrequent once a month. Now it's an injection. The only risk is really infections. So that's something that we have to be mindful of. So far we haven't seen any significant downstream effects with Dara. Pomalidomide, again, it's sort of in line with Revlimid. So there is a risk of second cancers that comes up also with Revlimid in these agents. Risk of blood clots, infections again. But I will say because you're a perfect example of that. You've been on it for so long. I actually consider these to be overall very safe for long-term exposure. But in my mind, the ideal scenario would be, and hopefully we'll get there one day, is that somebody gets diagnosed with myeloma. We give them really, really effective therapy and then we stop. And hopefully we cure a subset of those patients and then treat who needs to be treated if they have a relapse. Kind of like they do with lymphoma and some of the other diseases where they give a combination therapy that cures some patients. And then some will relapse and then we treat those perhaps the way we treat myeloma today, but we're just not quite there yet. Yes. Can you just expand a little bit on CAR-T's effectiveness in remission and frequency of recurrence with CAR-T, sometimes in a very short period of time, and why you see that big variability there? You mean in terms of the different patterns of relapse post CAR-T? Yeah, so this is all because think about the people coming into these shawls. Everybody's different. Some people have had myeloma for 20, 25 years. Some people have had myeloma for three years and they've gone through five lines of therapy. The patient profile is very different and these studies are also 100 patients. We're not talking thousands of patients. Now we're getting the real world data now because we've treated so many on the commercial aspect of things. But this just comes down to the biology of the disease for some patients. And then also not everybody is going to have the same benefit with each therapy. So we see that all the time. We have patients that got what we consider to work for majority. It may not work for that person. So right now, unfortunately, it's trial and error. I wish we had tools to say, okay, your myeloma response to Velcade, yours response better to Revlimid type drugs. We don't have that right now. So until we develop that, you're always going to have this kind of mixed bag in terms of some people benefiting, other people don't. I've also had patients that get, let's say, a BCMA CAR, don't really have a great response, get a different kind of CAR-T. So on a clinical trial and I've been in remission for three years. So it's really finding the right thing for the right patient. But I will say for CAR-T cells, especially CAR-VICT, you are seeing mostly across the board responses, but you still will have always those patients that relapse early because of their disease biology. Yes. Is stem cell transplant a one-time deal? Let's say, hopefully, it'll never relapse, but when the time comes, would that be considered again or not? So it's a good question. It's something that we have studied for a long time, actually. Some parts of the world still do two transplants, back to back, actually. They will get one and then they'll get another one within three to six months. Why? Because there have been some studies showing that benefits particularly high-risk patients. So if you hit their disease twice with the high-dose chemo, you tend to actually have improvement in overall survival in some of those studies. There's that data that's there, but we then did studies in the US and parts of the world that had access to some of these therapies that you can give until it stops working or give them for maintenance and actually did not see the benefit of the transplant. So the reason why some other countries still do it is that they can't give Revlimid for 10 years. They can't give Dera-Tumorab when they want. So while it's super expensive and the healthcare costs are definitely an important topic, but when you're talking on an individual basis, you and I are going to make that decision because of your disease and what we can get access to. So we have the ability to give all these drugs here, which leads to longer remissions and that way you can avoid a second transplant. So I rarely have second transplants in my practice. There is always that handful of patients that have had eight, nine years, 10 years response post-transplant. They still have their cells. Why don't we just do another one? It's a reasonable consideration, but honestly most people choose to just do something else now because we have so much more available. Yes? So kind of a follow-up to one of the earlier questions is it seems like there's always this balance between hit it hard, but then maybe what survives can really, the selective pressure of that could lead to a very aggressive form that's harder to battle. So do you see that coming up with these board joints and all? And then really, but more specifically in the relapse setting, is there a case to be made, for example, I've been on a darahom that's only half as long, maybe 44 cycles, but maybe dropping the palm or something so that you're like decreasing that list if you're like MRD negative. Yeah, so that's exactly right. So we have to have it in some kind of an organized fashion because if you just did it offhand, we don't know, right? We don't know is it the darah or is it the palm or is it the combination? Most likely it's the combination because they work hand in hand, all these therapies is what's keeping your disease in remission. So it's very difficult, especially if you're tolerating it, for us to voluntarily stop one of them because we're worried and that we're going to then cause a disease relapse when it could have been avoided for several years. And then why those several years are so important is because of, well, look what happened in the last three years. Patients have options to things now that three years ago they didn't, right? So keeping the disease away is the most important thing. And right now after initial therapy, every relapse it is until it stops working. So we don't have data to say you can do that, but we're looking at that now, looking at MRD, et cetera. The selective pressure question, I mean, I think, you know, so what she's alluding to is, you know, you have the disease, but you may be kind of brewing the resistance essentially with a different clone or a different version of the disease that may be a bit more resistant or harder to treat. But, you know, because our therapies keep improving, I think I'm less and less worried about that now, to be honest, than I used to be because, you know, we have all these other things available. Yes? I had a patient that while on maintenance, all the blood work remains stable, it got better, but the platelets kept dropping. Only that one blood test. So what does that mean? Yeah. So remember, these are therapies that have side effects to your normal blood cells too, right? So you have a predilection to have more neutropenia or low white counts. Some people have low platelets. You always want to make sure there isn't something else going on, right? So I always say, like, you know, is there something else in the bone marrow that's preventing the platelets from being made as good as the next person? Is there some other medication you're on that may impact platelet production? So we look at, we do kind of a comprehensive evaluation, but over time it could just be the dose of Revlimid. So, you know, that drug has such a huge dose range, as you all know. You have some patients on two and a half milligrams of Revlimid every other day, and they've been stable for years, just to give you an example, and others that can tolerate 25 milligrams, no problem, right? So you have to find what the right dose is for you. And I think as time goes on, we also feel more and more comfortable tweaking it, right? Because we're less worried about an early relapse. With new therapies now in the forefront, Bi-Specifics, CAR-T, do you find, sorry, do you find any barriers to treatment aside from supply chain, for example, institutional or insurance company approval given the expense on the limited... Yeah, no, I think it's a big concern of mine. We haven't seen it play out yet, because I can see it from an insurer's perspective, and if they pay for one CAR-T, now you've got two more Bi-Specifics coming in that same patient, right? And they may start to say, well, this patient has already had a CAR-T or whatever. Hopefully it doesn't come to that, right? But I do worry about that, because these are super expensive therapies, and hopefully we just have access to it so we can go ahead and treat with what we think is best. I've had some patients that had a CAR-T on a clinical trial and then still had approval for a CAR-T on the commercial side, because clinical trial paid for that first CAR-T, but I know insurance is very much looking at this because you're kind of going through all these therapies together. In terms of our ability to give it, I think we have to bring this outpatient. We can't admit...if you think about it, you have somebody admitted for CAR-T, even going before that, you have somebody admitted for a transplant, then eventually they're admitted for CAR-T, then they're admitted for three different Bi-Specifics. Think about how many people you can have in the hospital, and everybody's at different stages, right? You could have a flu or myeloma patient just getting these therapies, and that's what's happening and we don't have the space. You have to safely give this outpatient, I think that's step one. We're looking at best ways to do that, to kind of manage the CRS outpatient and kind of have maybe preventative measures to prevent CRS, which is really the big concern. I think once we fix that part, we should be able to scale up. Bi-Specifics, I think, will be fine, because they're just like giving any other therapy. We just have to expand our infusion centers and have more clinic space. CAR-T, I think we have to just make sure that we can do the collection and kind of have the ability to treat as many patients as we can. That has more components to it. It's not ordering a drug, right? You have to have the T cell collection and shipped and returned. I'm hoping that we'll have more and more ability to do that. I think the outpatient piece there will help, too. I just wanted to make a comment. I think outpatient is great. I had a transplant and the hospitalization was miserable. I would have given anything to do it on an outpatient basis. It wasn't that big a deal. I give you tons of commendations for doing it on an outpatient basis now, because it's best for patients. Well, I appreciate that, but I also wish that message is disseminated amongst patients, because the first reaction I get is, no way, I want to be monitored. Well, I tell them, well, you're still going to be monitored actually the same exact way. It's just that you're not being woken up at four in the morning for vital signs, right? But it's very difficult when a patient you guys know obviously better than me. When you're in that position, you're very nervous. You're scared. You want the best care. You want the monitoring to be continuous, right? Who doesn't? I think it's our job to kind of ... This happens with experience over time. As more patients go through it, they speak about their experience and other people feel more comfortable. We cannot create a system that has the potential to put anybody in harm's way, right? I think that's really important, but I will also tell you there are some real logistical issues with outpatient treatments. The hotel people stay, right? Cost, we have to make sure that we're not putting a financial burden on patients is to be outpatient, right? The hospital, on one end, they can have everything paid for by insurance if they're in the hospital, on the other end. If they have to be 30 days in a hotel in a different city coming from four or five hours away, right? And caregiver support, right? That's the number one thing actually that we've come across with outpatient use. You have to have somebody there with you 24-7, and a lot of people can't. They'd rather have the care in the hospital because they don't have a caregiver. It's a lot of components to this to make it operationalized for everybody, but we hope that we're able to solve some of those as time goes on. I think if you could segmented parts of the process in terms of as you look at the two weeks stay, that would be so helpful. Because for so much of the time, one did not need constant monitoring. When you're in the nadar, I was glad he was there. Yeah. So, yeah. It was... But if he could break it down from a cost perspective, a bed perspective, if there was literature studies and that piece of it, I think it would be fabulous and it would be so much more patient-centered and cost effective. We've already seen that with some of these bi-specifics. There's some data already showing that if you do a hybrid approach, sort of what you're describing where you do a little bit inpatient, more outpatient, it's much less costly. Yeah. And I think it's going to be some kind of a hybrid approach for sure. So, at the start of the pandemic, we lost several members of our support group who were waiting for CAR-TE because of the protection issues. So, it's great to see the bi-specifics now showing up. But I guess since they're both FDA approved, is it possible, for example, if you're waiting for CAR-TE or maybe you had your cells collected but then your disease is really aggressive, is there some way to play with those a little bit? Great question. And one, we don't yet know the answer to because on one end, you don't want to... Yeah, you don't want to exhaust your T cells. Right. You don't want to... It's almost like giving the myeloma a preview of what's coming with CAR-TE and maybe having it prepare, right? The other end, you need to do what you need to do, right? So right now, we haven't used bi-specifics as a bridge to CAR-TE, which is what you're talking about. But I do think that's a really important question we need to answer because if that's safe to do, I think that solves a lot of problems actually because you then don't have to wait because you're already on some treatment that's actually effective most of the time. You don't have to be on the bite forever. And you don't have to be on the bite forever. To me, that could be like the perfect scenario, but we have to prove it. The other issue with that is to get insurance approval for all these therapies, they follow the same process. So you have the CAR-TE approval and we have a whole team that like once I say, okay, this person, can we just make sure that they're, you know, prior often everything is all set, they will go through that process. Then I tell them, oh, yes, but can you also do it for the bi-specific? Now, if you're an insurer, you're getting two requests for two... So which one is it, right? So that's the real world channel. So really, now the big decision is CAR-TE or bite, not like sometimes you are specific to my alone and where is that? Right. But we do what we have to do because I've had that exact scenario happen several times where people are waiting and we say, well, you know, we have to kind of bail on that plan and, you know, we'll kind of go with the bi-specific now. And, you know, and then some people respond to it and they're like, okay, I'm responding, I'm good. I don't need to go through it, right? Because it's like in some ways it's easier. And it's 140, so... Final question? I'm an observer, not a patient, but the head scratcher for me is you're administering simultaneously an immunosuppressant, a universal immunosuppressant, DEX, and immunostimulators. Was that by trial and error and what's the theoretical basis? Great question. I mean, we've been trying to get rid of dexamethasone for years for all of you, right? Because that's the number one drug in every patient's journey that they're like, you know, get me off of it, right? So you're absolutely right. We don't give steroids with bi-specifics though for that reason. We do for the first couple of doses to prevent kind of a reaction mostly, but we don't give it as sort of routine with these new immune therapies. So it is changing, I guess, in some of the circumstances, but many others it does still augment the response to the other drugs. So we do give it, but we try to taper people off of it. All right. Thank you, everyone.