(Guest Lecture): November 2022 - How Myeloma Frontline Therapy is Changing - Ajai Chari, MD

So how is frontline therapy for myeloma changing? So I think it's always challenging because in these kinds of audiences, there are people who are very new to myeloma and there's people who know really a lot. So I'm going to divide it to make it simple. Myeloma 101 is everything in yellow. Myeloma 201 is the next few slides. So for all the topics, the take home message. So when I began fellowship, we had these two classes of drugs, steroids and conventional, everybody's favorite, steroids. Conventional chemo is the second category. But now we have four additional categories. So IMIDS, proteasome inhibitors, immunologic approaches, and this XPO inhibitor. And you actually have sponsors representing all of these four columns, which is pretty cool, right? They're all here. And it's like a math question. When you have this many choices, what are the number of combinations and sequences? It's really an endless question. So I'm going to divide my discussion here into four questions. What's our goal? The role of monoclonal antibodies, the role of transplant and CAR-T's. So let's start with the goal. Our goal is really a deep and durable response. So this is your Myeloma 101 version. The depth means we are able to detect such microscopic amounts of disease that our treatments need to be really good because we can detect more and more residual disease. So we really want to eradicate myeloma everywhere. And this is what makes myeloma unique and different than other cancers, because you can't just look at the bone marrow, you can't just look at the blood, you can't just look at the imaging. You got to look at it all. And that's why blood, your favorite, the urine studies, the imaging, PET scans, MRIs, and the bone marrow. And then we need to not only eradicate it, but you have to keep it there because so what if it's gone, if it comes back quickly, that's not enough. And what we know is that the deeper and longer lasting remissions are, that's going to translate into living longer, which is ultimately the goal for all of us. So ideally, we want to not just do that, but with as little therapy as possible. And our best chance of achieving this goal is actually in the newly diagnosed setting. So with that, let's go to the 201. So we know that historically, it's not a good idea to save your good drugs for later because not every patient is going to get to every line of therapy. And as you keep treating patients on the right side, the durations of these remissions diminish. So we want to use our best drugs up front and to eradicate that disease. This is a war against cancer, and you've got to get that enemy suppressed as much as possible. But that doesn't mean everybody needs every drug forever. We need to be thoughtful about that, but it just means you have to hit the disease hard. So let's now move to monoclonal antibodies. So the 101 version of this is that in patients who are not getting a transplant, daratumumab with lenalidomide index, the DRD, as we call it, is a game changer. Longer myeloma remissions, actually these numbers are astounding. We'll see the numbers. And patients are actually living longer as a result of that. For the transplant patients, daratumumab given with bortezomib lenalidomide index or Velcade revelamid index, as you might know, DVRD is looking really promising. And many US doctors have adopted this. And we can talk a little bit more about that. So myeloma 202 version, if you really want to know why is DRD such a game changer, these are all the regimens that we could typically use in patients without transplants. So there's this study on the left called the VRD Velcade Revdex versus Revdex, RBD-Lite, this European regimen, GeraVMP, the Maya regimen, which is the DRD, and the tourmaline. So what is this graph showing? It's showing you the blue line is what's the experimental on. So what are we trying to do better than? And the pink arm is the control. So let's zoom in on Maya. That's the one that's a game changer. So revelamid index typically works for 34 months. And when you add Dara, we don't even know how long it lasts. It's over 56 months. And it's blowing everything else on this table out of the water. Now we always do say don't do cross-study comparisons, but what you can see at the top is really what's the value add. And you can see that the addition of Dara to Mammoth extends, it's 50% better. And as a result, people are living longer. So this is why this is a game changer. Dara, revelamid index is the unprecedented people's remissions are lasting actually longer than what you would expect with transplant, which is really a game changer for these typically look at the age of these patients at 73. So for older patients to be having this kind of outcome is why this is such an exciting time. Yeah. Again, I really think so first thing to mention here is just because we start with that, I think doesn't mean you have to keep everybody with all of these drugs forever, right? So you got to beat the myeloma to a pulp, but I encourage you all to talk to your team about reducing these drugs, because if you're doing well, do you really need that initial dose forever? Can you reduce the lenalidomide maybe because of fatigue, diarrhea, rash, low blood count? And also your favorite drug, dexamethasone. I think it's always interesting when you ask a patient, are you tolerating dex? Usually they're fine, but it's the partner who's like, oh, no, I know when it's a dex day, right? But you don't need to torture somebody with those drugs if you've got a deep remission, right? You can back off and keep it there with as little as possible. So the transplant group, this is the, so everybody here gets transplanted and there's three kind of DERA tumor-Mab based studies here, combining with Velcade thalidomide dex in Europe, in the US study Velcade Reblement dex, and then the DERA Carpepilsen dex. So the number of chemotherapy cycles varies from like anywhere from four to 12. But what you see here is that the addition of DERA in these studies, the middle one, the Griffin is the one that's the US study, 55% better remission duration with the addition of DERA. So that's pretty impressive. And so for that reason, we really, a lot of us have adopted this. Important things for you to know about this is get your COVID vaccinations. So we are living in a whole new era, you know, even for Dr. Patel, who's our most junior person here, but COVID is new for all of us, right? So COVID wasn't around and it's really changed. And I really emphasize for all myeloma patients, because the addition of DERA tumor-Mab type The CD38 does blunt the antibody response to vaccines. So it's important to try to get vaccinated as much as possible beforehand. Get those boosters. That's really important. And contact your doctor if you get COVID diagnosed, because there are treatments for COVID, as you know, that can come in pill and injection forms, but they need to be given within five days of symptoms. So if you don't test promptly, if you don't notify your healthcare team promptly, you might miss those windows. And also you need to let your team know about any antibiotics or infections you're getting, because one of the downsides of the monoclonal antibodies like CD38 is increased risk of infection, typically respiratory and urinary. So if you're getting a lot of those, you need to notify your team, because there are things we can do, like giving you a medication called IVIG, intravenous immunoglobulin, which can really put a stop to that. But we don't need to give it to everybody. Really depends on. So the interesting thing, I've just shown you all this amazing data for the DERA tumor-Mab, and I was just at a meeting yesterday. I'm assuming all my colleagues, do you guys all use DERA frontline? Yeah. Okay. So you're seeing all four of us, you know, there's this joke. If you ask four myeloma doctors a question, you usually get five answers, but here you got one answer. The interesting thing is when you look at 2022 data, anybody want to take a guess of what percentage of US patients are getting frontline DERA? 8%. This is why meetings like this need to be done. This is why we need advocacy groups, because changing practice, you have all of this data. These are high impact publications, oral presentations at national meetings. Why is this not being translated? And it's because community doctors, which is the vast majority of where patients are being treated, not in academic medical centers, are busy treating a lot of other cancers. As you know, you know, myeloma is going to be a very small fraction. The big four, breast, prostate, colon, GI. And so to keep up with this is really challenging. So how do we do that better? Patients need to be their advocates. You need to learn. You need to work with a consultant and an expert. And in the video era in New York, who wants to drive into Manhattan? I always say you don't get points for suffering, right? So if you can get good care without having to come to Manhattan, and now we have video visits, right? So I have a patient just the other day, one of my colleagues in the community, she called like, I have this patient, I don't know what to do, but she doesn't want to come to the city. I'm like, we'll do a video visit. Let's figure it out, right? Like, I don't care. I mean, of course, my hospital wants me to have patients come to get in chemo, but that doesn't matter to me. And to be fair, they were actually they're very cool with us being a referral center and not doing everything on site. So my point is, we need to even though we have all of this data, if you're not actually implementing it, patients aren't benefiting. And part of the other reason I'm working with community doctors is there's like, I've been giving this regimen VRD forever, and people do great. Why should I do anything more? Right. But that's 2008, right? And that's a Fergie song, I think. Okay. So moving to transplant, what is this is your myeloma 101? What's the role of transplant in 2022? So let's just clarify what transplant is, because I think there's a lot of misconceptions. It's high dose mouthplant chemo. Mouthplant is a drug that's been around. It was one of those drugs that's been around for many, many years, even when I was in med school, and it kills everything in the body that grows quickly. And that includes cancer. But to avoid the bone marrow killing, you need your stem cells collected. So the real term is really high dose mouthplant chemo with autologous stem cell rescue, right? So those stem cells don't do anything to the myeloma without that mouthplant that preceded it. And so that's probably the main contributor for why younger patients have been living longer over time. Study after study has shown that when you do a transplant, the duration of myeloma remission is extended. And conversely, because people also talk about the risk of transplant, right? Could it create harm? No study has shown harm with transplant. So that's really important to keep in mind, and I'll show you why in a second. But I know many of you have been through transplant. It does have an impact on your quality of life. No one's denying that. People do feel worse. It lasts about three months. And there's data for that. I'm not just saying that because, you know, the health care team can say what they want, but it's you all that actually go through it. And finally, once those stem cells are collected, they don't have an expiration date. So that's pretty good. There's no time stamp. 15 years, 20 years, we've used old cells. However, I ask the question, especially to my patients as they're getting older, if you're going to collect your cells and you're already around 70 or older, are you really going to be more excited about doing transplant when you're older? When guess what? More things happen. Heart disease happens. Kidney things happen. People get tired. People get less fit. So if you're going to think about it, what are we waiting for? Right. Oh, actually, one more point. The decision whether or not to do transplant should be based more on fitness. So in medicine and in oncology in particular, we're moving away from age and like how fit is this person? Are they like a good 70? Are they a Jane Fonda 80 or are they like a wheelchair bound 80? Right. How do they respond to their initial therapy and how do they tolerate the initial therapy? So if you get DRV or DRD and you're having rashes from Revlimid and you're having neuropathy from the Velcade and you're not getting into deep remission, well, transplant looks more compelling. If you're in a complete remission and no side effects, then it's a trickier choice. But that decision doesn't have to be made on day one of chemo. You can give a few cycles and then think about it. So there shouldn't be this pressure like you must do this. We have to debulk the disease anyway. So myeloma 202 version, if you look at Medicare, the SEER data, the US statistics about survival, this is over time. So the black is in the oldest era when Karina was not even born. And then the newest is at the very bottom, the lightest color. And so what you see is at the bottom right panel is the 80 plus year olds. Between 1973 to 2009, there's no improvement in outcomes. When you go to 60 to 80, 66 to 80, there's slight improvement. When you start to get to the 50s and below 50, that's where you see the real improvement. And this is not with any of the fancy drugs that we've been all excited about. And so we only got the lidamide bortezomib len in 2000. So why were those things happening? I would argue it's because of transplant, right? Because that's the only thing we had for all those years. So when you look at these three pivotal studies that looked at transplant versus no transplant, the number of chemo cycles differ. So one is the French study. You probably heard a lot of press recently about the determination study, which is the US study. And then there's an Italian study. And they tell you all the same message. At the top, you can see there's between a 35 to 55% improvement in the duration of remission with a transplant. I'll call you some special things in the bottom. In the French study, which has the longest follow-up, about a third of patients with transplant have not relapsed even after eight years, which is, again, very impressive because these patients aren't getting CAR-Ts and bispecifics. This is just classical treatment. And with determination, again, this one actually showed a 224% improvement in high-risk patients, right? So particularly for high-risk disease, there seems to be a role for transplant. So what about the patient experience? This is the quality of life data that I was showing you that, basically, shows that when you look at overall health, physical functioning, role functioning, are you able to do things, side effects, the red curve is the transplant. And it is worse for three months after transplant, but then it resolves, right? And so this is an old 80s commercial. Some of you might remember, where's the beef, right? These three little ladies are looking at the burger and looking for the beef. And so my point with this slide is I know some of you, there's a lot of emotion with transplant. I feel like people come into this with like, I want transplant, I don't want transplant. I maintain equipoise. I would be happy to throw out transplant because I don't want my patients to lose hair and get admitted and have diarrhea and lose weight. But show me the data. And what I mean by that is it's not good enough to just show that you're equivalent. You have to show superiority because remember, all of these new regimens do not have the follow-up of transplant. I just showed you four decades of outcomes with transplant. Show me that with new regimens and I'm happy to change. But until then, it's like a legal court system, right? In this country, innocent till proven guilty, right? It's the prosecutor has to prove that the innocent is not guilty, is guilty. And here, if transplant is innocent, we need to do better than transplant and happy to do those with different strategies. And that takes us to, I think, our last topic, which is CAR-T's, Dr. Patel will talk more about that in her section. But at a high level, you take out your T cells, which is different from your stem cells, different immune cells. You genetically modify them to make them angry and you put them back to kill the myeloma, right? So that's basically what CAR-T is. So will it be a first choice? Maybe, but we need comparison. It's that same question I just asked, right? How are they going to compare head to head? So what are some reasons to think about CAR-T early? Well, the efficacy, you know, historically to get a new drug approved in myeloma, when you've exhausted all those drugs I showed you on the table, it was about 20 to 30 percent remit response rate for lasting about three months. CAR-T's are working in, say, 80 to 100 percent of patients, right? It's blowing that out of the water. So like 80 to 100 is the new 20 to 30. It's a game changer. So with that kind of response rate and durability, especially with this Cilta cell or CAR-VICT, is the brand name. These are, keep in mind, those, these are first generation CARs. We just started doing these, right? So we're very early. And these was in patients who've been totally beaten up with therapy, five, six different regimens of chemotherapy. So if we're getting that kind of response in these heavily treated patients, the question, of course, is how well might it do as you move up? Patient experience cannot be emphasized. When we have more and more choices, like the risk and benefit profile are comparable, your experience matters more, right? And you know what? I have so many patients that have gone to CAR-T and if it wasn't for COVID, it's the first time in their myeloma journey that they're untethered, untethered from the cancer center. You don't need to be coming in for your weekly, monthly visits. You just travel the world. And some of our patients, I just had a patient who was finally able to go visit her family in Australia and Paris because she had, you know, penta refractory multiple lines of therapy and it's a game changer. Safety is the big question, of course, when you're moving something earlier. So far, we don't see any increase in toxicity with less heavily treated patients, so that's encouraging. What about the cons of CAR-T? Is it going to be feasible? If your myeloma is rapidly progressing, it's hard to get through the process of collecting cells and then getting to actual CAR-T. And there's a tremendous limitation of slots. Every site has many, many more patients that are waiting for CAR-T than can get CAR-T. And efficacy, again, going back to my where's the beef question, we need long-term data, right? So far, these are, we have about probably maximum two to three year follow-up, but that's not enough. When you have a transplant outcome of eight years, it's really, really need more long-term data, both in terms of the durability of response. We need to know that even MRD negative patients, which means you can't detect disease. Some of those patients relapse too. So especially for, we know that some of the places where CAR-T is not end all and be all is for high risk disease, particularly myeloma outside of the marrow. We call that extra medullary disease. And also not all CAR-Ts are created equal. So that's another reason not to jump up. And finally, safety. We don't have as much data in elderly people. So really frail elderly in particular, the safety and real failure, bulky disease. We don't have long-term data yet on these products. COVID related deaths have been known, infections, neurologic concerns, secondary cancers we don't have. And so I think in the interest of time, I'll skip this slide, but this basically tells you about how these cells are collected. And then this just shows the dramatic difference in how historically the response rate and remission duration for pomalidomide, carfilzomib, Dara, cellynexor, and how long the remissions lasted. And look at Cilticell, which is carvicti. It just blows that out of the water. This is a game-changing time. And so some examples of studies in newly diagnosed patients at the top where you're comparing, for example, Dara VRD with Cilticell or carvicti versus transplant. So that's an important head-to-head study for high risk patients going straight to CAR-T. Also the role in the post-transplant setting. So a lot of different studies that are ongoing. And then my other, I was asked to debate at European Hematology Society, CAR-T versus BISpecific. So which one will win? And one thing I just saw, which I think was, so I asked you what percentage of newly diagnosed patients are getting Dara, what percentage of patients in the US are getting transplant. This is a little bit older data, but the blue is the transplant patients, 12%. I was in Australia last week, their number is 70%. And I think part of that is if you don't have as many drug choices, you have to go with what you have, right? But this is the data. And my point with that is, you know, we all want these CAR-Ts, which is like the Rolls Royce Phantom. But the reality is, it's the Corollas of the world that are making the world go round. And I'm not making a cost comparison here. BISpecifics are going to be just as expensive to give. But what I'm saying is that there's 50 million Corollas being sold globally and far fewer Rolls Royce. So until CAR-Ts become more widely available, it's going to be hard to do that. And then I just want to end on a really positive note, because I think we were asked to be talking about Cure, which I don't think we need to talk about enough. So this is not just me saying there's Cures, this is data. So this is data from the International Myeloma Working Group, which was almost 7,300 myeloma patients from various studies around the world who got transplant. And look at what... So the way you read these curves is that if somebody's relapsing, the curve goes down, and if they're not, then it's flat. What you're seeing at this bottom is there looks like to be a tail. These 15% of patients have not relapsed with 20 years of follow-up. So we are curing myeloma, and we need to do that in more numbers of patients. And we need to know whom we're curing so that we can discontinue therapy. But the Kaiser Manning patients have not been cured. So again, I don't want you to think like, okay, I'm cured, I don't need chemo, but we need to know who those are. And we are doing better, because if you look at the gap... So the red line is what the age-expected survival is, and in the black line is what myeloma is. And you can see with the most recent curves, that blue curve, which is the most favorable risk patients, they're approaching much, much closer to that flat line. But then the high-risk patients, we have a lot of work to do. And so this is why I said in my introductory thing, which is that we have to stop treating myeloma as a one-size-fits-all. These patients are going to do very differently. We need to be thoughtful about how long those well-behaved patients, the good myelomas, can we discontinue therapy. And at the other extreme, we need to do a lot better for those high-risk patients. And I just wanted to thank my entire team at Mount Sinai, and of course, the patients and caregivers. Another... all of the progress is because you all have participated in clinical trials. Without that, we would be stuck where Dr. Patel joined us many years ago. Thank you for your attention. Happy...