(Guest Lecture): May 2022 - Translating Ideas Into Treatment - Dickran Kazandjian, MD

I do want to thank the organizers, Greg and everyone, for inviting me and inviting us. I think this is really important for me and Dr. Langer for twofold. One is to be able to speak to patients about myeloma and what the recent progresses are, but also to highlight what we're doing here in South Florida. In my talk, I'm going to try to be in transition of what we're doing here and how we do it in Miami, along with what's the next and best going on. I may be talking about Miami, but pretty much everything I say is really can be extrapolated to the whole country. Just an overview, I want to hit three major points here. First is how we treat newly diagnosed myeloma in Miami and the clinical benefit of the standard treatments we use. Number two is how do we incorporate new therapies into treatment, including the NICD-38 monoclonal antibodies that we've heard about a lot today. And lastly, talk a little bit about CAR-T therapies and bispecific therapies. So the treatment paradigm, we haven't really talked about this, but when patients first develop newly diagnosed myeloma, how do we treat it? And so I try to make this slide a basic slide, which is we start off with a combination therapy, usually including a proteosome inhibitor and an immunomodulatory drug. We usually typically treat for about six to ten cycles or six to ten months. Somewhere in between, after about four months, most of our patients who would be transplant eligible or I like the term fit or candidates for transplant may get stem cell harvest midway. And then after about, like I said, at about eight to ten cycles after combination treatment, if the serum shows that a patient is in complete response, we would do a bone marrow biopsy and evaluate for minimal residual disease negativity that we've heard of a lot today. And based on that, usually we have a conversation and include the patient as a decision between the patient and the physician on whether we go straight to maintenance or we actually go through a high dose melphalan and autologous transplant. So moving from doublets to triplets, so this is a little I wanted to put it in a little bit of a historical background. So novel therapies began to be approved in the mid 2000s, roughly, with the first ones being like thalidomide and bortezomib and then melanolidomide. Many patients, even in the 2010s, were still receiving doublets. And we can see that very clearly here if we look at the Mayo SMART guidelines from 2013. At least for standard risk and even potentially for intermediate risk patients, it wasn't even recommended to get both a proteosome inhibitor and a immunomodulatory drug. And let me just take two steps back and not assume that everyone knows, but when I say proteosome inhibitor, I mean drugs such as bortezomib or Velcade or the newer ones like Kyprolis or carfilzomib. And the immunomodulatory drugs are like thalidomide, lenalidomide, pomalidomide. So triplets and relapsed refractory myeloma. It was around the 2010s where we started seeing data in the more refractory population on how three drugs were always better than two novel drugs. And here's just like one example using Kyprolis. Kyprolis was initially approved in 2012 by the FDA. And here is one of the important studies that actually showed adding Kyprolis or carfilzomib, same drug, to lenalidomide and dexamethasone made an impact. Both in progression free survival, meaning the time it took for the myeloma to come back and how long patients lived. So moving doubles to triplets. So it wasn't really till 2017 when the results of this study called SWAG 0777 really reset the thermosome. Of this study called SWAG 0777 really reset the thermostat and satisfied kind of the whole feel that three drugs were definitely better than two in the upfront setting. And this was published in the Lancet and, as you can see by the title, it compared bortezomib and lenalidomide and dexamethasone compared to just lenalidomide and dexamethasone. And here again, these are Kaplan-Meier curves, they can be a little confusing looking at, but the take home message was patients, if you receive the three drugs compared to the two drugs, it took longer for the myeloma to come back and also you live longer if you got the three drugs compared to the two drugs. So and the follow up study basically it confirmed that with the average overall survival in with the three drugs, meaning how long patients live, that median still hadn't been met, meaning that patients were still doing so well, not dying, that the average can't even be figured out just yet. So what comes after novel triplet combinations with the establishment of novel triplet combinations? Standard for newly diagnosed myeloma, really the focus has moved on to three important areas. A lot of these, I think all these areas we already hit. So just to put it in perspective in this talk, we're talking about the establishment of minimal residual disease negativity as an important prognostic marker and early endpoint potential in clinical trials. Number two, the development of novel now from triplet to quadruplet based therapies. And the specific patient tailoring of the use of delayed high dose melphalanin with stem cell support or as we know with transplant. So MRD negativity. So these are just like you can see many of these slides and basically or many of these studies and they all show the same that in patients who reach or retain minimal residual disease negativity or overall do better than those who don't. And here are two meta-analyses. So what a meta-analysis for those who may not know is two groups and one was Dr. Langren's group, but the other one, Dr. Munshi's group where they look through the literature, got all the data and pooled kind of all the data together to see what the benefit of minimal residual disease negativity is. And then the other one is the the two groups that show the data together to see what the benefit of minimal residual disease negativity was. And in both cases, the important take home messages, MRD was probably like found as the most prognostic marker, both in terms of how long the myeloma stays away and how long a patient lives. So next moving on, we had the arrival of the NICD-38 monoclonal antibodies, the efficacy observed with NICD-38 diratumumab and its approval really revolutionized the way we treat myeloma currently. Shortly after, isopuximab was also approved with a similar mechanism of action. And with the new novel era of novel quadruplet based therapies, really the efficacy observed with diratumumab and its approval revolutionized the treatments again of myeloma and really opening up a conversation on how can we add or how can we add this fourth drug to the upfront setting in the treatment of newly diagnosed multiple myeloma. The first studies that tested this added diratumumab to less, for us probably in this room, less well known myeloma treatments. These are older treatments that are mostly currently used in Europe and Asia, not so much in the United States, but it was like a proof of principle that adding diratumumab to these regimens actually helped patients live longer. And then the Griffin study was really important too, that D'Sha alluded to it. This was an important study because it added diratumumab to a relevant triplet combination that we do use in the United States. And here we can see the results and again, the take home messages that we get from the patient was that it was a very important study because it's really important to add this to the treatment. So, we added diratumumab to a relevant triplet combination that we do use in the United States. And here we can see the results and again the take home messages basically the four drugs, so diratumumab plus Velcade Revlimid and dexamethasone or lenolamide and bortezomib and dexamethasone patients did better in terms of response rate. So, given the results of the diratumumab VRD and newly diagnosed myeloma, really the next natural question is, can we expand on that? So, can we expand on that by maybe changing out the Velcade or the bortezomib to a newer generation proteasome inhibitor, namely carfilzomib? So that gave rise to the Manhattan Project that was led by Dr. Langren in New York. So, in the study, you can see patients with newly diagnosed myeloma received eight cycles of the four drugs and patients did not receive default autologous transplant either. And when we look at the results again, they see an MRD negativity rate of 71%. So, these MRD negativities is basically a response that's one step even deeper than a complete response that we typically hear about CR. And speaking of functional cure, Dr. Morgan alluded to it also in here, when we have 88% of the patients who have remained MRD negative for at least one year, meaning they have sustained MRD negativity, that's the kind of endpoint we're talking about as we get closer to a functional cure. Another study, a similar study to the Manhattan, it's called the Master Study, kind of a similar idea, really the only difference was, or one of the major differences was this study incorporated high dose melphalan with stem cell support and also was adapted in how many cycles of consolidation with DRKRD patients received. But really the point of this slide is, again, you have CR rates 86% and more denegativity, very high also. So, role of early versus delayed transplant in this three to four drug era. The question is, well, if our drugs are getting so much better now, do we still need to use, you know, high dose melphalan? At least do we need to use it for every patient? And so that gives rise to, or gave rise to the IFM 2009 study. This was a study that was conducted in France, and sort of its parallel sister arm was actually also being conducted at the same time, led by the Dana Farber, and that we'll talk about in a second here. But long story short, the take home message is patients got VRD, which again stands for bortezomib, lenalidomide, and dexamethasone. Both groups got that, but one group did not get the high dose melphalan and the other group got it. And so what happened? So as you can see the results on the right, actually, the median progression free survival was a little bit higher in those groups that got the high dose melphalan, but patients did not live longer by getting autologous transplant. And so I think, you know, it's kind of like you can always use the same arguments to kind of argue for or against high dose melphalan and an auto transplant. But really, one of the ways I explain it is like, at the end of the day, high dose melphalan is just another therapy, a therapy that's fairly toxic, as those may know who needed it. And so, instead of getting that therapy, you could potentially get some other therapy. And so in these trials that compare transplant, yes or no, it's like comparing a whole nother drug, yes or no. Well, maybe instead of getting, if you're on VRD, instead of getting transplant, maybe you can just get diuretumumab or something else that is better tolerated. So there's different ways of approaching this but the important key take home was that using current state of the art, which I think at this point is with proteasome and an immunomodulatory drug, a front combination. No study has really shown that patients live longer by receiving autologous transplant. On a side note, this kind of advanced quickly here, let me see. And this actually, Dr. Richardson is going to actually present in the plenary session in a couple of weeks here at the annual oncology meeting about the results from from the US kind of population of that study. So why wait until relapse for high dose therapy and transplant anyway. So why are we talking about this so much. So, high dose melphalan, don't get me wrong, it really revolutionized the way myeloma was treated. It was pretty dismal before high dose melphalan was being used. So with the introduction of novel therapies in the early 21st century, they've been incremental and even exponential improvement in different efficacy and how well drugs work. And in the current era where we have three and four drug novel combinations. Really, we asked the question, do we still need transplant for every patient. I personally think transplant and high dose melphalan is an important tool for doctors to have in their toolbox. But I don't necessarily think that every patient really needs it. And so why are we talking about this? Well, there are toxicities involved in receiving the transplant. Centers have gotten much better and sort of the acute mortality from infection is much less but but it's nevertheless is still there. And here are other things more longer term toxicity, and that we're thinking about secondary cancers including secondary like blood cancers. Here on the left, it was a study done by the Swedes that basically they showed that patients who develop second cancers meaning the leukemias and the myelodysplastic syndrome were more likely to be exposed to melphalan. And on the right, you can see a group down our group led by Dr. Moore actually showed specific tattooing of like the DNA and those patients who were exposed to melphalan. And so where do we stand. So here we have the advanced study this is a study that's led by. This is a study that's been led by Dr. Langren and and there's multiple sites that are including including MDN Anderson, where three, three drug VRD is compared to three drug KRD which is compared to four drugs the direct to map KRD. So the response assessment is done, then we look to see how patients are doing. Once they're assigned to the specific therapy arm. And then they get after stem cell harvest you get a total of another four cycles of therapy on your respective arm and next generation sequencing is done to look for minimal residual disease negativity. And if you're MRT positive then we recommend high dose melphalan and transplant, if you're not you go on to receive maintenance therapy. So this is what we're really focused on at Sylvester for newly diagnosed myeloma patients that are fit. So what about in patients who wouldn't be, you know, candidates for autologous transplant anyway I mean I think this study called the Maya study really revolutionize how we treat this, this population and in time and time again that we see this, this combination of direct to my map with linoleum I'd index and method zone has been not only associated with the myeloma not coming back, but also by living longer. And these are the curves that that show us that. So how do we do it in Miami. So, more specifically, like I mentioned about 90% of my patients are enrolled on this advanced study that I just, I just presented this patients of course something that don't want to be on a trial or for other reasons, do not enroll in that, or if we have concerns for neuropathy or we have concerns for cardiac history you know may lead us to do one or the other. But really we reserve off of a clinical trial we may use care or direct to map care ID when we are concerned about neuropathy. So, autologous bortezomib is associated with neuropathy as many of you know, high dose mouth land and transplant is really reserved for those for those patients who don't reach MRD negativity. We give indefinite maintenance with linoleum I'd that's been fairly well established at that frequency. Less fit patients received their tuna when a little might index and method zone. And we have a lot of patients that have a lot of MRD that they receive and the patients have significant cardiac problems and usually treat with. We try to avoid the cartels and and use bortezomib. So how about, so everything I've been talking to you about so far has really been, you know, newly diagnosed multiple myeloma. A lot of the relapse refractory myeloma drugs and a novel immunotherapies were already discussed but just to just to summarize I mean, look, this is the the doctors follow look how many different things you could potentially be used to treat it's kind of all over the place so that's how you have to really know but I will focus on what the important thing is like biggest news in 2021 and 2022 were really the approvals of both car teeth. Carty therapies. Again, car teeth therapy this was discussed by Dr. Shaw. But basically these are a drug called IDA cell and then so to sell the very similar and the preparation is a little similar. It's yet to be determined which one is better or not although if you ask, I think a lot of doctors have their own biases, but I won't mention that. Again, the biggest thing we worry about with this is like neurotoxicity and the cytokine release syndrome. So moving on to buy specific so what is car tea, what is by specific. They don't sound similar but a lot of us, the discussions are about doing one or the other why are these two drugs being kind of compared. So what I would actually think about it is on the left we have, you know, what a car tea looks like basically when you have your own tea cells taken out and engineered in the lab grown in the lab and infused back into to do the work against myeloma cells. And so that's, as you probably remember from high school biology that's doing something ex vivo right not in the body but ex vivo. So the next logical question is instead of going through all that, is there a way to do that in the body. So the body cells don't have to be taken out and re infused. And that's really what by specific antibodies try to do and that's what you can see on the right where instead of re engineering your own T cells, you basically throw in an adapter, it's kind of like think of a Lego adapter that that ties the myeloma cell into the T cell. And that's what a by specific antibody pretty much does. And so a lot of the side effects and a lot of the, the clinical benefit of them are actually similar to car T. And so here's a slide of like the pros and the cons, I mean just to go through this quickly. I think the by specifics hat to have a lot of pros you don't have to wait for them they're available to you, it's not your own cells don't have to be processed, that you don't have manufacturing problems as much. Because of that. And I think the biggest negative compared to car T is that you need, at least, as of now you need continuous therapy right it's not just a one shot deal. And if this is giving you a headache is supposed to. The point is there's all these by specific antibodies, so it's pretty amazing how many we have, and some of our, some of them are subcutaneous some of them, some of them are intravenous some of them are once a week some of them are every other week but really the point is that if you look at that column that says or are that stands for overall response rate like, like how many patients my lomas are getting better with the specific drug. They're all about the same right between 60 to 80%. So that's really what what the take home is for that. Anyway, what about Sylvester What are we doing well we've opened many many trials already I think in the car T space, our first really important trials and be the car to to five that we're opening and it's really test whether or not you need lent a little or you can get a one shot of a car T. So other important we have a number of by specifics, I heard a lot of people alluding to the try specific that you know the my own McCrack released I guess on Twitter. So we have a study with that and we have a study that's very similar to the land to map which is the antibody drug conjugate but the payload. So in conclusion, treatment of newly diagnosed like moving forward from novel triple therapies to quadruplets that are tumor map when a little my index and methods and is showing unprecedented results. So in conclusion, treatment of newly diagnosed like moving forward from novel triple therapies to quadruplets that are tumor map when a little my index and methods and is showing unprecedented results for patients less fit. So improving less people require early high dose chemotherapy with transplant maintenance line a little mine remains the gold standard in terms of maintenance therapy exciting time for targeted immunotherapies both car T and by specific antibodies are showing And moving forward, I think strategies will involve or aim to incorporate immunotherapies to even more upfront settings and even possibly aggregate like the need for autologous transplant in the near future, as studies are done. And so I think we're in good shape. My Loma is doing well. I'll transition now, maybe a little PR for our program here at Sylvester. So that's we have our beautiful campus in downtown Miami. In the one year Dr. Langer mentioned we've grown to six physicians. We actually are very pro patient we guarantee visits within a week of getting a call patients don't have to wait for months like like some other some other groups. And what's really nice is that there's a strong satellite network and so Dr. Langer and and I also see patients in Coral Gables, which is the Lennar main campus University Miami main campus area and Dr Hoffman also sees patients on the north suburbs in And so we have a lot of patients where we see them you have to travel a little while to get to us but mostly therapy is actually maybe closer to their home at the various. sites that are actually available. So, this is our program I wanted to, you know, highlight the most important things as was already mentioned is really you guys and all of you. It's always a team I think when a, when a patient of mine is very happy with the results I always say it takes both of us, it really does. And, and in particular with clinical trials you know when I came from the NIH, NIH is 90 99% of my patients with clinical trials. If we didn't have you guys participating in trials I wouldn't have had a job there so so thank you for all you do and I highly encourage continuing to do that. And I just want to thank you for your attention.