(Guest Lecture): Emerging Treatments | Experts Discuss Relapsed/Refractory Myeloma, Amyloidosis

you [Music] so I'm gonna just talk about some emerging therapies for myeloma I know it's been a long way for most of you so I'll try to keep it up as simple and efficient as possible and thankfully when Nina presented all the immunotherapy she basically highlighted the most important emerging therapies that are happening right now as you all know or as many of you know myeloma has been with us for a very very long time so the oldest known case of myeloma in a skeleton was more than four thousand years before Christ from a mercurial site in the Neolithic Age from Vienna so this is you know so this is a disease that has been with us for a very long time but we've had effective therapy for myeloma only since about 1960 so considering the whole duration that humanity has suffered with this disease and what we have achieved in the last 40 years we are really making a lot of progress in the last less than half a century in fact so this is the skeleton that I talked about and this is the these are the curves that I showed up so basically myeloma has been with us for many many centuries and Yeon's actually and most of the progress has happened the last 50 years so you can see every every five year period that you get diagnosed later in the course of history your mynova tends to do better so already the people from 2005 to 2010 we're doing better than the people who were diagnosed between 2000 to 2005 and this is just the proportion surviving the most important part realize that the improvement is actually happening the first five years so we actually made it past five years you have access to a lot more therapy that happens from during that time so that those are the emerging therapies that we talked about and again I'm sure you've seen the slide in the earlier sessions so we have drugs that traditional chemo and we have drugs and now we used to call normal agents whenever the young guy that was in the 2000s but now they're older novel agents a yes and then we have newer novel agents like car fuels of may pomalidomide and a bin stacked examing or named Lara ah relax over there - mmmm yellow Joseph ma'am antibodies and then there's a whole bunch of future products including immunotherapy and that some of some of which were touched upon by dr. Shah so our goal with all these new drugs and clinical trials is to make my lumen just part of history and that in the future we have really good options for patients who are diagnosed so one of the most frequent questions I get is from patients this are these new drugs or chemotherapy so you know the answer is I really don't know what is chemotherapy anymore so the word chemotherapy means something a chemical used for treatment so in that case everything that we use is a chemical that's used for treatment for myeloma on on the other hand chemotherapy in people's minds is something that causes you to lose your hair throw up all the time and get the specific set of complications that are related to cellular death of a lot of collateral cells you know you give the treatment with traditional chemo to kill myeloma but you end up killing a whole lot of other cells and that causes damage back from that sense most of what we're going to discuss is not traditional chemotherapy those are these are treatments that you would use just to specifically target myeloma cells so if that's the one aspect in which we've made a whole lot of progress in the last 10 to 20 years in fact the targeting of cells has become so much better that we are not causing so much damage to the body but doesn't mean that these drugs don't have side effect we have their unique side effects just as dr. Schar talked about the CRS Sybil Rome in the neurotoxicity etc so with that again you know just as a caveat many doctors nurses many people in the hospital that you go if they say you know are you on chemotherapy they mean you know whatever drug they have not specifically meaning traditional chemotherapy so we give for example a very targeted drug like in our selects which is a monoclonal antibody has to be shown in this slide that daleks is a we call it chemotherapy oh you should need you need to go to the chemo room to get our selects but that actually is not traditional chemotherapy it is a highly targeted drug and it basically taxes on this to this this surface protein on the surface of myeloma cells so myeloma cells have many surface proteins on their self on the cell wall on the cell membrane and dars legs just homes in on one particular protein convert cd38 and this is a c-38 antibody so it is a form of a subliminal therapy in that it is a immune molecule that goes and attaches to the myeloma cell however it only works while you give the agent so in fact well the main difference between passive immunities like Norris Alex and active in your therapies like what dr. Shah mentioned the car T cells is that the car T cells is living cell therapy and it kind of creates an immune memory which if we are very successful in inducing can function like a permanent a new memory and that's why there was so much talk about cure with car T cells although it is not yet born out so far beyond the early stages of car T cells but monoclonal antibodies like doors legs are acid in them now right now we have a one of the newest drugs that God I approved for myeloma or literally within the last two weeks has been something called DARS let's fast fro and if anybody in this audience has had our selects they know that if the major problem is that you have to be in the hospital for a long time to get it especially the first few times you do it's almost a whole day of getting it so that you don't get a reaction to that drug now we have a new agent called the dorsal x fast row which is a shark it's a subcu injection so you don't it's not an IV anymore you don't need a line you don't need an IV infusion and this is another thing that makes patient convenience one of the top factors improves quality of life and increasingly we have clinical trials where we are using this drug to in long term maintenance so you know when we talk about acknowledging therapies it's not just new drug I said we're talking about you're also talking about using older drugs in better ways so for example daleks was initially approved like oral drugs are in myeloma for people who had relapsed after multiple therapies so people who really had options those are the people who go on the initial trials and then in the drug went fine initially gets approved it is usually have proven that population we call that relapsed refractory myeloma it means your myeloma that has come back multiple times and it means myeloma that is refractory or doesn't mean it doesn't work most drugs that we have don't work against at myeloma so then you end up getting a new drug such as the ours Alex and this Dalek started in that area of myeloma and slowly has made its way to frontline treatment now we have several regiments where Daleks used up track so we what we find in myeloma is that when we get a new class of drugs such as you know this antibody we find that when we move it in combination with other drugs that are traditionally already established and move it to the frontline patients we get even better response and all our philosophies is based on combination treatments and use using the best treatment up front so that patients get the longest possible remission up front so with them with all of this we have we're going to talk about by specific antibodies which doctors already talked about so I'll just skip my end and just highlight what you need to know in terms of clinical trials let me talk about some novel targets and some new takes on old drugs so you know some of the traditional chemo therapies some of the traditional molecules like solid amide analogs are all coming back in a new better improved versions so relapsed refractory disease we already talked about what that means one of the newest approved classes of drugs is this new drug called cell next door which was approved less than a year ago and this drug basically works best for a type of my for patients of multiply bigtrack relapsed myeloma and the way in which it works is by blocking export of proteins out of the new case so essentially when you have basically a type of myeloma called 17 related myeloma 17p makes a protein and when if you don't have the 70 be mod chromosomes or the gene in your myeloma cells you don't make that protein and if you don't make that protein the cells find it very difficult to die off so for many people it's only it's not an absolute lack of making the protein it's just a deficiency in that amount of protein that you make and what this mode drug does it it traps the 17p proper generated protein called the p53 protein inside the nucleus so the cell nucleus tries to export it out but this drug blocks the export of that protein and then it stays in the nucleus and when you give other drugs on this tumor suppressor protein is able to kill off the myeloma cell so this is a class of drug known as nuclear export inhibitors and most of you would not have received this drug however it's an oral drug and it just certainly extended the life of many patients already and again like every other drug that's been my discovered or invented in myeloma it has started off with patients who have absolutely refractory disease where nothing else is working and we hope to move it to earlier lines of therapy and we also hope to get second generation third generation nuclear export inhibitors and you use them in a more safe fashion so this is a study that led to its approval is called Expo vo that is the name and essentially for patients who had extremely refractory disease this drug was effective in producing a response in at least twenty six percent of those patients in fact even in patients who had relapsed after Carty the drug was useful and these are patients who had a response and you can see that their probability of survival was significantly better and mostly no more than half of them were going out beyond or eighteen months or so so this is just another tool in the box in the toolkit and as again as anyone knows as we get more weapons or more tools in our box to treat myeloma we actually get more ways of combining those tools and we also get more ways of more regimens built in so for example this drug was approved in combination with dexamethasone already we have combinations such as a balanced L index or with Touma member rozalex NCAA next door so when we were starting with the our slacks we did not know that there would be a Sicilian X or a few years later now that we have a sill in X or B try to see what what happens when we combine both and in patients who had our selects naive or who had never seen the our selects a response rate with that combination is 77% for our selects alone the response rate is not that high so it means that the combination is better and new combinations are being explored all the time so there is another drug again which is not yet approved but for myeloma but it is already available for couple of other indications suggest several types of leukemia and this drug is called Veneto class that this drug basically is again a agents that promotes cell death and that because cancer cells try to create molecules in themselves which prevent cell that so the cell death in in the context of what we are talking about is called apoptosis and cancer cells create pro-apoptotic proteins or attempt a bit of a problem so they deplete those and they try to evade cell death so by using agents that promote cell that such as Vanita plaques we actually can cause more cancer cells to die off again in myeloma it seems to be particularly effective for a type of myeloma known as translocation 11:14 myeloma which correlates with a higher ratio of production of this molecule bcl-2 molecule so so the here is the efficacy data from the when it applies as you can see patients with the 11:14 subtype of myeloma are in this green curve and there are the people who maximally benefit from this drug when you look at our patients and non 11:15 patients they did not have as much of that effect as the 11:15 patients so this drug is particularly being explored in 11:15 myeloma patients and if you now have a biomarker for response for this drug so that's the 1114 marker and if you have this type of myeloma and the 11:14 myeloma you really need to go on trial at some point that uses this drug and it can also be obtained outside of clinical trials but we have insurance a issues getting it because this drug is not been approved for Milo myself as you can see the 11:15 patients the response rates up to 40% so one of the caveats is that there was a large trial that was being done for this vinacapital ex agent and this drug that's in this trial we had to stop it early because there was significant higher toxicity in patients who got the when inter-class combination and that's when we figured out that maybe you should not be using engine implications at this time we should be using it specifically in 11:15 patients so the benefit is seems to be limited to those patients because it is a toxic drug to use for it when you use it for all the patients so it's all about risk versus benefits so the risk of toxicity is higher and the patients who don't have the 11 for Damon mutation um again everyone here know somewhat a little mild and lenalidomide or Revlimid and homilist pomalidomide those are all a class of drugs that begins in a family called it mid family so immunomodulatory family is the expansion of that so in that family of drugs we have another agent coming down the pike now that's called I burned abide and the I bird of my trial was reported about a year ago at ASCO and as you can see patients with refractory myeloma relapsed refractory myeloma who had multiple prior therapies and who had prior usage of lenalidomide or Revlimid for later my and produce some inhibitor such as well kill and disease progressing within 60 days of their last therapy so that means they had fairly bad myeloma they had seen at least three of the major agents in myeloma and they had actually disease that was taking off within 60 days of their last therapy they entered the study and the better mind was used in multiple combinations by itself with eczema thisone alone with DARS LX and EX an episome with al-qaida in dexamethasone and confusion women dexamethasone so with all of these age combinations it was shown to be highly effective with about 35 percent response rates and in page to a refractory which means absolutely not responding to lenalidomide or pomalidomide even their a drug or uber termite which is in the same class of drugs as those agents that we mentioned has a 35% response rates I which means that this has a unique activity and even in patients who have who had seen prior Revlimid or homilist the band amide is able to induce response does this very promising for patients and in this flocculation where patients who are director man and bomb refractory which means they had that both of these drugs but not working but I better Mike worked about 30% of the time and again you know don't be disappointed it by that 30% number that 30% is what we usually see for a new drug except for Carty most of the drugs that have newly discovered start in patients who have had multiple therapies and 30% actually good number for a new drug in a very very frankly population of patients as Nina mentioned BCM a or b cell maturation and antigen is the new target this is a target on the surface of the myeloma cells and we have several approaches targeting that so she already mentioned about the car t-cell so we won't talk more about that there are many many agents in clinical trials right now you saw the most recent update of the data from which is going to be presented at ASCO that's what showed and we talked about the special side effects again at this time I would emphasize that no copy cells have been approved for myeloma so car t-cells to obtain car t-cells you need to join a clinical trial right now number two if you've if you already seen a type of car T cells their way if you've got these trials I'll take a patient has already seen one copy for a second car t track number three if you have newly diagnosed myeloma know for example or myeloma that has only relapsed one time there are very few car T cells that will take prilosec take you and most of the cartridges are the vast majority of kharkiv trials right now are for patients who have multiple relapsed myeloma or very high-risk myeloma or myeloma that has relapsed in a year of treatment or something really something that bodes poorly for the patient those are the patients who need to go to party so if you're doing really well on maintenance and nothing's happening you were stable remission going on you cannot join in a car key trial so I get this question all the time including that's why means you know just because there's something out there we don't need to use it in fact if I were a patient I wouldn't want to use car key unless I absolutely need it so then and if we have if you can afford the luxury of letting the technology make sure a bit will be better so the people who need car T right now other people are actively relapsing or people have some high-risk features or people are running out of options we already talked about this with dr. sha so the one car key that's going on is the BB to one to one which we think is going to heading towards approval the other one that's heading towards approval is the Elkhart be 38 which is the other most active car t cell and so a quick stop to see you know I totally that that means should look at the technology make sure and if we can afford the luxury of waiting for that we actually will end up using it more effectively it is a little disappointing to many of us that car these are you know not giving us a cure that we expected in fact the other two diseases where it's approved lymphoma I'm leukemia we have at least a proportion of patients getting cured with car T so how how can that happen in myeloma there are so many combinations that are being explored and that was a question in the chat box to are people exploring combinations to prevent relapse after car T definitely yes multiple targets are being addressed in that sometimes the same VCM a target that the car tip used sometimes something else using it in earlier disease setting actually instead of waiting for the myeloma to be multiply relapse we have to do it in clinical trials and use it earlier and see if we can do it right after transplant instead of a transplant before a transplant many many many many scenarios where we can use it I then change the Kartini composition in the car T's is living cell therapy and there are different types of T cells that become car T cells you can change the function of the cut that the cells proportion of cells that are memory t-cells etc and then change the targets that you are using for Carty such as you know we are only doing it VCA me right now change to something else change the construct of the Karthi change the manufacturing of McCarty there's so many other things that will happen so this technology is in its earliest phase and there's so much so much activity going on and we also have to think about off-the-shelf car things that may be coming to wherever you don't need to wait for the car need to come and we just talked about this ways of reducing the relapse this was also a question in the chat box and I said to be addressed alive so there are many ways that patients can relapse after Carty so one of them is that the car T antigen can disappear from the surface of myeloma cell the seconds then the cart itself can disappear there's no memory of the car T's and they've gone after a while um they may not expand when they're putting the patient there are some changes or there could be changes in the environment of where the myeloma cell is living which inhibits the T cells from killing the my leg muscles all of these are mechanisms that have been identified and these are all the mechanisms that people are working on to reduce relapse after car key again this is dr. Shah addressed this drug which is called Balanta map it used to be called GSK two eight five seven nine month six this is a drug that actually is an off-the-shelf option for patients with multiple myeloma again targeting the same thing the BCM a target that the car keys current car keys are addressing in the initial study from the dream one study we had a response rate from 60% in the dream to study which is a follow-on study which actually took on patients who are even more advanced disease the response rate drop but still it is a new class of drugs it is an off-the-shelf agent if you in anybody meeting it can take it off the shelf and use it again right now it is not yet approved I'm hoping very much for my patients that will get approved Basu so this is the part to study that we talked about in patients who had try and direct mmm the response rates that are actually a little over and the patients overall just higher again I'm not going to go into details because doctors already talked about and then you know we're talking about emerging therapies so one of the most active emerging therapy field that think about is what are the monotonal antibodies that we have so monoclonal antibodies are these guided missiles that go and homed in on a single target or sometimes they do it to target within the myeloma cell or outside with myeloma cell so we have a whole bunch of drugs everybody has heard about this new drug called ice a taxi map or which is a new enticing 38 antibody in the same way in a stereo map and it's got and just got approved by the FDA so it's another option for myeloma patients we actually don't know if patients who have failed their timmmmm will respond to the ice attack see map or quite servers they have a whole lot of other monoclonal antibodies that are bound to the bound with a warhead that delivers a tiny dose of chemotherapy that's the warhead which on the surface of the myeloma cells so even if they antibody itself doesn't kill the myeloma cell the warhead built it myself and dr. Shah already talked about the my specific antibodies and this is a whole new approach again it brings an immune cell in combination with a myeloma cells okay one end of this velcro it's a double edge 1200 in fact so one end sticks to the myeloma cell the other end catches the passing-by immune cells and the immune cells now force to interact and kill off the myeloma cells one of the problems that happens when you have myeloma is that myeloma cells have found a way of evading your immune system they basically found out some way to turn off your immune system and if your immune system can make up that might eventually be the way to cure myeloma so um unless we have a persistent police force in our bodies that's policing the myeloma and killing killing off the cells as they try to rise up we will not be able to control myeloma otherwise it's a life long chemotherapy so it's metal to have an immune approach and that's the best thing that we can do so the show already talked about one of the armed CC 9 3 2 6 9 which is one of them there are so many others in development in fact there are at least 7 in development that I am aware of and probably a few more that I am not aware there is another axis on the myeloma cells you we're talking only about the BC ma at this point there is a ligand or there is a similar agent to BC ma called April and Tassie these are all similar to be CMA in the same super family and they were all stimulation of you know engaging with these molecules causes the myeloma cell to survive and proliferate so by blocking them we can actually create drugs that can kill myeloma cells outside of BC ma targeting so those anti April antibodies that are in clinical trials and several other methods are blocking this so in summary you know we have a whole variety of immune strategies that are in development many of them have been touched upon my doctor shop and again going back how do we put this all together how what does the emerging field so one of the approaches is to do master protocols where we basically take you know patients and profile them for minut alterations in their genes and find out what drives the myeloma in that particular patients it's basically a personalized approach so you can actually find patients who are for example have the 1115 mutation and we already talked about it we have a miniature plaques etc also working in working in this myeloma and then at the other extreme we may have patients who have absolutely no detectable Rhodes notations that we find for them we have a backbone regimen and then we build that one new agent at a time on top of that and we test a bunch of patients with that regimen and feel finally promising we'll take it to further development we find that patients have not responded the backbone judgment would still have conferred a response on the patient and then we would draw up that age the whatever agent we added and want to just a new agent similar thing for waste mutation said to be fine so this is a interesting approach called a master approach which actually speaks some drug development and everybody knows now that you know we are speeding up development and I think with the co 8 crisis health care has again become a major focus in this country and there's a lot more money for research hopefully I would think after this or ends and there is a urgency that will help everyone with healthcare problems so there are many many myeloma precision medicine try and some of them I have summarized here so all of them are specifically looking at targeting specific mutations or patient specific alterations in myeloma patients so that it becomes a personalized therapy for its small subgroup of myeloma patients some of the other emerging drugs that I want to talk about is one is nel flu fen you know everything anyone who's had a transplant for my Lachman has heard of the drug nel fly that's been a drug since that's been around since 1950s onwards it's a very old chemotherapy drug and it turns out that you can actually package that drug in a different way so that you need far less of that drug and it's more specific to the myeloma cells if you combine it with a specific protein and that is this new drug called nel flusha it is actually an advanced development we have had several trials with this drug and it is actually again I think fairly close to approval with might happen in the next job year or so another agent is the CLR 131 that dot dr. character and others have worked on which is again in radio targeting of myeloma cells with a specifically targeted approach there is another drug that I am very interested in it's called the cd47 don't eat me molecule so when you have a cancer cell and an immune cell sometimes the cancer cell shows aids protein on a surface like this on the cartoon here which basically tells the immune cells to stay away so it's called that don't eat me molecule or cd47 and there are a whole variety of drugs that are being developed that actually can break down that interaction so basically it can either cover up this don't eat me molecule so that the immune cells will eat them or it can block that you know do we call this point drugs checkpoint inhibitors and that's one of the drugs that I am involved with is called a or 176 and then there is you know we talked about the my specific antibodies we have also have try specifics and then we have car t-cells which only look at molecules from the surface of the myeloma cells if you want to look at a target within the myeloma cell inside of the myeloma cell there is a different kind of cellular therapy called TCR cells so this whole lot of approaches that are coming and again you know even men you know my main message to anyone on this call who's got the disease to deal with is that even when things are looking bad this and there may be hope from clinical trials so always be on the lookout for clinical trials there are many websites that summarize all these clinical trials um and again the definitely website is clinical trials.gov which is you know our government-sponsored website but anybody doing a clinical trial in the United States and possibly around the world has to register their trial so if you can actually look up for myeloma you might find and the the the places where the trial is running is already there and you can actually contact or you can ask your doctor to find a clinical trial for you so then no please don't give up folks without thinking of clinical trials again you know we ensure that dr. Carroll another stop and morning about mmm profiler and other trials that look at risk assessment in a new way by you know beyond the traditional approaches such as fish and we have new tools that have been developed in in the modern era one of the things that everyone is excited about this is called single-cell RNA sequencing which basically tells us what specific proteins are getting turned on between the myeloma cells and you can actually identify patients who are either responding to treatment or failing treatment and then look at these and then decide what drives those kind of changes so we can actually predict and define who's responding who's good likely to respond and who's going to fail and these are things that will be useful later on in the next couple of years these kind of technologies will become more widespread and patients have been to significantly going to benefit so in conclusion I would say that a significant myeloma of progress has been made in the myeloma armamentarium even within the past 12 to 18 months we've had say next about you have the fast-acting the subcutaneous doors Alex you've had Isaac sexy mare so pre agents have been approved again literally within the last less than a year um we have a lot of newer therapies are coming immune therapies then dr. short touched upon and the non immune therapies that we talked about and there are piece of personalizing myeloma care we already have transfer 11:14 myeloma that might benefit from Bonita plaques and then our goal is to create these and move it forward so that we use the most appropriate treatment for the most appropriate type of myeloma that you may have it is not one disease there's multiple different types of diseases which deferring response is based on what we use and eventually I have no doubt that there will be a potential cure among one of these so the main message from from me is to look for a clinical trial whenever possible it's very difficult to give an emerging income medicine talk that's applicable to everyone across the board but the persons who benefit most from clinical trials some people have multiple relapses but even if you have not had my almond relapses even if you are newly diagnosed patients with my location with myeloma I truly believe that joining a clinical trial is always the best option so looking for clinical trials we already talked about and then you know always go to a trusted website don't just Google so um in summary I again thank the organizers Jenny and Greg and all my co-panelists for this and again you know we take questions now [Music]