(Guest Lecture) When and How you Become Refractory to a Drug and How to Find the Best Next Treatment

today is when and how you become refractory to a drug and how to find the next treatment. Now Dr. Nadim's presentation is going to focus a lot on how myeloma specialists sift through the lots and lots of choices. I don't even know how to count how many. Various choices in the myeloma arsenal to discover what is the next best treatment for my patient. We can also discuss how you become refractory biologically a little bit in the talk and then as you guys have questions about that in the Q&A we can explore that more. We look forward as I said to learning with you today. It is now my pleasure to introduce Dr. Omar Nadim to you. He completed his internal medicine residency training at Dartmouth-Hitchcock's Medical Center and his Hematology-Oncology Fellowship at the Warren Alpert Medical School of Brown University. He joined the Jerome Lippert Multiple Myeloma Center at Dana-Farber Cancer Institute in 2018 where he is a senior physician and serves as the clinical director of the Myeloma Immune Effector Cell Therapy Program and as the clinical director of the Center of Prevention of Progression. He is an assistant professor of medicine at the Harvard Medical School and is board certified in internal medicine, hematology, and medical oncology. He is an associate director of the Myeloma Clinical Research Program and serves as a principal investigator on several clinical trials ranging from precursor plasma cell disorders to relapse and refractory multiple myeloma. His research interests include MGUS and smoldering myeloma and immunotherapy in multiple myeloma with particular focus on CAR T cell therapy. We are really looking forward to your presentation Dr. Nadim and as a true myeloma specialist we're just so excited to learn from you. Thank you for being here. Thanks Audrey and thanks for having me. Let me share my screen. Great. So hello everyone. Thanks everyone for joining. It's my pleasure to be here today to discuss with you relapse multiple myeloma in particular. When do we treat relapse disease and how do we choose our treatment for when a patient relapses? So we'll cover a lot today and it's going to range from talking about some of our recent approvals and how do we navigate all the different options that we have that Audrey mentioned and what are the tools that we have in the clinic to help distinguish what treatment is best for which patient. These are my disclosures. So as you all are very much aware the field of myeloma is just you know becoming just drowning in success when it comes to just the availability of some of these newer therapies. It started in the 60s with very few therapies mainly an oral chemotherapy drug called melphalan and some steroids and then we went on to some combination chemotherapy regimens in the 80s. High dose dexamethasone was found to have some benefit in the late 80s and then came stem cell transplantation that was validated in several clinical trials in the 90s and became standard of care for patients that were transplant eligible. And then really since the late 90s early 2000s is where you've just had an explosion of therapeutics. It started with thalidomide which showed benefit in multiple myeloma and that led to discovery of lenalidomide, a revlimid that is very commonly used and that combination with steroids was shown to be better than anything else that we had seen you know prior to that time. And then bortezomib which is a proteasome inhibitor that is also called Velcade which was in development at that time was combined with lenalidomide and that showed superiority to some of the other regimens that we had seen and then that regimen of lenalidomide bortezomib and dexamethasone became standard of care for newly diagnosed multiple myeloma in the late 2000s. And then since then approximately starting from around 2015 or so we've had second generation of proteasome inhibitors and immunomodulatory drugs and we had our first discovery of a class of new drugs called monoclonal antibodies of which daratumumab is the one that's most commonly used initially starting in the relapse setting and now making its way to frontline therapy. And then really over the last few years we've now had the next renaissance of myeloma therapeutics mainly with agents that are utilizing the immune system so immunotherapy particularly targeting BCMA with two approvals for CAR T cell therapy and just a few months ago our first approval ever of a new class of drugs called bispecific antibodies teclistumab which was approved for patients with relapse refractory multiple myeloma. And there's a lot more going on in the field that we won't have time to cover today with some of the you know new even newer targets newer generation of agents that's right around the corner so it's safe to say a lot of progress has been made in the field of multiple myeloma and now it's a matter of figuring out which one of these combinations you know fits which patient the best. So with that as you can imagine you know the survival for patients with multiple myeloma has improved significantly you know starting from the 60s timeline that I shared before. In fairness we don't really even have the most up-to-date data for what an average survival of a myeloma patient is today because a lot of the data that we have is you know old already because of these newer approvals. So we're always lagging when it comes to the average survival of a myeloma patient by approximately five to ten years because you know that's how long it takes some of these newer trials to mature for us to know what we're seeing but safe to say you know it's improving significantly and and we are hopeful that we're on the cusp of cure for a subset of patients with multiple myeloma with some of our newer therapeutics. So we have clearly very long term survivors and maybe some of you that are attending this presentation today that have had the disease for many many years and in some instances even over a decade. So a lot of progress you know and it's translating into these improvement and survival for patients with multiple myeloma. So before we get to relapse refractory multiple myeloma and the treatment options you know it is important to talk about frontline therapy because what we do in the frontline setting really dictates what we do in the relapse setting for the most part. So I wanted to just spend a few minutes going over some of the recent data in frontline setting and then we'll spend majority of the time talking about the options in the relapse refractory setting. So as you all know initial therapy is called induction therapy that's when you are first diagnosed with multiple myeloma and we choose that front front line therapy. We still break down the you know the the patients based on their transplant candidacy and that really is a marker of their fitness their ability to handle high dose chemotherapy. So we still you know think about each patient when they come in with newly diagnosed myeloma as to you know would they be a candidate at some point for stem cell transplantation. So that with that being said you know that's not something that we always offer to patients it all depends on you know there's a lot of factors that go into that decision making but generally speaking our intensity of therapy is a bit different whether you're transplant eligible or transplant ineligible. But generally speaking it involves induction therapy with or without transplant and something called consolidation therapy which means that it's more you know essentially a more intensified therapy post transplant and then everybody nowadays goes on maintenance therapy and the goal of maintenance therapy is to keep the disease away ideally with as low dose and minimal therapy as possible to you know again keep the disease away but also limit the side effects that patients may have from therapy and this is now very much tailored to an individual patient depending on how they did with their induction therapy and frontline course and also based on their toxicities. So typically with this approach as I mentioned your patients will sometimes present with smoldering myeloma or MGUS which is the asymptomatic stage of multiple myeloma and then if they do develop some you know progression of multiple myeloma they'll get frontline or induction therapy with or without transplant usually will go into some form of a remission and then go on maintenance therapy and then over the course of their lives they will experience in majority of cases several relapses. So relapses are defined as you know when the disease markers start to rise or if there's new organ damage that's occurring you know from the presence of or reemergence of multiple myeloma and patients are obviously as you know very much followed closely in their maintenance phase and remission phase to assess for some of these changes so that way you can prevent some of these complications but invariably you'll have a relapse and then at that point go on to a second line therapy and then that usually would work for a while and then again de-escalates over time and then you know then the numbers may start to rise again and then you get your next therapy. So a patient can have many relapses over a long period of time and then eventually their disease becomes what we call refractory which means that their disease is no longer responding to either that particular agent they were just on or in some cases the class of agents that they've been on because they've had exposure to all the all the agents in that particular class and that's something that is more and more difficult to manage because of you know the fact that a disease has essentially morphed into a tougher version of the disease that existed before but the good news is we keep getting newer therapies and a lot of these trials are done in these refractory patients and at that point we're then able to you know hopefully lead to the approvals by the FDA and then offer it to patients that are in that position in the in the real world. It is important to highlight that you know we should always choose our best therapy at any given time so you know historically we've had this mantra that perhaps we shouldn't use up all of our agents early because what are we going to do later? I think that is no longer the case because what we want to do is give our best therapy because that's what leads to the longest and best outcomes and as you can see here with this particular slide the frequency of patients getting second, third, fourth line therapy and beyond decreases significantly and this has many reasons why because either there may be other complications that have occurred that have not allowed a patient to get to third or fourth line of therapy. Sometimes it's where you're treated a lot of times there's you know different availability of certain drugs and you're not able to kind of offer some of these therapies that we're using quite routinely in third or fourth or fifth line of therapy you know at some of the bigger sort of more tertiary care centers so a lot of factors that come in so that's why you can't guarantee at any given point that you're going to get subsequent line of therapy so you might as well get what's best at any given point whether that's first line, second line, and beyond and we really you know try to offer that to as many patients as possible. So starting with frontline therapy the the regimen that really took off as I mentioned earlier was the regimen of lenalidomide, bortezomib, and dexamethasone or the RVD regimen and this was based on this SWOG study that was done showing and comparing it to a doublet of just lenalidomide and dexamethasone so it was a three drug versus a true two drug trial and what this study showed is that patients that got the three drugs you know did much much better not only did they have improvement of what we call progression free survival meaning their disease stayed away for much longer than those that were just on the two drugs but there was also an improvement in overall survival particularly in patients that were a bit younger so this is why this regimen became FDA approved and became our most commonly used frontline regimen for a long long time well over a decade and to some extent still used quite a lot in the frontline setting. And then that particular trial looked at it just in the absence of stem cell transplant and then simultaneously we were studying this in the context of stem cell transplant so the the determination trial led by my colleague Dr. Richardson here at Dana-Farber looked at the same regimen of RVD either with stem cell transplantation or with the deferred stem cell transplantation arm so essentially what that meant is everybody will get three cycles of RVD in the non-transplant arm you will have your stem cells collected and then complete the cycles of RVD to get to eight cycles and then just go on lenalidomide or Revlimid maintenance. However, in the transplant arm you would get a total of five cycles of RVD and instead get high dose chemotherapy and stem cell transplantation and then go on to to Revlimid maintenance and the Revlimid maintenance in this particular study was continued until it stopped working so patients would stay on it for years on end and what this trial showed was that patients that got a stem cell transplant stayed in remission longer by approximately 21 months so so the transplant arm the average time until their disease came back was 67 months versus 46 months in patients that did not have a transplant so it's approximately four years versus five and a half years however despite that benefit of the disease staying away longer we did not see a difference in overall survival which means that because patients are able to get subsequent therapies with all these options that we have over time the survival advantage is just not seen now you could argue that you know we still haven't even reached median overall survival in this trial which means that you know more than half the patients are still alive now going on you know six seven years of follow-up which is you know kind of a testament to how long patients are living with multiple myeloma so it could be that you see you know some differences over time but so far we haven't really seen that and and you know this is something that we discuss with each patient that's deciding upon transplant you know should you do it should you not do it this is the data and you know on one end you can argue that you know you can get the longest permission possible by the other end you can argue well you're not living much longer so why would you do it and this is a very nuanced discussion we look at many factors your eligibility for transplant your fitness your ability to handle the high dose chemo the disease related factors how's your disease responded so far to treatment and then you know we also look at what kind of risk of myeloma you have do you have any high risk features etc so lots go on goes after this decision but this is the data and the other thing to note in patients that get transplanted tend to have more toxicity as expected they're getting high dose chemotherapy so they see you know we see lower blood counts in them although that is usually short term but some of that could linger for some patients afterwards where we have some difficulty in giving them maintenance therapy because their counts are a bit lower than they were before the transplant and it is important to note that patients that do get a transplant tend to have a slightly higher incidence of developing some other cancers in particular different forms of leukemia so because the chemotherapy that you receive a transplant can damage the bone marrow although it's still pretty rare we are seeing a signal in the transplant arm versus a non-transplant arm so these are some things and nuances to discuss with your physician when you're making this decision about whether you go forward with this or not the other thing that's happening is the addition of daratumumab or that monoclonal antibody that was approved in 2015 to frontline therapy so now this was a trial called the griffin trial that was done here in the us that basically took that rvd regimen that i just went over and added daratumumab to it so this particular trial looked at four drugs now versus three drugs and this was not a transplant versus no transplant trial everybody in this study was transplant eligible and got transplanted but it's looking to see if you add daratumumab to the frontline regimen what happens right and then the maintenance part of this trial if you did receive daratumumab as part of your induction therapy you actually also receive that as part of your maintenance therapy for up to two years so you received daratumumab once a month for two years along with the revlimid whereas in the triplet arm you only received revlimid just like i reviewed with the determination trial right before and what this trial showed on the left is the response rates in patients that received the four drugs and you can see over time you start to see deeper and deeper responses where the complete remissions or complete responses were seen in 80 over 80 percent of patients and it was about 60 percent in patients that just got the three drugs so you know again we're taking what we've already learned about how to manage frontline myeloma and now taking it one step further with the addition of these agents and and this is really translating into very very good outcomes so now what we're looking to see is well with this addition sure you saw higher rates of responses or deeper responses but what does that translate into and with the most recent update that we saw you start to see you know benefit now in progression free survival which means that again the same thing i said before how long does it take for patients to get to their next line of therapy and you're starting to see quite a benefit at four years now where 87 percent of patients are progression free with the quadruplet and and 70 percent of progression free with the triplet and this is something that we're now using quite regularly for patients in the frontline setting so so then a little my maintenance or relevant maintenance again remains the standard of care but we're now seeing some data with what i just went over where you're kind of adding for example direct to a map to the maintenance setting and and more and more patients are receiving a lot of these agents on the frontline setting the determination trial further supported continuation of maintenance until it stopped working versus a fixed duration which was studied before but the results from the most recent trials support that if you give revlimid until it stops working the patient stay in remission longer and now since we're looking at several other trials of using two agents for maintenance this is where the field is shifting because this is leading to longer and longer remissions for patients and over time the next step of this is going to be well you certainly and i'm sure many of you that are attending this presentation have been on maintenance therapy and don't have evidence of disease the question that commonly gets asked well how long do i have to stay on this for do i really need to take revlimid i'm in year five post transplant and i still don't see my m protein or or the blood looks good what do i do now we're looking at trials to look at some of these response-based adaption of therapy so for example if you are what we call minimal residual disease negative or mrd negative can we take you off maintenance you know that's an important research question going forward that's going to hopefully answer some of these questions for all of us so that way we can then decide what is the best duration of maintenance therapy and other therapies depending on how you're doing with therapy up until that point so that really sets the stage as to what's going on in the frontline setting and and it's so important because most of the patients again going into the relapse setting even the first relapse are now refractory very commonly to lenalidomide or revlimid and the reason for that is because they're on it so their disease is now resistant to that particular agent at the time of relapse and frequently we're now seeing resistance to even daratumumap at the time of relapse because they're on a lot of times both of these agents right so so what do you do in that particular scenario because a lot of these approvals that occurred in the relapse setting actually included some of these agents you know we looked at essentially several combinations that included daratumumab and lenalidomide etc those are some of the trials that i'll go over shortly but they did you know they're no longer applicable to this population because you've already had these agents and your disease is getting resistant to it why does it become resistant to these agents it's not entirely clear you know there's not like one specific mutation that occurs or or you know for example daratumumab targets was called cd38 it's not that suddenly cd38 isn't there anymore it's just that the immune micro environment around the myeloma cells you know which is very complicated develops mechanisms of resistance so it's it's you know it's very unique to each individual agent it's not like we have a particular test that will tell us okay now your disease is refracted daratumumab you should now receive this that or the other so what we're left with is several of these approvals that you can see on this slide several different combinations that have been studied in patients that have had refraction as to either bortezomib or lenalidomide or both and we look to see which drug are you coming off of and which one are you most likely to not only benefit from but also tolerate but over time we go through many of these combinations that you see on this slide and then move on to you know subsequent lines of therapy and ultimately now what we're doing in patients that have had four or more relapses is offering them car T cell therapy or ticklistimab which is a form of immunotherapy that i'll go over shortly so when choosing you know which treatment we should choose these are all the factors that we look at so we look at frailty you know how old are you what is your performance status meaning how fit you are do you have any comorbidities for example diabetes heart disease any of these things that may impact our choice of agent because some of them will worsen some of those baseline underlying conditions so we look at the factors that you have present you know at the time of the relapse we look at disease morbidity what that means is you know what has a disease kind of caused so far in your disease course do you have kidney disease from ulcer myeloma a lot of our agents have you know are cleared by the kidney so if your kidneys are not functioning normally we may not be able to offer you that particular treatment do you have bone disease a lot of times patients symptomatic with bone disease and we tend to prefer certain agents and patients that have bone disease and then refractory disease as i mentioned you know what are you coming off of which will then dictate what we use later we look at your risk so you know patients sometimes will present with certain high risk features in the original bone marrow biopsy certain mutations we check for that help us you know sort of get a sense as to what sort of disease aggressiveness that we're dealing with so that's why another bone marrow biopsy at the time of relapse may tell us do you still have those mutations or do you now have new ones and if you have new ones are any of those high risk mutations now which then may allow us to perhaps reach for some of our more potent therapies at that time of relapse so that way we don't you know let the disease get any worse and evolve any further treatment history i talked about and then lifestyle this is really important you know as you know very well you know patients all these treatments have different schedules so some are ivy some are shots some are pills some are given once a week some are given you know every two weeks and all these factors all these things come into play when you're you know traveling from far away and you know the point is if people are living with multiple myeloma for a long period of time where we're trying to until we can cure it at least have this be a chronic illness well then you have to have you know lifestyle factors that are in consideration we want you to live your life and we want you to live your life with as little side effects as possible and as little disruption as possible and that's why a lot of times myeloma therapy comes in these phases where you have like an intense phase where the treatment is way more frequent but then over time it'll become less and less and these are some discussions we have when we have so many options to choose from we look at lifestyle factors as well and we want to really preserve that quality of life for patients as much as possible so here are just some trials i don't want to spend too much time on the specifics but you know all these agents that were approved pomalidomide daratumumab carfilzomib selenex or venetoclax these are all new drugs they were all compared to their counterpart doublets and showed superiority and they all became FDA approved really based on some of these trials with the absence of venetoclax which i'll get over shortly but ultimately what this has allowed is several of these combinations you know to be used in clinic and then some other trials looked at triplet studies in comparing them now to lenalidomide and dexamethasone so that particular doublet and all these trials looking at exasumib, elotuzumab, carfilzomib, daratumumab again all showed superiority over the doublet now you could argue well you're looking at three drugs versus two drugs of course it's going to be better but remember at the time these studies were constructed you know we didn't really know that so these were these trials take a long time to mature and now we're kind of moving on from that three to the four drug you know platforms but these the trials that allowed all these options to be available for patients and now we have so many to choose from depending on these circumstance some of the newer trials that i wanted to go over one particular trial is this trial called the Kandor trial that looking at a combination of carfilzomib, daratumumab, and dexamethasone and this trial compared this to a doublet of carfilzomib and dexamethasone and this particular combination of what for short that we call it dkd really led to pretty substantial improvement in progression free survival in patients that got this particular triplet and the overall response rate was 84 in the relapse setting and a lot of these were deep responses so patients developed actual mrd negative disease so we were very excited about this combination i would say in patients that have not had daratumumab in frontline setting let's say being treated with the triplet got rvd went on to revlimid maintenance and are now progressing and we think they need the best next line regimen this is one that we reach for quite a lot is this carfilzomib daratumumab dexamethasone backbone similarly there's another cd38 monoclonal antibody very similar to daratumumab called isotuximab that is also now fda approved for multiple myeloma in the relapse setting and this was a very similar regimen to what i just went over but now using this particular antibody and comparing it to the same doublet again showing very very impressive results so that this combination seems to work really really well together because a lot of times i get asked by patients well why can't why can't you do one at a time why can't you give me this and then give me the other one afterwards well we're noticing from a lot of these trials that these combinations are the what work much much better right so they give it together you get a much deeper response you get the disease a bit harder and that usually leads to a longer duration of response which is what we you know really really look for going forward so this is another combination that's very commonly used now in the clinic and that same cd38 antibodies also approved with pomalidomide so the other oral immunomodulatory drugs similar to revlimid the pomalist combination with isotuximab is also very very efficacious and which one of these do we choose it really depends on again some of those preferences that we talked about oral therapy versus iv therapy elotuzumab is in another agent that's been approved in patients that have relapsed refractive multiple myeloma this is a different monoclonal antibody that's also been around for a while so we use that in certain circumstances and then selenexor which is an oral new drug something targets something called xp01 has been compared has been combined with bortezomabidexamethasone versus just bortezomabidexamethasone alone also showed improvement so this is an oral drug that is approved for patients of one to three prior lines of therapy and in some circumstances we use that depending on what they've had in the past and then there's vanetoclax vanetoclax is another oral drug that is not yet fda approved but about 15 percent of myeloma patients have this mutation called the 1114 translocation and it seems to be really really active against that subset of patients with multiple myeloma and this particular trial called the bellini trial showed that in patients that had the 1114 translocation really really benefited from this particular agent and the patient that didn't conversely did not benefit and there was some question whether they were actually you know potentially harmed on this study that a higher rates of infections etc hence it led to a pause in the development of this particular drug but now several trials are ongoing in just the 1114 patients and that seems to be really really promising and we hope to have that agent available soon and then there's bcma and bcma is a term that you may have heard of a lot recently what this is is a new target that's been discovered on multiple myeloma cells and the good news about it that it's it's highly expressed universally on the myeloma cells and not on a lot of other normal tissues so this is this really created an entirely new target for patients with multiple myeloma therapeutics and with that came so many different ways to attack bcma so we have car t-cell therapy we have two of these approved that i'll go over shortly we have bispecific antibodies that are you know one of those is approved so far we previously had a drug approved called belantamab mafidotin or blend rep that was also targeting bcma but using a different mechanism of action that is no longer on the market but you know we've been using it for many years actually after its approval and we hope that it's going to make its way back as some of the other trials mature but safe to say bcma as a target has really really been important and impactful in management of patients with relapse refractory multiple myeloma so going over some of these currently approved bcma therapeutic options so car t-cell therapy something that i'm sure you all have heard of there's a lot of buzz about it it's been approved for patients with lymphoma and leukemia for many many years and myeloma trials were ongoing and led to its first approval in 2021 what this is is essentially taking your own t cells which is part of your immune system taking them out through a mechanism or a method called a pharesis essentially filtering them out out of your blood shipping them to a manufacturing facility which will then take your own cells genetically modify them to recognize multiple myeloma cells and what it would recognize on the myeloma cell is this bcma target so these cells will then you know they'll grow them they'll modify them and they'll send them back to us and then patients will receive these t-cell infusions and what that has shown is really really impressive results in patients that have multiple myeloma so our first approval was with this car t-cell product called ida cell or abeckma and again this is targeting bcma and our second approval that came last year is with another bcma targeting agent called silta cell or carvicti they're very much alike they both target bcma they have their car t-cell products the only difference is that the carvicti product has two ends that go and find bcma as opposed to one on on abeckma and talking first about abeckma the reason why it became approved is that patients that received this infusion these are all patients that have had on average six lines of therapy so they've had all the drugs that we've talked about up until now and in patients that received this had a response rate of about 73 and that translated into an average time until the the cell stopped working at approximately nine months and if you got the higher doses it was actually closer to a year so that is what led to the fd approval of abeckma and then came silta cell just last year as i mentioned so this product looked even better the response rate instead of 73 was almost 100 and majority of these responses were very much deep responses where patients were achieving complete responses and mrd negative disease and what this translated into is that instead of lasting a year it seems to be lasting two years or beyond so that's what led to this product's approval now these products right now sit in patients that have had four or more lines of myeloma therapy and that's where you're able to get access to this so there is some some nuances with that which i'll get into shortly and and just to talk a little bit about the differences between the two they both cause a very similar side effect profile you know cytokine release syndrome or crs is basically this fever immune activation phenomenon that occurs after car t cells a lot of times you know these are given in the hospital for that reason so that way you can be managed with some of these toxicities it happens a bit early with car with abeckma it happens a week later with carvicti so there's timing is a bit bit different between the two there is a bit of a delayed neurological toxicity that can be seen in a handful of patients with with carvicti that we don't tend to see really with with abeckma so there's some subtle differences that we go over with patients when we're deciding between the products but in terms of effectiveness you know we tend to see much much better results so far with carvicti and we're now pooling the real world data as we're treating more and more patients with it to see if this translates into you know what we saw in the clinical trials and hopefully it will as we've seen with the with the data with abeckma that it did actually you know look very similar to what happened in the clinical trials and you probably know the availability has been a bit of an issue with these car t products we tend to you know have a lot of patients that you know are either eligible for or interested in it but have only been able to treat a handful of patients so far because of just the supply issues so you know just our center to give you an idea we were treating only a couple a month for quite a while and now we're getting up to six eight even ten a month in certain certain certain months depending on availability so it's really improved but still not enough yet to meet the demand particularly with the carvicti product and then just just ending a bit talking about bi-specific antibodies so this is you know basically our most recent approval so what these are are antibody drugs they're essentially like daratumab for example it's a shot and and on one end the shot will find the t cell and bind to the t cell on the other end it'll bind to the bcma and this kind of brings them together and that's basically what the car t cells do right they kind of they're t cells that go find the myeloma cells now you have a drug that's essentially doing that and ticlistamab or ticvali is one of our is our first approval of bi-specific antibodies in myeloma and it basically targets bcma as i mentioned as the car t product and what this trial showed again very similar that it about 63 percent of patients responded to it and about 40 percent of those had a complete response so these numbers are perhaps not as you know potent or impressive as what we saw with carvicti but they do look actually not that dissimilar to what we saw with the first approved car t product so clearly a fair bit of activity in as a single agent right so we're now studying this in combinations and a lot more going on in trials but as a single agent you know these results are actually pretty good and in what this translating into is a median progression free survival of approximately a year the same thing that we saw with the first car t product the difference is it's you know it's a shot there's no time for manufacturing there's really no availability issues and you can just give it to patients so that's what we're doing a lot of since its launch is treating several patients with this product as opposed to car t cells in many circumstances either based on availability or based on just the you know necessity of the disease needing more urgent treatment a lot of times patients can't wait to get the car t slot and then wait for the manufacturing so this is a very nice option now to have with patients and the approval for this sits exactly where it sits for car t cell therapy where patients have to have four or more lines of therapy the safety profile of this looks very similar to what we saw previously with car t cells actually looks a bit better when it comes to the rates of cytokine release syndrome and you know the reduction in blood counts etc there is a signal for infections though so this is one thing that we're really really mindful of there's a lot of infections seen on this study some of it is a marker of you know what we see in the typical myeloma patients with relapse disease anyways but there is definitely a predilection for infections here with this particular product so we give a lot of times prophylactic medications to prevent infections and also immunoglobulin infusions called IVIG to limit the risk of infections as much as possible and as I mentioned this is this agent since it's now approved is being studied in lots of randomized phase three trials in patients in earlier lines and also looking at a newly diagnosed patient so all these drugs usually start in the relapse setting and they make their way to frontline therapy just like we saw with some of our previous approvals and then one other bispecific antibody to know about is a drug called talcuitamab this is another very similar one end binds to the t cell but instead of binding to bcma which is what all the CAR-Ts and the other bispecific do this one binds to a new target called GPRC5D so this is a brand new target and this particular agent has been in development now for a few years and the most recent results that were presented at our ash meeting this previous year which is where this data is from you know basically showing that approximately three quarters of patients are responding to this particular agent and it's given either weekly or every two weeks or studying both both combinations and what this is translating into very similarly is approximately a year of response so you know again an entire new target brand new drug and hopefully we'll see this in the clinic in the not so distant future to have another option for biospecific antibodies which is very exciting so so you have to say like I mentioned lots going on a lot of bispecifics that are in development targeting bcma several targeting you know other newer targets such as GPRC5D and another one that I didn't get into today called fcrh5 so lots going on we'll have to then figure out how do you sequence all these immune therapies you know do you give bcma followed by GPRC5D vice versa and that's where you know a lot of research is ongoing now and will continue to be going forward so just to kind of end in bcma therapy in 2023 what is the most optimal method to deliver bcma therapy as I mentioned CAR T cells tend to have the highest response rates but there are some challenges including availability manufacturing toxicity etc. Bilanthium amafidone as I mentioned is not on the market now but did have its issues with the toxicities that we saw particularly with the eyes so we'll see if that makes a comeback in the future it is an agent that we were using quite a lot prior to having a lot of the other available options but I still think there's room for it and and for the right patient it can be a really really fantastic drug and then these bispecific antibodies they may strike the ideal balance they're off the shelf they're outpatient lower toxicities and we're going to be studying this in new combinations and then the question is if you get CAR T can you get bispecifics even if it's targeting the same exact target like bcma we don't really know yet some of these trials did look at cohorts that had prior bcma therapies and we are seeing responses but we don't yet know what the right sequence is so typically what I say is go for the best therapy as I said before what's available what we think you'll tolerate as long as it's you know shown good activity data that's the one to go for and then with all these new targets in development we'll see you know how what is the best therapy for your disease you know at the time of relapse and then again which line of therapy will be administering these bcma therapies in the future right now four prior lines of therapy but we know as I talked about in the beginning of the presentation so many patients around lenalidomide maintenance dara maintenance they go through all these combinations actually now way earlier than where the current approval sits so in a lot of circumstances we're giving several therapies just to get to you know the approval for CAR T cells and that's not ideal in my opinion so studies that are ongoing in earlier lines will really help with that and there's also now head-to-head studies looking at CAR T cells and comparing it to stem cell transplantation so to summarize in relapse myeloma we always stratify by refractoriness so kind of what was your disease most recently on that is not it's not resistant to and then we look to see do you have a high risk relapse or a clinical relapse or do you just have your blood markers going up and we're not seeing any other symptoms right so on one end people may develop kidney failure and new bone lesions that are painful very different scenario than somebody who just has their m protein rising very very slowly month in and month out and we do break it down with those two particular subgroups and if you have kind of the more symptomatic relapse and if your disease has not seen a cd38 monoclonal antibody like daratumumab we tend to choose daratumumab based regimens in particular in in combinations with that carfilzomib dexamethasone regimen that I mentioned if you're already coming off of daratumumab then we usually don't continue it we will then switch you to a lot of different combinations as I've listed there and there's so many of these ones that are approved to choose from and patients will go with one depending on how they do may go to the other etc and if you have more of a kind of a gradual endometrial relapse you perhaps don't need to go to some of these sort of more potent therapies again that's a bit controversial in some cases we do but generally speaking there are some combinations that are listed here using a drug called hexazomib or elotuzumab that tend to be a bit gentler perhaps less side effects it may not be as involved and that could be an in-between option before you go on to some of these other therapies but ultimately patients will cycle through a lot of these therapies and then go on to some of these newer therapies such as car t cell sticholistumab and in some cases selenex sorter this is just something to keep in mind as we think about disease relapses going forward so to conclude multiple bioloma treatments have improved significantly as you've seen leading to unprecedented improvement in outcomes the transplant decision you know is very individualized now particularly with these quadruple drugs that we're using seeing impressive results so that is a discussion to have with your patient if that's the right treatment option for you we talked about maintenance therapy looking at lenalidomide but now we're also looking at combinations and then relapse myeloma when it occurs we use several of these combinations and then choice really depends on many factors including refractionist, toxicities, comorbidities we talked about bcma immunotherapies these usually sit after you've had several of these combination therapies for relapse disease but car t cells and bispecifics are something that we're not routinely using in the clinic and then beyond that i think we're going to be looking at newer targets like the gprc5d target as i mentioned along with several other newer you know non-immunotherapy agents that are also in development so the future is very bright but you know i think the progress is really really impressive and we hope over time we're able to individualize therapies even more for for patients like you so you can benefit for as long as possible until we can cure this disease and that is it i thank you for your attention happy to answer any questions awesome thank you nocturnal deem that was awesome it was a lot of information but very well spoken and i would love if you feel comfortable sharing a copy of your slides with the participants so that they could go over it again as several asked for the ability to review and you will also be getting the recording as well to anybody who's watching this so you can also hear what he has to say over and over again well there's lots of great questions here as expected so let's get started and try to answer as many as possible a question here if you only had a partial response to a particular drug does that mean that you are refractory or could it still work later in a new combination yeah that's a great question so um you know partial response implies that the drug clearly was active right so they did lead to reduction in the you know either the m protein or the burden of disease it depends on where you are right so if you're in the frontline setting a lot of times we expect to see better responses than just the partial response nowadays with some of these active regimens so in some cases you know we do tweak it a bit perhaps to kind of get a bit of a deeper response you know that could include a transplant or or swapping out one of the drugs for the other so it doesn't necessarily mean your disease is refractory what that means is that it's still responding but perhaps not responding as much as you know we would like however some people can stay in a partial response for a long time so response is only part of the story it's all about how long can you keep the disease you know at bay and in some cases you know that is their best response and then as long as the drugs that they're on is keeping it there we don't necessarily make a change just just for the sake of making a change so refractory and relapse for that matter really means that the disease is growing on that particular regimen and then you're at risk for developing some of the complications from that relapse yeah definitely i think in today's day and age of mrd which is wonderful but sometimes we look over the benefit of stable disease and how that can be just as advantageous sometimes another great question here from sam he says using bcma as a target may come with a lot of side effects since healthy cells will be hit as well how serious is this drawback of using bcma as a target yeah another another great point so and that's true not just with bcma but even with a drug like daratumumab right it targets cd30a and we have cd30a in our normal plasma cells and some other cells so you're always going to have some you know on target off tumor effects which basically means that you're killing you know normal things that have that particular target so the good news is with bcma it's universally on myeloma cells and plasma cells for the most part and we don't see too many off target you know effects with bcma but and the but with that comes immunosuppression right so when you are suppressing your normal healthy plasma cells and you know to some extent maybe b cells it's the risk of infections right so we're not just seeing that with car t's we're seeing that with ticklist ab as I just mentioned same exact mechanism so that's why that's one of those necessary evils good news is with car t it is you know kind of more in the acute setting you see it and then over time some of those levels will gradually improve but that can take a while and as I mentioned we give immunoglobulin infusions etc to kind of help improve the immunity you know quite regularly in patients with car t cell therapies and also with ticklistabab and I think this is just one of those things where you know we are looking now at perhaps less frequent dosing for ticklistabab right now it's given once a week maybe that's too much right particularly patients are responding and they're you know several months into their treatment maybe after six months or so for example you can go to once a month or twice a month it's not yet approved that way but I know we're looking at it and and you know maybe that's going to help right so you kind of don't have so much suppression of your normal plasma cells and perhaps you're then able to have you know a bit of a better healthier immune system yeah and that's one of the great things I think as we continue to see these approvals is real world data can help adjust so that it's as effective as possible so yeah thank you back to kind of the talking about stable disease and the benefits of that cindy is wondering she's been on revelament alone as a maintenance therapy would you recommend asking her doctor about adding daratumabab even though she's had stable disease so you're going to get I think some different answers to that question because I think what we're all in a way struggling with because we don't know is how much should you be chasing that mrd negative disease or that deep response right we do know in patients that get complete responses and mrd negative disease as a whole tend to stay in remission longer right it just makes sense you have less disease right and that means it is the treatment is very effective and it puts you in this really deep remission and that transits into a longer remission however that doesn't really account for the biology of your particular myeloma which I think is more important right so when you have patients with high risk disease for example that achieve even mrd negative disease they relapse still earlier than patients that have for example you know standard risk disease right so so response is only part of the story so what I usually tell people is you know if you've been on a regimen for a long time we don't think you're at risk for sort of imminent threat to your body perhaps you don't have high risk disease or any high risk markers and you know you've been stable there's no reason to kind of change your therapy just based on that particular reason because then you're going to cycle through some of these therapies perhaps unnecessarily and take on some of the side effects that come with you know invariably any therapy so it's a very individualized decision and it has a lot of factors that we look at including how long you've been on that particular regimen with the biology of your diseases do you have any high risk features how you're tolerating maintenance so we use all those factors to make a decision but just purely having stable disease does not necessarily mean you need to add something yeah yeah good point okay we have a couple questions here about the side effects regarding um to i'll ask two of the questions here it says uh but is no neuropathy mean on the treatment list does that mean that neuropathy is not a side effect of carfilzomib and then the other question is regarding heart or kidney issues do you see this um frequently developed in people taking caprolis and especially on clinical trials yeah so to the first point carfilzomib is one of our proteasome inhibitors that has the lowest incidence of peripheral neuropathy so bortezomib tends to have the highest and then loro or xazomib is somewhere in the middle and carfilzomib is the lowest uh with that being said carfilzomib has the highest incidence of having you know cardiovascular and renal toxicity compared to some of the other proteasome inhibitors right so we typically will see high blood pressure sometimes fluid retention uh sometimes heart failure and some more serious cardiac events that can occur in patients with carfilzomib and that's been you know true over many trials that have used this particular agent so that's why we're so careful and this is exactly the example of individualizing therapy if somebody has cardiac disease and peripheral neuropathy right i mean which one do you choose right so for example we would avoid carfilzomib in patients for the most part that have cardiac disease however you know in some instances if they have stable cardiac disease we now know how to dose carfilzomib a lot better than we did even you know a few years ago so we rarely would give it twice a week now we used to give it twice a week all the time we used to give ivy fluids tons of ivy fluids with it before now we don't right so the once a week dosing lower dosing frequent cardiac monitoring you're able to get a lot of patients even with underlying cardiac disease you know through the the treatment course right but it's but it's you know we it's tend to be you know mostly avoided or we're just very very careful in patients that have some underlying cardiac disease but in patients that don't and have peripheral neuropathy that cannot get any more bortezomib but that's going to make it worse it's an ideal agent right because we don't expect it to worsen toxicity yeah yeah we have a patient here who is in the hospital for three weeks has been told by pulmonary doctor that has a drug toxin that he has a drug toxicity in the lungs with patients like this that tend to have infections and drug toxicities and things like that do you recommend staying off of darslex or other immunosuppressing treatments or what is the future like for patients that have complications like that yeah so um yes so if you're admitted with any kind of presumed or suspected drug toxicity then we hold any agents that may be contributing and for the most part unless there's a really critical need to give myeloma therapy we tend to hold all myeloma therapy you know once you're admitted dealing with you know a complication right and then it's the matter of teasing out which in which of the agents you've been on has the highest incidence of something like that right so we don't typically see the highest incidence of pulmonary toxicity with with deritumab but we sometimes see what's called pneumonitis with pomalidomide for example just to give you an idea and sometimes see some cardiac and you know as I mentioned toxicity with carfilzomib so it really depends on what you're on typically we would hold it you know work it out make sure there's no other infection there's nothing else going on that may explain what the findings are in the lung because a lot of times you know there's no test to check for drug toxicity you know that could be contributing to the pulmonary findings so you know usually we have a pulmonologist on board and kind of help manage that and then when we feel like we've kind of had you recover from that particular piece of it then it's a matter of kind of introducing perhaps that agent or avoiding it if we if you're convinced that's what it came from but usually at a lower dose and then kind of doing it more gradually yeah okay thank you very much a couple questions here about immunotherapies so Joseph's wondering about the CAR-T treatment specifically time treatment is you know wait time is around six to nine months for a lot of patients right now does allogeneic CAR-T offer a hope to reduce these wait times and can you briefly explain allogeneic CAR-T for people who might not be familiar sure so allogeneic essentially means that it's from a donor and there are some CAR-T products that are being studied where it's like a you know essentially coming from somebody else not your own t-cells so as I mentioned with the autologous t-cells which is what the ones that are approved they're your own t-cells they get genetic modified and then put back into you and that takes time right you have to do the collection you have to do the manufacturing but if you have pool donors that have already kind of donated their t-cells you can then modify those and take off a few things on their cells so that way your body doesn't reject them and then put them into you and then see if you get the same benefit that has been studied it's still in clinical trials there's a few that look promising but I would say as a whole we haven't seen the same level of activity that we've seen with the autologous CAR-T cell products which is what's led to you know its delay in development and and it's also because the cells because they're foreign they don't grow as robustly as the autologous CAR-T cells do so we're figuring out ways to kind of improve that expansion of CAR-T cells from a donor that come into the body so that's all being studied I don't think that's going to solve the problem of the wait time in any kind of a sort of immediate future what has helped with that significantly is Ticklistomab so we now have patients that have been on these CAR-T cell therapies that are getting Ticklistomab and actually in fairness we have a bit of a wait time for that now because we can't you know we have to admit patients for approximately a week for Ticklistomab because they have to get a few doses in the hospital that's not that dissimilar to a CAR-T cell hospitalization duration actually and then because the hospitals are so full we can only admit a handful a week etc at this time so so but it's nice to have different options and I honestly think in many circumstances they're interchangeable you know sure you're seeing more benefit let's say perhaps with CAR-VICTi and if you want to wait for that I think that's reasonable but there's also a risk in that right so if it's six to nine months out you know I just think every situation is different do are do we feel confident that with what we have available between now and then we can keep your disease stable so that we can get to that T cell infusion the worst is when you're waiting for something and there's other good therapies already available and then you're not able to get to the T cell infusion because you got sick or some of that complication occurred which unfortunately happens all too frequently so I was like I said in the beginning take what's available yeah there's a lot of options now and to me they are in the world of BCMA therapies relatively interchangeable for the time being yeah great point let's talk a little bit more about toclostomab how many cycles of toclostomab are recommended and how frequently yeah it's once a week so the first week you get three doses actually because that's the step up doses that are done in the hospital and then after that it's once a week that's where the approval is now like I said before we're already looking at ways to kind of reduce that once you get beyond like let's say the six month mark mainly to try to limit toxicity and we see responses and in some of the other products even when people have been offed some of these bispecific antibodies their disease doesn't just come roaring back immediately so there's some immune effect that lingers beyond stopping the therapy so I personally think they don't need to be given once a week with that being said we don't know yet so we can't just start you know experimenting with that obviously with individual patients in clinic we have to wait for the data but I think there's some more flexibility it's it's you know I think trying to kind of mirror what we're doing with daratumumab or kind of how we started with daratumumab you know it's given weekly for a couple of months and every two weeks eventually once a month are we going to get to that kind of a schedule with toclostomab and the bispecifics I think so but we have to wait but right now it is weekly okay thank you Cindy has two other great questions one is how manageable is CRS? Yeah so we have gotten a lot of experience with CRS you know we have CAR T cell products you know in trials for a long time we've been managing CRS with approval lymphoma products for a long time and you know it's it's something that we are comfortable managing with that being said you know people can get sick from it you know you get a fever most of the time it's a fever particularly with these bispecific antibodies that's basically it they don't usually get sick enough to drop their blood pressure or oxygen levels requiring let's say intensive care unit stay etc we tend to see more of that with CAR T cell therapies but even then it's actually pretty low one reason for that is we're so proactive now in managing CRS so when people get a fever we typically would give Tylenol and give some fluids etc and if that lingers let's say for many more hours we then give this medicine to kind of block it called toclostomab and before we were waiting to give that after people got really sick and then now we've learned you can give it earlier and kind of prevent patients from getting that sickness so it's very manageable now but you do need to be at a center that is experiencing and managing it because these are brand new drugs for a lot of centers and if they haven't seen it before that's where I typically would worry but I think for the most part all of these agents right now are still being given in academic centers that have been doing this for a long time. Yeah I would agree with that. Another great question here is when you relapse on a three drug regimen how do you know which drug you're refractory to? Yeah no that's a great point we assume all right because you've been on all and obviously your disease figured out a way to evade whatever we were doing with that being said that doesn't mean you can't go to a similar drug you know in the same class in the future right so we see this let's just say patients have been on DeraTumorMap and they were on DeraRVD then got on to DeraMaintenance for example and then and let's just say they stopped DeraTumorMap right over time and then you know can their disease still respond to that agent sometime in the future? We have seen that right are those like robust responses where then they'll respond again for many many years not always but it depends on what you're combining it with right so a lot of these drugs work together because more and more people are progressing now and multiple agents we tend to switch all of them if possible right so it really depends on the sequence of how they got there what we think they may tolerate but for the most part if they're progressing on that combination it's really all the drugs together. Awesome thank you. Two more questions and then we'll finish up for today one is are there any studies or data to support Isotuximab from moving from a bi-weekly to infusion to subq as well as monthly similar to DeraTumorMap? Yes they're in studies now looking at the subq formulation and then I expect and hope that's going to be approved you know soon I don't know exactly when but they're looking exactly that because I think what's happened with Isotuximab is when it was first being developed the benefit of it was that it was actually shorter infusion didn't require as long of an infusion as Dera used to be and you know the weekly dosing etc the schedule was a bit more manageable even though it was kind of every two weeks eventually then what happened is when Dera became subq that advantage went away for Isotuximab right so but we are seeing some interesting things with Isotuximab I think some of the trials that I mentioned before in combination both the pomalidomide and carfilzomib they look pretty good now they haven't been compared head-to-head to DeraTumorMap but if you just look at each individual trials you know you tend to see pretty significant activity with the Isotuximab combination and there's some slight differences between the two drugs so is it better we don't know right but I do think there's room for it and I tend to use it a lot in pages that have the scenario I described before had DeraTumorMap had some combinations and then are you know we think they may respond to another CD38 antibody sometimes we'll reach for Isotuximab in that particular scenario so I do know they're looking at that and looking at the subq formulation awesome thank you now before I ask our last question I want to apologize to the audience we're definitely not getting to all the questions there's a lot of unanswered questions here you've provided excellent questions that have provided for a really great discussion so I'm thankful for you and if you really want to get your question answered we can set you up with a medical professional on our team who can help guide you to certain specialists ask your questions too okay so the last question here is regarding targets so a couple people asked if kappa or lambda could ever be used as a target in myeloma treatment good point um yeah it hasn't been looked at to that degree quite yet but it does make you wonder right because essentially that's the protein that your disease is making but it you know it's expressed obviously at the myeloma cellular level but we haven't found stable enough you know drugs to kind of just just target that the other challenging thing that occurs and some of you may have experienced this is that the disease doesn't always make the same you know amount of protein over the course of you know the disease history so like for example when you may have first been diagnosed and if you're let's say igg kappa myeloma you may have high light chains high igg im protein but you know when you're in a third fourth relapse you're not seeing the same degree of you know production of these of these antibodies so they lose expression of some of these these markers and then they don't produce as much of the the protein so we don't know if that's going to have the same benefit at that stage versus let's say an earlier stage so i think that plays into it to some extent but you know it is something that right now we're not necessarily looking at. Thank you a couple people are wondering if you're available for telehealth visits i don't know Dana Farber's policy. Yeah it's depending on what state you're in and i know we're trying to expand that more and more so i would suggest that they reach out to our new patient coordinators the numbers on our website and they'll tell you if you're eligible for that kind of consultation. Perfect thank you so much Dr. Nadim for your time today do you have any closing statements for the group? No i really enjoyed these sessions i know we covered a lot of stuff today that the goal here wasn't to like kind of have you remember all the combinations but it's more to kind of give you an idea as to what is available to you and then it's really kind of talking with your physician and figuring out your best regimen so it's been a pleasure i really enjoy these and then hopefully you all benefit from all the all the work that's going on in this field. Yeah thank you so much Dr. Nadim we appreciate you have a great day. You too bye. To the group we're just going to finish with a couple of outro announcements so that you're aware of when we're meeting next and a couple other resources that might be of benefit to you. Join us in April as this chapter meets every other month we're going to be discussing how fast multiple myeloma can progress and what happens biologically when it does. We also invite you to use our connect group to stay connected with relapse and refractory myeloma patients or caregivers that are in the same situation as you in between our meetings. You can answer questions or ask questions you can share pictures share good news and bad news and connect with each other through that group and that link will be sent to you in our follow-up email. Other events you might be interested in tomorrow we have two we have our Black Myeloma Health Chapter this is a big celebration of Black History Month and we're talking about the hope in Black Myeloma we invited three Black Myeloma specialists to come speak to us tomorrow it's going to be a great two-hour event. Then that night as our minimal residual disease chapter we're going to be discussing if MRD negativity is the end goal and understanding why and when it's important that's a big question in the myeloma world today. On the 28th at 6 30 pm eastern is our Florida myeloma chapter so if you're regionally in Florida or occasionally visit and like to join the group we're going to be having a group discussion on how to talk to your friends and family about the myeloma diagnosis. The link to sign up for any of these events and even more events I did not mention is found at the bottom of the slide and will be included in our follow-up email. Another thank you to our sponsors Mr. Meyers-Squibb, GSK, Genentech, Abbey and Amgen and thank you to each of you for helping us build this myeloma community. I appreciate each of you and hope you have a great rest of your day thank you all bye-bye.