(Guest Lecture): November 2023 - Early Relapse Approaches Using Monoclonal Antibodies

Thank you to the healthy people for organizing this wonderful event and inviting me to give a talk and all the patients who are here, you know, and people who are giving one of the weekends, you know, to be here to listen to us. So I'm one of the new faculty in Mayo Clinic Phoenix, just started in October, kind of moved in the middle of the heat wave in Arizona, so that was kind of an interesting experience. So I don't have any conflict of interest, no disclosures. So as I begin the talk, what I'm going to focus on are what a monoclonal antibodies, how do they improve care, triplet combination versus quads, what's the best answer for our patients, and then what are the options at first relapse. So the first topic I'll talk about is what are monoclonal antibodies and how do they improve care. Just to give you a little bit of a background, the first patient that we know in medical literature was described as having multiple myeloma was this 39-year-old lady who presented with multiple spontaneous fractures, and this was way back in 1844 that was described by a physician named Solly. And unfortunately, as you can imagine, the treatment options were not that great at that time. What she was advised was to try some rhubarb and orange peel, and you know, as was the case for most, I guess, diseases back then, the treatment was that you go to the beach and have a change of air. So fortunately, we've made a lot more progress now. We don't have to give rhubarb and orange peel to our patients. We have multiple new therapies which have been approved in a span of the last 15 years especially, and then focusing upon the monoclonal antibodies, we have had a slew of new approvals in the last couple of years. So what we have now is, as we see over here, is a myeloma cell, and we have all these weapons now at our disposal that we can use to try to eradicate as much as possible, and as well as put patients into as deep a response as possible. And so these are the different monoclonal antibodies. Some of them, you know, I'm sure many of you are already familiar with, have already been approved. Some of them are under clinical trials. And so we have, you know, our CD38 antibodies, diuretumumab, and acetuximab. And the way these antibodies are essentially acting upon the myeloma cells is we have these molecules on the surface of the myeloma cells, which are what we call as receptors. And these antibodies are designed that they will go and kind of attach themselves to these receptors. And so depending upon which receptor they're attaching or which molecule they're attaching on the surface of the myeloma cell, you have that as the particular antibody. So if you have an antibody which is attaching itself to the CD38 receptor or molecule on the myeloma cell, it becomes an anti-CD38 antibody, which we have the diuretumumab and acetuximab. And then, you know, we have the SLAMF, which is elotuzumab. And then more recently, I think many of you would be familiar with teclistumab and darquitumab and ratumab, which have been approved recently. And some of the other different targets, which are undergoing active investigations and, you know, are being studied in clinical trials. And so I'm going to talk about some of the monoclonal antibodies highlighted. I think the other speakers are going to talk about the bispecifics. So just to give you kind of a very brief idea about what these monoclonal antibodies are. So you have the three which are approved, darquitumumab, acetuximab, and elotuzumab. And when we use the term MAB, it means basically the short form for monoclonal antibody. And the term which is in front of it denotes where the antibody has been manufactured from. So these antibodies are kind of designed to mimic human antibodies as much as possible. So that's why when we use the term muMAB, we are calling it as a human IgG kappa. When we use the term zimab, it's chimeric, meaning some part of it is designed like a human, some part of it is not human. And then you have the humanized, which is human-like, elotuzumab. And this is the mechanism of action for these medications. And then you have the different ways by which you can administer these medications. We know the darquitumumab can be given subcutaneously or IV. The other two are available as IV formulations. So the mechanism of action is a little bit more complicated than simply saying that they go and attack the myeloma cells and they attach to the surface of the myeloma cells. So there are three different broad ways by which these antibodies work. The first is, if you see, it attaches onto the surface of the myeloma cell, and it also attaches to a cell on the immune system. And so it kind of tries to bring this immune cell closer to the myeloma cell and telling them that, giving them a signal that, hey, you need to go and kill these myeloma cells. These are the bad cells. So you have something which is what we call as ADCC, which is when the immune cell is secreting certain chemicals or enzymes, which kind of punches holes in the myeloma cell and makes them leak out the contents and die. And then there's a term that we use at ADCP, which is one of the immune cells goes ahead and kind of eats up the myeloma cell. So that's what these monoclonal antibodies are doing. They're bringing the myeloma cell and our immune cells kind of closer to each other so that they can recognize that these are not good cells and they can go and attack them. The other mechanism which happens is myeloma often kind of has an effect on your immune microenvironment in the sense that some of the cells which are supposed to down-regulate the immune system get active and they kind of interfere with the function of your normal immune cells to go and attack the myeloma cells. So one of the functions of these monoclonal antibodies is that it kind of shifts a balance towards kind of waking up your immune system so that they can go and try to kill off the myeloma cells. And lastly is the direct effect where they kind of go directly on the surface of the myeloma cell and that sets into motion a series of events within the cell which ultimately causes cell death. And somewhat similar is the mechanism of elotuzumab except it's a different target than the CD30A target for Dara and esatuximab. So you know as Dr. Fonseca had mentioned if you look at the progress overall that has been made for our patients with myeloma if you look back 20-25 years ago the five-year relative survival for our patients was about one-third patients were living at the five-year mark. What has happened is with the introduction of these monoclonal antibodies now you know we are seeing almost 60 percent of our patients still alive at the five-year mark and of course you know if you look at the breakdown of the contribution of different therapies now you know RVD and you know these triplets used to be the standard of care for a while for frontline therapy and their incorporation has added almost one and a half years of benefit to survival for our patients and some of these new and novel therapies like daratumumab carfelsumab has added almost two and a half years. So the outcomes for our patients have improved significantly now that more and more of these therapies are available for our patients. So then jumping on to the next question is triplet versus quads what's the best answer for the patient? So this is not an easy decision to make you know it's not like this is the best treatment and this is what you should be on. There are a number of different factors that you have to consider you know when you're trying to treat the patient because every patient is different every patient is their own book in a way of the disease so you have to individualize the treatment and you have to take into account patients own wishes as well. So you know one of the first questions we ask about you know myeloma for frontline treatment the first thing is whether patients are transplant eligible versus ineligible and that is kind of the main decision point for most for many of us and I'll touch upon this a little bit later and then of course you know you have to look at the patient you know you can have the best treatments you can have the best drugs but you know if the drugs is causing it's a potential to cause bad toxicities to the patient then it's not safe to be on those treatments so you have to look at the comorbidities and how fit the patient is and some of the factors are also about what kind of disease you have if you have the high risk versus what we call is a standard risk disease and then the psychosocial factors you know many patients don't have resources many patients have transportation issues many patients don't have access to good clinical trials so and they don't have good social support so all of those are important factors which go into play when we're deciding what would be the best treatment in a particular situation all right so so when I talk about high risk features and some of these are terms are probably familiar when you guys must have had discussions with your hematologist is you know when we look at the DNA of the plasma cells we are seeing certain changes certain mutations which we would call as a high risk versus what we would call as a standard risk and so some of these mutations are highlighted over here and someone presenting with circulating plasma cells certainly is a bad risk factor as well so like I said for a newly diagnosed myeloma the first question which comes to our you know our mind when we're deciding upon treatment is whether the patient is transplant eligible versus ineligible and that kind of gives you an idea about you know how intense induction therapies we can use in these kind of situations and ultimately will the patient go for a transplant and the transplant eligibility is not like a it's there's a criteria that different institutions use but it's not like a cookie cutter kind of approach that if you have to meet all these criteria to kind of label someone as transplant eligible there are patients who we call transplant eligible but they may choose at some point that they don't want to go for a transplant so it more gives you an idea as to who would be a good candidate for intense induction more intense induction therapies and so age you know age is like I say it's not an absolute number it's more the physiologic age of the patient so patients have had transplant when they were 75 years old patients have had maybe younger patients were not fit enough to go through a transplant and there's something what we call is a performance status which is a very easy tool for us to kind of assess pretty quickly as to how fit someone is and so we have a scale from zero to five and you know and if a patient is found decently functionally active decent performance status we would say okay this patient could be a candidate for transplant. Organ function is important you know you need to have healthy liver kidneys and lungs for to go through the transplant the only exception is obviously kidney function we transplant patients with myeloma who are even on dialysis or who you know kidneys have been affected by myeloma and then psychosocial support we all know that I'm sure some of you have gone through transplant and so its entire process where patients are explained that they have to stay within a certain distance of the hospital they have to have a caregiver present if the transplant is being done as an outpatient so all of those are important factors which come into play. So for the longest period of time you know the triplet induction were kind of established as the standard of care for our transplant eligible patients and this is based upon very robust data that we have over here with high response rates and you know the determination study the one in the middle was the one which looked at giving RVD upfront doing a transplant consolidation and followed by our RevLivid maintenance till the time of progression and that's kind of mimics the most common practice that we have seen for the last couple of years and so you saw that patients had a high you know MRD negative rates high CR rates and a PFS for all comers was you know pretty good almost up to like seven years. So the question was that is four drugs better than three drugs can we improve responses in patients if we use four instead of three medications and one of the first trials to kind of attempt to answer that question was the Cassiopeia study and this used a regimen for people who may not be aware the D stands for data V is Velcade or Bortezomib, T is thalidomide which is used in Europe we don't use it over here anymore and D is dexamethasone so it compared adding data cumumab which is one of the monoclonal antibodies to the kind of RVD of Europe which is VTD and as you can see patients in general had a higher deeper response rates and as Dr. Fonseca mentioned about the curve the top part of the curve the blue curve is the data VTD the quadruplet which showed a better response compared to patients who were on the tree drug regimen and the responses improved over time there was improvement in what we call as progression free survival which is you know when your disease progresses and you have to change treatments but the overall survival was not different for the patients and the problem is that if you add more things to the stew you are more likely to cause a bad reaction and so if you look at the toxicities more blood related toxicities greater you know you patients had more lowering of the white count the platelets their hemoglobin obviously their infusion related reactions which will happen with data cumumab and what was seen is that maybe there was a little bit of a it was a little bit tricky taking these patients up for transplant because more patients needed additional treatment to help mobilize their stem cells or to collect their stem cells at the time of transplant when they're taking both when they're taking data in combination with the imid which was halidomide so the trial which kind of changed the practice patterns a lot here in the US was the Griffin study which looked at giving data tumumab in combination with RVD versus giving RVD alone and this compared the two treatments for the patients and so the treatment was that the patients either got RVD or data RVD followed by a transplant then they got some more chemotherapy the same chemo for consolidation and then maintenance the difference was the maintenance used in Griffin was data, tumumab and revlimid together which is usually not the common practice you know in the outside of a clinical trial setting and then what they were looking at is what was the response rates of patients post the transplant and the consolidation and so if you look at the response rates the stringent CR is you know when there's no evidence of the protein in your blood your bone matter is completely clear of the plasma cells so you had a higher stringent response rate with data RVD compared to RVD so basically patients had deeper responses when we used a quadruplet instead of the triplet and if you look at the the response says if you look at if you focus upon the blue part of these bars that is the response is the CR rates and as you can see the azoret part increases over a period of time that means more and more patients as they were on maintenance as after consolidation more and more patients gradually had deeper responses over a period of time and this was the MRD negativity rate so as you can see as more time passes the bars increase in size meaning more and more patients went into deeper MRD negativity as they were longer they were on on therapy and so Arise and again the same side effects profile was noticed that okay you had better responses using quadruplet therapy but at the cost of more toxicities more anemia meaning your hemoglobin went down more lowering of your white cell count more lowering of your platelets and in general this might have been the experience of some of the patients here that it causes such a suppression the diuretumor map in combination with these drugs of your immune system that you get more prone to upper respiratory tract infections diarrhea some of the patients you know even end up on IVIG to support them when they're on these kind of treatments and again similar experience was seen with stem cell mobilization there was more difficulty in patients who had diuretumor map as induction therapy a lower amount of stem cells were collected compared to patients who are on rvd and so this was the update of the study this was a more longer term follow-up and as you can see the four-year progression pre-survival for patients who were on the quadruplet was better compared to the patients who were on the triplet however the overall survival still remains the same for the patient it has not been reached for either group suggesting that both triplets and quadruplets are pretty good actually treatments and so there's another study being done in europe which is going which is comparing the same treatments drvd versus rvd and that study the results are awaited and actually probably will be available pretty soon and so so rvd was happens to be the most common induction therapy that is used for our patients and these studies looked at adding data to the rvd arm some of the patients sometimes are put on krd which is k stands for carfilzomib which is a type of proteasome inhibitor related to welcate but it's given iv instead of welcate you know which is given subcutaneously and this was a trial it wasn't a randomized trial this was basically just giving this quadruplet to patients and looking at the responses and this was a study more to see that if you could use mrd as a marker to decide when you can stop therapy in the patients and if you look at the table the table the hrca means if you remember the risk ratification of the patients what kind of dna changes or mutations are considered to be high risk and so they looked at three different population of patients the zero one are the ones which did not have any high risk mutations one is when they had one high risk mutations and two is when they had two or more high risk mutations so as you look at the responses pretty good mrd negative response with all three risk group patients even the high risk patient had a pretty good mrd response negative response of almost 80 percent however as you can look at the 36 month pfs and there was an update that was recently published in last month you look at the pfs of these patients for the really high risk group patients where they have more than two high risk mutations their pfs was only 50 percent so very high initial responses transplant but they kind of lost the response after a period of time and so this is what the study summarized and then i just wanted to put this in many patients may have had experience with iv data tumor map but nowadays we're using subq data tumor map so the efficacy is the same this was looked at a clinical study as you can see the two curves are kind of superimposed on top of each other so not a big difference and so for our practice and for most practices most patients have switched over to subq form of data tumor map obviously because it saves infusion time and this graph in the bottom shows you the patient preference and the patient satisfaction of therapy and the blue line represents the subq data and the red line represents the the red data the iv data as as you can see much many more patients understandably were satisfied with subq rather than iv data and the other anti cd38 antibody which is available is isatoximab it is an iv anti cd38 antibody and this was another study to kind of highlight the point that when you use four drugs you get a higher response rates and if you look at the table the mrd negativity rates were higher when we use isatoximab which is kind of a similar or in the same class of drugs as data tumor map compared to the control which was rvd so the the take-home point through all of these you know trials and presentations has been that you get deeper responses for patients more mrd negativity more you know complete responses if you use a quadruplet versus a triplet so for transplant eligible patients quadruplet induction utilizing some form of an anti cd38 antibody a proteosome inhibitor an imid along with dexamethasone probably is the best option for most patients based upon the higher you know the more deeper complete response and mrd negativity rates and however there's a little bit of a caveat that this has been a challenge with most myeloma studies because there still hasn't been seen an overall survival benefit with using quadruplet versus triplets and that could be many of these patients when they're relapsing they're getting good second and third line drugs so we haven't seen that survival benefit but certainly there has been very robust data on progression free survival benefit and certainly you know with higher risk you know high reward strategy you can end up with more toxicity greater hematologic toxicities like anemia thrombocytopenia with dilatumor and some of the things that you know unique side effects that's important to remember for anti cd38 antibodies is increases your risk of shingles it can affect your blood group blood group typing for transfusion so i'm sure all of you who have been on these medications have always had their blood typed before they end up on these treatments and one of the things that sometimes we see as a question when patients come from outside is doctor you know my disease hasn't gone away i see still see this igg kappa on my blood tests you know and i've been on therapy for so long and it's a small amount of igg kappa so i'm not in complete response so what is important to remember is that if you look if you remember the structure of the daratumor map and isotoxamab it's an it's an antibody it's an igg kappa so it is going to show up many times in your you know fixation and some of your blood tests so it's important to remember that that you know if you're seeing this antibody in your blood doesn't mean that you're not in remission we use mass spectrometry in our lab at mayo so that can tell us whether the protein that we are seeing the igg kappa is a direct human map or is that you know the patient's original protein and so jumping quickly for transplant in a jibble patient again the same factors are you know come into play you know you have to look at someone's comorbidities how frail these patients are these are we talking about a much older patient population so all of those are important considerations when we decide upon what treatment would be best in their situation and the goal is to kind of achieve a functional cure in my opinion that you know if you look at the average life if you look at the average life expectancy of these patients with their with their comorbidities and with the other health challenges and frailty you kind of want to have the disease in a good control um maybe you know very aggressive disease control is not the key over here you just want to keep the disease under control and achieve what we call is a functional cure where patients may pass away from something else rather than the myeloma itself so um you know for a long period of time rvd triplet or rd for some of the more frailer patients was most was the most commonly used regimen but the one that we are now most centers have adapted to is the drd regimen which is using direct umumap the anti cd38 antibody in combination with the rev limit and dexamethasone and this was studied in a in a big clinical trial on as a maya study which looked at giving the triplet versus the doublet for a transplant ineligible patients and as you can see the data which has been reported out the pf as a progression free survival is is more than five years you know for a patient who are on drd compared to patients who are in rd and the overall survival has not been read so patients are still living quite longer and if you look at the five-year overall survival significantly better with drd compared to rd for a patient so this is a um i would say a kind of when you decide upon patients versus risk versus benefit discussion so it's a moderately intensive therapy with i would say a favorable risk profile so the given the fact that so many of our patients are doing so well on this regimen so this is kind of i would say maybe the standard of care right now for our transplant ineligible patient so the question comes is we have seen quadruplets being used for our transplant eligible patients what about the transplant ineligible patients is a quadruplet four drugs better than three drugs and so there was a study this was looking at vmp which is msml falan very old-fashioned drugs which i have never used personally excuse me and so they found you know pretty much the same experience with quadruplet that they were higher cr rates and higher mrd negative rates again you know we have a more frailer patient population for the transplant ineligible patients so you had more toxicity more risk of infections if you use four drugs instead of three and so we have ongoing studies to kind of help answer the question whether four drugs is better than three drugs for our transplant ineligible patients and they're comparing different triplets with quadruplets and those will hopefully give us the answer whether you know drd is good enough or using a quadruplet would be a better in this population so so what i would summarize for our transplant ineligible patients is that triplet is still the standard of care and quadruplet will be based upon these clinical studies but you know even for some of the very frail patients even rd using a doublet would be a pretty reasonable option and finally i'm going to talk about what happens at first relapse so again you know the decisions which go into play when you're deciding about what treatment is best to use when patient relapses the prior history is very important you know what treatment patient has been on already what has been the duration and the depth of response you know with those treatments again comorbidities and toxicities of the drugs certain high-risk features if patient is progressing within like two years of their primary therapy that kind of gives us a sign that they have a little bit of a high-risk disease and then if they acquire certain more mutations that will also give like deletion 17p that gives you an idea that this has patient has a cancer or myeloma which is behaving very aggressively and then again the same thing about psychosocial factors what kind of social support they have what are the access if they have any access to clinical trials which are usually you know we usually don't have enough clinical trials for older patients but even then you know if you're living in the community driving you know coming two hours to mayo or to other bigger tertiary center may not be an option in your case so these are the different classes of drugs which we use at relapse and basically I didn't want to like confuse the audience with too much information about you know what raw regimens are there's like hundreds of different you know permutations and combinations which can be used but essentially what I wanted to focus upon is if you look at each of these drugs they were comparing a triplet at relapse versus a doublet which is using three drugs versus two drugs at relapse one of those drugs was always dexamethasone basically so you find the responses are always better using a triplet versus a doublet for most of the patients and so this was a data tumor map and all the list of studies where they have combined with different other agents and this was chyprolis or carfilzomib and this is isatoximab which was combining with pomalidomide which is a drug related to revlimid and then isatoximab combining with carfilzomib which is related to velcade but broadly the principles of therapy that you need to keep in mind is that triplet therapy has better outcomes compared with doublet at the time of relapse and when you're changing treatments at least one of the drugs should be one that you haven't been exposed to before it is a new class of drugs which works in a different mechanism by the one that you have been on and there's a term that we use called as linaletomide refractoriness and there's not there's not a clear definition but we typically say that if someone has progressed on full dose of revlimid or on the maximum tolerated dose of revlimid then we would call it revlimid refractory and so if you're on maintenance after transplant for instance maybe you're on a lower dose at 10 milligrams so you technically may not be called as revlimid refractory in that situation so if you are revlimid sensitive then the option is that if you've been on a CD38 antibody then you combine it with a PI and you combine it with revlimid and the second generation PI that can be used is carfilzomib which is an IV infusion there's another medication called exasumab which is an oral but personally I don't think the responses are that great with that particular medication so if you're going to combine an PI with revlimid I think probably carfilzomib would be the better option and then if you haven't been on a CD38 antibody then dilatumab in combination with revlimid and dex works really well in this situation we have data from the Pollux study which showed really great outcomes for these patients but I think you know more and more patients are going to be refractory to revlimid and so if you have been exposed to a CD38 antibody you've been on continuous maintenance with such an antibody on a clinical trial then you have to use a second generation image like formalidomide and you can combine with a second generation proteasome inhibitor like hyprolis and use a combination or you can even use an alkylated agent like cyclophosphamide in that situation however if you haven't been exposed to a CD38 antibody then usually using that in combination with another agent is the way to go so this will be the last slide so if you look at you know the overall trajectory for our patients the journey you know when they have multiple myeloma so you have the transplant eligible transplant ineligible patient they get the first initial induction therapy they have a median pfs of three to five years but as we go down through the lines of therapy the median pfs or the response rate starts going down for our patients and what is also important to note is if you look at how many patients get to second or third line therapy so you have you know about 80 percent of the transplant eligible patients they get to second line therapy but only 50 percent of a transplant eligible patients get to second line therapy and the attrition and the rate keeps goes down as with further lines of therapy so that kind of gives us an eye that kind of gives us a signal that we need to move more effective therapies further and further into the front line for the treatment for the patients so to summarize you know despite improvements in frontline treatment options for our patients most will eventually relapse and the next challenge in my opinion are the triple refractory patients who have been exposed to pis imits and CD38 antibodies and penta refractory patients and what has happened is now that more and more patients are getting CD38 antibodies in the front line setting there are more and more clinical trials going on looking at giving some of the other novel therapies like CAR T and bispecific antibodies as well in the earlier lines of therapy for our patients so thank you thank you all for listening patiently you