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

you [Music] so I wanted to talk about immunotherapy for multiple myeloma as I have self diagnosed myself as a millennial so we call up the millennial era then hopefully I'll be able to get through most of this in 20 minutes I'm at the University of California in San Francisco and would love to see any of you there anytime okay so before we proceed with talking about the specific immunotherapies I think it's really important to note that myeloma is sort of a disease of immunologic chaos if you will the myeloma cell itself the plasma cell is part of the immune system and as many of you know as we get older it tends to develop more on older people and sometimes we think that's because the immune system is exhausted and other times we just don't know what the reason is and we can't tell if the myeloma develops more because of an exhausted immune system and then we give drugs like dexamethasone which may further exhaust it or if it's just out of the bag no matter what but that being said it does give us a reason to consider that the immune system maybe if we could turn it on its head could possibly be used to help fight myeloma and here you can see that there are different ways that the myeloma cell could be attacked by the immune system for example we'll talk about engineered T cells or car T cells there are also some native T cells that should be doing the work but maybe need a little boost from cytokines there's some data out there within K cells being used against myeloma and then our cooperative group has been using it dendritic cell myeloma a fusion vaccine as well which you can see here there are also a vast majority a vast number of antibodies out there probably but you know most about is Dera to my map and now ISA tucks them out which which attacks cd38 and then there's a low tooth in that which goes against cs1 now we know that BZ ma may also be attacked by an antibody but actually this may be best done by a by specific antibody which I'll explain later or an antibody attached to a warhead also known as an antibody drug conjugate so as you can see there are many ways that the immune system could interact with multiple myeloma and we'd really love to take advantage of that to improve outcomes for our page so of course immunotherapy has become the hot topic and of course I did steal the slide sort of the mean from ash about this but you know now all the attention from all the other therapies is being put on immunotherapy and I wanted to highlight the three types of immunotherapy that are really being discussed including car T cells by specifics and antibody drug conjugates so many of these immunotherapy is actually most of the ones we'll be talking about today targets something called B cell maturation antigen or B CMA b CMA itself is a member of the TNF receptor family so it's a bunch of proteins that are on the cell surface and the function of B CMA is to regulate B cell proliferation and survival and the maturation of plasma cells so it has a function plasma cells and we know that it's expression and activation is associated with myeloma cell growth and survival but I think the most important thing about B CMA is that is exclusively expressed on the surface of plasma blast and differentiated plasma cells basically anything having to do with the plasma cell and why this is so important is that it's generally not expressed on other important cells like neutrophils or other cells like t-cells and that's important because you always want to find a very specific antigen if you're going to have a very potent therapy you want that antigen to only be on the bad cells and not on the good cells and so this is a very good antigen in in order for us to target so what our car t-cells I think many of you know what they are already so generally T cells in our body should be functioning to limit viruses other infections and also actually provide tumor immunity but they don't always do the right job but can we take them to do the right job and so it tastes cell that is part T cell takes the both best of both worlds we take your own T cells and engineer them to express an antibody like molecule on the surface so antibodies are very specific for antigens so they combine the specificity of an antigen and antibody towards an antigen or antibody towards a tumor protein and the efficacy of a T cell and we have several generations most of which for the purpose as of myeloma have been second-generation car t-cells with four 1vb ligand stimulation or zeta stimulation but just to point out here the t-cells are always the ones that we think of as having a lot of efficacy against viruses and tumor surveillance in our body and now we can engineer them to be specifically targeting these tumor cells so that's just been a really nice forward in progress of cancer immunotherapy in general and as you know this has actually been done in other cancers before myeloma specifically non-hodgkin lymphoma and childhood leukemia and so we've been taking a page out of their book to see if we can make differences for myeloma patients targeting VCM a so probably the most famous to date study and long-term study in America that we've had is this Bluebird study now Celgene now BMS but the the product is called BB 2121 and the reason I use this slide is so that anybody who's considering Carty therapy would kind of get an idea of what they're in for so for kartik therapy the patient comes to the center and undergoes a Luca phoresis and this is similar but less involved in the stem-cell collection this is a cell collection but not the same way that you had your cells collected during a transplant this is generally a one-day procedure and actually oftentimes by peripheral IV you don't necessarily need a large catheter and once those cells are collected they go off to a factory and it takes about this has ten days both the reality is because of all the quality testing etc it takes about four to five weeks for those cells to come back to your hospital once they do you'll be given three days generally of chemotherapy a combination of a drug called therapy and another drug which many of you have had before cyclophosphamide and these two trios basically make room for the T cells so that they don't get rejected by the normal T cells that haven't been engineered that are in your body and then on the day of the infusion the patient is given one single infusion of these cells very similar to a blood transplant or even the stem cell infusion you may remember and then they're observed very closely and we'll talk about that in a minute so the original data that was presented several years ago at ASCO and then published in the New England Journal was updates on the phase one of this BB two and two and cartee cell as you can see here they tested several doses but they kind of clumped together what they thought was the effective doses 150 to 800 million cells as a flat dose or one-time dose for patients and here you can see they had an overall response rate of 85% now remember these patients had a set median of seven lines of prior treatment so you can imagine that's a pretty heavily pretreated patient population so 85% response rate was actually very good and they as you can see here the median progression-free survival and that means how long did half of the patients go before their disease came back or something else happened was about a year eleven point eight months although better in the patients who were MRD negative so I always say you can see this as half-empty or half-full certainly we never had myeloma therapy for this heavily pretreated patients that was this effective but again we don't see that that curve has been completely flattened it's not plateaued and so as of now it's not still a cure but it is a very effective therapy the adverse events that are very important for us and we've learned a lot about this I'm going to talk more about this in detail but just so you know two-thirds of the patients did have cytokine release syndrome which I'll detail a little bit later in the talk but it really wasn't non manageable only a few patients have what we call high-grade CRS similar with neurotoxicity a third of patients had it but really only one of the patients in the trial had a very significant neurotoxicity other than that there are low blood counts and you can expect that if you undergo Carty therapy it's very expected we tend to take that in stride because we're so used to that with various chemo therapies from myeloma but I would say in my experience this is actually fairly well tolerated this is actually hot off the press originally hot off the press in December but now actually just published in fast right format for ASCO upcoming next month or at the end of this month and you can see here this is the phase two trial so this is the next trial that they had with a lot more patients they had here they report on 128 but in the ultimate abstract I believe it's closer to 140 and this three doses of cells the same BB 2121 cells and as you can see now the phase twos tend to be a little bit different than the phase ones and so the data may be a little different in this particular trial the patients that went on this trial were actually worse they were they were having actively progressing disease it's not surprising to me that their overall response rate here as you can see in the total group was 73% a little lower and their progression-free survival was eight point six months a little lower than we saw but I just want to point out here excuse me that what we're looking for is the 450 dose and the reason I highlight that is that that is the dose if they're going to probably be going forward with to ask the FDA as the recommended dose because it was fairly well tolerated and the outcomes are actually better 81% overall response rate and a progression-free survival and duration of response which is actually closer to what they'd seen before eleven point three months so we look forward to hopefully at some point getting approval for this although I think we're gonna have to wait at least a few more months thus far the other trial that has some long term follow-up is one that was done in China this is the legend to trial and I want to talk about it because we were very impressed with the original data presented three years ago now and they've done a lot of follow-up now their duration of response is 27 months which is actually significantly more than the trial that I just talked to you about and we don't like to compare trials to each other because it's really apples and oranges and particularly in this case this patient population was less heavily pretreated in China and there's a little bit less known about who these patients were and how sick they were so it might be that these were better patients or this is a better t-cell therapy but what will help us to understand that is the Carta to study because this legend card t-cell was then bought by Janssen and brought over here to do a trial in the United States so the car titude one study has been recently completed and the first part of the data about 25 27 patients was presented and ash this past year so very similar designed to what I told you already about the BB 2121 the patients were enrolled they were with my luma service 29 patients and slight differences in the patient population but generally the same those patients also got bridging sorry those patients also had a phoresis and then had a time of manufacturing for both trials you can consider doing bridging chemotherapy and that's something that you may do if the patient is too sick to wait a few weeks ultimately the patients went on to get a very similar chemotherapy of lympho depletion the flu Durbin and cytoxan and then got their cells infused and then were followed closely so the response data initially was presented and ash by my good friend dr. de Midori and you can see here a hundred percent of patients responded in this first cohort that's that was presented a very interesting I thought because it's a very good response rate and actually they are having an update and ASCO the the right now the published abstract states that the response depth is actually even better so 76 percent of patients ended up in a stringent CR and 97% basically all but one patient ended up in a B GPR or better so that's actually very impressive all of their patients became MRD negative at some point at the 10th to the minus 5 level so that's really impressive data and I think what's really important for us to remember is that responses are not the end-all be-all for car t-cells anymore we were all very much impressed with a hundred percent 80% etc response rate but for us now knowing that these can be effective therapies we want to know for how long and so we've really shifted our focus from response rate and how much how many people responded at all to how long did they respond and one thing you're going to hear more and more about from data is duration of response so if you have a response how long can you expect to stay there because ultimately if you're a patient that is probably what you care about and so I'm really hoping that will emphasize that data even more as time goes on this t-cell was a little bit different than the others but generally well tolerated basically most of their patients had some sort of CRS but as you can see it was pretty well tolerated and manageable similar for neurotoxicity and I think that we as practitioners are getting better at that just like we got better with transplant and as time goes on and more Haitians are getting car teeth there people be better at managing these side effects while we're on the topic what art Carty associated side effects so I think the one that's probably most talked about is cytokine release syndrome and this is a systemic inflammatory response that occurs as the car tees are activated and expanded basically I tell patients it's the worst flu you ever had and that's sort of basically what's going on right because the T cells which are trained to fight infections think that there's a giant infection of B CMA going on and so they get very excited and make you feel horrible and patients most typically will have fever that's sort of the hallmark symptom and they can't have a lot of fatigue as well we really are wanting to know when patients have fever immediately and many of them may end up going to the hospital if this was an outpatient party but if they're already admitted we jump on that very quickly and sometimes we think that the high disease burden may be associated with more severe CRS which would make sense of course the more antigen or protein that you have that the t-cells are acting against it may change how likely they are to be activated this is really a slide just so you understand what you've probably heard CRS management is it's generally supportive care we give tylenol for fevers of course we make sure that there's antibiotics on board etc but I'd say what we use the most is a drug called Tosa lose amount and Tosa losing that is is an antibody against the il-6 receptor io6 is this protein here that does tend to cause inflammatory downstream effects and we have a lot more experience using it now and we don't think that it affects the ability of the T cells to kill but rather sort of like tylenol does with fever just takes down the symptoms and so we do use that pretty judiciously now if the CRS is persistent despite just losing that we do use steroids or maybe more steroids and in very severe conditions me consider another dose of cyclophosphamide really - in that case really silenced the T cells because of course we don't want anything bad to happen to the patient we always want to first do no harm what about neurotoxicity this is something that has been talked about a little less common as you saw from the data then CRS but it does have and it can be manifest by any of these symptoms that you can see here basically I think the best way that I've always described it is the patient kind of seems drunk and and they may say yeah I totally remember what happened but then they can't tell you exactly what was going on or are very simple questions once you start digging in there you'll realize that they don't necessarily know what you're saying or it's very confusing to them and it's very hard of course patients are trying to do the best they can during this situation so I really love it when caregivers are around because they're often the first people to notice this and the reality is there are multiple reasons why a patient may have neurotoxicity in the setting of course the card t-cells maybe they just have a fever being the hospital that can be very off-putting for many patients on maybe they were on dexamethasone also the food air beam may have some effects but neurotoxicity is real and it has to be recognized very quickly and we now use this ice scoring that you see on the right sort of an evolved scoring from a previous car tox ten and what this does is really I think it does really let us see if the patients are focused so these are not neuro tests like can you walk across the hall this is really about can you concentrate focus and have attention can you write something down and that's really what we see is the hallmarks of neurotoxicity and and this can be used to to put into a score so we can figure out how serious their neurotoxicity is or we call ICANN's immune cell effector associated neurological syndromes so it's just easier for me to say neurotoxicity but the correct term is ICANN's management for neurotoxicity we actually in our hospital though not all hospitals do this we give all patients undergoing Carty for myeloma seizure prophylaxis with keppra I try to start that before because it can make people a little bit drowsy so I try to start that during their LD chemotherapy but generally steroids are the mainstay of management of this neurotoxicity again if necessary we can increase steroids or gives like with cyclophosphamide other toxicities associated with car t-cells definitely low blood counts and I think all of you have experience with this so we give supportive care there seems to be a little bit of inflammation going on with this bone marrow they start in the bone marrow so these t-cells may actually cause not only killing of the myeloma cells but sort of a side in inflammation in the bone marrow while they're doing that and that can actually manifest as very low counts and a high ferritin and then syndrome we call macrophage activation like syndrome so similar but not necessarily definable by seeing more macrophages in the bone marrow and we've started to use this drug and a kenra to try to combat this and this actually is a competitor for aisle one and we actually but we've actually had a good amount of success using this because it does go to the root of the problem as far as the inflammation goes so you may hear of both of totalism at four CRS and maybe steroids for neurotoxicity and then anakinra for this type of a syndrome and then there's immuno suppression and I think this is real and this is something that we really have to work with our community providers so if you get a car t-cell for example at a specialized hospital and then you go home there has to be good communication very similar to what you had maybe if during your transplant where the myeloma doctor or the transplant doctor was communicating with your local doctor well the party doctor should do the same you should look at the immunoglobulin G levels which tend to be suppressed as a side-effect and you may need a Vig which we initially do tend to give if the immunoglobulin levels below 400 that's very arbitrary it's not proven but we certainly don't want people to get into trouble and we give antibiotics prophylaxis during the Kartini certainly during your tinea and antiviral prophylaxis at least for six months similar to the transplant so moving on from car tease there are other things that are looking at P CMA including something called by specific T cell engagers and so you can see this is an abstract that was presented by dr. Costa who you saw before today by specific T cell engagers or bites are basically a way to have an antibody hook on to a tumor antigen in this case B CMA and a T cell or what I call it the eHarmony of immunotherapy as you can see here so new t-cell is this molecule looks on going to t cell and this part 2the to the tumor cell and look now the T cell is now very close to the tumor cell and can cause killing of the tumor cell this is an interesting trial that was presented at this year's ash and the reason I like this is because as you can see here initially these patients are getting this drug and this is not ass out there because it's just a drug they're getting in weekly and then it goes down to every two weeks but eventually it goes down at every four weeks and I think that's really important because if we're going to have a drug it's got to be friendly to give to a patient in the real world here you can see that there were some low blood counts and they also had some CRS but they really didn't have very much neurotoxicity so this tends to be a little bit different of side effects more affecting accounts maybe causing a little more infection definitely causing CRS but all of that is manageable and as you can see here in their highest doses I was actually very impressed by this data that they got close to 90 percent response rate here another they're still working on which doses are the best and instill the study is ongoing but the reason I was interested to see this data is because you're getting response rates that are very close to or just the same as Carty data but you don't have to manufacture cells so this is what we call an off-the-shelf therapy so I'm looking forward to more data about this what about antibody drug conjugates galantamine methadone is a drug from GSK that actually uses targeting of B CMA as you can see here but on the edge of it it has this warhead this MMA F and it allows for deployment of this warhead specifically into this plasma cell and I think although there may be some immune effects going on I think the vast majority of the work is being done by these warheads and so that's where this drug gets its efficacy the original study to look at this was called the dream one and the patient population here was a little bit less heavily pretreated than the Carty population and actually lesser of them have been exposed to dara to a map which was a requirement for all the parties studies and the flight studies in the initial dream one they saw a response rate of 60% and a progression free survival of 12 months which was very impressive but since then they've published the dream to study and this dream to actually makes the patients feel a little bit more sicker if you will they're more heavily pretreated and they had to be refractory to and image a proteasome inhibitors is something like Revlimid Velcade and an anti cd3 cd38 antibody so these are really the truly relapsed refractory myeloma patients one of the things that they looked at in this study was two different doses and the reason they looked for that is because one of the side effects of this drug because of the toxin that it uses is ocular toxicity or carrot top of me and that is manifest by these little globules of inflammation that that are in the cornea and the reason it's important is because of course we want to be able to see and this is a quality-of-life issue and the company is very aware of this and based on that they've been trying to do the best they can to find the optimal dose that will give efficacy but minimize toxicity and so they were looking at two different doses here basically as you can see here for either the doses the responses were similar in the thirties 31% 34% in a three point four group the carrot-top a--they was 43% grade one and two so something that's tolerable but but symptomatic and then 21% had prayed three and I think if anything is it is is something that has to be known about this chart is you have to educate your patients that they may have irritation of the cornea why is this important because the solution for that is actually stopping the drug and you can stop the drug and give a pause and some people have done that and you may or may not need to take the drug for a few weeks and you can pause but this is one of the ways that we're learning to use the drug a little better even though it's supposed to be every three weeks if there are eye symptoms maybe we can pause let those get better take a dose down and then read oh so we're learning more about this as we're getting on as you can see here the median progression-free survival you know when I originally saw this data I thought well that's not so much three months five months but I think more importantly and we don't have this data yet is the median duration of response that is if you get the drug if you can tolerate it any response and you respond what is the duration of this how long are you going to benefit and I and I think now we know that the median duration of follow-up right now is six point three months and so for the people who have responded those people are still responding so I'm looking forward to longer-term follow up from this data because I don't think we truly know the true extent of it yet and I think it'll help us to position this against the other immuno therapies speaking of which I think one of the most common questions I get is comparing options so Carty versus by specific versus antibody drug conjugates they're different and I don't think they're competing I just think that we have different myeloma patients with different needs and different locations and and one solution may not be the best for all patients and that's why it's good that we have three solutions evolving so Carty requires a specialized center usually it's a one-time deal that's what I like about the most the one and done it's two months of real investment but you can have some talks to see as we've talked about and I I think financial toxicity may be very important by specifics we don't know the logistics I think maybe the first dose people may want to get at a specialized center but then it's off the shelf and it could be very community friendly similar to other drugs like clinic - mmmm but the length of dream is not known because you don't know people could be on this forever and even though there's CRS it's actually tolerable maybe some infections but I think the cost it may rival I mean if you're giving us forever versus one time then we really don't know if there will be differences of cost similarly antibody drug conjugates I think this is the most community friendly try that there is it's off the shelf every three weeks maybe the original study had some limited cycles and maybe that's possible but I think corneal toxicities are important of course this is something that is a quality of life and we don't know how long that people are gonna take it in the cost and so I think you know everything is negotiable and something that we should consider that every treatment is not same for every person in it really have to tailor according to patient's goals quality of life limitations and other factors that may not have anything to do with their disease so in future considerations we are looking at allergenic Carty cells that eliminates the need to engineer your own T cells and those would be off the shelf maybe car T cells can look at not just one target like PCM a but B CMA and something else a lot of work going on with novel engineering options to make cells last longer and finding new antigens to make them better at targeting my maybe moving it earlier line a lot of trials looking at this now I would say hashtag be like Dara right now Dara to mem AB is just coming to the front line and I and I think that's one of the things that it's gain is coming to the front line it's more efficacious and then looking at earlier clinical trial endpoints because of course I'm a millennial and I hate to wait who wants to wait for all this PFS right we'd like to see earlier endpoints and I think Mr D will become part of this by the way if you are wondering what a mile lineal is it's a mile uma millennial and this is the criteria for Izzo's I have a self-proclaimed millennial because I've never given thalidomide or oral mouthful and of course it's like what's the big deal about 80% response rate right we care about duration of response and we not sir we're using during salmon anymore and we always look at Mr D and of course we have to be on Twitter so this is my definition of a millennial although rough alphonse like I had a good one and thinks that pulse Tex is a Dutch EBM ban which I thought was pretty funny with that I'd like to say thank you so much for your time and hopefully you've got a little bit information on my limit immunotherapy this is our team in San Francisco the four of us here we always like to hang out and even in the setting of social distancing we kept six feet apart from each other which doctored show at my side I thought was a pretty cool album cover and most importantly we had our annual Cinco de Mayo luma celebration through zoom across the country with various investigators you may recognize here on the screen shot and with that I'll say thank you and I'll be happy to take any questions you [Music]