Good morning, everyone. And it's great to see everyone who came out this morning. It's a pleasure to be here in sunny Miami. And as Jenny noted, I actually moved here quite recently. It's been in the last, less than two months since I arrived. I was in Seattle for about 20 years before that. And I came here to take over as chief of the stem cell transplant and cell therapy program here. So that includes CAR T cell therapy as well as transplant. And I'm also very integrated with the outstanding myeloma group here. And I know Ola Langerin has built just an incredible program here. And I know you're hearing from many of my colleagues today. You've heard from some already. You'll hear from folks later. And hopefully we'll be able to address lots of questions for you. I have been in the CAR T cell space for many years since the very early days. Early days being just going back into the 2015 to 2017 time period when we really started to get things going there. It is, as I will discuss here in the first slide, a rapidly changing space. In fact, I'm actually giving a talk this afternoon back in Miami. It's something called the CAR T cell large symposium. I gave a talk two weeks ago and I gave a talk a few weeks before that. And my brother, who is visiting me, said to me, aren't they getting tired of hearing what you have to say? And the interesting thing is I've had to change my slides every time in the last month. And that speaks to the rate of change that's going on in myeloma. This is sort of a depiction of that. You can see here on the slide the early interventions. And way back in the beginning we just had steroids. Then we had some other chemotherapy drugs. Finally in the 80s transplant became an option for patients. And then it's really escalated from there. What does that mean? I mean, it's never obviously a good time to have a diagnosis of multiple myeloma, but there are better times and worse times. And now is a far better time if you have to be diagnosed with myeloma than it would have been for someone who is diagnosed back when I started treating patients 20 years ago with myeloma when the anticipated survival for patients was dramatically shorter. And I think everybody knows that. This slide is just evidence of that. It's in flux. The only thing I'd say is if you look at the rate of improvement, you know what percentage of patients, everybody wants to know how long am I going to live. All I can say is it is exponential in its growth. It is not linear. So that improvements in survival are dramatically getting better and better, sometimes by the month at least based on the data. So it's important to bear that in mind. But the overall message is things look good. We're doing very well. And yet we still, as everyone I think knows, need to do better. So let's talk about CAR T cells a little bit. I'm not sure the different folks in the audience may have different familiarity with it. So I'm just going to walk you through the basic notion behind it. CAR T cells basically amount to taking a patient's own T cells, cells that are a critical part of your immune system, from the body, essentially filtering them out through a process of leukophoresis where we collect those T cells and then genetically modify them. We modify them so that rather than seeing the enemy as being an infection or some foreign invader, which our immune system is designed to do, we've now caused them to see the tumor cells, the cancer, as the enemy. So we've leveraged their power but done it in a way that targets tumor cells. And that's through this modification. We insert a gene. We make them into what we call chimeric T cells, chimeric antigen receptor T cells. So they are modified. When we do that, we have to grow them up. Now, that process has been changing. In the current approved drugs, the CAR T cells that are approved right now, it can take six, eight weeks or longer to generate those cells. And that is an issue. There are a lot of measures that are going on to speed that up. We had our own trials early on. We had our own CAR T cell trials in Seattle that I headed up. And on those studies, it took 17 days to produce them. So better, but still 17 days is a long period of time to wait. And it ended up being about a month by the time someone came in, went through the process and then got the cells. There are now processes where the turnaround time in the future, I think, might be in the order of three to five days or less. And so that's promising. And I think that's going to be important because some people can't wait two months to get their therapy. Anyway, right now, we have to grow up these cells and then infuse them into the patient whose cells we got them from in the beginning. Now, when those cells go in, they expand massively. In the same way their immune system responds, when you get a bad infection, you get a fever, you feel awful. That is in part a function of these cells expanding in your body to respond to the infection and then cytokines that come along with that. Same thing occurs, except we get a massive expansion of this particular cell that we've put in, and those cells are particularly targeted to the tumor cells. They can then go in and kill the tumor cells with the goal, of course, of eliminating all of them. So now, Jenny asked me to sort of cover a pretty broad range of things in half an hour. I could spend a week talking about these things. I will try to address the questions raised. We may not get to everything. But one question I think people have is, what is this BCMA thing and is it a good target? BCMA is B-cell maturation antigen. An antigen is basically a protein that sits on the surface of your cells. Our cells have all kinds of different proteins that sit on their surface. The kind you want to target in cancer is a target or a protein on the surface that is unique to the cancer. If it's on all your normal cells and you target it, we're going to cause a problem and not do you any favor, right? If it isn't at a high level on those cells, may not be such a great target. If it falls off, may not be a great target. If you lose it, may not be a great target. A lot of work goes into identifying good targets on tumor cells. And certainly BCMA has many promising aspects, but it's not perfect. This is a problem in cancer. Many targets are not perfect. BCMA is a pretty darn good one because it's restricted to tumor cells, at least plasma cells and those that become malignant for the most part. And some other cells, B-cells, that you don't need to survive necessarily. That's what makes it a good target and that's why so many people have focused on it. So, you know, we draw these little cartoons. I don't know if this point works. Yeah, we draw these little cartoons. That's BCMA. On the surface of cells, BCMA can be at varying levels. It is not a super high antigen target, meaning that when we think about CD38, the target of daratumumab, CD38 is probably, depends on which patient you look at, but the surface density of that antigen, the number on each cell, can be in the hundreds of thousands. We've documented it could be around 200,000, but some people it's 40,000, some people it's 700,000, probably around 200,000. These guys can be quite a bit lower, as I'll show you in a minute. In fact, in the thousands or lower. Now, does that matter? It might, and we'll talk about that. What we did early on when we were trying to identify a good target, we were part of the process of figuring out is BCMA a good target for myeloma? And so we did studies, we looked at 22 patients. What we found in those patients is that pretty much everybody had it. On the surface of their cells, some people, the double pluses, had relatively high levels, some people the single plus, lower levels, and then plus minus pretty darn low levels. And so you can see the distribution, but not a perfect target, but a pretty good one. Okay, I'm going to jump to a patient. Now, I know there are many patients in the room. I'm sometimes hesitant to show patient images. I don't want to cause anyone distress at the same time. As you'll see, it's important to share data and to share what we know about the disease, right? On our trials, I will tell you, the studies that we did were for patients who had disease where they were essentially out of options. In general, we're talking about 12 or more different lines of therapy before they went on to our study. Some patients had 17 different lines, including experimental therapies, et cetera. This was a patient who, when she came in for our study, was in severe pain. This is a scout film, a PET scan, and you can see all those black spots, except the areas in the brain a little bit and her bladder, everything else except maybe the kidneys as well. That's myeloma. And she was in severe pain. She was requiring IV pain medications on a regular basis, admitted to the hospital multiple times before we treated her. We weren't even sure we were going to be able to get her to the CAR T cells because of her pain. She saw the pain service 37 times in 90 days. You get the idea. We treated her. Now, again, those are her kidneys, that's her bladder, and that's her brain. All those other lesions three months after therapy were gone, and in fact, she never saw the pain service following therapy at least. After one week, she was off all pain medications and didn't see the pain service again. So dramatic, right? It's not only in our studies that we've seen these things. We know that the pain service is not just a result of these things. We know, this is evidence, BCMA is a pretty good target, obviously, right? It worked here. It worked incredibly well for the patient. Her pain went away. Dramatic improvement. Quality of life improved. And that's just a further close-up showing you the same thing. Okay, so what are these CAR T cells in a little more detail? These are cartoons. I'm not going to go through all the various aspects. Don't worry about the various aspects of this other than to say there are currently two approved CAR T cell products from the FDA. One is IDA cell, the other is CILTA cell. There are differences between them. We'll talk a little bit about that in a minute. But some of the differences, the way these CAR T cells are designed, the genetic modification I mentioned to you that we put in, involves different modifications. These are what we call a sort of modular design. You can shift things around when you design the CAR T cells. I don't want to make it sound too easy. It's not. But you can change different elements when you're making this genetic, when you're setting up the system by which you can modify the cells. And that can matter because it can impact how long the cells persist for. It can impact how fast they expand. It can impact how well they bind to the target. So many aspects that can be modified and changed. You also have to do it in a way that's safe. You have to demonstrate that it's safe. That's why these things take years to generate. But they're two approved. They're two approved. The first one out the gate was IDA cell. It has some differences with the second approved agent, CILTA cell. And we'll talk a little bit more about what that means functionally in a second. In our own study, and again, this is just to sort of get into the proof of the value of the target of BCMA. So these are 25 patients we treated, not with CILTA cell or IDA cell. This is with our own CAR T cell product that we developed in collaboration with Juno Therapeutics in Seattle now. It's owned by BMS. But what I want to point out to you is, so the patients who went on to our study, this is the percent of their marrow, percent plasma cells in the bone marrow before they receive therapy. So generally speaking, save for one, I think where it says less than 3%, we're talking about patients who had, you know, up to 90% or greater of the marrow was full of disease. You can see what happened. The patients generously, as part of the study, allowed us to get a bone marrow biopsy on day 14. And I can tell you, I had never before been stopped by the pathologist in the elevator to ask what's going on. We're looking at these marrows. They went from 90% to zero. And so that is something we saw. Again, evidence of the potency of the target. And it pretty much did it universally. I know there's discussion about the loss of the target and we'll talk about that a little bit more in a second. But early on, initially, it looks still to be a pretty good target. You know, we didn't pre-screen these patients for whether or not they had BCMA on the surface of their cells. And as you can see, all of the patients except for one by day 30 had no detectable plasma cells in their bone marrow. That was by microscopic evaluation and by flow cytometry. So, and here I'm just highlighting a couple of examples of particular notable drops within 14 days of receiving the therapy. We also saw, not surprisingly, I presume everyone in the room is somewhat familiar with the blood markers for myeloma. If not, it sounds like you can go to Health Tree and you can get fully educated on it. But the bottom line is we've got some good markers, right, to follow the disease, the light change, the monoclonal protein. And the light change in particular, monoclonal protein takes a while to go away. If you stop all production tomorrow and a patient doesn't go away the next day, its half-life is at least three weeks. But in our studies, it actually has a longer tail. We've seen no myeloma in a patient by any detectable measure except the monoclonal protein for a month, sometimes for almost out to a year in patients. So it can clear out slowly. The light change is not so much. They have a rapid clearance. Their clearance is measured in hours, six to eight hours. So they're actually probably a better quickie test, you know, for looking at these questions about responsiveness. And you can see in both cases, drop down dramatically. So the first drug approved, IdaCell, how did it look? Well, 82% of patients at the approved dose level, the highest dose level, it was 450 times 10 to the six cells, just the total number of cells put in. 82% response rate. There was a complete response rate of 39%. If you look at everyone, 128 patients who got the drug, including at the low doses, the response rate was 73%. Now I'll tell you, you know, the car that we used I have a bias here, I will openly admit, but ours, we also escalated the doses. We actually saw 100% response rate as we went up, even at the lowest doses of the car. But that just speaks to the differences in the car design. And we know that with IdaCell, in terms of the progression-free survival, how long before the myeloma comes back and you have to do something else for it, is measured, it is somewhere, depending on which studies you look at, between 10 and 12 month period of time. So pretty good, but not great. Now remember, the people going on these studies, many of them had pretty bad disease and a lot of disease before they went on to the trials because these are trials that were done for patients where the indication was that they had failed most of standard therapeutics, right? Still, it's not a home run. I had patients when we opened our study, I remember one in particular, I got a call from overseas in Europe, a physician who wanted his brother-in-law to get our CAR T cells. He had smoldering myeloma. Of course I said, no, not a good idea and we shouldn't give you an experimental agent for smoldering myeloma. It might be fine for the rest of your life or for many, many years without any intervention. But it speaks to, there was a delta between excitement level about the treatment and realities. People thought this was going to be curative therapy. The goal is just to be curative therapy. I don't think we can say that reliably right now. We can say it's highly effective. Now, Silt-A-Cell, that's the drug that Janssen came out with, second approved CAR T cell. The overall response rate is definitely better with Silt-A-Cell. The overall response rate, 97.9%, virtually all, similar to kind of what we saw with the CAR that we had developed as well. And a dramatic and very impressive fraction of the patients who achieve what we were calling, still are calling, the nomenclature may change in the not-to-distant future, but these are patients who achieve the stringent complete response. So very potent. And that has resulted in what appear to be longer windows of time before progression. And here, the data presented here was at 27 months, 55% of the patients had not yet progressed. So looks good, looks more promising. A lot of people feel that, hey, this looks to be maybe a more effective drug. I think it probably is a more effective drug. However, I caution comparisons to, the only way to really do a true comparison is to have a randomized study where you give one or the other drug because the patient populations are different and they could be very different. And so people are, everybody wants to compare, you want to know what's going to be best for me, gee, I better compare the studies, but I caution against doing that too much in this setting because these studies, and we probably won't get a study unless the FDA were to mandate a head-to-head study comparing the two. So we're left to try to extrapolate. I'm showing you what the data is, but I just would caution against trying to say for sure that one versus the other can be decided based on data from trials where they only look at one drug and not the other drug. Okay, back to our patient. So delightful patient, terrific response, as I mentioned. She was deeply grateful for that response. Her quality of life dramatically improved and then she relapsed. 13 months after therapy, her disease came back. So what do we know? We know this works. We know it drops the disease down dramatically and we know we had someone who really was out of options who for 13 months did well and we know that we're not doing well enough. So a very potent tool and yet not one that is perfect. This field is in its infancy. I mentioned, we've been doing, I've been treating myeloma for 20 years. Cartesia therapy has come along. The first published study, I think, was maybe 2016, 2017. So it has a pretty short history, right? If you look at the history of transplant, if you look at the history of other interventions, we have a much longer history of knowledge behind those things and we made modifications. Patients do much better today with an autologous transplant than they did in the past because we got better at managing the side effects of the disease. We're going to get better at managing this too and hopefully we'll also do a better job of making this work. We're using the same transplant regimens, high dose melphalan that we were using in the beginning. That's not going to happen here. We're going to continue to have new iterations, new agents, new targets, new ways of designing this modular CAR T and make it better and better. So why do people relapse? Well, one reason people relapse, we think, and we noticed this early in our studies, this was a very early trial, is that the target density goes down. The number of receptors doesn't stay high at the same level, it drops off and that might be a reason, might be a reason why patients relapse. What we saw is, if you just look, these are the first handful of patients who relapse on the first study that we did and you can look at the level of the target, that's the orange bar, before they got the treatment and then when the disease came back, that's the propo bar. So there was a drop off both in the absolute number of targets on the cells and the percentage of the cells that had the target on them. So I posited this idea that maybe we could do something to increase the target density and it turns out there's an enzyme that cuts BCMA from the surface and has it float off into the circulation, something called gamma secretase. Gamma secretase is an enzyme that cleaves BCMA from the surface of cells and gamma secretase inhibitors were developed for Alzheimer's disease for a totally different reason, they didn't really work well. Actually, I don't think those studies were designed well and they may work better than people thought but nonetheless, they kind of fell off the, you know, a bunch of companies developed them and then they fell away. Well, it turns out that we were able to repurpose them. One company, Eli Lilly, still had it on the shelf. We showed our collaborators then at Juno Therapeutics our data which demonstrated that we could significantly increase the target density. They licensed the rights to the drug from Eli Lilly and we opened the first in human clinical trial where we combined the gamma secretase inhibitor with the CAR T cells for the purpose of increasing the target density. Here's the trial design. I say the one I think particularly important I think particularly novel part of it was well, there were a few novel parts because it was the first in human trial to ever do this but we actually had patients just take that gamma secretase inhibitor it's an oral pill three times in one week and then we had a bone marrow biopsy beforehand their baseline one. We got another one at the end of that week before any CAR T cells to see what it did to the level of the target. The green bars are the level of the target after three doses. The red bars are the level before the three doses. So we saw a median 12 fold and up to 157 fold increase in target and all of the patients except one patient number 11 there all the rest of the patients responded to the treatment responded to the CARs that patient did not increase the density of the BCMA target that patient also didn't respond to the CAR T cells and had progressed by day 30. It's still not a home run in fact most of the patients on the study not all of them have relapsed. Now interestingly the very first patient who we treated we were trying to understand why got the lowest dose of CAR T cells this was a dose escalation study we started a low dose and went up very low dose of CAR T cells that patient is now more than five years out without relapse. So that's pretty good. Unfortunately again it's not a home run but it's a very good result unfortunately again it's not a home run most of the other patients have relapsed I will tell you though this was the first in human clinical trial we had to design this trial in a way to convince the FDA to let us do it it was designed for safety that means when we gave the gamma secretase inhibitor we only did it for three weeks after the CAR T cell was infused so you got it beforehand during that run in period three doses and then three doses a week for three weeks and then we stopped because we didn't want to cause any safety concerns so we were able to demonstrate we were able to demonstrate you could significantly increase the target we did this in patients who were heavily pre-treated with lots of prior therapy we think that there's a signal here that bears further pursuing and we've published the results of this recently in a major journal but here patient who received you know similarly to what I showed you before this patient had lots of disease had a great response to therapy but unfortunately this patient too relapsed he's still alive years out afterwards and on other therapy but relapsed after this treatment so one of the things Jenny asked me to mention to talk about was you know are there limitations who shouldn't get CAR T cells because we opened our study the study that I ran in Seattle it was not a study that was a big pharma trial we designed the trial ourselves there's some advantages to that for these early studies because we could include whomever we wanted and we had a different mentality I think than some you know I understand why large pharma companies need to get the indication they don't want to make a misstep if they took patients who are too sick they may never get far enough down the road to actually get the drug approved right so I understand that but we didn't have that same limitation we let patients with worsening kidney function go on to our studies we let patients who already received a BCMA targeted therapy go on to our studies we let patients with prior allergenic transplant go on to our studies and we had no age cut off for our studies it turns out that age is really not a limitation to CAR T cells for transplant there's not an absolute cut off generally most folks will say over age 75 we're probably not doing many autologous transplants that cut off doesn't exist we've treated patients with CAR T cells into their 80s and beyond if a patient has significant kidney compromise it is probably not a good idea the bite therapies may be better it has to be done very cautiously sometimes you can reduce the doses of the chemotherapy with the CAR T cells and get away with it in patients who simply can't wait right now if that production takes 8 weeks or more and there are some cases where the production has failed and they're waitless because there are not enough resources to make CAR T cells for everyone at this juncture there are people who just can't wait that's a limitation to using this therapy in patients who recently received other BCMA targeting therapy based on what I showed you and what I'll show you in a minute that might be a reason to think about not coming right in going after the same target again but as I think was alluded to by Dr. Coffey earlier there are other targets now being explored GPRC5D with CAR T cells it might make sense to go after one target with a bite and the other with the CAR T cells or FCRH5 there are a couple others in the pipeline another limitation is geographic access there are people who just simply live too far away from centers that provide this therapy and can't be there usually one has to be there for about a month after receiving the therapy but you also have to come in and get the cells made and you know it's a huge economic burden it's actually an issue with disparities and care right because only the people who can afford to be off work and have a loved one off work with them and afford to stay somewhere far away have access this is a major issue in the space that we have to battle against to sort of level the playing field for everyone frail patients again not age but I will tell you that there's a level patients develop cytokine release syndrome we haven't gotten into all the detail again for one time but what are the toxicities and side effects of CAR T cells a major one is cytokine release syndrome and neurotoxicity I'll touch upon a little bit more in a minute but cytokine release syndrome can be quite severe patients get fevers up into the 105 range they can feel awful like the worst influenza infection of their lives or beyond and so if someone is truly frail and in bad shape and at significant risk for infections we've seen instances someone is bed bound then develops cytokine release syndrome then needs lots of steroids that is a set up for infection and complications and the last thing we want to do is give someone this therapy and end up shortening their life from an infection doesn't matter if we knock their myeloma back into oblivion hopefully if you're not around because you get an infection we didn't do you a service just because we knocked the myeloma back and so we have to be cautious about that and that feeds into infection risk and then I mentioned this neurological risk this has been seen more actually with CAR VicD than with Ibexma Ibexma so I2Cell versus Cilticell more with Cilticell and this phenomenon has essentially we're not longer calling it like Parkinsonian symptoms but it has an overlap with Parkinson's like symptoms or worse where patients have actually in some cases developed a locked in type syndrome where patients can't move and can't function and it has resulted in patient death not in huge numbers but it is a serious issue and it can happen in people who otherwise were quite functional so it is a reason to be cautious especially when we start thinking about bringing these therapies into earlier lines right where people have alternatives but these are very effective therapies there is still possibility that you're taking on risk that could result in complications that would shorten life okay so should we give CAR T cells earlier in therapy leading right into that you know if you would ask that and this is what I mentioned in the beginning back at a month ago when I gave a talk the answer is the answer was there are no approved CAR T cell therapies that is not the case now the FDA has now they had what they call ODAC meeting they looked at both of the two approved CAR T cells the IDA cell CAR T cell got an indication and approval that approval was for that was based on this trial the CARMA 3 trial but the bottom line is patients that had two to four lines of prior treatment other combinations of therapy two to four different combinations of therapy and had to be refractory to a proteasome inhibitor a imid immunomodulatory drug glycolinalidomide and a CD38 drug or they had to be triple class refractory and exposed to those drugs and what happened well if you just look at this is a progression free survival curve I know we didn't have time to get into what these things mean too much but basically it's the probability you know the percentage of patients who have progressed over time and so you can see if you look at 12 months these are for patients who had at least two prior lines of therapy dramatic improvement dramatically better in terms of progression free survival for the patients who got CAR T cells versus those who did not however that is not born out to an overall survival advantage so in other words the fact that a patient doesn't progress doesn't necessarily mean they're going to live longer because it could be that the treatment causes other complications and leads to early deaths in some folks or other things that ends up bringing those curves together and so far those curves are together on these studies it was still reason enough I think it's pretty compelling and it was what convinced the FDA to approve this drug after two prior lines of therapy and yeah here's the survival curve so basically they're overlapping in other words do better in terms of progression but not necessarily yet in terms of survival that could change we've seen these things change this is early days over time so we'll learn more as we go so what about Cilticell the other drug well I'm going to just make a long story short and say that based on the trials there it was approved after one prior line of therapy so if you have one prior line of therapy and one line of therapy with induction if someone gets a transplant is your initial therapy and a transplant that's considered one prior line of therapy actually it's induction therapy transplant and maintenance that's all one line of therapy it would be indicated after that if someone didn't get a transplant and got induction therapy and then the disease relapsed that too would be considered one prior line of therapy but again here's the progression free survival nice separation of the curves this got the indication after one rather than after two prior lines of therapy so then the question becomes should we be doing this for everyone now right now we can because we can does it mean we should and that is a very complicated question that I don't know the answer to yet I am a big believer in CAR T cell therapy I think that there are patients for whom it makes sense to go in early and I think there are many patients as well for whom it makes sense to use other options why well at least for now I don't know that we well we do know this we know insurance companies right now are loathed to pay for doing this more than once if you get the CAR T cell therapy early and it's a very expensive therapy in the order of you know insurance companies will get billed four hundred five hundred thousand dollars for the treatment so you can imagine why they're not excited to do this multiple times right if you exhaust the option early I don't know what's going to happen in the future and what they're going to say and what is going to happen in the space if we have new iterations and better cars and more effective cars low cost low cost look it could be that the answer is going to be yeah they're going to say yeah give those to patients at the same time it could be a limitation and if there are other very effective therapies available one has to consider that I think I think every patient should be looked at as an individual and that there shouldn't be any broad strokes where somebody says oh yeah after one line of therapy I should get CiltaCell now because it's approved I definitely would advise against that but it is nice to have it in our you know sort of quiver of arrows you're going to call it our arsenal I try to avoid military metaphors if I can for health care but sometimes you have to so it is nice to have it as an option but it doesn't necessarily mean that we should do it for everyone I will say however there's some very nice studies that have come out around quality of life demonstrating this is in the patients not in the upfront state but patients who had many many prior lines of therapy those original studies that I showed you initially not surprisingly quality of life goes down but that's like for about a week or so by the time you get out to a month this is very recently published data just published I don't know if I have a slide here actually I think just just came out at the end of last year maybe even later but so you can see at one week this is quality of life for patients it went down and then it went back up so you know by by less than a month people's quality of life was better than it was at their baseline and it continued to improve we've seen that we mentioned that patient who had severe pain and whose pain went away right so we know the quality of life can be improved and now here's another study yeah this is one just came out in March this year just published again looking at a whole bunch of quality of life measures CAR T cells versus standard of care not CAR T cells and the quality of life measures really favor the CAR T cells across the board in almost all instances so important to understand right that one of the advantages to this therapy is for now although unfortunately the disease comes back it is sort of one and done therapy people get the treatment they can have infectious risk they do have to be monitored I'm not trying to make paint too rosy of a picture but at the same time generally what I hear from patients is being off of revelment being off of maintenance therapy has been a blessing for them even if they if the disease ultimately comes back and I will tell you as a myeloma provider we were so encouraged by those early responses you can imagine and I shared the pain with so many patients in whom we saw these amazing responses and then having to tell people that the disease is back it was a little bit akin for me to when you know when we're in training as physicians and we see a patient who's whose oxygen level is low and you give them face mask of oxygen and they you know they go from blue to pink and they feel really good this is a little bit like that it's like giving somebody an oxygen mask but then when it comes back it's like taking the oxygen mask away that's our charge that's why we have to do better in this space here's an example of such a patient this is one of the patients who I treated this guy couldn't he was basically not able to do anything different from the other patient I mentioned but his functional status he had pain he was tied to ongoing therapy and he sent me this email after his one year check you know basically and this was not an exaggeration he was a surfer and he was back surfing and he had a grandkid and so dramatic improvement in the quality of his life and I had another patient similar story been on treatment for five years health was bad he went white water rafting on day 180 I might not have told him to do that but he did it on day 180 okay so I mentioned though there are new approaches coming and I think that we have to do better because this disease comes back right one aspect is looking at other targets maybe they're better targets maybe they're combinations you know dual targeting going after BCMA with something else there are other alternative strategies Allogeneic CAR T cells are in their infancy I'm not sure where things are going to go that would be not using your own but donor T cells from someone else advantage there is you don't have to wait for the production the idea is they could be off the shelf one of the problems with CAR T cells that we think is that they become exhausted CAR T cells can only kill for so long and we need to figure out how to keep them active as active killers of the target because if they become exhausted they might stick around but not do anything we want to enhance their function and we want to do things to understand the surrounding environment around the myeloma cells because that can be protective that can prevent the CAR T cells from working that can allow the myeloma to come back so I just mentioned some of this but basically I'm just showing you here there are many ways that we think we can make CAR T cells better different targets different design of the car that might make it persist longer might allow it to have retain what we call its effector function the measures that I mentioned that we were studying maybe we can modify the target in a way that makes it a better a better target and potentially eliminate all the disease early because as was mentioned and I think you'll hear more from Dr. Diamond later on there is this risk of of losing the target having mutations as the disease progresses that risk goes up maybe the harder we hit it early might be the best approach I don't know yet I'm not telling you that because I don't want people to run for the door saying okay give me that CAR T cell after one line of therapy we don't know right? so we need to understand this we're in partnership with patients every time a patient is on a clinical trial they are helping to understand what the right course forward is and it's important to know for these trials we will never design a trial where we know that one thing is better than the other that would be unethical you have to have equipoise you have to believe that what you're doing the intervention you're giving at least is good and maybe better than the standard of care right? but at the end of the day until you do a trial to assess this you don't know you can end up seeing much faster responses and then having patients with complications die earlier and at the end of the day you actually did nobody any favor but it might look good early on that's the whole reason that we do these trials okay a couple of last few things and I will probably add over time so that patient who I mentioned the delightful patient who had a response and progressed also allowed us to take her cells for research purposes beyond just the trial even before she enrolled in the trial we actually took her cells and put them into a humanized mouse model this is something that is in development it's been very challenging to do this because mice have very different immune systems this mouse has been modified to see human cells as like you know themselves and we actually just put 82,000 of her myeloma cells in it took a long time we put it into a bone marrow on one side and we ultimately found myeloma on both sides we found it in the side that we put it in and the other side and we found the human multiple myeloma engrafted we could monitor it we could follow the light chains so this mouse in some ways was a mini-me for the patient the reason that that's important is it might provide an avenue for assessing different therapeutics from a patient if you can take someone's myeloma cells put them into a mouse and assess varying therapeutics that will tell us something more about how effective a therapy might be for an individual patient however big caution there these are not human beings right they do not have the same immune system it could be that the outgrowth of the myeloma in the mouse is different from how it would grow in a patient it may not develop the same mutations so I don't want to overplay this point but I do think it's important direction for the science where we might be able to develop some models in which we could assess the disease outside of a patient and then use it to help to understand the biology of the disease in the patient and this we could follow the same patient same M spike was in the mouse that was in the patient the light chains are the same we could monitor the disease in that setting and the hope is that we can use those models to explore disease further and then we could look at combinations with other therapies okay so I'll just close with this point I was asked many years ago to give a talk to donors I was invited to this donor event in a fancy place where there were lots of well-heeled donors there and they told me I was allowed to make one slide to explain to the donors what was important about the research we were doing in myeloma so in my early days in my clinic I would see patients with lymphoma and myeloma you know we all became more specialized by the time I left Seattle my clinic was essentially all myeloma patients but the arm that you see there that was a patient of mine with lymphoma and that patient who had Hodgkin lymphoma received treatment from me and a couple years out from her therapy actually too soon for my liking I have to say we usually wait five years before we tell someone like with Hodgkin lymphoma that they are effectively cured but this patient I think was about three and a half years she came back to me and I just noticed this is not I did not take this picture I'll tell you how we got the picture in a second because I don't take pictures of my patients but I just noticed something sticking out of her stomach and I said do you have a tattoo because I had noticed it before and she said oh yeah that's my survivorship tattoo and by the way you're on it so those are my initials that then let's see Amy Batchelder she was the physician assistant working with me Janice Lloyd was our nurse so the patient had tattooed and she put a survivor and so first of all I said there was a fellow with me in the room I said to the fellow oh yeah this happens all the time and she said then I told the patient that she put me in an awkward position because I have to go home and tell my wife that my name is tattooed on another woman's arm and it turns out that this patient the reason I have this picture is she wrote her PhD I think it was a PhD thesis at least her master's thesis on survivorship tattoos so she had this as a sort of you know a statement that she had survived her disease and she wanted to to get her certificate and she had to get her certificate and she had to get her certificate and she had to get her certificate and she had to get her certificate and she had to she wanted to to wear it on her on her arm so I showed that and I said that's our goal in myeloma our goal is to have people who feel confident enough to put survivorship tattoos in their arm and I showed the hummingbird because one of my patients with myeloma who was very dear to me and who allowed us to get samples from her early on that helped us get a major federal grant who we treated for many years with lots of different rounds of therapy but she ultimately succumbed to her disease and when she was in hospice her family described that there were multiple hummingbirds that flew outside of the window and I went to her memorial service and they gave everyone including my wife a piece of jewelry with a hummingbird on it and so it's a reminder to me of that patient who did well for many years but ultimately succumbed and the patient who could be cured with a lymphoma the delta between those two things and what I told the donors is help us get from one place to the other so I think we all share that view I'll just close with thanking all the people here at Sylvester Dr. Langren and his team and the folks you'll hear from today Dr. Diamond, Coffee the whole team here an outstanding myeloma group our cell therapy program and transplant program all of our funders and most importantly the patients who make the research that we do possible and really are our collaborators in this effort to improve things the most important thing for me is the most humbling thing I would say is the number of people is the number of folks and I'm sure you guys have heard it the number of patients who will sign up for research studies and they will say I understand that this is probably not going to help me but it might help someone with this problem down the road and I want to do that so I'll just close with that and thank everyone for their attention