(Guest Lecture): Relapsed Refractory Multiple Myeloma - Krina Patel, MD, MSc | RT Irvine, CA Nov 5, 2022

I think Dr. Chari did a fantastic job with that introduction of newly diagnosed and in relapsed refractory. And I, once I get my slides up, I really don't have as much data on all of our CAR T's and vice specifics because as you heard, 90%, 100% response rates is something we've never seen. But basically, what I want to talk about is the concepts and sort of why we're seeing these things and sort of where we want to go in the future with these relapsed refractory treatments. And what we're doing right now for early relapse versus these new therapies are in late relapse, which is a problem. We can't get all our patients to these therapies because of access or because if their myeloma is high risk, you know, we talk about risk, thankfully, high risk myeloma is about 20-25% of patients. But if you have high risk disease, which is about 50% of my patients, it's really tough. You know, we get through these therapies so fast that I really want to get them to these other therapies. So I think that in the next year, we're going to see all the data from the earlier lines of some of these immune therapies. And what I've gotten to see some of my patients on those trials where we really changed outcomes for both standard risk and high risk, but to add years and years to my high risk patients is what really tells me that these new therapies are going to change everything by the time they're all retired, but I'll still be around. But hopefully, again, just curing everybody and then hanging out and giving talks everywhere, right? Of how we did it. How they helped me help everybody else in the future do it. Okay, so relapsed refractory and what's myeloma? There we go. Okay, so my overview, really, I'll just talk about the implications of being relapsed refractory. What does that mean? We throw these words around all the time. And my patients usually like what is that? And then the new and old targets. So I'll talk a little bit about translocations and deletions and what we're learning about the inside of that myeloma cell, what's driving that myeloma and can we use therapies to specifically go after, you know, certain changes that patients have certain fish aberrations or cytogenetic changes? That would be an ideal thing to have biomarkers that tell me the day I see a myeloma patient, based on everything I know on their cytogenetics, their fish, what's on the outside of the cell. So I know exactly which of these therapies to give them. But we're not there yet. And it's probably gonna take a while. And so really, you know, we're learning more so I'll give you a little bit of that. And then overcoming clonal heterogeneity and evolution. So I'll talk a little bit about what our myeloma cells when we have mGus or smoldering myeloma versus when you have active myeloma and then what treatments can do, you know, to change what your myeloma is doing over time. And then specifically, I'll talk about the by specifics and ADCs and Dr. Brede has actually going to talk about the CAR-Ts today. So what is relapsed disease? So obviously, you know, the cancers come back. And as you saw, you know, we are caring about 15% of patients, which is great. But we want that to be 70 8090%. Right? So how do we improve that? But for most patients, it is going to come back probably multiple times. Our goal is to make that time farther and farther each time with these new therapies so that we have even other better therapies until we can finally cure more people. And in clinical, so there's people who clinically relapse, meaning that they have organ involvement, and that's causing symptoms. And again, these are the crab criteria we always talk about. So the calcium being high because there's bone disease, or anemia or kidney function issues that happen. And really, we don't want to get to this if we can find a way to treat patients before they get to this. That's what we want to do because this is what causes symptoms, right? However, sometimes we can't actually catch it happens in between. Then there's progressive disease as a biochemical progression. So that's where I, you know, really want to make sure I'm watching my patients very closely. And when I see these numbers go up, right, those proteins in the blood, the urine on scans, even if we see something early, this is where I want to catch my patients so that I can treat them earlier, to make sure they don't have those clinical side effects afterwards, which can then affect your ability to go on clinical trial, things like that. And then refractory disease, again, means that the cancer stopped responding to a treatment. So a lot of patients will potentially, you know, stop treatment because they've done so well for a long time. And if it's been many years before you relapse, then we don't call that refractory. But if you're on a drug, let's say you're on, you know, lenalidomide or deratumab and you're relapsing on that, for instance, during maintenance, that means you're refractory to that drug. And why that matters is when we look at these clinical trials, you know, we talk about patients who are triple refractory versus penta refractory. And it's really all those different lines of therapy. So we have our proteasome inhibitors, our immunomodulatory drugs, you know, as Dr. Shahari showed our monoclonal antibodies. If those three drugs, the deratumab or the, you know, bortezomib or velcades and the lenalidomide, if you've relapsed on all of those while being on it, we call that triple refractory. Then you add the other ones, so pomalidomide and carfilzomib. When you have all five of those, we call that penta refractory. And what it tells us is that the myeloma is more aggressive now. And when we do clinical trials for relapsed refractory patients, when a drug first comes into the market, someone says, oh, I found something. I mean, I want to try this in myeloma patients. It's usually in our really relapsed refractory patients that we started in. But once we know it's safe and it's working, then we start moving it up. And so that's what, you know, in terms of clinical trials for relapsed refractory patients, this is what it means. And then coming back to the goals. So really, we know, as Dr. Shahari said, the response when patients respond, when we see their numbers go down, the better response the patients have that complete remission or the MRD negativity, the minimal residual disease negativity where we do a bone marrow, we can't find that myeloma, the PET scans are clean. We know that leaves leads to better survival. So the myeloma stays down longer. And then it actually improves quality of life too, right? So our goal is always quality of life is just as important as that survival piece, because I, you know, I want patients to have a good quality of life as they're living longer. And so that's, I think, coming back to that, decreasing the dose, or stopping certain medications once it's working. And if it's causing side effects, it's so important to talk to your doctors about bring up the fact that, oh my gosh, I'm having this numbness tingling. I'm having some balance issues, because we don't want that as, as your quality of life, we can actually stop it and turn that around. And they all go together. So the other important piece, as I said, you know, patients can have different types of myeloma. So myeloma is not the same. I joke to my fellows that multiple myeloma really is because there's multiple myelomas out there that people have different types of disease. And so there's some patients in that green where we are just seeing that M protein go up a little bit, and it can go up and down over time. And it's not doing anything. It's sort of like an M-GUS again, we just monitor it, right until it gets to a certain level. And then I'll say, okay, maybe we need to start treatment. So my standard disease patients who have been doing really well for a long time, I just sort of watch. And then when we get to a level, we say, okay, let's look for clinical trials that might be appropriate, or let's do this next therapy before you have, you know, active disease in your symptom in your organs. Then there's high risk patients. So my high risk patients, I take those changes a little bit more seriously. You know, if it gets that M protein gets to point five, or where, you know, starting to someone has, you know, some pain, I quickly do MRIs, because high risk patients usually relapse faster, and I want to catch it much faster. And then the red is really, again, where we don't want to get, but sometimes patients have symptomatic or extra medullary disease, especially our high risk patients. So those are my patients I wish I could have treated, you know, weeks ago or months ago. And it tells us how much time we have for clinical trials. So for anything that's out there, that's really exciting, more green or yellow urine, that is much easier for us to get to, you know, those newer therapies faster. And then coming back to Dr. Chari's point, he probably recognizes some of these slides, because there is. He's so great. Why reinvent the wheel, right? So really, it's your risk and benefit. So patient related, you know, so if someone already has neuropathy, that's really bad from diabetes, I don't want to add to that. So I might change their therapy based on that. And then looking at disease related. So what is the rate of growth of that myeloma? Do I need to do something aggressive? Or hey, it's just slowly waking up that I can kind of, you know, give something that's going to knock it right back down without causing major issues. And then treatment related is so important. So coming back to it again, I wish I could take a myeloma, test it and know exactly which treatments to give when, but I can't, I don't have that. So what I do have is how patients actually reacted and how they responded to prior treatment. So if in first line, you know, we saw that this patient just did really well with this drug, then I know that in the future, a drug in that same category is probably going to work a lot better for that patient. Now, some patients, everything works. So we have all these options. But for some folks, certain different types of drugs work better. So that that piece is really, really important as well. Okay, so coming to the clonal heterogeneity. So that, you know, the diagram on the left is sort of in the bone marrow. We, you know, initially those green cells are all normal B cells, the normal B cells and plasma cells we have that give us immunoglobulins that help us fight infections. And when patients get MGUS, all of a sudden there's one or two of those cells, those plasma cells that got some kind of change. You know, the fish studies that we look at the cytogenetics, which is, I call it the DNA of the cells, you know, it's like the hardware of the cells, something happened where they're becoming the same cell again, and they're making a protein that doesn't do anything. It's not helping us fight infections. And that's where we see an M protein, we call it MGUS, it's not causing problems. And then as patients turn into smoldering myeloma, so not everybody with MGUS gets myeloma, right. And so this is why we don't treat those patients. But about 1% chance per year for those patients to get smoldering disease. Smoldering means now we have more myeloma cells, you know, maybe 20, 30%. And they're still not causing problems. But we know those patients are at higher risk of eventually getting myeloma for many years. But as these steps go on, you get more and more of these myeloma clones, different plasma cells that are a little bit different from each other. And why that's so important is that, you know, when we're treating, so that was until myeloma, but each time we treat, as Dr. Chary said, you know, until I came along, basically that every time you treat that time period of when that myeloma stays in remission or response, it's hibernating, becomes shorter and shorter, because now we're getting more myeloma cells that are getting smarter and they're acting differently than each other. So one drug doesn't work. And why we talk about combination therapy is for this reason, so that we can kill all these different myeloma, you know, clones with different drugs that can actually hopefully knock all of them down. So there's not one thing that I can give that will kill all those different clones, especially as patients become more relapsed refractory until the immunotherapy came. So I'll talk about that in a second. So again, Dr. Chary's lovely chart here, repetition works. So really, you know, in terms of what do we use for first relapse or second relapse patients right now, what's approved are therapies that are combination like daratumumab, homilidomide, immunomodulatory agent, and dexamethasone, right? That's a triplet that's approved in second, third line of treatment, or daratumum or esotuximab with carfilzomib and dexamethasone. So lots of different combination therapies with some of those older drugs that we've had. And then the newer immunotherapy, these are the ones I call real immunotherapy. And basically the CAR-Ts, the idocaptagene, the siltocaptagene, and then of course, tachlistamab just got approved last week or a couple weeks ago in the US, the bispecific, those are approved in fifth line patients, right? So you have to have relapsed multiple times. If we can get clinical trials for earlier, I really try to get my patients on that. But really, until we have it approved earlier, that's for a later line therapy. So again, for most patients in second, third, and fourth line, I'm using all these other drugs and different combinations based on what they've, you know, what they actually did well with before, what kind of disease they have, how quickly do I need to get it down. So all those plus all the patient related, you know, comorbidities, etc. that we talked about. Okay, so then two ways that we're looking at relapsed, or just myeloma in general, so immunotherapy, instead of looking at the genetics of the cell to see what, you know, how do I treat this, it's these things called antigens. So all of our cells have these flags that tell us what that cell is in our different cells in our body, and it helps us figure out how to get something to that cell to kill it. So the antigens are really important that you pick something that's only on myeloma and not on your normal cells, because otherwise you'll get really bad toxicity. So initially, in lymphoma, in leukemia, they found something called CD 19. So they've had this for a long time, we tried it in myeloma, it doesn't work very well. So until we really figured out that BCMA or B cell maturation antigen, which is on myeloma cells, 95% of patients have this, and it's usually on all the myeloma cells. So even though we talked about those different clones, all the different clones will still have this target on there, this flag. So now we have all these options of putting a T cell, the CAR T cell, right, you have this receptor that you put in there, and it's night vision for those T cells, we grow them, then we give them back to you. So now they're like, you know, soldiers going in directly killing that myeloma based on that flag that they're finding. And then the other, you know, bispecifics, so I call those handcuffs or magnets on one end, they can actually pull the T cell and they have a flag for the T cell on there, CD3, and then they have the BCMA or some of the other targets we'll talk about. And then they put them together and they activate the T cell so that the T cell can actually kill within your own body. So we're not taking them out and making new CAR, the receptor in there, but still they'll take your own T cells and bring them together and kill. And then what was really, really exciting in the last couple of years is now we have new flags that we found on myeloma, which are lymphoma, leukemia colleagues don't necessarily have. So GPRC5D is another great target that's on myeloma cells. It is on some skin cells and other things, but nothing that's been known to be vital. So, you know, like your heart or anything like that. But it's another flag on myeloma that we can use to get these bispecifics. There's CAR-Ts that are in early studies now that are looking at really good responses. And then the FCRH5, another big target, again, most patients with myeloma have this on their cells. So, you know, these are all targets that are 90 to 100%. We see them on all myeloma patients. And so when I said earlier today that I'm really excited about combination therapy, this is really what excites me, that we talk about chemotherapy being combined together. And so what about immune therapy? So right now we don't do this, but really the future trials are going to hopefully look at the patients who don't, let's say, get that four or five years from their CAR-T right now. Can we combine these to kill all the different clones that myeloma has with different targets and different mechanisms of action? So bispecific and a CAR-T or other regular treatment like daratumumab and bispecific. So there's studies with daratumumab and tacustumab, for instance, looking at pure immunotherapy, but combining them to see if we can kill all those myeloma cells once and for all. Okay. And then to kind of, you know, I'm an immunotherapy person, so I talk about that all the time, but there's also lots of things that are going on in the targeted world. So coming back to multiple myeloma and the changes we see in those plasma cells. And again, no one has 100% of any of these in their myeloma, but most people have one or two of these. Some folks don't have any, but really these are all those different genes that can be changed in the myeloma that helped make it become myeloma or just tells us it's a little bit more aggressive. So there's different high-risk features. I'm not going to go into all of that, but what's really, really exciting is that for patients who have 11, 14, so chromosome 11 and chromosome 14 in the myeloma cell, something happened with them where they got translocated. This is not something people are born with. It's not, you know, a genetic abnormality that puts you at higher risk of myeloma. We don't have that, but in the myeloma cell, when it becomes myeloma, we can find this in about 15 to 20% of patients. And what it does is that there is at the bottom, I'm not going to go too much into it, but there's a protein inside the cells that it makes high, something called BCL2. BCL2 is something that tells your cells to keep growing, to keep expanding. Usually all our cells know when to die. When they've done their job, they shut off. BCL2 tells it, nope, just keep growing, keep growing, keep growing. And there's a drug called Venetoclax that we use in leukemia that actually blocks BCL2. So for those patients, the 15, 20% of patients that have this, Venetoclax has been this amazing drug that it's a targeted drug. And this is with Velcade, Bortezoma, but you can see the lighter purple line. Patients are doing, you know, this was 36.8 months that most patients stayed in remission versus the placebo arm, which is the darker purple line, which is 9.3 months. So this is one of our first sort of treatments that we have for specific changes, genetic changes for myeloma. And hopefully, you know, there's going to be more and more as we're learning that we can have targeted therapies too. So really combining, you know, immunotherapy and targeted therapy is a sort of, we're hoping to go in the future. And so with that, you know, I think a combination therapy. So in second and third, fourth relapse right now, really that combination therapy, because of those different clones, we want to knock it down. That's really the goal right now. And single agent really doesn't work. So I've had some patients getting just one or two drugs where they don't have a great response. And we don't want, we know that that doesn't work. We want the combination therapies. But once you have a great response, coming back to what Dr. Chari said, decreasing the doses so that we can make sure you don't have toxicity, right? That quality of life piece still has to be really, really with the other part of it. So, and what I'm really excited about is that these new antigens and these new targets we're finding are making us smarter so that we can target those myeloma cells better and hopefully decrease toxicity and really kill every last myeloma cell possible. And again, I think this afternoon, you'll talk a lot more about the supportive therapy, but infections, especially with our CAR-Ts and our bispecifics right now, most of my patients are getting infections that we didn't necessarily see before. So if you're getting fevers or anything's happening, talk to your doctor so we can look for those. That supportive therapy piece is so important for our patients to survive and have good quality of life too. These are great therapies, but they don't come out, they do have toxicity that we have to manage and make sure nothing bad happens. So with that, I would like to thank all our patients and caregivers. Again, without all of our brave people here, all my patients that take that chance to get a better life, I can't imagine having to make that decision, but because of that, you're helping so many other people and hopefully we can finally cure this for more and more patients.