(Guest Lecture): October 2023 - Where We've Been, Where We're Going

For those of you who don't know me, my name is Andrew Cowan and I'm the clinical director of multiple myeloma at Fred Hutch. And today what I'm going to be talking about, I'm going to be kind of setting the stage for our fabulous speakers that are coming after me, talking a little bit about where we are with current myeloma upfront therapy, talking about really some of the very fascinating history of CAR T cells and how we got to where we are. I'm going to let my colleagues Dr. Banerjee and Dr. Cicero talk a little more in detail about those therapies, but I'm going to kind of bring you all up to speed on how we got there because that's actually a really fascinating history. But to start, I'm going to kind of talk a little bit about where we are today. And I know a lot of you, this is very familiar, but I think, you know, most of us, the faculty were just at the International Myeloma Society meeting in Athens and so that was a couple weeks ago. I can share with you kind of some recent updates from that. I think that there's some new thoughts about what constitutes high risk that I think are probably going to change some of our practice. For patients who are newly diagnosed nowadays, we would typically start, I think most of us are kind of routinely utilizing the four drug combination. So that's the RVD-DARA or DARA-RVD or sometimes maybe DARA-KRD. And so, you know, for anyone who was treated maybe, you know, five or ten years ago, that's a shift, right? Because I think, you know, ten years ago, you know, we were still using Cyborg-D and then five years ago was RVD and now we have a four drug combination. And I'll explain some of the data for why that's become more routine. Three drug combinations are still used. I guess, you know, if we're going to be consistent, I struggle to see where I would use that in a patient who is transplant eligible. But certainly they're still used and they work and, you know, it wouldn't necessarily be wrong to use one, but I think that, you know, the data for the four drugs are just so compelling. And then stem cell transplant, even with these really, really effective therapies, is still a very important part of treatment. And for someone who's eligible, which is typically based not on just on age, but on sort of overall assessment of fitness and functional level, we do recommend that. And then for maintenance, lenalidomide has yet to be toppled off the throne for sort of, you know, most patients with multiple myeloma. Although there are some really promising drugs, the cell mods, ibertamide and mizigtamide, and ibertamide in particular may have a much better tolerability profile. And so, you know, my hope would be, and I'm sure we'll see studies of this in the future, that we can investigate some of these other cell mods as potentially alternative approaches for maintenance for standard risk patients. But lenalidomide is still kind of the standard. And for high risk, typically, I think most of us who treat multiple myeloma across the country tend to prefer the two drug combinations for a prolonged period of time. Typically a proteasome inhibitor like Velcade or maybe carfilzomib, plus an immunotoric agent, or a CD30 agent in imid. And I think, you know, there's data that can support each. For patients who either don't want to do a transplant or are not transplant eligible, the DERA-RD combination is very powerful. That's a very effective combination. In my opinion, you know, for me, that's kind of what I generally give for the non-transplant eligible patients, mainly because there's no neuropathy. And neuropathy, as many of you know, is so impactful. I don't need to tell this crowd that. It can be so tough, even if it's grade one or two. We, you know, in oncology, we grade neuropathy and we'll say, oh, it's just a grade two. That can be really tough. I mean, that could be, you can't get up some stairs because you can't flex your foot. I mean, these are really, neuropathy is a big deal. And in my opinion, if we can avoid neuropathy, that's a win. So DERA-RD is a very powerful combination, but, you know, so is RVD. And there's actually going to be a study that compares the two run by one of our national cooperative group trials. So it'll be really interesting to see how, you know, what the results of that are. And that study is open now, I think, at some places across the country. And then supportive care is a very critical part of myeloma treatment. And it begins from the time of diagnosis throughout. And that's not the focus of what I'm talking about today. You'll hear about that from some of the other speakers. So what is what are the data for the four drug combination? I'm going to review this briefly. I know many of you are familiar with this, but just, you know, just so we're all on the same page, it was the Griffin trial of which we were a site at an at. At Fred Hutch, my colleague, Dr. Silverman, was also one of the PIs at OHSU. And so this was a randomized phase two study. Most of our studies that are randomized are phase three. But this was a phase two. Don't let that detract from the findings. So that study compared the DERA RVD combo to the standard RVD, which we used to use for many years, combined with transplant, consolidation and maintenance. And just the biggest difference here is the maintenance that patients received who got DERA. They got two years of DERA tumor map maintenance plus lentilidomide and then continued lentilidomide after that. One question that commonly comes up is what's the deal with consolidation? I mean, that's not something we normally do. And this is something that, you know, is a pet peeve of mine that seems to persist as sort of a study designed for clinical trials in multibiloma. Just know that consolidation is not something we generally do. We typically would kind of try to get the maximal benefit with the treatment before transplant rather than giving more therapy afterwards. Although sometimes we do. It's just not that common. So basically this study compared the RVD to the DERA RVD. All the patients got a transplant and then DERA maintenance or R maintenance. The primary endpoint, which is how the folks who design these studies decide what is important about a study was the rate of stringent CR at the end of consolidation. And what stringent CR means is no evidence of monoclonal protein in the blood or the urine, normal free light chains and a bone marrow biopsy that's negative by flow or by inside true hybridization. And so this study met that endpoint. They showed that there was a dramatic reduction improvement, sorry, in the rate of stringent CR in the patients who got the DERA RVD combination. And the overall the response rates were very high. You can see that 99 percent of patients responded. So we are now in an era with modern induction therapies where we're seeing almost 100 percent of patients respond, which is just incredible. The other take home point of this and these were data that were presented by my colleague and friend Dr. Soporov from Utah at the IMS meeting last year. The other take home point is MRD negativity rates deepened over time in the DERA RVD group. And you can see this shown nicely here. The percentage of patients who achieve MRD negativity and the test that we often use to test for this is a PCR test. Typically Clonoseq is the assay that we use. And there is a dramatic difference, as you can see here, in the percentage of patients who achieve that MRD negativity, which is all of you know is associated with the associated with better long term outcomes. And you know, MRD negativity is often you know what we talk about when we talk about a goal for treatment. And so I think you know it doesn't you know a picture tells a thousand words here and you can tell that that this is just a DERA RVD transplant. DERA maintenance is a very effective powerful combination for achieving deep responses. The time to MRD negativity was also improved and it looks like you know patients who you know who are achieving MRD negativity, most of them are going to get there by nine to 12 months. And you can see that we just get much higher percentage of patients getting to the MRD negative state with the DERA RVD treatment. And you can see that in the top dotted line. The other thing that we look at in oncology is what we call progression free survival. You know I'm not going to get into the weeds on this but just you can kind of think of this as like how effective a treatment is at keeping someone in remission. Remission remember we know that remission doesn't mean it's gone away and it's never going to come back. But we know what remission means in myeloma is that there's no evidence of disease in the blood and things are not progressing clinically. And so the DERA RVD improved that at four years the PFS rate for the DERA RVD combination was 87 percent which is really remarkable. The other study that you know really I think is important in the modern era and this is the determination study that you know many of you are familiar with here. This was the study that was performed in the U.S. that compared RVD followed by lenalidomide maintenance to RVD transplant and Len maintenance. And so the question here remember the question with the Griffin study was is DERA RVD better than RVD when we use a transplant. The question here was is RVD alone equivalent or not as good as RVD plus transplant because even five or ten years ago folks were asking well gosh RVD is so great maybe we don't need to do transplants. And so that's kind of where what what the impetus for the study was. And you can see here that you know even even with the RVD regimen which isn't quite as good as DERA RVD we're still seeing a pretty significant benefit in terms of how long folks stay in the hospital. We're still seeing a pretty significant benefit in terms of how long folks stay in remission when they get a stem cell transplant. And so it's trans. This is the data these were published last year. My my the former clinical director of our program Dr. Libby was very involved with this. Many of you know Dr. Libby and he was one of the co-authors on this paper. So we contributed quite a bit to this study. The other thing that I want to mention and this is you know a shout out to Dr. Silverman wherever she is one of the later speakers is you know looking at quality of life in patients receiving these regimens. You know I think one thing that commonly comes up when we talk about adding drugs or adding therapies is how is this going to impact my patient's quality of life or from a patient standpoint how is this going to make me feel better because really you know we don't just care about living longer we want to feel better. We want to have better quality of life. And I am really pleased that this was part of this study because these types of assessments are so important to understand how our therapies affect patients. And so they included these P.R.O. assessments which are basically questionnaires that assess how people are feeling their functional status on several different domains. And I'm not going to get into this because I don't think we have quite enough time but just know that these are questionnaires that assess how people are doing in terms of quality of life. And what they showed for on the Griffin study was that both DERA-RVD and RVD resulted in reduction in pain symptoms which is I think you know anecdotally which is you know what we observe when we start treatment is that we see improvement in disease related symptoms. Fatigue symptoms were also better and in particular they noted that patients who got the DERA-RVD regimen had a greater reduction in fatigue symptoms at maintenance month 24 which is really important you know especially when we're concerned about treatments adding fatigue. It actually seems like the DERA tumor map arm patients had less fatigue over time. So that that's a counter argument to saying you know adding more treatment makes things worse in terms of fatigue. It's actually not what the data show. So switching gears a little bit I'm going to talk a little bit about high risk multimiloma. I know this is a common topic you know at least in my conversations with patients you know what's high risk. What do we do about high risk. How do we manage it differently. And you know I think this is something that is an evolving field. Certainly there was a lot of chatter discussion about this at IMS and you know some potential new ways of thinking about high risk were presented. So I'm going to go over you know what what we consider to be high risk. You know in particular I would say the presence of two or more high risk features. And you know for those you know who are familiar with this remember the high risk we defined by the FISH changes the chromosomal changes in the myeloma cells themselves and the ones that I'm sure many of you are familiar with for high risk would be the deletion 17P the chromosome translocations between chromosomes 1416, 414 or 1420 and the 1Q gain or amplification or duplication depending on which nomenclature you prefer. And so if you have two or more of those features that consistently seems and I'll show you some of this data to be associated with the highest risk of having more aggressive type of myeloma. If you see more aggressive it just means myeloma that has that is more likely to come back. But a caveat to all this is that these I would I would take these high risk markers as almost you know like a horoscope in the paper. They're certainly not perfect. You know and you know the question comes up a lot. You know Doc I you know I was high risk when I got diagnosed that was 10 years ago. I've been on maintenance for 10 years. Am I still high risk? And you know I think yes we would have said you were high risk when you got diagnosed 10 years ago but now it's been 10 years and you're still on maintenance and that doesn't that's not behaving like high risk. What does high risk behave like? This is what high risk behaves like. So this was an analysis from the Griffin study and the master study looking at patients who got frontline deratumab based quadruplets and they basically analyzed the impact of having either no high risk markers one high risk marker or two or more high risk markers. And you know don't you know I don't want to make too much of this here but you know this curve here remember this is the progression free survival. This is the percentage of patients surviving without progression. You can see here this curve right here looks dramatically different from these other two and that's the folks who had two or more high risk features. We see that not only in terms of survival but also the progression free survival and this has been duplicated in other analyses. So it seems really that nowadays you know one high risk feature is still something we would take seriously but it's the two high risk features that I think really are becoming more of a sort of defining feature of what we would consider to be high risk multimiloma. So how do we handle how do we manage high risk multimiloma better? There's a bunch of approaches that have been studied. I'm going to highlight two that I think are most interesting but I'll also make a comment and I think the comment is these approaches are really exciting. They're resulting in better outcomes for high risk patients. However they have a high burden of prolonged treatment you know prolonged as my colleague Dr. Banerjee would say time toxicity which is the amount of time that you have to spend in the infusion center or going to pick up prescriptions or dealing with revlimid you know toxicities which everybody is familiar with. And so that to me is where we really need to improve because I really feel like this is a lot to try to accomplish and it's I think it's challenging to try to adhere to these very complicated treatment regimens that almost seem like you know for those that are familiar with this acute lymphoblastic leukemia which is a you know a disease that's most common in in in younger adults has a very complicated multi-year treatment regimen that is very difficult to get through and that's what this is starting to look like to me. So enough commentary what are the studies. So this is the study this was a study from England. It was called the optimum Muc9 and basically you know if you were high risk patients on this study got DERA RVD followed by transplant followed by DERA RVD followed by DERA VR followed by DERA R. So this is this is a lot more involved than the sort of Griffin regimen and sorry that's DERA CRVD so they added Cytoxin and they compared it to sort of a group of patients from another study who were similar. So it's not really a randomized study. So this is how the treatments were given and you know what they showed was you know pretty you know if you compare to sort of an analogous group of patients who got a lesser treatment regimen the patients on this optimum did much better. So you know it's certainly encouraging that we can sort of move the needle with high risk but again you know my criticism is this is this is a lot this is a lot of treatment. Same goes for the GMMG HD concept study. This was presented also at IMS the paper was just published in a large journal called the Journal of Clinical Oncology. So it's out there now and basically this was a study for patients with high risk multimiloma and it was those ones that I mentioned the 1Q GAIN DEL17P 1416 414 1420 plus revised ISS 2 or 3. Those patients were eligible for the study if they were newly diagnosed and they got which is another CD38 monoclonal antibody with KRD and you know this this this question of whether carfilzomib is better for high risk is something that's still I think you know debated amongst experts in the field but I'm not going to get into that but that's what they used in this study design. So patients got ISA KRD transplant ISA KRD and then ISA KR maintenance for 26 cycles. So this is a this is a high burden of treatment. They showed pretty impressive results though as one would expect based on the results of this other study. They got they got ninety sixty seven percent of patients in the transplant eligible arm achieving MRD negativity which is pretty incredible for a group of patients who traditionally haven't done that well. I'm going to skip over this stuff in the interest of time but I think you know suffice to say there's been a lot of work done in high risk multimiloma. There's a lot more work that will be done using CAR T cells earlier using by specific antibodies earlier. I think those are really exciting especially using CAR T cells. Maybe there's a potential for even in high risk having very few drugs for maintenance or maybe having no drugs for maintenance. Maybe that's a little bit too ambitious but I think we can get there. So the summary so far the quadruple therapy with CD38 and RVD improves PFS and plus MRD connectivity and also improves health related quality of life as assessed by PROs. The high risk multimiloma is still a challenge. I feel that the burden of treatment is an issue and that's something we need to work on but you know I think if we can move the needle for outcomes that's that's still a win. So shifting gears a little bit and I'm going to try to set the stage for my colleagues. What is a chimeric antigen receptor? So this we're kind of going to start talking a little bit about CAR T cells. So this is a this came from a publication by Brian Till and Olly Press. Olly Press used to run the lymphoma group at Fred Hutch. This is from 2009 and what they're talking about in this publication was the idea of combining and I'll explain this so don't worry a TCR complex with the specificity of an immunoglobulin to create what they called a CAR TCR. I think this is amazing. I mean they were studying this Dr. Press and others at Fred Hutch long before this became a commercialized therapy. So we have a long history of innovation in this area Fred Hutch. So why do this? Well what the TCR complex does. So what is a TCR? T cell receptor. This is found on the surface of T cells. This is the protein that lets a T cell kill another cell that's infected or has a virus or another cancer cell. The problem with a TCR complex as sort of a therapy is that it requires another protein to bind to it called the MHC complex and so it's more logistically challenging to design therapies utilizing a TCR complex. What they noted, what them and others noted, I just want to also be clear these Dr. Press and Dr. Till were not the first to notice this, was that an immunoglobulin which is an antibody right, these have a much greater ability to bind specifically to other markers on a cell surface without having another signal required. So they said what if we combine an immunoglobulin with a TCR complex to try to create T cells that can kill cancer cells. They called it a CAR-TCR which is pretty prescient I would say in terms of what came in the coming years. This work and others at other institutions like Memorial Sloan Kettering led to this explosion in the early 2010s of these therapies trying to develop these therapies called CAR-T cells and they were first studied in lymphoma as many as you know with the target of CD19 and they improved on the CAR, the protein on the T cells that lets the T cell recognize the cancer cell. They used to talk about first, second, third generation CARs and I think that's kind of a moot point now but just know that these iterations are what have led to us having effective CAR-T cells. CAR-T cells are synthetic molecules designed based on principles of T cell receptor, remember I talked about that and also signaling through the T cell to tell the T cell to attack the cancer cell. CAR-T cell manufacturing is a very involved process as some of you might know. Right now the biggest bottleneck for creation of CAR-T cells is really the leukophoresis. If we want to do a leukophoresis for a multiple myeloma patient getting carbic D or a BACMA we have to compete with every other product at our center so there's only a certain number of slots to do leukophoresis and so this is probably I guess at this point maybe our biggest limitation because leukophoresis and manufacturing is a very intensive process, requires a lot of resources. So basically what we do is we take the T cells, we select them out from a product, they get transduced with a lentiviral vector so we actually use a virus to inject the DNA into the T cells, it's really cool. This is basically genetic engineering and then we expand the T cells using proteins called cytokines and then we formulate a product and then we purify it, we have to make sure it passes all the quality control testing and then we get it ready to give to the patient. I know I'm almost out of time here but my colleague Dr. Banerjee is going to talk quite a bit about CAR-T cells and bispecifics and so I'll just set the stage by saying where are we now? We have approvals for CILTA cell and IDA cell, these are BCMA CAR-T cells in 2020 and we have been treating patients for almost two to three years now with commercial products and the current approval is only for folks who have already had the kind of Griffin-like therapy, the CD38, the IMID, the PI and more than four lines of therapy. Although I think probably in the next year we'll see that the FDA will, based on the CAR-Titude IV study, say that we can give CAR-T cells to folks who've had less lines of treatment. The manufacturing problems are improving but there's still other bottlenecks that sort of limit the availability to patients. With that, thank you for your attention and you can email me if you have questions so feel free to jot this down quickly and remember there will be time for questions at the end of the session so thanks.