(Guest Lecture): March 2024 - Exploring the Myeloma Toolbox

Thanks everyone for staying after lunch. The title of my talk is exploring the Myeloma Toolbox. I'm going to focus in the next half hour about talking about therapies that are not FDA approved multiple myeloma but are things that we are finding useful for the treatment of the disease. Some of these are more established and more well studied. Some of these are kind of more an early investigation but they are going to be therapies that are separate from the immunotherapies like the CAR T cells and by specifics that were discussed by my colleagues earlier. These are my disclosures. In terms of the agenda for this half hour, I'm going to talk about three different categories. One is targeting fish abnormalities. As Dr. Kumar talked about earlier, patients often have different fish abnormalities at diagnosis and sometimes this can help guide treatment. One area that has been looked at is in translocation 1114 disease, BCO2 inhibitors have been active in this area. I'll talk about some of the data behind that. Mention a slide on MMSET which is an area where patients with 414 potentially could benefit. Then I'll move to modulating the immune system with cell mods. The two particular ones, ibertamide and mezigdemide. Lastly, I'll talk about some of the antibody drug conjugates. This includes Bilanthamab, Maffodotin and Modacophus alpha. Talking about targeting fish abnormalities, about 20% of patients with multiple myeloma harbor this 1114 translocation. In a related disease, amyloidosis, this can be about 50% of patients with amyloidosis. What this translocation leads to is it leads to these cells being more dependent on a pathway called the BCO2 pathway. BCO2 is usually responsible for regulating cell growth and cell death. There's always a push and pull for these things. BCO2 particularly is a bad marker. It promotes cell growth. What it does is it binds to these two molecules, BIM and BACs, and prevents them from going to the cell mitochondria and causing cell death. Venetoclax binds to BCO2 and then allows the freeing up of these BIM and BACs molecules and is able to trigger apoptosis or cell death. In patients with this 1114 translocation, there's this regulation of this pathway. Targeting this is thought to be effective. Initial Phase I data did show that there is a 40% single agent response rate, which means that this agent does work in about 40% of patients at the beginning. We always need these bigger Phase III studies to confirm those results. There was a trial that was done called the Bellini trial several years ago that looked at testing Venetoclax in combination with other myeloma drugs and seeing if that led to better outcomes. This is a study that didn't select for that 1114 population yet. It was all comers with multiple myeloma, but it randomized patients to getting either Venetoclax, Bortezomib dexamethasone, or Placebo Bortezomib dexamethasone and looked at the primary endpoint, which Dr. Kumar talked about, progression-free survival or how long patients were able to have their disease under control or stayed alive for. These are a little small. The point of this talk today is mainly to give you some information generally and not delve too much into the details. Essentially, the study did find that the overall response rate was higher with Venetoclax compared to Placebo. If you look at the middle panel here, again, these curves are on the y-axis, progression-free survival. The percentage, if it's closer to 100% continuously, is better. If the line was more flat and up at the top, that would be better. The blue line, which is Venetoclax, looked better than Placebo overall. The downside of this trial was that the overall survival, the panel on the bottom here showed that the lines were switched, so more people were dying who got Venetoclax in combination with these other therapies. This prompted the investigators to look more in detail about why this was the case. We looked specifically at the 11-14 subset of patients, the patients that have that actual translocation. Some of the data is on the right panel here, and it shows that the separation of the curves is much bigger, which suggests that the Venetoclax is much better as well. This prompted the field to take a look at this more carefully. The FDA actually, at the time of this trial, put Venetoclax on a hold, but then later on when some of this data and some other data showed that in the 11-14 it may be beneficial, this reopened the field in myeloma, looking at Venetoclax for treatment of 11-14 translocated myeloma. This brings us to the Canova trial, which was a trial that was just presented last year at the International Myeloma Meeting. This was a trial that was geared specifically at that 11-14 translocated myeloma and randomized patients to getting Venetoclax and dexamethasone or pomalidomide and dexamethasone, which is an established regimen that's active in multiple myeloma. Again, they're looking at progression-free survival as the primary endpoint. What this trial showed was that although the curves showed that the line in green, which is the Venetoclax and dexamethasone, was superior than pomalidomide and dexamethasone, the median progression-free survival was 9.9 months versus 5.8 months. The statistical significance was not met. This is really important in our trials to meet statistical significance. That's what the FDA determines as whether or not a drug can get approved or not. The fact that it didn't meet that statistical significance despite having numerically a better progression-free survival meant that it hasn't been FDA approved in the treatment of this. The study investigators also did some additional analysis to figure out why. There's a lot of reasons why this could have been the case, but on a post-hoc analysis where they looked at patients in a different way, they were able to determine that there was a way of looking at it where the Venetoclax arm did look better if they accounted for people starting new therapies when they were on the pomalidomide. In fact, if you look at the response rates, it is higher in the Venetoclax dexamethasone arm than in the pomalidomide dexamethasone arm. The overall response rates were 62% versus 35%. The responses were deeper, more VGPRs, 39% versus 14%, and more MRD negativity. This suggests that this drug does work, but just because of the design of the therapy and maybe the effects are a little bit more modest, but regardless, I think we in practice have seen that it has worked as well. If you look at also time to next therapy or how long this treatment can go on for, it also favored the Venetoclax dexamethasone arm at 21 months versus 8.3 months. The toxicity profile, you don't have to read all of this, but it was fairly comparable between the two arms. There was actually higher rates of lowering of the blood counts of pomalidomide and dexamethasone, maybe a little bit more diarrhea with Venetoclax and dexamethasone, and the overall survival, which was concerning in the Bellini trial, was no longer seen. It actually favored the Venetoclax arm at 32 months versus 26 months. All of this data suggests that Venetoclax is active, but maybe as a single agent with dexamethasone, it's not quite active enough. There have been other studies looking at adding Venetoclax in combination with other well-known myeloma therapies like daratumumab and carfilzomib. In all of these studies, the addition of Venetoclax has led to greater overall response rates, 96% with the Daraven dexam and 92% with the Carfilzomib dexam, including higher rates of MRD negativity. These are agents of these regimens we do use in clinic often in patients with the 11-14 translocation, in the one or more lines of therapy. How about other Bcl2 inhibitors? There are several others that are under development, including sonrotoclax, which was presented at this last ASH. These are even more selective for Bcl2 and thought to lead to even better responses. A lot of these studies are still early in development to be seen in the next several years. I think in conclusion, I think these Bcl2 inhibitors have definitely shown clinical efficacy for patients with the 11-14 translocation. There is maybe a more modest activity with single agent Venetoclax. With a lot of our myeloma drugs, we don't often use just one or two drugs in the relapse setting. We often use three or sometimes even four. Combinations are where things are likely. Because of the negative results of the Canova trial, the FDA is not going to approve Venetoclax. The main problem that that gives is that insurance coverage for Venetoclax may be challenging. But some patients are able to still get it because there is a lot of data that suggests that it is efficacious. Personally, and I know some of my colleagues as well, would consider using Venetoclax as options, even after the first line of therapy, potentially in combination with other effective agents. Toxicities to monitor include lowering of the blood counts, infection, and GI upsets, including diarrhea, abdominal discomfort. But in general, most patients are able to tolerate Venetoclax fairly well. I'm just going to spend one slide talking about 4-14 multiple myeloma, which compromises about 15 to 20 percent of newly diagnosed cases. This is a fish abnormality that's thought to confer high-risk disease. What happens in the pathophysiology of this is that there is an enhancer region which is translocated from one area to another area, which means that the MMSET gene, which is normally responsible for cell growth, is put under a promoter that is more active. The more of these MMSET molecules are made, and it then leads to downstream effects that make the myeloma grow more. This is a selective agent that's thought to bind to these MMSET and inhibit its action. Potentially, it could be useful in these patients with 4-14 translocated multiple myeloma. We actually have this trial open at UCSF, so that's an available option for patients who need it. It's still early, so we don't have any information about efficacy, how it works yet. It's still kind of first in human right now. Now I'm going to move on to modulating the immune system via cell mods. Cell mods are cereblon E3 ligase modulators. What they do is that they lead to the destruction of these transcription factors called icaros and ielos. These are function in a similar manner as lenalidomide, irrevlamid, and pomalidomide and pomelist, but they're more potent than they are. These are some of the newer agents that we have and are under investigation. The two main ones that are being looked at the most are ibertamide and mezigdemide. In terms of potency for them, ibertamide and mezigdemide are much more potent at degrading icaros and ielos. Mezigdemide the most and ibertamide just under that as well. Some of the data for ibertamide has come out in the last two years. Initially, it was tested as a single agent. At the beginning, we like to make sure that it's safe and efficacious. Ibertamide was tested with dexamethasone. Overall, the response rates in these patients who have often three or more prior lines of therapy was about 26 to 32 percent. The duration of responses were around seven months or so. This particular compound, ibertamide, had an overall fairly good safety profile. There were some grade three toxicities, but mainly these were kind of lowering the blood counts, which we also see with lenalidomide and pomalidomide. There were minimal other non-hematologic side effects. At ASH in 2022, there was an update that basically showed that patients who had prior BCMA therapies like CAR-Ts and bispecifics, about 37 percent of patients were able to respond to this therapy. More recently, at ASH in 2023, the EMN 26, a European trial that looked at using this agent in maintenance after stem cell transplant, found that it was safe and improved responses in about 40 to 50 percent of patients that were getting maintenance therapy, suggesting that in the future it may be an option in the maintenance setting. So what are the next steps for ibertamide? The study I just kind of quoted was a phase one, two study, and often we need to test things in a phase three study. And so they're looking at using this drug in the upfront setting in a European study where it's being combined with isotuximab, bortezomib, and dexamethasone and comparing it to isarVD to see if that beats it out. And that you know, that trial is ongoing. As maintenance post-transplant, there are several trials looking at this as well. One of them, the Excalibur trial, is randomizing patients to get linalytomide or ibertamide after transplant. And then there's a kind of a French study that's kind of doing a similar approach. And then in the relapse setting, as single agents, you know, the efficacy was only about 20-35 percent. But in combination, you know, that's where these therapies are more active. And so there is an Excalibur trial that's looking at ibertamide in combination with other antimyloma therapies. And just a kind of shout out that we are also opening, you know, a trial that's combining ibertamide with telketamab in patients with two to three or more lines of therapy. The combination is thought to be potentially synergistic because, you know, these cell mods can kind of boost some parts of the immune system and also lower rates of potential T cell exhaustion. And so this is a trial that, you know, Dr. Martin had started up and we're hoping to open across the University of California consortium in the near future. So the next cell mod that I wanted to talk about is mesigdemide. So this is, you know, as I talked about earlier, an even more potent cell mod. And in the phase one study, it had an overall response rate of about 55 percent in combination with dexamethasone. And then, you know, the phase two was looking more specifically at a bigger population and found that the overall response rate was around 41 percent in about 100 patients that were treated. And how long this therapy seemed to work was about eight months. But again, these are still kind of early trials in the phase two setting. Of note, even though that this drug is more potent, it led to kind of higher rates of neutropenia or lowering of the white blood cell count. And so, you know, that's compared to ibertamide, which I talked about, just talked about. It seemed to lead to more lowering of the blood counts. And so it is being also tested in subsequent trials, mainly in the relapse population in combination with other myeloma therapies. In the successor one and successor two trials, which is combining mesigdemide with falcade or mesigdemide with carfilzomib. And then Dr. Kumar is opening a trial here sponsored by BMS of mesigdemide and elnuctimab. So again, combining the cell mod with a bi-specific antibody to try to potentiate the bi-specific antibody. So that should be opening in the near future as well here at UCSF. I'm going to skip this slide because I just talked about a lot of it. But I think so in conclusions, these therapies are not yet available, but hopefully they will be in the near future. Ibertamide is being investigated in potentially earlier settings, and it leads to maybe less cytopenias, and it doesn't seem to have a lot of significant other toxicities. One thing that's of interest is that, as many of you know, with stem cell transplant and lenalidomide maintenance, there is some concern for secondary malignancies or malignancies down the road. But there's some thoughts that these more selective immunomodulatory drugs may lead to less of this effect. And so that will be to be seen in future studies. And then mesigdemide is being used more in the later line therapies because it does have a more potent, more significant neutropenia risk. But it is a very active agent as well. So these agents are very exciting because not only can they be combined with other therapies that we had and potentially making it better, but they can also potentiate these immunotherapies, leading to more immunostimulatory effects and downregulating these suppressive Tregs, which is one of the things that these therapies do. And then also, as we talk about more and more immunotherapies, there's some concerns that giving immunotherapies back-to-back may exhaust some of the immune system cells. And this may give a break between some of the cellular therapies that we're using and these immunotherapies that we're using. So lastly, I'm going to talk about some antibody drug conjugates. So antibody drug conjugates are basically a drug that has an antibody that targets a certain marker on a cell surface. And the drug conjugate part, it's conjugated, meaning it's linked to usually some cytotoxic or a payload that is like a toxin or a poison or a chemotherapy. So Bilanthamamaphodotin, this was a drug that was talked about three years ago already. And it's a drug that has, on one end binds to BCMA and on the other hand, has a payload called MMAF, which is a chemotherapy agent. So what it does is it brings this into the cell and then it causes the myeloma cells to die from this chemotherapy. And it was available in the market in 2020, up until 2022. And this was initially based off of the DREAM2 study that was kind of a, it just looked at Bilanthamab, it didn't have a comparison arm, but it looked at patients with three or more kinds of therapies. And what it found was the overall response rates were around 30 to 35%. And because at that time we did not have BCMA CAR T cells, no bi-specifics, the FDA gave an accelerated approval for this drug at that time, based off of these results. With the idea with these accelerated approvals that there are larger therapies that look to confirm the results. One thing Dr. Wolf mentioned as well is that this drug was found to have a high degree of keratopathy or toxicity to the eye. And in about 70% of patients, this was seen. And some of these in about half of the patients was grade three or four in severity. And so this was definitely a toxicity that was being, you know, that we've seen in clinic when we used it and it is important. And so where does this drug kind of affect? It mainly affects the cornea. And so this is a kind of a depiction of the eyeball and it's on the kind of outer surface of it. And it's because of the payload itself is kind of toxic to this area. And because of these toxicities, there was actually a whole REMS program, which you may be familiar with because it's also used in lenalidomide. But this program where patients had to get an eye exam before every dose of of belantamab. So it was not the most convenient medication to give. However, you know, we definitely have patients who have had responses to it and patients can respond long to it as well. But why was it pulled off the market? This was because of the DREAM 3 study, which randomized this drug to pomalidomide and dexamethasone. And this was kind of reported out at the end of 2022. And it randomizes patients to these two therapies. And what it essentially found was that the progression free survival, although numerically again, it was better for the belantamab arm, it didn't meet statistical significance. So because of that, you know, the FDA wouldn't, you know, doesn't usually like to give approval for that setting, even though it had overall response. The median duration of response seemed longer. And there is no difference in overall survival, but it was pulled off the market in November of 2022. However, there are other ongoing DREAM studies that looked at this drug. And, you know, Dr. Chari had kind of hinted at one of them was the DREAM 7 study that was combining this belantamab drug with bortezomib and dexamethasone and comparing it against their bortezomib dexamethasone for the three labs refractory multiple myeloma. That this study was able to meet its primary endpoint, the progression free survival was longer at 36.6 months versus 13.4 months. And this was statistically significant. So this was, you know, very recent data presented in the last month or so. And what the study also found was that the overall response rates were higher, 82% versus 71%. And the median duration of response, how long it works for was higher as well, 35 months versus 18 months. However, you know, as we anticipate, there were high rates of ocular toxicities. Almost 80% of patients had some abnormalities in the eye with this compared to only 30% of treatment. So clearly, you know, based off this data, it seems maybe a more effective combination, but the toxicity profile is different and potentially maybe more. And as Dr. Chari also brought up, as we're using more BCMA-directed therapies like Bispecifics and CAR-T, how using this earlier, how it would affect those things down the road because you're targeting the same kind of BCM target. So that's something to be seen. So I think in conclusion for this drug, it's currently off the market, but you know, with the results of Dream7, it may be back on the market in the near future in combination with, you know, Bortezumib dexamethasone on the label. But in the era of these other BCMA-directed Bispecifics and CAR-T, the kind of utility of it may, you know, remains to be seen. Potentially, it could be an option for maybe patients who have relapsed after these Bispecifics or CAR-T's, BCMA-CAR-T's or Bispecifics who still have that marker because this doesn't depend on your innate, you know, your immune system as much because it's directed chemotherapy to those cells. So that may be a population. The dosing is also a little convenient. It can be given every three weeks to every six weeks, so that may work for some patients as well. So that's another area. And then lastly, this is the last drug molecule I'm going to talk about. It's moducofusp-alpha. So this is a first in class immunocytokine that's designed to deliver interferon-alpha, kind of a cytokine immune kind of molecule that triggers the immune system to be active. And it has one end that binds the CD38, so it brings this cytokine to the myeloma cells. And it's thought to activate these other immune cells that then kind of get rid of the multiple myeloma. And this study was done in patients who had three or more prior lines of therapy. They were allowed to have prior CD38 antibodies, so they could have had daratumumab or esatuximab. And what the study essentially showed was that even the response rates were around 43%, and even patients who were previously refractory to daratumumab or esatuximab with that CD38 antibody were able to respond to this at 39%. The follow-up is still quite short, you know, but it seemed like the patients who responded, the median duration was about 12 and a half months, so we'll have to kind of follow up on some of the future results from this study and future studies as well to know of its long-term benefits. But it is an exciting kind of other therapy to add into our toolbox potentially in the future. And then in terms of toxicities, it seems like the main ones were mainly, again, blood counts. There are always some concerns with these interferons, which kind of modulate the immune system, whether it would affect sometimes cognition, because interferon is an old drug that's been used in other conditions, and it has some kind of depressed mood and other things, but they didn't see that with this molecule, so that's favorable as well. And I think that's actually, my last slide is here, so I think, you know, these new therapies are continuing to expand our myeloma toolbox, and I think, you know, the immunotherapies that we have are all very exciting, but also we need some of these targeted therapies to give, you know, potentially the immune cells a break a little bit. And I think learning how to optimize combinations of these sequences, those are likely the ways to get a long-term success for the treatment of multiple myeloma. I want to thank all of you for staying and Health Tree for organizing everything, and the rest of my team at UCSF for all their care and for patients. Yeah.