iwHRMM 2024 | CAR therapies in high-risk myeloma: current data, their role in high-risk subgroups, & the potential of alloCARs

Ajai Chari:

Hello, welcome to the CAR-T high-risk discussion. My name is Ajai Chari, University of California San Francisco. 

Krina Patel:

Hi, and I’m Krina Patel at MD Anderson Cancer Center in Houston, Texas. 

Ajai Chari:

So we had some really exciting talks, including one by my co-chair, Dr Patel. The first segment though was given by Dr Mina, and it was about CAR-T in functional high-risk. Curious to get your thoughts on that discussion. 

Krina Patel:

Yeah. I mean, these are the patients I’m taking to CAR-T early, right? Right now, now that we have second line indication, it’s our patients that sometimes they have high-risk features like high-risk cytogenetics or, you know, R-ISS stage three when they’re diagnosed, but sometimes they don’t. And really this group of patients are the ones who relapse early after transplant. Now, the trials that we talked about, you know, KarMMa-2, CARTITUDE-2, they were, I think they defined it a little bit differently, but, you know, within one year of transplant or within 18 months of treatment relapsing after the first sign. And so again, the functional high-risk. And I think, you know, these are the patients that don’t make it to fourth, fifth line because they just blow through all therapy. And so I think both trials, even though there’s still not a cure and there’s, you know, there’s not a plateau, it’s still PFS and still getting that time off therapy so that they can get the next therapy, I think was still pretty impressive. And so, again, these are the patients that I’m actually treating in the real-world early line so that they can hopefully change their outcomes. 

Ajai Chari:

Yeah, totally agree. I think, well, cilta-cel’s label now is one prior line of therapy in len-refractory, so it allows us to use it earlier. So I think some other interesting points he made is that this functional high-risk probably counts for 15 to 20% of patients, including in the era of quadruplet therapy, right? So that’s kind of, I think, surprising to hear. And he’s hinted that maybe… how do you identify functional high-risk before it actually happens and maybe MRD could be used as a surrogate, right? That if somebody’s not attaining MRD negativity or sustaining it, that might be somebody that you would be worried about. 

But one thing I guess that we also raised is, in the bispecific discussion there was some preliminary data that teclistamab works better in less heavily treated patients. But do you think CAR-T works better in less heavily treated patients? 

Krina Patel:

So I know I think this is a controversial topic to some degree because I don’t think we have that much data and the data we do have does seem to be overlapping. But I also think that there’s just so many other things with CAR-T that really like when that patient’s going in and on a clinical trial versus when I can take someone in the real world is so different. The rules for clinical trials really limit access to our patients, and so I think some of these patients we just gave bridging therapy to and just hoped that they would get through. And a lot of the patients, especially on KarMMa-2 B, these patients were blowing through their, you know, and then we just got them to their cells. And so those are patients that don’t do as well, including toxicity. 

Thankfully, both of these studies didn’t show an increase in toxicity in that earlier line, just sort of like the bigger trials have, KarMMa-3 and CARTITUDE-4, but I do think that the high-risk patients actually do better when they go earlier. I think with standard risk, I don’t know yet, right? So this is where I don’t take everybody right at second line because we have other options. I still talk about it because there are some patients that five, six years later, they’re still not on treatment. So, you know, I think we’re still learning that piece, but hopefully with the other trials like CARTITUDE-5 and -6 and earlier line, longer follow-up, maybe we’ll see, and some of the real-world data, maybe we’ll see that there’s a group of patients that should all be going in second line. 

Ajai Chari:

I think the point of disease control is probably one of the most important messages from KarMMa-3 and CARTITUDE-4, the randomized study, because the limitation of those single-arm studies is that if patients are going in with worse disease, and that’s the reason their PFS was shortened, that’s obviously very expected, right? People who do better do better, people who do poorly do poorly. But I think the randomized studies told us that if your disease is not controlled, you have a higher risk of AEs, deaths, and you don’t even get to the actual CAR-T. So I think a really important message. 

The next exciting talk was given by yourself and the role of CAR-T in certain high-risk subgroups. Would you like to share your thoughts on that? 

Krina Patel:

I think it’s really important because in myeloma we have so many patients that are excluded from trials, right? And it’s usually our high-risk patients. And again, we understand it’s for safety, et cetera. And there’s such a small subpopulation, but when we add them all together, it ends up being a lot of patients that you don’t know how they’re going to do because they weren’t represented. So I talked a little bit about plasma cell leukemia, patients with primary or secondary plasma cell leukemia. We talked a little bit about patients with CNS disease from myeloma, which, now that we have all these therapies and our patients are living longer, we actually are seeing more CNS disease than we did a decade ago, right? So what do we do with that? And then also a little bit about patients with extramedullary disease, paraskeletal versus extramedullary. Again, these are all patients who tend to do poorly with a lot of our therapies. So doing something like CAR-T would be great. 

So again, not very much data, but we have some retrospective data from our U.S. Myeloma and Immunotherapy Consortium. And so I think with plasma cell leukemia and CNS disease, the biggest message is if you take patients after they’ve been treated for those things; so for CNS disease, radiation, IT, chemo potentially, and plasma cell leukemia, decreasing their actual plasma cell burden in their blood first before apheresis and actual cells, patients do really well. So I think just the function of CAR-T by taking T-cells out of the blood and putting a CAR into it, when patients have plasma cells in their blood, it’s a little bit harder. You can do it because we can do it in ALL and leukemia, but it does make it a little bit more difficult to actually manufacture the cells. Again, these are small numbers but we’ve seen it become a problem. And then it’s really making sure the toxicity again. So if someone had active CNS disease going in, we have seen patients with prolonged ICANS or neurotox. And so, again, you can do it, but you have to do it in the right sequence and make sure you’re treating patients for the CNS disease first. But then those are the patients that actually do really well with this. So we’ve seen patients that are, you know, a couple of years out already having this really aggressive disease, but still with myeloma controlled. And so, again, it’s just learning how to do it correctly. 

And then the EMD patients, I think, again, you know, we do have EMD patients on trials. And there’s been a couple of trials where patients actually did well, and one of them, anito-cel, which is a little bit different in terms of the way their CAR-T is. It’s not a normal scFv, but small number of patients, there’s only 13 patients that had EMD, but they actually did just as well, not just response, but even in their PFS, right, which is really important. And again, I think their Phase II study is going to be presented soon, so I’m excited to see that and then hopefully gets approved as well. And the question is, do these T-cells localize better to the EMD or, you know, what is the reason that maybe they’re doing just as well? But for patients who don’t do as well or don’t respond to the CAR-T, I think we talked about radiation, right? Really helping kill the myeloma, but increasing the immune system, especially the microenvironment within that disease, it’s usually different genotypically than the bone marrow involvement, and so just figuring out how to actually treat all these different myelomas, especially relapsed or refactory patients. 

I don’t know your thoughts on patients that have these aberrant types of myeloma. 

Ajai Chari:

I think you put it really well. I mean, I think particularly these subgroups are often not well represented in clinical trials. And the issue is that, even though our induction therapies are getting better, we’re going to be still struggling with these patients, right? And so I think the theme, which goes to the first segment again, was like for plasma cell leukemia and CNS myeloma, having had a history of it is okay if you can control it going into CAR. Right? And that was your message from this segment. 

And then the EMD, I think historically almost no studies have shown in randomized prospective trials that EMD does better particularly or it does as well as non-EMD. But I think the anito-cel data will need to see mature follow up with larger numbers. But definitely, I think this theme of controlling disease, doing the best you can at each line is important. 

So the third question, you know, I joked that we have two political parties, right? CAR-T’s and bispecifics, but there’s this third party, which is a little bit of a hybrid, allogeneic CARs. What are your thoughts on the role of this third party? 

Krina Patel:

Yeah, I think the potential is amazing, right? And I’m all about off-the-shelf. Again, I think we have ways to make autoCARs hopefully shorter, and that’s great. But if you just have them already in your freezer and a patient needs to go, we talk about the dropout with autoCAR, that during that bridging time, some patients we just can’t control their disease. And so I think that could solve all those problems. And I think potentially these T-cells have never seen myeloma, they’re from normal donors, you can pick certain T-cells that you want that you can’t do with patients who have already had treatment or even had MGUS, as we talked about, that T-cells change, your immune system changes. And so I think, again, the potential is there. I think there’s great science being done to try to decrease the host-versus-graft, where you actually take out the T-cells and the NK-cells, we talked a little bit about NK-cells as well, but I think right now we’re doing high dose lymphodepletion to do that which is really hard for our patients, so I think again finding ways to do that without that high dose lymphodepletion and finding ways that these T-cells can stick around and kill the myeloma the way our auto CAR-Ts do it really is the key point. And again there’s different ways we can do that but I think we just need more data from the the trials that are ongoing. 

Ajai Chari:

Yeah I agree. I think the bispecifics are typically giving off-the-shelf PFS of about a year. CARs, autoCARs, cilta-cel, probably the best PFS we’ve seen. If you can get to that, the PFS is three years. So the question is, where would alloCARs need to be in that space? You want the off-the-shelf of bispecific, but you want the treatment-free interval from an autoCAR. I think, as you alluded to, he showed data that if you try to give an alloCAR without more aggressive lymphodepletion, you don’t get expansion of the CAR because of the host-versus-graft effect. And the concern is strategies have been very high dose conditioning or including anti-CD52, which we know these patients with BCMA, advanced myeloma, are already struggling with infection, now you go in and wipe out every last lymphocyte that they have, and they’re really going to be having a lot of infectious complications. And that was seen already in preliminary data. So I think the key will be how do you get alloCARs delivered safely, have expansion, but have a PFS that’s somewhere between those two products of bispecifics and CARs. So we’ll stay tuned for the third-party system. 

Krina Patel:

For sure. And I think, again, off-the-shelf or one and done is the advantage compared to bispecifics. And we see infections with bispecifics and we’re having to treat people with IVIg and prophylaxis, which, we can do that. But I think, an allo, especially if it does work well and you can then just, you know, give IVIg for the first six months and then their immune system actually is better, patients actually do better, you know, in terms of quality of life, as well as their efficacy. So I agree, I think it’s worthwhile looking at and doing. But I think we still have a little ways to go before we have our first alloCAR product. 

Ajai Chari:

Great. Well, thank you to my co-chair, Dr Patel. I really hope you found this interesting.