In a forward-looking discussion on the future of CAR T-cell therapy, Lisa Hatfield, who brings the perspective of living with multiple myeloma, speaks with Dr. Krina K. Patel of The University of Texas MD Anderson Cancer Center about the innovations shaping the durability of CAR T responses in myeloma.
Dr. Patel explores why earlier use of CAR T and optimized bridging therapy can improve outcomes, highlights emerging dual-target and combination CAR T strategies, and explains how advances in immune health, antigen targeting, and minimal residual disease (MRD) detection may lead to longer-lasting remissions. She also discusses retreatment strategies, including second CAR T therapies, and shares an [ACT]IVATION tip to help patients better understand durability, relapse risk, and evolving treatment options.
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Transcript
Lisa Hatfield:
Dr. Patel, while CAR T has been transformative for many patients with multiple myeloma, durability remains a key question, particularly around relapse, antigen loss, and T-cell exhaustion.
This is also where much of the current innovation is focused, so from your perspective. What advances are you most encouraged by when it comes to improving the durability of CAR T responses in myeloma, and what should patients be paying attention to as this field continues to change?
Dr. Krina K. Patel:
Yeah, so I will tell you what looks to be the easiest way to improve efficacy and durability of efficacy is going earlier, and getting better bridging. So, those two things already, from late line to early line, have really changed the way we give CAR T, even on trials versus standard of care. You know, in clinical trials, you have to, you can only give certain types of bridging, you have to give it a certain amount of time, certain washout times. In some trials, you have to still have active IMWG amount of disease before you can get your cells.
Versus in the real world, I can give it whenever I want to, right? I don’t have to worry about an M protein being a certain level, so it makes it a little easier now. It used to be hard to give something standard of care, and now, in early line, it’s so much easier to give CAR Ts. I think the, you know, the biggest trials that I think will change efficacy, even from just going early and getting better bridging is going to be the combination study, so there’s CAR Ts that go after both CD19 and BCMA, there are studies that go after GPRC5D and BCMA, so I think some of those combination studies look really good. There’s another trial with GPRC5D CAR Ts with a CELMoD combination, or a bispecific BCMA combination. So again, different mechanism plus different targets. I think those are some of the bigger ones that, for those patients who, you know, don’t respond to the initial CAR T by itself, we’ll have to figure out who those are. So, coming back to one of your questions earlier on CARTITUDE-1, you know, the biology between the patients who did really well for 5 years or didn’t do well for 5 years wasn’t actually very different. So in terms of EMD or high risk, it really was, they had less tumor burden, so again, that bridging that worked better, and their T cells were better. In the translational data, they looked at, their T cells just looked healthier in different markers they look at.
And so, again, going earlier, you’re going to get better bridging, and you’re going to have better T cells, but there are probably some patients that have optimal T cells, and others that maybe don’t. And so that’s the next part of us learning, is how do we improve the immune system so that when we even make the CAR Ts, that we get that longer response. In terms of antigen loss, like, losing the BCMA or the GPRC5D, or whatever target we’re going after, thankfully, in CAR T, we don’t see it as much, and we definitely don’t see it as much as lymphoma sees it with their targets. Maybe 5 percent of patients really just lose BCMA altogether.
Some people, you know, you will see a dim in BCMA, and then 6 months, you know, later, you might see an increase if there are still myeloma cells around. But really, the name of the game is kill every myeloma cell you can, in terms of that MRD, in terms of imaging.
And our patients that get in that CR MRD undetectable, those are our patients that do really, really well for a long time, and that T-cell exhaustion, because it’s a one and done, and you can get years before you need treatment again, most people, their T cells do really well over time. They actually come back to normal, and then, again, you don’t really see a loss of that antigen.
So this is a little bit different than bispecifics, where, you know, we do talk a lot more about antigen loss or mutations of antigens like BCMA. Because when you’re getting continuous therapy, your myeloma’s going to, you know, keep getting hit, and it’s going to learn how to mutate. And then same thing with the T-cell exhaustion. If you’re getting continuous therapy, even if it’s once a month, we’re using those T cells, right? And so they’re constantly being kind of engaged again, so CAR T is a little bit different in terms of the resistant mechanisms compared to bispecifics for that reason.
Lisa Hatfield:
So if a patient has had a CAR T therapy and maybe gone 4 years, their T cells have come back, now they’re starting to show signs of relapse, can they have another CAR T, and would you go for a different target, or could you use the same one?
Dr. Krina K. Patel:
Yeah, no, great question, and we’ve done it all. So, small numbers, but we’ve had some patients that got CAR T initially with BCMA on a trial, and then when we got standard of care, they were able to get a CAR T as standard of care, and patients have done really well. With that, part of it is because they responded to the first CAR T so well, maybe. That’s why they responded to the second CAR T so well, but now we have the GPRC5D studies, CAR T studies, where patients can have had a prior BCMA CAR T, and a lot of our patients have, so they are all getting second CAR Ts.
I will say I think those patients of mine are doing better than the ones who got the bispecific and then tried to go to CAR T. Again, I don’t have data yet, just, you know, what I see so far, we’ll see what happens long-term with the big data sets. I think we’ve had one patient with three CAR Ts that they were getting on different trials. I will say the one thing that I worry about too many CAR Ts would be the lymphodepletion chemo. You know, they are alkylator therapies. The risk of secondary cancers, we have seen that with the CAR Ts, just like we do with transplant.
So, that’s the one thing I want to watch out for and say, you know, who are the patients that are at risk of secondary cancers versus who is not? And, you know, should we be limiting how many CAR Ts we do? I don’t think two CAR Ts make a difference, but again, after that, I think we just need more data.
Lisa Hatfield:
Okay, thank you. And do you have an [ACT]IVATION tip regarding durability of CAR Ts for patients? Maybe questions they can ask about that?
Dr. Krina K. Patel:
Yeah, I think different CAR Ts have different durability, and so really, you know, when you’re discussing options for CAR Ts, you have to put that in line with the toxicity profile.