A New Wave of Progress in The Treatment of Multiple Myeloma: Translating Evidence to Clinical Practice - Episode 17
Key opinion leaders consider the potential for CAR T-cell therapy in earlier lines of therapy for patients with multiple myeloma.
Ajai Chari, MD: As a follow-up question, I guess we’ll go to Rafael first. How early do you want to use CAR [chimeric antigen receptor] T-cell therapy?
Rafael Fonseca, MD: As early as possible…. I think we need to be positive about this because we’re learning about the toxicities. We’re learning about the long-term outcomes with CAR T. But if those results apply, then as we were saying at the beginning, it makes sense to use them up front. Where are we with that? Well, we saw the CARTITUDE-2 clinical trial, which was presented at ASH [American Society of Hematology annual meeting], but it was also updated here, which the response rate is exactly the same as CARTITUDE-1, 95% or 97%.
Ajai Chari, MD: It’s hard to be better than that.
Rafael Fonseca, MD: How can you improve on that? Now, it should be said that when you have clinical trials that have patients with 1 to 3 prior relapses, you might have more aggressive biology than the patient who is already in the sixth and seventh relapse, because just by the definition you have somehow shown that you can get to that line of therapy. I don’t necessarily think of it differently. It’s just very active. The results are really showing the CR [complete response], so we can talk more about this. But I think this is for the early relapse, 1 to 3 prior lines of therapy like INSPIRE and all those trials. We obviously want to push further, and maybe we’ll talk about that with MRD [minimal residual disease]-positive patients. And why not, even in the future frontline therapy, we saw some data presented here. But I think the data presented were really exciting. Again, a follow-up to what we saw at the ASH meeting. That has the real potential of displacing what would be the treatment for the first relapse over the next 5 years. We’ll have to see how that plays out, and what are we going to do with the other drugs? If they work even better post-CAR T cells, then the summation of all of that might even be better. We’ll have to see how that plays out.
Ajai Chari, MD: There’s the theoretical concern that when we’re using exhausted, beat-up patients’ T cells, and moving them up front, could there be a risk? So far, CARTITUDE-2 reassures us by saying up front for the early part of it, we’re not seeing much. I’m curious if anybody’s concerned about more delayed issues in terms of up front with the follow-up we have.
Krina Patel MD: I think the toxicity piece will be about the infections and what are we doing in terms of risk-benefit. The more patients who end up getting a deeper response, if you get a 100% CR rate, we’re done, and it wins. But I think there are certain toxicities, like the neurotoxicity, things like that, if we really can make sure they’re OK, then I think this replaces that.
Ajai Chari, MD: What about secondary malignancies, which is brought up?
Krina Patel MD: We do see secondary malignancies in these really relapsed/refractory patients, even with fludarabine, Cytoxan [cyclophosphamide]; it’s a lot lower dose than high-dose melphalan. Again, some of these trials are going to use Len [lenvatinib] maintenance. And so, this question does lenalidomide add to that secondary malignancy? Definitely, these are things that we need to look at. As of right now, I don’t think so. I think it’ll be less, just based on the dose of the alkylating agent, and this really is the cell doing it, but again, we need data.
Ajai Chari, MD: I think it’s easy to get accelerated approval because it’s such a dire need, but the ability to move it to the front, we really need typically randomized studies to put it in context.
Cristina Gasparetto, MD: There was an interesting presentation from Moffitt [Cancer Center], on real-life CAR T cells. They showed that if you had received BCMA [B-cell maturation antigen] before, the patients were not doing very well, but they do well if they receive CAR T cells and then you put them on a bispecific.
Krina Patel MD: We’re going to present that for ASH because we’re getting more data. The response rate for the real world was 86%, which was phenomenal to see, and these are 77% of patients who wouldn’t have gone on the KarMMa trial. The PFS [progression-free survival] was a little lower, around 8.9 months, even though the average number of cells was 415 million. We did have a lot of patients with extramedullary disease and a lot of disease going in. However, if you had a prior BCMA, which is about 35 patients, and now we have about 45, that was the one multivariate where your response rate was still around 76% but your PFS was lower, around 5.8 months. But again, coming back to Rafael’s point, there were patients mostly who had ADCs [antibody-drug conjugates], but also bispecifics, and a few who got CAR T before, and the PFS was different. We haven’t reported it yet. Our paper is about to come out, but there was a difference. However, we need to look at timing. We need to look at how long they were on those drugs and what kind of response they had before. I think some of those numbers are small. We can skew it, but I agree with you that we have to look at it a bit more.
Cristina Gasparetto, MD: That was just a signal, something to think about. Because we have seen bispecifics after other BCMAs including the CAR T cells, with some activity. I was perplexed.
Krina Patel MD: It’s definitely something we need to learn more about as we have more patients in the real world, very different than our trials.
Cristina Gasparetto, MD: Particularly if we use it earlier and then we exhaust other possibilities for later.
Ajai Chari, MD: Speaking of earlier, are you willing to go to the newly diagnosed?
Krina Patel MD: Yes. There are trials that are already happening, right?
Ajai Chari, MD: You guys want everything; everything for everyone.
Krina Patel MD: Of course. High-risk, especially, right? As Cristina alluded to, our high-risk patients and what Rafael said, we can’t even get them to the fourth or fifth line. They’re already relapsing ahead of that. In some of the earlier trials like CARTITUDE-2 and others, we see some of those high-risk patients getting great responses. We need more long-term data. But if we say that CAR T changes outcomes in terms of your response after, changes your immune system, changes your clones, whatever it is, you could make huge differences for those high-risk patients.
Ajai Chari, MD: It’s also worth adding that with these less heavily treated patients, your bridging chemotherapy can be more effective so that the toxicity could also be improved.
Krina Patel MD: Exactly, to get to the CAR T and not fall apart during bridging.
Omar Nadeem, MD: One thing to note for that, which we don’t fully know yet, is in a minimal residual disease state, are you going to get the same durability of these CAR T cells in the response? We think that the expansion would be the same. You’re seeing some good encouraging results in earlier lines, but we don’t know that.
Krina Patel MD: We don’t have it published yet. Yes, definitely.
Omar Nadeem, MD: Yes. I think that’s something….
Krina Patel MD: Hopefully, that will be published soon. I would like for people to publish that, but I agree. That’s a huge question because if you can get an expansion, that’s the perfect time to go, right? Just like when we talk about transplant or allo [allogeneic] transplant, why do we wait till it’s low?
Rafael Fonseca, MD: Someone could make the argument that bispecifics are potentially very good there.
Transcript edited for clarity.