CAR-T Bests Standard Options in Lenalidomide-Refractory Multiple Myeloma

According to results of CARTITUDE-4, a phase III study involving patients with lenalidomide (Revlimid)-refractory multiple myeloma in first relapse, a single infusion of ciltacabtagene autoleucel (cilta-cel; Carvykti) improved progression-free survival (PFS) compared with standard options in this setting.

Findings from the study on cilta-cel, a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, were presented at the recent American Society of Clinical Oncology (ASCO) annual meeting.

MedPage Today brought together three expert leaders in the field: moderator Sarah A. Holstein, MD, PhD, from the University of Nebraska Medical Center in Omaha, is joined by Brea C. Lipe, MD, of the University of Rochester Medical Center in New York, and Monique Hartley-Brown, MD, of the Dana-Farber Cancer Institute in Boston, for a virtual roundtable discussion. This second of four exclusive episodes focuses on the CARTITUDE-4 results.

Following is a transcript of their remarks:

Holstein: I think we might want to switch gears and talk about CAR T-cell therapy and some of the really exciting data that was presented at ASCO and simultaneously published in the New England Journal of Medicine looking at cilta-cel CAR-T therapy in earlier lines of therapy with the CARTITUDE-4 study. Dr. Lipe, could you provide us with an overview of that study?

Lipe: Yeah, so this was a highly anticipated study, CARTITUDE-4, and it randomized patients to either standard of care versus CAR T-cell therapy. And the standard-of-care arms were mandated to be either pomalidomide [Pomalyst], bortezomib [Velcade], [and] dexamethasone; or daratumumab [Darzalex], pomalidomide, and dexamethasone. So patients were randomized to either one of those standard-of-care options -- so that was dealer's choice -- versus CAR T-cell therapy.

So eligible patients -- this was a relatively large study, about 419 patients have been treated -- patients had had one to three prior lines of therapy that could include a PI [proteasome inhibitor] and an IMiD [immunomodulatory drug], but they must have been len [lenalidomide]-refractory.

So in this trial, 208 patients got cilta-cel, and then 211 were randomized to the standard of care. And again, the provider got to pick which one they went on, and most of the patients ended up going on DPd [daratumumab, pomalidomide, and dexamethasone]. That was 183 patients versus just 28 patients on the PVd [pomalidomide, bortezomib, and dexamethasone] arm.

In this trial there were no manufacturing fails. The baseline characteristics were relatively well balanced, and the median follow-up right now is 16 months. The primary endpoint was a reduced risk of progression or death with the cilta-cel and that was met. So it was a 74% reduction in the risk of progression or death. So we don't yet have median PFS or the longer-term data, but that's sort of what we're all waiting on. At least what we can say now is that the response rates were incredibly high and the depth of response was good for these patients.

Holstein: Thank you. So we'll have to wait to see what the FDA does with this data, but Dr. Hartley-Brown, when you saw this data, assuming that the FDA approves it, for let's say one prior line of therapy, would you automatically offer cilta-cel for everybody or what are your thoughts?

Hartley-Brown: Well, cilta-cel -- as we clearly know, it got approval [in 2021] -- it's doing a great job in terms of response rates in our patients beyond one line of therapy. So I'm excited about cilta-cel. However, I would say that we still have to remember that there are CRS [cytokine release syndrome] rates as high as in the 76% range. We also have to remember that there are cytopenias that we have to deal with -- and pretty severe cytopenias -- in pretty much all the patients. So these are toxicities that we have to be very much aware of, especially given the fact that some of these patients, especially patients who go on next-line cilta-cel, have already seen anti-CD38 monoclonal antibody therapy. So they're very much immunocompromised, both from the hypogammaglobulinemia level as well as from just suppression through other means, as well as their T-cell milieu being affected and exhausted with this type of a therapy.

So all of those things come into play when I think about patients. And as much as I would love to give it to all patients, I think we have to be realistic. We have a lot of therapies now, and it's not going to be a one size fits all. We're going to have to kind of pivot and adjust things and learn how to manage these types of medications in patients who may be more prone to some of the adverse effects of the therapy.

Another thing I would also mention is there is evidence of using some of these prophylactics, like tocilizumab [Actemra] and anti-IL-6 therapy, to try to mitigate some of the CRS, but we still have some patients who are at high risk for this, and that's going to be important when we start rolling this out in an earlier line of therapy.

Holstein: Thank you. And there was some interesting neurotoxicity that I haven't honestly seen before reported. I think there were 16 patients reported to have cranial nerve palsies, which is a bit unusual, and they also reported something called CAR-T-related peripheral neuropathies, which I haven't seen other studies report. Dr. Lipe, what was your takeaway about the [neurotoxicity] signal? Do you think we fully understand it at this point?

Lipe: We definitely don't. I mean, and I saw some of this when we've done some of these and the palsies are -- it's hard. And if we're treating patients who are further away, one of the challenges that we face is trying to get patients in and getting them treated, and then when they live far away, it can be difficult to access the neurologic care that you need and the follow-up. So I think that's one thing that we have to keep in mind as we're all trying to incorporate this for our patients who live near and far.

But I think that one of the things that has to be mentioned is that it's great that we might have data to move this into earlier-line therapies, but we still can't get it for the patients who are at the very end stage of their disease. So how we're going to move it up when we don't have the manufacturing capacity to treat the patients who are already eligible is something that I'd like to see addressed.

I think the other thing that hasn't been mentioned that is critically important is that when we use this drug in the refractory setting, we see high response rates and good durability for that setting. But a lot of times when patients are progressing after their CAR T-cell therapy, they're so hard to treat. And in this trial when we moved it earlier, I think we just have to wait and see how long the responses last. I think we're all hoping that it lasts much longer, but if that doesn't happen and these patients are as refractory and as their disease comes back as aggressively as we have seen with some of the later CAR T-cell therapies, I think we have to reevaluate what we're doing in this patient setting.

Holstein: I think that's a really interesting point. I've definitely seen what feels like more extramedullary relapses post CAR-T and the later lines of therapy. And it'd be really interesting to see whether that same pattern of relapse is occurring with these earlier lines of therapy. And I think the access to care is a significant issue. There's already published data out there showing access to bispecifics and CAR-T trials or approved agents is not equitable across different patient populations. And I really am concerned that this is only going to be accentuated when we move it into earlier lines of therapy. Dr. Hartley-Brown, do you have any comments on that issue?

Hartley-Brown: I agree with you both, and that's why I say we still have a lot to learn with these therapies. There is clearly a discrepancy when it comes to the availability of many of these therapies to marginalized populations and patients who live very far away from tertiary care centers.

So how do we reach those patients? How do we allow them access to these therapies? That's one thing. But also how do we allow for proper management of these therapies and mitigating the side effects of these therapies in those types of settings? Especially recognizing that literally the location that these patients may be able to access, may not have the institutional resources to provide optimal supportive care. And so that's definitely something I think strongly about when it comes to our patients and how best we can allow for equitable care across all of our patients.

Holstein: Thank you. Well again, I think we're all going to be waiting -- for either the end of this year, beginning of next year -- to hear what the FDA is going to do, both with respect to using ide-cel [idecabtagene vicleucel (Abecma)] in earlier lines of therapy from the KarMMa-3 trial, as well as cilta-cel from this CARTITUDE-4 study. And there are really significant differences in the patient populations between KarMMa-3 and CARTITUDE-4. And we could probably spend a half-hour just talking on that topic, but we don't have time today, but I think it is going to make our discussions of which product and which patient population to use even more difficult moving forward.

Click here to watch the other videos from this ASCO roundtable series on multiple myeloma.

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