乌鸦传媒

A , which was recently presented at the American Society of Clinical Oncology (ASCO) annual meeting, showed that ciltacabtagene autoleucel (cilta-cel; Carvykti) improved outcomes compared with standard of care among lenalidomide (Revlimid)-refractory patients with functional high-risk multiple myeloma.

乌鸦传媒 brought together three expert leaders in the field -- moderator Joseph Mikhael, MD, is joined by Amrita Krishnan, MD, and Tulio Rodriguez, MD, all of City of Hope in Duarte, California -- for a roundtable discussion. This third of four exclusive episodes focuses on the results of the subgroup analysis of CARTITUDE-4.

Click here to watch more videos from this roundtable series.

Following is a transcript of their remarks:

Mikhael: Let's move to yet another hot topic. As we think about this roundtable discussion of ASCO key abstracts, arguably one of the hottest areas of discussion right now is, what are we doing in early relapse? As of April 4 and April 5, we now have CAR T-cell therapy available as early as first relapse. Obviously in the last couple of months, not everybody at their first relapse goes straight to CAR T-cell therapy. And so there's been a lot of discussion around who should be best prioritized for that.

And, interestingly, we have an abstract looking here at the subgroup analysis of CARTITUDE-4 and, quickly, CARTITUDE-4 was that study that took patients with one to three prior lines of therapy and gave them cilta-cel, one of the two CAR-T's that we have, and compared it to what would've been typically standard therapy in one to three prior lines of therapy, triplets like DPd [daratumumab (Darzalex), pomalidomide (Pomalyst), and dexamethasone] and DVd [daratumumab, bortezomib (Velcade), and dexamethasone] and clearly demonstrated a dramatic benefit. Whereas those triplets provided about a year of progression-free survival, the cilta-cel provided over 2 years, and that's what led, obviously, to the approval.

But, here, a subgroup analysis is now presented in those functional high-risk patients. So, Tulio, maybe the first question to you is, right now, who are you tending to think about wanting to get to CAR T-cell therapy after one or two prior lines? I mean, knowing that there's logistical considerations that we can't get everybody, there aren't enough slots.

I think Dr. Krishnan once said it's like getting Taylor Swift tickets. It's expensive. You likely have to travel. The expectations are high once you get them. But getting those CAR-T slots can be challenging. But even if you had more slots or in a world where there was less limitation, who are you tending to want to move towards CAR-T earlier on in your practice?

Rodriguez: So, basically, those patients who failed stem cell therapy early or those who failed the immunomodulator, proteasome, and monoclonals, that they fail all groups of drugs that we have available today. But this trial breaks that notion that cellular therapy, in the broad definition of the term, did not have a role for early relapses. I don't know if you remember that second transplant used to be an option for these patients who were relapsing, except for those who were relapsing within 18 months because we were kind of getting, perhaps, median progression-free survival of 6 months or so.

Mikhael: Half of what you'd had the first time, so it didn't make sense to go up. So you give it in those who had a short PFS the first time.

Rodriguez: Right, even though you had stem cells in the freezer, you were not using them. This study though, with a median follow-up of 12 months, you still have no median progression-free survival achieved with CAR T-cells. And we're talking about patients with functional high risk defined by relapses within 18 months, either from stem cell transplant or standard therapy.

So, I think that it's a very provocative study. My way of thinking on eligibility for these CAR T-cells have changed because it seems like absolutely early during the course appears to be very beneficial. And with that in mind, it's hard then to start thinking on other therapies when you show the enormous difference between CAR T-cells and standard of care.

Mikhael: And I know you and I have discussed this before, Amrita, around the functional high risk, and that's who primarily at City of Hope we've been prioritizing towards getting an earlier CAR-T. Does this study reassure you that is the right thing to do? Do you plan to continue to do that on the basis of this?

Krishnan: Actually, it's funny, you said something in a meeting a few days ago, and it's the same thing I'm putting in my talk, which is that it's a calculus, right? So we're putting in multiple variables to come up with for each patient, and part of those variables is this idea of functional high risk. Having said that, you have to recognize our definitions of functional high risk are still inadequate. So, for example, early relapse, actually 22% of patients who early relapse have ISS [International Staging System] stage I disease or normal cytogenetics.

So we're not very good at predicting. We have disease biology, we have dynamic features, which is what CARTITUDE-4 did in terms of the cohorts, and also CARTITUDE-2, which looked at patients who got less than a CR [complete response] after the transplant. Both of them sort of picked this dynamic model.

I think if you're using T-cell therapies, we need to start incorporating other things -- T-cell fitness, also think about other disease features, extramedullary disease, for example, tumor microenvironment. So, I think, I never took multivariable calculus ... but that's what we need now. We need so many more variables put in there. And then the biggest variable we need to add is toxicity.

Mikhael: Absolutely.

Krishnan: We may think, yes, the side effect profile is acceptable, but acceptable in advanced disease is very different than what's acceptable in early relapse.

Mikhael: I want to spend a minute on that. I just think it's so important. We are myeloma doctors. We've been doing this for 20 years. We are just so excited to see the kind of depth and duration of response with CAR-T that we've never seen before. But as I speak to every single medical student, resident, fellow, junior faculty who works with me, my three-word mantra is "safety is paramount."

And I don't want to overstate it, but I clearly do not want to understate it, that there are some patients that really struggle. There's often the short-term toxicities that I think we're getting better at managing, but there is still a group of patients that experience a longer term, whether they be infection, whether it be cytopenias, or maybe most worrisome, some of the neurological toxicities that we're seeing, the Parkinsonian effects and so on.

I do hope that we continue to shrink that number. I think we've done that to a certain degree with enhancing our bridging therapy and not reinfusing T-cells into a patient who has very active disease, almost kind of like as a transplanter, you don't want to give the melphalan to someone whose disease is raging. We like to have it in control, but I think you're right. I don't think we fully captured all those variables that are going to help us determine that risk-benefit ratio.

Then, of course, the patient preference. I mean, I think we have to incorporate that. We have to have the discussion. It's not just saying, oh, you're functional high risk, thou shalt have a CAR-T. Right? We need to keep coming back to the same notion, and I know I'm very sensitive to this because I'm a fan of communication, but it's just so important for us in a shared decision-making model to have that communication with a patient because some of these toxicities are unpredictable. Maybe someday an AI model is going to figure it all out ... but I assume that both of you agree with me when it comes to just that importance of recognizing the huge potential benefit of CAR-T, but the absolute risk of toxicity.

Rodriguez: Absolutely. One of the problems with those models is, how do you integrate a mix of variables that some of them ... diagnosis and others, you have to wait until you get the response to therapy. Because when you talk about toxicity and you're talking about early relapses at 18 months, 12 months, you cannot do that on day one. So you have to come up with a model that you use 2 years later for someone that is then progressing. So it's very challenging. And how do we incorporate how much value one of these variables has?

Mikhael: It's a dynamic. I mean, we have the same challenge in smoldering myeloma, don't we? I mean, you can't just with one patient at one point say, you have these three variables, therefore you're going to progress quickly or not. Sometimes we need time to see, just like our colleagues in solid tumors, a PSA [prostate-specific antigen], one value of PSA may not tell you the whole story. You need a chart.

Rodriguez: It's a kinetic, right?

Mikhael: Yes, a kinetic movement. So I think the jury to some degree is still out, but I think I can conclude this part of our discussion by saying I think we are seeing that at least in a significant fraction of functionally high-risk patients, they can really benefit from a CAR T-cell therapy when compared to the triplets that we're typically giving them. But we still need to learn a lot more.

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