A New Wave of Progress in The Treatment of Multiple Myeloma: Translating Evidence to Clinical Practice - Episode 14
Shifting their focus to CAR T-cell therapies, expert hematologist-oncologists review data from the CARTITUDE-1 trial of cilta-cel and its subgroup analyses.
Ajai Chari, MD: We’ll move to the other exciting T-cell redirection modality. I know Dr Patel is champing at the bit. We’re going to talk about CAR [chimeric antigen receptor] T-cell, the updates on CAR T and other emerging therapies, and the treatment of myeloma. We have 2 commercially available CAR Ts now: ide-cel [idecabtagene vicleucel], and cilta-cel [ciltacabtagene autoleucel]. For cilta-cel [ciltacabtagene autoleucel], we got an update at ASCO [American Society of Clinical Oncology Annual Meeting] from Saad Usmani on CARTITUDE-1. Basically, cilta-cel [ciltacabtagene autoleucel] is a lentiviral vector with 2 llama binding domains. In a heavily treated patient, it has unprecedented results with a median PFS [progression-free survival] still not reached, a median OS [overall survival] still not reached with a follow-up of 21.4 months. Some people seem to be not impressed—that comes across as blasé. That’s amazing, right?
Krina Patel, MD: It’s amazing.
Ajai Chari, MD: As time goes by, we’re not hitting a median. I have a just couple of patients in clinic who’ve passed 3 years. Are we getting to that elusive plateau that we’ve all been looking for?
Krina Patel, MD: I’m not holding my breath. For myeloma, we always hope. I hope there’s a percentage of patients who don’t relapse…. That would be a huge game changer, but I need follow-up data.
Ajai Chari, MD: Yeah. Since you jumped in, tell us: the efficacy we covered, but what about toxicity?
Krina Patel, MD: In general, in CAR T we see more grade 1/2 CRS [cytokine release syndrome], but some patients will get grade 3. There is some ICANS [immune effector cell-associated neurotoxicity syndrome], but it’s less than 5% for most patients, so that’s tolerable. Most patients do get tocilizumab. About 95% to 97% of patients end up getting to tocilizumab. It works really well at taking care of those CRS issues. The neurotoxicity for cilta-cel [ciltacabtagene autoleucel] is a small 9% grade 3—not ICANS and more motor neuropathy than happened in the original study. The mechanism of action was possibly BCMA expression in our neurological system. What’s going on? We need to learn a lot more about that.
My takeaway is we need to watch these patients because that happened after 45 days. Now that it’s standard of care, we need to make sure patients know what to look for and call us if something like that is happening. The good thing is that once they’ve done other patients on the study and other studies, the main issue is bulk of disease. Patients aren’t going with a lot of bulk of disease. It seems to not happen as often. There was still 1 patient who had it happen in the earlier trials. It’s the education piece and us being very vigilant about it.
Ajai Chari, MD: There’s a 95%-plus response rate, and it has not reached PFS or OS median. Omar, who should get cilta-cel [ciltacabtagene autoleucel]?
Omar Nadeem, MD: Everybody. [Laughter.] Anyone who has access to it. We know what the toxicity profile looks like as a class and as a drug. We’re comfortable managing CRS. The benefit is so pronounced that it should be offered to most patients who are eligible. The eligibility of CAR T-cell therapy does cover a lot of patients with myeloma even as they get older. We’re able to get them through that initial acute toxicity of CRS, which happens about a week later with cilta-cel [ciltacabtagene autoleucel]. If you manage that well, we’re not seeing outside this delayed neurological signal. We have to wait and see how that pans out in the real world. If they’re done with that hospitalization or that phase of therapy, they could benefit for a long time on no therapy. Patients with myeloma look forward to that. They’ve been on therapies for so long, and this is a great opportunity at that stage. They’ve had a median of 6 lines of therapy, as they have in the trials, and can benefit from that. You can apply this to most patients. We just have to clarify what happens with that neurological toxicity, particularly in older patients.
Ajai Chari, MD: You’re going to tell us a little about subgroup analysis, but before that, you brought up an important point. I’m curious: across the board, are there patients who are CAR T eligible but not transplant eligible, or vice versa? How would you respond to that question?
Krina Patel, MD: I definitely have more patients who are CAR T eligible than transplant. However, we still need to learn as we’re going into the real world, which patients maybe shouldn’t go. In the lymphoma world, we’ve seen dementia worsen sometimes. If a patient can’t tolerate 1 to 2 liters of fluid—with CRS, you might need that—those are the patients to whom I say, “Let’s hold off.” If there’s another comorbidity, this isn’t the right thing for you. For patients with renal failure, there’s a huge question. We’ve done real world with patients with a GFR [glomerular filtration rate] of less than 30, but the fludarabine with CAR makes me a little worried. Something like a bispecific might be better for those patients. We’ve dose reduced and done a lot of things that patients have gotten through. We need a lot more data for those patients.
Ajai Chari, MD: Any other takers on that. Do you agree?
Rafael Fonseca, MD: That’s a hard-to-beat summary. Honestly, those are the few patients you might think wouldn’t do it. In general, transplant is being challenged. No. 1 is because there are more patients who want or are going to be eligible for CAR T cells but are between the ages of 70 and 75 because of MAIA. There’s a real possibility that we’ll see shrinkage of transplant and an expansion of CAR T cells. We can talk more later, but with more CAR T cells earlier, we saw some data for that presented as well.
Cristina Gasparetto, MD: The only problem is that we can get it for all the patients. If we have a patient with aggressive relapse, we can bring it. Those are patients we cannot bring to CAR T cell, right? For several reasons, they can wait. The ideal patient is progressing but you can hold them tight, bridging to the CAR T cell. But if they’re aggressive with lots of tumor burden, that’s probably the most difficult.
Ajai Chari, MD: It sounds like neuro, cardiac, renal, and explosive disease…. Omar, can you tell us a little more about any subgroup analyses that might help shed some light on cilta-cel [ciltacabtagene autoleucel] activity?
Omar Nadeem, MD: Overall, this is a small study set that we’re looking at across the board. It’s very difficult to find subgroups within this heavily pretreated population. But there was a signal toward patients who had some extramedullary disease or plasmacytomas that did not benefit as much in that population. That’s 1 of the hardest populations to treat with any agent. I’d still argue that they still had a response that was better than anything else they would have gotten at that level. But it raises the question: why? Is it something about their disease biology, or is it something about the penetrance of CAR T cells in those locations leading to less of a response? I don’t think we have any idea exactly what’s going on there. Is it a class effect or is it the patients we’re selecting who have such aggressive disease that we’re not able to capture a response?
Ajai Chari, MD: I’ve noticed that for all the T-cell redirections, we’re seeing this as a theme: extramedullary, ISS3 [International Staging System stage III], and perhaps heavy marrow burden. But extramedullary is complicated because, quite honestly, many of these patients wouldn’t be alive today. We’re seeing patients coming to the table—about half are high risk. They’re going to have extramedullary disease. To differentiate and tease that apart, we’re going to need randomized studies. To answer that, it’s not like these patients have other options. Perhaps these are the subgroups that we need to do combination strategies or maintenance for.
Rafael Fonseca, MD: There might be a practical solution in the real world. I distinctly remember…patients with a plasmacytoma that was perfect everywhere else, except for that plasmacytoma. I lean to say not that that’s a more aggressive portion but more on the delivery of T cells. I don’t know. That’s a hypothesis. Thinking about the radiation of plasmacytomas is perhaps 1 way to think about this. I don’t think we have the effect in those masses.
Krina Patel, MD: We have a clinical trial that opened for the same thing. We’re radiating patients who are post–standard of care, who still have an active plasmacytoma because there are thoughts that you get your endogenous TCRs [tumor-reactive T-cell receptors], etc, when you radiate. I agree 100%. Those are the patients that we need to do something else for.
Ajai Chari, MD: We’re seeing that across all the T cells. Bispecifics and CAR T have more extramedullary relapse, and I’ve seen a lot of patients who have had focal radiation and been able to stay on the bispecific.
Transcript edited for clarity.