A roundtable discussion, moderated by Thomas Martin, MD, of the UCSF Helen Diller Family Comprehensive Cancer Center, focused on CAR T-cell therapy considerations in the treatment of multiple myeloma, including data on approved CAR-T options and a look at the pipeline. Dr. Martin was joined by a panel that included Sagar Lonial, MD, FACP; Peter Voorhees, MD; and Shambavi Richard, MD.
In the next segment of the roundtable series, Drs. Martin and Voorhees discuss patient characteristics and populations that are suited for CAR-T therapy in myeloma.
Dr. Martin: I want to go to where we think the space where CAR T cell is going to be the best, but also really about choosing the correct patient for CAR T-cell therapy. Right now, we have the availability of chimeric antigen receptor (CAR) for late-line therapy, patients who’ve had four or more prior lines of therapy. When you guys think about who’s the patient you’re going to select to go forward with CAR T-cell therapy, what are the caveats of that and what are the characteristics of that patient population that you move forward with? Peter, how do you choose your patients in North Carolina?
Dr. Voorhees: The first question is “When should people start thinking about CAR T-cell therapy and if they’re not being treated by our institution, when should regional providers refer their patients for CAR T-cell therapy?” At least with the existing regulatory approvals, I would say as soon as you start fourth-line therapy, you get them to see us right at that point, and if they respond to that fourth-line therapy, that’s great. They’ve had four prior lines of therapy, they’ve got good disease control going into apheresis, you’ve got something that you can bridge them with. As soon as you start fourth-line therapy, it’s time to go, because that fourth-line therapy is not going to produce a durable response in the overwhelming majority of cases. That’s when the patient should be considered, that’s when the patient should be referred. I think that the backlog of apheresis slots has gotten a bit better as manufacturing capacity has increased somewhat.
We all have clinical trials with bispecifics and CAR T-cell therapies and then we have commercial approval of teclistamab, the first BCMA bispecific antibody. All of that I think has alleviated some of this backlog at a lot of our centers, so patients can get in and get apheresis a bit faster. We still have progress to be made on that front, but we’re doing better now than we were before. Interestingly, when we did the real-world analysis of idecabtagene vicleucel (ide-cel), 75% of the patients that were reported on were not eligible for the KarMMa trial. There were four big buckets [of] why that was the case. One was prior BCMA-targeted therapy, so there was a cohort of patients that had prior BCMA-targeted therapy. Renal dysfunction was another one, cytopenias was another one, and then an Eastern Cooperative Oncology Group (ECOG) performance status of two.
In spite of the fact that three-quarters of the patients in this real-world experience would not have been eligible for the initial phase II KarMMa trial, we had very good overall response, identical progression-free survival, very similar cytokine release syndrome, and immune effector cell-associated neurotoxicity syndrome rates. I guess what I would say is, you can be somewhat flexible. I would argue that a frail patient probably is not a good patient for CAR T-cell therapy. I think you’ve got to be very careful with patients who have pre-existing cytopenias and a large burden of disease going into CAR T-cell therapy. If you don’t have a pool of stem cells to boost them on the outback of things, they can experience very prolonged cytopenias that can be quite problematic.
There was a signal toward inferior progression-free survival for those patients that had an ECOG performance status of two in the real-world experience. Again, if a patient is frail, I’m probably thinking about commercial teclistamab over a CAR T-cell product. We’re starting to get more experience doing CAR T-cell therapy in patients with renal impairment. I think for folks that have creatinine clearances of 30 mL/min or better, I’m very comfortable in that situation. We’re starting to get anecdotal experience in dialysis-dependent patients, and as long as you modify the fludarabine appropriately, it can be done, but you got to be really careful about who you’re selecting in that circumstance.
Dr. Martin: Yeah, we’ve told our local docs, please start counting lines of therapy because it’s very important these days and we’re a little slower in California in general, so we tell them to try to get them to us maybe even when they start their third line of therapy, so that we can see them. I love the thought that if they’re responding to fourth-line therapy, that you then take them to CAR T cell while they’re responding to their fourth line. Is that what I heard?
Dr. Voorhees: Yes.
Dr. Martin: Which is great. Then when you choose a regimen for the fourth line, are there any drugs that you would tell the local doc to avoid prior to the collection of CAR T cells?
Dr. Voorhees: Yeah, I think anything that’s rough on T cells is something that you need to avoid. I know that we use bendamustine-based therapies, Dr. Lonial’s favorite agent for treatment of relapsed/refractory multiple myeloma, but bendamustine is sometimes used, but that’s very harsh on T cells. In fact, it is an alternate lymphodepletion regimen for CAR T-cell therapies. Avoiding bendamustine-based therapies, avoiding alkylator-based therapies in general, I think pace-based, decept-based infusional therapies could potentially pose problems at the time of apheresis. Now, just given the space in which these agents are currently approved, sometimes we have no choice, and we have to use these things because there’s really nothing else to offer the patient to get them to apheresis. But if you’re in a circumstance where you can avoid it, I would absolutely avoid it.