Frontline CAR-T Use and the 'Sweet Spot' for Treatment Sequencing

By Thomas Martin, MD, Sagar Lonial, MD, FACP, Shambavi Richard, MD, Peter Voorhees, MD - Last Updated: April 28, 2023

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, the panel addresses the potential for frontline CAR-T use and gives their opinion on the ideal sequencing of CAR T-cell therapy in myeloma.

Dr. Martin: Sagar, there are some studies planned for using it in frontline. Can you tell us about that?

Dr. Lonial: Yeah, I think there are two trials using ciltacabtagene autoleucel (cilta-cel) early on: one in a transplant-ineligible or “choosing not to go down the transplant road” [setting], which I think is an interesting phrase. I know that many of us in the field are moving more toward “frailty” rather than transplant-eligible or -ineligible. This sort of straddles that line in many ways, but it’s a regimen that uses bortezomib/lenalidomide/dexamethasone (VRd) followed by either lenalidomide/dexamethasone maintenance, similar to the SWOG-777 trial or VRd followed by cilta-cel. I think the indication here is really to look for that middle ground of people that perhaps don’t want to go to transplant early on. I think it does become an interesting proposition for somebody in their 50s or 60s who could do quite well with transplant, but this may be a trial that they choose to go down the road with.

I think it’ll bring the question of can you use a chimeric antigen receptor (CAR) as alternative consolidation without maintenance as a way to really try and prolong progression-free survival (PFS) in this patient population. The second trial is CARTITUDE-6, which is really looking at the transplant-eligible patient population and asking whether CAR can be an alternative consolidation there. Daratumumab/VRd for both groups, stem cell collection, and transplant after four for one group followed by daratumumab/VRd consolidation and two years of lenalidomide maintenance versus six cycles of daratumumab/VRd, CAR-T collection, and CAR-T infusion in the experimental arm. I think both of these are trying to bring it up earlier.

I think, again, the real question is, “Who’s going to be the right patient population for CARTITUDE-5, the VRd followed by lenalidomide/dexamethasone versus a CAR?” and “Is two years of lenalidomide maintenance really sufficient for the control arm in CARTITUDE-6?” Our group would argue it’s not, but certainly I think there’s no consensus on how long we give lenalidomide maintenance after a transplant patient.

Dr. Martin: Excellent. Sagar, when you think about where you’d like to use CAR T-cell therapy, where do you think it’s going to be used? Is it going to be used frontline? Is it going to be used early relapse? Is it just going to be saved for later relapse? Where do you think the best, the sweet spot, is going to be for CAR T-cell therapeutics?

Dr. Lonial: Well, I suspect if you ask each of us, we’re going to give you a different answer for that. I think that the data for high-dose therapy and melphalan as consolidation is so good, you can’t just be as good to replace it. For an example, if you look at the VRd 1,000 series, now if you’re a standard-risk patient, you get VRd induction, single transplant, and continuous lenalidomide maintenance, your median PFS is 80 months; that’s a pretty high bar for a CAR-T with no maintenance to be able to get over, and the cost is pretty reasonable, outside of the lenalidomide maintenance, and lenalidomide is about to go generic.

Again, thinking about where this can work, if it truly is one and done, it’s a different discussion, but if it requires a year or two of maintenance on the back end of a CAR to try and mop up minimal residual disease, then I think we have to start looking at quality of life, cost, as well as long-term benefit. That’s why I said earlier, response rates are great; PFS is what patients really care about. I think we have to be cautious about using early endpoints to predict long-term outcomes.

Dr. Martin: Completely agree. Peter, Sagar said we’d get different answers from everybody. What do you think, where’s the sweet spot going to be for CAR T-cell therapies?

Dr. Voorhees: I do think consolidation therapy in the frontline setting makes the most sense for a number of different reasons. I think that practically speaking, it’s much easier to navigate CAR T-cell therapy in that particular circumstance. You’ve got good disease control going into apheresis; you’ve got something that you can use during bridging to further cytoreduce disease, and there is a signal toward better side effect profile with regard to cytokine release syndrome (CRS), neurotoxicity, and hematologic toxicity when the burden of disease is low, going into CAR T-cell therapy. Cohort 2c of KarMMa-2—that was also presented in December, their initial results using CAR T-cell therapy after transplant, which is another way you could possibly do this for folks that are not in complete response—look really good. I agree with Sagar, if CAR T-cell therapy as consolidation therapy in the frontline is going to become a reality, it’s going to have to be done in a way that the costs are made up in the long run.

I don’t know if it has to be a no-maintenance strategy after CAR T-cell therapy, but it definitely has to be a limited duration, one, at most two, you’ve got to be able to recoup those increased upfront costs, because it’s not just the CAR T-cell therapy itself and the management of CRS, immune effector cell-associated neurotoxicity syndrome, etc. You’re giving these patients intravenous immune globulin monthly, for two years in many cases, for example. The costs that are incurred as a result of CAR T-cell therapy are considerable. I do think early relapse is going to be a lot easier to navigate for the very same reasons as well. Having something effective that you can use before apheresis and during bridging is a game changer for these products.

Dr. Martin: Thank you Peter. Shambavi, what do you think? Because I’m curious on what you think from the Sinai perspective.

Dr. Richard: I’m going to be more optimistic for the CAR-T group. I think as of right now, there’s a role for CAR-T in all of this. There’s a lot of trials going on in the newly diagnosed in addition to CARTITUDE-2 with cohorts E and F, and then there’s the CARTITUDE-5, and CARTITUDE-6, and then even daring to bring in these first-in-human dual targeted [agents] into newly diagnosed [patients]. I mean I think that’s amazing. I think the field is moving very quickly. I think the advantages to CAR-T, I think the single important thing that speaks to me is when patients are going through CAR-T and they come out of it, they are just feeling so much better than after they’re going through the transplant, or coming out of the transplant, or going through any other [situation] where they’re just constantly on some kind of maintenance treatment.

I do think that we probably would have to put them on some maintenance, but it’s probably not going to be indefinite lenalidomide maintenance as we’ve been touting right now. I think that’s going to make a difference to their wellbeing, to how well they feel. I’m going to say that if it’s even as good as transplant, but with a lot less morbidity, then why would I not choose that rather than a transplant? It’s something to argue, and debate, and to think about, but I think that the horizon looks good for CAR-T. I’m thinking that as we get better at understanding it, and using it well, and bettering the constructs and things like that, we should hopefully get to a place where we are replacing transplants with CAR-T.

Dr. Martin: I completely agree with all of you, and when somebody asks me newly diagnosed, first relapse, or late relapse, I say, “Yes, yes, yes. I think we are going to use CARs in almost all the spaces and we’re going to be able to innovate with CARs much more than we’ve been able to innovate with autologous transplant, thankfully.” We’re going to change the binders, we’re going to change the signaling domain. We’re going to change how many times, or how many different antigens we can target. But the bottom line, as Sagar has been saying, is that it’s really not about overall response rates [that] are really high. It’s about that plateau, and we need to get to the plateau, and nothing has shown a plateau at this point.

Continue on to watch the next roundtable segment.

Post Tags:Myeloma Roundtable
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