Bispecific Versus CAR T-Cell Therapy for Myeloma, Bridging Therapy Needs for CAR-T

By Thomas Martin, MD, Sagar Lonial, MD, FACP, Shambavi Richard, MD, Peter Voorhees, MD - Last Updated: May 1, 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 choice between treating multiple myeloma with a bispecific agent or CAR T-cell therapy.

Dr. Martin: Dr. Richard, Peter said a few things about the other options out there. When you see a patient and you have the option now of a bispecific T-cell engager or a chimeric antigen receptor (CAR) T-cell therapy, how do you choose between those two?

Dr. Richard: Yeah, I think this question now is becoming very key. We actually had a publication from our institution by Oliver Van Oekelen, MD, in Blood this year that looked at outcomes of salvage treatments and from two institutions, Mount Sinai and from Memorial [Sloan Kettering Cancer Center]. There were 79 patients on this with a median follow up of 21.3 months. Long story short, T-cell engaging therapy is really head and shoulders above other standard-of-care approaches, no matter what line of therapy post-relapse after CAR-T you use them. Intuitively, it makes sense to try to switch targets. If a patient is at all a clinical trial candidate, then I try to do that with one of the bispecifics, and we have several in our clinical trial armamentarium to see if they would fit one of those. We do have [teclistamab] commercially approved, I tend to not use that immediately after failure from a BCMA unless I can prove that it has been a long time since their CAR-T or some such thing.

But other options that I have used very effectively are selinexor and selinexor-based regimens. That’s another thing as a bridge. It may not last indefinitely, but people have been able to stay on it for at least six months or so post-CAR-T relapse. I have tried that. If they have 11;14 [translocation], then I try to use a venetoclax-based regimen. These are some of the various things I’ve tried, and if not, actually another thing that I’ve really used, especially for patients who are relapsing aggressively, is a transplant-based approach. BCMA followed by a stem cell boost really does have pretty good response rates even in the post-CAR-T relapse. It’s a great temporizing measure before getting them onto something else.

Dr. Martin: Back to big alkylator, if needed, to salvage the people. Just the way the CAR T-cell therapeutics work, we obviously have to harvest some T cells and then we send them out for manufacturing. These days it can take anywhere between six and eight weeks before you get the product back to be infused. We have to keep the patients stable during that period of time. Sagar, what do you guys use at Emory for bridging-based therapy? Is there any best regimen in your hands?

Dr. Lonial: Yeah, I think bridging is really the variable that we don’t talk a lot about because it can impact the response rate post-CAR and it can impact the toxicity post-CAR as well. Certainly, in the early trials, whether it’s KarMMa or CARTITUDE, these are patients with large tumor burden, unlikely to respond to any bridging that we were allowed to give on the trial. Yet there was a big difference in response to bridging between the ciltacabtagene autoleucel (cilta-cel) early trials and the KarMMa trials, with almost nobody responding to bridging in the early idecabtagene vicleucel (ide-cel) trials and a much larger proportion responding in the cilta-cel trials, which tells you that while we add up resistance to X, Y, and Z lines of therapy, that there are differences between these patient populations that we need to take into account. When we think about bridging, the ideal case is that we don’t bridge at all. That, to me, is the best-case scenario.

To speak to what Pete and Shambavi were talking about before, in a newly diagnosed patient that has had a good response, no bridging is a much more doable proposition because they’re pan-sensitive and you likely have a good disease status when you go in. However, many of our patients don’t have that as a luxury, even in second or third relapse where their disease is marching at a pretty significant rate. As Dr. Voorhees suggested, our last choice is DCEP [dexamethasone, cyclophosphamide, etoposide, and cisplatin] or chemotherapy-based approaches. We’ll recycle things that we’ve done before, find whatever you haven’t used or a combination you haven’t used. One thing that we often go back to in the bridging context is a lot of patients have seen carfilzomib in combinations, but they got low doses of carfilzomib at 27 or 36.

I go back to 56 twice a week and combine it with something in that context. And 56 twice a week is able to overcome CAR resistance at the lower doses a significant number of times. That’s often an approach we take. But a question I was actually curious for both Pete and Shambavi is, is in those earlier relapse trials that you mentioned, we’re comparing progression-free survival between two products, but the rates of bridging may have been different between those two products as well, which tells you about the tempo the patients are bringing into their relapse. I know you guys each covered those early relapse trials. Were they similar? Were they dissimilar? I’m curious. I’m taking you off script here, Tom.

Dr. Richard: No, you’re definitely right, because that bridging thing did make a considerable difference. Now, I haven’t looked specifically at the data to see where exactly these patients were at, at their various phases when they went into this, but I think if we take it down to real world now as the way we use [ide-cel] and [cilta-cel], we have now our own control group, and we treat them very similarly in terms of trying to bridge them, to really minimize their tumor burden prior to. I think that these questions will just become clearer as we go along. But I think—all things being equal and trying to level the playing field—I still think that with the cilta-cel, that different CAR construct probably is the reason for getting those more improved progression-free survivals, and we’re still seeing that.

Dr. Voorhees: I was just going to say on the KarMMa-3 trial, I’ll actually need to dig down deep into the manuscript to look at the bridging therapy and the response to bridging therapy. But Sagar, to your point, you’re absolutely correct. I think that we’re always in dangerous waters when we’re comparing across trials. I think as we move the CAR T-cell products into earlier lines of therapy, there’s going to be more variables that could significantly impact longitudinal outcomes for these. We’ll need to look at those very carefully when we’re making conclusions about whether one is better than the other.

Dr. Martin: It’s a race to the plateau, right? It’s a race to see who can actually generate a very long-term response. That’s financially that becomes a very successful therapy because the more patients are off therapy, the more savings there are from myeloma therapeutics.

Continue on to watch the next roundtable segment.

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