T Cell-Directed Therapies Are Rapidly Expanding for Myeloma

In an interview with Pharmacy Times, Rahul Banerjee, MD, FACP, discussed his presentation at the International Myeloma Society 2024 Annual Meeting on T cell-directed therapies for myeloma. Banerjee addressed factors to consider when selecting a regimen, the available treatments in this category, and their key differences.

Q: Can you review the available T cell-directed therapies for myeloma?

Rahul Banerjee, MD, FACP: Absolutely. So, the short answer is that the number of therapies is constantly evolving, so what I'm saying now may be inaccurate even 6 months from now. But as of now, I would say we have CAR T-cell therapies and we have bispecific antibodies as the T cell-redirecting therapies. For the CAR T therapies, we have cilta-cel, which is ciltacabtagene autoleucel, and ide-cel, or idecabtagene vicleucel, that are both CAR T therapies, both targeting BCMA—B-cell maturation antigen—on myeloma cells. And then in the bispecific arena we have several BCMA bispecifics, so teclistamab and elrenatamab. There's another one, linvoseltamab, that may be approved probably by the time that this goes to press. And those are all BCMA-targeting. And then there's a GPRC5D-directed CD3 T-cell engager, taquetamab, as well.

Q: What are the key differences in these drugs?

Banerjee: Absolutely. So, I think at the broadest level, what I tell patients is that bispecifics are easier on the way in, to get someone onto a bispecific, but CAR T is easier on the way out, after one's received that treatment. So, remember that autologous CAR T therapies like ide-cel and cilta-cel, they're kind of bespoke. They're personalized. We take a patient's own T cells out in real time, manufacture them, insert the CAR to make them CAR-positive T cells, and put them back in. That process can take about 2 months, often, for that manufacturing time or the “vein to vein time” between collection and actual CAR T-cell administration before the T cells are collected. That process can also be pretty tricky for patients, and so we often talk about this “brain to vein time” between me coming up with the word CAR T, the patient getting collected, and getting CAR T. And that can sometimes be several months, like 4 or 5 months, versus for a bispecific the brain to vein time—again, some of these are subcutaneous injections, not really vein—but the brain to vein is more like 2 or 3 weeks when I decide that someone needs a bispecific antibody. We can move on it like that. We need to get insurance approval, you know, some centers do inpatient, so if you're doing inpatient bispecific, we need to find a hospital bed, and after that, you're good. So, coming into things, I think bispecifics are definitely easier. And for patients who have, you know, rapidly growing disease, I think a bispecific is a better bet for them.

However, on the other side, CAR T, I would say, has the advantage profoundly. So, one, I think CAR T, at least in the studies we've seen—CAR T and bispecifics have not been compared head to head in myeloma—but if you look, for example, at cilta-cel in the CARTITUDE-1 study, and these were a patient who were heavily pre-treated, you know, at least 4 prior lines of therapy, you saw that the median PFS was almost 3 years, 35 months. And so that's very impressive compared to our bispecifics, where typically the PFS is more like the 18-month range. That's even more impressive when you remember that with CAR T therapy, it's a 1-time infusion. That doesn't mean that you're done forever after CAR T; you're still coming in once a month for blood work, possibly intravenous immunoglobulin, IVIG. You know, sometimes you need other antimicrobials and so forth. You're not completely out of the woods. But with a CAR T you're not getting anti-myeloma therapy continuously. We don't have a system post CAR T maintenance for bispecifics. You need to keep dosing the drug because remember that a bispecific is not permanently redirecting that T cell. It's temporarily redirecting that T cell to fight off the myeloma. And therefore, the studies are constantly getting better. But there was a time when every bispecific was every one week until progression. Now, a lot are moving to every 2 weeks or every 4 weeks, and there are studies ongoing, even stopping bispecifics. But that is not the routine. And to be honest, I've had patients where I say, “Hey, you probably could stop the bispecific,” and they get nervous about it, right? Because we're used to this paradigm of treat until progression and our patients are, too.

So, I think for patients who can get both CAR T and a bispecific, I would prefer a CAR T first, and we'll come back to that question later, just because, again, the efficacy benefit and this idea of lower time toxicity for patients is pretty profound. However, not everyone can get the CAR T. The other thing I mentioned, that some patients truly cannot get the CAR T for clinical reasons, because their disease is rapidly progressing, or disease related reasons, I should say, because the disease is rapidly growing and trying to get T cells collected and manufactured. It's not practical. I will say, to be fair, that there are some patients where I possibly would not consider them to be CAR T eligible, but potentially bispecific eligible, often are older and frailer patients, and particularly those with cardiac comorbidities, where CAR T is a little bit of an uncontrolled explosion in terms of the risk of cytokine release syndrome, CRS, right? You can try to shape the T cells from the outside as they come in, but these are living CAR T, living T cells, and they'll grow, proliferate, grow, proliferate, etc. And people can have high-grade toxicities, higher rates of ICANS neurotoxicity. There are delayed toxicities we've seen, like Parkinsonism and, again, nerve palsies. With bispecifics you typically don't see that much of it, because, again, it's a very controlled explosion. We actually give step-up doses, right? A very small dose, see what happens, [then] a bigger dose, see what happens. Sometimes even 3 step-up doses until the full dose. So, you know, I have a patient this week where we talked about this, and I would say, “Look, you know, she's in her 80s, she has some cardiac issues.” When the time comes, I'm going to go for a bispecific and not CAR T.