Recent Advances in the Treatment of Relapsed/Refractory Multiple Myeloma - Episode 16

Novel CAR-T Therapies in Relapsed/Refractory MM and Identifying the Right Patients for CAR-T Therapies

, , , ,

Experts discuss emerging BCMA-targeting CAR T-cell therapies under investigation for treating multiple myeloma and barriers to CAR T access.

Nina Shah, MD: Sagar, it’s great to have something that’s approved, but what about access? Has access to CAR [chimeric antigen receptor] T-cell therapies impacted your approach? How are you identifying patients for therapy? How are you getting them there? What are you using to get them there? Do you ever use ADCs, antibody-drug conjugates, to bridge them not necessarily between apheresis and LD [lenalidomide (Revlimid), dexamethasone] chemotherapy but rather just to get them to an apheresis slot?

Sagar Lonial, MD, FACP: The real challenge that we’re all struggling with is access. On the commercial side, you’re lucky if you get 1 or 2 slots a month. On the investigational side, everybody’s fighting for the same slots as well. We’re all very limited in terms of what we can do, so when the question is who you can give it to or who you want to give it to, it’s whoever is relapsing in the right way at the right time if the right slot opens up. It’s highly selective in terms of who goes on these trials. That’s an important caveat on how to interpret the data. Yes, these are 7, 8, 9, 10, 11 prior lines of therapy, but they’re 7, 8, 9, 10, 11 prior lines of therapy who can wait long enough to find a slot and do well enough during bridging that they can get to infusion of the product. It’s a very selected group of patients.

We’re using whatever we need to use as either prior to bridge or bridging therapy. A lot of times, that involves the use of DCEP [dexamethasone, cyclophosphamide, etoposide, cisplatin], as Ola mentioned earlier, and sometimes stem cell reinfusion after DCEP because they’ve got such bad counts after chemotherapy-based approaches, especially in fifth and sixth line. But we certainly use belamaf [belantamab mafodotin (Blenrep)] or other approaches before we’ve apheresed people, or as a single dose to bridge in between collection and infusion of the drug.

Nina Shah, MD: Yes, and sometimes you have no control over when the person is going to have that apheresis slot. I agree. The logistical aspect has been a new challenge for us. We’re so used to writing chemotherapy and getting it done. This has been a different workflow for a lot of us.

Josh, we’re talking about cilta-cel [ciltacabtagene autoleucel] and ide-cel [idecabtagene vicleucel], but there are other CAR Ts targeting BCMA [B cell maturation antigen] that are being developed. Maybe you could give us a bit of overview. Some of them were updated this past year at ASH [American Society of Hematology Annual Meeting] or ASCO [American Society of Clinical Oncology Annual Meeting], including bb21217 as well as the FasT CAR T, which targets both BCMA and CD19. There was also the dual-targeted BCMA that was published back at ASCO. Are any of these new BCMA-targeting CAR Ts, including things I didn’t mention, on the horizon to make our treatment effects even better?

Joshua Richter, MD: Yes. CAR Ts are great. The question is how we augment them. There are a number of strategies that are explored here. One has been the bb21217 protocol, which exposes the sample ex vivo to a PI3 [phosphoinositide 3] kinase inhibitor in the hopes of engendering a more memory phenotype like CAR T. The question still remains, is optimizing CAR T all about that initial expansion and cytokine release to get a big time cell kill early on? Does it matter what type of CAR T you have 9, 12, or 24 months out? Or is there a Goldilocks perfect combination and you need both? This is some great data that’s being explored by Noopur Raje, MD, [Massachusetts General Hospital] and her group to see if engendering high levels of T cells later on may optimize and prevent early relapse from CAR T.

The dual CAR Ts are fascinating. There are a number of them coming out. There’s a BCMA-CD19 and a CD38-CD19. I don’t know that we know what the single optimal target is—let alone dual—especially with the interesting data. It’s non-BCMA coming out from Sham Mailankody, MBBS, [Memorial Sloan Kettering Cancer Center] and his group about the GPRC5D [orphan G protein–coupled receptor class C group 5 member D] target. Dual may be better, or other targets. A lot of this has been early in the clinic, with handfuls of patients being treated. We need to see more follow-up.

Then there’s a study by our colleagues at Massachusetts General Hospital. I still have to wrap my head around how this study was constructed using a computational-derived triple helix protein scaffold that comes with an AM/FM clock radio. It’s the next-next-next generation of things, besides having to have several degrees. The question is, can we optimize that engagement of the CAR T and reduce immunogenicity? Because that may have some issues with mechanisms of resistance.

There are a number of strategies out there, including some work presented at this year’s ASH by Andrew Cowan, MD, [University of Washington, Fred Hutchinson Cancer Research Center] about incorporating gamma secretase inhibitors to augment BCMA expression. There are many studies. We need more time to sort it out.

Nina Shah, MD: Yes. I make a joke about it. I make a table every year after ASH that I call the House of CARs because there are so many different CARs that are being developed. Some are your garden variety approach to BCMA, but it’s exciting to see all these new approaches. Hopefully we can get a better idea of how to improve on the already dramatic results that we’re seeing. We talked a little about how this is a one-and-done treatment. That’s definitely 1 of the outstanding characteristics about CAR T cells. Sagar, I want to talk a little about the toxicities that we see with CAR T cells. Maybe you can talk about cytokine release syndrome [CRS], neurotoxicity, and cytopenias, and what we can do to either treat or prevent these particular adverse effects.

Sagar Lonial, MD, FACP: The 3 adverse events that you described aren’t unique to CAR T cells in myeloma. In fact, they may be somewhat less common in BCMA-targeted CAR T cells than we’ve seen in CD19 in lymphoma and ALL [acute lymphoblastic leukemia]. But CRS is probably 1 of the big ones. Cytokine release syndrome is in many ways a good thing. It’s a sign that the T cells are growing and activated. Managing how to do that is certainly important, and early use of tocilizumab [Actemra]—you’ve got the hashtag for that—is certainly 1 way to approach preventing the development of grade 3/4 CRS. Very close monitoring and being in a center that does this enough that they recognize early CRS is important. Even though many patients may be cytopenic at this time point, it’s important to not say, “This must be neutropenic fever and we’re just going to treat it like that.” Taking the shotgun approach of covering all your bases is important. With that approach, you can reduce the rate of severe grade 3/4 CRS pretty significantly.

For neurotoxicity, it’s more surveillance than anything else, early intervention when you begin to see things like ICANS [immune effector cell-associated neurotoxicity syndrome], and early use of corticosteroids. There was hesitancy on corticosteroids early on, but those approaches can be effective. For cytopenias, it’s supportive care more than anything else. As we’re seeing less grade 3/grade 4 CRS, we’re seeing less in terms of chronic cytopenias, like they do in CD19-directed CAR T cells, but it’s still there. I have a patient who has a platelet count of 18 three -and -a -halfyears after CAR T-cell therapy because CRS wiped out his marrow. These are things that can be managed, but you have to be aware of them.

Nina Shah, MD: Yes, more experience is always a good thing for all of us. It’s been nice over the past 3 years to get our hands dirty and try to figure out the best way to approach these patients. I also agree with you regarding tocilizumab. As you mentioned, I have the #notocishame. That’s true, because we know that giving tocilizumab isn’t necessarily a bad thing as far as CAR T-cell efficacy for BCMA-directed CAR T. Those are some things to take as we get this into the standard of care.

Transcript Edited for Clarity