Managing Toxicities in BCMA/GPRC5D-Directed Therapies in Multiple Myeloma

The emergence of BCMA- and GPRC5D-directed therapies, including CAR T-cell therapies and bispecific antibodies, has changed the treatment landscape for multiple myeloma. While offering unprecedented efficacy, these innovative modalities are accompanied by unique and critical adverse effect profiles that require specialized management.

Prior to the upcoming 2025 Immune Cell Effector Therapy (ICE-T) Congress, CancerNetwork® hosted a panel discussion revolving around adverse effects and access to CAR T-cell therapy and bispecifics. The panel consisted of Prerna Mewawalla, MD, director of Apheresis in the Division of Hematology and Cellular Therapy at Allegheny Health Network and associate professor at Drexel University College of Medicine; Shebli Atrash, MD, medical oncologist at Atrium Health Levine Cancer Institute and clinical associate professor at Wake Forest University; and Jeries N.J. Kort, MD, assistant professor of Hematologic Malignancies and Cellular Therapeutics at Kansas University Medical Center.

They focused on the most common adverse effects they see with BCMA- and GPRC5D-directed therapies, providing a comparative analysis of their management in the context of CAR T and bispecific antibodies. The discussion highlighted the importance of proactive, modality-specific strategies, from swift intervention for cytokine release syndrome (CRS) and neurotoxicity in CAR T-cell therapy, to aggressive infection prophylaxis and management of unique dermatologic and oral toxicities associated with GPRC5D-directed bispecific antibodies.

Transcript:

Mewawalla: When it comes to CAR T, the top 3 toxicities are [CRS], neurotoxicity, and prolonged cytopenias. [Some] of the things that we also have to watch out for are some long-term neurotoxicities as well. To manage these toxicities, it’s very important to have very clear protocols for managing CRS as well as neurotoxicity, early use of tocilizumab [Actemra] availability, and escalation to ICU [intensive care unit] as needed. When it comes to bispecifics, the CRS, which is seen as much lower, tends to be mainly grade 1/2 and much easier to manage. Very rarely do you see neurotoxicity with bispecifics, but with BCMA bispecifics, something to always watch out for is the risk of infections. The things you have to do are using prophylactic IVIG, irrespective of IgG level; using acyclovir, antiviral prophylaxis; using PJP [Pneumocystis jirovecii pneumonia] prophylaxis; and monitoring CMV [cytomegalovirus] and treating it preemptively, if needed.

With GPRC5D [agents like talquetamab-tgvs (Talvey)], the [adverse] effects seen are unique, mainly with skin/nail changes, as well as dysgeusia. The biggest thing with that is educating the patient and telling the patient that this is expected [and] going to happen; managing it preemptively; and letting them know about using things like Aquaphor, using topical steroids as soon as [symptoms] get worse, using oral zinc, [dexamethasone] rinses, and all the strategies to treat as well as prevent these toxicities from happening.

Kort: Usually, with CAR T cells, we focus a lot on this early CRS and neurotoxicity that can happen, but later on, we’re seeing more of that delayed neurotoxicity that we’re seeing more with CAR T compared with bispecific antibodies. We’re learning more about it and how to manage it. At the same time, prolonged cytopenia seems to also be a common theme for patients who receive CAR T-cell therapy at later stages in their disease, with less of that we’re seeing when we’re bringing it earlier in lines of treatment. In bispecific antibodies, we’re seeing more low-grade CRS and usually manageable CRS, and barely any immune effector cell-associated neurotoxicity syndrome [ICANS] or neurotoxicity. However, we’re seeing more infections. Infection risk with bispecific antibodies in the long run seems to be even higher than CAR T cells, and it’s probably for that chronic stimulation and chronic engagement with the target that’s continuous.

Of course, used prophylactic antibiotics, antivirals, and IVIG is very important, but addressing and managing the infection whenever it happens is also of utmost importance. We’re now learning more that adjusting the dose of the bispecific antibody and the frequency of giving the bispecific antibody also helps to decrease that risk. That’s one of the most important risks that I educate my patients on with bispecific antibodies. Specifically, with GPRC5D, on top of the oral toxicity and the skin toxicity that were mentioned before, we’re also seeing a few patients who are starting to notice having cerebral toxicities after long-term exposure. This is still rare, and we’re still trying to characterize it better, but that’s not the theme. It’s just one of the few toxicities that we [must also manage].

Atrash: I want to make 1 more comment here about the importance of identifying the most common [adverse] effects in BCMA bispecifics, which are the infections, and the importance of differentiating infections from CRS. While CRS could happen during the startup dosing, we should not think of CRS at a later stage with the treatment. Even when we manage CRS, we should be cognizant of the risk of infection because a patient could have an infection in the startup dosing. I agree with the comments just stated about GPRC5D-directed bispecific antibodies. I just want to add that we’re still learning about movement disorders, but it looks like it’s something we have to watch out for, even though it’s extremely rare.