Assessing GPRC5D-Targeted CAR T Therapy for R/R Multiple Myeloma

The GPRC5D-targeted chimeric antigen receptor (CAR) T-cell therapy BMS-986393 (Bristol Myers Squibb) has shown efficacy in patients with relapsed/refractory multiple myeloma (RRMM) with a manageable safety profile. These data, from a phase 1, first in human trial (NCT04674813), were presented at the European Hematology Association (EHA) 2023 Congress, held June 8-11, both virtually and in Frankfurt, Germany, by Susan Bal, MD, assistant professor of medicine at University of Alabama – Birmingham.

CGTLive’s sister site, OncLive, spoke with Bal to learn more about BMS-986393 and the trial assessing the therapy. She discussed the updated data, the progress of the trial, and more reserach to be done.

CGTLive: Tell us about the trial assessing BMS-986393 and the data seen so far.

Susan Bal, MD: BMS 986393 is a second generation, autologous, novel GPRC5D-directed CAR T-cell. GPRC5D is an orphan receptor with unclear physiologic function, but it happens to be expressed on multiple myeloma cells. Luckily, its expression is fairly limited to myeloma, so it's been shown to be an effective therapeutic target, as we knew from some of the data from bispecifics in the setting. in the initial study we looked at patients with relapsed/refractory multiple myeloma, at least 3 prior lines of therapy, including an immunomodulatory agent, proteasome inhibitor, and a CD38 monoclonal antibody. In our study, prior BCMA therapy was permitted. So, in our cohort of about 67 patients that were available for the safety analysis, we had patients with high risk cytogenetic features and the median prior lines in this population was about 4, so a relatively heavily pretreated population.

Most of the toxicities were predominantly hematologic, which we anticipated. We were pleasantly surprised, however, to see that only about a quarter of the patients had these toxicities, and they were all grade 1/2. In fact, up to 77% of the patients did not require any interventions for these toxicities. So really a favorable safety profile. We did see some treatment-related adverse events, such as cytokine release syndrome in about 87% of the patients, fortunately, high grade cases continued to be less than 5%. We also saw some immune effector cell-associated neurotoxicity syndrome (ICANS) in about 10% of the patients, mostly grade 1/2, which was reversible both with and without corticosteroids. We did see some non-ICANS neurotoxicity such as dizziness in about 10% of the patients. One patient had grade 3 dizziness which had fortunately improved to grade 2 by data cut off. And then we saw a less frequent incidence of other neurotoxicities such as ataxia, paraesthesia, etc, which are fortunately not high grade. But,we are cognizant of these non-ICANS toxicity, and it'll be important to follow this data setas we enroll more patients to truly understand the risk benefit profile.

The efficacy evaluable data set was about 52 patients so far as of March 2023. What we saw was overall, all patients in all doses responded. The overall response rate for the entire cohort so far appears to be about 86.5% with a complete response rate of about 39%. About half of those patients had received some sort of prior BCMA-directed therapy, and in that subset we saw a response rate of 76%. In the patients who had not had any prior BCMA therapy we saw a response rate of 96%. So overall, I think it looks encouraging, both in patients who are exposed and unexposed. So that was reallygreat to see that efficacy data, although the minimal residual disease data are less mature.

What are the next steps you’d like to research?

As a whole, our field is really interested in sequencing now that we have more immunotherapeutic options. I think that GPRC5D and BCMA expressions are independent of each other. So really there’s no strong reason for BCMA therapy to be used first. I think GPRC5D could even precede BCMA therapy, because what we're seeing is thereare less incidents with BMS 986393, we have seen a lower profile of skin and nail toxicities and a much-improved profile of high-grade infection. Of course, there's the question of, do they need to be sequenced? Or can we combine them?

For BMS 986393, we are in the process of continuing dose expansion.So it's really going to be important to define that initial safety, and really understand better some of the early signals of non-ICANS neurotoxicity we're seeing, I think it's going to be really important to refine the final dose that goes into the expansion and finalize the recommended phase 2 dose.So far, all doses appear to be active. The question will be about persistence of these CAR T-cells and durability of these responses. The question that remains in my mind is, are some of these responses going to be more durable at intermediate to high doses? We need to still wait for that data. Beyond that, I'm excited to see this moving to earlier lines of therapy, knowing what we know from the current data. I know CAR T-cells are, if anything, safer when moved to patients with less disease burden, less refractory disease. So,I'm hopeful to see some data in earlier line settings as well as in combination with other therapies. As we understand the sequencing better, we'll be able to further define where in the treatment landscape this fits.

Transcript edited for clarity. Click here for more coverage of EHA 2023.

REFERENCE

Bal S, Berdeja J, Htut M, et al. BMS-986393 (CC-95266), A G protein–coupled receptor class C GROUP 5 member D (GPRC5D)–targeted CAR T-cell therapy for relapsed/refractory multiple myeloma (RRMM): results from a phase 1 study. Presented at: EHA 2023 Congress. Abstract #S193