CAR T-Cell Therapy Targets GPRC5D in Multiple Myeloma

Susan Bal, MD

March is Multiple Myeloma Awareness Month. This month, Targeted Oncology is highlighting research in the field of myeloma treatment.

GPRC5D, a receptor expressed on multiple myeloma cells, has become a promising target for novel immunotherapeutic strategies, generating significant excitement and potential for enhancing the armamentarium against relapsed multiple myeloma.

In August 2023, the FDA-approved drug talquetamab (Talvey), a T-cell engager targeting GPRC5D, based on positive results from the phase 2 MonumenTAL-1 study (NCT04634552) for the treatment of patients with relapsed multiple myeloma.

Now, further studies are evaluating chimeric antigen receptor (CAR) T-cell therapies as a strategy for targeting GPRC5D, a phase 1 study (NCT04674813) of BMS-986393 (CC-95266) of which findings were presented at the American Society of Hematology 2023 Annual Meeting.

According to Susan Bal, MD, the potential of GPRC5D is present and encouraging. However, these are still questions regarding how it can be best used within the myeloma treatment landscape.

In an interview with Targeted Oncology^TM, Susan Bal, MD, assistant professor, hematology, medical oncology, University of Alabama at Birmingham (UAB), UAB Health, O’Neal Comprehensive Cancer Center, discussed GPRC5D as an immunotherapeutic target in multiple myeloma and findings from a phase 1 study evaluating a novel CAR T-cell therapy working to target GPRC5D.

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Targeted Oncology: Can you discuss GPRC5D?

Bal: GPRC5D is an orphan receptor that's been described by some of the work led by Dr. Eric Smith [MD, Cellular Therapeutics Center, Department of Medicine, Memorial Sloan Kettering Cancer Center]. It's expressed on the surface of multiple myeloma plasma cells, but luckily is not very expressed on the surface of normal tissues other than certain parts of the heart keratinized tissue. It's really shown to be a promising therapeutic target for myeloma. We now have FDA approval for talquetamab as well, which is a T-cell engager targeting GPRC5D. We have data from this study and several others which show that targeting GPRC5D can be a promising therapeutic target for relapsed myeloma.

What research has been done evaluating GPRC5D?

GPRC5D as a target has been evaluated by several studies, both in the context of T-cell engaging therapies, such as talquetamab, which is a T-cell engaging antibody that binds CD3 on 1end and the GPRC5D receptor on the other end. It has shown promising efficacy and has received FDA approval. It has response rates that are in the mid 70s range, 73% to 74%, with the recommended phase 2 dose. With that product, we have seen that there is increased toxicity that affects the typical heart keratinized tissues, including a relatively high incidence of rashes, weight loss, disgeusia, as well as nail changes. But it is an efficient agent.

The same target, GPRC5D, has also been targeted by CAR T cells. The first of that data was seen from an academic CAR T-cell study that came out of the Memorial Sloan Kettering [MSK], where there was a small pilot study of 17 patients that were evaluated with this CAR T-cell therapy. The [CAR T-cell therapy] itself was prepared and manufactured at MSK. In a very heavily pretreated population, we saw response rate across the study of about 71% and at the maximum tolerated dose, which was determined to be 150 million cells, it was about 58%.

What can you discuss about the investigation of BMS-986393?

This product, BMS-986393, is a second generation autologous CAR T-cell that's also targeting GPRC5D. It is similar to the MSK product with some differences in manufacturing. In the phase 1 program so far, which is still ongoing, about 84 patients were treated at the data cutoff. The safety profile looks manageable, with toxicities being limited in the sense that it affects only about a quarter or less of the patients. These are low-grade. There were no grade 3 or higher events seen. These were transient to lasting just about under 4 weeks on our study, so self-resolving. These are significantly less than what has been seen with the T-cell engaging strategy.

In terms of efficacy, we did see a significantly high efficacy. The recommended phase 2 dose has been determined to be 150 million CAR T cells. At this dose, the overall response rate was 91% with a complete response rate of 48%. I think it is efficacious. We did see [cytokine release syndome] in the context of the CAR T cells, which affected about 89% of the patients who were treated at the recommended phase 2 dose. Interestingly, there were no grade 3 or higher events at this dose. We also [saw] some non-eye cancer toxicity, which was seen in the MSK study as well. So far, about 9 patients have had this toxicity; most are low-grade. We are still fully understanding why these occur and where patients are more likely to have this, but some of that data is ongoing. These appear to be mostly dose-related, occurring with increased frequency of the higher doses. So far with the follow-up that we do have, they appear to be stable and somewhat improving.

What are the specific patient subgroups that exhibited particularly favorable responses?

One of the most important things that we saw on this study is that at the recommended phase 2 dose, we saw not only excellent responses overall, but when we look at, particularly some of the high-risk subsets that are traditionally high-risk, such as high-risk cytogenetics, patients who have extramedullary disease, patients who have had prior BCMA-directed therapy, we see uniformly high responses with this product. I think that is exciting and encouraging as we did not find any particular subgroups that benefited more than the other. But we did see that the traditionally high-risk patients benefited quite well from this product, which is exciting.

Considering the evolving field of CAR T-cell therapies, what do these updated data suggest about their potential role?

As we have seen from some of the other studies of CAR T cells and myeloma, particularly those that target B-cell maturation antigen, CAR T cells are definitely moving up. We saw results from the CARTITUDE-4 study [NCT04181827], which shows promising efficacy in the 1, 2, 3 prior line therapy. In the context of this study, we are looking at GPRC5D directly to CAR T cells in early lines of therapy. Our current phase 1 program is exploring that as well. We are really excited to see how this does in that early line setting.

What should a community oncologist know about the growing role of GPRC5D?

GPRC5D overall is an important target in myeloma. There remain several questions about the adequate sequencing of this approach in the current landscape of all of the development that we are lucky enough to have in myeloma. But I would say that talquetamab is already approved, but we are still understanding what is the best way to target the GPRC5D receptor. In my opinion, given the differences in toxicity that we have seen, this receptor may be better targeted with a 1-time strategy of CAR T cells compared [with] the T-cell engagers.

The toxicity profile seems to be a little bit different. Also, patients enjoy being off therapy. They value that. So I do think that more data will come. This is still of course early in study. We have a phase 2 study plan. We have a combination phase 1 study plan. And so as this gets closer and closer to approval, the important thing is to refer the patients early, because we have these amazing treatments that are available to their patients and we can help the greater myeloma community.

REFERENCE:

1. BMS-986393 (CC-95266), a G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory multiple myeloma (RRMM): updated results from a phase 1 study. 2023;142(suppl 1):219. doi: 10.1182/blood-2023-181857