Early-phase CAR-T for multiple myeloma shows ‘amazing’ safety, ‘encouraging’ efficacy
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Results of a phase 1 trial for chimeric antigen receptor T cells targeting an orphan receptor in patients with relapsed or refractory multiple myeloma “thrilled” researchers, based on data presented at ASH Annual Meeting and Exhibition.
Recipients of the autologous CAR T cells (BMS-986393, Bristol Myers Squibb), which target GPRC5D, had an 86% overall response rate across all tested doses and a 91% ORR at the phase 2 recommended dose.
“You’re thinking about how this pertains and compares with other things that are already FDA approved,” Susan Bal, MD, malignant hematologist and assistant professor at the University of Alabama, told Healio. “We see cytokine release syndrome, some neurotoxicity and low blood counts with CAR T cells. When you compare this with other CAR-T, I think it performs favorably.”
Healio spoke with Bal about the trial, the results, the future of the study and more.
Healio: Why does this antigen hold promise for treatment?
Bal: GPRC5D is an orphan receptor present on the surface of myeloma cells. It has limited expression on normal tissues, and in preclinical models we’ve seen GPRC5D-directed therapy is effective at cancer killing, so in that way this is a very promising target. In fact, another agent targeting GPRC5D using a T-cell bispecific antibody— talquetamab (Talvey, Janssen) — is currently FDA approved, with an overall response rate in the mid-70s based on the two dose levels. So, we know that this is an effective target.
Healio: What are the results so far?
Bal: Most of the patients had side effects that included hematologic toxicities, such as low blood counts, which was very consistent with what we’ve seen with other CAR T cells in myeloma. We saw CRS in 76% of the patients treated in the study; less than 4% had grade 3 or higher events. At the recommended dose of 150 million CAR-T cells, 89% of the patients had CRS, but all of these events were grade 1 or 2, and there were no grade 3 or higher events, which is amazing.
In terms of other toxicities normally seen with CAR T cells, immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in a small number of patients, and at that recommended phase 2 dose, we only saw one subject having a low-grade event.
The GPRC5D antigen is expressed on the surface of hard keratinized tissues like the oral cavity. It’s present on nails and on the skin. With talquetamab, we see rash, taste changes, weight loss, nail changes, and some significant impairing of quality of life in about 60% to 70% of cases. For this CAR-T targeting the same antigen, because it targets the antigen in a different way, we saw a lot less of those side effects relating to GPRC5D, and these were more transient and low-grade events. All patients recovered with a median time of about a month, which was encouraging.
Healio: Did any unexpected toxicities occur?
Bal: We saw some unusual non-ICANS–type neurotoxicity in the study — dizziness, ataxia, dysarthria, some coordination issues — but that was limited to less than 10% of the patients on the study, with grade 3 or higher events in a small number of patients. We are still trying to better understand which patients experience this toxicity and things we can do to perhaps mitigate or treat it.
Healio: How did the CAR-T perform in terms of efficacy?
Bal: We saw an overall response rate in the entire study of about 88% and a complete response rate of about 45%. At the recommended phase 2 dose, we saw an overall response rate of 91% with a complete response rate of 48%. The results are very encouraging.
Healio: How does the safety of this CAR-T compare with talquetamab?
Bal: It’s very similar in the low blood count risk. At least so far, it looks better in terms of the cytokine release syndrome and ICANS risk. The skin, nail and oral cavity side effects are much better with the CAR-T we evaluated than has been observed using the FDA-approved T-cell engager talquetamab.
Healio: How would you characterize the results?
Bal: We’re very pleased with the results. We started seeing responses very early into the study.
Healio: How does this treatment work with other CAR-Ts?
Bal: There are two other FDA-approved CAR T cells for this disease, but they both use a different target known as B-cell maturation antigen, or BCMA. Those treatments are not curative, so patients will continue to relapse, and we need more treatments targeting different antigens. Patients receiving our CAR-T targeting GPRC5D benefited whether they had prior BCMA-directed CAR-T or not. It appears that responses to this CAR-T are independent of BCMA-directed therapy and patients are doing very well, whether they receive our investigational CAR-T before or after because the responses are uniformly high so far.
Healio: What are the future plans for the study?
Bal: A phase 2 trial for this product is already planned that should be opened in April 2024. The trial will include patients with quadruple class-exposed relapsed myeloma and will evaluate efficacy at the recommended phase 2 dose. Another phase 1 study will open this month or early next month that will evaluate combining this CAR-T with other agents in patients with multiple myeloma to see if we can improve responses by adding other myeloma treatments after this CAR-T.
Reference:
- Bal S, et al. Abstract 219. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
For more information:
Susan Bal, MD, can be reached at sbal@uab.edu.
Perspective
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Chakra P. Chaulagain, MD, FACP
There are two approved B-cell maturation antigen (BCMA)-directed CAR T-cell therapies — ide-cel and cilta-cel — for relapsed refractory myeloma with excellent efficacy. Similarly, teclistamab and elranatamab are two anti-BCMA bispecific T cell engager therapy (BiTe) that are approved for use after four prior lines of therapy. They have high efficacy, albeit less than that seen with anti-BCMA CAR T-cell therapies. Despite unprecedented rates of deep response with anti-BCMA CAR-T and BiTe therapies, unfortunately relapses are common; therefore, alternative strategies are needed after failure of anti-BCMA-directed therapies in relapsed myeloma.GPRC5D (G protein-coupled receptor, class C, group 5) targeted BiTe and CAR T-cell therapies have the potential to meet this unmet need for patients with heavily pretreated, BCMA-exposed refractory patients. In August 2023, talquetamab — a CD3-engaging bispecific antibody that targets GPRC5D — was approved for relapsed refractory multiple myeloma with at least four prior lines of therapy based on the MonumenTAL-1 trial. Talquetamab is the first drug class to be approved that targets GPRC5D in myeloma, confirming GPRC5D as an active immunotherapeutic target in multiple myeloma. This has led to the development of GPRC5D-targeted CAR T-cell therapy in multiple myeloma (BMS-986393), and updated preliminary clinical trial results were presented in December at ASH Annual Meeting and Exposition in San Diego. An exceptionally high overall response rate of 91% and complete response rate of 48% were seen in patients who received the phase 2 recommended dose, and the responses were independent of prior BCMA-directed therapies.
As expected with other CAR T-cell therapies, the most common side effects included hematologic toxicities (eg, neutropenia, thrombocytopenia). Cytokine release syndrome was seen in 76% of the patients but most cases were grade 1 or grade 2. At recommended phase 2 dose, immune effector cell-associated neurotoxicity syndrome (ICANS) occurred at low grade in only one patient. GPRC5D is expressed in oral cavity, nails and skin, and that is why talquetamab is known to cause taste changes (dysgeusia), weight loss, and skin and nail changes in significant number of patients. But with GPRC5D CAR T-cell therapy, only transient self-limited lower-grade events were observed. Non-ICANS–type neurotoxicity (dizziness, ataxia, dysarthria) was seen in about 10% of cases. There was signal toward a better CRS and ICANS toxicity profile compared with approved BCMA-directed CAR T-cell therapies and a potentially better skin, nail and oral toxicity profile compared with talquetamab, but this needs verification in larger studies. Hopefully the planned phase 2 trial will provide further insights in this area.
Overall, GPRC5D-targeted CAR T cells in myeloma may meet an unmet need if approved. The fact that it is effective in relapsed myeloma after prior BCMA-directed therapies — including BCMA-CAR-T — is very encouraging. However, CAR T-cell therapies in myeloma do come with several practical difficulties. The technically demanding nature of CAR T-cell therapies has restricted its availability to major academic centers. A broader utilization of CAR T-cell therapy in myeloma is not possible for the community oncology practices that treat the majority of myeloma in the United States. Post-CAR T-cell therapy care requires special attention to the management of hypogammaglobulinemia with IV immune globulin and infection prophylaxis with appropriate antimicrobial agents due to high risk of infections. BiTe therapies have the potential for wider utilization in community practices but, again, the risk of CRS and ICANS continues to deter practicing hematologists/oncologists for the widespread adoption.
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