Targeting GPRC5D Impacts Survival of Heavily Pretreated Patients With Relapsed/Refractory Multiple Myeloma

Jack Khouri, MD

Assistant Professor Department of Medicine

Case Western Reserve University School of Medicine

Hematology and Medical Oncology

Cleveland Clinic

Cleveland, OH

At a live virtual event, Jack Khouri, MD, discussed how treatment options for patients with relapsed/refractory multiple myeloma have evolved with the use of bispecific antibodies giving physicians the opportunity to target BCMA and GPRC5D on the plasma cell. By targeting these proteins, bispecific antibodies can induce lysis of the myeloma cell and lessen the burden of disease. Here, Khouri looks at the rationale and results of this treatment method.

TREATMENTS TARGETING BCMA AND GPRC5D

For these patients who are triple-class refractory, and potentially patients [who are refractory] after at least 4 lines of therapy, we have a lot of approved therapies. This is where [chimeric antigen receptor (CAR)] T cells and bispecific antibodies come into play…. The way these therapies work is that they all bind to the B-cell maturation antigen [BCMA], which is essential for the survival of the plasma cell.¹ We have 2 CAR T-cell constructs approved [in this space] currently, idecabtagene vicleucel and ciltacabtagene autoleucel [cilta-cel],^2,3 and the way CAR T cells target BCMA here is that the CAR receptor binds to BCMA, which leads to the activation of the T cell that was previously collected from the patient. So, autologous T cells, once they’re bound to BCMA, they release...disruptive mediators that lead to the lysis of the [disease] cell.⁴

Bispecific antibodies, the third class of these BCMA targeted therapies, act as a bridge between the T cell and the myeloma cell. By forming this immunologic synapse, they also activate the T cell, which leads to the destruction [of the myeloma cell].⁵ Most of these bispecific antibodies target BCMA, although there was one that was recently approved that targets GPRC5D, which is a novel target [also on the surface of the myeloma cell].⁶

We still don’t really know what the function of [GPRC5D] is. We know it’s present on malignant plasma cells, it’s present on cells in hair follicles, the tongue, skin, and a certain part of the brainstem, but it’s not really present on normal plasma cells. We still need to understand what this protein does, but it’s really present on malignant plasma cells in a high concentration, which is why it is thought to be a good target.⁶

ADDRESSING RELAPSED/ REFRACTORY PATIENTS

This leads us to talk about a whole new category of patients. We used to talk a lot about triple-class refractory patients, and these are the patients [who] are refractory to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies. With all these BCMA-targeted therapies, we are now seeing more…patients who are relapsing after [using them]. This is leading us to a new category of patients whose disease is challenging to treat. These are the patients who relapsed after CAR T-cell therapy and after BCMA-targeted bispecifics, which led to this terminology of quad-class refractory... to include this category of patients who are relapsing after BCMA-targeted therapies. [There are also] hexa-refractory patients with myeloma, meaning it’s not penta-refractory anymore and you must add that BCMA targeted therapy to this classification here.

So, [there are many] mechanisms of relapse. With CAR T-cell therapy, we see a lack of persistence of CAR T cells [and then] we do see a little bit of antigen escape, which leads to a loss of function of CAR T cells, although it’s not the most common reason for relapse after CAR T-cell therapy.⁷ [To address] the antigen escape, what we’re trying to do is increase the concentration of the antigen on the surface of the cell. There was a study...that looked at adding a γ-secretase inhibitor to CAR T-cell therapy, and the γ-secretase itself is an enzyme that cleaves BCMA off the surface of the cell.⁸ [Thus, by] inhibiting the enzyme you can potentially increase the concentration of BCMA on the cell and potentially improve CAR T-cell therapy efficacy. The results were promising, and that’s one strategy we’ve been testing.

[Also], having fully human CAR T cells can potentially improve their persistence because [the patient] has less immunity to the incoming cells, so potentially [it could] lead to better expansion and that’s also in clinical trials. Now, another thing that we can do after [the patient] relapses is start getting another protein on the surface of the cell. This is where GPRC5D comes [into the conversation]...with CAR T-cell therapy, bispecific antibodies, and potentially antibody-drug conjugates. There are many things that we can do for these patients and a lot of them are still in clinical trials, but there’s 1 active drug that is already approved, which is [talquetamab-tgvs (Talvey)].⁹

RESULTS OF TARGETING GPRC5D

About 26% to 31% of the patients [in the MonumenTAL-1 (NCT03399799) study] had really high-risk disease, with high-risk cytogenetics and/or extramedullary involvement, and these are the patients [who] are the most challenging [to treat].¹⁰ Many other patients were penta-refractory and all of them were triple-class exposed, so all of the patients had received at least 1 immunomodulatory drug and daratumumab [Darzalex], which is an anti-CD38 antibody. So, [it was a] very heavily pretreated population, and about [one-third] of the patients were [considered] high risk. The results of the study showed that the response rate was in the 70% range [among patients given 0.4 mg/kg and 0.8 mg/kg of talquetamab (Figure¹⁰)].

Most patients who had prior CAR T-cell therapy responded [to this therapy], as opposed to patients who had a prior bispecific antibody. It seems like patients who had CAR T-cell therapy and a bispecific antibody do fare better [with talquetamab] because the T cells are potentially less exhausted from the continuous stimulation by the prior bispecific antibody. The median duration of response was not reached in the 0.8-mg/kg dose arm, but the progression-free survival was about 14.2 months for that cohort. The duration of response for either dose was 11.3 months.¹⁰

SAFETY WITH BISPECIFIC ANTIBODIES

As we see with this class of therapy, hematologic toxicities are common. Neutropenia, thrombocytopenia, and anemia, most of these hematologic toxicities resolve in a month or two, so they’re not persistent....¹⁰ Infections are not as common with this medication. GPRC5D is not really present in normal plasma cells, which is different from BCMA, where BCMA is present on normal and malignant plasma cells. GPRC5D is way more common on malignant plasma cells, which is why there is little depletion of normal plasma cells and the risk of infections…is seen way less with [talquetamab].¹¹ And infections do happen, but grade 3 infections are not as common as with BCMA targeted therapies, which is very important to note here.¹⁰

As we see with bispecifics, cytokine release syndrome [CRS] is common. Close to 80% [of patients on this trial] had CRS that was mostly grade 1 or 2 mild CRS.¹⁰ [This would consist of ] a fever, maybe hypoxia that you can correct with a nasal cannula, and hypotension that you can correct with intravenous fluids. The drug is given in a ramp-up fashion, like teclistamab [Tecvayli], either in 2 step-up doses or 3 step-up doses depending on which dose [the patient is given]. Initially, it’s given in the hospital like what we do with the other bispecifics.

The best way to mitigate [CRS] is by reducing the disease burden, which is something that I’ve been trying to do with the patients [whom] I’m taking to CAR T-cell therapy, if we have the luxury of time. If we can give them more treatment before CAR T-cell therapy, we can potentially mitigate a lot of the toxicities. CRS is one of [these toxicities], but we have [also] been seeing some neurological toxicities that are a little delayed with CAR T-cell therapy, especially with cilta-cel,¹² such as [Parkinson-like] syndromes and other movement disorders. Those seem to be related to how much disease burden [the patient] had going into CAR T-cell treatment. For example, patients with more extramedullary disease, or more than 60% plasma cell burden in the bone marrow, those are the ones [who] if we could potentially reduce their disease burden…would be better for avoiding these toxicities. But again, with a lot of these patients we can’t do much.

_References

_{1. Yu B, Jiang T, Liu D. BCMA-targeted immunotherapy for multiple myeloma. J Hematol Oncol. 2020;13(1):125. doi:10.1186/s13045-020-00962-7}

_{2. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. Updated March 29, 2021. Accessed December 5, 2023. https://tinyurl.com/ysmckz5v}

_{3. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. Updated March 7, 2022. Accessed December 5, 2023. https://tinyurl.com/5h6w3rn2}

_{4. Sammartano V, Franceschini M, Fredducci S, et al. Anti-BCMA novel therapies for multiple myeloma. Cancer Drug Resist. 2023;6(1):169-181. doi:10.20517/cdr.2022.138}

_{5. Lancman G, Sastow DL, Cho HJ, et al. Bispecific antibodies in multiple myeloma: present and future. Blood Cancer Discov. 2021;2(5):423-433. doi:10.1158/2643-3230.BCD-21-0028}

_{6. van de Donk NWCJ, O’Neill C, de Ruijter MEM, Verkleij CPM, Zweegman S. T-cell redirecting bispecific and trispecific antibodies in multiple myeloma beyond BCMA. Curr Opin Oncol. 2023;35(6):601-611. doi:10.1097/CCO.0000000000000983}

_{7. Zhang X, Zhang H, Lan H, Wu J, Xiao Y. CAR T-cell therapy in multiple myeloma: current limitations and potential strategies. Front Immunol. 2023;14:1101495. doi:10.3389/fimmu.2023.1101495}

_{8. Pont MJ, Hill T, Cole GO, et al. γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019;134(19):1585-1597. doi:10.1182/blood.2019000050}

_{9. FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. FDA. Updated August 10, 2023. Accessed December 5, 2023. https://tinyurl.com/mwbhzxde}

_{10. Touzeau C, Schinke C, Minnema M, et al. S191: pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (bsab), for relapsed/refractory multiple myeloma (RRMM). Hemasphere. 2023;7(suppl 3):e5955094. doi:10.1097/01.HS9.0000967676.59550.94}

_{11. Pillarisetti K, Edavettal S, Mendonça M, et al. A T-cell-redirecting bispecific G-protein-coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma. Blood. 2020;135(15):1232-1243. doi:10.1182/blood.2019003342}

_{12. Cohen AD, Parekh S, Santomasso BD, et al. Incidence and management of CAR T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies. Blood Cancer J. 2022;12(2):32. doi:10.1038/s41408-022-00629-1}