Future Implications of Targeting GPRC5D in Multiple Myeloma

Nearly 35,000 new cases of MM, a hematologic malignancy resulting from malignant overgrowth of monoclonal plasma cells in the bone marrow, are expected in the United States each year.¹ MM is the second most diagnosed hematologic malignancy, accounting for approximately 1% of all cancer types and has an incidence rate of 4 to 5 cases per 100,000 persons per year in the United States.² Median overall survival (OS) of low-risk patients approaches 10 years; however, high-risk patients have a median OS of only 3 years.³
 
The spectrum of treatment modalities for this disease has expanded significantly with the introduction of novel agents, including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Despite these considerable advances, most patients with MM eventually relapse and will need additional therapies.² However, advances in understanding mechanisms for immune evasion and suppression have led to development of numerous other immunotherapies for patients with R/R MM, including CAR T-cell therapy, antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and cancer vaccines.⁴ These advances may eventually lead to more durable and prolonged outcomes for patients with R/R MM.
 
Karen Louw, NP, specializes in early-phase clinical research in MM at the Center of Excellence for Multiple Myeloma at Mount Sinai Hospital in New York City, New York. She completed her Bachelor of Science in Nursing at the University of Wisconsin-Milwaukee and earned her Master of Science degree at the Hunter-Bellevue School of Nursing in New York City. She is board-certified with the American Nurses Credentialing Center as an adult and geriatric primary care nurse practitioner.

Specific chromosomal mutations in MM, including t(4;14) and del(17p), confer a worse prognosis and are considered high-risk. Can you discuss risk assessment in the context of available novel therapies for patients with R/R MM?

Since we live in an era of the genome project and have access to an array of diagnostic and genomic testing tools and chromosomal analyses, we encounter many mutations. Some are what we call not “druggable.” In fact, there are not a lot of therapies to specifically address most mutations. Prognosis in patients with MM remains heterogeneous and depends on variables including disease burden, tumor biology, and treatment. Although our understanding of molecular risk is rapidly evolving, it is generally agreed that certain high-risk markers confer a worse prognosis, including del(17p), t(14;16), and t(14;20). Determining the optimal therapy for patients with high molecular risk remains a challenge.³
 
The high-risk cytogenetic aberrations, for example translocations such as t(4;14), used to fall into a high-risk category. We now consider that to be an intermediate category, thanks to ongoing research and advances in targeted therapy. While t(4;14) was previously thought of as a poor prognostic indicator for overall response rate and overall survival, we have been able to overcome those poor prognoses such that this mutation is no longer considered high risk with the advent of therapy targeted at a specific translocation. However, it is still important to look at the breadth of these aberrations, given that they might be good clinical targets, while moving certain “traditional” high-risk indicators and aberrations into an intermediate- and potentially low-risk category.

The identification of specific target antigens — CD3, CD38, CD138, CD47, SLAM7, B-cell maturation antigen (BCMA), GPRC5D — expressed on the surface of malignant MM plasma cells has led to development of various immunotherapies for management of R/R MM. Can you briefly review key immunotherapeutic regimens for R/R MM, such as CAR T-cell therapy, ADCs, BiTEs, monoclonal antibodies, and bispecific antibodies?

I am very fortunate to work in several target antigen research groups, specifically in studies of GPRC5D, BCMA, and CAR T-cell therapies. I am excited by recent developments such as the FDA breakthrough therapy designation for talquetamab, a bispecific antibody targeted to both GPRC5D and CD3 receptors for patients with R/R MM.⁵ Looking towards the future of CAR T-cell therapy, we are very hopeful that selected regimens will enable patients with R/R MM to enjoy periods of sustained remission that could improve their overall survival. With MM, we normally tell our patients that the first remission is usually the longest.
 
Our goal, as these patients relapse or become refractory to certain therapies, is to be able to move them onto treatment with a bispecific agent, CAR T-cell therapy, or a combination of these 2 approaches. We can then take these patients out of that R/R poor prognostic realm and into a sustained durable remission for a prolonged period of time. A recently approved CAR T-cell therapy, ciltacabtagene autoleucel, has demonstrated sustained survival and remission in patients with R/R MM.⁷
 
The BiTE class also shows great promise because of its ability to conjugate different types of antibodies, grab on and target specific antigens, and recruit T cells to induce cancer cell apoptosis, with virtually no significant side effects.⁸ Other effective therapies for R/R MM include the anti-CD38 monoclonal antibody daratumumab⁹ and the ADC belantamab mafodotin,¹⁰ which are both approved by the FDA.
 
The original chemotherapy regimens that we used 20 years ago and still employ today carry significant side effects that persist years beyond treatment. With bispecific agents thus far, we are not seeing those side effects. An important caveat, of course, is that we must await more complete long-term data as these agents come to market in the United States and around the world.

Although BCMA-specific CAR T cells have remarkable efficacy in R/R MM, resistance and relapse still occur with single-target immunotherapy. GPRC5D may be an attractive target in CAR T-cell therapy for R/R MM. What are the overall efficacy data on emerging CAR T-cell therapies targeting GPRC5D? 

In the autologous setting, CAR T-cell therapy comprises drawing T cells from the patient, genetically engineering CAR onto that patient’s T cells, and returning these cells to the patient. The engineered T cells essentially function as a homing device for cells expressing that antigen, engaging it on the myeloma cells and inducing a cytotoxic effect.
 
While CAR T-cell immunotherapy is a dramatic advance in the management of R/R MM, we have seen that BCMA-targeted monotherapy with conventional CAR T-cell therapy has led to treatment resistance.
 
The mechanisms underlying development of resistance to anti-BCMA CAR T-cell therapies are largely unclear. Research suggests that resistance may be due to tumor heterogeneity and what is characterized as “antigen escape,” a partial or complete loss of target BCMA antigen expression.¹¹ BCMA is also coexpressed on normal B lymphocytes; consequently, BCMA CAR T-cell therapy could also introduce on-target off-tumor effects, perhaps seeking and binding to CD38 cells or an antigen. These on-target off-tumor effects also can trigger B-cell aplasia, neutropenia, and immunosuppression that leads to increased risk of infection.¹¹ In theory, a next-generation CAR T-cell therapy targeting GPRC5D will not have those effects. Given that myeloma cells are now understood to express GPRC5D, the current bispecific antigen therapy enhances outcomes.

The bispecific antibody talquetamab, which binds to GPRC5D and CD3 to induce T-cell-mediated killing of GPRC5D-expressing MM cells, received FDA breakthrough therapy approval for R/R MM. What key clinical trials data led to its approval?

In June, the GPRC5D-specific antibody talquetamab received the FDA’s breakthrough therapy designation for R/R MM among patients who were heavily pretreated and previously received at least 4 lines of treatment. The most recent data is from the MonumenTAL-1 study (ClinicalTrials.gov Identifier: NCT03399799). In this study, patients receiving a 405 µg/kg weekly dose or an 800 µg/kg biweekly dose of talquetamab both demonstrated a consistent overall response rate. With a median follow-up of 13.2 months, 70% of response-evaluable patients treated with the 405 µg/kg dose achieved a response, 56.7% achieved a very good partial remission or better, 6.7% had a complete response, and 23.3% had a stringent complete response.^5,6 The median follow-up of 13.2 months is very important because when patients are first diagnosed with MM, their initial period of remission is usually the deepest and the longest; once they relapse, that response time shortens and we are not always able to get them back into remission.
 
The data from this study proved that talquetamab conferred a state of remission and achieved a very good partial remission in nearly 60% of the patients treated with the 405 µg/kg dose, which is incredible. It is also impressive that the investigators were able to achieve a 6.7% complete response in patients who were heavily pretreated and statistically would not be expected to go into remission — that was the most clinically meaningful finding that led to the breakthrough designation. In terms of the safety profile of talquetamab, cytokine release syndrome (CRS) was one of the most common side effects, occurring in at least 76% of patients.⁶ Most cases were low-grade CRS events managed with tocilizumab and steroids. Patients responded to the tocilizumab and steroid regimen and were able to continue therapy.

Ongoing studies are evaluating combination regimens to identify potential synergies between immunotherapeutic agents. What is your experience with the combination of the monoclonal antibody daratumumab and talquetamab, pairing BCMA- and GPRC5D-targeting for patients with R/R MM following multiple lines of therapy?

Results of the phase 1b TRiMM-2 study (ClinicalTrials.gov Identifier: NCT04108195) of talquetamab in combination with the anti-CD38 antibody daratumumab showed a high rate of response in patients with R/R MM who were heavily pretreated. With a median follow-up of 5.1 months, the overall response rate was 80.4% among all response-evaluable patients, with 62.7% achieving a very good partial remission or better and 29.4% achieving a complete response or better.^5,12 These responses are notable because some occurred in patients who had been refractory to anti-CD38 treatment, one of the earlier BCMA-directed therapies for patients with MM. That speaks to our ability to achieve better outcomes with the synergistic effect of adding a GPRC5D-targeted agent to the anti-CD38 agent daratumumab.

What are your final thoughts on the future of R/R MM therapies?

I have seen so many patients deal with the treatment challenges of heavily pretreated MM, and the newer treatments and emerging potential therapies offer an exciting future. We are now able to offer CAR T-cell therapies that can be instituted after as few as 4 lines of prior therapy instead of 13 lines (as I have seen in practice), and those patients have deeper responses and bigger survival curves. It is gratifying to see these agents and genomic technologies come to the forefront of treatment for patients with MM. There is also the potential for ongoing research to uncover therapies for patients who were newly diagnosed that lead to durable survival with fewer adverse events or side effects related to therapy. We envision a future scenario in MM in which we are no longer looking at a 2-year or 5-year survival following diagnosis, but at open-ended survival time. These new immunotherapies — CAR T-cell and bispecific therapies in particular — have led to longer survival times with fewer side effects, improving the outlook for our patients with R/R MM.

This Q&A was edited for clarity and length.

References

1. Golden E, Ingram S, Schade H, Matous J, Gregory TK. Novel therapies in BCMA-exposed relapsed/refractory multiple myeloma: the anti-BCMA therapy-refractory patient. touchREVIEWS in Oncology & Haematology. 2022;18(1):59-65. doi:10.17925/OHR.2022.18.1.59

2. Kumar SK, Rajkumar V, Kyle RA, et al. Multiple myeloma. Nat Rev Dis Primers. 2017; 3:17046. doi:10.1038/nrdp.2017.46

3. Lancman G, Tremblay D, Barley K, et al. The effect of novel therapies in high-molecular-risk multiple myeloma. Clin Adv Hematol Oncol. 2017;15(11): 870-879.

4. Shah N, Aiello J, Avigan DE, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma. J Immunother Cancer. 2020;8(2):e000734. doi:10.1136/jitc-2020-000734

5. Minnema MC, Krishnan AY, Berdeja JG, et al. Efficacy and safety of talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): updated results from MonumenTAL-1. J Clin Oncol. 2022;40(suppl 16):8015. doi:10.1200/JCO.2022.40.16_suppl.8015

6. Janssen presents updated results evaluating first-in-class GPRC5D bispecific antibody talquetamab in heavily pretreated patients with multiple myeloma. Janssen Biotech, Inc. Published June 10, 2022. Accessed September 13, 2022. https://www.jnj.com/janssen-presents-updated-results-evaluating-first-in-class-gprc5d-bispecific-antibody-talquetamab-in-heavily-pretreated-patients-with-multiple-myeloma

7. Martin T, Krishnan A, Yong K, et al. Comparative effectiveness of ciltacabtagene autoleucel in CARTITUDE-1 versus physician’s choice of therapy in the Flatiron Health multiple myeloma cohort registry for the treatment of patients with relapsed or refractory multiple myeloma. EJHaem. 2022;3(1):97-108. doi:10.1002/jha2.312

8. Alhallak K, Sun J, Jeske A, et al. Bispecific T cell engagers for the treatment of multiple myeloma: achievements and challenges. Cancers. 2021;13(12):2853. doi:10.3390/cancers13122853

9. Usmani, SZ, Nahi H, Plesner T, et al. Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma: final results from the phase 2 GEN501 and SIRIUS trials. Lancet Haematol. 2020;7(6):e447-e455. doi:10.1016/S2352-3026(20)30081-30088

10. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21: 207-221. doi:10.1016/S1470-2045(19)30788-0

11. Teoh PJ, Chng WJ. CAR T-cell therapy in multiple myeloma: more room for improvement. Blood Cancer J. 2021;11:84. doi:10.1038/s41408-021-00469-5

12. van de Donk NWJC, Bahlis N, Mateos M-V, et al. Novel combination immunotherapy for the treatment of relapsed/refractory multiple myeloma: updated phase 1b results for talquetamab (a GPRC5D x CD3 bispecific antibody) in combination with daratumumab. Abstract presented at: European Hematology Association 2022 Hybrid Congress; June 9-12, 2022; Vienna, Austria. Abstract S183.

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