The Evolving Treatment Landscape of Multiple Myeloma: GPRC5D-Targeted CAR T-Cell Therapy

Multiple myeloma (MM) is the second most common hematologic malignancy; it is estimated to impact nearly 35,780 individuals (19,520 men and 16,260 women) in 2024, according to the American Cancer Society.¹ MM is incurable, but is considered highly treatable, largely due to development of innovative therapies and advancing these effective therapies to earlier lines of treatment for patients. However, there remains an unmet need among high-risk patients in both newly diagnosed and relapsed settings, which emerging treatments like G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted chimeric antigen receptor (CAR) T-cell therapy seek to address.^2,3

Continued research into GPRC5D-targeted CAR T-cell therapy is needed to identify methods of overcoming toxicities to improve treatment response rates and overall health outcomes for patients with MM. Image Credit: © Animager - stock.adobe.com

Standard-of-care treatment practice for MM traditionally includes immunomodulatory agents, proteasome inhibitors, dexamethasone (Decadron; Merck), or chemotherapy, followed by autologous stem cell transplantation. However, the success of these therapies is often impacted by the high tendency for patients with MM to relapse and develop drug resistance. Compared with traditional first-line treatment of MM, advanced therapeutic approaches with different mechanisms of action, namely immunotherapeutic treatments and bispecific antibodies, offer more targeted treatments that have demonstrated potent efficacy in pretreated patients.³

“We're bringing more effective therapies up earlier in lines of treatment. So instead of waiting for relapse refractory to introduce some different treatments, now we're saying, ‘what do we do if we move that earlier?’” said Ryan Haumschild, PharmD, MS, MBA, CPEL, vice president of ambulatory pharmacy at Emory Healthcare Winship Cancer Institute, in an interview with Pharmacy Times. “So now starting maybe triplets or quadruplets in the frontline setting, introducing innovative combinations earlier, such as bispecifics, [and] looking at cell therapies. We’re [moving] those up in earlier lines of therapy.”³

CAR T-cell therapy is a novel immunotherapy that involves collecting a patient’s T cells and engineering them to express receptors, called CARs, that target and destroy specific antigens found on the surface of cancer cells. Once modified and multiplied, the T cells are reintroduced to the patient’s immune system to seek out and attack malignant cells. Clinical trials have shown efficacy and improved patient responses when targeting proteins with high expression in MM, such as cluster of differentiation 38, B-cell maturation antigen (BCMA), and GPRC5D.⁴

In a recent discussion with Pharmacy Times, Omar Nadeem, MD, clinical director of the Myeloma Immune Effector Cell Therapy Program at the Dana Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, discussed data and promising outcomes associated with GPRC5D-targeted CAR T-cell therapy from the CC-95266-MM-001 (NCT04674813) study, which was presented at the European Hematology Association 2024 Hybrid Congress.

“GPRC5D is a new target that's been discovered on the [MM] cells,” Nadeem said. “We now have several agents that are either in development or [are] already approved for targeting GPRC5D that have led to pretty impressive results.”

Approximately 90% of patients with MM exhibit high expression of GPRC5D, an orphan protein and emerging therapeutic target, found on the surface of cancer cells with an unknown ligand. In MM, GPRC5D mRNA is highly expressed in the bone marrow and is associated with more genetic abnormalities and aggressive disease, but the exact role of GPRC5D in worsening disease is not fully understood.^2,5

In the phase 1 CC-95266-MM-001 multicenter, open-label study, Nadeem and his colleagues assessed the safety and preliminary efficacy of GPRC5D-targeted CAR T-cell therapy at varying dosages in participants with relapsed/refractory (R/R) MM. Data from cohort C, whom had received 1 to 3 prior treatments and were mostly refractory to immunomodulatory agents and proteasome inhibitors, demonstrated promising overall response (ORR) and complete response rates (CRR).⁶

“In that early line population, the [ORR] was 96%, with a [CRR] that was 42%,” Nadeem said. “These numbers look in line with what we had seen in the heavily pretreated cohort. So, responses do seem to be quite high in both early and late-line therapy in this phase 3 trial.”

GPRC5D CAR T-cell therapy does present with toxicities, resulting in various adverse effects (AEs) for patients receiving treatment. Typical AEs of CAR T-cell usually include cytokine release syndrome (CRS) and neurotoxicity; however, patients being treated with GPRC5D-targeted therapies are presenting with additional symptoms like dysgeusia, an altered perception of taste, as well as nail and skin changes.

“GPRC5D has very unique toxicities associated with it. We see very high rates of dysgeusia, in particular, and weight loss in patients that are receiving talquetamab [Talvey; Janssen Biotech, Inc], which is the bispecific antibody that targets GPRC5D,” said Nadeem. "That has been quite a limiting factor in terms of its widespread use in the clinic and has significant quality-of-life implications when patients do have these tastes changes that then lead to weight loss.”

Continued research into GPRC5D-targeted CAR T-cell therapy is needed to identify methods of overcoming toxicities to improve treatment response rates and overall health outcomes for patients with MM. In an interview, Haumschild shared potential early intervention opportunities clinicians can take to get ahead of AEs associated with bispecifics and CAR T-cell therapy.

“We've managed cell therapy for a while, but I think with bispecifics, we're seeing less CRS, but maybe delayed CRS,” he said. “So how are we getting ahead of it? We're looking at pre-treatment options, looking at developing outpatient infrastructure, like an intermediate care center, where those patients can arrive and be treated and evaluated in a timely manner.”

The CC-95266-MM-001 study will continue with a phase 2 trial, which will assess the efficacy of GPRC5D-targeted CAR T-cell therapy at a dose of 150 million cells. The preliminary results from phase 1 have promising implications for the evolving therapeutic landscape of MM treatment in high-risk patients, offering them advanced treatments that improve their treatment responses, reduced AEs, and enhanced overall quality-of-life post-treatment.

“What we're seeing so far is a very high response rate with a 1-time CAR T-cell infusion, both in patients that have had multiple relapses, and also now in earlier lines of therapy,” Nadeem shared. “We see lower incidence of infections that we sometimes see with BCMA-targeted therapy, and we're seeing much lower on-target off-tumor effects that are transient. So, hopefully that'll lead to the ideal balance of high efficacy and low toxicity in patients that are treated with this particular product.”

References

1. Key statistics about multiple myeloma. American Cancer Society. January 19, 2024. Accessed July 1, 2024. https://www.cancer.org/cancer/types/multiple-myeloma/about/key-statistics.html
2. A novel bispecific anti-GPRC5D × CD3 antibody: a new treatment paradigm in multiple myeloma. Pharmacy Times. May 21, 2024. Accessed July 1, 2024. https://www.pharmacytimes.com/view/a-novel-bispecific-anti-gprc5d-cd3-antibody-a-new-treatment-paradigm-in-multiple-myeloma
3. From research to practice: new treatment modalities for patients with multiple myeloma. Pharmacy Times. June 20, 2024. Accessed July 1, 2024. https://www.pharmacytimes.com/view/from-research-to-practice-new-treatment-modalities-for-patients-with-multiple-myeloma
4. CAR T-cell therapy and its side effects. American Cancer Society. March 1, 2022. Accessed July 1, 2024. https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/car-t-cell1.html
5. Rodriguez-Otero P, van de Donk N.W.C.J., Pillarisetti K, et al. GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review. Blood Cancer J. February 2, 2024. doi: 10.1038/s41408-023-00966-9
6. CC-95266-MM-001: A Study of CC-95266 CAR-T Cells in Subjects With Relapsed or Refractory Multiple Myeloma (CARTITUDE-4). NCT identifier NCT04674813. National Library of Medicine. January 26, 2024. Accessed July 1, 2024. https://clinicaltrials.gov/ct2/show/NCT04674813