On August 24, 2024, the 12th Lu Daopei Hematology Forum successfully concluded. At the forum, Dr. Zhenyu Li from The Affiliated Hospital of Xuzhou Medical University delivered a compelling presentation titled "GPRC5D CAR-T Therapy for Relapsed and Refractory Multiple Myeloma". He shared insights into the application of GPRC5D-targeted CAR-T cells and BCMA/GPRC5D dual-target CAR-T cells in relapsed and refractory multiple myeloma (R/R MM), as well as the commonalities and differences observed in clinical studies of various types of CAR-T cells. Hematology Frontier presents a summary of the key points from his presentation for our readers.

Anti-GPRC5D Single-Target CAR-T Therapy in R/R MM

In 2023, Professor Li’s team published a single-arm, phase II clinical study on anti-GPRC5D single-target CAR-T therapy in R/R MM in the Journal of Clinical Oncology. A total of 37 R/R MM patients were screened, and 33 received GPRC5D-targeted CAR-T cell infusions. Of these, 12 patients (36%) had International Staging System (R-ISS) stage III disease, 11 (33%) had extramedullary disease (EMD), 12 (36%) had high tumor burden, and 13 (39%) had high-risk cytogenetics. Nine patients (27%) had previously received BCMA-targeted CAR-T cell therapy.

The results showed an overall response rate (ORR) of 91%, with a median time to first response of 0.5 months and a median time to the best response of 1.8 months. Compared to baseline, within one month of treatment, patients who responded showed a significant reduction in serum monoclonal immunoglobulin G (IgG), kappa light chains, and lambda light chains.

Among the nine patients who had received previous BCMA CAR-T cell therapy, six had relapsed MM, and three had progressive disease (PD) following BCMA CAR-T treatment. Remarkably, all nine patients (100%) responded to anti-GPRC5D CAR-T therapy, with four achieving complete remission (CR) and two achieving very good partial responses (VGPR).

The most common adverse events (AEs) were hematologic toxicities. Cytokine release syndrome (CRS) occurred in 25 of 33 patients (76%), with no observed cases of grade 3 or higher CRS. Among the 32 patients who survived more than three months, nine (28%) experienced grade 1 nail changes, which improved without intervention.

Levels of IL-6, ferritin, and C-reactive protein (CRP) peaked on days 14 and 7 post-CAR-T infusion. Peak levels of IL-6, ferritin, and CRP were higher in patients with CRS compared to those without CRS, and these markers significantly increased during CRS compared to baseline.

Overall, anti-GPRC5D CAR-T therapy for R/R MM demonstrated good safety and efficacy, making it a viable alternative for patients who had previously received BCMA CAR-T therapy.

Anti-BCMA/GPRC5D Dual-Target CAR-T Therapy in R/R MM

In 2024, Professor Li’s team published a phase I, single-arm, single-center clinical study on anti-BCMA/GPRC5D dual-target CAR-T therapy in The Lancet Haematology. A total of 21 patients with R/R MM were included, 11 (52%) of whom expressed both BCMA and GPRC5D. Additionally, 10 patients (48%) had high-risk cytogenetics, and four (19%) had EMD.

The overall response rate (ORR) was 86%. In the dose-escalation trial, the ORR for dose level 1 (0.5×10⁶/kg) was 33%, 100% for dose level 2 (1.0×10⁶/kg), 92% for dose level 3 (2.0×10⁶/kg), and 100% for dose level 4 (4.0×10⁶/kg), though dose level 4 exhibited higher toxicity.

In the BCMA/GPRC5D dual-positive group, the response rate was 82%, while in the BCMA+GPRC5D- group, it was 83%. The BCMA-GPRC5D+ group had a 100% response rate.

One notable case involved a 58-year-old male with cranial EMD, where CAR-T cells were detectable in cerebrospinal fluid. After three months, his cranial EMD had completely disappeared.

The study did not reach median response duration, progression-free survival (PFS), or overall survival (OS), but the estimated 10-month PFS rate for CAR-T infusion patients was 67%, with levels 2 and 3 achieving an 84% PFS rate.

Hematologic toxicity was the most common AE, with 71% of patients developing CRS, all of which were grade 1–2. Hematologic toxicity was dose-dependent.

CAR-T cell expansion correlated with infusion dose and clinical response, but BCMA/GPRC5D expression was not associated with CAR expansion or clinical response.

In summary, increasing target coverage did not lead to higher incidence or severity of CAR-T-associated toxicities. The study demonstrated promising clinical efficacy, particularly in BCMA or GPRC5D antigen-negative patients. However, more patients previously treated with BCMA or GPRC5D CAR-T are needed to validate these findings.

Comparing Different CAR-T Therapies for R/R MM

In 2022, Professor Li’s team published a study comparing different CAR-T therapies for R/R MM. The results showed that the transduction efficiency of anti-BCMA/GPRC5D dual-target CAR-T and anti-GPRC5D CAR-T was similar, while anti-BCMA CAR-T exhibited relatively higher transduction efficiency.

Preclinical studies demonstrated that anti-BCMA/GPRC5D dual-target CAR-T cells could clear MM cells expressing only BCMA, only GPRC5D, or both BCMA and GPRC5D. In vitro, anti-BCMA/GPRC5D dual-target CAR-T cells exhibited similar activity against MM cells compared to anti-BCMA or anti-GPRC5D CAR-T cells.

Clinical trials showed that GPRC5D CAR-T achieved an ORR of 91%, CD19+BCMA CAR-T had a 92% ORR, and anti-BCMA/GPRC5D dual-target CAR-T achieved an 86% ORR. Toxicities mainly included neutropenia, anemia, and thrombocytopenia, with CRS rates of 76%, 95%, and 71%, respectively.

In conclusion, while different CAR-T cell types showed similar early responses, larger sample sizes and longer follow-up periods are needed to evaluate long-term outcomes. Anti-BCMA/GPRC5D dual-target CAR-T showed better safety than CD19+BCMA CAR-T but was similar to GPRC5D CAR-T.

GPRC5D CAR-T in Other Centers

The MCARH109 study reported a partial response (PR) rate of 71% across all dose groups, with CRS occurring in 88% of patients. Neutropenia occurred in 100% of patients, and 88% experienced thrombocytopenia. The OriCAR-017 study reported an ORR of 100%, with 30% of patients experiencing nail changes. The BMS-986393 study found a neutropenia rate of 69% and an ORR of 75% in patients who had previously received BCMA therapy, while the ORR was 94.4% in the same group. CRS occurred in 84% of cases. The CT071 study reported a 90% ORR, 50% CRS rate, and relatively low rates of hematologic toxicity.

Multiple centers have shown similar overall response rates for GPRC5D CAR-T. In Chinese clinical trials, extracorporeal toxicities, such as nail changes and taste disorders, seem less common. However, cerebellar diseases remain difficult to manage and require further research.

Dr. Zhenyu Li Ph.D., Chief Physician, Ph.D. Supervisor Director of the Hematology Department, The Affiliated Hospital of Xuzhou Medical University Deputy Director of the Jiangsu Bone Marrow Stem Cell Research Institute Member of the Hematology Branch of the Chinese Medical Association Member of the Plasma Cell Disease Group, Hematology Branch of the Chinese Medical Association Member of the Multiple Myeloma Committee, Hematology Branch of the Chinese Medical Association Committee Member of the Hematologic Oncology Committee, Chinese Anti-Cancer Association President-Elect of the Hematology Branch of the Jiangsu Medical Association Deputy Chairperson of the Hematology Branch of the Jiangsu Medical Association Recipient of Jiangsu’s “333 Talent Program” and “Six Talent Peaks” programs As the principal investigator, he has led two National Natural Science Foundation projects, one sub-project of the National Key Research and Development Program, and one clinical project from the Jiangsu Science and Technology Department. He has published papers as a corresponding author in JCO, Blood, Lancet Haematology, JTCT, BMT, and other journals. Research Focus: Basic and clinical research on multiple myeloma.