DISCUSSION
cerebral hemorrhage, tumor, Leukopenia, abnormal coagulation, neutropenic, MM, High-grade hematologic toxic, thrombocytopenia, CRS, infection, hemorrhage, Anemia, deaths
CEREBRAL HEMORRHAGE, TUMOR, LEUKOPENIA, ABNORMAL COAGULATION, EMD, THROMBOCYTOPENIA, INFECTION, HEMORRHAGE, ANEMIA, EVENTS
Treatment with GPRC5D CAR T cells resulted in high antitumor activities in patients with R/R MM in the phase Ⅱ study. The responses were observed in 91% of the treated patients, and CRs or better were observed in 64%. The fact that MRD-negative responses occurred in approximately 80% of the patients highlights the depth of response induced by anti-GPRC5D CAR T-cell therapy. The patients were refractory to available therapies with multiple high-risk features, including 73% of patients with a high tumor burden, high-risk cytogenetic abnormalities, EMD, or failed BCMA-directed CAR T-cell therapies. Responses were observed in all these subgroups. Our study demonstrated that anti-GPRC5D CAR T-cell therapy induced encouraging efficacy in the R/R MM populations, especially in those who have failed in anti-BCMA CAR T-cell therapy or progressed after responding to the treatment.Recently, Mailankody et alBCMA-targeted CAR T-cell therapy has shown unprecedented results in treating R/R MM.In this study, peak levels of GPRC5D-CARs amplification appeared to be lower in patients without clinical responses than in those with responses, but the difference was not statistically significant, and it may be related to the small number of patients without responses (n = 3). In addition, two patients with GPRC5D-CARs amplification at 7 months remained in sCR, which further supported the necessity of effective amplification of GPRC5D-CARs for clinical responses. We also analyzed the expression of GPRC5D on plasma cells before CAR T-cell therapy. There was no significant difference in response rates between the high GPRC5D expression cohort and patients with low GPRC5D expression. Previous studies have shown that ATRA induced significant amounts of GPRC5D expression,Therapy-related AE, CRS in particular, is an important consideration for a new CAR T-cell product, which might elicit exacerbation of conditions and treatment-related deaths. The incidence of CRS was less than 80%, and all cases were grade 1 or 2 in our study. In the study by Mailankody et al,High-grade hematologic toxic events were common but transient. Leukopenia was mainly observed after lymphodepleting chemotherapy. No severe infection occurred during the neutropenic phase, which was shortened by injection of granulocyte colony-stimulating factor. Anemia and thrombocytopenia were present in some patients before lymphodepleting chemotherapy, and further decreases were not remarkable during CAR T-cell therapy. One patient died of cerebral hemorrhage. The patient had a very low platelet count throughout treatment, but had no abnormal coagulation leading to the hemorrhage, and we presume that cerebral hemorrhage might be attributed to the severe thrombocytopenia. Because of the relatively short follow-up period, the dynamics of humoral immune reconstitution cannot be fully reflected, but IgM is the earliest to recover, similar to the anti-BCMA CAR T-cell therapy that we reported previously.Dermatologic and oral AEs have been reported in previous studies involving GPRC5D-targeted therapy in patients with R/R MM.Some limitations should be considered in our study. The study population was only from China and was less heavily pretreated than some of the previous CAR T studies,In conclusion, anti-GPRC5D CAR T-cell therapy induced a high response rate, and the grades of all CRS events were 1 to 2, with low incidence of ICANS in the study. Anti-GPRC5D CAR T cells might be a very potential candidate treatment for patients with MM progressed after anti-BCMA CAR T-cell therapy or refractory to anti-BCMA CAR T cells.