Background: GPRC5D, a type-C 7-pass transmembrane receptor protein, is predominantly expressed on malignant plasma cells from MM patients. The autologous GPRC5D-directed CAR-T cell (OriCAR-017), owning to an additional proprietary Ori element, is the 2nd generation CAR-T cell with improvement in expansion and durability. Methods: The primary objective of this study was to evaluate safety and tolerability of OriCAR-017. Key enrolment criteria included measurable MM adults, R/R or intolerant to established therapies. Patient received lymphodepleting chemotherapy with fludarabine 30mg/m²/d and cyclophosphamide 300mg/m²/d for 3 days followed by a single infusion of OriCAR-017. The trial followed 3+3 design with 1×10⁶/kg, 3×10⁶/kg and 6×10⁶/kg CAR⁺ T cells cohorts. Results: Eleven patients were enrolled and underwent apheresis during June 9, 2021 and January 31, 2022. 9pts have completed infusion and 8pts available for efficacy and safety evaluation, the 9th pt completed infusion at January 23, 2022. 2 pts were suspended infusion due to rapid disease progression. Of the 9 infused pts, median age 65 years (range41-71) and a median of 6 (range3-17) prior therapy lines; 3 (33.0%)/1 (11.0%) triple-class/penta-drug exposed; 2 (22.0%)/1 (11.0%) triple-class/penta-drug refractory; 4 (44.0%) prior BCMA CART therapy. Five out of 6pts had high-risk cytogenetic profiles including 2pts with del(17p). No dose-limiting toxicities occurred. The most common TEAEs were neutropenia (G3/4 100%), thrombocytopenia (G3/4 100%), leukopenia (G3/4 100%), lymphopenia (G3/4 100%) and anemia (G3/4 87.5%). All pts experienced CRS with 7pts in G1, 1pt in G2. All CRSs were rapidly relieved after conventional intervention(tocilizumab and steroids). The median onset time was 3 days (range0-8), median duration 6 days (range5-8). No neurologic toxicities were reported. No nail disorders were reported. 8pts avaliable for efficacy evaluation, median follow up time was 109.5 days (range32-195 days). A 100.0% ORR were observed with 3pts CR/sCR, 2pts VGPR, 3pts PR. Three out of 4pts with prior BCMA CAR-T therapy were available for efficacy evaluation-1sCR, 1VGPR, 1PR. After infusion, 8pts were MRD negative in the bone marrow by flow cytometry (10^-5) at day 28, 5pts continued at month 3 and 1pt at month 6. Robust OriCAR-017 expansion in peripheral blood by using qPCR for 8pts, median peak was 507,463.6copies/ml (range152093.7 – 1121996.9), median time to peak expansion was 10 days (range7-14). Conclusions: In this phase I study, OriCAR-017 was showed safe and impressive efficacy in RRMM patients. Majority of AEs were transient and manageable. 100% ORR and 100% MRD negative rate, along with favorable safety support OriCAR-017 to be a competitive therapy for RRMM. Furthermore, patients who had relapsed from BCMA CAR-T therapy may still benefit from OriCAR-017. Clinical trial information: NCT05016778.