INTRODUCTION: We conducted a single-arm, open-label dose-exploration study to evaluate the safety and efficacy of the histone deacetylase inhibitor tucidinostat combined with bortezomib, liposomal doxorubicin, and dexamethasone (C-PDD) in treating relapsed and refractory multiple myeloma (RRMM) patients. METHODS: Eighteen patients were enrolled from August 2020 to May 2021, receiving 21-day cycles of C-PDD. RESULTS: Eighteen cases were analysed, with a median prior treatment line of 2 (range: 1-4). The median number of completed treatment cycles was 4 (range: 1-8). The overall response rate was 57%, including 14% complete response, 14% very good partial response, and 29% partial response. Both bortezomib-sensitive and refractory groups had a response rate of 57%. The response rate was 100% in patients with extramedullary extraosseous involvement. The median follow-up was 42 months (range: 3-44), with median progression-free survival of 7 months and median overall survival of 24.5 months. Grade 3-4 haematologic adverse events included thrombocytopaenia (50%), neutropenia (33%), and anaemia (33%). Non-haematologic adverse events were mostly grade 1-2, with 1 case of grade 3 peripheral sensory neuropathy. CONCLUSION: The C-PDD regimen showed efficacy in RRMM, including bortezomib-refractory disease and EME patients. The optimal dose and combination need to be explored in the future.