The prognosis of multiple extramedullary plasmacytomas (MEP) and plasma cell leukemia (PCL) is extremely poor, with the median overall survival (OS) of only 8 months with standard chemotherapy. Innovative treatment approaches incorporating various strategies are required to improve outcome. From November 2019 to September 2021, a total of 12 newly diagnosed MEP or PCL patients were enrolled in our department. An intensive chemotherapy treatment as VRD-PDCE consisted of bortezomib, lenalidomide, dexamethasone plus cisplatin, pegylated liposomal doxorubicin, cyclophosphamide and etoposide was first proposed. Disease activity and toxicity were evaluated after each cycle. Of the patients receiving therapy achieved a rapid and sustained response, and the overall response rate (ORR) was up to 75%. Nine patients achieved partial response (PR) or better, the response was the best response and the median time to best response was 4 cycles. Median overall survival (OS) and progression-free survival (PFS) were 24 (5-30) months and 18 (2-23) months. The toxicities were acceptable and there was no treatment related mortality. Our intensive treatment showed encouraging results in terms of disease control and improving survival, VRD-PDCE may be a novel regimen which is feasible and generally well-tolerated in MEP or PCL patients.