BACKGROUND: The existing risk models for multiple myeloma (MM) are suboptimal for the stratification of patients with primary plasma cell leukemia (pPCL), a rare and peculiar MM. In this study, we aimed to develop a staging system for pPCL defined as the presence of ≥ 5% circulating plasma cells (CPC) according to the new diagnostic criteria, utilizing one of the largest series of patients with pPCL. METHODS: This multicenter retrospective study included 340 patients with pPCL (the training cohort) from 25 centers nationwide in China. The prognostic impact of baseline characteristics and cytogenetic abnormalities was evaluated. Univariate and multivariate analyses were conducted to identify variables predicting overall survival (OS) to develop a staging system. Its performance was then validated in an independent cohort (n = 80). Genome-wide DNA and RNA sequencing were performed to explore the molecular basis for inter-stage clinical heterogeneity. RESULTS: Del(17p), t(4;14), and t(14;16), but not 1q+, were verified as high-risk cytogenetic abnormalities (HRCAs) of pPCL. HRCA, elevated LDH, and thrombocytopenia had the highest impact on OS and were used to create a simple algorithm, stratifying patients with pPCL into stages I, II, and III, with median OS of 54.1, 24.0, and 5.4 months (II vs. I: HR, 1.986; 95% CI, 1.034-3.814; P = 0.0394; III vs. II: HR, 3.206; 95% CI, 1.757-5.852; P = 0.0001) in the training cohort and 62.1, 31.6, and 21.8 months (II vs. I: HR, 2.013; 95% CI, 0.954-4.251; P = 0.0664; III vs. II: HR, 2.694; 95% CI, 1.136-6.392; P = 0.0245) in the independent validation cohort. The accuracy (c-index 0.711) was higher than other models. Moreover, patients with different stages had highly diverse genomic and transcriptomic aberrations. CONCLUSIONS: We propose a pPCL-specific staging system based on LDH, thrombocytopenia, and cytogenetic abnormalities, which warrants further validation, particularly in a prospective setting.