The diagnosis of primary plasma cell leukemia (pPCL) has been made by quantifying circulating plasma cells (cPCs) morphologically on a peripheral blood (PB) smear. However, this technique is not sufficiently sensitive. Multiparametric flow cytometry (MFC) provides a readily available and highly sensitive method to identify and quantify cPCs that could complement PB smear assessment. However, an optimal quantitative cutoff for cPCs by MFC to identify pPCL has not been established. Thus, a total of 591 patients newly diagnosed multiple myeloma (NDMM) patients who had their PB samples evaluated morphologically by PB smear and immunophenotypically by MFC prior to beginning therapy were evaluated. The presence of >200 cPCs/microliter (L) by MFC (N=25 or 5% of the total population) was chosen to identify patients with >5% cPCs by PB smear with a specificity of 99% and a sensitivity of 77%. For patients with >200 cPCs/L by MFC compared to the remainder of the cohort, the median TTNT was 18 vs. 30 months and the median OS was 38 vs. 70 months respectively. Thus, MFC assessment of PB can be utilized in conjunction with the morphological assessment of a PB smear to aid in improving the identification of pPCL among NDMM patients. This article is protected by copyright. All rights reserved.