The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Careful evaluation of peripheral blood for the presence of circulating plasma cells by morphologic assessment or by flow cytometric analysis is an essential component of the diagnostic workup in all patients with newly diagnosed multiple myeloma (MM) to timely differentiate between MM and primary plasma cell leukemia (pPCL), which is the most aggressive plasma cell dyscrasia. The improvement in survival over time is more modest in pPCL, compared with what has been achieved in MM. pPCL is currently defined by the presence of ≥ 5% circulating plasma cells. However, this cutoff is now challenged by new data, from three large cohorts of patients with newly diagnosed MM, showing that a threshold of 2% circulating tumor cells (CTCs) by flow cytometry can be used to identify a subset of patients with ultra-high-risk MM with comparable prognosis as patients with pPCL. These patients may benefit from more intensified first-line therapies, or from enrollment into specific clinical trials, designed for ultra-high-risk MM and pPCL. Apart from differentiating MM from pPCL, the quantification of CTCs is also useful for risk stratification in MM. The detection of CTCs above a threshold of 0.01%-0.07% (much lower than the threshold to define pPCL) appears to be an independent predictor of poor clinical outcomes in newly diagnosed MM. Additional studies, including transplant-ineligible patients or with incorporation of novel immunotherapies, are needed to identify a definitive prognostic CTC cutoff. The next step will be the incorporation of CTC detection into existing staging systems to improve risk stratification and treatment personalization.