Plasma cell leukemia (PCL) is a rare aggressive variant of multiple myeloma (MM) characterized by a fulminant course and poor prognosis. The median survival is measured in months. Therapy and prognosis partially depend on whether the disease presents de novo or as a secondary process involving the leukemic transformation of a previously diagnosed MM. Secondary PCL represents a terminal event for refractory/relapsed MM and is usually not responsive to any treatment modality. The optimal regimens for the treatment of primary PCL have not been firmly established. Induction with combination chemotherapy, followed by high-dose chemotherapy (preferably within the setting of a clinical trial), is the current recommended approach for eligible patients.