Plasma cell leukemia (PCL) is a rare and aggressive form of plasma cell dyscrasias. Its special biological characteristics may play an important role in the poor outcome when treated with conventional therapy or even with stem cell transplantation. New treatment approaches based on the biology of this disease are mandatory. Here we present three cases of primary PCL with adverse cytogenetics (deletion 13q14 and translocation 4;14) and specific immunophenotypic features (CD27 antigen strong expression) in which excellent response and sustained remission was achieved with the combination of bortezomib and dexamethasone. The possible role of these biological characteristics is been analyzed.