In order to evaluate putative changes of major adhesion molecule expression on plasma cells (PCs) associated with malignant transformation, tumor spreading, and immortalization, we have quantified and compared the expression of CD56, CD44, CD11a, CD49e, and CD45 RO/RA on normal PCs, malignant PCs from multiple myeloma patients in chronic phase, in accelerated phase with or without extramedullary progression, and from human myeloma cell lines. Plasma cell phenotype was defined with the use of two-color immunofluorescence in combination with B-B4 or anti-CD38 antibodies. We found that all the adhesion antigens were expressed on normal PCs. Malignancy was characterized by an overexpression of CD56, whereas extramedullary spreading was associated with a dramatic down expression of CD56. Although CD44 remained unchanged, the subpopulation of PCs expressing CD11a, CD49e, and CD45RA/RO were significantly reduced during malignancy, and each of these negative subpopulations increased during disease acceleration. We demonstrated that CD11a and CD49e expression were correlated and defined the same subpopulation of PCs. The phenotype of HMCLs was similar to the expression profile of patients in accelerated phase with extramedullary spreading. In conclusion, we show that significant changes of PC phenotype were associated with malignancy, were correlated with the disease evolution, and could be of diagnostic and prognostic value in individuals with monoclonal gammopathy and patients with multiple myeloma.