We report on the different expression of CD56 and CD44 in plasma cells (PCs) simultaneously collected from bone marrow, extramedullary locations and peripheral blood in seven patients with multiple myeloma. Extramedullary PCs showed absence of CD56. In the bone marrow, however, subsets with varying CD56 expression were found in five out of seven patients, with one subset corresponding to that of extramedullar PCs. This differs from the de novo downregulation of CD56 in PC leukaemia, and suggests different mechanisms of spread of myeloma cells. CD44 expression was generally upregulated on extramedullary PCs. In three of the patients we investigated the clonal origin of extramedullary myeloma cells by sequencing the variable portion of the heavy chain immunoglobulin gene in phenotypically defined PCs isolated from different locations. In each patient we found malignant PCs with different homing behaviour originating from a common precursor cell.