Although multiple myeloma (MM) is characterized by a monoclonal expansion of plasma cells, it has been assumed that the tumor clone also includes more immature B cells. We could demonstrate by DNA sequence analysis of the variable region in immunoglobulin (Ig) heavy chain genes, that myeloma patients have peripheral blood monoclonal B cells that have not switched their Ig isotype but are somatically hypermutated. This finding suggests that myeloma originates from a germinal center B cell of the lymph node, most probably a memory B cell or B lymphoblast. The identification of these cells in the peripheral blood circulation implies that they must be equipped with homing receptors that allow them to migrate from the lymph node to the marrow environment. Within the marrow compartment these precursors will receive the appropriate differentiation signals to become mature tumor cells. The growth and survival of these bone marrow (BM) plasma cells is believed to be regulated by a functional interplay with the surrounding marrow stroma involving different adhesive mechanisms and the action of several cytokines. We found that myeloma plasma cells express several adhesion molecules (ICAM-1, N-CAM, CD44, VLA-4). Myeloma cell lines can bind to purified fibronectin (FN) using mostly the VLA-4 receptor. However this interaction contributes only partially to binding with intact stromal layers. In contrast, the post-HDM aplasia was significantly shortened in two of the schedule B patients (3 to 10 days) and was followed by a 25- to 165-fold increase in CD34+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)