Multiple myeloma (MM) is a B cell neoplasia characterized by an accumulation of clonal plasma cells (PCs) in the bone marrow (BM). The growth and survival of MM plasma cells is regulated by their network with the microenvironment, mainly with the stromal cells. However, although bone marrow stromal cells have been shown to take part in the pathogenesis of the disease, it is still unknown whether these cells play an active or passive role. Namely, whether normal stromal cells simply supply the demand of MM plasma cells, or, during the course of the disease, they acquire abnormal characteristics becoming pathological. To address this question, we designed an in vitro co-culture model in which PCs isolated by immuno-magnetic separation from MGUS and MM patients are crossed with BM stromal cells (BMSCs) derived from MGUS and MM patients. As a result, four type of co-cultures were obtained: MM-BMSCs/MM-PCs, MM-BMSCs/MGUS-PCs, MGUS-BMSCs/MM-PCs, MGUS-BMSCs/MGUS-PCs. After two days of co-culture in a serum free medium, we evaluated the survival of MM-PCs or MGUS-PCs for each combination. We also quantified by ELISA assays in the supernatants of the same cultures, the level of several growth factors (IL-6, IL-8, VEGF, MIP-1a, MIP-1b, RANTES, MCP-1, TGF-b, SDF-1) to evaluate the possible influence of these cytokines on plasma cells. Multivariate general linear models were applied to compare survival in the different combinations of BMSCs and PCs, also accounting for the various growth factors. MM-BMSCs showed to support the survival of both MM-PCs and MGUS-PCs significantly better than MGUS-BMSCs (p=0.0007). However, in the combination MGUS-PCs/MGUS-BMSCs plasma cells survived statistically better than in that MM-PCs/MGUS-BMSCs (p=0.00003). As regards the cytokines, IL-6, IL-8, VEGF, MIP-1a, MIP-1b, and RANTES did not show to be significantly associated with plasma cell survival in all settings. TGF-B and SDF-1 levels were significantly associated with better survival of both MM-PCs and MGUS-PCs when cultured with MM-BMSCs compared to MGUS-BMSCs (p=0.0001 and p=0.038, respectively), while MCP-1 was significantly associated with reduced survival of MM-PCs and MGUS-PCs in the same setting (p=0.006). In conclusion, these data favours the concept that the behaviour of stromal cells may change during the transition from the condition of MGUS to the overt state of myeloma, evolving from a simple role of a spectator to that of an actor. It also appears that overt MM plasma cells have the highest need for cytokine supply and therefore are more dependent on BMSCs activity.