Multiple myeloma (MM), the second most common hematological malignancies, is characterized by an expansion of malignant plasma cells (PCs) in the bone marrow (BM). Despite the development of novel therapies, MM remains an incurable disease with a 5-7 year survival expectancy. MM is usually proceeded by an asymptomatic premalignant state of clonal PC expansion, i.e. MGUS. Progression of MGUS to MM is a multistep process, which is partially dependent on the acquisition of genetic alterations. However, the fact that MM cells strongly depend on the human BM environment (BME) to survive and expand indicates the crucial role of the BME in the etiology of MM.This project aims to study the BME in MM, in relation to disease progression from MGUS to MM, in order to understand the effect of the BME on the tumor cell, supplying new clues on the necessary factors for MM growth. To this end, I will compare BM stromal cells (BMSCs) from MGUS and MM patients, and those from healthy volunteers, on genomic, molecular, and functional level. Data from these studies will be implemented in a novel human MM model. Since this model is based on BMSCs, it enables to study the role of the BME derived from (1)“healthy” BMSCs, genetically manipulated and (2) MM-derived BMSCs. Both approaches allow analyzing the effect of the BME on MM outgrowth. Moreover, in the second approach the effect of MM-derived BMSCs on the proliferation and survival of MGUS-derived PCs will be analyzed to decipher the role of the BME in disease progression. These experiments will show if the BME can induce the progression of MGUS to MM or that secondary genetic aberrations in MGUS-derived PCs are needed. Taken together, this project will clearly contribute to the understanding of how MM cells use and/or manipulate the BME to survive, progress and expand, but even so important how they develop therapy resistance, information necessary to develop innovative therapeutic strategies and to improve patient’s quality of live