Insulin like growth factor binding protein 7 (IGFBP7) is a secreted protein binding insulin like growth factor-1 (IGF-1), insulin, vascular endothelial growth factor A (VEGFA), and activin-A. It antagonizes bone morphogenetic proteins (BMPs) and is involved in the pathophysiology of solid and haematological malignancies. We have analysed the BMP antagonist expression profile in a large series of newly diagnosed multiple myeloma patients and found insulin like growth factor binding protein 7 to be downregulated in most cases. We identified methylation as the underlying cause for IGFBP7 silencing in myeloma cells. Higher IGFBP7 expression levels in primary myeloma cells were associated with poorer event-free and overall survival in two independent cohorts comprising 948 newly-diagnosed myeloma patients. The predictive value of IGFBP7 arises from a strong link between IGFBP7 and the translocation t(4;14) associated oncogene MMSET, known to predict poor prognosis in myeloma. In the myeloma microenvironment, IGFBP7 expression in stromal cells is reduced after co-culture with myeloma cells which might be involved in the osteoblast suppressive effects observed in multiple myeloma. IGFBP7 was able to overcome the inhibitory activity of activin-A on osteoblast formation and low expression of IGFBP7 in myeloma cells was associated with advanced myeloma bone disease. Our data reveal IGFBP7 as a marker of high-risk disease in multiple myeloma. In myeloma cases with high IGFBP7 expression the downregulation of this molecule in the microenvironment might be counterbalanced by production in myeloma cells, possibly explaining the correlation of higher intrinsic IGFBP7 expression/translocation t(4;14) and absence of advanced bone disease.