Microenvironmentally secreted proteins such as R-spondins collaborate with HS-decorated syndecan-1 to activate Wnt/ligands, leading via Frizzled to β-catenin–mediated induction of multiple downstream targets critical for MM cell growth and survival, including c-Myc and cyclin D1. Interruption of this process (eg, at the level of HS via monoclonal antibodies or heparitinase) can block this sequence of events, leading to inhibition of MM cell proliferation. It is possible that disabling this process at a more distal point (eg, by β-catenin antagonists) might recapitulate these effects. mAb, monoclonal antibody.