Poor outcome in multiple myeloma is linked to high expression of HPSE and correspondingly high serum levels of shed Sdc1.6, 10, 11, 12, 15, 21 Here, we show using myeloma cells, and extending the finding to endothelial cells as well, that an active motif in shed Sdc1 promotes an invasive phenotype by coupling VEGFR2 to VLA-4. Here, KDR is linked to plasma cell myeloma.