Despite considerable advances, multiple myeloma (MM) remains incurable and the development of novel therapies targeting the interplay between plasma cells (PCs) and their bone marrow (BM) microenvironment remains essential. We investigated the effect of various agents in vitro on the proliferation, phenotype, morphology, actin polymerization and migration of MM cells and, in vivo, the tumour growth of L363-bearing non-obese diabetic severe combined immunodeficient mice with a deficient interleukin-2 receptor gamma chain (NSG). In vitro, we observed a dose-dependent cytotoxicity with bortezomib and sorafenib. Using RPMI8226 cells co-expressing histone 2B-mCherry and cytochrome c-GFP, bortezomib- and sorafenib-induced apoptosis was confirmed, and both agents combined showed synergism. Sorafenib induced CD138-downregulation and abolished CXCL12-induced actin polymerization. L363 cells expressed CCR4 and CCR5 and migrated to their common ligand CCL5. Chemotaxis to BM stroma cells was notable and significantly reduced by sorafenib. Downregulation of phospho-ERK appeared relevant for the inhibition of actin polymerization and chemotaxis. Sorafenib alone, and combined with bortezomib, showed substantial antitumour activity in L363-bearing NSG. Correspondingly, sorafenib induced clinical responses in MM-/AL-amyloidosis patients. We conclude that, in addition to the cytotoxic and anti-angiogenic effects of sorafenib, blocking of MM cell migration and homing represent promising mechanisms to interrupt the interplay between PCs and their supportive microenvironment.