Pharmacological targeting of Ikaros by the immunomodulatory drug lenalidomide ameliorated the response of MM cells to LPS in a CD180-dependent manner <i>in vitro</i> and <i>in vivo</i> Thus, the CD180/MD-1 pathway may represent a novel mechanism of growth regulation of MM cells in a BM milieu and may be a therapeutic target of preventing the regrowth of dormant MM cells.<b>Significance:</b> This study describes a novel mechanism by which myeloma cells are regulated in the bone marrow, where drug resistance and dormancy can evolve after treatment, with potential therapeutic implications for treating this often untreatable blood cancer.<i></i>.