The two major signaling cascades we identified, TGFβ signaling through its signal transducers SMADs and circadian rhythm regulation by RORA and Rev-ErbA, integrate immunoglobulin trait modulation, TH17 cell differentiation, and bone morphogenesis, and may provide a mechanistic link between the predisposition markers and intrinsic multiple myeloma biology. Here, RORA is linked to plasma cell myeloma.