A promiscuous array of mutations activate the classical and alternative NFκB pathways in MM. (A) Mutations of several genes (CD40, TACI, LTBR, CYLD, TRAF2, TRAF3, cIAP1, cIAP2, NIK, NFκB1, NFκB2, BTRC, CARD11, IKBIP, IKBKB, MAP3K1, RIPK4, TLR4, and TNFRSF1A) that result in activation of the NFκB pathways have recently been identified. (B) In PCs and early during neoplastic transformation, the cells are dependent on extrinsic ligands (BAFF and APRIL) to activate the NFκB pathway. With tumor progression, the cells acquire mutations that result in constitutive activation of the NFκB pathway and stromal independence or other mutations as yet unknown, which substitute for the requirement for NFκB activation. Different therapeutic interventions that may be effective at the distinct stages of tumor progression are shown at the bottom.