On the other hand, discoveries that multiple myeloma patients with inactivating mutations in c-IAP1 and 2, as well as knockouts and knockdowns of c-IAP1/2, have constitutive activation of non-canonical NF-κB pathway definitively demonstrated the seminal role of c-IAP E3 ligase activity in the suppression of NIK and non-canonical NF-κB signaling (49–52). This evidence concerns the gene NFKB1 and plasma cell myeloma.