Multiple myeloma(MM)is a malignant plasma cell neoplasia,accounting for about 10%hematopoietic cancers and 1%of all cancers.Survival of MM patients has significantly improved after the approved treatment with the proteasome inhibitor bortezomib and immunomodulatory drugs(IMiDs)including thalidomide and its derivatives lenalidomide and pomalidomide.IMiDs were recently shown to bind and activate the E3 ubiquitin ligase CRL4(CRBN)to promote the proteasomal degradation of two transcription factors IKZF1 and IKZF3,which are essential for MM cell survival.Since bortezomib inhibits the degradation of IKZF1 and IKZF3,it is difficult to mechanistically justify the better clinical response in MM patients treated with both IMiDs and bortezomib than IMiDs alone.We performed a CRISPR-based genome-wide knockout screen for pomalidomide resistance and found that CRBN is inherently unstable.When unbound to CRL4,CRBN is targeted by another ubiquitin ligase SCF(Fbxo7)for ubiquitination and degradation,a process negatively regulated by the COP9 signalosome.Inactivation of SCF(Fbxo7)or treatment with bortezomib stabilizes CRBN.IMiDs further promote the loading of CRBN to CRL4,leading to enhanced turnover of IKZF1 and IKZF3 and synergistic inhibition of MM cell proliferation.We also identified a novel phosphorylation-dependent signaling cascade that activates the CRL4 ubiquitin ligase.Serendipitously,two anti-myeloma drugs,dexamethasone and panobinostat,which have been approved for combination therapies against MM,activates the responsible kinase.Our findings provide a mechanistic framework to guide future combination therapies with IMiDs to maximize IMiD efficacy to treat MM.