Anti-myeloma mechanisms of the selective NF-κB inhibitor QNZ

Multiple myeloma (MM) is a plasma-cell malignancy driven by dysregulated NF-κB signaling, promoting tumor survival, proliferation, and chemoresistance. Given observed overexpression of NF-κB components in MM cell lines, we evaluated the selective NF-κB inhibitor QNZ (EVP4593) for anti-myeloma activity. QNZ selectively reduced viability and inhibited proliferation of MM cells in vitro and ex vivo, though stromal contact partly attenuated its cytotoxicity. QNZ dose-dependently suppressed MM xenografts, increased apoptosis, and reduced proliferation, while preserving MM plasma cell identity. Mechanistically, QNZ triggered mitochondrial, caspase- (cleavage of pro-caspase-9, -8 and -3) and PARP-mediated apoptosis with downregulation of Mcl-1, dismantled pro-survival NF-κB/Akt/c-Myc signaling with concomitant mTOR modulation, and induced cell-cycle perturbation accompanied by altered phospho-ATM and decreased levels of key regulators (SIRT1, Chk2/p-Chk2, Cdc2/p-Cdc2, p-4EBP1, CDK4, cyclin A2, and cyclin B1). Transcriptomic profiling demonstrated that QNZ treatment induced extensive gene expression reprogramming in MM cells, prominently upregulating stress- and metabolism-associated genes including DDIT3, PHGDH, SESN2, and NFE2L1, consistent with activation of ER stress-mediated apoptotic and amino acid metabolic pathways. Finally, QNZ displayed significant synergy with proteasome inhibitors and IMiDs, particularly second-generation carfilzomib and pomalidomide, as well as with dexamethasone and melphalan, providing a strong preclinical rationale for clinical evaluation of QNZ in MM.