Multiple myeloma (MM) remains an incurable disease, at least for the big majority of patients, in spite of the great progress with new drugs in the last years. New treatment strategies are needed to improve the outcome of patients. NF-κB activation in MM is caused by mutations in the factors involved in the NF-κB pathways contributing to their dysregulation and by signals from the bone marrow microenvironment. Agents with NF-κB inhibitory activity enhance the anti-MM effects of conventional chemotherapeutic agents. Bortezomib was the first approved member of a new class of anti-MM agents, the proteasome inhibitors. At least, five proteasome inhibitors of the next generation with greater efficacy (carfilzomib, marizomib (salinosporamide A, NPI-0052), threonine boronic acid-derived proteasome inhibitor CEP-18770, the peptide-semicarbazone S-2209, the tripeptide mimetic BSc2118, and MLN9708/2238) have been recently tested in preclinical models of MM. Carfilzomib has been recently approved for the treatment of patients with MM who have received at least two prior therapies, including bortezomib and immunomodulatory derivatives (IMiDs, thalidomide, lenalidomide or pomalidomide). More specific IκB kinase inhibitors were also used in preclinical studies. The analysis of MM genomes revealed also mutations in genes for histone methyltransferases (HMTases), histone demethylase (UTX) and serine/threonine protein kinase BRAF. Aberrant histone 3 lysine 27 trimethylation (H3K27me3) by mutant HMTases or UTX induces overexpression of the homeobox A9 (HOXA9) gene. HOXA9 is normally expressed in primitive bone marrow cells and is silenced when cells differentiate. HOXA9 is a MM oncogene and targeting of its expression by histone deacetylases inhibitors or by a phosphoinositide 3-kinase (PI3K) inhibitors through an epigenetic mechanism involving H3K27me3. Mutant BRAF kinase small-molecule, ATP-competitive, a highly selective, potent and orally bioavailable inhibitors (GDC-0879, PLX 4032 and PLX 4720) are already under investigation and PLX 4032 is in phase II and phase III clinical trials. Two key signaling pathways involved in the regulation of MM cell growth are the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways and their inhibition are anti-proliferative and pro-apoptotic and can overcome the development of resistance to common drugs.