The combined pathways of the anticancer drugs bortezomib, lonafarnib and COX-2 inhibitors in multiple myeloma. NF-κB is constitutively activated in myeloma cells, leading to overproduction of IL-6 by myeloma cells and cells in the microenvironment. Up-regulation of IL-6 leads to activation of Akt and the Ras-MAP kinase cascade. Therefore, bortezomib, which primarily activates the ubiquitinylation and degradation of NF-κB, blocks multiple growth and survival pathways of myeloma cells, including the Jak/Stat, Akt, and Ras-MAP kinases, resulting in growth arrest by preventing the phosphorylation and, thereby, degradation of the p21 and p27 cyclin-dependent kinase inhibitors and inactivation of modulators of p53 activity (eg, mdm2 and 14-3-3). Down-regulation of Akt activity also results with a decrease in the phosphorylation and activation state of antiapoptotic proteins (eg, Bcl-2, Bclx/l) and proapoptotic proteins (eg, bad and caspase-9). In addition, by direct targeting of NF-κB and indirect targeting of the Ras-MAP kinase pathway, bortezomib exerts antiangiogenic and antimetastatic effects by down-regulating VEGF and c-myc and by down-regulating adhesion molecules on myeloma cells. Lonafarnib is a blocker of farnesyl transferase and may be able to synergize with bortezomib by intensifying the suppression of IGF-1, which acts as growth factor in a different pathway that is not directly linked to the IL-6/NF-κB pathway. Like bortezomib, COX-2 inhibitors block the NF-κB, Akt, and the MAP kinase pathways, albeit through a yet-to-be-identified mechanism.