Peripheral neuropathy following bortezomib therapy in multiple myeloma patients: association with cumulative dose, heparanase, and TNF-α.

Multiple myeloma (MM) is a plasma cell neoplasm which constitutes about 10% of all hematologic malignancies. Despite bortezomib is a promising new generation of drugs for MM, its clinical use is limited by peripheral neurotoxicity in the vast majority of patients, which can be severe and require a reduction of dose or even treatment withdrawal. Tumor necrosis factor-α (TNF-α), as the most important inflammatory factor, could induce the inflammatory response and expression of heparanase (HPSE), which may play a crucial role in peripheral neuropathy after chemotherapy. However, the role of TNF-α in bortezomib-induced peripheral neuropathy (BIPN) has not been reported. In this study, treatment-emergent neuropathy was assessed by total neuropathy score and electrophysiological examination. The expression level of TNF-α and HPSE were evaluated by enzyme-linked immunosorbent assay. The effects of anti-TNF-α on the evolution of neuropathy were tested in rat models of neurotoxicity. The results indicated that with the augment of cumulative dose of bortezomib, the incidence of neuropathy was increased. Moreover, bortezomib administration induced the expression of TNF-α. With the increased expression of TNF-α, neuropathy was exacerbated. TNF-α-induced expression of HSPE was secondary to the development of neuropathy. Co-administration of anti-TNF-α in bortezomib therapy has a potential neuroprotective effect on BIPN in rats. TNF-α participates in the pathogenesis of BIPN, which represents an attractive target for future therapeutic intervention.