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

  • Weiwei Zhao
  • Wei WangEmail author
  • Xiaoyun Li
  • Yijun Liu
  • Haiyan Gao
  • Yongfang Jiang
  • Ying Wang
Original Article


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.


Multiple myeloma Bortezomib Peripheral neuropathy Heparanase Tumor necrosis factor-α 



This work was supported by the Second Affiliated Hospital of Harbin Medical University.

Funding information

This work was financially supported by grants from the Youth Science Fund of the Natural Science Foundation of China (81001051), Postdoctoral Science Foundation of China (2015M580270), Postdoctoral Science Foundation of Heilongjiang Province (LBH-Z15129), and the Young and middle-aged Science Foundation of Harbin Medical University (KYCX2018-15).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All institutional and national guidelines for the care and use of laboratory animals were followed.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Weiwei Zhao
    • 1
  • Wei Wang
    • 1
    Email author
  • Xiaoyun Li
    • 1
  • Yijun Liu
    • 1
  • Haiyan Gao
    • 1
  • Yongfang Jiang
    • 1
  • Ying Wang
    • 1
  1. 1.Department of HematologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinPeople’s Republic of China

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