open access

Vol 52, No 4 (2021)
Review article
Submitted: 2021-08-02
Accepted: 2021-08-02
Get Citation

Peripheral neuropathy in patients with multiple myeloma: molecular effects of bortezomib

Karolina Łuczkowska1, Bogusław Machaliński1
DOI: 10.5603/AHP.2021.0071
·
Acta Haematol Pol 2021;52(4):375-381.
Affiliations
  1. Department of General Pathology, Pomeranian Medical University, Szczecin, Poland

open access

Vol 52, No 4 (2021)
REVIEW ARTICLE
Submitted: 2021-08-02
Accepted: 2021-08-02

Abstract

Multiple myeloma (MM) is a B cell neoplasm characterized by uncontrolled growth of malignant plasma cells within the bone marrow. The introduction of new treatment regimens and medicinal substances, particularly proteasome inhibitors (e.g. bortezomib or carfilzomib) and immunomodulatory drugs (e.g. lenalidomide, pomalidomide, and monoclonal antibodies), have radically changed MM therapy by improving the response rate and progression-free survival. However, these potentially effective drugs are associated with a number of side effects, the most serious of which include peripheral neuropathy, which appears in 40% of MM patients with bortezomib treatment and up to 70% with thalidomide treatment during long-term exposure. Usually, symptoms of neuropathy disappear after drug discontinuation or dose reduction. However, as a result, the effectiveness of the treatment is lowered and survival time is reduced. The pathogenesis of chemotherapy-induced peripheral neuropathy  is not fully understood. Current research focuses on areas such as the change in the expression of genes responsible for the proper functioning of the nervous system, neuroprotective protein factors, oxidative stress, pro-inflammatory factors and epigenetic changes (miRNA, DNA methylation or histone acetylation). Thoroughly elucidating the mechanisms responsible for the development of chemotherapy-induced peripheral neuropathy will allow us to reduce/eliminate this side effect and improve quality of life for patients.

Abstract

Multiple myeloma (MM) is a B cell neoplasm characterized by uncontrolled growth of malignant plasma cells within the bone marrow. The introduction of new treatment regimens and medicinal substances, particularly proteasome inhibitors (e.g. bortezomib or carfilzomib) and immunomodulatory drugs (e.g. lenalidomide, pomalidomide, and monoclonal antibodies), have radically changed MM therapy by improving the response rate and progression-free survival. However, these potentially effective drugs are associated with a number of side effects, the most serious of which include peripheral neuropathy, which appears in 40% of MM patients with bortezomib treatment and up to 70% with thalidomide treatment during long-term exposure. Usually, symptoms of neuropathy disappear after drug discontinuation or dose reduction. However, as a result, the effectiveness of the treatment is lowered and survival time is reduced. The pathogenesis of chemotherapy-induced peripheral neuropathy  is not fully understood. Current research focuses on areas such as the change in the expression of genes responsible for the proper functioning of the nervous system, neuroprotective protein factors, oxidative stress, pro-inflammatory factors and epigenetic changes (miRNA, DNA methylation or histone acetylation). Thoroughly elucidating the mechanisms responsible for the development of chemotherapy-induced peripheral neuropathy will allow us to reduce/eliminate this side effect and improve quality of life for patients.

Get Citation

Keywords

bortezomib-induced peripheral neuropathy, multiple myeloma

About this article
Title

Peripheral neuropathy in patients with multiple myeloma: molecular effects of bortezomib

Journal

Acta Haematologica Polonica

Issue

Vol 52, No 4 (2021)

Article type

Review article

Pages

375-381

DOI

10.5603/AHP.2021.0071

Bibliographic record

Acta Haematol Pol 2021;52(4):375-381.

Keywords

bortezomib-induced peripheral neuropathy
multiple myeloma

Authors

Karolina Łuczkowska
Bogusław Machaliński

References (57)
  1. Dimopoulos MA, Terpos E. Multiple myeloma. Ann Oncol. 2010; 21: vii143–vii150.
  2. Corre J, Munshi N, Avet-Loiseau H. Genetics of multile myeloma: another heterogeneity level? Blood. 2015; 125(12): 1870–1876.
  3. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014; 28(5): 1122–1128.
  4. Mikulasova A, Smetana J, Wayhelova M, et al. Genomewide profiling of copy-number alteration in monoclonal gammopathy of undetermined significance. Eur J Haematol. 2016; 97(6): 568–575.
  5. Walker BA, Wardell CP, Johnson DC, et al. Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. Blood. 2013; 121(17): 3413–3419.
  6. González D, van der Burg M, García-Sanz R, et al. Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma. Blood. 2007; 110(9): 3112–3121.
  7. Chesi M, Nardini E, Brents LA, et al. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet. 1997; 16(3): 260–264.
  8. Iida S, Rao PH, Butler M, et al. Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. Nat Genet. 1997; 17(2): 226–230.
  9. Lauring J, Abukhdeir AM, Konishi H, et al. The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood. 2008; 111(2): 856–864.
  10. Smadja NV, Bastard C, Brigaudeau C, et al. Groupe Français de Cytogénétique Hématologique. Hypodiploidy is a major prognostic factor in multiple myeloma. Blood. 2001; 98(7): 2229–2238.
  11. Mikkilineni L, Kochenderfer JN. CAR T cell therapies for patients with multiple myeloma. Nat Rev Clin Oncol. 2021; 18(2): 71–84.
  12. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020; 95(5): 548–567.
  13. Richardson PG, Sonneveld P, Schuster MW, et al. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol. 2009; 144(6): 895–903.
  14. Prince HM, Schenkel B, Mileshkin L. An analysis of clinical trials assessing the efficacy and safety of single-agent thalidomide in patients with relapsed or refractory multiple myeloma. Leuk Lymphoma. 2009; 48(1): 46–55.
  15. Chen D, Frezza M, Schmitt S, et al. Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets. 2011; 11(3): 239–253.
  16. Staff NP, Grisold A, Grisold W, et al. Chemotherapy-induced peripheral neuropathy: a current review. Ann Neurol. 2017; 81(6): 772–781.
  17. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011; 12(5): 431–440.
  18. Lakshman A, Modi M, Prakash G, et al. Evaluation of bortezomib-induced neuropathy using total neuropathy score (reduced and clinical versions) and NCI CTCAE v4.0 in newly diagnosed patients with multiple myeloma receiving bortezomib-based induction. Clin Lymphoma Myeloma Leuk. 2017; 17(8): 513–519.e1.
  19. Grammatico S, Cesini L, Petrucci MT. Managing treatment-related peripheral neuropathy in patients with multiple myeloma. Blood Lymphat Cancer. 2016; 6: 37–47.
  20. Adams J, Kauffman M. Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest. 2004; 22(2): 304–311.
  21. Field-Smith A, Morgan GJ, Davies FE. Bortezomib (Velcadetrade mark) in the treatment of multiple myeloma. Ther Clin Risk Manag. 2006; 2(3): 271–279.
  22. Cavaletti G, Gilardini A, Canta A, et al. Bortezomib-induced peripheral neurotoxicity: a neurophysiological and pathological study in the rat. Exp Neurol. 2007; 204(1): 317–325.
  23. Meregalli C, Canta A, Carozzi VA, et al. Bortezomib-induced painful neuropathy in rats: a behavioral, neurophysiological and pathological study in rats. Eur J Pain. 2010; 14(4): 343–350.
  24. Meregalli C. An overview of bortezomib-induced neurotoxicity. Toxics. 2015; 3(3): 294–303.
  25. Landowski TH, Megli CJ, Nullmeyer KD, et al. Mitochondrial-mediated disregulation of Ca2+ is a critical determinant of Velcade (PS-341/bortezomib) cytotoxicity in myeloma cell lines. Cancer Res. 2005; 65(9): 3828–3836.
  26. Landowski TH, Megli C, Dorr RT, et al. Calcium-mediated mitochondrial perturbation is a critical determinant of Velcade (PS-341/bortezomib) cytotoxicity in myeloma cell lines. Proc Amer Assoc Cancer Res. 2005; 65(9): 3828–3836.
  27. Zhuang GZ, Keeler B, Grant J, et al. Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway. PLoS One. 2015; 10(3): e0118273.
  28. Meyer M, Matsuoka I, Wetmore C, et al. Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA. J Cell Biol. 1992; 119(1): 45–54.
  29. Vargas MR, Pehar M, Cassina P, et al. Stimulation of nerve growth factor expression in astrocytes by peroxynitrite. In Vivo. 2004; 18(3): 269–274.
  30. Mousavi K, Jasmin BJ. BDNF is expressed in skeletal muscle satellite cells and inhibits myogenic differentiation. J Neurosci. 2006; 26(21): 5739–5749.
  31. Grasman JM, Kaplan DL. Human endothelial cells secrete neurotropic factors to direct axonal growth of peripheral nerves. Sci Rep. 2017; 7(1): 4092.
  32. Nakahashi T, Fujimura H, Altar CA, et al. Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Lett. 2000; 470(2): 113–117.
  33. Nockher WA, Renz H. Neurotrophins in clinical diagnostics: pathophysiology and laboratory investigation. Clin Chim Acta. 2005; 352(1-2): 49–74.
  34. Leßmann V, Brigadski T. Mechanisms, locations, and kinetics of synaptic BDNF secretion: an update. Neurosci Res. 2009; 65(1): 11–22.
  35. Paczkowska E, Kaczyńska K, Pius-Sadowska E, et al. Humoral activity of cord blood-derived stem/progenitor cells: implications for stem cell-based adjuvant therapy of neurodegenerative disorders. PLoS One. 2013; 8(12): e83833.
  36. Paczkowska E, Piecyk K, Luczkowska K, et al. Expression of neurotrophins and their receptors in human CD34+ bone marrow cells. J Physiol Pharmacol. 2016; 67(1): 151–159.
  37. Paczkowska E, Łuczkowska K, Piecyk K, et al. The influence of BDNF on human umbilical cord blood stem/progenitor cells: implications for stem cell-based therapy of neurodegenerative disorders. Acta Neurobiol Exp (Wars). 2015; 75(2): 172–191.
  38. Azoulay D, Lavie D, Horowitz N, et al. Bortezomib-induced peripheral neuropathy is related to altered levels of brain-derived neurotrophic factor in the peripheral blood of patients with multiple myeloma. Br J Haematol. 2014; 164(3): 454–456.
  39. Mallet ML, Hadjivassiliou M, Sarrigiannis PG, et al. The role of oxidative stress in peripheral neuropathy. J Mol Neurosci. 2020; 70(7): 1009–1017.
  40. Weniger MA, Rizzatti EG, Pérez-Galán P, et al. Treatment-induced oxidative stress and cellular antioxidant capacity determine response to bortezomib in mantle cell lymphoma. Clin Cancer Res. 2011; 17(15): 5101–5112.
  41. Janes K, Doyle T, Bryant L, et al. Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase. Pain. 2013; 154(11): 2432–2440.
  42. Jannuzzi AT, Arslan S, Yilmaz AM, et al. Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib. Redox Biol. 2020; 32: 101502.
  43. Hung AL, Lim M, Doshi TL. Targeting cytokines for treatment of neuropathic pain. Scand J Pain. 2017; 17: 287–293.
  44. Zhao W, Wang W, Li X, et al. Peripheral neuropathy following bortezomib therapy in multiple myeloma patients: association with cumulative dose, heparanase, and TNF-α. Ann Hematol. 2019; 98(12): 2793–2803.
  45. Alé A, Bruna J, Morell M, et al. Treatment with anti-TNF alpha protects against the neuropathy induced by the proteasome inhibitor bortezomib in a mouse model. Exp Neurol. 2014; 253: 165–173.
  46. Piperdi B, Ling YH, Liebes L, et al. Bortezomib: understanding the mechanism of action. Mol Cancer Ther. 2011; 10(11): 2029–2030.
  47. Weinhold B. Epigenetics: the science of change. Environ Health Perspect. 2006; 114(3): A160–A167.
  48. Fernández de Larrea C, Martín-Antonio B, Cibeira MT, et al. Impact of global and gene-specific DNA methylation pattern in relapsed multiple myeloma patients treated with bortezomib. Leuk Res. 2013; 37(6): 641–646.
  49. Kuehbacher A, Urbich C, Zeiher AM, et al. Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res. 2007; 101(1): 59–68.
  50. Adamia S, Fulciniti M, Avet-Loiseau H, et al. Biological and therapeutic potential of Mir-155, 585 and Let-7f in myeloma in vitro and in vivo. Blood. 2009; 114(22): 833–833.
  51. Luczkowska K, Litwinska Z, Paczkowska E, et al. Pathophysiology of drug-induce peripheral neuropathy in patients with multiple myeloma. J Physiol Pharmacol. 2018; 69(2).
  52. Łuczkowska K, Rogińska D, Ulańczyk Z, et al. Molecular mechanisms of bortezomib action: novel evidence for the miRNA-mRNA interaction involvement. Int J Mol Sci. 2020; 21(1).
  53. Łuczkowska K, Rogińska D, Ulańczyk Z, et al. Effect of bortezomib on global gene expression in PC12-derived nerve cells. Int J Mol Sci. 2020; 21(3).
  54. Lü S, Wang J. The resistance mechanisms of proteasome inhibitor bortezomib. Biomark Res. 2013; 1(1): 13.
  55. Allmeroth K, Horn M, Kroef V, et al. Bortezomib resistance mutations in PSMB5 determine response to second-generation proteasome inhibitors in multiple myeloma. Leukemia. 2021; 35(3): 887–892.
  56. Furukawa Y, Kikuchi J, Furukawa Y, et al. Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma. J Clin Invest. 2015; 125(12): 4375–4390.
  57. Łuczkowska K, Sokołowska K, Taryma-Lesniak O, et al. Bortezomib induces methylation changes in SH-SY5Y neuroblastoma cells that may play a significant role in development of resistance to this compound. Sci Rep. 2021; 11(1): 9846.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk, Poland
tel.:+48 58 320 94 94, fax:+48 58 320 94 60, e-mail: journals@viamedica.pl