title: Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial.
abstract: BACKGROUND
  Bortezomib-induced peripheral neuropathy is a dose-limiting toxicity in patients with multiple myeloma, often requiring adjustment of treatment and affecting quality of life. We investigated the molecular profiles of early-onset (within one treatment cycle) versus late-onset (after two or three treatment cycles) bortezomib-induced peripheral neuropathy and compared them with those of vincristine-induced peripheral neuropathy during the induction phase of a prospective phase 3 trial.
  
  
  METHODS
  In the induction phase of the HOVON-65/GMMG-HD4 trial, patients (aged 18-65 years) with newly diagnosed Salmon and Durie stage 2 or 3 multiple myeloma were randomly assigned to three cycles of bortezomib-based or vincristine-based induction treatment. We analysed the gene expression profiles and single-nucleotide polymorphisms (SNPs) of pretreatment samples of myeloma plasma cells and peripheral blood, respectively. This study is registered, number ISRCTN64455289.
  
  
  RESULTS
  We analysed gene expression profiles of myeloma plasma cells from 329 (39%) of 833 patients at diagnosis, and SNPs in DNA samples from 369 (44%) patients. Early-onset bortezomib-induced peripheral neuropathy was noted in 20 (8%) patients, and 63 (25%) developed the late-onset type. Early-onset and late-onset vincristine-induced peripheral neuropathy was noted in 11 (4%) and 17 (7%) patients, respectively. Significant genes in myeloma plasma cells from patients that were associated with early-onset bortezomib-induced peripheral neuropathy were the enzyme coding genes RHOBTB2 (upregulated by 1·59 times; p=4·5×10(-5)), involved in drug-induced apoptosis, CPT1C (1·44 times; p=2·9×10(-7)), involved in mitochondrial dysfunction, and SOX8 (1·68 times; p=4·28×10(-13)), involved in development of peripheral nervous system. Significant SNPs in the same patients included those located in the apoptosis gene caspase 9 (odds ratio [OR] 3·59, 95% CI 1·59-8·14; p=2·9×10(-3)), ALOX12 (3·50, 1·47-8·32; p=3·8×10(-3)), and IGF1R (0·22, 0·07-0·77; p=8·3×10(-3)). In late-onset bortezomib-induced peripheral neuropathy, the significant genes were SOD2 (upregulated by 1·18 times; p=9·6×10(-3)) and MYO5A (1·93 times; p=3·2×10(-2)), involved in development and function of the nervous system. Significant SNPs were noted in inflammatory genes MBL2 (OR 0·49, 95% CI 0·26-0·94; p=3·0×10(-2)) and PPARD (0·35, 0·15-0·83; p=9·1×10(-3)), and DNA repair genes ERCC4 (2·74, 1·56-4·84; p=1·0×10(-3)) and ERCC3 (1·26, 0·75-2·12; p=3·3×10(-3)). By contrast, early-onset vincristine-induced peripheral neuropathy was characterised by upregulation of genes involved in cell cycle and proliferation, including AURKA (3·31 times; p=1·04×10(-2)) and MKI67 (3·66 times; p=1·82×10(-3)), and the presence of SNPs in genes involved in these processes-eg, GLI1 (rs2228224 [0·13, 0·02-0·97, p=1·18×10(-2)] and rs2242578 [0·14, 0·02-1·12, p=3·00×10(-2)]). Late-onset vincristine-induced peripheral neuropathy was associated with the presence of SNPs in genes involved in absorption, distribution, metabolism, and excretion-eg, rs1413239 in DPYD (3·29, 1·47-7·37, 5·40×10(-3)) and rs3887412 in ABCC1 (3·36, 1·47-7·67, p=5·70×10(-3)).
  
  
  CONCLUSIONS
  Our results strongly suggest an interaction between myeloma-related factors and the patient's genetic background in the development of treatment-induced peripheral neuropathy, with different molecular pathways being implicated in bortezomib-induced and vincristine-induced peripheral neuropathy.
authors.affiliation: Department of Haematology, Erasmus MC, Rotterdam, Netherlands. a.broyl@erasmusmc.nl
authors.forename: Annemiek
authors.initials: A
authors.lastname: Broyl
authors.forename: Sophie L
authors.initials: SL
authors.lastname: Corthals
authors.forename: Joost Lm
authors.initials: JL
authors.lastname: Jongen
authors.forename: Bronno
authors.initials: B
authors.lastname: van der Holt
authors.forename: Rowan
authors.initials: R
authors.lastname: Kuiper
authors.forename: Yvonne
authors.initials: Y
authors.lastname: de Knegt
authors.forename: Mark
authors.initials: M
authors.lastname: van Duin
authors.forename: Laila
authors.initials: L
authors.lastname: el Jarari
authors.forename: Uta
authors.initials: U
authors.lastname: Bertsch
authors.forename: Henk M
authors.initials: HM
authors.lastname: Lokhorst
authors.forename: Brian G
authors.initials: BG
authors.lastname: Durie
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001897:Boronic Acids / Q000009:adverse effects*; D000069286:Bortezomib; D016009:Chi-Square Distribution; D005060:Europe; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D009367:Neoplasm Staging; D016017:Odds Ratio; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011719:Pyrazines / Q000009:adverse effects*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014750:Vincristine / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D014750:Vincristine; D000069286:Bortezomib