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

Summary 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. Findings 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