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.

摘要

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=4.5x10(-5)), involved in drug-induced apoptosis, CPT1C (1.44 times; p=2.9x10(-7)), involved in mitochondrial dysfunction, and SOX8 (1.68 times; p=4.28x10(-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=2.9x10(-3)), ALOX12 (3.50, 1.47-8.32; p=3.8x10(-3)), and IGF1R (0.22, 0.07-0.77; p=8.3x10(-3)). In late-onset bortezomib-induced peripheral neuropathy, the significant genes were SOD2 (upregulated by 1.18 times; p=9.6x10(-3)) and MYO5A (1.93 times; p=3.2x10(-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=3.0x10(-2)) and PPARD (0.35, 0.15-0.83; p=9.1x10(-3)), and DNA repair genes ERCC4 (2.74, 1.56-4.84; p=1.0x10(-3)) and ERCC3 (1.26, 0.75-2.12; p=3.3x10(-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=1.04x10(-2)) and MKI67 (3.66 times; p=1.82x10(-3)), and the presence of SNPs in genes involved in these processes-eg, GLI1 (rs2228224 [0.13, 0.02-0.97, p=1.18x10(-2)] and rs2242578 [0.14, 0.02-1.12, p=3.00x10(-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, 5.40x10(-3)) and rs3887412 in ABCC1 (3.36, 1.47-7.67, p=5.70x10(-3)). INTERPRETATION: 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.