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=3·3×10⁻³). 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).

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.

Funding

German Federal Ministry of Education and Research, Dutch Cancer Foundation Queen Wilhelmina, European Hematology Association, International Myeloma Foundation, Erasmus MC, and Janssen-Cilag Orthobiotech.

Introduction

Bortezomib (Millennium Pharmaceuticals, Cambridge, MA, USA) is a boronic acid dipeptide, which specifically inhibits the chymotryptic site of the 26S proteasome. In patients with newly diagnosed myeloma, bortezomib in combination with conventional drugs resulted in high rates of complete response and very good partial response.1, 2, 3, 4 This drug is generally well tolerated; however, one of its most frequent and potentially disabling side-effects is the development of a painful, sensory peripheral neuropathy,5, 6, 7 often requiring dose modification or discontinuation of bortezomib, which negatively affects clinical endpoints and quality of life.⁸ Grade 1 and 2 bortezomib-induced peripheral neuropathy can arise in 27–75% of patients with recurrent multiple myeloma and in 25–33% of those with newly diagnosed multiple myeloma, whereas grade 3 and 4 peripheral neuropathy might affect 0–30% of patients with recurrent disease and 0–18% of those with newly diagnosed disease.⁹ In most patients, this side-effect is reversible and does not seem to be affected by the number or type of previous treatments.⁷ Bortezomib-induced peripheral neuropathy results from axonal degeneration,10, 11 often occurring within the first cycles of treatment, and does not seem to increase after the fifth cycle of bortezomib.⁷

Little is known about the mechanism of bortezomib-induced peripheral neuropathy, but a multifactorial pathogenesis seems likely. Damage to mitochondria and endoplasmic reticulum through activation of apoptosis has been seen in dorsal root ganglia of mice given bortezomib.¹¹ Additionally, mechanisms such as dysregulation of mitochondrial calcium homoeostasis,¹² autoimmune factors and inflammation,¹³ and blockade of nerve-growth-factor-mediated neuronal survival through inhibition of the activation of nuclear factor κB (NFκB)⁶ could contribute to bortezomib-induced peripheral neuropathy. Evidence that multiple myeloma is also implicated in peripheral neuropathy was described by Ropper and Gorson¹⁴ in 1998. Baseline neuropathy is present in 15–20% of patients with newly diagnosed myeloma,15, 16 which might be of both axonal and demyelinating subtypes.¹⁴ The role of myeloma-related factors in peripheral neuropathy related to treatment is not clear. Bortezomib-induced peripheral neuropathy was noted at higher frequencies in patients with multiple myeloma than in those with solid tumours.¹⁷ Richardson and colleagues¹⁶ characterised the possible role of myeloma-related factors in bortezomib-induced peripheral neuropathy using plasma cells from patients with multiple myeloma. Additionally, we have noted that inherited single-nucleotide polymorphisms (SNPs) are associated with a higher probability of developing thalidomide-induced or bortezomib-induced peripheral neuropathy (Corthals SL, unpublished data). We therefore analysed myeloma-related gene expression and inherited patient variations as indicators of the potential risk of developing treatment-related peripheral neuropathy. We investigated whether particular molecular profiles were specific for early-onset versus late-onset bortezomib-induced peripheral neuropathy and compared these with genetic profiles associated with early-onset versus late-onset vincristine-induced peripheral neuropathy to elucidate molecular differences associated with the development of peripheral neuropathy after the different treatments.