Cytokine Dynamics in Bortezomib‐Induced Peripheral Neuropathy: Challenges in Translating Preclinical Findings to Humans

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BACKGROUND AND AIMS: Bortezomib-induced peripheral neuropathy (BIPN) remains a common treatment side effect in patients with multiple myeloma (MM). Data from rodent models indicate a role of proinflammatory cytokines in BIPN pathophysiology, making them potential therapeutic targets. We therefore tested cytokine levels throughout the course of BIPN in a cohort of MM patients. METHODS: We performed an interim analysis of a monocentric, non-randomized, observational study including 113 patients with MM. Three groups of patients-within their first cycle of BTZ treatment (FC), with ongoing BTZ treatment at the time of recruiting (OT), and with BTZ treatment in the past (PT)-were compared to controls. Sixteen FC patients were followed up for a median of 6 months. Serum TNF-α, IL-6, and CCL2, the cytokines most often implied in the animal models, were analyzed via the ELLA device. RESULTS: CCL2 levels were not different among our patient groups or in comparison with healthy controls. Compared to healthy controls, the FC group had the highest IL-6 levels, followed by the PT and then the OT group. The FC group also had higher TNF-α levels compared to all other groups. Six months after inclusion, patients showed a decrease in TNF-α levels compared to their baseline. There was no correlation between TNF-α levels and neuropathy severity or impairment in daily life. INTERPRETATION: Factors related to MM may influence systemic cytokine levels in BIPN patients, limiting conclusions on their role in BIPN pathophysiology and their utility as drug targets.

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