TrkA abundance is increased in cutaneous nerves in bortezomib-induced neuropathy

Tropomyosin receptor kinase A (TrkA), a high-affinity receptor for nerve growth factor (NGF), is implicated in nociception and local angiogenesis. We investigated TrkA localization and abundance in skin biopsies from multiple myeloma patients who developed peripheral neuropathy during bortezomib treatment. We recruited 50 multiple myeloma patients with bortezomib-induced peripheral neuropathy (BIPN), including 31 without pain and 19 with pain, and 27 matched healthy controls at University Hospital Würzburg (2021-2024). Skin biopsies from the distal leg were analyzed to determine intraepidermal nerve fiber density (IENFD) and area, TrkA mean fluorescence intensity (MFI) and gene expression levels. Additionally, the area of blood vessels and proximity to nerves was measured. BIPN patients exhibited significant sensory abnormalities, decreased IENFD, and increased TrkA protein abundance in surviving epidermal nerve fibers, correlating with cycles of bortezomib treatment. No substantial difference in TrkA gene expression was observed between groups. All BIPN patients demonstrated increased dermal vascularization compared with control, and only those without pain showed increased nerve-vessel interactions. These results suggest a strong association between dysregulated TrkA signaling and altered neurovascular interactions with small fiber pathology in BIPN.