Metastatic infiltration of nervous tissue and periosteal nerve sprouting in multiple myeloma induced bone pain

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin-gene related protein (CGRP+) and growth associated protein 43 (GAP43+) fibres occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone and found alterations in pathways associated with cell cycle, immune response and neuronal signalling. The MM transcriptional signature was consistent with metastatic MM infiltration to the DRG, a never-before described feature of the disease that we further demonstrated histologically. In the DRG, MM cells caused loss of vascularization and neuronal injury, which may contribute to late-stage MIBP. Interestingly, the transcriptional signature of a MM patient was consistent with MM cell infiltration to the DRG. Overall, our results suggest that MM induces a plethora of peripheral nervous system alterations that may contribute to the failure of current analgesics and suggest neuroprotective drugs as appropriate strategies to treat early onset MIBP. Significance statement Multiple myeloma induces periosteal nerve sprouting and metastasizes to the dorsal root ganglia, damaging blood vessels and causing transcriptional alterations that may mediate myeloma-induced bone pain. Conflicts of interest The authors declare no competing financial interests