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Impact of the sympathetic nervous system on multiple myeloma

Dear Editor,  Multiple myeloma (MM), the second most common blood cancer in the United States, is a neoplasm of immunoglobulin-producing plasma cells that depend on the bone marrow (BM) for growth and survival. Quintessential disease manifestations include a serum M-spike (paraprotein), osteolytic lesions, hypercalcemia, anemia and kidney damage. Owing to targeted myeloma drugs, newly developed immunotherapies and the refinement of therapeutic regimens that combine high-dose chemotherapy with autologous hematopoietic stem cell (HSC) transplants, the outcome of MM has significantly improved in recent years. Nonetheless, after a period of successful therapy, the great majority of patients relapse with drug-resistant disease that leaves few therapeutic options. Despite significant advances in our understanding of the mechanism with which the BM microenvironment (BMM) supports myeloma, little attention has been paid to an integral yet understudied player in the tumor microenvironment (TME): the autonomic nervous system (ANS). Autonomic nerves, which can be divided into an adrenergic "fight-orflight" sympathetic branch and a cholinergic "rest-anddigest" parasympathetic branch, interact with the BMM. In the past the ANS has been perceived as a passive bystander in myeloma and related blood cancers, yet increasing evidence reviewed in greater depth elsewhere implicates autonomic nervous input – particularly from the sympathetic nervous system (SNS) – in the natural history and outcome of myeloma. Here, we summarize findings on the role of the SNS in MM and point to knowledge gaps that may afford exciting opportunities for international research collaboration with myeloma and blood cancer centers in China.