Remarkable expression of vascular endothelial growth factor in bone marrow plasma cells of patients with POEMS syndrome

- BMPCs, mainly polyclonal, are the source of VEGF overproduction in POEMS patients.
- Monoclonal BMPCs have high IL-6 expression, and may trigger reactive plasmacytosis.
- Detectable monoclonal BMPCs at diagnosis were associated with inferior survival.

Vascular endothelial growth factor (VEGF) is pathognomonically elevated in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome. However, its source of overproduction is unclear. As clinical improvement is almost always associated with VEGF reduction after anti-plasma cell therapy, its increase at diagnosis has been attributed to the underlying monoclonal gammopathy, although direct evidence is still lacking. In the current study, we systemically measured VEGF levels in POEMS patients, before and after treatment. Bone marrow plasma cells showed remarkable VEGF expression, in both mRNA and protein levels, which decreased gradually in response to therapy. Of note, statistically linear correlations were observed between serum and bone marrow plasma cell VEGF levels (mRNA vs. serum, rho 0.343, p = 0.003; protein vs. serum, rho 0.644, p < 0.0001), supporting bone marrow plasma cells as the main source of circulating VEGF. Intriguingly, immunophenotyping revealed that bone marrow plasma cells were polyclonal in most patients at diagnosis. A clear monoclonal population, coexistent with polytypic cells, was only detectable in 11 cases (18%), in which comparable intracellular VEGF expression was observed between these two plasma cell populations (p = 0.594), while monoclonal cells showed higher intracellular interleukin-6 expression (p = 0.006). These patients had more serum monoclonal protein, less post-therapeutic complete remission, and inferior overall (p = 0.027) and progression-free survival (p = 0.002). Collectively, bone marrow plasma cells, mainly polyclonal population, are the major source of VEGF overproduction in POEMS patients.