Multiple Myeloma Gammopathies

POEMS syndrome remains a mystery after 40 years

To the Editor:

The acronym POEMS was coined by Bardwick et al. in 1980 to describe a paraneoplastic syndrome due to an underlying monoclonal gammopathy [1]. Although our understanding of its manifestations, treatment and prognosis has advanced in recent years, the critical genetic events occurring in its plasma cells are not fully elucidated. Chen et al. reported a highly heterogenous mutational profile in 42 POEMS patients [2]. The results were largely concordant with a previous study from Japan; however, significantly discordant findings were also evident [3].

Both studies utilized a two-step approach, whole exome followed by targeted sequencing, to tackle the somatic mutations in bone marrow plasma cells prepared by CD138 magnetic beads sorting. Of the seven recurrently mutated genes identified by Nago et al., five were validated by Chen et al. However, the later study reported a much higher mutation frequency (87.5% vs. 45.0%) as well as unique driver mutations associated with multiple myeloma in POEMS patients. Beside different sample size and sequencing depth mentioned by Chen et al., other possible explanations underlying the discordance also need to be considered, such as patient characteristics. Compared to the newly diagnosed cases with classic λ light chain-restriction in Chen’s study, Nago et al. included relapsed as well as non-λ cases. Of note, only one of the five (20.0%) relapsed patients had a mutation.

The real burning question is whether these mutations happen in the POEMS-specific clone, which only represents a minor population (median 14.7%) among bone marrow plasma cells and was not isolated in both studies [4]. In addition, this clone was only detected in 65.7% POEMS patients in a study when using routinely available diagnostic tools, including flow cytometry, immunohistochemistry, and/or in situ hybridization [5]. Even with the advance of deep sequencing technologies, the detection rate (50.0–82.8%) is still not satisfactory [4, 6]. Single-cell genomic sequencing has the potential to answer this question.

Markedly elevated circulating vascular endothelial growth factor (VEGF) level is a distinct feature of POEMS syndrome and could account for most of its clinical manifestations. The link between reported mutations and VEGF elevation is missing. Hypoxia-sensing pathway is the master regulator of VEGF expression, and mutations in its components, both hereditary (e.g., Chuvash polycythemia) and sporadic (e.g., glioblastoma multiforme) are associated with raised circulating VEGF [7, 8]. It is noteworthy that genes of hypoxia-sensing pathway were not included in the targeted sequencing panels of both studies. Their whole exome sequencing may not be capable to detect low frequency mutations due to the limited sequencing depth, which was also corroborated by the observation that targeted sequencing revealed more mutations in both studies. Given that alterations of hypoxia-sensing components usually lead to modest VEGF elevation, interactions with the currently reported POEMS mutations could be further explored.

Even though mechanistic questions are yet to be answered, revealing the genomic profile of POEMS deepens our understanding of this mysterious disease and its pathogenesis awaits the dawn hopefully in the near future.

References

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Correspondence to Chen Wang.

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Wang, C. POEMS syndrome remains a mystery after 40 years. Leukemia (2021). https://doi.org/10.1038/s41375-021-01168-7

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