The unclear role of VEGF in POEMS syndrome: therapeutic implications of neoangiogenesis in a rare plasma cell disorder

INTRODUCTION

POEMS (polyneuropathy, organomegaly, endocrinopathy, presence of monoclonal component, and skin changes) syndrome is a rare paraneoplastic syndrome due to a clonal plasma cell proliferative disorder. The disease can occur with a great variety of signs and symptoms; for this reason, it can be misdiagnosed at the onset and the treatment can be delayed. Some specific diagnostic criteria have been identified to ease the identification. The diagnostic criteria are divided as follows:

Mandatory major criteria:
(1) Polyneuropathy (typically demyelinating);
(2) Monoclonal plasma cell disorder (typically, λ-light chain restricted).

Other major criteria:
(1) Castleman disease;
(2) Sclerotic bone lesions;
(3) Vascular endothelial growth factor elevation.

Minor criteria:
(1) Organomegaly (mainly splenomegaly and hepatomegaly, sometimes lymphadenopathies);
(2) Extravascular volume overload (ascites and pleural and pericardial effusion);
(3) Endocrinopathy (mainly involving the gonadal axis, sometimes involving the adrenal and the thyroid axes);
(4) Skin changes (especially due to overproduction of melanin);
(5) Papilledema;
(6) Thrombocytosis/polycythemia.

The confirmation of diagnosis requires the coexistence of the mandatory major criteria with at least one of the other major criteria and one of the minor criteria.

The epidemiology of the disease is not well established given its very low incidence^[1].

THE MOLECULAR LANDSCAPE

VEGF is a ubiquitarious heterodimeric glycoprotein belonging to the family of growth factors. Several isoforms have been identified in humans: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, placenta growth factor, and endocrine gland-derived VEGF (EG-VEGF)^[2]. They are all involved in the process of vasculogenesis and lymphagenesis during the embryonic period and, after birth, in the process of physiologic and pathological angiogenesis. The signaling is mediated by the stimulation of ubiquitarious VEGF receptors (VEGFR) with an intracellular tyrosine kinase activity. The interaction between VEGF and its receptor plays a leading role in the tumorigenesis: in the pathologic microenvironment, hypoxia, due to the waste of energy by the proliferating cells, stimulates the VEGF/VEGFR binding. This cooperation induces migration of inflammatory cells; the subsequent proangiogenic cytokines storm favors the creation of new aberrant vascular networks, resulting in tumor growth and metastatic dissemination.

The pathogenic mechanism of POEMS syndrome is far from being fully understood, but increased production of VEGF by clonal bone marrow plasma cells could be one of the driving forces, as suggested by a Chinese study^[3] [Figure 1]. In this study, serum VEGF levels were measured using an enzyme immunoassay in 62 patients affected by POEMS syndrome, at the onset and after standard treatment with lenalidomide and dexamethasone. VEGF mRNA expression in the bone marrow plasma cells at diagnosis was notably higher than in samples sourced from patients with other plasma cell neoplasms. After induction therapy, the normalization of VEGF serum was observed in 49.2% of POEMS patients, most of them also achieving a complete hematologic response. The same study revealed in the 62 patients the presence of polyclonal plasma cells, beyond the monoclonal population: even if there is no substantial difference in the intracellular VEGF levels, the monoclonal counterpart produces higher levels of cytokines, such as IL-1β and IL-6. These cytokines are responsible for the overproduction of VEGF. On the other side, Nagao et al.^[4] performed targeted sequencing of 20 cases with POEMS searching for possible driver mutations: in all patients, recurrent mutations in seven genes were identified, but surprisingly none of these concerned VEGF genes family.

Figure 1. Mechanism of production of VEGF and possible mechanism of action in the pathogenesis of POEMS syndrome. VEGF: Vascular endothelial growth factor; VEGF-R: VEGF receptor.

THE CLINICAL UTILITY

CONCLUSION

POEMS syndrome is a rare paraneoplastic disease with a multiorgan involvement which could result fatal in some cases. The mechanism leading to this syndrome is not known, but a central role seems to be played by VEGF. Despite the pathogenic importance of this cytokine, the attempts to use it as a marker disease and a therapeutic target are anecdotal and often unsatisfactory. Due to the rarity of the disease, the main information about its treatment in general is based more on real-life experience than on randomized trials. At our Department of Translational and Precision Medicine, patients with POEMS syndrome have been successfully treated with alkylator-based therapy, followed by autologous stem-cell transplant, according to age and the presence of another comorbidity. Based on the extraordinary results shown in other plasma-cell neoplasms, immunomodulants and proteasome inhibitors, such as lenalidomide and ixazomib, respectively, either alone or in combination with high-dose steroids, and monoclonal antibodies targeting CD38 antigen, such as daratumumab, have been investigated in several clinical trials for patients with POEMS syndrome (NCT01816620, NCT02921893, and NCT04396496). The results from these trials are awaited.

Meanwhile, further efforts are required to better identify the real role of VEGF and clarify whether it can be used in clinical practice.