Successful bortezomib‐based treatment in POEMS syndrome

To the Editor: POEMS syndrome is a rare multisystem disease characterized by polyneuropathy (P), organomegaly (O), endocrinopathy (E), serum M-protein (M), and skin changes (S) (1–3). Up to date, there is no standard treatment for POEMS syndrome and no randomized controlled clinical trials of treatment for this disease available in the current literature (4). Recently, we successfully treated a POEMS syndrome patient, who was poorly responsive to conventional treatment, with bortezomib-based regimen. To our knowledge, this is the first case report of a POEMS syndrome patient treated with this regimen. A 37-yr-old previously healthy man was admitted for a 6-month history of progressive fatigue, weakness, and bilateral lower extremity edema. Three months before admission he started to have paresthesia involving both upper and lower extremities extending from distal to proximal. The patient presented with a number of clinical features of POEMS syndrome including paresthesia, splenomegaly, gynaecomastia, extremity edema, hydropericardium, hydrothorax, plethora, a monoclonal protein (IgA k) in serum, and elevation in serum level of vascular endothelial growth factor (VEGF; measured with ELISA Kit, Alpco Diagnostics Inc., Salem, NH, USA). According to the latest Mayo Clinic criteria (4), the POEMS syndrome was diagnosed. After several courses of conventional regimens [VAD (Vincristine, doxorubicin, dexamethasone), CMP (cyclophosphamide, melphalan and prednisone) and AD (doxorubicin and dexamethasone)], the patient had only slight improvement and failed to achieve remission (Table 1). With the patient’s informed consent and Ethics Committee approval, a trial of VDD regimen was carried out. The details were as follows: Bortezomib, at a dose of 1.3–1.6 mg ⁄m (initial cycle: 1.3 mg ⁄m in the first week, 1.6 mg ⁄m ⁄wk in following three weeks; next three cycles: 1.6 mg ⁄m ⁄wk · 4 wk in each cycle); 40 mg of Liposomal doxorubicin on the fourth day of the first week; and 10 mg of dexamethasone during the initial 4 days of first cycle. Each course was at 21 days interval. The patient gained complete remission (CR) after completing the four cycles of VDD regimen and has remained CR during follow up (for more than 7 months to date). The changes of clinical manifestations, laboratory parameters and radiology image are listed in Table 1. It is recently indicated that abnormal angiogenesis and inflammation play a crucial role in the pathogenesis of POEMS syndrome (5, 6). Amidst a large number of cytokines involved in this syndrome(4), VEGF, a proangiogenetic and ⁄or proinflammatory cytokine, has been suggested to act as a dominant initial mediator that widely interacts with other molecules, such as IL-1b, IL-6, and TNF-a, to increase vascular permeability and induce angiogenesis (7). Interestingly, in this patient, the serum level of VEGF dramatically decreased from 317.48 pg ⁄mL to 79.97 pg ⁄mL (normal range: 50–100 pg ⁄mL) following the treatment of bortezomib, a proteasome inhibitor that is approved for treating multiple myeloma and mantle cell lymphoma. It has been suggested that VEGF is synthesized and secreted from plasma cells (8). Therefore, we hypothesize that bortezomib decreases the serum level of VEGF by inhibiting clonal expansion of plasma cells (or their precursors), the subsequently normalized VEGF abolishes the abnormal angiogenesis and inflammation status in the patient with POEMS syndrome. The clinical improvement in this patient, including the polyneuropathy, skin changes (plethora), and extravascular volume overload, may be due to the normalization of serum VEGF after bortezomib treatment. On the other hand, the bortezomib-induced peripheral neuropathy as a possible side–effect should be considered. In this case, the agent was initiated at a relatively low dosage (1.3 mg ⁄m) (9) and subsequently increased to a higher dosage (1.6 mg ⁄m) because of no obvious side-effects observed in the first week. Although this patient did not develop obvious peripheral neuropathy after the treatment, the serious toxic side-effects (especially the peripheral neuropathy) induced by bortezomib should not be neglected. During the four-cycle course of treatment and the follow-up up to 7 months, the improvement in polyneuropathic symptoms was apparent and stable, demonstrating the benefits of bortezomib against neuropathy exceed its potential neurotoxic effects. Our experience in this case showed the safety, tolerance, and proper dosage of bortezomib in the treatment of POEMS syndrome, suggesting that the VDD regimen could be a potent and effective option for the treatment of POEMS syndrome, especially in the conventional therapy-resistant condition.