Patients with isolated bone lesion without bone marrow clonal plasma cells involvement can be treated with radiotherapy. Patients with a disseminated disease (more bone lesions and/or bone marrow plasmacytosis) are the candidates for systemic therapy. Systemic therapy includes corticosteroids, autologous stem cell transplantation (ASCT), induction therapy, alkylator-based therapy, thalidomide, lenalidomide, bortezomib, and bevacizumab.

• Patients with isolated bone lesion without bone marrow clonal plasma cells involvement can be treated with radiotherapy.^[1]
• Patients with a disseminated disease (more bone lesions and/or bone marrow plasmacytosis) are the candidates for systemic therapy.^[1]

• More than 50% of patients treated with radiotherapy show a significant improvement of neuropathy.^[2]
• Maximal response to radiotherapy, i.e., improvement of neuropathy, can not be attained until 2–3 years since the first evidence of the effect of therapy.^[3][4]
• Improvement of anasarca, papilledema, pulmonary hypertension and skin changes may occur within months after the end of radiotherapy.^[3][4]
• Radiotherapy can be considered as primary therapy if the bone lesion is large despite an infiltrated bone marrow.
• Radiotherapy can also be considered in relapsed patients with 1 or 2 bone lesions on positron emission tomography (PET).

• Corticosteroids can attenuate the symptoms for a short time without affecting the progression of the syndrome.^[5]

• It is considered the preferred initial therapy in young patients.^[6]
• It is associated with a durable response even if patients experience a relapse of the disease.^[6]
• A retrospective study of the Plasma Cell Disorder sub-committee of the Chronic Malignancy Working Party of the European Society for Blood & Marrow Transplantation showed the 1-year non-relapse mortality to be 3.3%.^[7]
• Young patients can be ineligible for ASCT in the presence of serous cavity effusion, renal impairment, pulmonary hypertension, and severe end-organ dysfunction.
• It is a lethal procedure and can result in engraftment syndrome (fever, rash, diarrhea, weight gain, and respiratory problems that occur 7–15 days since stem cell infusion).^[8]

• Induction therapy involves cyclophosphamide or lenalidomide, thalidomide or bortezomib in combination with high-dose dexamethasone.^[9]
• In patients with an overproduction of IL-12 and VEGF, induction therapy can modify the hypercytokinemia status, improving clinical condition and can control disease severity making patients eligible for ASCT.^[9]
• The use of induction therapy before ASCT can also decrease the incidence of peritransplant complications.^[10][11]
• Induction therapy before mobilization (i.e., stimulation of stem cells out of the bone marrow into the bloodstream) reduces the levels of cytokines and also reduces the risk of inadequate mobilization.

• It is the treatment of choice for patients who are not suitable for ASCT.
• It consists of melphalan or cyclophosphamide plus corticosteroids.^[2]
• It is associated with a 2-year overall survival (OS) rate of 78%.^[2]
• Adverse effects of this therapy include hematologic neoplasia such as leukemia and myelodysplasia.
• In the first prospective clinical trial, 81% of the patients showed hematologic response and 100% of the patients showed improvement in neurological symptoms and reduction on VEGF levels.^[12]
• Data on the long term effect of this therapy is still unavailable.^[12]

• It has been tested in POEMS syndrome due to its antiangiogenic, anti-inflammatory, and immunomodulating properties.
• A multicenter, randomized, double-blind study showed a reduction of VEGF serum level with thalidomide.^[13][14]
• Neurotoxicity, a serious side effect, limits the use of thalidomide.^[15][14]

• It appears to be the most promising drug for the treatment of POEMS syndrome.
• It has been reported to have a long-lasting response and good tolerability.^{[16][17][18][19][20]}
• A retrospective pooled analysis of 51 subjects treated with lenalidomide showed a 12-month progression free survival (PFS) rate of 93% and a 24-month rate of 47%.^[21]
• Lenalidomide, as an induction therapy before the transplant, can improve the patient clinical status and decrease transplant-related morbidity.

• Bortezomib, alone or in combination, can be used in newly-diagnosed and in relapsed patients.^[22][23][24]
• It is associated with highly satisfactory responses on neuropathy, serum VEGF level, and extravascular overload.^{[22][23][25][24]}
• It is, however, also associated with a potential risk of progression of existing neuropathy.

• Bevacizumab has anti-VEGF properties and can result in a rapid decrease in the serum VEGF levels.^[26]
• It is not, however, associated with clinical improvement.^[26]
• Bevacizumab causes sudden VEGF removal, causing the collapse of newly-formed fragile vessels and resulting in an increase in capillary leakage.^[27]

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