What is the recommended treatment for POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes)?

Treatment of POEMS Syndrome

First-Line Treatment Selection Based on Disease Extent

For localized disease with solitary or limited sclerotic bone lesions (1-3 lesions) without bone marrow involvement, radiation therapy is the definitive first-line treatment, achieving 97% 4-year overall survival and 52% 4-year failure-free survival. 1, 2, 3

For disseminated disease with diffuse sclerotic lesions or bone marrow involvement, systemic chemotherapy followed by autologous stem cell transplantation (ASCT) in eligible patients is the recommended approach. 1, 2, 3

Radiation Therapy for Localized Disease

• Radiation alone improves symptoms in 50-70% of patients with localized plasmacytoma 1, 2
• This approach is curative for patients without bone marrow involvement and limited bone lesions 1, 4
• Large bone lesions may require adjuvant radiation approximately 6 months after chemotherapy 1

Systemic Therapy Regimens for Disseminated Disease

Preferred First-Line Systemic Options

Melphalan-dexamethasone is the most established regimen, achieving 81% hematologic response and 100% improvement in neuropathy in prospective trials. 1, 2, 3

Lenalidomide-dexamethasone is preferred in patients with pre-existing severe neuropathy due to lower neurotoxicity risk. 1, 3, 4

• The French prospective trial used lenalidomide/dexamethasone for 2 induction cycles followed by high-dose therapy or radiation, or for 9 cycles followed by 12 cycles of lenalidomide monotherapy, demonstrating rapid neurologic responses 1
• Lenalidomide-based regimens are the first choice in patients with neuropathy 1

Autologous Stem Cell Transplantation

ASCT should be offered to eligible younger patients with disseminated disease after induction chemotherapy, achieving 100% clinical improvement and excellent long-term outcomes. 1, 2, 3, 5

• Progression-free survival rates are 98%, 94%, and 75% at 1,2, and 5 years respectively in transplanted patients 1
• Induction therapy before ASCT may improve stem cell harvest and decrease transplantation-related morbidity 5
• Transplantation-related morbidity and mortality has significantly decreased over the past 5 years 5

Agents to Avoid or Use with Extreme Caution

Thalidomide-based regimens should be avoided as first-line therapy due to high neurotoxicity risk that can worsen pre-existing neuropathy. 1, 2, 3

Bortezomib-based combinations are not recommended as first-line therapy despite high response rates (81% hematologic response) due to induced neuropathy risk. 1, 2, 3

• While a 2021 study showed bortezomib plus dexamethasone achieved 88.1% neurologic response with only 2 patients developing grade-1 reversible neuropathy 6, the European Myeloma Network guidelines emphasize caution due to neurotoxicity concerns 1
• Bortezomib should be reserved for patients who have failed other therapies or have renal dysfunction where its efficacy may outweigh risks 1

Bevacizumab (anti-VEGF therapy) is not recommended despite reducing VEGF levels, as several deaths have been reported. 1

Critical Timeline Expectations

Neurologic improvement significantly lags behind hematologic response, with maximum neurologic response expected after 2-3 years of successful therapy. 1, 2, 3

• Optimal response on FDG-PET may lag by 6-12 months after treatment 1, 2
• Continue treatment even if immediate neurologic improvement is not apparent, as this lag is expected and does not indicate treatment failure 7

Monitoring Parameters

Serum VEGF levels should be monitored as a marker of disease activity and treatment response. 1, 2, 3

• VEGF levels are markedly elevated in POEMS syndrome and correlate with disease activity 1
• 100% VEGF response was achieved with melphalan-dexamethasone in prospective trials 1

Additional Monitoring Requirements

• Endocrinopathy management: Address thyroid, adrenal, and gonadal dysfunction 2, 3
• Thrombotic risk: Monitor for thrombocytosis and consider prophylaxis 2, 3
• Pulmonary and cardiac assessment: Regular monitoring with pulmonary function tests and echocardiography 2, 3

Common Pitfalls to Avoid

Do not use radiation alone for disseminated disease—it is not curative and systemic therapy is mandatory. 1, 7

• Patients treated only with radiation had inferior progression-free survival and overall survival, mainly because these patients were sicker at treatment initiation 1

Do not discontinue therapy prematurely due to lack of immediate neurologic improvement—the expected lag time is 2-3 years for maximum response. 1, 7

Do not use plasma exchange or immunoglobulin treatment—these are not recommended for POEMS syndrome. 8