Abstract
POEMS syndrome (acronym of: polyradiculoneuropathy, organomegaly, endocrinopathies, monoclonal protein and dermopathy/§skin) is a rare multisystemic disease due to an underlying plasma cell neoplasm. The pathogenesis of the syndrome is not well understood. Other names of the POEMS syndrome that are less frequently used are osteosclerotic myeloma, Takatsuki syndrome, or Crow-Fukase syndrome.
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1 POEMS Syndrome
1.1 Introduction
POEMS syndrome (acronym of: polyradiculoneuropathy, organomegaly, endocrinopathies, monoclonal protein and dermopathy/skin) is a rare multisystemic disease due to an underlying plasma cell neoplasm. The pathogenesis of the syndrome is not well understood. Other names of the POEMS syndrome that are less frequently used are osteosclerotic myeloma, Takatsuki syndrome, or Crow-Fukase syndrome.
1.2 Clinical and Laboratory Manifestations
• Male predominance • Age (maximun incidence): 50–60 years
Polyneuropathy | Typically demyelinating. Peripheral, ascending, symmetrical, and affecting both sensation and motor function. It is the dominant characteristic |
Organomegaly | Hepatomegaly (50%), splenomegaly, or lymphadenopathy |
Endocrinopathy | Present in 84%: gonadal, thyroid, pituitary, parathyroid, pancreatic, adrenal (in order of frequency, and many times multiple) |
Monoclonal protein | Almost always λ light chain. Usually Ig A or IgG and ≤ 3 g/dL. Bone marrow smear: <5–10% plasma cells |
Skin changes | Hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, white nails, plethora, acrocyanosis, flushing |
Other important manifestations | – Sclerotic bone lesionsa (95%) – Castleman disease (in 11–30%) – Papilledema (in one-third of patients) – Extravascular volume overload – Thrombocytosis (in 54%) – VEGFb elevation |
1.3 Diagnosis
Not all the features within the acronym are required to make the diagnosis. There are other relevant features not included in the POEMS acronym also important: PEST (papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis/erythrocytosis), elevated VEGF levels, abnormal pulmonary function tests, and a predisposition to thrombosis. There is a Castleman variant of POEMS syndrome that may be associated with a clonal plasma cell disorder. When Castleman disease variant of POEMS syndrome occurs without evidence of plasma cell disorder, then this entity should be considered separately.
1.3.1 Criteria for the Diagnosis of POEMS Syndrome
The diagnosis of POEMS syndrome is confirmed when:
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Both mandatory major criteria +.
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another of the other 3 major criteria +,
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at least one of the minor criteria.
Mandatory major criteria |
Polyneuropathy Clonal plasma cell dyscrasia (monoclonal immunoglobulin) |
Other major criteria |
Castleman disease Sclerotic bone lesions VEGF elevated |
Minor criteria |
Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy) Extravascular volume overload (edema, pleural effusion, or ascites) Endocrinopathya Skin changes Papilledema Thrombocytosis/erythrocytosisb |
Other symptoms and signs |
Digital clubbing Weight loss Hyperhidrosis Low vitamin B12 values Diarrhoea Pulmonary hypertension/restrictive lung disease Thrombosis |
1.4 Prognosis
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Chronic course, median survival of nearly 14 years, rarely progression to multiple myeloma.
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The number of POEMS features does not affect survival.
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Risk factors associated to better survival → albumin > 3.2 g/dL, achievement of a complete hematological response and younger age. Lower VEGF levels, better response to treatment.
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Risk factors associated to shorter survival → clubbing, extravascular volume overload, respiratory symptoms, papilledema, and coexisting Castleman disease.
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Thrombocytosis and high bone marrow infiltration are associated with risk of cerebrovascular accidents.
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Patients candidates for radiation therapy have a better overall survival.
1.5 Standard treatment
Need to differentiate between POEMS with chronic inflammatory demyelinating polyneuropathy and CANOMAD (chronic ataxic neuropathy with opthalmoplegia, M-protein, cold agglutinins, and disialosyl antibodies).
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In case of an isolated bone lesion (or multiple, but localized):
Radiotherapy (e.g., 35–50 Gy) to affected site(s) → improve the symptoms of POEMS syndrome and can be curative
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Rest of patients (disseminated disease):
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→ Lenalidomide + dexamethasone is mainstay of frontline therapy
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→ Alternatives include melphalan + dexamethasone, thalidomide + dexamethasone, bortezomib + dexamethasone (these last two agents are of limited use due to the intrinsic risk of peripheral neuropathy), cyclophosphamide ± dexamethasone
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→ Plasmapheresis, IgIV, IFN-α, tamoxifen, trans-retinoic acid, bevacizumab (anti-VEGF agent), argatroban, and strontium-89 (mostly single case reports)
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→ Attention to supportive care is mandatory (physical therapy, orthotics, etc.)
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→ Autologous HCT (see Sect. 83.1.6)
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1.5.1 Response Criteria
Monitoring the response to treatment in POEMS syndrome is a challenge. Patients must be followed carefully comparing the deficits to baseline. VEGF is an imperfect marker due to discordances between disease activity and response. The size of monoclonal protein is typically small making standard multiple myeloma response criteria inapplicable. Patients can present clinical benefit without M-protein response therefore a clinical scoring system which can focus on organ-specific response would be useful clinically. So, response criteria for POEMS syndrome could be done as follows: hematological response using a modified amyloid response criteria; VEGF response; CT/PET response; and a simplified organ response (polyneuropathy assessment, pulmonary function tests, and extravascular overload).
1.6 Autologous Hematopoietic Cell Transplantation (Autologous HCT)
Background | – In multiple myeloma → autologous HCT → high rate and depth of responses – In amyloidosis, a disease with similarities to POEMS syndrome with “low tumor” burden → autologous HCT → long remissions obtained |
Indication | POEMS syndrome with disseminated disease: |
• Good general condition | |
• Either upfront or after suitable induction therapy (lenalidomide + dexamethasone), though mostly after induction to control symptoms prior to autologous HCT | |
Conditioning | Melphalan 140–200 mg/m2 |
Stem cell sourcea,b | PBSC, mobilization with G-CSF ± Cy (1.5–3 g/m2). Mobilize early if lenalidomide+dexamethasone used. |
Morbidity | High rate of engraftment syndrome (up to 50%) (see Chap. 20), important to recognize and treat promptly with prednisone. In these cases, higher than expected transfusion need and delayed engraftment. No organ toxicities as observed in amyloidosis |
Mortalityc | As in other autologous HCT, recently reported 3.3% 1-year NRMd |
Responsec,d | Hematological CR can be achieved by 3 months post-autologous HCT, but neurologic response is usually delayed to 6–9 months, but full recovery can take up to 2–3 years. PET/CT evidence of response can take upto 12 months |
2 Monoclonal Ig Deposition Disease
2.1 Introduction
Monoclonal Ig deposition is a clonal plasma cell discrasia in which light-chain and/or heavy-chain subunits of Igs form nonfibrillar deposits in various tissues, causing organ dysfunction. Light-chain deposition disease is the most common of these entities.
2.2 Clinical Manifestation/Laboratory
Kidney | Always affected. Immunofluorescence shows deposition of light chains along glomerular and tubular basement membranes → nodular glomerulosclerosis. Deposits are nonfibrillar, almost always composed Ƙ chain and do not stain with Congo red dye → nephrotic syndrome, hypertension, and rapidly progressing renal insufficiency |
Heart and liver | Less frequent affected. Restrictive cardiopathy, myocardial infarction, cholestatic jaundice, hepatic failure |
Monoclonal gammopathy | Electrophoresis, immunofixation of serum and/or urine, serum-free light chain measurement |
2.3 Diagnosis
Biopsy of the affected organ (almost always kidney).
2.4 Treatment
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Controversial, not standard due to the low incidence. Conventional chemotherapy commonly used for MM is unsatisfactory.
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Melphalan + Prednisone
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VAD
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Thalidomide ± DXM, bortezomib + DXM
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Autologous HCT (see Sect. 83.2.5)
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2.5 Autologous Hematopoietic Cell Transplantation (Autologous HCT)
Background | – As in POEMS syndrome (see Sect. 83.1.6) |
Indication | – Patients in good general condition and with basic requirements for autologous HCT – Patients not responding to previous MM-like treatment |
Conditioning | Melphalan 140–200 mg/m2 |
Stem cell source | PB, mobilization with G-CSF ± Cy (3 g/m2) |
Morbidity | Some patients require hemodialysis (HD) before and during the procedure. In that case, melphalan should be administered after HD |
Mortality | As in other autologous HCT |
Response | In the few cases reported: – Hematological responses are described secondary to the control of the monoclonal gammopathy. – It can improve renal function. In selected cases, kidney transplantation could be an option if the patient achieve a CR and remain in HD. |
Further Reading
Batalini F, Econimo L, Quillen K, et al. High-dose melphalan and stem cell transplantation in patients on dialysis due to immunoglobulin light-chain amyloidosis and monoclonal immunoglobulin deposition disease. Biol Blood Marrow Transplant. 2018;24:127–32.
Cook G, Iacobelli S, Van Biezen A, et al. High-dose therapy and autologous stem cell transplantation in patients with POEMS syndrome: a retrospective study of the Chronic Malignancy Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2017;102:160–7.
D’Souza A, Lacy M, Gertz M, et al. Long-term outcomes after autologous stem cell transplantation for patients with POEMS syndrome: a single-center experience. Blood. 2012;120:56–62.
Dispenzieri A. POEMS syndrome: 2017 Update on diagnosis, risk-stratification, and management. Am J Hematol. 2017;92:814–29.
Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and long-term outcome. Blood. 2003;101:2496–506.
Dispenzieri A, Lacy MQ, Hayman SR, et al. Peripheral blood stem cell transplant for POEMS síndrome is associated with high rates of engraftment syndrome. Eur J Haematol. 2008;80:397–406.
Girnius S, Seldin DC, Quillen K, et al. Long-term outcome of patients with monoclonal IgG deposition disease treated with high-dose melphalan and stem cell transplantation. Bone Marrow Transplant. 2011;46:161–2.
Hassoun H, Flombaum C, D’Agati, et al. High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease. Bone Marrow Transplant. 2008;42:1–8.
Jurczyszyn A, Olszewska-Szopa M, Vesole D. POEMS syndrome—clinical picture and management. Current Knowledge. Clin Lym Myel Leuk. 2023; https://doi.org/10.1016/j.clml.2023.04.008.
Kourelis TV, Buadi FK, Kumar SK, et al. Long-term outcome of patients with POEMS syndrome: an update of the Mayo Clinic experience. Am J Hematol. 2016;91:585–9.
Li J, Zhang W, Jiao L, et al. Combination of melphalan and dexamethasone for patients with newly diagnosed POEMS syndrome. Blood. 2011a;117:6445–9.
Li J, Zhou DB, Huang Z, et al. Clinical characteristics and long-term outcome of patients with POEMS syndrome in China. Ann Hematol. 2011b;90:819–26.
Pozzi C, D’Amico M, Fogazzi GB, et al. Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors. Am J Kidney Dis. 2003;42:1154–63.
Rovira M, Carreras E, Blade J, et al. Dramatic improvement of POEMS syndrome following autologous haematopoietic cell transplantation. Br J Haematol. 2001;115:373–5.
Tovar N, Cibeira MT, Rosiñol L, et al. Bortezomib/dexamethasone followed by stem cell transplantation as front line treatment for light-chain deposition disease. Eur J Haematol. 2012;89(4):340–4.
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Cook, G., Rovira, M. (2024). Poems Syndrome and Disease Produced by Other Monoclonal IGs. In: Sureda, A., Corbacioglu, S., Greco, R., Kröger, N., Carreras, E. (eds) The EBMT Handbook. Springer, Cham. https://doi.org/10.1007/978-3-031-44080-9_83
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