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POEMS Syndrome and Disease Produced by Other Monoclonal Immunoglobulins

  • Gordon Cook
  • Montserrat RoviraEmail author
Open Access
Chapter

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.

82.1 POEMS Syndrome

82.1.1 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.

82.1.2 Clinical and Laboratory Manifestations

POEMS predominate in male being the age of maximum incidence (50–60 years).

Characteristic manifestations are:

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% of patients: 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 to 10% plasma cells.

Skin changes: Hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, white nails, plethora, acrocyanosis, flushing.

Other important manifestations are:

Papilledema (in one third of patients)

Extravascular volume overload

Sclerotic bone lesionsa (95%)

Thrombocytosis (in 54%)

— VEGF elevationb

— Castleman disease (in 11–30%)

aRadiology and CT/PET can be useful

bVEGF = Vascular endothelial growth factor is the cytokine that correlates best with disease activity. The helpful cutoff for plasma and serum VEGF levels for diagnosis are >200 pg/mL (specificity 95%, sensitivity 68%) and >1920 pg/mL (specificity 98%, sensibility 73%), respectively

82.1.3 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.

Clinical criteria for POEMS diagnostic are shown in Table 82.1.
Table 82.1

Criteria for the diagnosis of POEMS syndrome

The diagnosis of POEMS syndrome is confirmed when:

— Both mandatory major criteria +

— Another of the other three major criteria +

— At least one of the minor criteria

Mandatory major criteria

Other major criteria

Polyneuropathy

Castleman disease

Monoclonal immunoglobulin

Sclerotic bone lesions

VEGF elevated

Minor criteria

Other symptoms and signs

Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)

Digital clubbing

Weight loss

Hyperhidrosis

Extravascular volume overload (edema, pleural effusion, or ascites)

Low vitamin B12 values

Diarrhea

Pulmonary hypertension/restrictive lung disease

Endocrinopathya

Skin changes

Thrombosis

Papilledema

Thrombocytosis/erythrocytosisb

Adapted from Dispenzieri (2017)

aHypogonadism is the most frequent, and because of the high prevalence of diabetes mellitus and thyroid abnormalities, these two last abnormalities alone are not sufficient to meet this minor criterion

bAnemia and/or thrombocytopenia are rare, unless associated with Castleman disease

82.1.4 Prognosis

Chronic course, median survival of nearly 14 years, rarely progression to multiple myeloma.

The number of POEMS features does not affect survival.

Risk factors associated to better survival are: albumin >3.2 g/dL, achievement of a complete hematological response and younger age. Lower VEGF levels, better response to treatment.

Risk factors associated to shorter survival are: clubbing, extravascular volume overload, respiratory symptoms, papilledema, and coexisting Castleman disease.

Thrombocytosis and high bone marrow infiltration are associated with risk of cerebrovascular accidents.

Patients candidates for radiation therapy have a better overall survival.

82.1.5 Standard Treatment

82.1.5.1 In Case of an Isolated Bone Lesion (or Multiple, But Localized)

Radiotherapy to affected site(s) improves the symptoms of POEMS syndrome and can be curative.

82.1.5.2 Rest of Patients (Disseminated Disease)

– MEL/DEX

– LENA/DEX, THAL/DEX, BOR (these last two agents are of limited use due to the intrinsic risk of peripheral neuropathy), CY/DEX.

– Plasmapheresis, IVIg, IFN-α, tamoxifen, ATRA, bevacizumab (anti-VEGF agent), argatroban, and strontium-89 (mostly single-case reports).

– Attention to supportive care is mandatory (physical therapy, orthotics, etc.).

– Auto-HSCT.

82.1.5.3 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 MM 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).

82.1.6 Autologous HSCT (Table 82.2)

Table 82.2

Main characteristic of auto-HSCT for POEMS disease treatment

Background

— In MM, another gammopathy, auto-HSCT, has a high rate of responses

— In amyloidosis, a disease with similarities to POEMS syndrome with “low tumor” burden, auto-HSCT offers encouraging results

Indication

POEMS syndrome with disseminated disease and:

— Good general condition

— Without response to standard treatment (MEL + DEX 2–3 months)

— With high-risk factors (?)

Conditioning

MEL 140–200 mg/m2a

Stem cell source

PBSC, mobilization with G-CSF ± CY (3 g/m2)b,c

Morbidity

— High rate of engraftment syndrome (up to 50%) (see Chap.  42), important to recognize and treat promptly with PRD. In these cases, higher than expected transfusion need and delayed engraftment

— No organ toxicities as observed in amyloidosis

Mortality

As in other auto-HSCT, recently reported 3.3% at 1-year NRMd

Responsed,e

Usually delayed, from 6 months post-auto-HSCT to 24–72 months

aWith lower dose, inferior responses

bMobilization failure is described, for this reason if there is no response after three courses of MEL + DEX, proceed to mobilization

cThe incidence of engraftment syndrome can be reduced if mobilization is done with CY + G-CSF

dCook et al. (2017)

eIn the largest series, 3-year PFS 84% and OS 94%, and 5-year PFS 74% and OS 89%

82.2 Monoclonal Ig Deposition Disease

82.2.1 Introduction

Monoclonal Ig deposition is a clonal plasma cell dyscrasia in which light-chain and/or heavy-chain subunits of Igs form non-fibrillar deposits in various tissues, causing organ dysfunction. Light-chain deposition disease is the most common of these entities.

82.2.2 Clinical Manifestation/Laboratory

Kidney

— Always affected: nephrotic syndrome, hypertension, and rapidly progressing renal insufficiency

— Immunofluorescence shows deposition of light chains along glomerular and tubular basement membranes → nodular glomerulosclerosis

— Deposits are non-fibrillar, almost always composed of κ chain, and do not stain with Congo red dye

Heart and liver

— Less frequently affected: restrictive cardiopathy, myocardial infarction, cholestatic jaundice, hepatic failure

Monoclonal gammopathy

— Electrophoresis, immunofixation of serum and/or urine, serum-free light chain measurement

82.2.3 Diagnosis

Based on the biopsy of the affected organ (almost always kidney)

82.2.4 Treatment

Controversial, not standard due to the low incidence. Conventional chemotherapy commonly used for MM is unsatisfactory. Possible alternatives are:

– MEL + prednisone

– VAD (vincristine, doxorubicin, DEX)

– THAL/DEX, BOR/DEX

– Auto-HSCT (see Table 82.3)
Table 82.3

Main characteristic of auto-HSCT for monoclonal Ig deposition disease treatment

Background

— As in POEMS syndrome (see Table 82.2)

Indication

— Patients in good general condition and with basic requirements for auto-HSCT

— 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, MEL should be administered after HD

Mortality

As in other auto-HSCT

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 achieves a CR and remain in HD

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Authors and Affiliations

  1. 1.Haematology and Myeloma Studies, Leeds Cancer CentreSt James’s University HospitalLeedsUK
  2. 2.Hematology Department, Hospital Clínic de BarcelonaUniversity of BarcelonaBarcelonaSpain

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