Monoclonal Antibodies

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MONOCLONAL ANTIBODIES (M-proteins)

Monoclonal Gammopathies of Unknown Significance (MGUS)
General characteristics
General clinical features
Specific associated clinical syndromes
Testing

Neoplastic & Systemic Disorders
Cryoglobulinemia
IgG & IgA MGUS
IgM MGUS
Multiple myeloma
Osteosclerotic myeloma
Waldenström's macroglobulinemia

Monoclonal Gammopathies of Unknown Significance (& Other) ⁷

General characteristics of M-proteins
- Types of light chain: κ > λ
- Quantity: < 3 g/dl
- Urine monoclonal: Rare
- Marrow plasma cells: < 5%
- Skeletal lesions (X-ray): Absent
- CBC: Normal
- Organomegaly: None
- Clonal cells: CD38+, CD56+, CD19-
Immunoglobulin (Ig) heavy chain class

Patient group (%) IgG IgM IgA IgD Biclonal Light chain

All M-proteins 70 15 12 < 1 3 3

Polyneuropathy & MGUS 35 50 12 3
Testing ¹⁸
- Detection of M-protein: Serum & Urine
  - Neurology: Test with most sensitive method
  - Sensitive clinical methods: Immunofixation ²/Immunotyping
- After M-protein found
  - CBC with smear
  - Chemistry panel with Ca⁺⁺ & Creatinine
  - Urine protein: 24 hour
  - Serum protein concentration
  - Serum protein electrophoresis (Serum monoclonal protein concentration)
  - Serum free light-chain ratio (κ & λ free light chains)
  - X-ray skeletal survey
    - Detects both lytic & blastic lesions
    - With > 1.5 g/dl of M-protein or other features suggesting myeloma
  - IgM M-protein: Look for Antigen target
  - Cryoglobulins
  - Cold agglutinins
  - Bone marrow biopsy
    - Indications
      - Very elevated immunoglobulin class of M-protein: > 1.5 g/dl of M-protein
      - Low level of other immunoglobulin class
      - Abnormal skeletal survey
    - Normal bone marrow value: < 5% plasma cells in bone marrow
  - LDH & β2-microglobulin: ? Myeloma
- Other
  - ? 24 hour urine for Bence-Jones protein
  - Mass spectrometry methods: May be more senstitive for clonal peptides ¹⁷
General clinical & laboratory features ³
- Progression to Neoplasms or other systemic disorder: 30%
  - General
    - May progress to neoplasia at time of dx or during follow-up
    - Overall risk of progression to neoplasm
      - 1% per year
      - 12% at 10 years
      - 25% at 20 years
      - 30% at 25 years
    - Risk of progression at 20 years related to M-protein concentration
      - 0.5 g/dl: 14%
      - 1.5 g/dl: 25%
      - 2.0 g/dl: 41%
      - 2.5 g/dl: 49%
    - Risk factors
      - Initial concentration of serum M-protein high: > 1.5 g/dl
      - IgM or IgA M-protien
      - Not: Urinary light chain; Low other Ig class
      - Higher plasma cells in bone marrow: 6% to 9%
      - Serum free light-chain ratio: Progression at 20 years
        
        Normal (0.26 to 1.65): 13%
        
        Abnormal: 35%
      - Frequency of progression with no risk factors: 5% at 20 years
    - M-protein types: IgG 70%; IgA 12%; IgM 15%; Biclonal 3%
    - Light chains: κ 61%; λ 39%
  - Myeloma 14%: Relative risk 25x
    - Lytic
    - Osteosclerotic
  - Lymphoma (IgM) 5%: Relative risk 2x
  - Plasmacytoma 4%: Relative risk 9x
  - Chronic lymphocytic leukemia 3%: Relative risk 1x
  - Waldenström's macroglobulinemia 2%: Relative risk 46x
  - Amyloidosis: Overall 9%; Relative risk 8x; Often with myeloma
- M-protein disappeared: 6%
  - Usually with low initial concentrations of M-protein
  - Usually associated with some treatment
  - Only 1% disappeared spontaneously
- No associated systemic disorders: 65%
  - Monoclonal gammopathy of unknown significance (MGUS)
  - Light chain: kappa more often than lambda
  - Epidemiology
    - Normals: MGUS occur more commonly with increasing age
      - < 40 years: 2% of patients with MGUS
      - 1% to 3.2% of patients > 50 years
      - 2% to 5.3% of patients 70 to 79 years
      - 6% of patients > 80 years
    - Male > Female
    - Afro-Americam 2x > White
  - Malignant transformation over long term: 6% to 25%
Neuropathy
- Occurs in 5% to 28% of MGUS
  - IgM: 31%; Waldenstrom's 46%
  - IgG: 6%
  - IgA: 14%
- IgM MGUS most common
  - Specific syndromes associated with IgM binding to neural antigens
  - 50% have anti-MAG binding
- Treatment of neuropathy: General principles
  - Depends on clinical syndrome & underlying disorder
  - Sensory symptoms treated symptomatically unless disabling
  - IgG & IgA MGUS more responsive to plasma exchange than IgM
  - CIDP treated with same regimen as idiopathic disease
  - Cyclophosphamide + Plasma exchange protocol may be effective
Specific associated clinical syndromes
- Amyloidosis
  - IgA
- Cryoglobulinemia
- IgG & IgA MGUS
  - Neuropathy
  - May progress to
    - Multiple myeloma
    - Other plasma cell neoplasms
- IgM MGUS: Syndromes ¹³
  - General
    - MYD88 L265P mutations may be more common that IgM MGUS without related disease
  - Syndromes related to antigenic target of IgM antibody
    - Decorin (BJ): Myopathy
    - GALOP antigen: Gait disorder & polyneuropathy
    - GD1b ganglioside (without GM1 binding): Ataxic sensory neuropathy; Ophthalmoplegia
    - GM1 ganglioside: Motor neuropathy
    - GM2/GalNAc-GD1a ganglioside: Demyelinating, Sensory neuropathy
    - Myelin-associated glycoprotein (MAG): Sensory ± Motor neuropathy; Gait disorder; Tremor
    - Neurofilaments
    - Sulfatide: Sensory ± Motor neuropathy
    - TS-HDS
    - Tubulin: CIDP
  - Other syndromes
    - Amyloidosis
    - IgM deposition
    - Cryoglobulinemia
    - Cold agglutinin disease
    - IgM MGUS may progress to
      - Lymphoplasmacytic lymphoma
      - Other B-cell lymphoproliferative disorders
      - IgM multiple myeloma
- Myopathy
- Multiple myeloma
- Neurolymphomatosis
- Osteosclerotic myeloma
- POEMS Syndrome
- Waldenström's macroglobulinemia: IgM
  - Amyloid-like

Neoplastic & Systemic Disorders

IgG & IgA MGUS

General
Amyloid IgA (λ > κ)
Nemaline rod myopathy (IgG)
POEMS (IgAλ)
Scleromyxedema (IgGκ)

General issues
- MGUS: Monoclonal Gammopathy of Unknown Significance
- Long term: Increased risk of myeloma in 10 to 20 years (1% - 2%/ year)
- Follow-up evaluation: Test quantitative immunoglobulins every 1 to 2 years.
Polyneuropathy
- IgA MGUS ¹⁴
  - Sensory PN
    - M-protein: κ type
    - Some with severe & selective sensory loss
  - AL amyloidosis (15%)
    - M-protein: λ > κ type
    - Clinical ²⁰
      - Onset ages: 6th to 8th decade
      - Sensory
        
        Loss: Small > Large fiber modalities
        
        Neuropathic pain: Less than ATTRv amyloidosis
      - Autonomic dysfunction (67%): Blood pressure; GI dysfunction
      - Systemic
        
        General: Fatigue, Weight loss (50%)
        
        Cardiac failure: Edema; Dyspnea; EKG pseudoinfarct pattern; NT- proBNP high
        Renal: Proteinuria, nephrotic
      - Diagnosis: May require biopsies of several tissues
      - Hematological disorder
        
        Multiple myeloma: Often
        
        MGUS: Some
        
        IgA M-protein detected: Before or during neuropathy evaluation
    - Pathology
      - IgAκ: Amyloid in muscle
      - IgAλ: Amyloid in nerve
  - IgA MGUS with Demyelination (5%)
    - M-protein: λ type
    - POEMS-like syndromes
    - Pathology
      - Widened myelin lamellae (Segmental)
      - Annular binding of IgA to myelin
  - Diabetic neuropathies (5%)
  - Chemotherapy-related (30%): Especially with myeloma
- Clinical: Other
  - Motor: Strength mildly reduced or Normal
  - Distribution: Symmetric; Distal; Feet & Hands
  - Treatment: More responsive to plasma exchange than IgM MGUS
- Pathology
  - Axon loss ± Myelin pathology
Scleromyxedema ¹⁰
- Epidemiology: > 200 patients; Male:Female = 1.2
- Diagnostic criteria
  - Skin
    - Clinical: Papular & Sclerodermoid eruption
    - Pathology: Mucin deposition, Fibroblast proliferation & Fibrosis
  - Serum: Monoclonal gammopathy
  - No thyroid dysfunction
- Clinical
  - Onset
    - Age: Middle aged adults; Mean 6th decade
    - Skin disorder
  - Skin
    - Disseminated papules, plaques & infiltrative lesions
      - Symmetric
      - Distribution: Face, Glabella & Ears; Neck; Arms; Mid-back
      - Flesh colored
    - Histology
      - Accumulation of mucopolysaccharides (Mucin): Hyaluronic acid; In upper dermis
      - Fibroblast proliferation
      - Inflammation: Occcasional; Perivascular
    - External link: Skin
  - Myopathy
    - Frequency: 25%; Range 10% to 50%
    - Weakness
      - Proximal
      - Symmetric
      - Neck
      - Bulbar
        
        Dysphagia (30% to 100%): Upper Esophagus
        
        Dysarthria
        Tongue
    - Laboratory
      - Serum CK: Mildly elevated (60%)
      - Aldolase: High
      - EMG: Irritative myopathy
    - Pathology
      - Myopathic: Degeneration & Regeneration
      - Vacuoles: Rimmed
      - Inflammation
        
        Lymphocytes: Scattered or Foci
        
        Large PAS-positive perimysial cells
    - Treatments
      - IVIg
      - Prednisone
      - Methotrexate (IV)
      - Thalidomide
  - CNS (10%)
    - Encephalopathy: Stroke; Seizures; Psychosis
  - PNS: ± Polyneuropathy (Axon loss)
  - Vascular: Raynaud's; Telangectasia; Ischemia
  - Other systemic
    - Weight loss
    - Interstitial lung disease
    - Esophageal dysmotility
    - Cardiomyopathy
    - ? Thyroid
  - Associated neoplasm: Myeloma in 10%
  - Course: Variable
    - Spontaneous resolution to Progressive disability
    - Mortality with Cardiopulmonary or CNS disease
- Laboratory
  - M-protein (85% to 100%): κ > λ; IgG
  - Thyroid function: Normal

IgM MGUS ¹²

Age: Median 74 years; Range 24 to 94 years
Clinical: See specific associated syndromes
Laboratory
- IgM M-protein
- Total IgM: < 3 g/dl
- Bone marrow plasma cells < 10%
- No anemia or constitutional signs
Prognosis for malignant transformation
- Rate: 1.5% per year
- Risk factors: High IgM, especially > 1.5 g/dl; Low albumin
- Lower risk for malignant transformation than IgA
- Associated disorders: Waldenström's macroglobulinemia; Lymphoma (Non-Hodgkins); CLL; Amyloid

Waldenström's macroglobulinemia (Lymphoplasmacytoid lymphoma) ¹⁵

Tumor type
- Non-Hodgkins lymphoma: Low grade
- Diagnostic features
  - Lymphoplasmacytic lymphoma
    - ≥ 10% clonal cells in bone marro
    - Tumor cells have B-cell markers
  - IgM M-protein
- Premalignant phases
  - IgM MGUS
  - Smoldering/Asymptomatic WM
- Mutations
  - MYD88^L265P : 90% frequency; Also common in IgM MGUS; Longer survival
  - CXCR4^WHIM-like: 30%; More aggressive disease
  - TP53 (10%): Worse prognosis
Epidemiology ⁵
- Males > Females
- Age: Typical 50 to 80 years; Median 65 to 71 years; 1.4% < 40 years
- White > Black
- Family history: Reported; May occur in monozygotic twins
- Incidence
  - 1,500 patients per year in US
  - 10% to 20% as common as myeloma
  - Males: 0.92/100,000 person-years
  - Females: 0.30/100,000 person-years
- Possible environmental associations: Leather, rubber dyes, paint
Clinical
- Peripheral Neuropathy (5% to 30%): Multiple types
  - Associations
    - Serum viscosity: High
    - IgM binding to specific antigen
  - Myelinopathy
    - IgM binding to MAG (4%)
    - Myelin wide-spacing
  - Multifocal mononeuropathy: Associated with serum hyperviscosity
  - Amyloid, light chain: 10%
  - Amyloid-like
  - Axon loss predominant
    - Most common type
    - Some patients with IgM binding to Sulfatide or TS-HDS
  - Cryoglobulins
  - Drug-related: Vinca alkaloids; Bortezomib; Lenalidomide
- Myopathy: IgM binding to Decorin (Chondroitin sulfate moiety)
- Central Nervous System
  - Ischemia
  - Hemorrhage
  - Myelopathy
  - Bing-Neel Syndrome: Direct infiltration of CNS by malignant cells; 1% of WM ¹⁹
- Systemic
  - General: Lassitude; Weight loss; Weakness
  - Raynaud's phenomenon
  - Hematologic
    - Anemia
    - Serum Viscosity: High
    - Clotting disorders
  - Organomegaly: Liver, Spleen, Lymph nodes
- Prognosis
  - Slowly progressive
  - Survival
    - Median 77 months; 20% at 10 years
    - Age < 45 years: 86% 10 year survival
  - Death related to: 1° Disease; Mixed cytopenia; 2nd neoplasm; Increasing IgM
  - Reduced with: Age > 65 years; High β2-microglobulin; Low albumin; Low hemoglobin; High IgM > 3
- Initial treatments
  - Symptomatic patients
    - Rituximab + Bendamustine
    - Zanubrutinib
    - Tirabrutinib
  - Rituximab alone
    - IgM-related neuropathy
    - Hemolytic anemia
    - Cryoglobulinemia, symptomatic
Laboratory
- Serum
  - IgM M-protein
    - Level: Normal or High
      - May be very high: > 3 grams/dl
    - Frequency: 100%
    - Class: Usually κ light chain (79%)
    - Antigen targets
      - Polyneuropathy: TS-HDS (20% of WM)
      - Demyelinating neuropathy: MAG (3% of WM)
  - High sedimentation rate: 50%
  - Hyperviscosity may occur
  - Cryoglobulinemia: 10% total; Clinical manifestations in < 5%
  - Cold agglutinins: 10%
  - Circulating tumor B-cells
- Bone marrow
  - Cell infiltration: Lymphoplasmacytic lymphoma
  - B cells
    - Express
      - Monoclonal surface & cytoplasmic IgM
      - Variable proportion may coexpress IgD
      - CD19; CD20; CD22; CD79
      - Not CD10, CD23, CD27, IgG, IgA
    - 6q21 deletions: 40% to 60%
    - Origin in post follicular cell stage
    - Somatic hypermutation
- No lytic bone lesions
- Genetics

Cryoglobulinemia ¹¹

Cryoglobulins: Definitions
- Immunoglobulins that reversibly precipitate at temperatures < 37°C
  - Precipitate in vitro at 4°C
  - Redissolve at 37°C
- Essential cryoglobulins: No cause found
Epidemiology
- Clinical: 1:100,000
- More common in Southern Europe
- Common age range: 45 to 65 years
- Female > Male: 2.5:1
Properties of cryoglobulins
- Constituents
  - Immunoglobulins: Polyclonal, Monoclonal, or Both
- Solubility Properties
  - Temperature: Precipitate when cooled; Dissolve when heated
  - Other factors: pH; Cryoglobulin concentration
- Other components of cryoglobulin precipitates
  - Antigens: Viral (Hepatitis C RNA)
  - Complement (Early components, C4)
  - Lipoproteins; Fibronectin
Diagnostic testing for cryoglobulins: Serum should be kept warm before testing
Associated disorders
- Monoclonal antibodies (MGUS)
- Infection
  - Hepatitis C: ~50%; Types II & III
  - Other occasional associations: Hepatitis A or B; HIV; EB-virus; Bacterial infections
- Immune disorders
  - Tests: Collagen Vascular Screen; Rheumatoid factor
  - Disorders: Vasculitis; Lupus; Rheumatoid arthritis; Scleroderma; Sjögren's; Membranoproliferative glomerulonephritis
- Lymphoproliferative disorders
  - Myeloma
  - Lymphoma: Hodgkins; Non-Hodgkins (B-cell)
  - Macroglobulinemia
  - Leukemia: Chronic lymphocytic; Hairy cell
  - Immunoblastic lympohadenopathy
- Idiopathic (14%)
Types of cryoglobulins
- I: All Monoclonal; Ig, or, rarely, Light chains
  - Often IgM
  - Disease associations
    - B cell lymphoproliferative disorders
    - Myeloma
    - Waldenström's
    - Chronic leukemia & lymphoma
  - Vascular signs: Purpura, Raynauds
  - Self aggregate via: Rheumatoid factor activity or Non-covalent interactions
  - Features associated with: Hyperviscosity; Thrombosis
- II: Mixed Polyclonal (IgG) & Monoclonal (usually IgMκ)
  - IgM has rheumatoid activity vs IgG Fc moiety
  - Often associated with Hepatitis C (80% to 90%)
    - Chronic antigen simulation
    - B-cell population expanded: VH1-69 clonal predominance
    - SNP association: NOTCH 4 intron; Between MHC HLADRB1 & HLADQ1
- III: Polyclonal Ig
  - IgM & IgG
  - Disease associations: Chronic infections (Hepatitis C virus (HCV); Connective tissue disorders
- General
  - Clinical
    - Neuropathy & Systemic signs with types II & III
    - Meltzer triad: Purpura; Weakness; Arthralgia
  - Mixed cryoglobulinemia: Both Type II & type III cryoglobulinemia
    - Immune complexes composed of: IgG (Polyclonal) + IgM (Monoclonal (Type II) or Polyclonal (Type III))
    - Associated with: Infections (HCV); Immune disorders (Sjögren & SLE); Neoplasms
  - IgM component: Rheumatoid factor activity; Binds to Fc portion of IgG
  - Symptomatic cryoglobulinemia: Increased lymphoma risk
Systemic clinical features
- Symptomatic disease: Occurs in < 15% of patients
- Skin
  - Purpura (palpable)
  - Vasculitic changes (Leukocytoclastic)
  - Urticaria, Cold-induced
- Arthralgias (42%): Hands & Knees
- Renal
  - Especially Membranoproliferative glomerulonephritis, type I
  - Associated with: Cutaneous vasculitis
- Hepatic
- Hematologic: Clotting disorders; Hypertension
- Weight loss
- Weakness (45%)
- Sicca syndrome (6%)
- Neurologic diagnoses (55%): Especially Type 1 cryoglobulinemia
- CNS (1%): Seizures; RPLE
Laboratory
- Complement
  - C4: Low
  - CH 50: Low
  - C3: Normal
- Rheumatoid factor: Often positive
- Serum antibodies to
  - Hepatitis C virus (90%)
  - Hepatitis B: Some patients
  - Anti-Nuclear antibodies
- Clonal B-cell infiltrates: Bone marrow or Liver
Neuropathy ¹
- Frequency
  - 26% to 60%
  - Common in Southern Europe
  - Possibly more common with higher levels of cryoglobulins
  - Most associated with type II cryoglobulinemia
- Onset
  - Course: Acute, Subacute or Chronic
  - Age: Adult, 40 to 80 years
  - Dysesthesias (55%)
  - May be presenting feature
- Clinical types
  - Multifocal mononeuropathy
    - Course: Acute or Subacute
    - Pattern: Distal > Proximal; Asymmetric
    - More common with type III cryoglobulinemia
    - Electrodiagnostic: Axonal loss, patchy
    - Pathology
      - Vasculitis
      - Micro-vascular occlusion
      - Perineuritis
      - Axonal loss: Differential fascicular
  - Sensory Neuropathy
    - Clinical
      - Sensory > Motor
      - Distribution: Distal; Symmetric or Asymmetric
      - Discomfort: Paresthesias; Pain; Restless legs
      - Slowly progressive
      - More common with type III cryoglobulinemia
    - Laboratory
      - Serum
        
        Rheumatoid factor (75%)
        
        Low C4 complement factor (50%)
        
        Antibodies: ANA; Anti-Mitochondrial (75%); Anti-Thyroid (75%)
      - Electrodiagnostic: Axonal loss; Small CMAPs & SNAPs
      - Nerve pathology: Axonal loss; Epineurial vessel inflammation
  - Small fiber neuropathy
    - Cryoglobulin levels: Lower than for symmetric large-fiber polyneuropathy
  - VII paresis
- Hepatitis C positive cases (50%)
  - Onset: More acute
  - Motor: More severe
  - Systemic: More cutaneous, liver & rheumatoid factor
  - Pathology: ? More vasculitis
- Pathophysiology
  - Impairment of vasa nervorum microcirculation
    - Intravascular deposition of cryoglobulin
    - Ischemia
  - Necrotizing vasculitis
    - Longstanding cryoglobulin precipitation
    - Complement fixation
    - Rheumatoid factor activity
  - Vessels involved
    - Size: Small
    - Types: Arterioles, Capillaries, Venules
  - Inflammation
    - Lymphocytes & Monocytes
    - Not: Polymorphonuclear neutrophils
Treatment
- Immunomodulating agents
  - Corticosteroids
  - Immunosuppression
  - Rituximab ⁴
  - Plasma exchange
  - IVIg
- Hepatitis C: Interferon α-2a
- Prognosis
  - Better with: Female; Younger age; Low HCV levels at onset; Not type 1b
  - Responsive features: Purpura; Liver function; Constitutional symptoms
  - Neuropathy: More responsive with mononeuritis type

Multiple Myeloma

Onset
- Age: 5th to 8th decade; Peak in 7th decade
- Features: Fatigue, lethargy, anemia, hypercalcemia, bone pain
Systemic features
- Skeletal lesions: Lytic; Bone pain
- Hematologic: Marrow-plasma cells > 10%; Abnormal CBC
- Organomegaly
- General: Fatigue, Lethargy
Cord & Root lesions
- Due to vertebral disease
  - Neoplasm extending into extradural space
  - Frequency: 5% of myeloma
- Pain: Focal & Back
Polyneuropathies
- General
  - Frequency: 1% to 8%
  - Especially frequent (30% to 50%) with osteosclerotic lesions
- Amyloidosis
  - 6% to 15% of myelomas
  - 30% to 40% of neuropathy in myeloma
  - λ > κ chain; Light chain > Whole Ig
  - Distal; Symmetric; Sensory > Motor; Axonal
- ? M-protein related
  - Sensory-Motor
  - Axonal ± Demyelination
  - More commonly IgG or IgA
- General patterns of neuropathy in myeloma without amyloidosis
  - Onset: Before or after diagnosis of myeloma
  - Sensory loss
    - Most patients
    - Panmodal
    - Anatomy: Distal; Symmetric
  - Motor: Some patients (~20%)
    - Distal weakness
    - Legs > Arms
    - Weakness may be severe in rare patient
  - Autonomic: Usually normal
  - Electrophysiology: Axonal loss
  - Treatment: Poor response
- Toxic (due to chemotherapy)
  - Thalidomide
  - Bortezomib ⁶
- Infiltration of nerve by plasma cells ⁸
  - Onset: Initial sign of myeloma relapse
  - Clinical
    - Sensory: Paresthesias; Numbness; Pain
    - Weakness: Asymmetric; Distal > Proximal
    - Tendon reflexes: Present or absent
    - Course: Progression over weeks
  - Laboratory
    - Systemic: May occur with normal bone marrow
    - NCV: Axonal neuropathy; Conduction block
    - Nerve pathology: Plasma cell invasion; Differential fascicular involvement
Laboratory
- Anemia: Eventually present in 100%
- Hypercalcemia
- Immunofixation
  - Serum M-protein: 90%
  - Urine M-protein 78%
- M-protein: Common features
  - γ or μ heavy chain
  - κ light chain
  - Urine monoclonal: 65%
  - Usually IgG or IgA
  - IgM (0.5% of myeloma)
    - Bone marrow: Plasma cell proliferation
    - Neuropathies not clearly reported
    - Rule out Waldenström: Lymphoplasmacytoid proliferation in marrow
- Diagnosis: Plasma cells increased in bone marrow
- Nerve & Muscle biopsy: Rule out amyloidosis
External links

Osteosclerotic myeloma

From M. Al-Lozi Osteosclerotic myeloma in patient with POEMS

Peak incidence: 40 to 50 years
Systemic features
- Skeletal lesions: Sclerotic
- Hematologic
  - Marrow-plasma cells < 5%
  - Normal CBC
  - Platelets increased
- Organomegaly
M-protein
- Heavy chain class: Usually α or γ
- Light chain class: Usually λ
- Present in 80%
- Low levels: < 3g/dl; Median = 1.1 g/dl
- Urine monoclonal: Rare
- Occasional cryoglobulinemia
Neuropathy
- Occurs in 50%
- Weakness: Proximal & Distal
- Sensory loss: Large > Small fiber
- Electrodiagnostic: Demyelination; Long distal latency
Some patients with POEMS Syndrome
CSF: High protein; No cells
Testing
- Lesions detected on x-ray, less often by bone scan
- May be multiple lesions
- Especially in spine, ribs, pelvis
- Normal bone marrow, CBC, quantitative immunoglobulins, urine
Treatment
- Radiation and/or Surgical excision of bony lesions
- Neuropathy improves in 50% after 3 months
- Late recurrence of myeloma may occur

Neuropathy with Amyloid-like depositis ⁹

Epidemiology: > 10 patients
Clinical
- Onset
  - Ages: 60 to 75 years
  - Sensory loss & Discomfort
- Neuropathy
  - Asymmetric
    - Patterns: Multiple mononeuropathies; Mononeuritis multiplex
    - May become symmetric & confluent with progression
  - Sensory loss
    - Distal
    - Legs then Arms
    - Panmodal
    - Sensory ataxia
  - Pain
  - Weakness
    - Distal
    - Hands & Feet
    - Later in course in most
  - Autonomic
    - Anhidrosis
    - Orthostatic intolerance
    - Erectile dysfunction
    - Course: Not common early; May occur late
  - Tendon reflexes: Reduced distal > proximal
  - Course: Progressive
- Skin lesions: Nodules in 1 patient; May contain amyloid-like material in dermis
- Cardiac & Renal function: Normal
- Treatment
  - Rituximab, repeated
  - Bendamustine
Laboratory
- NCV: Axon loss, motor & sensory
- M-protein: IgMλ > IgMκ
- IgM levels: Very high; 1g/dl to 3g/dl
- Waldenström's macroglobulinemia (80%)
- Nerve biopsy
  - Axon loss: Patchy or Multifocal
  - Amyloid-like deposits
    - Shape: Amorphous
    - Location: Endoneurial
    - Congo red: Negative
    - Methyl violet: Negative
    - Contain
      - IgM; μ heavy chain + κ or λ light chain
      - No amyloid signature proteins
    - PAS+
    - Amorphous
    - Location: Endoneurial; Perivascular
    - Ultrastructure: Granulofibrillar
  - Epineurium
    - Perivascular inflammation (2 patients): Polyclonal; CD3 & CD20 cells
    - Neovascularization
    - Hemosiderin

Monoclonal Gammopathy–associated Glycogen Storage Myopathy (MGGSM; VAMMGAS) ¹⁶

Epidemiology: 4 patients
Clinical
- Onset age: 37 to 56 years
- Weakness
  - Onset: Subacute
  - Pattern: Proximal + Axial
  - Dysphagia (50%)
  - Head drop (50%)
- Myalgias
- Weight loss
- Possible treatments: Immunomodulation; Stem cell
Laboratory
- M-protein
  - IgGκ
  - 1 patient with POEMS & additional IgAλ
- Serum CK: 1,400 to 2,900
- EMG: Myopathic; Complex repetitive discharges
- Muscle pathology
  - Glycogen-filled vacuoles: Similar to scleromyxedema
  - C_5b-9: On muscle fiber surfaces
- Muscle MRI: Normal or Posterior leg & thigh involvement

International Myeloma Foundation
International Waldenstrom's Macroglobulinemia Foundation

Return to Neuromuscular Home Page

References

1. JNNP 1996;60:661-666, J PNS 2002;7:59-64
2.Clin Chem 1988;34:2196-2201; J Neurol Sci 1993;1209:93-98
3. NEJM 2002;346:564-569
4. Blood 2003;Online January
5. J Clin Oncol 2000;18:214-226
6. Br J Haematol 2005;129:776-783
7. N Engl J Med 2006;355:2765-2770
8. Neurology 2006;66:917–918
9. J Peripher Nerv Syst 2012;17:182-190, Neurol Neuroimmunol Neuroinflamm 2016;3:e220, Neuromuscul Disord 2023;33:391-395
10. Current Opinion Rheumatology 2014;26:658-662, Acta Myol 2019;38:13-16
11. J Neurol Sci 2019; Online Jan, J Autoimmun 2019 Aug 2
12. J Neurol 2022 May 3
13. Haematologica 2023 Apr 6
14. Eur J Neurol 2025;32:e70087
15. Am J Hematol 2025 Mar 17
16. Eur J Neurol 2025;32:e70026
17. Crit Rev Clin Lab Sci 2025:1-19
18. JAMA Intern Med 2025;185:450-456
19. Cancers (Basel) 2025;17:3358
20. Blood Adv 2026 Jan 27

1/29/2026

	Immunoglobulin (Ig) heavy chain class
Patient group (%)	IgG	IgM	IgA	IgD	Biclonal	Light chain
All M-proteins	70	15	12	< 1	3	3
Polyneuropathy & MGUS	35	50	12		3

MONOCLONAL ANTIBODIES (M-proteins)

Monoclonal Gammopathies of Unknown Significance (& Other) 7

Neoplastic & Systemic Disorders

Monoclonal Gammopathy–associated Glycogen Storage Myopathy (MGGSM; VAMMGAS) 16

Monoclonal Gammopathies of Unknown Significance (& Other) ⁷

Monoclonal Gammopathy–associated Glycogen Storage Myopathy (MGGSM; VAMMGAS) ¹⁶