MONOCLONAL ANTIBODIES (M-proteins)

Monoclonal Gammopathies of Unknown Significance (MGUS)

• General characteristics
• Types of light chain: k > l
• Quantity: < 3 g/dl
• Urine monoclonal: Rare
• Marrow plasma cells: < 5%
• Skeletal lesions (X-ray): Absent
• CBC: Normal
• Organomegaly: None

• Testing
• For M-protein: Serum & urine
• Optimal clinical method: Immunofixation
• Quantitative immunoglobulin: < 3 g/dl
• ? 24 hour urine for Bence-Jones protein
• After M-protein found
• X-ray skeletal survey

• Antigen target of IgM M-protein
• Cryoglobulins
• Bone marrow biopsy

• General clinical features
• Associated systemic disorders: 35%
• Neoplasms 26%: May occur at time of dx or during follow-up

• Waldenström's macroglobulinemia 2%
• Amyloidosis 9%: often with myeloma
• No associated systemic disorders: 65%
• Monoclonal gammopathy of unknown significance (MGUS)
• Light chain: kappa more often than lambda
• Normals: MGUS occur more commonly with increasing age

• Neuropathy
• Occurs in 5% of MGUS
• 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
• Cryoglobulinemia
• IgG & IgA MGUS Neuropathy
• IgM MGUS: Several syndromes depending on antigenic target of antibody
• BJ antigen: Myopathy
• GALOP antigen: Gait disorder & polyneuropathy
• GD1b ganglioside (without GM1 binding): Ataxic sensory neuropathy
• GM1 ganglioside: Motor neuropathy
• Myelin-associated glycoprotein: Sensory ± motor neuropathy
• Sulfatide: Sensory ± motor neuropathy
• Tubulin: CIDP
• Multiple myeloma
• Osteosclerotic myeloma
• POEMS Syndrome
• Scleromyxedema
• Waldenström's macroglobulinemia

Neoplastic & Systemic Disorders

• IgG & IgA MGUS
• Long term: Increased risk of myeloma in 10 to 20 years (1% - 2%/ year)
• Test quantitative immunoglobulins every 1 to 2 years.
• Neuropathy
• Sensory > motor; Symmetric
• Axonal
• Treatment: More responsive to plasma exchange than IgM MGUS
• POEMS Syndrome
• Scleromyxedema
• M-protein: l
• Skin

• Myopathy:

• Vascular: Raynaud's; Telangectasia; Ischemia
• Other: Weight loss; ± Neuropathy; Interstitial lung disease; ? Thyroid
• Course: Variable - spontaneous resolution to progressive disability

• Waldenström's macroglobulinemia
• Patients: Males; 50 to 80 years
• Neuropathy (5%): Demyelinating with Anti-MAG antibodies
• Myopathy: Anti-BJ antibody-associated
• Central Nervous System: Ischemia; Hemorrhage; Myelopathy
• Systemic
• General: Lassitude; weight loss; weakness
• Raynaud's phenomenon
• Hematologic: Anemia; High serum viscosity; Clotting disorders
• Organomegaly: Liver, Spleen, Lymph nodes
• No lytic bone lesions
• Bone marrow: Malignant plasmacytoid cells
• Serum
• > 3 grams/dl IgM M-protein
• IgM M-protein usually k light chain
• High sedimentation rate

• Osteosclerotic myeloma
• Systemic features
• Skeletal lesions: Sclerotic
• Hematologic: Marrow-plasma cells < 5%; Normal CBC
• Organomegaly
• M-protein
• Usually IgG or IgA lambda
• Present in 80%
• < 3g/dl
• Urine monoclonal: Rare
• Neuropathy
• Occurs in 50%
• Weakness: Proximal & distal
• Sensory loss: Large > small fiber
• Electrodiagnostic: Demyelination with long distal latencies
• 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

• Cryoglobulinemia
• Immunoglobulins that precipitate when cooled & dissolve when heated
• Testing
• Serum should be kept warm before testing
• When cryoglobulins are detected, test for

• Types: Neuropathy & systemic signs with types II & III
• I: All monoclonal Ig, or rarely light chains

• II: Mixed polyclonal (IgG) and monoclonal (usually IgMk)

• III: Polyclonal Ig
• Systemic
• Skin: Purpura; Vasculitic changes
• Organ: Arthralgias; Renal; Hepatosplenomegaly
• Hematologic: Clotting disorders; Hypertension
• Weight loss
• Associated disorders

• Antibodies to Hepatitis C virus
• Neuropathy¹
• Pattern

• Pain & paresthesias
• Hepatitis C + cases (50%)

• Electrodiagnostic: Axonal loss
• Pathology: Vasculitic changes; Micro-vascular occlusion
• Treatment
• Corticosteroids; Immunosuppression; Plasma exchange
• Interferon a-2a with Hepatitis C

• Multiple myeloma ^{2, 3, 4}
• Onset
• 5th to 7th decade
• Fatigue, lethargy, anemia, hypercalcemia, bone pain
• M-protein: common features
• g or m heavy chain
• k light chain
• Urine monoclonal: 65%
• Systemic features
• Skeletal lesions: Lytic
• Hematologic: Marrow-plasma cells > 10%; Abnormal CBC
• Organomegaly
• Neurologic manifestations
• Cord & root lesions due to vertebral disease
• Polyneuropathy: Occurs in 3% to 5%
• Amyloidosis

• M-protein related: Sensory-motor; Axonal ± Demyelination
• Toxic (due to chemotherapy)

International Myeloma Foundation

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5/31/97

References

1. JNNP 1996;60:661-666