What type of immunoglobulin (Ig) is overproduced in macroglobulinemia?

Macroglobulinemia and IgM

Macroglobulinemia refers to the overproduction of monoclonal IgM. The correct answer is C: IgM.

Definition and Diagnostic Criteria

Waldenström macroglobulinemia (WM) is characterized by:

• Presence of monoclonal IgM protein in serum
• Bone marrow infiltration with lymphoplasmacytic cells (>10%)
• Typical immunophenotype (surface IgM+, CD19+, CD20+) 1

The diagnosis requires both the presence of IgM monoclonal protein and lymphoplasmacytic infiltration of the bone marrow, distinguishing it from other monoclonal gammopathies such as IgG or IgA-producing disorders 1.

Clinical Manifestations Related to IgM

The pentameric structure of IgM makes it particularly prone to causing clinical manifestations:

1. Hyperviscosity syndrome

   • Due to the large molecular size of IgM (pentameric structure)
   • Can occur when IgM levels exceed 5,000 mg/dL 2
   • May require plasmapheresis for immediate relief 2

2. Peripheral neuropathy

   • Often associated with anti-myelin-associated glycoprotein (anti-MAG) antibodies 1
   • Treatment-related neuropathy should be considered when selecting therapy 2

3. Other IgM-related complications

   • Cold agglutinin disease (frequently associated with IgM-κ monoclonal protein) 1
   • Cryoglobulinemia (IgM precipitation at lower temperatures) 1
   • Amyloidosis 2

Monitoring and Response Assessment

Response to treatment in WM is primarily measured by changes in serum IgM levels:

• Complete Response (CR): IgM in normal range, disappearance of monoclonal protein by immunofixation 2
• Very Good Partial Response (VGPR): ≥90% reduction in serum IgM 2
• Partial Response (PR): ≥50% but <90% reduction in serum IgM 2
• Minor Response (MR): ≥25% but <50% reduction in serum IgM 2
• Progressive Disease (PD): ≥25% increase in serum IgM 2

Treatment Considerations

Treatment is only initiated when the disease becomes symptomatic:

• Anemia (hemoglobin <10 g/dL)
• Thrombocytopenia (<100 × 10^9/L)
• Symptomatic hyperviscosity
• Bulky lymphadenopathy or organomegaly
• Symptomatic neuropathy or cryoglobulinemia 2, 1

First-line treatment typically includes rituximab-based regimens, often in combination with other agents such as bendamustine, cyclophosphamide, or bortezomib 1.

Clinical Pearls

• IgM flare: Rituximab can cause a transient increase in serum IgM levels in 30-80% of patients, which may exacerbate IgM-related complications 2
• Plasmapheresis should be considered before rituximab treatment in patients with IgM >5,000 mg/dL to prevent hyperviscosity complications 2
• Bortezomib-containing regimens may be preferred for patients with very high IgM levels or hyperviscosity 2
• The L265P mutation in MYD88 is detectable in more than 90% of WM patients 3

Understanding that macroglobulinemia specifically refers to the overproduction of monoclonal IgM is essential for proper diagnosis and management of this condition.