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Macroglobulinemia

(Primary Macroglobulinemia; Waldenström Macroglobulinemia)

By

James R. Berenson

, MD, Institute for Myeloma and Bone Cancer Research

Last full review/revision Sep 2019| Content last modified Sep 2019
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Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins. Manifestations may include hyperviscosity, bleeding, recurring infections, and generalized adenopathy. Diagnosis requires bone marrow examination and demonstration of M-protein. Treatment includes plasma exchange as needed for hyperviscosity, and systemic therapy with alkylating drugs, corticosteroids, nucleoside analogs, ibrutinib or monoclonal antibodies.

Macroglobulinemia, an uncommon B-cell cancer, is clinically more similar to a lymphomatous disease than to multiple myeloma and other plasma cell disorders. Cause is unknown, although certain gene mutations have been associated with the disorder. Men are affected more often than women; median age is 65.

After myeloma, macroglobulinemia is the 2nd most common malignant disorder associated with a monoclonal gammopathy. Excessive amounts of IgM M-proteins (monoclonal immunoglobulin protein, which may consist of both heavy and light chains or of only one type of chain) can also accumulate in other disorders, causing manifestations similar to macroglobulinemia. Small monoclonal IgM components are present in the sera of about 5% of patients with B-cell non-Hodgkin lymphoma; this circumstance is termed macroglobulinemic lymphoma. Additionally, IgM M-proteins are occasionally present in patients with chronic lymphocytic leukemia or other lymphoproliferative disorders.

Clinical manifestations of macroglobulinemia, including bleeding, recurrent infections, generalized adenopathy, hepatosplenomegaly, and less commonly hyperviscosity, may be due to the large amount of high molecular weight monoclonal IgM proteins circulating in plasma, but not all patients develop problems related to high IgM levels. Some of these proteins are antibodies directed toward autologous IgG (rheumatoid factors) or I antigens (cold agglutinins). About 10% are cryoglobulins. Amyloidosis occurs in 5% of patients.

Symptoms and Signs

Most patients are asymptomatic, but many present with anemia or manifestations of hyperviscosity syndrome: fatigue, weakness, skin deposits. skin and mucosal bleeding, visual disturbances, headache, symptoms of peripheral neuropathy, and other changing neurologic manifestations. An increased plasma volume can precipitate heart failure. Cold sensitivity, Raynaud syndrome, or recurring bacterial infections may occur.

Examination may disclose lymphadenopathy, hepatosplenomegaly, and purpura (which rarely can be the first manifestation). Marked engorgement and localized narrowing of retinal veins, which resemble sausage links, suggests hyperviscosity syndrome. Retinal hemorrhages, exudates, microaneurysms, and papilledema occur in late stages.

Pearls & Pitfalls

  • Marked engorgement and localized narrowing of retinal veins, which resemble sausage links, suggest hyperviscosity syndrome.

Diagnosis

  • Complete blood count (CBC) with platelets, red blood cell indices, and peripheral blood smear

  • Serum protein electrophoresis followed by serum and urine immunofixation and quantitative immunoglobulin levels

  • Plasma viscosity assay

  • Bone marrow examination, including tests for specific mutations such as MYD88 and CXCR4

  • Sometimes lymph node biopsy

Macroglobulinemia is suspected in patients with symptoms of hyperviscosity or other typical symptoms, particularly if anemia is present. However, it is often diagnosed incidentally when protein electrophoresis reveals an M-protein that proves to be IgM by immunofixation. Laboratory evaluation includes tests used to evaluate plasma cell disorders (see Multiple Myeloma) as well as measurement of cryoglobulins, rheumatoid factor, and cold agglutinins; coagulation studies; and direct antiglobulin (Coombs) test.

Moderate normocytic, normochromic anemia, marked rouleau formation, and a very high erythrocyte sedimentation rate (ESR) may occur. Leukopenia, relative lymphocytosis, and thrombocytopenia are occasionally found. Cryoglobulins, rheumatoid factor, or cold agglutinins may be present. If cold agglutinins are present, the direct Coombs test usually is positive. Various coagulation and platelet function abnormalities may occur. Results of routine blood studies may be spurious if cryoglobulinemia or marked hyperviscosity is present. Normal immunoglobulins are decreased in half of patients.

Immunofixation electrophoresis of concentrated urine frequently shows a monoclonal light chain (more often kappa [κ]), but gross Bence Jones proteinuria is unusual. Bone marrow studies show a variable increase in plasma cells, lymphocytes, plasmacytoid lymphocytes, and mast cells. Periodic acid-Schiff–positive material may be present in lymphoid cells. Lymph node biopsy, done if bone marrow examination is normal, is frequently interpreted as diffuse well-differentiated or plasmacytic lymphocytic lymphoma. Plasma viscosity is measured to confirm suspected hyperviscosity and when present it is usually > 4.0 (normal, 1.4 to 1.8 mPa.s [milliPascal second]).

Treatment

  • Plasma exchange (only when hyperviscosity is present or prior to rituximab for patients with high IgM levels)

  • Corticosteroids, alkylating drugs, nucleoside analogs, monoclonal antibodies (especially rituximab)

  • Other drugs, including Proteasome inhibitors (bortezomib or carfilzomib), immunomodulatory agents (thalidomide, pomalidomide, or lenalidomide), ibrutinib, idelalisib, or combinations (especially rituximab with ibrutinib)

The course is variable, with a median survival of 7 to 10 years. Age > 60 years, anemia, and cryoglobulinemia predict shorter survival (for review, see [1, 2]).

Often, patients require no treatment for many years (1). If hyperviscosity is present, initial treatment is plasma exchange, which rapidly reverses bleeding as well as neurologic abnormalities. Plasma exchange often needs to be repeated.

Corticosteroids may be effective in reducing tumor load. Treatment with oral alkylating drugs may be indicated for palliation, but bone marrow toxicity can occur. Nucleoside analogs (fludarabine and 2-chlorodeoxyadenosine) produce responses in large numbers of newly diagnosed patients but have been associated with a high risk of myelodysplasia and myeloid leukemia. Rituximab can reduce tumor burden without suppressing normal hematopoiesis. However, during the first several months, IgM levels may increase, requiring plasma exchange. The proteasome inhibitors bortezomib or carfilzomib and the immunomodulating agents thalidomide, lenalidomide, and pomalidomide are also effective in this cancer. Ibrutinib, a Bruton tyrosine kinase inhibitor, and idelalisib, a PI3K inhibitor, are also effective in these patients. The combination of ibrutinib with rituximab is especially effective as initial therapy.

Treatment references

  • Oza A, Rajkumar SV: Waldenstrom macroglobulinemia: Prognosis and management. Blood Cancer J 5(3):e296, 2015. doi: 10.1038/bcj.2015.28

  • Gertz MA: Waldenstrom macroglobulinemia: 2019 update on diagnosis, risk stratification, and management. Am J Hematol 94:266–276, 2019. doi: 10.1002/ajh.25292

Key Points

  • Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins.

  • Most patients are initially asymptomatic, but many present with anemia or hyperviscosity syndrome (fatigue, weakness, skin and mucosal bleeding, visual disturbances, headache, peripheral neuropathy, and other neurologic manifestations).

  • Do serum protein electrophoresis followed by serum and urine immunofixation, and quantitative immunoglobulin levels.

  • Treat hyperviscosity using plasma exchange, which rapidly reverses bleeding as well as neurologic abnormalities.

  • Corticosteroids, fludarabine, rituximab, proteasome inhibitors (bortezomib and carfilzomib), immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), ibrutinib, idelalisib, or the combination of ibrutinib and rituximab may be helpful; alkylating drugs can be used for palliation.

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