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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 Oct 2021| Content last modified Nov 2021
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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, generalized adenopathy, and hepatosplenomegaly. 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.

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 Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more Non-Hodgkin Lymphomas ; this circumstance is termed macroglobulinemic lymphoma. Additionally, IgM M-proteins are occasionally present in patients with chronic lymphocytic leukemia Chronic Lymphocytic Leukemia (CLL) Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more or other lymphoproliferative disorders.

Clinical manifestations of macroglobulinemia include bleeding, recurrent infections, generalized adenopathy, and hepatosplenomegaly. Less commonly, patients develop hyperviscosity due to the large amounts of high molecular weight monoclonal IgM proteins circulating in plasma, but most patients do not 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 Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more Amyloidosis occurs in 5% of patients.

Symptoms and Signs

Most patients are asymptomatic, but some 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 Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular failure causes shortness of breath and fatigue, and right ventricular failure causes peripheral and abdominal fluid... read more Heart Failure (HF) . Cold sensitivity, Raynaud syndrome Raynaud Syndrome Raynaud syndrome is vasospasm of parts of the hand in response to cold or emotional stress, causing reversible discomfort and color changes (pallor, cyanosis, erythema, or a combination) in... read more 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 a 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 a hyperviscosity syndrome.

Diagnosis

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

  • Serum protein electrophoresis followed by serum and urine immunofixation, quantitative immunoglobulin levels, and serum free light chain levels

  • Plasma viscosity assay

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

  • Sometimes a 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 Multiple Myeloma Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing... read more Multiple Myeloma ) as well as measurement of cryoglobulins, rheumatoid factor, and cold agglutinins; coagulation studies; and a 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 cold agglutinins, cryoglobulinemia, or marked hyperviscosity is present. Normal immunoglobulins are decreased in half of the 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 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)

  • Chemotherapy, especially the alkylating agent bendamustine in combination with rituximab

  • Other drugs, including proteasome inhibitors (bortezomib or carfilzomib), and immunomodulatory agents (thalidomide, pomalidomide, or lenalidomide), Bruton tyrosine kinase (BTK) inhibitors (eg, ibrutinib) alone or in combination with rituximab, phosphoinositide 3-kinase (PI3) inhibitors (eg, idelasib), or a mammalian target of rapamycin (mTOR) inhibitor (eg, everolimus)

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] Treatment references 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... read more ).

Corticosteroids may be effective in reducing the 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 combination of this monoclonal antibody with bendamustine is highly effective.

The proteasome inhibitors bortezomib or carfilzomib and the immunomodulating agents thalidomide, lenalidomide, and pomalidomide are also effective in this cancer.

Recently, ibrutinib, a BTK inhibitor, and idelalisib, a PI3K inhibitor, have been shown to be highly effective for treating these patients. The combination of ibrutinib with rituximab is especially effective as initial therapy. Newer analogs of ibrutinib such as acalibrutinib and zanubrutinib have shown promise, decreasing disease activity and possibly causing less toxicity. Two other classes of drugs, PI3 kinase inhibitors such as idelalisib, and mTOR inhibitors, including everolimus, have been used effectively for previously treated patients.

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: 2021 update on diagnosis, risk stratification, and management. Am J Hematol 96:258–269, 2020.

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, everolimus, or the combination of ibrutinib and rituximab may be helpful; other alkylating drugs can be used for palliation.

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