Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins. Manifestations may include hyperviscosity, bleeding, recurrent 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, Bruton tyrosine kinase (BTK) inhibitors, venetoclax, or monoclonal antibodies.
(See also Overview of Plasma Cell Disorders.)
Macroglobulinemia, an uncommon B-cell cancer, is clinically more similar to a lymphomatous disease than to multiple myeloma and other plasma cell disorders. The cause is unknown, although certain gene mutations have been associated with the disorder. Males are affected more often than females. The median age of patients is 70 years (1).
After myeloma, macroglobulinemia is the second 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 uncommonly of only 1 type of chain) can also accumulate in other disorders, causing manifestations similar to macroglobulinemia. Patients with myeloma rarely show IgM monoclonal protein, but these patients present with the typical pathological and clinical features of myeloma. Importantly, these patients lack the MYD88 marker that is the hallmark of macroglobulinemia. Small monoclonal IgM components are present in the sera of approximately 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 include bleeding, recurrent infections, generalized adenopathy, anemia, neurologic symptoms, 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 occurs in 5% of patients.
Довідковий матеріал загального характеру
1. Castillo JJ, Olszewski AJ, Kanan S, Meid K, Hunter ZR, Treon SP. Overall survival and competing risks of death in patients with Waldenström macroglobulinaemia: an analysis of the Surveillance, Epidemiology and End Results database. Br J Haematol 2015;169(1):81-89. doi:10.1111/bjh.13264
Symptoms and Signs of Macroglobulinemia
Most patients are asymptomatic, but some present with anemia or manifestations of hyperviscosity syndrome (eg, 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 a hyperviscosity syndrome. Retinal hemorrhages, exudates, microaneurysms, and papilledema occur in late stages.
Цінні поради та підводні камені
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Diagnosis of Macroglobulinemia
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 immunofixation proves is IgM.
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 a direct antiglobulin (Coombs) test.
Moderate normocytic normochromic anemia, marked rouleau formation (clusters of 3 to 12 red blood cells that occur in stacks), 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 one-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. When hyperviscosity is present, plasma viscosity is usually > 4.0 milliPascal-second (normal, 1.4 to 1.8 milliPascal-second) (1). Retinal fluorescein angiography can also be used to demonstrate hyperviscosity.
Довідковий матеріал щодо діагностики
1 Gertz MA: Waldenstrom macroglobulinemia: 2023 update on diagnosis, risk stratification, and management. Am J Hematol98:348-358, 2023. doi:10.1002/ajh.26796
Treatment of Macroglobulinemia
Plasma exchange (only when hyperviscosity is present or prior to rituximab for patients with high IgM levels)
Corticosteroids, alkylating agents, nucleoside analogs, monoclonal antibodies (especially rituximab)
Combination drug therapy, especially the alkylating agent bendamustine in combination with rituximab
Other medications, including proteasome inhibitors (bortezomib or carfilzomib), immunomodulatory agents (thalidomide, pomalidomide, or lenalidomide), Bruton tyrosine kinase (BTK) inhibitors (eg, ibrutinib, acalabrutinib, zanubrutinib), and the B-cell lymphoma-2 (BCL-2) inhibitor venetoclax, alone or in combination with rituximab, phosphoinositide 3-kinase (PI3) inhibitors (eg, idelalisib), 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]).
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 the tumor load. Treatment with oral alkylating agents 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 and carfilzomib and the immunomodulating agents thalidomide, lenalidomide, and pomalidomide are also effective in macroglobulinemia, especially when used in combination with other agents.
BTK inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, have shown high levels of activity. Acalabrutinib and zanubrutinib cause less toxicity than ibrutinib. MYD88 and CXCR4 mutational status can predict the likelihood of response to these medications.
The BCL2 (BCL-2 apoptosis regulator) inhibitor venetoclax has shown significant clinical activity (2).
Two other classes of drugs, PI3 kinase inhibitors such as idelalisib, and mTOR inhibitors, including everolimus, have been used effectively for previously treated patients.
Довідковий матеріал щодо лікування
1. Oza A, Rajkumar SV: Waldenstrom macroglobulinemia: Prognosis and management. Blood Cancer J 5(3):e296, 2015. doi: 10.1038/bcj.2015.28
2. Castillo JJ, Allan JN, Siddiqi T, et al: Venetoclax in Previously Treated Waldenström Macroglobulinemia. J Clin Oncol 40(1):63–71, 2022. doi:10.1200/JCO.21.01194
Ключові моменти
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), Bruton tyrosine kinase inhibitors (ibrutinib, acalabrutinib, zanubrutinib), the BCL-2 inhibitor venetoclax, idelalisib, everolimus, or the combination of ibrutinib and rituximab may be helpful; other alkylating agents can be used for palliation.
