Other plasma cell dyscrasias include MGUS, solitary plasmacytoma of bone (SPB), solitary extramedullary plasmacytoma, Waldenström's macroglobulinemia, amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, and heavy-chain diseases.
Monoclonal gammopathy of unknown significance (MGUS) occurs in 1% of normal individuals > 40 years old, and its frequency rises progressively with age. Recent studies indicate that the diagnosis of symptomatic multiple myeloma is always preceded by monoclonal gammopathy for 2 or more years.
Common laboratory features of MGUS are listed in Table 2.
Approximately 25% of patients with this disorder develop multiple myeloma, macroglobulinemia, or non-Hodgkin lymphoma over 20 years. The initial concentration of serum monoclonal protein > 1.5 g/dL, non–IgG-type paraprotein, and abnormal serum free light-chain ratio are significant predictors of disease progression at 20 years. The long period of stability supports annual monitoring with serum electrophoresis and blood counts and suggests that chemotherapy may be withheld until there is evidence of progression to myeloma.
Approximately 3% of patients with myeloma have solitary plasmacytoma of bone (SPB).
All patients have either no myeloma protein or very low levels in serum or urine (Table 2). MRI may reveal abnormalities not detected by bone survey and may upstage patients to multiple myeloma. Persistence of monoclonal protein for more than 1 year after irradiation predicts early disease progression to multiple myeloma.
Management of SPB consists of radiation therapy (at least 45 Gy). Multiple myeloma becomes evident in most patients over time, so only 20% of patients remain free of disease for more than 10 years. The median time for disease progression is approximately 2 to 3 years.
In contrast to SPB, solitary extramedullary plasmacytoma is often truly localized and can be cured in up to 50% of patients with localized radiation therapy (45–50 Gy) and/or resection. Careful observation after treatment is nonetheless warranted.
This uncommon disease is characterized by lymphoplasmacytic bone marrow and tissue infiltrate in addition to elevated IgM production. The mutation pattern analysis suggests that final transformation occurs in the postgerminal center IgM memory B cell. Corresponding with variation in cell morphology, there is variation in the immunophenotype. Mature plasma cells exhibit CD38 antigen; however, lymphoid cells are typically positive for CD19, CD20, and CD22.
Waldenström's macroglobulinemia usually affects people in the fifth to seventh decades of life and can cause symptoms due to tumor infiltration (marrow, lymph nodes, and/or spleen), circulating IgM (hyperviscosity, cryoglobulinemia, and/or cold agglutinin hemolytic anemia), and tissue deposition of IgM (neuropathy, glomerular disease, and/or amyloidosis). Neuropathy may be due to the IgM antibody reacting with myelin-associated glycoprotein.
With hyperviscosity syndrome, patients may have visual symptoms, dizziness, cardiopulmonary symptoms, decreased consciousness, and a bleeding diathesis.
Therapy for hyperviscosity consists of plasmapheresis followed by chemotherapy to control the malignant proliferation. Patients with poor performance status and elderly patients who are unable to tolerate chemotherapy may be maintained with periodic plasmapheresis.
Alkylating agents used in combination with steroids or purine analogs remain the mainstay of therapy. Alkylating agents alone or in combination with steroids effect a 50% reduction in paraprotein in about half of patients, and the median survival time is around 5 years. The purine analogs fludarabine (Fludara) and cladribine(Drug information on cladribine) (Leustatin) elicit a more rapid response than other agents, with a response rate of more than 75% observed in a small series of patients. Preliminary results of a large, American multi-institution evaluation of fludarabine reported partial responses in only 33% of patients.
Purine analog therapy may result in significant myelosuppression in later cycles of therapy and prolonged immunosuppression with increased opportunistic infections. Purine analogs are effective salvage options in patients refractory to or relapsing following alkylator therapy. Patients refractory to one purine analog are rarely salvaged by a different purine analog. Patients with resistant relapse are less likely to benefit from purine analogs (response rate, 18%) and should be considered for more intensive intervention, including high-dose therapy.
Other treatment options
Rituximab (Rituxan), an anti-CD20 monoclonal antibody, is effective in Waldenström's macroglobulinemia, because the CD20 antigen is usually present on the lymphoid cell component of macroglobulinemia. Preliminary results indicate that about 30% of previously treated patients (refractory or relapsing off therapy) may benefit from rituximab.
Striking activity of thalidomide(Drug information on thalidomide) in multiple myeloma has prompted its use in Waldenström's macroglobulinemia. In a series of 20 patients receiving thalidomide, 25% achieved a 50% reduction in paraprotein. Higher doses of thalidomide were not well tolerated in an elderly cohort of patients. Interestingly, preliminary results of bortezomib(Drug information on bortezomib)-based therapy in relapsed Waldenström's macroglobulinemia have been very promising. In contrast, lenalidomide has proved less useful, primarily because of myelosuppression.
High-dose therapy with autologous bone marrow or blood stem cell rescue has been effective in achieving 50% reduction in paraprotein in almost all patients in small pilot trials.
Amyloidosis occurs in 10% of patients with multiple myeloma. This infiltrative process results from organ deposition of amyloid fibrils, which consist of the NH2 terminal amino acid residues of the variable portion of the light-chain Ig molecule. The abnormal protein is produced by clonal plasma cells.
These include the nephrotic syndrome, cardiomyopathy, hepatomegaly, neuropathy, macroglossia, carpal tunnel syndrome, and periorbital purpura.
Serum and urine immunofixation studies show a monoclonal immunoglobulin in approximately 80% of patients. Measurement of serum free light chain may provide a marker to evaluate response to therapy. The light chain is more frequently of the λ than κ type. Diagnosis can be made by the presence of apple-green birefringence on polarized light examination of subcutaneous fat aspirates stained with Congo red. Elevated serum B-type natriuretic peptide levels may indicate cardiac involvement, which, in the majority of patients, may be confirmed with echocardiography.
Treatment of primary amyloidosis (AL; monoclonal protein–associated)
Survival of patients with amyloidosis is variable. Patients with congestive heart failure have a median survival of only 4 months. Oral MP extends the median survival to 17 months, as compared with 13 months in untreated patients. Complete hematologic response is rare; similarly, reversal of organ damage is uncommon.
In a large cohort of patients receiving high-dose melphalan(Drug information on melphalan) with stem cell support, a complete hematologic response was observed in 47% of patients with at least 1 year of follow-up. However, the transplant-related mortality is high with high-dose therapy (14% to 37%). Complete hematologic response was associated with improved clinical response (improved organ function) and survival. Complete hematologic response in the absence of cardiac involvement predicted excellent outcome (1-year survival, 91%). Phase I and II studies have also shown encouraging results with bortezomib as well as lenalidomide, both in newly diagnosed and more advanced disease.
Patients with the overlap syndrome of myeloma and AL amyloidosis should be treated aggressively for myeloma; response can be seen in terms of both myeloma and resolution of amyloid symptoms.
Clinical features and course
The POEMS syndrome is a rare plasma cell dyscrasia that presents with peripheral, usually sensorimotor, neuropathy; monoclonal gammopathy (IgA λ being more common); sclerotic bone lesions, noted in nearly all patients; and organomegaly, endocrinopathy, and skin changes.
Other features include hyperpigmentation, hypertrichosis, thickened skin, papilledema, lymphadenopathy, peripheral edema, hepatomegaly, splenomegaly, and hypothyroidism. Diabetes mellitus is not part of this syndrome.
Compared with patients with symptomatic myeloma, individuals with POEMS syndrome are younger (median age, 51 years) and live longer (median, 8 years). The clinical course is commonly characterized by progressive neuropathy.
Plasmapheresis does not appear to be of benefit in POEMS syndrome, and patients are often treated similarly to those with myeloma. Patients presenting with isolated sclerotic lesions may have substantial resolution of neuropathic symptoms after local therapy for plasmacytoma with surgery and/or radiotherapy. Autologous stem cell transplantation has been pursued in selected patients and has been associated with prolonged progression-free survival.
Heavy-chain diseases are rare plasma cell dyscrasias characterized by the production of heavy-chain Ig molecules that lack light chains (IgG, IgA, IgM).
α Heavy-chain disease
This condition results from lymphocyte and plasma cell infiltration of the mesenteric nodes and small bowel and has features of malabsorption, such as diarrhea, weight loss, abdominal pain, edema, and nail clubbing. The heavy-chain molecule may be detected in serum, jejunal secretions, and urine. There is an association with infection with Campylobacter jejuni and α heavy-chain disease. Large proportions of patients can benefit from antibiotic therapy directed at this infection.
γ Heavy-chain disease
Patients with γ heavy-chain disease may present with fever, weakness, lymphadenopathy, hepatosplenomegaly, and involvement of Waldeyer's ring. Eosinophilia, leukopenia, and thrombocytopenia are common. Treatment with regimens similar to those used for non-Hodgkin lymphoma may be effective.
μ Heavy-chain disease
This condition is seen exclusively in patients with chronic lymphocytic leukemia (CLL). Vacuolated plasma cells are common in the marrow, and many patients have κ light chains in the urine. Therapy is similar to that used for CLL (see chapter 31).