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Myeloma and paraproteinaemias 

Myeloma and paraproteinaemias

Chapter:
Myeloma and paraproteinaemias
Author(s):

Robert A. Kyle

and S. Vincent Rajkumar

DOI:
10.1093/med/9780199204854.003.220405_update_002

Update:

Management—discussion of use of lenalidomide after autologous stem cell transplantation; detailed presentation of new data regarding treatment options in patients not eligible for stem cell transplantation; update on new novel agents.

Updated on 29 May 2014. The previous version of this content can be found here.
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date: 28 March 2017

The paraproteinaemias are a group of neoplastic (or potentially neoplastic) diseases associated with the proliferation of a single clone of immunoglobulin-secreting plasma cells.

Monoclonal gammopathy of undetermined significance (MGUS)

This asymptomatic condition of unknown cause is characterized by a serum paraprotein concentration under 30 g/l, less than 10% monoclonal plasma cells in the bone marrow, and no evidence of end-organ damage (CRAB) hypercalcaemia, renal insufficiency, anemia, and bone lesions related to the plasma cell proliferative process.

Epidemiology and prognosis—MGUS is found in 3% of people aged over 50 years and in 5% of those over 70 years. The risk of progression to multiple myeloma or a related disorder is about 1% per year, with factors increasing the risk being higher concentration of the monoclonal protein, some particular types of monoclonal protein (IgA and IgM > IgG), or an abnormal serum-free light chain ratio.

Management—the monoclonal protein in the serum and urine should be monitored, together with re-evaluation of clinical and laboratory tests, to determine whether multiple myeloma or a related disorder has developed.

Multiple myeloma

Multiple myeloma accounts for about 10% of haematological malignancies, with the clonogenic cell appearing to arise from the germinal centre, circulate in the peripheral blood, and home to the bone marrow by means of adhesion molecules. The cause is unknown, but conventional cytogenetics reveals an abnormal karyotype in 35% of patients, and fluorescence in situ hybridization (FISH) reveals specific primary translocations or chromosomal deletions in >90% of patients. High-risk myeloma is characterized by the presence of del 17p, t(14;16) and t(14;20) and occurs in 15–20% of patients with multiple myeloma.

Clinical features—the commonest symptoms are weakness and fatigue, and bone pain is present at diagnosis in almost two-thirds of cases. Other presentations include acute infection, renal failure, hypercalcaemia and amyloidosis.

Investigations—a paraprotein is found in the serum (usually >30 g/litre) or urine at diagnosis in 97% of cases. The bone marrow usually contains more than 10% plasma cells, with the presence of monoclonal κ‎ or λ‎ in their cytoplasm being useful for differentiating monoclonal from reactive (polyclonal) plasmacytosis. Conventional radiographs show lytic lesions, osteoporosis or fractures in almost 80% of patients at diagnosis.

Treatment and prognosis—some patients are asymptomatic and should not be treated, but most have symptomatic disease at diagnosis and require treatment, for which first-line options—aside from supportive care—are: (1) Autologous peripheral stem-cell transplantation—this comprises (a) 3 to 4 months of induction therapy (e.g. lenalidomide plus dexamethasone or bortezomib plus dexamethasone), (b) collection of peripheral stem cells utilizing granulocyte colony-stimulating factor (G-CSF), (c) preparative or conditioning treatment (e.g. high-dose melphalan), (d) infusion of the previously collected peripheral blood stem cells. (2) Chemotherapy—for patients who are not eligible for stem cell transplantation (on account of excessive risk), the standard of therapy has been melphalan and prednisone (or combinations of alkylating agents) for the past four decades, but the addition of thalidomide, bortezomib, and lenalidomide has produced much better results. Patients with relapsed refractory disease are usually treated with thalidomide, bortezomib, or lenalidomide, all with dexamethasone. The median duration of survival is about 6–7 years.

Waldenström’s macroglobulinaemia

Waldenström’s macroglobulinaemia (WM) is characterized by the presence of an IgM paraprotein and evidence of lymphoplasmacytic infiltration of the bone marrow. Characteristic symptoms include chronic nasal bleeding or oozing from the gums, and blurring or loss of vision, with retinal vein engorgement and flame-shaped haemorrhages commonly seen and typical of symptomatic hyperviscosity syndrome. Symptoms and findings of hyperviscosity are quickly controlled by plasmapheresis. Rituximab, a monoclonal antibody directed against the CD20 antigenic determinant, produces a response in about 50% of patients. Bortezomib is also an active drug in WM. Chlorambucil, given continuously or intermittently, has been an active therapeutic agent for approximately 50 years. The median duration of survival is about 5 years.

Primary amyloidosis (AL)

Primary amyloidosis is characterized by tissue deposition of fibrils consisting of monoclonal κ‎ or λ‎ light chains. Weakness, fatigue, and weight loss are the commonest initial symptoms. Characteristic findings include periorbital purpura (15% of cases), macroglossia (10%), nephrotic syndrome/renal failure (25%), and congestive heart failure (20%), but virtually any organ system can be affected.

Standard treatment is with melphalan plus dexamethasone or bortezomib with dexamethasone. Prognosis is generally poor, although this varies greatly depending on the associated organ involvement), but survival has improved. Autologous peripheral blood stem cell transplantation has produced encouraging results, but patients with significant cardiac involvement should be excluded.

Other conditions

Rare paraprotein disorders include plasma cell leukaemia; nonsecretory myeloma; POEMS syndrome (osteosclerotic myeloma)—characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes; solitary plasmacytoma of bone; extramedullary plasmacytoma; and heavy chain diseases.

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