Myeloma : Genetics

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Image Description

Conventional cytogenetics and molecular cytogenetics (using FISH) reveal abnormalities in 30% and 90% of multiple myelomas respectively. They include both structural and numerical abnormalities of chromosomes and range from trisomies, partial or complete deletions, and translocations.

Translocations involving immunoglobulin heavy-chain locus at chromosome 14q32 are found in between 55% and 70% of myelomas. A number of proto-oncogenes, including cyclin D1, cyclin D3, and FGFR3 are involved as partner genes with the IgH locus. Partial or complete deletion of chromosome 13 (13q14) is found in about 40% of myelomas and 70% of plasma cell leukemias by FISH.

Del 17p involving P53 tumor suppressor gene is associated with poor prognosis. Acquisition of MYC rearrangements have been associated with progression to plasma cell leukemia - a highly aggressive variant. K-ras mutations are seen in 30% to 40% of cases and are considered to be early events in disease progression.

About the Disease

Plasma cell disorders are B-cell neoplasms composed of plasma cells or lymphocytes that secrete a monoclonal immunoglobulin (Ig) or Ig fragment. They are responsible for about 15% of deaths caused by lymphoid malignancies in the US. The monoclonal Ig, usually identified by serum or urine protein electrophoresis, is known as the M component. Sometimes the M component consists of only light chains or heavy chains. Free light chains are referred to as Bence-Jones proteins when they are excreted in urine. The WHO Classification (2008) of plasma cell neoplasms includes the following: Monoclonal Gammopathy of Undetermined Significance (MGUS): MGUS refers to an asymptomatic patient with an M component (<3 gm/dl) in their blood. It is the most common plasma cell disorder and is seen in about 5% of individuals >70 years of age. About 1% of MGUS patients per year develop multiple myeloma, amyloidosis, macroglobulinemia, or other lymphoproliferative disorder. The median interval between the diagnosis of MGUS and the development of malignancy is about 10.5 years. Plasma Cell Myeloma: Multiple myeloma (MM) is a plasma cell neoplasm of older individuals that is characterized by scattered tumorous masses causing lytic bone lesions in the axial skeleton, hypercalcemia, renal damage, and acquired immune abnormalities. Solitary Plasmacytoma: About 3% to 5% of patients with plasma cell disorders present with solitary bone or soft tissue mass. An M component may be found in serum or urine in a small percentage of cases. Solitary bone plasmacytoma slowly progresses to multiple myeloma in most cases. Extraosseous plasmacytomas involve lungs, nasopharynx, oropharynx, or nasal sinuses and can often be cured by resection. Immunoglobulin Deposition Diseases: This group includes primary amyloidosis (PA) and light- or heavy- chain deposition disease. Immunoglobulins are deposited in various tissues eventually leading to organ failure. About 20% of PA patients have multiple myeloma (MM). The remainder don't meet the criteria for MM but have a small M component and increased plasma cells in bone marrow. Osteosclerotic Myeloma (POEMS Syndrome): Osteosclerotic myeloma is usually associated with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin lesions (POEMS syndrome). Some patients also develop Castleman's disease, serous effusions, and thrombocytosis.

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