University of Virginia Health System

Multiple Myeloma (MM), Myelomatosis, and Other Monoclonal Gammopathies

Introduction:

A group of disorders characterized by the clonal proliferation of plasma cells, plasmacytoid lymphocytes, mature lymphocytes, or a combination in the bone marrow and/or extramedullary sites. The clonal cells, by definition, produce and secrete a monoclonal immunoglobulin (Ig) or an Ig subunit, either light chains only or truncated heavy chains without attached light chains. A monoclonal Ig or subunit can be identified in the serum and/or urine in 99% of cases of multiple myeloma (MM); in those cases in which a monoclonal Ig or subunit is not found, the clonal cells are producing a monoclonal Ig or subunit, but are not secreting it (nonsecreter MM).

From both a clinical and laboratory standpoint, these disorders are a diverse group. The frequency of each disorder (adapted from Kyle RA, Rajkumar SV. Hematol-Oncol Clin North Am 21:1093, 2007)

• Multiple Myeloma (MM) (represents 15-20%)
• Is a disseminated clonal plasma cell proliferation in the bone marrow of the axial skeleton.
• Plasmacytomas (represents 2% or less)
• Intraosseous- a solitary, clonal plasma cell tumor localized to bone
• Extramedullary- a solitary, clonal plasma cell tumor localized to other organs or tissues
• Waldenstrom's macroglobulinemia (WM) (represents 2% or less)
• Is a disseminated clonal proliferation of plasmacytoid lymphocytes with a variable component of clonal lymphocytes and plasma cells in the bone marrow of the axial skeleton, and in most cases, in the peripheral blood, spleen and lymph nodes that produce and secrete a monoclonal IgM.
• Primary amyloidosis (represents 10%)
• Is a plasma cell proliferation in the bone marrow of the axial skeleton manifested clinically by the deposition of a proteinacious material (amyloid) in vessels and other tissues and organs, resulting in organ dysfunction. The major component of the amyloid is derived from the hypervariable portion of the clonal light chains, and rarely from the heavy chain component.
• Monoclonal light and heavy chain deposition diseases
• Organ dysfunction due to the deposition of clonal light chains or truncated heavy chains or a combination in various tissues and organs.
• Monoclonal gammopathy of undetermined significance (MGUS) (represents 60% or more)
• Is a clonal proliferation of plasma cells in the bone marrow of the axial skeleton that secretes a monoclonal Ig or subunit not associated with any clinical or laboratory manifestations attributable to the monoclonal Ig or the plasma cell process itself. The level of the monoclonal Ig or subunit found in the serum and/or urine is small, and the degree of plasmacytosis in the bone marrow is <10%. This entity has been referred to as benign, essential, idiopathic, cryptogenic, or non-myelomatous monoclonal gammopathy. In a 25 year follow-up of a large cohort of patients with MGUS, only 30% progressed to multiple myeloma or other plasma cell disorders requiring treatment (Kyle RA, et al. N Engl J Med 346:564, 2002)
• Smoldering MM (represents <5%)
• This term is used when the criteria for MM is met based on ≥10% plasma cells on a bone marrow aspirate), but without evidence of any organ dysfunction attributable to the monoclonal Ig or subunit. In contrast to patients with MGUS, the progression to overt MM occurs earlier and more frequently, but some smolder without progression for several years. Again, the level of the monoclonal Ig is usually smaller when compared to overt MM (Greipp PR, Kyle RA. Blood 62:166, 1983)
• A monoclonal Ig or subunit may be found in association with chronic B cell lymphocytic leukemias, other B cell lymphocytic leukemias, and other lymphoproliferative disorders (lymphomas), autoimmune disorders, peripheral polyneuropathy, POEMS syndrome, dermatologic disorders such as lichen myxedematous, diffuse plane xanthomatosis, and other conditions. These associations represent <5% of all cases.
• Heavy-chain diseases (represents <1.0%)
• These are clonal plasma cell proliferations with a variable clonal lymphocytic component that may occur in the bone marrow, lymph nodes or other organs (e.g. G-I tract). The clonal cells secrete truncated heavy chains without light chains attached. They represent a diverse group of clinical disorders, and are quite rare.

General References:

• Wells JV, Fudenberg HH. Paraproteinemias. Disease- a Month. February, 1974
• McKenna RW, Kyle RA, Kuehl WM, et al. Plasma cell neoplasms. In Swerdlow SH, Campo E, Harris NL, et al, eds, WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press, 2008, p200
• Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Hematol Oncol Clin North Am 21(6):1093, 2007
• Greipp PR, Kyle RA. Clinical, morphological, and cell kinetic differences among multiple myeloma, monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Blood 62:166, 1983
• Kyle RA, Therneau TM, Rajkumar SV, Offord JR. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 346:564, 2002
• Kyle RA, Gertz MA. Monoclonal gammopathies of undetermined significance. Hematol Oncol Clin N Am 13(6):1181, 1999
• Buxbaum J, Gallo G. Nonamyloidotic monoclonal immunoglobulin deposition disease. Hematol Oncol Clin N Am 13(6):1235, 1999