Myeloma and Monoclonal Gammopathy of Uncertain Significance (MGUS)

Clinical Features
Laboratory Diagnosis
Cytogenetics
Outcome and Therapy

CLINICAL FEATURES

Multiple myeloma is a disorder characterised by the following features :
- bone marrow infiltration with clonal plasma cells.
- lytic bone lesions.
- paraproteinaemia and immunoparesis.
Paraproteins are commonly IgG, IgA or light chain only. IgD and IgE myeloma is exceedingly rare.
The concentration and physicochemical properties of paraproteins contribute to the development of renal failure, hyperviscosity and amyloidosis.
Overt peripheral blood involvement is rare but can be demonstrated in the majority of cases by sensitive techniques such as flow cytometry and PCR^[1,2].
Circulating plasma cells in excess of 1 x 10⁶/l is associated with a poor outcome.

Myeloma must be distinguished from monoclonal gammopathy of undetermined significance (MGUS). This is done on the basis of paraprotein concentration, level of plasma cell infiltrate and the presence or absence of other clinical features^[3].

A) Morphology

Bone marrow aspirates contain >10% morphologically atypical plasma cells.
Where the number of plasma cell is between 5-10% in the aspirate specimen the distinction between myeloma and MGUS depends on other clinical and biochemical features.
In the trephine biopsy the neoplastic plasma cells show an interstitial or diffuse pattern of infiltration. Normal plasma cells are perivascular in distribution
Plasma cell morphology is usually abnormal with increased cell size, prominent nucleoli, vacuolated cytoplasm and multi-nucleated cells.


Myeloma plasma cells in bone marrow.	Binucleate BM plasma cell (centre).	Myeloma BM trephine biopsy.

B) Immunophenotype

Myeloma plasma cells are characterised by:

Clonal cytoplasmic IgG, IgA or light chain only.
The phenotype: sIg^-, CD20^-, CD19^-, CD38⁺, CD45^-, CD138⁺, CD56^+/-.

Myeloma plasma cells are phenotypically abnormal and can be distinguished from normal on the basis of their reduced expression of CD19 and CD45 and increased expression of CD56 and CD138.

Immunoglobulin genes show hypermutation with no intraclonal diversity implying that the disorder arises from a cell that has passed through the germinal centre^[4-6].



Three-colour flow cytometric analysis of myeloma (red) and normal (blue) bone marrow. Initial gate is set around the CD38⁺ CD138⁺ 'plasma-cell' fraction (left-hand plots), then further gates applied to exclude B-cell progenitors and other contaminating cells (not shown). The middle and right-hand plots show the plasma-cell phenotypes: CD45^weak CD19^- CD56⁺ for myeloma plasma cells, CD45⁺ CD19⁺ CD56^- for normal plasma cells.

CYTOGENETICS

Aneuploidy is detected in 90% of cases with FISH-based techniques^[7,8].
Karyotypes are commonly complex.
Monosomy 13, 13q-, 11q abnormalities and chromosomal translocations are associated with a poor prognosis^[9,10].
A number of chromosomal translocations into the IgH locus at 14q32 have been identified recently. These include t(11;14), t(4;14), t(6;14) and t(14;16) which result in the deregulation of cyclin D1, FGFR3, IRF4 and c-maf respectively^[11-14].

OUTCOME AND THERAPY

Melphalan remains the gold standard treatment^[16].
Bisphosphonates appear to reduce the incidence of bony complications^[18,19].
The median survival of all patients is 3-4 years^[15].
Poor prognostic groups are identified by high beta₂-microglobulin or high number of circulating plasma cells at presentation.
The outcome is affected by major complications including the development of renal disease and amyloidosis
The aim of conventional therapy is to induce a period of plateau in which the patient is asymptomatic and the paraprotein and beta₂m levels are stable. This can be achieved in around 50% of patients with melphalan.
High dose chemotherapy with stem cell support in younger patients may induce a complete remission and improved overall outcome has been reported. These results await confirmation.

Monoclonal Gammopathy of Uncertain Significance (MGUS)

The distinction between myeloma and MGUS is based on:

Low and stable levels of paraprotein (IgG < 35g/l or IgA < 20g/l or urinary free light chain < 500mg/24hrs)
Absence of lytic bone lesions
Absence of renal impairment, anaemia or hypercalcemia.
Low levels of marrow plasma cells < 5%
Mixture of normal and neoplastic marrow plasma cells as identified by flow cytometry.

Low levels of paraprotein are often detected in asymptomatic patients. Only a small proportion of patients progress to myeloma.

Solitary Plasmacytoma of Bone

This is also part of the spectrum of myeloma.

Patient present with a single lytic bone lesion but the routine bone marrow is normal or shows only a very low level of abnormal plasma cells
In some patient MRI may show additional asymptomatic bone lesions
About 50% of patients progress to overt myeloma in 10 years. The prognosis is therefore much better than for typical myeloma
Solitary plasmacytomas at other sites are very rarely associated with myeloma

[ Home Page ] [ Site Map ]

Comments & feedback to: admin@hmds.org.uk
[URL: www.hmds.org.uk/myeloma.html]