Multiple myeloma (published in 2004)

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Written1998-01Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2004-06Franck Viguié
Laboratoire de Cytogenetique - Service d'Hematologie Biologique, Hopital Hotel-Dieu - 75181 Paris Cedex 04, France

(Note : for Links provided by Atlas : click)

1. Identity

ICD-Morpho 9732/3 Plasma cell myeloma / Multiple myeloma
Atlas_Id 2038
Note see the more recent paper on Multiple Myeloma

2. Clinics and Pathology

Disease multiple myeloma (MM) is a malignant monoclonal plasma cell proliferation. Monoclonal gammopathy of unknown significance (MGUS) and smoldering myeloma (SMM) are premalignant states susceptible to transform in MM
Phenotype / cell stem origin phenotype of mature terminally differenciated B-cell, but also with CD56 expression, which is not found in normal plasma cells; CD138+.CD38+ CD40+
Epidemiology multiple myeloma's annual incidence: 30/106; i.e. around 1% of malignancies in adults and 10% of haematologic malignancies; mean age: 62 yrs
Clinics patients may be asymptomatic at the time of diagnosis; bone pain; susceptibility to infections; renal failure; neurologic dysfunctions
Pathology MM staging: stage I: tumour cell mass 12/m2; Hb> 10 g/dl; serum calcium ¾ 120 mg/l; no bone lesion; low monoclonal Ig rate (IgG 1.2 X 1012/m2; Hb 120 mg/l and/or advanced lytic bone lesions and/or high monoclonal Ig rate (IgG > 70 g/l, IgA > 50 g/l, BJ urine > 12 g/day)
Treatment none before onset of symptoms; chemotherapy or BMT afterwards. Various new therapies, mainly acting by apoptosis induction in MM cells, are or will be involved in clinical trails (thalidomide, proteasome inhibitor PS-341, 2 methoxy estradiol, arsenic trioxyde, TNF alpha).
Prognosis evolution: multiple myeloma can evolve towards plasma cell leukemia, where plasma cell count is greater than 2000/ mm3; survival is highly variable (median is around 3 yrs); prognosis is according to the staging and other parameters (such as age, serum albumin, b2 microglobulin, C-reactive protein, and plasma cell labeling index); the karyotype is emerging as an important prognostic factor: median survival in case of a normal karyotype could be 4 yrs vs 1 yr in case of -13/del(13q) and/or 11q rearrangements (the chromosome anomalies with the worst prognostic impact)

3. Cytogenetics

Cytogenetics Morphological cytogenetic information is limited, as the malignant cells have a low spontaneous proliferative activity; abnormal karyotypes are found in 30-50% of cases, more often in advanced stages than in newly diagnosed patients (is this because chromosome abnormalities are secondary events, or because malignant cells have an increased proliferative activity in advanced stages: see below); karyotypes are complex; hyperploidy is found in 2/3 of cases; karyotypes may evolve from normal to abnormal during course of the disease;
- structural (and variable) anomalies of chromosome 1 are found in 30-40% of cases, 14q rearrangements in 25% of cases, 11q abnormalities in 20 %, t(11;14)(q13;q32) representing 10%; 6q anomalies represent 15% of cases; FISH is indicated, as metaphases are arduous to obtain in such a disease implicating mature cells, and tend to show that most cases bear chromosome anomalies, irrespective of the disease staging.
Cytogenetics Molecular All MM cells should express chromosome abnormalities, as strongly suggested by interphase FISH and CGH.
Aneuploidy is detected in 67-90% of cases, allowing to define 2 prognosis entities:
1) hyperdiploid sub-group with a significantly better overall survival, gains involving primarily +3, +5, +7, +9, +11, +15, +19, +21 and infrequent structural abnormalities.
2) hypodiploid group (+hypotetraploid cases by endoreduplication of a prior hypodiploid karyotype) strongly correlated with complex structural rearrangements, 14q32 translocations, del(13q)/-13 and a more aggressive evolution.
IG rearrangements: translocations involving 14q32 are found in at least 65-70% of patients, most of them result from short segments exchange and are detected quite exclusively by FISH. Five translocations involving IGH locus are particularly relevant and considered as very early primary events: t(4;14)(p16;q32), t(6;14)(p25;q32), t(11;14)(q13;q32), t(14;16)(q32;q23), t(14;20)(q32;q11). Other translocations involving IGH are rare or sporadic, they should be secondary and not mediated by specific recombination mechanisms.
Del13q/-13: 13q14.3 deletions emerge as a major independant pronostic factor, underevaluated by conventional cytogenetics; found by FISH in 20-30% of patients; associated with a significant lower rate of response to conventional chemotherapy, and to a shorter survival.

4. Genes involved and Proteins

Gene NameFGFR3 (Fibroblast Growth Factor Receptor 3)
Location 4p16.3
Note Involved in t(4;14)(p16;q32), approximately 15% of MM cases. FGFR3 (tyrosine kinase receptor) and MMSET (novel gene homologous to a Drosophila dysmorphy gene, see below)) are in opposite transcriptional orientation at 4p16. Both are involved in t(4;14). The translocation generates 2 fusion genes, IGH-MMSET on der(4) and FGFR3-IGH on der(14).
Gene NameNSD2
Location 4p16
Note involved in t(4;14)(p16;q32) (see above)
Gene NameCCND3 (cyclin D3)
Location 6p21.1
Note Involved in t(6;14)(p21;q32) (3-5% of MM cases). Detected quasi exclusively by FISH.
Gene NameCCND1 (B-cell leukemia/lymphoma 1)
Location 11q13.3
Note BCL1 (also called Cyclin D1 or CCND1) is involved in t(11;14) )(q13;q32) cases. Approximately 15-20% of cases. Same translocation as mantle cell lymphoma but IGH breakpoint different (IGHS vs IGHJ)
Gene NameMAF (v-maf musculoaponeurotic fibrosarcoma oncogene homolog (avian))
Location 16q23.2
Note basic zipper transcription factor, involved in t(14;16)(q32;q23) (5% of MM cases). Detected quasi exclusively by FISH
Gene NameMAFB (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B)
Location 20q12
Note MAF family basic region / leucine zipper transcription factor, involved in t(14;20)(q32;q11) (2% of MM cases)

5. Bibliography

Cytogenetic analysis of 280 patients with multiple myeloma and related disorders: primary breakpoints and clinical correlations.
Calasanz MJ, Cigudosa JC, Odero MD, Ferreira C, Ardanaz MT, Fraile A, Carrasco JL, Solé F, Cuesta B, Gullón A
Genes, chromosomes & cancer. 1997 ; 18 (2) : 84-93.
PMID 9115968
Cytogenetics and molecular genetics in multiple myeloma.
Feinman R, Sawyer J, Hardin J, Tricot G
Hematology/oncology clinics of North America. 1997 ; 11 (1) : 1-25.
PMID 9081201
Genetics and cytogenetics of multiple myeloma: a workshop report.
Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, Davies FE, Drach J, Greipp PR, Kirsch IR, Kuehl WM, Hernandez JM, Minvielle S, Pilarski LM, Shaughnessy JD Jr, Stewart AK, Avet-Loiseau H
Cancer research. 2004 ; 64 (4) : 1546-1558.
PMID 14989251
Cytogenetics of multiple myeloma: interpretation of fluorescence in situ hybridization results.
Harrison CJ, Mazzullo H, Cheung KL, Gerrard G, Jalali GR, Mehta A, Osier DG, Orchard KH
British journal of haematology. 2003 ; 120 (6) : 944-952.
PMID 12648063
Advances in biology of multiple myeloma: clinical applications.
Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC
Blood. 2004 ; 104 (3) : 607-618.
PMID 15090448
Multiple myeloma and chronic lymphocytic leukemia.
Rosen L, Vescio R, Berenson JR
Current opinion in hematology. 1995 ; 2 (4) : 275-282.
PMID 9372008
Hypodiploidy is a major prognostic factor in multiple myeloma.
Smadja NV, Bastard C, Brigaudeau C, Leroux D, Groupe Français de Cytogénétique Hématologique (GFCH).
Blood. 2001 ; 98 (7) : 2229-2238.
PMID 11568011

6. Citation

This paper should be referenced as such :
Viguié, F
Multiple myeloma
Atlas Genet Cytogenet Oncol Haematol. 2004;8(3):245-247.
Free journal version : [ pdf ]   [ DOI ]
On line version :
History of this paper:
Huret, JL. Multiple myeloma. Atlas Genet Cytogenet Oncol Haematol. 1998;2(1):18-19.

7. External links

COSMICHisto = - Site = haematopoietic_and_lymphoid_tissue (COSMIC)
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9732/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
Other databaseTumor Portal - Broad Institute
Other databasecBioPortal: Multiple Myeloma (Broad, Cancer Cell 2014)
Other databaseMultiple myeloma ( intOGen )
Other databaseMultiple Myeloma Overview - Disease Synopsis [canSAR]
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed

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