|| 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 < 0.6 X 1012/m2; Hb> 10 g/dl; serum calcium ¾ 120 mg/l; no bone lesion; low monoclonal Ig rate (IgG < 50 g/l, IgA < 30 g/l, BJ urine < 4 g/day); stage II: fitting neither stage I nor stage II; stage III: tumour cell mass > 1.2 X 1012/m2; Hb< 8.5 g/dl and/or serum calcium > 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)|
|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.
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