Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome

Avet-Loiseau, Hervé; Attal, Michel; Moreau, Philippe; Charbonnel, Catherine; Garban, Frédéric; Hulin, Cyrille; Leyvraz, Serge; Michallet, Mauricette; Yakoub-Agha, Ibrahim; Garderet, Laurent; Marit, Gérald; Michaux, Lucienne; Voillat, Laurent; Renaud, Marc; Grosbois, B.; Guillerm, Gaëlle; Benboubker, Lotfi; Monconduit, M.; Thiéblemont, Catherine; Casassus, Philippe; Caillot, Denis; Stoppa, Anne‐Marie; Sotto, Jean‐Jacques; Wetterwald, Marc; Dumontet, Charles; Fuzibet, J. G.; Azaïs, I.; Dorvaux, Véronique; Zandecki, Marc; Bataille, Régis; Minvielle, Stéphane; Harousseau, Jean‐Luc; Façon, Thierry; Mathiot, Claire

doi:10.1182/blood-2006-08-040410

Cited by 850 publications

(789 citation statements)

References 33 publications

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“…Interphase fluorescence in-situ hybridization (FISH) on the other hand, is able to analyze specific chromosomal changes with greater sensitivity, overcoming the problem of the lack of dividing cells required in metaphase karyotyping. The most widely recognized poor prognostic parameters by FISH include t(4;14), del(17p), 1q gains and t (14;16) [5,6]. High-throughput gene expression profiling studies are also showing promise in prognostication of MM [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era

et al. 2010

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Multiple myeloma is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several high-risk features of myeloma, the validity of conventional risk-stratification and prognostication systems needs to be reevaluated. We study the survival data of 261 previously untreated myeloma patients managed at our institution, where bortezomib became available from 2004 for the treatment of relapse disease. Patient and disease characteristics, and survival data were evaluated overall, and with respect to bortezomib exposure. Overall, the international staging system (ISS), metaphase karyotyping and interphase fluorescence in situ hybridization (FISH) were discerning of survival outcomes, where the median for the entire cohort was 5.2 years. However, when stratified by bortezomib exposure, only metaphase karyotyping was still discriminating of long-term prognosis. The presence of an abnormal nonhyperdiploid karyotype overrides all other clinical and laboratory parameters in predicting for a worse outcome on multivariate analysis (median survival 2.6 years, P 5 0.001), suggesting that bortezomib used at relapse is better able to overcome adverse risk related to high tumor burden (as measured by the ISS) than adverse cytogenetics on conventional karyotyping. Metaphase karyotyping provides additional prognostic information on tumor kinetics where the presence of a normal diploid karyotype in the absence of any high-risk FISH markers correlated with superior survival and could act as a surrogate for lower plasma cell proliferation. Am. J. Hematol. 85:752-756, 2010. V

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Section: Introductionmentioning

confidence: 99%

An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era

et al. 2010

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“…Subsequently, we examined the prognostic relevance of proliferation in two independent cohorts of myeloma patients treated with high-dose chemotherapy and autologous stem cell transplantation and its potential relation with current risk factors, i.e. serum β2-microglobulin (B2M), ISS, LDH, presence of the translocation t(4;14) 19 and gene expression-based high-risk signatures. 13,14 …”

Section: Introductionmentioning

confidence: 99%

Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma

Hose

Rème²,

Hielscher³

et al. 2010

Haematologica

195

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BackgroundProliferation of malignant plasma cells is a strong adverse prognostic factor in multiple myeloma and simultaneously targetable by available (e.g. tubulin polymerase inhibitors) and upcoming (e.g. aurora kinase inhibitors) compounds. Design and MethodsWe assessed proliferation using gene expression-based indices in 757 samples including independent cohorts of 298 and 345 samples of CD138-purified myeloma cells from previously untreated patients undergoing high-dose chemotherapy, together with clinical prognostic factors, chromosomal aberrations, and gene expression-based high-risk scores. ResultsIn the two cohorts, 43.3% and 39.4% of the myeloma cell samples showed a proliferation index above the median plus three standard deviations of normal bone marrow plasma cells. Malignant plasma cells of patients in advanced stages or those harboring disease progressionassociated gain of 1q21 or deletion of 13q14.3 showed significantly higher proliferation indices; patients with gain of chromosome 9, 15 or 19 (hyperdiploid samples) had significantly lower proliferation indices. Proliferation correlated with the presence of chromosomal aberrations in metaphase cytogenetics. It was significantly predictive for event-free and overall survival in both cohorts, allowed highly predictive risk stratification (e.g. event-free survival 12.7 versus 26.2 versus 40.6 months, P<0.001) of patients, and was largely independent of clinical prognostic factors, e.g. serum β2-microglobulin, International Staging System stage, associated high-risk chromosomal aberrations, e.g. translocation t(4;14), and gene expression-based high-risk scores. ConclusionsProliferation assessed by gene expression profiling, being independent of serum-β2-microglobulin, International Staging System stage, t(4;14), and gene expression-based risk scores, is a central prognostic factor in multiple myeloma. Surrogating a biological targetable variable, gene expression-based assessment of proliferation allows selection of patients for riskadapted anti-proliferative treatment on the background of conventional and gene expressionbased risk factors.

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“…The reported studies to-date produced conflicting results. Cyclin-D1 overexpression has been linked to the t(11;14) translocation and polysomy of chromosome 11 [11] but the presence of a t(11;14) seems to be a prognostically ''neutral'' genetic abnormality [12,13]. In our study, the patients were diagnosed with MM from Jan 1, 2000 until December 31, 2007 and we had no fluorescent In situ hybridization or caryotype data.…”

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confidence: 84%

Increased expression of cyclin‐D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents

et al. 2012

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Multiple myeloma (MM) comprises 1% of all malignancies and 13% of hematological malignancies in the Caucasian population. Yearly incidence is 4/100,000 in the US and is higher in blacks and males [1]. The pathogenesis of the disease is relatively unknown; several chromosomal abnormalities have been related to the development of the disease, but none is characteristic of MM. Cyclin-D1 is a protein encoded by the CCND1 (bcl-1) gene on chromosome 11q13, and is an important regulator of G1 to S phase progression.Overexpression or overactivity of the CCND1 is common in malignancies including MM, mantle cell lymphoma, breast cancer, and hepatocellular cancer [2][3][4]. Previous studies have shown that CCND1 is expressed in 50% of patients with MM and that CCND1 overexpression represents an unfavorable prognostic factor in MM [5,6]. However, a recent study in a small number of patients showed that overexpressed CCND1 in MM is an independent prognostic marker associated with a more durable response to bortezomib. The aim of our study was to evaluate the impact of the immunohistochemical expression of cyclin-D1 in the plasma cells of trephine biopsies on survival of newly-diagnosed patients with MM who were treated with novel agents. One hundred and thirty consecutive patients with newly diagnosed MM were evaluated (66 males and 64 females). All patients were diagnosed, treated, and followed-up in a single center (Department of Clinical Therapeutics, University of Athens Medical School, Athens, Greece). Clinical characteristics of the patients are depicted in Table I. The median age of the patients was 68 years (range: 35-85 years). Forty-five patients (35%) had advanced disease at diagnosis (Stage 3 according to international staging system (ISS)). One hundred and fifteen patients (pts) had symptomatic disease that required therapy: 29 (25%) received bortezomib-based regimens (15 patients VTD (Bortezomib, Thalidomide and Dexamethasone), 5 patients VMP, and 5 patients PAD (Bortezomib, Doxorubicin and Dexamethasone)), 31 (26%) received thalidomide-based regimens (21 patients melphalan prednisone and thalidomide (MPT) and 10 patients thalidomide, vincristine, doxorubicin, dexamethasone (T-VAD)), and 55 received conventional treatment (20 patients VAD and 35 patients melphalan and prednisone) as first-line therapy, while all patients received regimens containing bortezomib or an immunomodulatory agents at some point during the course of their disease. Nineteen patients (16.5%) received high-dose melphalan plus autologous stem cell transplantation (ASCT). The median follow-up time for these patients was 22 months.Among patients with symptomatic myeloma (N 5 115), positive staining for cyclin-D1 (Fig. 1) was found in 35 (30%) patients, for CD56 in 45 (39%), for CD117 in 94 (81%), and for CD27 in 72 (62%) patients. In patients with asymptomatic/smoldering myeloma, positive staining for cyclin-D1 was found only in 1 (7%) patient, for CD56 in 9 (64%), and for CD117 in 6 (43%) (P < 0.01 for all comparisons compared to symptomatic...

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Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome

Cited by 850 publications

References 33 publications

An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era

An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era

Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma

Increased expression of cyclin‐D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents

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