Stephane Minvielle

Bortezomib Plus Dexamethasone Induction Improves Outcome of Patients With t(4;14) Myeloma but Not Outcome of Patients With del(17p)

PURPOSEnCytogenetics is an important prognostic parameter in multiple myeloma (MM). Patients presenting with either t(4;14) or del(17p) are known to have a short event-free survival (EFS) and overall survival (OS). Some preliminary data suggest that bortezomib is able to overcome these prognostic parameters.nnnPATIENTS AND METHODSnA series of 507 patients with newly diagnosed MM who received four cycles of bortezomib-dexamethasone induction therapy before high-dose melphalan were analyzed for both t(4;14) and del(17p).nnnRESULTSnWe found that both t(4;14) and del(17p) remain prognostic parameters, even in the context of bortezomib treatment. However, it is important to note that bortezomib significantly improves the prognosis (in terms of both EFS and OS) of patients with t(4;14), compared with patients treated with vincristine, doxorubicin, and dexamethasone induction therapy. In contrast, no improvement was observed for del(17p) patients.nnnCONCLUSIONnShort-term bortezomib induction improves outcome of patients with t(4;14) but not the outcome of patients with del(17p). However, both abnormalities remain prognostic factors predicting both EFS and OS despite bortezomib induction.

Prediction of Survival in Multiple Myeloma Based on Gene Expression Profiles Reveals Cell Cycle and Chromosomal Instability Signatures in High-Risk Patients and Hyperdiploid Signatures in Low-Risk Patients: A Study of the Intergroupe Francophone du Myélome

PURPOSEnSurvival of patients with multiple myeloma is highly heterogeneous, from periods of a few weeks to more than 10 years. We used gene expression profiles of myeloma cells obtained at diagnosis to identify broadly applicable prognostic markers.nnnPATIENTS AND METHODSnIn a training set of 182 patients, we used supervised methods to identify individual genes associated with length of survival. A survival model was built from these genes. The validity of our model was assessed in our test set of 68 patients and in three independent cohorts comprising 853 patients with multiple myeloma.nnnRESULTSnThe 15 strongest genes associated with the length of survival were used to calculate a risk score and to stratify patients into low-risk and high-risk groups. The survival-predictor score was significantly associated with survival in both the training and test sets and in the external validation cohorts. The Kaplan-Meier estimates of rates of survival at 3 years were 90.5% (95% CI, 85.6% to 95.3%) and 47.4% (95% CI, 33.5% to 60.1%), respectively, in our patients having a low risk or high risk independently of traditional prognostic factors. High-risk patients constituted a homogeneous biologic entity characterized by the overexpression of genes involved in cell cycle progression and its surveillance, whereas low-risk patients were heterogeneous and displayed hyperdiploid signatures.nnnCONCLUSIONnGene expression-based survival prediction and molecular features associated with high-risk patients may be useful for developing prognostic markers and may provide basis to treat these patients with new targeted antimitotics.

Long-Term Analysis of the IFM 99 Trials for Myeloma: Cytogenetic Abnormalities [t(4;14), del(17p), 1q gains] Play a Major Role in Defining Long-Term Survival

PURPOSEnIn multiple myeloma, many prognostic parameters have been proposed. However, all of these predict shorter survival. To identify patients with a longer life expectancy, we updated the data of patients treated in the IFM (Intergroupe Francophone du Myelome) 99-02 and 99-04 trials.nnnPATIENTS AND METHODSnA series of 520 patients was analyzed. Median follow-up was 90.5 months. To perform a comprehensive analysis of the major prognostic factors, we reanalyzed all patients for 1q gains [in addition to updating del(13), t(4;14), and del(17p) analyses].nnnRESULTSnIt was possible to identify a subgroup of patients (representing 20% of total patients) with an 8-year survival of 75%. These patients were defined by the absence of t(4;14), del(17p), and 1q gain and β(2)-microglobulin less than 5.5 mg/L.nnnCONCLUSIONnWe propose that all patients with newly diagnosed multiple myeloma be evaluated for these three chromosomal changes, not only to define high-risk patients but also to identify those with a longer life expectancy.

The mannose 6-phosphate/insulin-like growth factor II receptor is a nanomolar affinity receptor for glycosylated human leukemia inhibitory factor.

Comparison of the binding properties of non-glycosylated, glycosylated human leukemia inhibitory factor (LIF) and monoclonal antibodies (mAbs) directed at gp190/LIF-receptor β subunit showed that most of the low affinity (nanomolar) receptors expressed by a variety of cell lines are not due to gp190. These receptors bind glycosylated LIF produced in Chinese hamster ovary cells (CHO LIF) (K d = 6.9 nm) but notEscherichia coli-derived LIF or CHO LIF treated with endoglycosidase F. CHO LIF binding to these receptors is neither affected by anti-gp190 mAbs nor by anti-gp130 mAbs and is specifically inhibited by low concentrations of mannose 6-phosphate (Man-6-P) (IC50 = 40 μm), suggesting that they could be related to Man-6-P receptors. The identity of this LIF binding component with the Man-6-P/insulin-like growth factor-II receptor (Man-6-P/IGFII-R) was supported by several findings. (i) It has a molecular mass very similar to that of the Man-6-P/IGFII-R (270 kDa); (ii) the complex of LIF cross-linked to this receptor is immunoprecipitated by a polyclonal anti-Man-6-P/IGFII-R antibody; (iii) this antibody inhibits LIF and IGFII binding to the receptor with comparable efficiencies; (iv) soluble Man-6-P/IGFII-R purified from serum binds glycosylated LIF (K d = 4.3 nm) but not E. coli LIF. The potential role of Man-6-P/IGFII-R in LIF processing and biological activity is discussed.

Bortezomib, Doxorubicin, Cyclophosphamide, Dexamethasone Induction Followed by Stem Cell Transplantation for Primary Plasma Cell Leukemia: A Prospective Phase II Study of the Intergroupe Francophone du Myélome

PURPOSEnPrimary plasma cell leukemia (pPCL) is a rare and aggressive malignancy with a poor prognosis. With conventional chemotherapy, patients typically die within 1 year. In all but one of the retrospective studies reported to date, bortezomib and lenalidomide seem to improve survival. We conducted a prospective phase II trial in patients with pPCL to assess the efficacy of an alternate regimen that combines standard chemotherapy, a proteasome inhibitor, and high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) followed by either allogeneic transplantation or bortezomib/lenalidomide maintenance.nnnPATIENTS AND METHODSnPatients 70 years old and younger with newly diagnosed pPCL received four alternating cycles of bortezomib, dexamethasone plus doxorubicin or cyclophosphamide. Peripheral blood stem cells were collected from responding patients with < 1% of circulating plasma cells before HDM/ASCT. As consolidation, young patients received a reduced-intensity conditioning allograft, whereas the remaining patients underwent a second HDM/ASCT followed by 1 year of bortezomib, lenalidomide, dexamethasone. The primary end point was progression-free survival (PFS).nnnRESULTSnForty patients (median age, 57 years; range, 27 to 71 years) were enrolled. The median follow-up was 28.7 months. In the intention-to-treat analysis, the median PFS and overall survival were 15.1 (95% CI, 8.4; -) and 36.3 (95% CI, 25.6; -) months, respectively. The overall response rate to induction was 69%. One patient underwent a syngeneic allograft and 25 HDM/ASCT (16 of whom subsequently received a reduced-intensity conditioning allograft and seven a second ASCT followed by maintenance).nnnCONCLUSIONnIn this prospective trial in patients with pPCL, we show that bortezomib, dexamethasone plus doxorubicin or cyclophosphamide induction followed by transplantation induces high response rates and appears to significantly improve PFS.

A 38-gene expression signature to predict metastasis risk in node-positive breast cancer after systemic adjuvant chemotherapy: a genomic substudy of PACS01 clinical trial

Currently, no prognostic gene-expression signature (GES) established from node-positive breast cancer cohorts, able to predict evolution after systemic adjuvant chemotherapy, exists. Gene-expression profiles of 252 node-positive breast cancer patients (median follow-up: 7.7xa0years), mostly included in a randomized clinical trial (PACS01), receiving systemic adjuvant regimen, were determined by means of cDNA custom array. In the training cohort, we established a GES composed of 38 genes (38-GES) for the purpose of predicting metastasis-free survival. The 38-GES yielded unadjusted hazard ratio (HR) of 4.86 (95% confidence intervalxa0=xa02.76–8.56). Even when adjusted with the best two clinicopathological prognostic indexes: Nottingham prognostic index (NPI) and Adjuvant!, 38-GES HRs were 3.30 (1.81–5.99) and 3.40 (1.85–6.24), respectively. Furthermore, 38-GES improved NPI and Adjuvant! classification. In particular, NPI intermediate-risk patients were divided into 2/3 close to low-risk group and 1/3 close to high-risk group (HRxa0=xa06.97 [2.51–19.36]). Similarly, Adjuvant! intermediate-risk patients were divided into 2/3 close to low-risk group and 1/3 close to high-risk group (HRxa0=xa04.34 [1.64–11.48]). The 38-GES was validated on gene-expression datasets from three external node-positive breast cancer subcohorts (nxa0=xa0224) generated from different microarray platforms, with HRxa0=xa02.95 (1.74–5.01). Moreover, 38-GES showed prognostic performance in supplementary cohorts with different lymph-node status and endpoints (1,040 new patients). The 38-GES represents a robust tool able to type systemic adjuvant treated node-positive patients at high risk of metastatic relapse, and is especially powerful to refine NPI and Adjuvant! classification for those patients.

Reply to W. Tapper et al

We appreciate the opportunity to reply to the comments by Tapper et al in relation to our study. To replicate our study, Tapper et al examined del(12p13.31) locus using fluorescent in situ hybridization in 256 patients newly diagnosed with multiple myeloma (MM), and found a trend for association with overall survival (P .06). After the publication of our work, we substantially increased the number of patients investigated for 12p13.31 deletion. The prognostic impact of this genetic lesion was confirmed in a larger cohort (n 455) of patients newly diagnosed with MM who were enrolled onto Intergroupe Francophone du Myelome clinical trials (Figs 1A and 1B). How can this apparent discrepancy between the study by Tapper et al and our study be explained? In

MB4-2 breakpoint in MMSET combined with del(17p) defines a subset of t(4;14) multiple myeloma with very poor prognosis

Multiple myeloma (MM) is a clonal plasma cell disorder, which remains incurable. The t(4;14) translocation is present in 15% of patients with symptomatic disease and, despite recent therapeutic improvements such as bortezomib treatment, still indicates a poor prognosis.[1][1],[2][2] However, t(4;14

Myélome de « ultra haut risque » : définition, identification, prise en charge

En depit de remarquables progres realises au cours des 10 dernieres annees, le myelome reste une maladie dont le pronostic est extremement variable. Le but de cette revue est d’essayer d’identifier les patients de « ultra » haut risque, et de proposer une orientation de prise en charge. Nous proposons de definir ces patients par un stade ISS 3, un indice de proliferation eleve, certaines anomalies chromosomiques comme la del(17p), et d’autres anomalies moleculaires en cours d’identification sur la base des techniques de genomique. Il faut ajouter a cette definition les patients se presentant d’emblee avec une forme leucemique, ainsi que les patients presentant un performans status altere ou d’importantes comorbidites. Aucun essai therapeutique n’a reussi, a ce jour, a ameliorer specifiquement la survie de ces patients. Nous proposons d’etablir des essais tres largement multicentriques, voire internationaux, specifiquement dedies a ces patients. Enfin, nous proposons d’inclure systematiquement des analyses pronostiques performantes (incluant la genomique) dans les essais industriels evaluant les nouvelles molecules afin d’en identifier certaines qui pourraient etre utiles a ce groupe de patients.