OP49 Multiple myelomas – dissecting distinct biological entities by gene expression profiling of plasma cells and microenviroment

Sessions / Symposia / Special Lectures of PMF and the pathogenesis of the associated bone marrow stromal reaction have provided both basic and clinical researchers with invaluable tools to develop effective targeted therapies for patients with PMF. At the forefront of these advances is the discovery that about half PMF patients harbor an activating point mutation in the JAK2 tyrosine kinase gene, the JAK2V617F. The same abnormality is present in about half ET patients and almost all PV patients. Novel treatment strategies are under investigation, including studies with immunomodulatory and antiangiogenic agents, hypomethylating agents, as well as with small molecule inhibitors of the JAK2 tyrosine kinase. In the current communication we will review the current status of experimental novel therapies for patients with ET, PV, and PMF.

Multiple myeloma and related disorders OP49 Multiple myelomas – dissecting distinct biological entities by gene expression profiling of plasma cells and microenviroment J.D. Shaughnessy, F. Zhan, B. Burington, J. Crowley, B. Barlogie. Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA Introduction: Survival of patients diagnosed with multiple myeloma (MM) can vary considerably. While most disease is initially responsive to intervention, a small subset is primary refractory and acquisition of drug resistance represents a difficult barrier to long-term disease control. Aim: We used genome-wide mRNA expression profiling to identify molecular signatures to improve risk stratification. Methods: We performed expression analyses, using Affymetrix U133Plus2.0 microarrays, on mRNA from CD138-enriched bone marrow plasma cells from 532 consecutive newly diagnosed patients treated with tandem stem cell transplants on two separate protocols at our center. We segregated gene expression levels into quartiles and performed log rank tests to identify genes whose expression extremes were linked to disease related death. Results: We identified 70 genes, 30% mapping to chromosome 1 (P < 0.001), that were linked to early disease-related death. Interestingly, we found that the majority of up-regulated genes in high-risk disease mapped to chromosome 1q and down-regulated genes mapped to chromosome 1p. The ratio of mean expression levels of upto down-regulated genes defined a high-risk score present in 13% of patients with shorter durations of complete remission, event-free and overall survival (training set: HR 5.16, P < 0.0001; test cohort: HR 4.75, P < 0.0001). The high-risk score was also an independent predictor of outcome endpoints in multivariate analysis (P < 0.0001) that included the International Staging System and high-risk translocations. The high-risk score frequency rose to 76% at relapse and

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predicted short post-relapse survival (P < 0.05). Multivariate discriminant analysis revealed that a 17-gene subset could predict outcome a well as the 70-gene model. Application of both 70-gene and 17-gene present model to independent data sets revealed its capability to identify high risk in multiple therapeutic settings. Conclusion: Expression profiling can be used to identify high-risk disease and guide therapeutic interventions.

OP50 Bortezomib in the treatment of multiple myeloma J. Blade. Institut of Hematology and Oncology, Hematology Department, IDIBAPS, Hospital Clinic, Barcelona, Spain Bortezomib (Velcade, Millenium Pharmaceuticals, Cambrige, MA, USA, formerly PS-341) has been approved by the FDA and EMEA for the treatment of patients with relapsed multiple myeloma (MM). In the relapsed/refractory setting, bortezomib, administered as single agent, produces a response rate ranging from 35 to 50% including up to 9% of CR. In addition, a subgroup analysis of the pioneer SUMMIT and CREST trials showed that the addition of dexamethasone in patients with suboptimal response to bortezomib resulted in an improved response rate in 18% and 33% of the patients, respectively. The APEX trial showed that in patients with relapsed MM who had received 3 or less lines of therapy bortezomib was superior to dexamethasone in response rate (43% vs. 18%), EFS and OS. More recently the association of bortezomib with pegylated doxorubicin (Doxil) was superior to bortezomib alone in response rate, EFS and OS. The association of bortezomib to other anti-myeloma agents such as, thalidomide, lenalidomide or cyclophosphamide with or without dexamethasone has resulted in a high response rate. The good results achieved with bortezomib as rescue treatment have prompted the use of this drug as part of up-front therapy. Bortezomib alone produces a response rate of 40% with 10% of CR. Jagannath et al reported a phase 2 trial in which dexamethasone was added to bortezomib if less than PR was achieved after 2 cycles or less than CR was reached after 4 cycles, attaining an overall response rate of 88% including 6% of CR. Harouseau et al combined bortezomib and dexamethasone as induction therapy as part of the pre-transplant regimen in younger myeloma patients and achieved a response rate of 66% with 21% of CR (electropheresis negative). In this study, the pos-transplant CR plus VGPR was 55%. Rosiñol et al used and alternating schedule of bortezomib and dexamethasone as induction pretransplant regimen. In the latter study, the overall response rate pretransplant was 65% with 12 CR (immunofixation negative) and the pos-transplant CR plus VGPR was 54%. The Intergroup Français du Myelome is conducting a phase 3 trial comparing VAD versus bortezomib plus dexamethasone as pre-transplant induction regimen with very encouraging preliminary results. Whether more intensive combinations such as bortezomib/thalidomide/dexamethasone, bortezomib/adri-