Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Blood (Impact Factor: 10.45). 05/2010; 115(21):4168-73. DOI: 10.1182/blood-2009-11-255620
Source: PubMed


The Total Therapy 3 trial 2003-33 enrolled 303 newly diagnosed multiple myeloma patients and was noted to provide superior clinical outcomes compared with predecessor trial Total Therapy 2, especially in gene expression profiling (GEP)-defined low-risk disease. We report here on the results of successor trial 2006-66 with 177 patients, using bortezomib, lenalidomide, and dexamethasone maintenance for 3 years versus bortezomib, thalidomide, and dexamethasone in year 1 and thalidomide/dexamethasone in years 2 and 3 in the 2003-33 protocol. Overall survival (OS) and event-free survival (EFS) plots were super-imposable for the 2 trials, as were onset of complete response and complete response duration (CRD), regardless of GEP risk. GEP-defined high-risk designation, pertinent to 17% of patients, imparted inferior OS, EFS, and CRD in both protocols and, on multivariate analysis, was the sole adverse feature affecting OS, EFS, and CRD. Mathematical modeling of CRD in low-risk myeloma predicted a 55% cure fraction (P < .001). Despite more rapid onset and higher rate of CR than in other molecular subgroups, CRD was inferior in CCND1 without CD20 myeloma, resembling outcomes in MAF/MAFB and proliferation entities. The robustness of the GEP risk model should be exploited in clinical trials aimed at improving the notoriously poor outcome in high-risk disease.

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    • "Despite recent therapeutic advances including novel agents, all patients ultimately relapse, and new therapeutic options are needed [18]. High-dose therapy with Melphalan at different doses was used before reinfusion of autologous peripheral-blood stem cells [19] and combination therapy with Melphalan and prednisone plus either thalidomide or bortezomib is suggested in patients who are not eligible for transplantation [2–20]. In this context, targeted therapies can find their place within the therapeutic arsenal against MM. "
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    ABSTRACT: Multiple myeloma (MM) is a B-cell malignancy of terminally differentiated plasma cells within the bone marrow. Despite intense research to develop new treatments, cure is almost never achieved. Alpha-radioimmunotherapy (RIT) has been shown to be effective in vivo in a MM model. In order to define where alpha-RIT stands in MM treatment, the aim of this study was to compare Melphalan, MM standard treatment, with alpha-RIT using a [213Bi]-anti-mCD138 antibody in a syngeneic MM mouse model. C57BL/KaLwRij mice were grafted with 1×10(6) 5T33 murine MM cells. Luciferase transfected 5T33 cells were used for in vivo localization. The first step of the study was to assess the dose-response of Melphalan 21days after engraftment. The second step consisted in therapeutic combination: Melphalan followed by RIT at day 22 or day 25 after engraftment. Toxicity (animal weight, blood cell counts) and treatment efficacy were studied in animals receiving no treatment, injected with Melphalan alone, RIT alone at day 22 or day 25 (3.7MBq of [213Bi]-anti-CD138) and Melphalan combined with alpha-RIT. Fifty percent of untreated mice died by day 63 after MM engraftment. In mice treated with Melphalan alone, only the 200μg dose improved median survival. No animal was cured after Melphalan treatment whereas 60% of the mice survived with RIT alone at day 22 after tumor engraftment with only slight and reversible hematological radiotoxicity. No therapeutic effect was observed with alpha-RIT 25days after engraftment. Melphalan and alpha-RIT combination does not improve overall survival compared to RIT alone, and results in increased leukocyte and red blood cell toxicity. Alpha-RIT seems to be a good alternative to Melphalan. Association of these two treatments provides no benefit. The perspectives of this work would be to evaluate RIT impact on the regimens incorporating the novel agents bortezomide, thalidomide and lenalidomide.
    Nuclear Medicine and Biology 05/2014; 41S:e30-e35. DOI:10.1016/j.nucmedbio.2014.02.008 · 2.41 Impact Factor
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    • "Myeloma cells harbor a high median number of chromosomal aberrations [2], [3] and multiple changes in gene expression compared to normal bone marrow plasma cells. This molecular heterogeneity is thought to transmit into very different survival times ranging from a few month to 15 or more years [4], with a median survival after conventional treatments of 3–4 years and 5–9 years after high-dose treatment followed by autologous stem-cell transplantation [5]–[7]. "
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    ABSTRACT: The glycome, i.e. the cellular repertoire of glycan structures, contributes to important functions such as adhesion and intercellular communication. Enzymes regulating cellular glycosylation processes are related to the pathogenesis of cancer including multiple myeloma. Here we analyze the transcriptional differences in the glycome of normal (n = 10) and two cohorts of 332 and 345 malignant plasma-cell samples, association with known multiple myeloma subentities as defined by presence of chromosomal aberrations, potential therapeutic targets, and its prognostic impact. We found i) malignant vs. normal plasma cells to show a characteristic glycome-signature. They can ii) be delineated by a lasso-based predictor from normal plasma cells based on this signature. iii) Cytogenetic aberrations lead to distinct glycan-gene expression patterns for t(11;14), t(4;14), hyperdiploidy, 1q21-gain and deletion of 13q14. iv) A 38-gene glycome-signature significantly delineates patients with adverse survival in two independent cohorts of 545 patients treated with high-dose melphalan and autologous stem cell transplantation. v) As single gene, expression of the phosphatidyl-inositol-glycan protein M as part of the targetable glycosyl-phosphatidyl-inositol-anchor-biosynthesis pathway is associated with adverse survival. The prognostically relevant glycome deviation in malignant cells invites novel strategies of therapy for multiple myeloma.
    PLoS ONE 12/2013; 8(12):e83719. DOI:10.1371/journal.pone.0083719 · 3.23 Impact Factor
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    • "With regard to high-risk myeloma, as defined by the 70- gene GEP signature, there are currently no studies assessing the impact of lenalidomide-based therapy on the survival of these patients when used in the relapsed setting. However, results of studies incorporating lenalidomide in the frontline treatment regimen (e.g., Total Therapy 3, incorporating multidrug induction therapy, tandem autologous stem cell transplantation, and maintenance with the combination of lenalidomide, bortezomib, and dexamethasone) suggest that the 70-gene GEP signature remains a predictor of poor survival outcomes [41]. Currently, it remains difficult to provide definite recommendations for the use of lenalidomide in relapsed patients with high-risk cytogenetics. "
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    ABSTRACT: In Canada, lenalidomide combined with dexamethasone (Len/Dex) is approved for use in relapsed or refractory multiple myeloma (RRMM). Our expert panel sought to provide an up-to-date practical guide on the use of lenalidomide in the managing RRMM within the Canadian clinical setting, including management of common adverse events (AEs). The panel concluded that safe, effective administration of Len/Dex treatment involves the following steps: (1) lenalidomide dose adjustment based on creatinine clearance and the extent of neutropenia or thrombocytopenia, (2) dexamethasone administered at 20-40 mg/week, and (3) continuation of treatment until disease progression or until toxicity persists despite dose reduction. Based on available evidence, the following precautions should reduce the risk of common Len/Dex AEs: (1) all patients treated with Len/Dex should receive thromboprophylaxis, (2) erythropoiesis-stimulating agents (ESAs) should be used cautiously, and (3) females of child-bearing potential and males in contact with such females must use multiple contraception methods. Finally, while Len/Dex can be administered irrespective of prior therapy and in all prognostic subsets, patients with chromosomal deletion 17(p13) have less favorable outcomes with all treatments, including Len/Dex. New directions for the use of lenalidomide in RRMM are also considered.
    Advances in Hematology 10/2012; 2012:621958. DOI:10.1155/2012/621958
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