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      Rationale and design of the German-Speaking Myeloma Multicenter Group (GMMG) trial ReLApsE: a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma

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          Abstract

          Background

          Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients.

          Methods/Design

          ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and - in absence of available stem cells from earlier harvesting - undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3 rd (arm A + B) and the 5 th lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS.

          Discussion

          This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. Trial registration: ISRCTN16345835 (date of registration 2010-08-24).

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12885-016-2321-2) contains supplementary material, which is available to authorized users.

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          Most cited references35

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          A Proportional Hazards Model for the Subdistribution of a Competing Risk

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            A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival.

            The presenting clinical features of 71 patients with multiple myeloma were correlated with myeloma cell mass (myeloma cells X 10(12)/m2 of body surface area) determined from measurements of monoclonal immunoglobulin (M-component) synthesis and metabolism. Bivariate correlation and multivariate regression analyses showed that myeloma cell mass could be accurately predicted from A) extent of bone lesions, B) hemoglobin level, C) serum calcium level, and D) M-component levels in serum and urine. Analyses of response to chemotherapy and survival indicated significant correlation with measured myeloma cell burden. The results were synthesized to produce a very reliable and useful clinical staging system with three tumor cell mass levels (Table 7). For clinical research purposes, multivariate regression equations were developed to predict optimally the exact myeloma cell mass. Thus, initial staging can be quantitatively related to followup using tumor cell mass changes calculated from changes in M-component production. Use of the clinical staging system sould provide better initial assessment and followup of individual patients, and should lead to improved study design and analysis in large clinical trials of therapy for multiple myeloma.
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              Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide.

              The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their antitumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the antimyeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells, but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone, and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion, further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to, and putatively resistant to, lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity and a possible biomarker for the clinical assessment of antimyeloma efficacy.
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                Author and article information

                Contributors
                marc-andrea.baertsch@med.uni-heidelberg.de
                Jana.Schlenzka@med.uni-heidelberg.de
                Elias.Mai@med.uni-heidelberg.de
                Maximilian.Merz@med.uni-heidelberg.de
                Jens.Hillengass@med.uni-heidelberg.de
                Marc.Raab@med.uni-heidelberg.de
                Dirk.Hose@med.uni-heidelberg.de
                Patrick.Wuchter@med.uni-heidelberg.de
                Anthony.Ho@med.uni-heidelberg.de
                Anna.Jauch@med.uni-heidelberg.de
                t.hielscher@Dkfz-Heidelberg.de
                C.Kunz@Dkfz-Heidelberg.de
                Steffen.Luntz@med.uni-heidelberg.de
                stefan.klein@umm.de
                Ingo.Schmidt-Wolf@ukb.uni-bonn.de
                martin.goerner@klinikumbielefeld.de
                martin.schmidt-hieber@helios-kliniken.de
                p.reimer@kliniken-essen-sued.de
                Ullrich.Graeven@mariahilf.de
                Fenk@med.uni-duesseldorf.de
                h.salwender@asklepios.com
                c.scheid@uni-koeln.de
                axel.nogai@charite.de
                m.haenel@skc.de
                w.lindemann@kkh-hagen.de
                H.Martin@em.uni-frankfurt.de
                Richard.Noppeney@uk-essen.de
                katja.weisel@med.uni-tuebingen.de
                Hartmut.Goldschmidt@med.uni-heidelberg.de
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                25 April 2016
                25 April 2016
                2016
                : 16
                : 290
                Affiliations
                [ ]Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
                [ ]Institute for Human Genetics, University of Heidelberg, Heidelberg, Germany
                [ ]Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
                [ ]Coordination Centre for Clinical Trials (KKS), University Hospital Heidelberg, Heidelberg, Germany
                [ ]Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
                [ ]Center for Integrated Oncology, Med. Klinik und Poliklinik III, University Hospital Bonn, Bonn, Germany
                [ ]Hematology, Oncology and Palliative Care, Community Hospital Bielefeld, Bielefeld, Germany
                [ ]Hematology and Oncology, Helios-Hospital Berlin Buch, Berlin, Germany
                [ ]Hematology, Oncology and Stem Cell Transplantation, Evangelisches Krankenhaus Essen-Werden gGmbH, Essen, Germany
                [ ]Hematology, Oncology and Gastroenterology, Maria-Hilf-Krankenhaus, Mönchengladbach, Germany
                [ ]Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Duesseldorf, Germany
                [ ]Hematology, Oncology and Palliative Care, Asklepios Klinik Altona, Hamburg, Germany
                [ ]Department I of Internal Medicine, University of Cologne, Cologne, Germany
                [ ]Internal Medicine III, Charité Campus Benjamin Franklin, Berlin, Germany
                [ ]Hematology, Oncology and Stem Cell Transplantation, Klinikum Chemnitz GmbH, Chemnitz, Germany
                [ ]Hematology and Oncology, Kath. Krankenhaus Hagen gem. GmbH - St.-Marien-Hospital, Hagen, Germany
                [ ]Hematology and Oncology, Goethe University, Frankfurt, Germany
                [ ]Hematology, University Hospital Essen, Essen, Germany
                [ ]Hematology, Oncology and Immunology, University of Tuebingen, Tuebingen, Germany
                [ ]National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany
                Article
                2321
                10.1186/s12885-016-2321-2
                4845347
                27114074
                b4ceb4f1-3a0e-4316-8053-67f16317f58f
                © Baertsch et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 10 September 2015
                : 15 April 2016
                Funding
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100006436, Celgene (US);
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100002429, Amgen (US);
                Funded by: Chugai
                Categories
                Study Protocol
                Custom metadata
                © The Author(s) 2016

                Oncology & Radiotherapy
                multiple myeloma,relapse,second-line treatment,lenalidomide,autologous stem cell transplantation,high-dose chemotherapy

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