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      Current Multiple Myeloma Treatment Strategies with Novel Agents: A European Perspective

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          Abstract

          This review presents an overview of the most recent data using the novel agents thalidomide, bortezomib, and lenalidomide in the treatment of multiple myeloma and summarizes European treatment practices incorporating these novel agents.

          Abstract

          The treatment of multiple myeloma (MM) has undergone significant developments in recent years. The availability of the novel agents thalidomide, bortezomib, and lenalidomide has expanded treatment options and has improved the outcome of patients with MM. Following the introduction of these agents in the relapsed/refractory setting, they are also undergoing investigation in the initial treatment of MM. A number of phase III trials have demonstrated the efficacy of novel agent combinations in the transplant and nontransplant settings, and based on these results standard induction regimens are being challenged and replaced. In the transplant setting, a number of newer induction regimens are now available that have been shown to be superior to the vincristine, doxorubicin, and dexamethasone regimen. Similarly, in the front-line treatment of patients not eligible for transplantation, regimens incorporating novel agents have been found to be superior to the traditional melphalan plus prednisone regimen. Importantly, some of the novel agents appear to be active in patients with high-risk disease, such as adverse cytogenetic features, and certain comorbidities, such as renal impairment. This review presents an overview of the most recent data with these novel agents and summarizes European treatment practices incorporating the novel agents.

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          Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial.

          In multiple myeloma, combination chemotherapy with melphalan plus prednisone is still regarded as the standard of care in elderly patients. We assessed whether the addition of thalidomide to this combination, or reduced-intensity stem cell transplantation, would improve survival. Between May 22, 2000, and Aug 8, 2005, 447 previously untreated patients with multiple myeloma, who were aged between 65 and 75 years, were randomly assigned to receive either melphalan and prednisone (MP; n=196), melphalan and prednisone plus thalidomide (MPT; n=125), or reduced-intensity stem cell transplantation using melphalan 100 mg/m2 (MEL100; n=126). The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00367185. After a median follow-up of 51.5 months (IQR 34.4-63.2), median overall survival times were 33.2 months (13.8-54.8) for MP, 51.6 months (26.6-not reached) for MPT, and 38.3 months (13.0-61.6) for MEL100. The MPT regimen was associated with a significantly better overall survival than was the MP regimen (hazard ratio 0.59, 95% CI 0.46-0.81, p=0.0006) or MEL100 regimen (0.69, 0.49-0.96, p=0.027). No difference was seen for MEL100 versus MP (0.86, 0.65-1.15, p=0.32). The results of our trial provide strong evidence to indicate that the use of thalidomide in combination with melphalan and prednisone should, at present, be the reference treatment for previously untreated elderly patients with multiple myeloma.
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            Recent major improvement in long-term survival of younger patients with multiple myeloma.

            In the past, most patients with multiple myeloma (MM) died within 5 to 10 years after diagnosis. Within the past decade, several new therapeutic interventions have been introduced, including autologous stem-cell transplantation, thalidomide, lenalidomide, and bortezomib. We estimated trends in age-specific 5- and 10-year relative survival of patients with MM in the United States from 1990-1992 to 2002-2004 from the 1973-2004 database of the Surveillance, Epidemiology, and End Results (SEER) Program. Techniques of period analysis were used to show most recent developments. Overall, 5-year relative survival increased from 28.8% to 34.7% (P < .001), and 10-year relative survival increased from 11.1% to 17.4% (P < .001) between 1990-1992 and 2002-2004. Much stronger increases were seen in the age group younger than 50 years, leading to 5- and 10-year relative survival of 56.7% and 41.3% in 2002-2004, and in the age group 50 to 59 years, leading to 5- and 10-year relative survival of 48.2% and 28.6% in 200-2004. By contrast, only moderate improvement was seen in the age group 60 to 69 years, and essentially no improvement was achieved among older patients. Our period analysis discloses a major increase in long-term survival of younger patients with MM in recent years, which most likely reflects the effect of recent advances in therapy and their dissemination in clinical practice.
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              Thalidomide and hematopoietic-cell transplantation for multiple myeloma.

              High-dose therapy with melphalan can prolong survival among patients with multiple myeloma. We assessed whether the addition of thalidomide, which has activity against advanced and refractory myeloma, would further improve survival. Between October 1998 and February 2004, 668 patients with newly diagnosed multiple myeloma received two cycles of intensive melphalan-based chemotherapy, each supported by autologous hematopoietic stem-cell transplantation. A total of 323 were randomly assigned to receive thalidomide from the outset until disease progression or undue adverse effects, and 345 did not receive thalidomide. The primary end point was the five-year event-free survival rate. Secondary end points were complete response and overall survival. After a median follow-up of 42 months among survivors, the thalidomide and control groups had rates of complete response of 62 percent and 43 percent, respectively (P<0.001), and five-year event-free survival rates of 56 percent and 44 percent (P=0.01). The five-year rate of overall survival was approximately 65 percent in both groups (P=0.90). Median survival after relapse was 1.1 years in the thalidomide group and 2.7 years in the control group (P=0.001). Severe peripheral neuropathy and deep-vein thrombosis occurred more frequently in the thalidomide group than in the control group. When incorporated into high-dose therapy for myeloma, thalidomide increased the frequency of complete responses and extended event-free survival at the expense of added adverse effects without improving overall survival. (ClinicalTrials.gov number, NCT00083551.). Copyright 2006 Massachusetts Medical Society.
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                Author and article information

                Journal
                Oncologist
                Oncologist
                oncologist
                theoncologist
                The Oncologist
                The Oncologist
                AlphaMed Press (Durham, NC, USA )
                1083-7159
                1549-490X
                January 2010
                19 January 2010
                : 15
                : 1
                : 6-25
                Affiliations
                [1] aWilhelminenspital, Vienna, Austria;
                [2] bAnkara University School of Medicine, Department of Haematology, Ankara, Turkey;
                [3] cDepartment of Hematology, Hospital Clinic, Barcelona, Spain;
                [4] dDivisione di Ematologia dell'Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Ospedale Molinette, Turin, Italy;
                [5] eDepartment of Haematology, St. Bartholomew's Hospital, London, U.K.;
                [6] fInstitute of Hematology and Medical Oncology, Seragnoli, Bologna, Italy;
                [7] gDepartment of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece;
                [8] hDepartment of Oncology, University Clinic Vienna, Vienna, Austria;
                [9] iUniversitätsklinik Würzburg, Medizinische Klinik und Poliklinik II, Würzburg, Germany;
                [10] jService d'Hématologie, Centre Hospitalier Universitaire (CHU), Lille, France;
                [11] kDepartment of Internal Medicine V, University of Heidelberg, Heidelberg, Germany;
                [12] lCentre René Gauducheau Nantes, Nantes, France;
                [13] mDivision of Oncology/Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland;
                [14] nDepartment of Oncology, University Hospital CHUV, Lausanne, Switzerland;
                [15] oDepartment of Medicine/Hematology and Oncology, University of Münster, Münster, Germany;
                [16] pHematology Scientific Center, Russian Academy of Medical Sciences, Moscow, Russia;
                [17] qInstitute of Cancer Research, Royal Marsden Hospital, London, U.K.;
                [18] rDepartment of Haematology, IRS-CSFU, University of Southern Denmark, Vejle Hospital, Vejle, Denmark;
                [19] sDepartment of Hematology, University Hospital of Salamanca, Salamanca, Spain;
                [20] tInstitute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah-Tiqva, Israel;
                [21] uAmmonite Systems Ltd., Faringdon, U.K.;
                [22] vDepartment of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands;
                [23] wVU University Medical Center, Department of Haematology, Amsterdam, The Netherlands
                Author notes
                Correspondence: Heinz Ludwig, M.D., Department of Medicine, Wilhelminenspital, Montleartstr. 37, 1160 Vienna, Austria. Telephone: 43-1491502101; Fax: 43-1491502109; e-mail: heinz.ludwig@ 123456wienkav.at

                Disclosures: Heinz Ludwig: Consultant/advisory role: ESMO; Honoraria: Amgen, Ortho Biotech; Research funding/contracted research: Mundipharma, Janssen-Cilag; Meral Beksac: Honoraria: Celgene, Janssen-Cilag; Joan Bladé: Honoraria: Celgene, Janssen-Cilag; Mario Boccadoro: Consultant/advisory role: Celgene, Janssen-Cilag; Research funding/contracted research: Celgene, Janssen-Cilag; Jamie Cavenagh: None; Michele Cavo: Honoraria: Celgene, Janssen-Cilag, Novartis; Meletios Dimopoulos: Honoraria: Ortho-Biotech, Millennium, Celgene; Johannes Drach: Honoraria: Celgene, Janssen-Cilag; Hermann Einsele: Honoraria: Celene, Ortho-Biotech; Thierry Facon: Consultant/advisory role: Janssen-Cilag, Celgene; Honoraria: Janssen-Cilag, Celgene; Hartmut Goldschmidt: Research funding/contracted research: Ortho-Biotech; Jean-Luc Harousseau: Honoraria: Celgene, Janssen-Cilag; Urs Hess: None; Nicolas Ketterer: None; Martin Kropff: Honoraria: Ortho-Biotech, Celgene; Larisa Mendeleeva: None; Gareth Morgan: None; Antonio Palumbo: Honoraria: Celgene, Janssen-Cilag; Torben Plesner: Honoraria: Janssen-Cilag; Research funding/contracted research: Janssen-Cilag; Jesús San Miguel: Honoraria: Millennium, Celgene, Janssen-Cilag; Ofer Shpilberg: None; Pia Sondergeld: None; Pieter Sonneveld: Consultant/advisory role: ASH, Celgene, Janssen-Cilag; Sonja Zweegman: None.

                The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

                A position paper of the European Myeloma Network (EMN).

                Article
                3563152
                10.1634/theoncologist.2009-0203
                3227886
                20086168
                669a3b4b-7661-4316-adef-93dbb0bf0794
                ©AlphaMed Press

                available online without subscription through the open access option.

                History
                : 26 August 2009
                : 11 December 2009
                Categories
                Academia–Pharma Intersect
                Myelomas

                Oncology & Radiotherapy
                bortezomib,lenalidomide,multiple myeloma,thalidomide
                Oncology & Radiotherapy
                bortezomib, lenalidomide, multiple myeloma, thalidomide

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