1;Copyright Page;5 2;Dedication;6 3;Foreword;8 4;Preface;10 5;Acknowledgements;12 6;Contents;14 7;Contributors;22 8;Part I History and Epidemiology;25 8.1;1: History of Multiple Myeloma;26 8.1.1;1.1 Ancient Origins;27 8.1.1.1;1.1.1 Early Well-Documented Cases;27 8.1.2;1.2 Henry Bence Jones (1813-1873);30 8.1.3;1.3 Other Contributions to Bence Jones Proteinuria;33 8.1.4;1.4 Other Early Cases of Multiple Myeloma;34 8.1.4.1;1.4.1 The Case of Dr. Loos;34 8.1.4.2;1.4.2 The First Myeloma Case in America;35 8.1.4.3;1.4.3 Recognition of the Poor Prognosis Associated with Bence Jones Protein;36 8.1.4.4;1.4.4 Case Series;36 8.1.4.5;1.4.5 Plasma Cells;36 8.1.4.6;1.4.6 Antibodies;37 8.1.4.7;1.4.7 Electrophoresis;37 8.1.4.8;1.4.8 Monoclonal Versus Polyclonal Gammopathies;38 8.1.5;1.5 Alkylator and Corticosteroid-Based Therapy;38 8.1.5.1;1.5.1 Urethane;38 8.1.5.2;1.5.2 Melphalan;39 8.1.5.3;1.5.3 Prednisone;39 8.1.5.4;1.5.4 Alkylator Combinations;39 8.1.6;1.6 Stem Cell Transplantation;40 8.1.6.1;1.6.1 Novel Agents;40 8.1.6.1.1;1.6.1.1 Thalidomide;40 8.1.6.1.2;1.6.1.2 Bortezomib;41 8.1.6.1.3;1.6.1.3 Lenalidomide;42 8.1.7;References;42 8.2;2: Epidemiology of Multiple Myeloma;47 8.2.1;2.1 Descriptive Epidemiology;48 8.2.2;2.2 Etiology;48 8.2.2.1;2.2.1 Tobacco;48 8.2.2.2;2.2.2 Alcohol;51 8.2.2.3;2.2.3 Diet;51 8.2.2.4;2.2.4 Obesity;51 8.2.2.5;2.2.5 Physical Activity;52 8.2.2.6;2.2.6 Hormonal Factors;52 8.2.2.7;2.2.7 Environment and Occupation;52 8.2.2.8;2.2.8 Ionizing Radiation;52 8.2.2.9;2.2.9 Inheritance;53 8.2.2.10;2.2.10 Medical History, Viruses, Immunological Conditions;53 8.2.3;2.3 Summary;53 8.2.4;References;55 9;Part II Pathophysiology;58 9.1;3: Molecular Pathogenesis of Multiple Myeloma: Chromosomal Aberrations, Changes in Gene Expression, Cytokine Networks, and th;59 9.1.1;3.1 Survival, Growth, and Inhibitory Factors of Normal Plasma Cells;60 9.1.1.1;3.1.1 Survival and Growth Factors of Normal Plasma Cells and Their Generation;60 9.1.1.2;3.1.2 Inhibitory Factors Expressed by Normal Plasma Cells;63 9.1.2;3.2 Chromosomal Aberrations;64 9.1.2.1;3.2.1 Background and Methods;64 9.1.2.2;3.2.2 Types of Chromosomal Aberrations;66 9.1.2.3;3.2.3 Association of Chromosomal Aberrations;67 9.1.2.4;3.2.4 Clonal, Subclonal, and Progression-Related Aberrations and Chromosomal Instability;67 9.1.2.5;3.2.5 Prognostic Relevance of Chromosomal Aberrations;68 9.1.3;3.3 Changes in Gene Expression in Multiple Myeloma;70 9.1.3.1;3.3.1 Gene Expression-Based Classifications in Myeloma;70 9.1.3.2;3.3.2 Gene Expression and Risk Stratification;71 9.1.4;3.4 Proliferation and Cell Cycle Regulation;72 9.1.4.1;3.4.1 "Potential to Proliferate" of Normal Plasma Cells;72 9.1.4.2;3.4.2 D-Type Cyclin Expression in Myeloma;73 9.1.4.3;3.4.3 Proliferation of Malignant Plasma Cells;73 9.1.5;3.5 Myeloma Cell Survival and Proliferation Factors;74 9.1.5.1;3.5.1 Interferon Alpha/Interleukin-6 Family and Activation of the JAK/STAT and MAP Kinase Pathways;75 9.1.5.2;3.5.2 Factors Activating the PI-3 and MAP Kinase Pathways: Insulin-Like Growth Factor 1, Heparin-Binding Growth Factors;76 9.1.5.2.1;3.5.2.1 Insulin-Like Growth Factor 1 (IGF-1);76 9.1.5.2.2;3.5.2.2 Insulin;77 9.1.5.3;3.5.3 Heparin-Binding Factors;78 9.1.5.3.1;3.5.3.1 Heparin-Binding Epidermal Growth Factors;78 9.1.5.3.2;3.5.3.2 Hepatocyte Growth Factor (HGF);78 9.1.5.3.3;3.5.3.3 Fibroblast Growth Factor (FGF);79 9.1.5.4;3.5.4 Factors Activating NF-Kappa B: BAFF Family;79 9.1.5.5;3.5.5 Hierarchy of Myeloma Cell Growth Factors and Potential Clinical Applications;79 9.1.6;3.6 Multiple Myeloma Cells and the Microenvironment;80 9.1.6.1;3.6.1 Pathogenesis of Myeloma-Induced Bone Disease;81 9.1.6.2;3.6.2 Patterns and Healing of Bone Defects;83 9.1.6.3;3.6.3 Therapeutic Strategies for Treatment and Prevention of Myeloma Bone Disease;84 9.1.7;3.7 Pathogenetic Model of Multiple Myeloma;84 9.1.7.1;3.7.1 Disease Activity, Tumor Load, and Molecular Characteristics of Myeloma Cells;87 9.1.7.1.1;3.7.1.1 Describing Disease Activity;87 9