Multiple Myeloma (eBook)

Copyright Page 5
Dedication 6
Foreword 8
Preface 10
Acknowledgements 12
Contents 14
Contributors 22
Part I History and Epidemiology 25
1: History of Multiple Myeloma 26
1.1 Ancient Origins 27
1.1.1 Early Well-Documented Cases 27
1.2 Henry Bence Jones (1813–1873) 30
1.3 Other Contributions to Bence Jones Proteinuria 33
1.4 Other Early Cases of Multiple Myeloma 34
1.4.1 The Case of Dr. Loos 34
1.4.2 The First Myeloma Case in America 35
1.4.3 Recognition of the Poor Prognosis Associated with Bence Jones Protein 36
1.4.4 Case Series 36
1.4.5 Plasma Cells 36
1.4.6 Antibodies 37
1.4.7 Electrophoresis 37
1.4.8 Monoclonal Versus Polyclonal Gammopathies 38
1.5 Alkylator and Corticosteroid-Based Therapy 38
1.5.1 Urethane 38
1.5.2 Melphalan 39
1.5.3 Prednisone 39
1.5.4 Alkylator Combinations 39
1.6 Stem Cell Transplantation 40
1.6.1 Novel Agents 40
1.6.1.1 Thalidomide 40
1.6.1.2 Bortezomib 41
1.6.1.3 Lenalidomide 42
References 42
2: Epidemiology of Multiple Myeloma 47
2.1 Descriptive Epidemiology 48
2.2 Etiology 48
2.2.1 Tobacco 48
2.2.2 Alcohol 51
2.2.3 Diet 51
2.2.4 Obesity 51
2.2.5 Physical Activity 52
2.2.6 Hormonal Factors 52
2.2.7 Environment and Occupation 52
2.2.8 Ionizing Radiation 52
2.2.9 Inheritance 53
2.2.10 Medical History, Viruses, Immunological Conditions 53
2.3 Summary 53
References 55
Part II Pathophysiology 58
3: Molecular Pathogenesis of Multiple Myeloma: Chromosomal Aberrations, Changes in Gene Expression, Cytokine Networks, and th 59
3.1 Survival, Growth, and Inhibitory Factors of Normal Plasma Cells 60
3.1.1 Survival and Growth Factors of Normal Plasma Cells and Their Generation 60
3.1.2 Inhibitory Factors Expressed by Normal Plasma Cells 63
3.2 Chromosomal Aberrations 64
3.2.1 Background and Methods 64
3.2.2 Types of Chromosomal Aberrations 66
3.2.3 Association of Chromosomal Aberrations 67
3.2.4 Clonal, Subclonal, and Progression-Related Aberrations and Chromosomal Instability 67
3.2.5 Prognostic Relevance of Chromosomal Aberrations 68
3.3 Changes in Gene Expression in Multiple Myeloma 70
3.3.1 Gene Expression–Based Classifications in Myeloma 70
3.3.2 Gene Expression and Risk Stratification 71
3.4 Proliferation and Cell Cycle Regulation 72
3.4.1 “Potential to Proliferate” of Normal Plasma Cells 72
3.4.2 D-Type Cyclin Expression in Myeloma 73
3.4.3 Proliferation of Malignant Plasma Cells 73
3.5 Myeloma Cell Survival and Proliferation Factors 74
3.5.1 Interferon Alpha/Interleukin-6 Family and Activation of the JAK/STAT and MAP Kinase Pathways 75
3.5.2 Factors Activating the PI-3 and MAP Kinase Pathways: Insulin-Like Growth Factor 1, Heparin-Binding Growth Factors 76
3.5.2.1 Insulin-Like Growth Factor 1 (IGF-1) 76
3.5.2.2 Insulin 77
3.5.3 Heparin-Binding Factors 78
3.5.3.1 Heparin-Binding Epidermal Growth Factors 78
3.5.3.2 Hepatocyte Growth Factor (HGF) 78
3.5.3.3 Fibroblast Growth Factor (FGF) 79
3.5.4 Factors Activating NF-Kappa B: BAFF Family 79
3.5.5 Hierarchy of Myeloma Cell Growth Factors and Potential Clinical Applications 79
3.6 Multiple Myeloma Cells and the Microenvironment 80
3.6.1 Pathogenesis of Myeloma-Induced Bone Disease 81
3.6.2 Patterns and Healing of Bone Defects 83
3.6.3 Therapeutic Strategies for Treatment and Prevention of Myeloma Bone Disease 84
3.7 Pathogenetic Model of Multiple Myeloma 84
3.7.1 Disease Activity, Tumor Load, and Molecular Characteristics of Myeloma Cells 87
3.7.1.1 Describing Disease Activity 87
3.7.1.2 Interpatient Heterogeneity: Many and Multiple Myelomas 88
3.7.2 Multistep Transformation of Myeloma Cell Model 89
3.7.3 Transformation of Bone Marrow Microenvironment Model 90
3.7.3.1 Features of Normal Plasma Cells as Explanation for Those of Myeloma Cells 90
3.7.3.2 Pre-MGUS-Stage 90
3.7.3.3 MGUS-Stage/Smoldering Myeloma 90
3.7.3.4 Symptomatic Myeloma 91
References 92
4: Angiogenesis and Vasculogenesis in Multiple Myeloma: Role of Inflammatory Cells 107
4.1 Introduction 107
4.2 Angiogenesis and Antiangiogenesis in Multiple Myeloma 108
4.3 The Role of Inflammatory Cells in Tumor Angiogenesis 109
4.4 The Involvement of Macrophages in Vascular Mimicry in MM 110
4.5 The Involvement of Mast Cells in Vascular Mimicry in MM 111
4.6 Vasculogenesis by Hematopoietic Stem and Progenitor Cells 112
4.7 Concluding Remarks 113
References 113
5: Immunology and Immunotherapeutic Approaches in Multiple Myeloma 116
5.1 Introduction 116
5.2 Myeloma-Associated Antigens 117
5.3 Vaccination 118
5.4 Immune Evasion 120
5.5 Regulatory T Cells 121
5.6 Humoral Immunotherapy 121
5.7 Adoptive Cellular Therapy 122
5.8 Conclusion 123
References 123
Part III Clinical Features 129
6: Monoclonal Gammopathy and Smoldering Multiple Myeloma: Diagnosis, Staging, Prognosis, Management 130
6.1 Definition of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (sMM) 131
6.2 Prevalence of MGUS 131
6.3 Differential Diagnosis and Diagnostic Assessment 133
6.3.1 Initial Diagnostic Assessment 133
6.3.2 Follow-up Recommendations 134
6.4 Risk Factors for Progression 135
6.4.1 Prognostic Factors for Progression for Patients with MGUS 135
6.4.2 Prognostic Factors for Progression of sMM 136
6.4.2.1 Immunophenotyping and Immunoparesis 138
6.4.2.2 Role of Imaging in Prognostic Evaluation of sMM 138
6.4.3 Genetic Risk Stratification 139
6.5 Etiology and Pathogenesis of MGUS and sMM and Considerations Regarding Primary Prevention 139
6.5.1 Population-Based Studies 139
6.5.2 Concept of Chronic Antigenic Stimulation 139
6.5.3 Molecular Genetics and Cytogenetics 140
6.5.4 Concepts for Secondary Prevention of Progression to Multiple Myeloma and Other Lymphoproliferative Diseases 141
6.5.5 Summary of Clinical Studies to Halt Progression 141
6.5.5.1 Bisphosphonates 142
6.5.5.2 Alkylating Agents and Corticosteroids 142
6.5.5.3 Thalidomide 142
6.5.5.4 Immunotherapy and Interference with Cytokine Network 143
6.5.5.5 Summary and Brief Outlook Regarding Clinical Studies 143
6.6 Summary and Conclusions 143
References 144
7: Imaging in Multiple Myeloma 149
7.1 Introduction 149
7.2 Imaging Methods 150
7.2.1 Morphologic Imaging 150
7.2.2 Functional Imaging 151
7.2.2.1 Dynamic Contrast-Enhanced MRI (DCE MRI) 151
7.2.2.2 Diffusion-Weighted Imaging (DWI) 151
7.2.2.3 Bone Scintigraphy and Positron Emission Tomography (PET) 152
7.3 Radiological–Pathological Correlation 152
7.4 Differential Diagnosis 158
7.5 Staging 159
7.6 Treatment Effects 160
7.7 Prognostic Factors 160
7.8 The Radiologist’s Tasks 161
References 161
Part IV Therapy 164
8: Novel Drugs in Myeloma: Harnessing Tumour Biology to Treat Myeloma 165
8.1 Introduction 165
8.2 Intracellular Drug Targets 166
8.2.1 Targeting Signalling Pathways Within Myeloma Cells 166
8.2.1.1 The Ras/Raf/MEK/MAPK Pathway 167
8.2.1.2 The Janus Kinase (JAK)/STAT Pathway 168
8.2.1.3 The Phosphatidylinositol-3 Kinase (PI3-K)/Akt Pathway 169
8.2.1.4 The Nuclear Factor-Kappa B (NF-kB) Pathway and the Ubiquitin Proteasome System 170
8.2.1.5 The Wingless/int (Wnt)/b-Catenin Pathway 172
8.2.2 Targeting the Unfolded Protein Response 172
8.2.3 Targeting Chromatin 173
8.2.3.1 Histone Deacetylase (HDAC) Inhibitors 174
8.2.3.2 Hypomethylating Agents 175
8.2.3.3 New Alkylators 175
8.2.4 Targeting Intracellular Cell Cycle Regulatory Proteins 176
8.2.4.1 Cyclin D Kinases 176
8.2.4.2 Aurora Kinases 176
8.2.4.3 Pim Kinases 177
8.2.4.4 Inhibitor of Apoptosis Proteins 177
8.3 Extracellular Drug Targets 177
8.3.1 Targeting Cytokines or Their Receptors 177
8.3.1.1 Interleukin-6 (IL-6) 178
8.3.1.2 Insulin-Like Growth Factor-1 (IGF-1) 178
8.3.1.3 Fibroblast Growth Factor (FGFR3) 179
8.3.1.4 Vascular Endothelial Growth Factor (VEGF) 179
8.3.1.5 Platelet Derived Growth Factor Receptor b (PDGFRb) 179
8.3.1.6 CD40 Ligand 180
8.3.1.7 B-Cell Activating Factor (BAFF) and a Proliferation-Inducing Ligand (APRIL) 180
8.3.1.8 TNF-Related Apoptosis-Inducing Ligand (TRAIL) 180
8.3.1.9 Fas 180
8.3.1.10 p38 mitogen-activated protein kinase (MAPK) 180
8.3.2 Targeting Myeloma Cell Adhesion Molecules 181
8.3.2.1 Stromal Cell Derived Factor-1 (SDF-1) 181
8.3.2.2 Cell Surface 1 Surface Antigen (CS1) 181
8.3.2.3 CD56 182
8.3.2.4 CD38 182
8.3.2.5 CD138 182
8.3.2.6 CD66 182
8.3.3 Targeting the Host Immune System 183
8.3.3.1 Immunomodulatory Drugs (IMiDs) 183
Thalidomide 183
Lenalidomide (CC-5013) 184
Pomalidomide (CC4047) 185
8.3.4 Targeting Bone Disease 185
8.3.4.1 Receptor Activator of NF-kB Ligand (RANKL) 186
8.3.4.2 Dickkopf-1 (DKK1) and Wingless/int (Wnt) 186
8.3.4.3 Macrophage Inflammatory Protein 1-a (MIP-1a) 186
8.3.4.4 Activin A 187
8.4 Conclusion 187
References 188
9: Firstline Treatment and Maintenance in Newly Diagnosed Multiple Myeloma Patients 202
9.1Frontline Treatment in MM Patients Eligible for High-Dose Therapy 203
9.1.1Induction Treatment: What Combination of New Drugs? 203
9.1.1.1Two-Drug Induction Regimens 204
Thalidomide-Based Induction Regimens 204
Bortezomib-Based Induction Regimens 204
Lenalidomide-Based Induction Regimens 204
9.1.1.2Three-Drug Regimens 204
Anthracyclins or Cyclophosphamide in Combination with Thalidomide, Bortezomib, or Lenalidomide 205
Bortezomib in Combination with Thalidomide or Lenalidomide 205
9.1.1.3Four-Drug Induction Regimens 206
9.1.2Autologous Stem Cell Transplantation Upfront or at the Time of Relapse? 207
9.1.3Maintenance/Consolidation Treatment 208
9.2Frontline Treatment in Elderly MM Patients 209
9.2.1What Is the Best Combination with Alkylating Agents? 210
9.2.1.1Thalidomide 210
9.2.1.2Bortezomib 211
9.2.1.3Lenalidomide 212
9.2.1.4Combinations of New Agents Plus MP 212
VMPT 212
9.2.2Firstline Treatment: Can New Agents Replace Alkylators? 213
9.2.2.1Thalidomide 213
9.2.2.2Lenalidomide 213
9.2.2.3Combinations of New Agents 214
Bortezomib and Thalidomide 214
9.2.3Can We Reduce Toxicities of New Drugs-Incorporating Regimens? 214
9.2.3.1Bortezomib in a Weekly Schedule 214
9.2.3.2Low-Dose Dexamethasone 214
9.2.3.3Prevention of IMiDs-Associated Venous Thromboembolism (VTE) 215
9.2.4Maintenance Therapy in Elderly 215
References 216
10: High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma 220
10.1Introduction 221
10.2Peripheral Blood Stem Cell Mobilization 221
10.2.1The Role of Adhesion Molecules 221
10.2.2The Role of Hematopoietic Growth Factors 223
10.2.3The Role of Cytotoxic Stem Cell Mobilization 225
10.2.4The Role of Pegfilgrastim for Stem Cell Mobilization 226
10.3High-Dose Therapy and Autologous Stem Cell Transplantation 228
10.3.1The Beginning of High-Dose Therapy in the 1980 228
10.3.2The Role of Purging of the Autograft 229
10.3.3The Role of the Conditioning Regimen 230
10.3.4Supportive Care During High-Dose Chemotherapy 231
10.3.5High-Dose Chemotherapy Is Superior to Conventional Chemotherapy 232
10.3.6Timing of High-Dose Chemotherapy 234
10.3.7Tandem Autologous Transplantation 234
10.3.8The Role of Induction Treatment 235
10.3.9The Role of Consolidation or Maintenance Treatment 236
10.3.10Prognostic Factors 237
10.3.11Targeted Versus High-Dose Chemotherapy 239
References 240
11: Therapy of Relapsed and Refractory Multiple Myeloma 252
11.1Introduction 253
11.2Diagnostic Workup of Patients at Relapse 253
11.3Conventional Treatment of Relapsed/Refractory Disease 253
11.4High-Dose Chemotherapy (HDCT) Supported by Autologous Stem Cell Transplantation 254
11.5Allogeneic Stem Cell Transplantation 255
11.6Thalidomide and Immunomodulatory Drugs 258
11.6.1Thalidomide as Single Agent and Combined with Corticosteroids 258
11.6.2Thalidomide in Combination with Chemotherapy/Corticosteroids 259
11.6.3Lenalidomide 262
11.6.4Lenalidomide Combination Therapies 262
11.6.5Pomalidomide 264
11.7Bortezomib 264
11.7.1Bortezomib Single Agent 264
11.7.2Bortezomib Combination Therapy 265
11.8Novel Proteasome Inhibitors 267
11.9Combination of Novel Agents 268
11.10Emerging Therapies and Novel Pathways 273
11.11Prognostic Factors 273
11.12Therapeutic Strategy for Relapsed/Refractory Myeloma Patients 273
References 276
12: Allogeneic Transplantation in Multiple Myeloma 285
12.1 Introduction 286
12.2 Myeloablative High Dose Conditioning 286
12.3 Molecular Remission 287
12.4 Source of Stem Cells 287
12.5 Reduced Intensity conditioning (RIC) 288
12.5.1 Retrospective Studies 288
12.5.2 Prospective Studies 288
12.6 How to Improve Results of Allogeneic Transplantation? 291
12.6.1 Donor Lymphocyte Transfusions 291
12.6.2 NK Cells Have Antimyeloma Effect and Moderate GVHD 292
12.6.3 Role of Immunosuppressive Agents in the Conditioning Therapy 292
12.6.4 Targeted Drugs Pretransplant or Posttransplant 293
12.7 Conclusions 293
References 293
13: Radiotherapy 297
13.1 Solitary Plasmocytoma 297
13.1.1 Diagnostic Workup 298
13.1.2 Radiotherapy of SBP 298
13.1.3 Radiotherapy of EP 299
13.1.4 Treatment Toxicity 299
13.2 Palliative Treatment of Multiple Myeloma 299
13.2.1 Pain Control 300
13.2.2 Recalcification 300
13.3 Total Body Irradiation (TBI) 301
References 302
14: Osteoplastic Procedures for the Treatment of Vertebral Complications in Multiple Myeloma Patients 304
14.1 Introduction 305
14.2 Osteoplastic Procedures 305
14.3 Balloon Kyphoplasty 305
14.4 Vertebroplasty 306
14.5 Comparison of Kyphoplasty and Vertebroplasty 307
14.6 Indications and Contraindications 307
14.7 Randomized Controlled Studies of Osteoplastic Procedures for Vertebral Osteoporotic Fractures 308
14.8 Studies Using Kyphoplasty and Vertebroplasty in Patients with Multiple Myeloma 309
References 316
15: Supportive Therapy in Multiple Myeloma 318
15.1 Introduction 318
15.2 Myeloma Bone Disease 319
15.2.1 Mechanisms of Bone Disease 319
15.2.2 Bone Fractures 320
15.2.3 Vertebral Lesions 320
15.2.4 Bisphosphonates 320
15.2.4.1 Adverse Events of Bisphosphonates 322
Osteonecrosis of the Jaw (ONJ) 322
15.2.4.2 Guidelines for the Use of Bisphosphonates 325
15.2.4.3 Prophylactic Measures for ONJ 325
15.3 Hypercalcemia 325
15.3.1 Diagnosis and Symptoms 325
15.3.2 Treatment of Hypercalcemia 326
15.3.2.1 Rehydration 326
15.3.2.2 Bisphosphonates 326
15.3.2.3 Calcitonin and Corticosteroids 327
15.4 Anemia 327
15.4.1 Pathogenesis of Anemia 327
15.4.2 Clinical Symptoms of Anemia 327
15.4.3 Treatment of Anemia 328
15.4.3.1 Transfusions 328
15.4.3.2 Erythropoiesis-Stimulating Proteins (ESAs) 328
15.4.3.3 Treatment Recommendations for ESAs 330
15.5 Infections 331
15.5.1 Causes of Infections 331
15.5.2 Prophylaxis of Infections 332
15.5.3 Vaccination 333
15.5.4 Treatment of Infections 333
15.6 Pain 334
15.6.1 Characteristics and Causes of Pain 334
15.6.2 Medical Pain Treatment 335
15.7 Renal Failure 336
15.7.1 Prevalence and Causes of Renal Failure 336
15.7.2 Management of Myeloma-Induced Renal Failure 337
References 337
Appendix: Staging and Prognosis Systems 345