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Recent Results in Cancer Research 183
Multiple Myeloma
Bearbeitet vonThomas Moehler, Hartmut Goldschmidt
1. Auflage 2011. Buch. xxiv, 340 S. HardcoverISBN 978 3 540 85771 6
Format (B x L): 16 x 24 cmGewicht: 866 g
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Contents
xiii
Part I History and Epidemiology
1 History of Multiple Myeloma ............................................................................ 3Robert A. Kyle and David P. Steensma
1.1 Ancient Origins ........................................................................................ 41.1.1 Early Well-Documented Cases ................................................................. 41.2 Henry Bence Jones (1813–1873) ............................................................. 71.3 Other Contributions to Bence Jones Proteinuria ...................................... 101.4 Other Early Cases of Multiple Myeloma ................................................. 111.4.1 The Case of Dr. Loos ............................................................................... 111.4.2 The First Myeloma Case in America ....................................................... 121.4.3 Recognition of the Poor Prognosis Associated with Bence Jones Protein ......................................................................... 131.4.4 Case Series ............................................................................................... 131.4.5 Plasma Cells ............................................................................................. 131.4.6 Antibodies ................................................................................................ 141.4.7 Electrophoresis ......................................................................................... 141.4.8 Monoclonal Versus Polyclonal Gammopathies ....................................... 151.5 Alkylator and Corticosteroid-Based Therapy .......................................... 151.5.1 Urethane ................................................................................................... 151.5.2 Melphalan ................................................................................................. 161.5.3 Prednisone ................................................................................................ 161.5.4 Alkylator Combinations ........................................................................... 161.6 Stem Cell Transplantation ........................................................................ 171.6.1 Novel Agents ............................................................................................ 17 References ................................................................................................ 19
xiv Contents
2 Epidemiology of Multiple Myeloma ................................................................. 25Nikolaus Becker
2.1 Descriptive Epidemiology ....................................................................... 262.2 Etiology ................................................................................................... 262.2.1 Tobacco ................................................................................................... 262.2.2 Alcohol .................................................................................................... 292.2.3 Diet .......................................................................................................... 292.2.4 Obesity..................................................................................................... 292.2.5 Physical Activity ..................................................................................... 302.2.6 Hormonal Factors .................................................................................... 302.2.7 Environment and Occupation .................................................................. 302.2.8 Ionizing Radiation ................................................................................... 302.2.9 Inheritance ............................................................................................... 312.2.10 Medical History, Viruses, Immunological Conditions ............................ 312.3 Summary ................................................................................................. 31
Part II Pathophysiology
3 Molecular Pathogenesis of Multiple Myeloma: Chromosomal Aberrations, Changes in Gene Expression, Cytokine Networks, and the Bone Marrow Microenvironment .................... 39Bernard Klein, Anja Seckinger, Thomas Moehler, and Dirk Hose
3.1 Survival, Growth, and Inhibitory Factors of Normal Plasma Cells ........ 403.1.1 Survival and Growth Factors of Normal Plasma Cells and
Their Generation...................................................................................... 403.1.2 Inhibitory Factors Expressed by Normal Plasma Cells ........................... 433.2 Chromosomal Aberrations ...................................................................... 443.2.1 Background and Methods ........................................................................ 443.2.2 Types of Chromosomal Aberrations ........................................................ 463.2.3 Association of Chromosomal Aberrations .............................................. 473.2.4 Clonal, Subclonal, and Progression-Related
Aberrations and Chromosomal Instability .............................................. 473.2.5 Prognostic Relevance of Chromosomal Aberrations .............................. 483.3 Changes in Gene Expression in Multiple Myeloma ................................ 503.3.1 Gene Expression–Based Classifications in Myeloma ............................. 503.3.2 Gene Expression and Risk Stratification ................................................. 513.4 Proliferation and Cell Cycle Regulation ................................................. 523.4.1 “Potential to Proliferate” of Normal Plasma Cells .................................. 523.4.2 D-Type Cyclin Expression in Myeloma .................................................. 533.4.3 Proliferation of Malignant Plasma Cells ................................................. 533.5 Myeloma Cell Survival and Proliferation Factors ................................... 54
Contents xv
3.5.1 Interferon Alpha/Interleukin-6 Family and Activation of the JAK/STAT and MAP Kinase Pathways ........................................ 553.5.2 Factors Activating the PI-3 and MAP Kinase Pathways:
Insulin-Like Growth Factor 1, Heparin-Binding Growth Factors ........... 563.5.3 Heparin-Binding Factors ......................................................................... 583.5.4 Factors Activating NF-Kappa B: BAFF Family ..................................... 593.5.5 Hierarchy of Myeloma Cell Growth Factors and Potential Clinical Applications ............................................................................... 593.6 Multiple Myeloma Cells and the Microenvironment .............................. 603.6.1 Pathogenesis of Myeloma-Induced Bone Disease .................................. 613.6.2 Patterns and Healing of Bone Defects ..................................................... 633.6.3 Therapeutic Strategies for Treatment and Prevention of Myeloma Bone Disease ........................................................................................... 643.7 Pathogenetic Model of Multiple Myeloma ............................................. 643.7.1 Disease Activity, Tumor Load, and Molecular Characteristics of Myeloma Cells .................................................................................... 673.7.2 Multistep Transformation of Myeloma Cell Model ................................ 693.7.3 Transformation of Bone Marrow Microenvironment Model .................. 70
4 Angiogenesis and Vasculogenesis in Multiple Myeloma: Role of Inflammatory Cells ............................................................................... 87Angelo Vacca and Domenico Ribatti
4.1 Introduction ............................................................................................. 874.2 Angiogenesis and Antiangiogenesis in Multiple Myeloma .................... 884.3 The Role of Inflammatory Cells in Tumor Angiogenesis ....................... 894.4 The Involvement of Macrophages in Vascular Mimicry in MM............. 904.5 The Involvement of Mast Cells in Vascular Mimicry in MM ................. 914.6 Vasculogenesis by Hematopoietic Stem and Progenitor Cells ................ 924.7 Concluding Remarks ............................................................................... 93
5 Immunology and Immunotherapeutic Approaches in Multiple Myeloma .................................................................... 97Christoph Schlude and Philipp Beckhove
5.1 Introduction ............................................................................................. 975.2 Myeloma-Associated Antigens ............................................................... 985.3 Vaccination .............................................................................................. 995.4 Immune Evasion ...................................................................................... 1015.5 Regulatory T Cells................................................................................... 1025.6 Humoral Immunotherapy ........................................................................ 1025.7 Adoptive Cellular Therapy ...................................................................... 1035.8 Conclusion ............................................................................................... 104
Part III Clinical Features
6 Monoclonal Gammopathy and Smoldering Multiple Myeloma: Diagnosis, Staging, Prognosis, Management ................. 113Jens Hillengass, Thomas Moehler, and Michael Hundemer
6.1 Definition of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (sMM) ........ 1146.2 Prevalence of MGUS............................................................................... 1146.3 Differential Diagnosis and Diagnostic Assessment ................................ 1166.3.1 Initial Diagnostic Assessment ................................................................. 1166.3.2 Follow-up Recommendations.................................................................. 1176.4 Risk Factors for Progression ................................................................... 1186.4.1 Prognostic Factors for Progression for Patients with MGUS.................. 1186.4.2 Prognostic Factors for Progression of sMM............................................ 1196.4.3 Genetic Risk Stratification ...................................................................... 1226.5 Etiology and Pathogenesis of MGUS and sMM and Considerations Regarding Primary Prevention ................................ 1226.5.1 Population-Based Studies ........................................................................ 1226.5.2 Concept of Chronic Antigenic Stimulation ............................................. 1226.5.3 Molecular Genetics and Cytogenetics ..................................................... 1236.5.4 Concepts for Secondary Prevention of Progression to Multiple Myeloma and Other Lymphoproliferative Diseases ............. 1246.5.5 Summary of Clinical Studies to Halt Progression ................................... 1246.6 Summary and Conclusions ...................................................................... 126
7 Imaging in Multiple Myeloma .......................................................................... 133Stefan Delorme and Andrea Baur-Melnyk
7.1 Introduction ............................................................................................. 1337.2 Imaging Methods ..................................................................................... 1347.2.1 Morphologic Imaging .............................................................................. 1347.2.2 Functional Imaging.................................................................................. 1357.3 Radiological–Pathological Correlation ................................................... 1367.4 Differential Diagnosis ............................................................................. 1427.5 Staging ..................................................................................................... 1437.6 Treatment Effects .................................................................................... 1447.7 Prognostic Factors ................................................................................... 1447.8 The Radiologist’s Tasks .......................................................................... 145
Part IV Therapy
8 Novel Drugs in Myeloma: Harnessing Tumour Biology to Treat Myeloma ................................................................................. 151Kevin Boyd, Faith E. Davies, and Gareth J. Morgan
8.1 Introduction ............................................................................................. 1518.2 Intracellular Drug Targets........................................................................ 152
xvi Contents
8.2.1 Targeting Signalling Pathways Within Myeloma Cells ........................... 1528.2.2 Targeting the Unfolded Protein Response ............................................... 1588.2.3 Targeting Chromatin ................................................................................ 1598.2.4 Targeting Intracellular Cell Cycle Regulatory Proteins .......................... 1628.3 Extracellular Drug Targets ...................................................................... 1638.3.1 Targeting Cytokines or Their Receptors.................................................. 1638.3.2 Targeting Myeloma Cell Adhesion Molecules ........................................ 1678.3.3 Targeting the Host Immune System ........................................................ 1698.3.4 Targeting Bone Disease ........................................................................... 1718.4 Conclusion ............................................................................................... 173
9 Firstline Treatment and Maintenance in Newly Diagnosed Multiple Myeloma Patients ............................................................ 189Murielle Roussel, Thierry Facon, Philippe Moreau, Jean-Luc Harousseau, and Michel Attal
9.1 Frontline Treatment in MM Patients Eligible for High-Dose Therapy ........................................................................... 1909.1.1 Induction Treatment: What Combination of New Drugs? ...................... 1909.1.2 Autologous Stem Cell Transplantation Upfront or at the Time of Relapse? ....................................................................... 1949.1.3 Maintenance/Consolidation Treatment ................................................... 1959.2 Frontline Treatment in Elderly MM Patients .......................................... 1969.2.1 What Is the Best Combination with Alkylating Agents? ........................ 1979.2.2 Firstline Treatment: Can New Agents Replace Alkylators? ................... 2009.2.3 Can We Reduce Toxicities of New Drugs-Incorporating Regimens? ..... 2019.2.4 Maintenance Therapy in Elderly ............................................................. 202
10 High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma .............................. 207Rainer Haas, Ingmar Bruns, Guido Kobbe, and Roland Fenk
10.1 Introduction ............................................................................................. 20810.2 Peripheral Blood Stem Cell Mobilization ............................................... 20810.2.1 The Role of Adhesion Molecules ............................................................ 20810.2.2 The Role of Hematopoietic Growth Factors ........................................... 21010.2.3 The Role of Cytotoxic Stem Cell Mobilization....................................... 21210.2.4 The Role of Pegfilgrastim for Stem Cell Mobilization ........................... 21310.3 High-Dose Therapy and Autologous Stem Cell Transplantation ............ 21510.3.1 The Beginning of High-Dose Therapy in the 1980 ................................. 21510.3.2 The Role of Purging of the Autograft ..................................................... 21610.3.3 The Role of the Conditioning Regimen .................................................. 21710.3.4 Supportive Care During High-Dose Chemotherapy ............................... 21810.3.5 High-Dose Chemotherapy Is Superior to Conventional Chemotherapy ............................................................... 21910.3.6 Timing of High-Dose Chemotherapy ...................................................... 22110.3.7 Tandem Autologous Transplantation ...................................................... 221
Contents xvii
10.3.8 The Role of Induction Treatment ............................................................ 22210.3.9 The Role of Consolidation or Maintenance Treatment ........................... 22310.3.10 Prognostic Factors ................................................................................... 22410.3.11 Targeted Versus High-Dose Chemotherapy ............................................ 226
11 Therapy of Relapsed and Refractory Multiple Myeloma .............................. 239Thomas Moehler and Hartmut Goldschmidt
11.1 Introduction ............................................................................................. 24011.2 Diagnostic Workup of Patients at Relapse .............................................. 24011.3 Conventional Treatment of Relapsed/Refractory Disease ...................... 24011.4 High-Dose Chemotherapy (HDCT) Supported by Autologous Stem Cell Transplantation ............................................. 24111.5 Allogeneic Stem Cell Transplantation..................................................... 24211.6 Thalidomide and Immunomodulatory Drugs .......................................... 24511.6.1 Thalidomide as Single Agent and Combined with Corticosteroids ........ 24511.6.2 Thalidomide in Combination with Chemotherapy/Corticosteroids ........ 24611.6.3 Lenalidomide ........................................................................................... 24911.6.4 Lenalidomide Combination Therapies .................................................... 24911.6.5 Pomalidomide .......................................................................................... 25111.7 Bortezomib .............................................................................................. 25111.7.1 Bortezomib Single Agent ........................................................................ 25111.7.2 Bortezomib Combination Therapy .......................................................... 25211.8 Novel Proteasome Inhibitors ................................................................... 25411.9 Combination of Novel Agents ................................................................. 25511.10 Emerging Therapies and Novel Pathways ............................................... 26011.11 Prognostic Factors ................................................................................... 26011.12 Therapeutic Strategy for Relapsed/Refractory Myeloma Patients .......... 260
12 Allogeneic Transplantation in Multiple Myeloma .......................................... 273Gösta Gahrton
12.1 Introduction ............................................................................................. 27412.2 Myeloablative High Dose Conditioning.................................................. 27412.3 Molecular Remission ............................................................................... 27512.4 Source of Stem Cells ............................................................................... 27512.5 Reduced Intensity conditioning (RIC) .................................................... 27612.5.1 Retrospective Studies .............................................................................. 27612.5.2 Prospective Studies.................................................................................. 27612.6 How to Improve Results of Allogeneic Transplantation? ....................... 27912.6.1 Donor Lymphocyte Transfusions ............................................................ 27912.6.2 NK Cells Have Antimyeloma Effect and Moderate GVHD ................... 28012.6.3 Role of Immunosuppressive Agents in the Conditioning Therapy ......... 28012.6.4 Targeted Drugs Pretransplant or Posttransplant ...................................... 28112.7 Conclusions ............................................................................................. 281
xviii Contents
13 Radiotherapy ...................................................................................................... 285Sonja Krause, Jürgen Debus, and Dirk Neuhof
13.1 Solitary Plasmocytoma ............................................................................ 28513.1.1 Diagnostic Workup .................................................................................. 28613.1.2 Radiotherapy of SBP ............................................................................... 28613.1.3 Radiotherapy of EP ................................................................................. 28713.1.4 Treatment Toxicity .................................................................................. 28713.2 Palliative Treatment of Multiple Myeloma ............................................. 28713.2.1 Pain Control ............................................................................................. 28813.2.2 Recalcification ......................................................................................... 28813.3 Total Body Irradiation (TBI) ................................................................... 289
14 Osteoplastic Procedures for the Treatment of Vertebral Complications in Multiple Myeloma Patients ................................................. 293Christian Kasperk and Ingo Grafe
14.1 Introduction ............................................................................................. 29414.2 Osteoplastic Procedures .......................................................................... 29414.3 Balloon Kyphoplasty ............................................................................... 29414.4 Vertebroplasty .......................................................................................... 29514.5 Comparison of Kyphoplasty and Vertebroplasty..................................... 29614.6 Indications and Contraindications ........................................................... 29614.7 Randomized Controlled Studies of Osteoplastic Procedures for Vertebral Osteoporotic Fractures .................................... 29714.8 Studies Using Kyphoplasty and Vertebroplasty in Patients with Multiple Myeloma ........................................................................... 298
15 Supportive Therapy in Multiple Myeloma ...................................................... 307Heinz Ludwig and Niklas Zojer
15.1 Introduction ............................................................................................. 30715.2 Myeloma Bone Disease ........................................................................... 30815.2.1 Mechanisms of Bone Disease.................................................................. 30815.2.2 Bone Fractures ......................................................................................... 30915.2.3 Vertebral Lesions ..................................................................................... 30915.2.4 Bisphosphonates ...................................................................................... 30915.3 Hypercalcemia ......................................................................................... 31415.3.1 Diagnosis and Symptoms ........................................................................ 31415.3.2 Treatment of Hypercalcemia ................................................................... 31515.4 Anemia .................................................................................................... 31615.4.1 Pathogenesis of Anemia .......................................................................... 31615.4.2 Clinical Symptoms of Anemia ................................................................ 31615.4.3 Treatment of Anemia ............................................................................... 31715.5 Infections ................................................................................................. 320
Contents xix
15.5.1 Causes of Infections ................................................................................ 32015.5.2 Prophylaxis of Infections......................................................................... 32115.5.3 Vaccination .............................................................................................. 32215.5.4 Treatment of Infections ........................................................................... 32215.6 Pain .......................................................................................................... 32315.6.1 Characteristics and Causes of Pain .......................................................... 32315.6.2 Medical Pain Treatment .......................................................................... 32415.7 Renal Failure ........................................................................................... 32515.7.1 Prevalence and Causes of Renal Failure ................................................. 32515.7.2 Management of Myeloma-Induced Renal Failure................................... 326
Appendix ................................................................................................................... 335
xx Contents
