Bortezomib in the Treatment of Multiple Myeloma (eBook)

Bortezomib in the Treatment of Multiple Myeloma 3
Preface 5
Contents 7
Bortezomib´s Scientific Origins and Its Tortuous Path to the Clinic 9
1 Introduction 10
2 Discovery and Key Features of the Ubiquitin-Proteasome Pathway 12
3 The Rationale for Generating Proteasome Inhibitors for Therapeutic Purposes 14
4 The Failed (But Scientifically Very Successful) Biotechnology Company, Myogenics/Proscript 15
5 From MG132 to Bortezomib 17
6 The 20S Proteasome (The Core Particle) 20
7 Understanding Bortezomib´s Selectivity 22
8 The 19S Regulatory Particle and the Role of ATP in Proteasome Function 24
9 Bortezomib´s Preclinical Trials and Tribulations 27
10 The Legacy of the Proteasome Inhibitors Outside the Clinic: Major Advances in Our Understanding of Cell Function 29
11 Some Lessons About Drug Development Learned from Bortezomib´s Success 30
References 31
Preclinical Activities of Bortezomib in MM, the Bone Marrow Microenvironment and Pharmacogenomics 36
1 Introduction 36
2 Biologic Sequelae of Proteasome Inhibition by Bortezomib (Velcade) 38
2.1 Targeting MM Cells 38
2.2 Targeting the BM Microenvironment 39
3 Phamacogenomics and Cytogenetics 41
4 Bortezomib-Based Novel Combination Strategies 41
4.1 Histone Deacetylase Inhibitors 41
4.2 Perifosine 43
4.3 Hsp90 Inhibitors 43
4.4 Lenalidomide (Revlimid) Plus Dexamethasone 44
4.5 IKKbeta Inhibitors 45
4.6 Aurora Kinase Inhibitors 45
5 Natural Products that Inhibit Bortezomib 45
Reference 46
Bortezomib and Osteoclasts and Osteoblasts 50
1 Introduction 50
2 Role of the Bone Marrow Microenvironment in Myeloma 51
3 Bortezomib in the Treatment of Bone Disease in MM 53
4 Summary 55
References 56
Bortezomib in the Upfront Treatment of Multiple Myeloma 60
1 Introduction 61
2 Bortezomib as Monotherapy 61
3 Bortezomib-based Combinations in Transplant Candidate MM Patients 62
3.1 Randomised Phase III Trials 62
3.2 Pilot Studies 64
3.2.1 Bortezomib Plus Dexamethasone 64
3.2.2 Bortezomib Plus Anthracyclines 66
3.2.3 Bortezomib Plus Alkylating Agents 67
3.2.4 Bortezomib in Combination with Immunomodulatory Drugs 67
Bortezomib Plus Thalidomide-based Combinations 67
Bortezomib Plus Lenalidomide-based Combinations 68
3.3 Impact of Bortezomib-based Combinations on Stem Cell Collection 68
3.4 Bortezomib as Part of the Conditioning Regimen for SCT 68
3.5 Role of Bortezomib as Consolidation/Maintenance Therapy 69
4 Bortezomib in Non-HDT/SCT Candidate Patients 69
5 Conclusions 71
References 72
The Use of Bortezomib in Autologous Transplantation for Multiple Myeloma 76
1 Introduction 76
2 Enhancing Transplant Efficacy: Improving Patient Selection 77
3 Enhancing Transplant Efficacy: The Role of Induction and Maintenance Therapy 78
4 Enhancing Transplant Efficacy: Improving Conditioning 78
References 81
Bortezomib in Relapsed and Relapsed/Refractory Multiple Myeloma 85
1 Single-Agent Bortezomib in the Relapsed/Refractory Setting 86
2 Combination Regimens Incorporating Bortezomib 87
3 Bortezomib and High-Risk Cytogenetic Features 91
4 Alternate Dosing Schedules Utilizing Bortezomib 92
5 Retreatment with Bortezomib 93
6 Conclusions 94
References 95
Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma: Principles of Identification and Management 101
1 Introduction 101
2 Clinical Trial Experience: Observations and Lessons 102
3 Clinical Characteristics of Bortezomib-Induced PN 102
4 Potential Mechanisms of Bortezomib-Induced Peripheral Neuropathy 103
5 Evaluation and Monitoring 104
6 Management 105
7 Future Directions 106
References 108
Bortezomib in Mantle Cell Lymphoma 112
1 Mantle Cell Lymphoma 112
2 Current Treatment of Mantle Cell Lymphoma 113
3 Bortezomib in the Treatment of Mantle Cell Lymphoma 114
3.1 Clinical Efficacy of Single-Agent Bortezomib 115
3.2 Safety and Tolerability Profile of Single-Agent Bortezomib 117
3.3 Biomarkers 118
3.4 Bortezomib Combination Studies 119
4 Second Generation Proteasome Inhibitors 122
5 Conclusions 122
References 123
Bortezomib in Waldenstrom´s Macroglobulinemia 127
1 Introduction 127
2 Bortezomib: Mechanism of Action 128
2.1 NF-kB Inhibition 129
2.2 Induction of Proapoptotic Pathways 130
2.3 Inhibition of Angiogenic Phenotype 130
3 Clinical Studies 131
3.1 Bortezomib Single Agent Therapy in Waldenstrom´s Macroglobulinemia 131
3.2 Bortezomib-Based Regimens in Waldenstrom´s Macroglobulinemia 132
4 Conclusion 134
References 135
Bortezomib in Systemic Light-Chain Amyloidosis 138
1 Introduction 138
2 Prognostic Features of AL 139
3 Assessing Response in AL 141
4 Therapy of AL 143
4.1 High Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation 143
4.2 Melphalan and Dexamethasone 143
4.3 MDex vs. SCT 144
4.4 Thalidomide and Lenalidomide 144
5 Bortezomib for AL 146
6 Conclusion 148
References 148
Second-Generation Proteasome Inhibitors 152
1 Introduction: Bortezomib and Beyond 152
1.1 Inhibition of the 26S Proteasome 153
1.2 Preclinical Activity of Bortezomib 154
1.3 Clinical Activity of Bortezomib 156
1.4 Limitations of Bortezomib 156
2 Second-Generation Inhibitors of the 26S Proteasome 157
2.1 Mechanisms of Activity 157
2.2 Reversible vs. Irreversible Proteasome Inhibition 160
2.3 Activity of Second-Generation Proteasome Inhibitors in Preclinical Studies 161
2.3.1 Single-Agent Activity 161
2.3.2 Activity in Bortezomib-Resistant Cells 162
2.3.3 Enhanced Activity in Combination 162
2.4 Clinical Studies of Second-Generation Proteasome Inhibitors 164
3 Other Therapeutic Targets in the Ubiquitin-Proteasome System 166
3.1 The Ubiquitin-Proteasome System Upstream of the 20S Proteasome 166
3.2 MLN4924: Nedd8-Activating Enzyme Inhibitor 167
4 Conclusion 169
5 Notes Added in Proof - Novel Second-Generation Proteasome Inhibitors 170
References 171
Index 180