| Bortezomib in the Treatment of Multiple Myeloma | 3 |
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| 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 |
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