Stakeholder Opinions Multiple Myeloma Exploring new targets for multiple drug therapy

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the multiple myeloma market 3
Related reports 4
Upcoming reports 4
CHAPTER 2 MULTIPLE MYELOMA OVERVIEW 6
Introduction 6
The underlying biology of multiple myeloma 6
Genetic abnormalities are characteristic of multiple myeloma cells 8
Multiple myeloma cells interact with the bone marrow environment to trigger molecular events 9
Diagnosis, classification and staging of multiple myeloma 10
Diagnosis and clinical manifestations of MM 10
Clinical features arise through the infiltration of malignant cells in the bone marrow 11
Disease classification 12
Monoclonal gammopathy of undetermined significance 12
Smoldering myeloma 13
Symptomatic disease 13
The International Staging System improves disease assessment 13
Risk factors 15
Age, gender and race 15
Epidemiology 16
Crude incidence of multiple myeloma 16
Forecast incidence of multiple myeloma to 2016 16
Incidence of multiple myeloma by country in 2007 17
Poor survival rates for multiple myeloma patients 18
Multiple myeloma is a disease of old age 19
CHAPTER 3 CURRENT MULTIPLE MYELOMA TREATMENT OPTIONS 20
Multiple myeloma treatment overview 20
Conventional therapies 22
Melphalan and prednisone 22
Dexamethasone 23
VAD and DVD regimens 23
Novel therapies 23
Thalomid (thalidomide) 24
Thalomid and dexamethasone 24
Thalomid and melphalan/prednisone 25
Revlimid (lenalidomide) 26
Revlimid and dexamethasone 27
Revlimid and melphalan/prednisone 31
Ongoing clinical trials 31
Velcade (bortezomib) 32
Velcade and Doxil 33
Velcade versus dexamethasone in relapsed/refractory MM patients 35
Velcade, melphalan/prednisone and Thalomid in relapsed patients 36
Ongoing clinical trials 36
First-line Velcade approval is likely 37
Stem cell transplantation 40
Maintenance therapy 41
Treatment of relapsed/refractory disease 42
Supportive care 43
CHAPTER 4 UNMET NEEDS 45
Multiple myeloma remains largely incurable 45
Optimal sequencing of drugs across different lines of therapy remains undetermined 45
Drugs with lower toxicities required for use in all MM patients 46
More novel therapies required for relapsed MM 48
Summary of unmet needs 49
CHAPTER 5 PIPELINE ANALYSIS 51
Multiple myeloma pipeline overview 51
Phase III product pipeline for multiple myeloma 51
Phase II product pipeline for multiple myeloma 51
Phase I product pipeline for multiple myeloma 54
Phase III drug profiles 55
Panobinostat (Novartis) 55
Key historical events 56
Clinical trials 57
Datamonitor comments 59
Tanespimycin (Kosan Biosciences) 60
Key historical events 60
Clinical trial data 61
Datamonitor comments 62
Key Phase II drug profiles 63
Actimid (pomalidomide, Celgene) 63
Key historical events 63
Clinical trials 64
Datamonitor comments 65
Alvocidib (flavopiridol, Sanofi-Aventis) 65
Key historical events 66
Clinical trials 66
Datamonitor comments 69
Denosumab (Amgen) 69
Key historical events 70
Clinical trials 70
Datamonitor comments 71
Romidepsin (Gloucester Pharmaceuticals/Astellas) 71
Key historical events 72
Clinical trials 72
Datamonitor comments 73
Torisel (temsirolimus, Wyeth) 73
Key historical events 74
Clinical trials 74
Datamonitor comments 75
VEGF inhibitors in Phase II development 75
Aplidin (plitidepsin, PharmaMar) 76
Aflibercept (VEGF Trap, Regeneron/Sanofi-Aventis) 76
Avastin (bevacizumab; Genentech/Roche) 77
Nexavar (sorafenib, Bayer/Onyx Pharmaceuticals) 78
Clinical development of VEGF inhibitors 79
Datamonitor comments 81
APPENDIX A 82
Bibliography 82
Journals 82
Websites 89
Other 91
Key opinion leaders interviewed 93
Abbreviations 94
List of tables 96
List of figures 97
About Datamonitor 98
About Datamonitor Healthcare 98
About the Oncology analysis team 99
Disclaimer 99
List of Tables
Table 1: Clinical features of MM 11
Table 2: Disease classification of MM 12
Table 3: The International Staging System for MM 14
Table 4: The Durie-Salmon staging system for MM 14
Table 5: Crude incidence rates (per 100,000) of MM, 2002 16
Table 6: Forecast incidence of MM, 2002-16 16
Table 7: Drugs approved for use in MM 22
Table 8: Phase III trial results for Thalomid combined with dexamethasone in patients with newly diagnosed MM 24
Table 9: Phase III trials of Thalomid and MP in elderly patients with MM 26
Table 10: Phase I/II study results of Revlimid and melphalan/prednisone therapy in newly diagnosed MM patients 31
Table 11: Ongoing Phase III trials for Revlimid therapy in MM 32
Table 12: Approved indications for Velcade in MM 33
Table 13: Phase I/II trials results of Velcade, melphalan/prednisone and Thalomid combined therapy in relapsed/refractory MM patients 36
Table 14: Ongoing Phase III trials for Velcade therapy in MM 37
Table 15: Supportive care therapies in MM 43
Table 16: MM treatment toxicities 46
Table 17: Pipeline drugs in Phase III development for multiple myeloma, 2007 51
Table 18: Pipeline drugs in Phase II development for multiple myeloma, 2007 52
Table 19: Pipeline drugs in Phase I development for multiple myeloma, 2007 54
Table 20: Panobinostat: key historical events 57
Table 21: Ongoing clinical trials for panobinostat in MM, 2007 58
Table 22: Tanespimycin: key historical events 60
Table 23: Ongoing clinical trials for tanespimycin in MM, 2007 61
Table 24: Phase I trial results for tanespimycin and Velcade in relapsed MM patients 61
Table 25: Actimid: key historical events 64
Table 26: Ongoing Phase II trial for Actimid in MM, 2007 64
Table 27: Phase I/II trial results for Actimid in MM 65
Table 28: Alvocidib: key historical events 66
Table 29: Ongoing clinical trials for alvocidib in MM, 2007 67
Table 30: Denosumab: key historical events 70
Table 31: Ongoing Phase II trial for denosumab in MM, 2007 71
Table 32: Romidepsin: key historical events 72
Table 33: Ongoing clinical trials for romidepsin in MM, 2007 72
Table 34: Torisel: key historical events 74
Table 35: Ongoing clinical trials for Torisel in MM, 2007 74
Table 36: Aplidin: key historical events 76
Table 37: Aflibercept: key historical events 77
Table 38: Avastin: key historical events 78
Table 39: Nexavar: key historical events 79
Table 40: Ongoing clinical trials for VEGF inhibitors in MM, 2007 79
Table 41: Abbreviations used in Stakeholder Opinions: Multiple Myeloma, 2007 94
List of Figures
Figure 1: B-cells develop into antibody-producing plasma cells 7
Figure 2: The formation of malignant plasma cells in MM 8
Figure 3: Inducible molecular events triggered by the interaction of MM cells and bone marrow milieu 9
Figure 4: MM incidence forecast, 2007-16 17
Figure 5: Incidence of MM in the seven major pharmaceutical markets, 2007 17
Figure 6: Survival rates over 10 years for MM patients in the US 18
Figure 7: Incidence rates (per 100,000) of MM according to age in the US 19
Figure 8: Treatment of newly diagnosed MM 21
Figure 9: Two Phase III trials of Revlimid therapy in patients with relapsed/refractory MM 28
Figure 10: Phase III trial results of Revlimid and dexamethasone in newly diagnosed MM patients 29
Figure 11: Phase III trial results for Revlimid and low dose versus high dose dexamethasone in newly diagnosed MM patients 30
Figure 12: Phase III trials results of second-line Doxil plus Velcade therapy in patients with relapsed/refractory MM 34
Figure 13: APEX study-randomized Phase III trial of Velcade therapy in patients with relapsed MM 35
Figure 14: Preliminary Phase III trial results for Velcade, Thalomid and dexamethasone in MM patients undergoing ASCT 39
Figure 15: Characteristics of MM disease progression 42
Figure 16: The MM product development pipeline 48
Figure 17: Summary of unmet needs in MM 50
Figure 18: Multiple mechanisms of HDAC inhibitors in tumor cells 56
Figure 19: Phase II trial results for alvocidib in relapsed/refractory MM patients 68