Myeloma Bone Disease (eBook)

Preface 6
Contents 8
Contributors 10
1 Clinical Presentation of Myeloma Bone Disease 12
1.1 Introduction 12
1.2 The Incidence of Bone Disease in Myeloma 14
1.3 Diagnosis of Myeloma Bone Disease 15
1.4 Pathogenesis of Myeloma Bone Disease 17
1.4.1 Bone Disease and Patient Prognosis 19
1.5 The Clinical and Economic Burden of Myeloma Bone Disease 20
1.6 Other Complications Associated with Skeletal Disease 21
1.7 Treatment of Myeloma Bone Disease 21
References 22
2 Imaging of Multiple Myeloma, Solitary Plasmacytoma, MGUS, and Other Plasma Cell Dyscrasias 25
2.1 Introduction 26
2.2 Overview of Imaging Correlates with Tumor Biology 27
2.3 Imaging of Multiple Myeloma 28
2.3.1 Role of the Metastatic Bone Survey (MBS) 28
2.3.2 Role of MRI 32
2.3.3 Staging of Multiple Myeloma 35
2.3.4 Role of 18 FDG PET or PET/CT 36
2.3.5 Brown Adipose Tissue 37
2.3.6 Role of 99m Tc-Sestamibi (MIBI) 39
2.3.7 Clinical Relevance of Imaging in MM and Related Diseases 41
2.3.7.1 Key Imaging Findings 41
2.3.7.2 Clinical Significance of Imaging Findings 49
2.3.7.3 Extramedullary Disease (EMD) 55
2.3.7.4 Detection of Infection 56
2.4 Imaging of Other Plasma Cell Dyscrasias 59
2.4.1 Monoclonal Gammopathy of Uncertain Significance (MGUS) 59
2.4.2 Solitary Plasmacytoma 60
2.4.3 Castleman's Disease 61
2.5 Waldenstrms Macroglobulinemia 63
2.6 Summary 64
References 67
3 Biochemical Markers of Bone Remodeling in Multiple Myeloma 73
3.1 Introduction 74
3.2 Markers of Bone Remodeling 75
3.3 Biochemistry of Bone Markers 77
3.3.1 Bone Resorption Markers 77
3.3.2 Bone Formation Markers 81
3.4 Markers of Bone Remodeling and Myeloma Bone Disease 82
3.5 Novel Markers of Bone Remodeling and Myeloma Bone Disease 89
3.6 The Effect of Novel Anti-myeloma Agents on Markers of Bone Remodeling 90
3.7 Conclusions 94
References 94
4 Radiation Therapy in Multiple Myeloma 100
4.1 Introduction 100
4.2 Considerations in the Radiation Therapy of Plasma Cell Malignancies 101
4.3 Considerations in Staging of Patients with Multiple Myeloma 102
4.4 Considerations in Use of Radiotherapy for Treatment of Multiple Myeloma 103
4.5 Considerations in Palliative Radiotherapy of Multiple Myeloma Patients 104
4.6 Total Body Irradiation and Bone Marrow Transplantation in Patients with Multiple Myeloma 105
4.7 Conclusions 106
References 106
5 Surgical Management of Bone Disease 110
5.1 Background 111
5.2 Clinical Presentations of Skeletal Damage in Patients with Multiple Myeloma 112
5.3 The Role of Surgery in the Management of Myeloma Bone Disease 113
5.4 Minimally Invasive Vertebral Augmentation 114
5.4.1 Vertebroplasty 114
5.4.2 Kyphoplasty 115
5.5 Practical Considerations 119
5.5.1 Indications 119
5.5.2 Methods 120
5.5.3 Diagnostic Workup 120
5.5.4 Timing of Vertebral Augmentation 121
5.5.5 Safety Considerations 121
5.6 Summary 122
References 123
6 Bisphosphonates in the Treatment of Myeloma Bone Disease 126
6.1 Introduction 127
6.2 Fracture Risk in MM 127
6.3 Bisphosphonates for the Treatment of Myeloma Bone Disease 128
6.3.1 Etidronate 128
6.3.2 Clodronate 130
6.3.3 Oral Pamidronate 130
6.3.4 Intravenous Pamidronate 131
6.3.5 Ibandronate 131
6.3.6 Zoledronic Acid 132
6.3.6.1 Phase I and II Trials 132
6.3.6.2 Phase III Trial: Zoledronic Acid vs. Pamidronate 133
6.4 Bisphosphonates for MGUS Patients 133
6.5 Bisphosphonates: Side Effects 134
6.5.1 Renal Issues 134
6.5.2 Osteonecrosis of the Jaw 135
6.6 Guidelines for the Use of Bisphosphonates in Multiple Myeloma 135
6.7 Antimyeloma Effects of Bisphosphonates 137
6.8 Conclusions 138
References 138
7 Osteonecrosis of the Jaw 142
7.1 Introduction 142
7.2 Clinical Presentation of ONJ 143
7.3 Incidence and Risk Factors of Osteonecrosis of the Jaw 145
7.4 Natural History of ONJ in MM Patients 146
7.5 Imaging Studies of ONJ 147
7.6 Pathogenesis of Bisphosphonate-Related Osteonecrosis of the Jaw 148
7.7 Therapeutic and Prevention Strategies 153
7.8 Summary 154
References 155
8 Murine Models of Myeloma Bone Disease: The Importance of Choice 159
8.1 Introduction 159
8.2 Models of Multiple Myeloma Bone Disease 160
8.2.1 The 5TMM Syngeneic Models of Multiple Myeloma 161
8.2.1.1 The 5T2MM Model 161
8.2.1.2 The 5T33MM Model 162
8.2.1.3 The 5TGM1 Model 163
8.2.2 The SCID Mouse Models of Multiple Myeloma 164
8.2.2.1 The SCID/Human Cell Line Models 164
8.2.2.2 The SCID/Primary Human Cell Models 165
8.2.2.3 The SCID-hu Model 166
8.3 The Importance of the Bone Marrow Microenvironment 167
8.4 The Importance of Selecting Appropriate Models 170
8.5 Conclusions 172
References 173
9 RANK Ligand Is a Therapeutic Target in Multiple Myeloma 177
9.1 Introduction 178
9.1.1 Myeloma-Associated Bone Disease 178
9.2 Preclinical Aspects 179
9.2.1 Osteoclastogenesis Is Regulated by RANK/RANKL/OPG Proteins 179
9.2.2 Expression of RANKL and OPG in Multiple Myeloma 180
9.2.3 Pharmacological Effect of RANKL Inhibition in Preclinical Models of Myeloma 181
9.3 Clinical Correlations of RANKL, OPG, and Myeloma Disease 182
9.3.1 RANKL Inhibition as Treatment of Myeloma Bone Disease 183
9.3.2 Phase 1 Study on Pharmacodynamics of Denosumab in Multiple Myeloma Subjects 183
9.3.3 Phase 2 Studies in Multiple Myeloma Subjects 184
9.3.4 Denosumab in Multiple Myeloma and Other Advanced Cancer Patients Previously Receiving IV BPs 184
9.3.5 Denosumab as Anti-myeloma Therapy in Treating Patients with Advanced Multiple Myeloma 185
9.3.6 Phase 3 Studies on Bone Metastasis-Related Complications 185
9.4 Conclusion 186
References 186
10 Osteoclast Activation in Multiple Myeloma 190
10.1 Introduction 190
10.2 Bone Marrow Niche in Multiple Myeloma 191
10.3 Mechanisms of Osteoclast Activation 193
10.3.1 Osteoclastogenesis 193
10.3.2 RANKL/OPG Ratio in MM 195
10.3.3 CCL3/CCR1 Pathway in MM 195
10.3.4 Other OC-Activating Factors in MM 196
10.3.5 MM-Induced OC Differentiation via BMSC and OB 196
10.4 Targeting Osteoclasts in Multiple Myeloma Bone Disease 196
10.4.1 Bisphosphonates 197
10.4.2 Denosumab 198
10.4.3 MLN3897 198
10.4.4 BAFF Neutralizing Antibody 198
10.4.5 RAP-011 199
10.4.6 DKK1 Antagonists 199
10.4.7 Thalidomide Analogues 199
10.4.8 Bortezomib 200
10.4.9 Signaling Pathways Inhibitors 200
10.5 Future Perspectives 200
References 201
11 Potential Role of IMiDs and Other Agents as Therapy for Myeloma Bone Disease 206
11.1 Introduction 206
11.2 Effects of IMiDs on OCLs 207
11.3 Inhibition of OCL Activity by Targeting Nuclear Factor-B (NF-B) Signaling 209
11.4 Targeting RANKL for Inhibition of OCL Activity 211
11.5 Targeting MIP-1 for Inhibition of OCL Activity 212
11.6 Targeting Signaling Pathways Relevant for OCL Activity and OCL Formation 212
11.6.1 Targeting ERK Signaling 212
11.7 Conclusions 213
References 214
12 Proteasome Inhibitors and the Wnt Signaling Pathway in Myeloma Bone Disease 217
12.1 Introduction 217
12.2 Targeting the Ubiquitin Proteasome System in Multiple Myeloma 218
12.3 Proteasome Inhibition in Myeloma Bone Disease 220
12.3.1 Preclinical Studies 220
12.3.2 Clinical Studies 222
12.4 Wnt Signaling Pathway in Bone Biology 225
12.5 Wnt Signaling in Myeloma Bone Disease 226
12.5.1 Dkk1 Expression 226
12.5.2 Mechanism of Action of Dkk1 in Multiple Myeloma 228
12.5.3 Wnt Signaling in Myeloma Cells 229
12.5.4 Targeting the Wnt Signaling Pathway in Myeloma Bone Disease 230
12.6 Conclusions 231
References 232
13 Mechanisms Involved in Osteoblast Suppression in Multiple Myeloma 236
13.1 Introduction 236
13.2 Osteoblast Formation: Role of Runx2 and Wnt Pathways 237
13.3 MM-Induced Suppression of Osteoblast Formation by Inhibiting Runx2 Pathway: Role of Cell-to-Cell Contact and Soluble Factors 239
13.4 Role of IL-3 in the Inhibition of Osteoblasts Formation by MM Cells 241
13.5 Role of Wnt Inhibitors in MM-Induced Osteoblast Suppression 241
13.6 Effect of MM Cells on Osteoblast Proliferation and Survival 243
13.7 Conclusions 243
References 244
Index 248

"Chapter 10 Osteoclast Activation in Multiple Myeloma (p. 183-184)

Sonia Vallet and Noopur Raje

Abstract Osteolytic bone disease affects more than 80% of multiple myeloma (MM) patients with a negative impact on both quality of life and overall survival. The pathogenesis of osteolytic disease resides in increased osteoclast (OC) activation along with osteoblast (OB) inhibition resulting in altered bone remodeling. OC number and activity in MM are enhanced mainly via cytokine deregulation within the bone marrow (BM) milieu and an imbalance of the OC/OB axis. Several novel agents are currently under investigation for their positive effect on bone remodeling via OC inhibition or OB activation. In addition to restoring bone remodeling, these drugs may inhibit tumor growth in vivo. Therefore, targeting bone disease is a promising therapeutic strategy not only with the goal of alleviating morbidity from bone disease but also resultant anti-tumor activity.

Keywords Osteolysis · MM niche · Osteoclast activation · Osteoblasts

10.1 Introduction

Osteolytic lesions are a pathognomonic feature of multiple myeloma (MM). More than 80% of MM patients develop osteolytic bone disease (OBD), frequently complicated by skeletal-related events (SRE) such as severe bone pain, vertebral compression fractures, and pathologic fractures resulting in a need for radiation or surgical fixation. Importantly, pathologic fractures affect 40–50% of MM patients increasing the risk of death by more than 20% compared to the patients without fractures [1, 2].

Therefore, OBD reduces not only patients’ quality of life but also survival. The pathogenesis of OBD in MM is primarily associated with generalized osteoclast (OC) activation. Bone marrow (BM) biopsies from MM patients show a correlation between tumor burden, OC number, and resorption surface [3, 4]. Although enhanced OC function is a key player in the development of OBD, a decrease in trabecular thickness and low calcification rate in BM biopsy specimens ofMMpatients with osteolysis suggest that osteoblast (OB) activity is also impaired [5].

Therefore, the bone remodeling balance in MM is disrupted by a deregulation of the OC/OB axis. Several novel agents are aimed at restoring bone homeostasis targeting either OC or OB activity. Interestingly, inhibition of osteolysis leads to reduced tumor growth in vivo [6, 7]. Therefore, novel agents targeting bone disease are promising therapeutic strategies for the treatment of MM. Optimal drug development requires further clarification of the pathogenesis of osteolysis as well as understanding the role of the microenvironment in the progression of myeloma."