Personalized Therapy for Multiple Myeloma

This book provides the clinician with concise, practical guidance on risk stratification and therapeutic decision making in patients with multiple myeloma. In addition, the available clinical trial and research data are summarized into meaningful reviews and evidence-based recommendations for treatment are presented. The coverage encompasses all phases and forms of disease, including high-risk myeloma. Over recent decades, greater understanding of the biology of myeloma has fostered the development of new, more effective drugs, leading to remarkable improvements in survival. To continue this momentum, several recent prospective trials have aimed to identify further potential therapeutic targets or to evaluate various combinations of anti-myeloma agents. The increasing abundance of management options makes the decision making complex in different phases of the disease. This book will offer the clinician valuable assistance in the choice and sequencing of therapies, highlighting the need for a personalized approach that reflects the growing recognition that myeloma is not one uniform disease. Preface 6 Contents 8 1: Risk Stratification in Newly Diagnosed Smoldering Multiple Myeloma 9 1.1 Introduction 9 1.2 Differential Diagnosis with Other Entities 10 1.3 Are There Risk Models Predicting the Progression Risk to MM? 12 1.3.1 Size of Serum M-Protein and the Extent of Marrow Involvement 12 1.3.2 Serum Free Light Chain Ratio 12 1.3.3 Immunophenotyping and Immunoparesis 13 1.3.4 Peripheral Blood Circulating Plasma Cells 14 1.3.5 Pattern of Serum M-Component Evolution 14 1.3.6 Bence Jones Proteinuria 14 1.3.7 Novel Imaging Assessments 15 1.3.8 Cytogenetic Abnormalities 15 1.4 Stratification and Management of SMM Patients 16 1.5 Conclusion and Future Directions 18 References 19 2: Risk Stratification in Newly Diagnosed Transplant-Eligible Multiple Myeloma 22 2.1 Introduction 22 2.2 Why Is Risk Stratification Important? 23 2.3 What Markers Determine the Risk? 23 2.4 What Is the Value of Combined Prognostic Models? 27 2.5 Does Depth of Treatment Response Affect Risk Stratification? 31 2.6 What About Imaging-Based Response for Risk Stratification? 32 2.7 Do Novel Therapeutics Ameliorate Adverse Impact of High-Risk Cytogenetics? 33 2.7.1 Impact of Proteasome Inhibitors 33 2.7.2 Impact of Immunomodulatory Agents 35 2.8 How Do We Prioritize Treatment for Transplant-Eligible Newly Diagnosed MM According to the Risk Category? 36 2.9 Summary and Conclusions 39 References 40 3: Risk Stratification in Newly Diagnosed Transplant Ineligible Multiple Myeloma 44 3.1 Introduction 44 3.2 Therapy Overview in Elderly MM Patients 45 3.2.1 Randomized Phase III Studies 45 3.2.2 Phase II Studies 46 3.2.3 Doublet Vs. Triplet Therapies 48 3.2.4 Adapted Therapies in Older Patients 49 3.3 Stratification by Disease-Related Characteristics 49 3.3.1 Cytogenetic Abnormalities 50 3.3.2 Combined International Staging System and FISH/Gene-­Expression Profiling Classifiers 52 3.3.3 Flow Cytometric Markers 53 3.4 Response to Treatments and Minimal Residual Disease 54 3.5 Stratification by Host Factors 55 References 61 4: Treatment of t(4;14) and del(17p) in Multiple Myeloma 66 4.1 Introduction 66 4.2 Diagnostic Procedures to Detect t(4;14) and del(17p) 67 4.2.1 Conventional Karyotyping 67 4.2.2 Fluorescence In Situ Hybridization (FISH) 67 4.2.3 Single-Nucleotide Polymorphisms (SNP)-Based Mapping Arrays 67 4.2.4 Comparative Genomic Hybridization (CGH) 67 4.2.5 Gene Expression Profiling (GEP) 68 4.3 High-Risk CA 68 4.3.1 IgH Translocations: t(4;14) 68 4.3.2 Genomic Imbalance: del(17p) and Other Deletions or Additions 69 4.3.3 Multiple Adverse CA 69 4.3.4 Good Combined with Adverse CA 70 4.4 Cytogenetic Risk Classifications 70 4.4.1 Risk Classifications Based on FISH 70 4.4.2 Risk Classifications Based on FISH and ISS 71 4.4.3 Risk Classifications Based on FISH, ISS, and LDH 71 4.4.4 Gene Expression Profiling (GEP) 71 4.4.5 mSMART 72 4.5 Treatment Options with Novel Agents for High-Risk Disease Characterized by t(4;14) and/or del(17p) 72 4.5.1 Thalidomide 72 4.5.2 Bortezomib 73 4.5.3 Novel IMiDs: Lenalidomide and Pomalidomide 74 4.5.4 Combined Proteasome Inhibition and Lenalidomide 74 4.5.5 High-Dose Therapy and ASCT 75 4.5.6 Allogeneic Stem Cell Transplantation 75 References 78 5: Treatment of Patients in First or Second Relapse 84 5.1 Introduction 84 5.2 Definitions of Relapse 84 5.3 Timing of Treatment 86 5.4 Immunomodulatory Drugs 86 5.4.1 Lenalidomide 86 5.4.2 Pomalidomide 88 5.5 Proteasome Inhibitors 89 5.5.1 Bortezomib 89 5.5.2 Carfilzomib 90 5.5.2.1 ENDEAVOR 91 5.5.2.2 Weekly Carfilzomib 91 5.5.3 Ixazomib 92 5.5.3.1 TOURMALINE-MM1 92 5.5.4 Proteasome Inhibitors Under Development 93 5.6 HDAC Inhibitors 93 5.6.1 PANORAMA 1 93 5.6.2 HDAC Inhibitors Under Development 94 5.7 Combinations of Immunomodulatory Drugs and Proteasome Inhibitors 95 5.7.1 Lenalidomide, Bortezomib, and Dexamethasone (RVD) 95 5.7.2 Carfilzomib, Lenalidomide, and Dexamethasone (KRd-ASPIRE Trial) 95 5.7.3 Carfilzomib, Pomalidomide, and Dexamethasone (KPd) 96 5.7.4 Pomalidomide, Bortezomib, and Dexamethasone (PVD) 96 5.7.5 Pomalidomide, Ixazomib, and Dexamethasone 97 5.8 Elotuzumab 97 5.8.1 ELOQUENT-2 98 5.9 Daratumumab 98 5.9.1 Combinations with Cyclophosphamide 99 5.9.1.1 Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) 99 5.9.1.2 Carfilzomib, Cyclophosphamide, and Dexamethasone (CCyD) 99 5.10 Salvage Infusional Regimens 100 5.10.1 Salvage Autologous Stem Cell Transplant 100 5.10.2 Allogeneic Stem Cell Transplant 101 5.11 Choice of Treatment 101 5.11.1 Retreatment 102 References 103 6: Treatment of Patients in Third Relapse and Beyond Including Double-­Refractory Disease 110 6.1 Introduction 110 6.2 Factors Affecting Selection of Therapy 112 6.2.1 Biochemical Versus Symptomatic Relapse 112 6.2.2 Patient Comorbidities 112 6.2.3 Prior Drug Exposures 112 6.2.4 Genomics 113 6.3 Currently Available Drug Classes 113 6.3.1 Carfilzomib 113 6.3.2 Ixazomib 114 6.3.3 Panobinostat 114 6.3.4 Pomalidomide 115 6.3.5 Salvage ASCT 115 6.4 Novel Drug Classes 116 6.4.1 Proteasome Inhibitor 116 6.4.2 HDAC6 Inhibitor 117 6.4.3 Cell Cycle Inhibitor 117 6.4.4 Apoptosis Inducer 117 6.4.5 Protein Kinase Inhibitors 118 6.5 Immunologic Approaches 119 6.5.1 Monoclonal Antibodies 119 6.5.2 Tumor Vaccination and Oncolytic Viruses 120 6.5.3 Allogeneic Stem Cell Transplant 121 6.5.4 Immune Modulators 121 References 122 7: Plasma Cell Leukemia 128 7.1 Introduction 128 7.2 Prognosis 129 7.3 Clinical Presentation 129 7.4 Diagnostic Evaluation for PCL 130 7.5 Therapeutic Options for PCL 130 References 135 8: Practical Considerations for Bone Health in Multiple Myeloma 137 8.1 Introduction 137 8.2 Pathophysiology of Multiple Myeloma Bone Disease 138 8.3 Imaging for the Diagnosis of Multiple Myeloma Bone Disease 138 8.4 Whole-Body X-rays (WBXR) 139 8.5 Whole-Body Low-Dose CT (WBLDCT) 139 8.6 Magnetic Resonance Imaging 140 8.7 PET-CT 146 8.8 Management of Multiple Myeloma Bone Disease 148 8.8.1 Etidronate 149 8.8.2 Ibandronate 149 8.8.3 Clodronate 149 8.8.4 Pamidronate 150 8.8.5 Zoledronic Acid (ZOL) 150 8.8.6 Adverse Events 152 8.9 Future Treatment Options 154 8.9.1 RANKL/RANK Pathway Regulators: Targeting the Osteoclast 154 8.9.2 Activin-A Inhibitors 156 8.10 Future Agents Targeting the Osteoclast 157 8.11 Wnt Pathway Regulators: Helping the Osteoblast 158 8.12 Antimyeloma Agents 158 8.12.1 Bortezomib 158 8.13 Immunomodulatory Agents 159 8.14 Other Novel Agents 160 8.15 Kyphoplasty and Vertebroplasty 160 8.16 Radiation Therapy 161 8.17 Surgery 161 References 162 9: Personalizing MM Treatment: Gaps in Current Knowledge 174 9.1 Introduction 174 9.2 Disease Heterogeneity 174 9.2.1 Challenges to Individualizing Therapy in MM 180 References 181 Front Matter ....Pages i-ix Risk Stratification in Newly Diagnosed Smoldering Multiple Myeloma (María-Victoria Mateos, Jesús San-Miguel)....Pages 1-13 Risk Stratification in Newly Diagnosed Transplant-Eligible Multiple Myeloma (Megan H. Jagosky, Alankrita Taneja, Manisha Bhutani)....Pages 15-36 Risk Stratification in Newly Diagnosed Transplant Ineligible Multiple Myeloma (Massimo Offidani, Laura Corvatta, Silvia Gentili, Elena Aghemo, Antonio Palumbo, Laura Maracci et al.)....Pages 37-58 Treatment of t(4;14) and del(17p) in Multiple Myeloma (Pieter Sonneveld)....Pages 59-76 Treatment of Patients in First or Second Relapse (Andrew J. Yee, Noopur S. Raje)....Pages 77-102 Treatment of Patients in Third Relapse and Beyond Including Double-Refractory Disease (Douglas Tremblay, Siyang Leng, Ajai Chari)....Pages 103-120 Plasma Cell Leukemia (Nisha S. Joseph, Amarendra K. Neppalli, Ajay K. Nooka)....Pages 121-129 Practical Considerations for Bone Health in Multiple Myeloma (Evangelos Terpos, Nikolaos Kanellias)....Pages 131-167 Personalizing MM Treatment: Gaps in Current Knowledge (Shaji Kumar)....Pages 169-178 This book provides the clinician with concise, practical guidance on risk stratification and therapeutic decision making in patients with multiple myeloma. In addition, the available clinical trial and research data are summarized into meaningful reviews and evidence-based recommendations for treatment are presented. The coverage encompasses all phases and forms of disease, including high-risk myeloma. Over recent decades, greater understanding of the biology of myeloma has fostered the development of new, more effective drugs, leading to remarkable improvements in survival. To continue this momentum, several recent prospective trials have aimed to identify further potential therapeutic targets or to evaluate various combinations of anti-myeloma agents. The increasing abundance of management options makes treatment decision making in different phases of disease. This book will offer the clinician valuable assistance in the choice and sequencing of therapies, highlighting the need for a personalized approach that reflects the growing recognition that myeloma is not one uniform disease.