This book presents paraproteinemia and the highly complex scientific information behind it to clinicians in a way they can understand and, ultimately, apply to their diagnostic and treatment practices. Paraproteinemia or dysproteinemia is characterized by the overproduction of an immunoglobulin by clonal expansion of cells from the B cells lineage which includes the plasma cells. The resultant monoclonal protein can be composed of the entire immunoglobulin or of its components. The identification and categorization of the different representatives of this group of disorders have traveled a long distance, but despite its high prevalence there is surprisingly limited evidence, in some areas, to guide the best clinical practice both at the time of diagnosis and during follow up. This book seeks to fill that gap.
The book is divided into three sections, introductory chapters, disease entities and experimental therapies. The text guides clinicians through these diseases and disorders. The group of renal diseases attributed to deposition of monoclonal immunoglobulins or their components are arranged as one disease category in order to simplify the understanding of these complicated diseases in plasma cell dysplasia. In emulation of this practical approach, at a larger scale, the volume editors and chapter authors attempt to encompass the whole spectrum of the paraproteinemias in this text. This will have the dual benefit of offering the audience a panoramic view of this group of disorders and simultaneously keeping them focused on its individual representatives. There have been many recent advances in diagnosis, risk stratifications, and management of many members of this group of diseases and they are explored in depth here.
This is an ideal guide for rheumatologists, hematologists, nephrologists, immunologists, oncologists, and relevant trainees caring for patients with paraproteinemia and related disorders.
Author(s): Gaafar Ragab, Luca Quartuccio, Hadi Goubran
Publisher: Springer
Year: 2022
Language: English
Pages: 397
City: Cham
Foreword
Preface
Contents
Contributors
Part I: Introductory Chapters
Chapter 1: The Phenomenon of Paraproteinemia
Introduction
Approaching Paraproteinemia
Definitions
Phenomenon
Proteins, Paraproteins, and Paraproteinemias
Disease and Disorder
The Nature of the Problem
The Structure of this Book
Conclusion
References
Chapter 2: B Cell in Health and Disease
Introduction
B-Cell Development
B Cells and Autoimmunity
B Cell and Immunodeficiency
B Cell and Malignancies
Conclusions
References
Chapter 3: Immunoglobulins, Structure, and Function
History
ImmunoglobulIns Structure
Immunoglobulins Function
Conclusion
References
Chapter 4: The Bone Marrow as a Hotbed for Plasma Cell Activation
Introduction
The Bone Marrow as a “Hotbed” for Plasma Cells in Health. The LLPC Niche
Cellular Components of the LLPC Niche. Attracting and Maintaining the LLPCs
Intrinsic Cellular Requirements for Longevity. The LLPC Niche Reshapes the PC Bioenergetic Profile
The LLPC Niche in Disease
The LLPC Niche in Infection/Vaccination
The LLPC Niche in Antibody-Mediated Autoimmune Diseases
The LLPC Niche in PC Malignancies. MM and MGUS (Fig. 4.4)
Conclusion
References
Chapter 5: Animal Models in Monoclonal Immunoglobulin-Related Diseases
Introduction
Animal Models Investigating Specific Paraproteinemias
The MM Family of Disease Entities (Including Lymphoplasmacytic Lymphoma, Plasmacytoma, Primary Light Chain Amyloidosis and Non-proliferative Monoclonal Gammopathy)
Induced Models
Cell Transplantation Models
“Modified” SCID Models
Transgenic Models
B-Cell NHL
Cell Transplantation Models
Transgenic Models
Models for the Pathologies Resulting from the Paraproteinemias
Models of Diseases Caused by Deposition of Single Ig Chains
Purified Human Ig Light Chain Injection Models
Transgenic Models
Hybridoma Cells Engineered to Secrete Ig Fragments
Direct Plasma Cell Engineering
LMP2A Transgenic Models
Monoclonal Light Chain-Induced Proximal Tubulopathy
AL and Related Diseases
Randall-Type Monoclonal Immunoglobulin Deposition Disease (MIDD)
Myeloma Cast Nephropathy (MCN) Models
MGUS/MGRS
Models of Disorders Involving Deposition of Complete Monoclonal Ig Molecules (Two Heavy Chains and Two Light Chains)
Murine Ig3 Hybridoma Model
Immunotactoid Glomerulopathy
Proliferative Glomerulonephritis with Monoclonal Ig Deposits
Conclusions
References
Chapter 6: An Approach to the Diagnosis of Paraproteinemia
Introduction
When to Suspect the Presence of Monoclonal Gammopathy
Clusters of Clinical Symptoms that Can Provide Clues to MG Diagnosis
Fundoscopic Examination May Detect the Following
Imaging Findings that Can Help to Suspect Paraproteinemia
Laboratory Findings that Raise Suspicion of MG if Unexplained by Other Causes [26–28]
Proceed Further Towards Establishing Complete Diagnosis
Imaging for a Suspected Case with Paraproteinemia
Laboratory Evaluation of Suspected Paraproteinemia
Complete Blood Count (CBC) and Blood Smear
Blood Chemistry Tests
Protein Electrophoresis and Immunofixation
Mass Spectrometry-Based Methods
Serum Free Light Chain Ratio
Heavy/Light Chain Immunoassay
Quantitative Total Immunoglobulin Testing
Western Blot Analysis
Serum Viscosity
Serum β2M and LDH Levels
Bone Marrow Examination
Flow Cytometry
Cytogenetic Analysis and Risk Stratification
Tissue Biopsy and Histopathological Examination
Other Modalities
Conclusion
References
Part II: Diseases and Disorders
Chapter 7: Amyloidosis: Pathogenesis, Types, and Diagnosis
Introduction
Pathogenesis
Amyloid Protein Nomenclature and Classification
Epidemiology
Diagnosis
References
Chapter 8: Amyloidosis: Clinical Manifestations and Treatment
Introduction
Clinical Presentation
Systemic Amyloidosis
Localized Amyloidosis
Diagnosis
Treatment
Conclusions
References
Chapter 9: Primary Light Chain (AL) Amyloidosis
Introduction
Diagnosis
Staging and Risk Assessment
Response Assessment
Management
Direct Anti-Amyloid Therapies
Supportive Care
Conclusions
References
Chapter 10: Monoclonal Immunoglobulin Deposition Disease
Introduction
Pathology
Light Microscopy
Immunofluorescence
Electron Microscopy
Other Patterns of Glomerulonephritis Associated with Monoclonal IgG Deposits and Monoclonal Gammopathy of Unknown Significance
Extrarenal Histology
Clinical Presentation and Diagnosis
Renal Involvement
MIDD and Hematological Malignancies
Diagnosis
Extrarenal Involvement
Liver
Heart
Neuropathy
Lungs
Other Localizations
Natural History and Prognosis
Treatment
Conclusions
References
Chapter 11: Multiple Myeloma
Introduction
History of Myeloma
Epidemiology
Predisposing Factors
MGUS-SMM-MM as a Disease Continuum
Smoldering Myeloma
Management of SMM
Risk Stratification Studies in SMM
Trials of Therapeutic Interventions in SMM
Clinical Presentation of Myeloma
Initial Workup
Risk Stratification Tools
Classification and Risk Stratification Based on Cytogenetics
Treatment and Goals of Care
When to Treat:
Available Systemic Myeloma-Directed Treatments
Treatment Algorithm
Therapeutic Approach at Diagnosis
Therapeutic Approach for Relapsed and Refractory Myeloma
Role of Radiation Therapy
Role of Surgical Interventions
Response Evaluation
Myeloma Survivorship
Conclusions
References
Chapter 12: Monoclonal Gammopathy of Undetermined Significance (MGUS) and Highlight on Monoclonal Gammopathy of Neurological Significance (MGNS)
Introduction and Classification
Prevalence
Racial/Ethnic Differences in Prevalence
Age and Sex
Immunoglobulins
Associations
Risk Stratification and Progression
Risk Stratification
IgM MGUS
Non-IgM MGUS
Light Chain MGUS
Monoclonal Gammopathy of Renal Significance (MGRS)
Monoclonal Gammopathy of Neurological Significance (MGNS)
Comparison Between the Progression of Different Subclasses
Diagnosis
Laboratory Assessment (Table 12.1 Illustrates the Routine Testing for all MGUS Patients)
Bone Marrow Examination
Imaging
Monitoring
Conclusions
References
Chapter 13: Monoclonal Gammopathy of Renal Significance: An Insight
Introduction
Background
Epidemiology
Classification of MGRS
Clinical Presentation
Progression
Evaluation of Suspected MGRS
Treatment of MGRS
Renal and Supportive Care
Clone-Directed Therapy
MGRS with Plasma Cell Dyscrasia with IgG, IgA, or FLCs Only Clone
MGRS with B-Cell Clone with IgM M-Paraprotein
Conclusions
References
Chapter 14: Waldenström Macroglobulinemia
Epidemiology
Etiology
Pathophysiology
Clinical Presentation
History
Physical Examination
Complications
Diagnosis
Differential Diagnosis
Prognosis
When to Treat WM?
How to Treat WM?
Treatment of Hyperviscosity
Definitive First-Line Therapy
Role of Stem Cell Transplant in WM
Response Criteria
Treatment of Relapsed WM
Conclusion
References
Chapter 15: IgG4-Related Disease Overview: Pathology, Clinical Picture, and Treatment
Introduction
Clinical Picture
Presentation
Organs Affected
Damage
Disease Subsets
Pathology
Diagnostic Considerations
Treatment
Glucocorticoids
Conventional DMARDs
Biologic Agents
B-Cell-Depleting Strategies
Non-Depleting B-Cell Strategies
Approaches Targeting T Lymphocytes
Conclusions
References
Chapter 16: Type I Cryoglobulinemia
Introduction
Pathophysiology
Epidemiology
Manifestations
Skin Manifestations
Neurological Involvement
Kidney Involvement
Rheumatologic and Systemic Symptoms
Hyperviscosity Syndrome
Cryoglobulin Diagnosis
Cryoglobulin Identification
Indirect Diagnosis
Underlying Disease
Treatment and Prognosis
Conclusion
References
Chapter 17: Paraproteinemias Associated with Autoimmune Diseases
Introduction
Monoclonal Gammopathy and Autoimmune Diseases
Amyloidosis and Autoimmune Diseases
Serum Immunoglobulin-Free Light Chain Levels and Their Significance in Autoimmune Diseases
Conclusions
References
Chapter 18: Infections and Paraproteinemia
Introduction
Potential Infectious Triggers of Paraproteinemia
Bacterial Triggers of Paraproteinemia
Viral Triggers of Paraproteinemia
Fungal and Parasitic Triggers of Paraproteinemia
Multiple Myeloma
Infections Associated with MM
Treatment-Associated Infections in Multiple Myeloma
Clinical Management of Infections in Multiple Myeloma
Chemoprophylaxis and Vaccination in Patients with Multiple Myeloma
MGUS
Waldenström’s Macroglobulinemia
IgG4-Related Disease
Systemic Lupus Erythematosus
Cryoglobulinemia
Amyloidosis
Discussion and Conclusions
References
Chapter 19: Paraproteinemia in Autoinflammatory Diseases
Introduction
Paraproteinemia and Autoinflammatory Diseases
Schnitzler’s Syndrome
VEXAS Syndrome
POEMS Syndrome
Monoclonal Gammopathy, Arthralgias, and Recurrent Fever Syndrome
Mullins’ Syndrome
Conclusions
References
Chapter 20: Paraproteins Associated with Malignancy
Introduction
Available Data
Data from Case Reports
Data from Case Series
Confounding Factors
Counter Arguments
Summarizing Remarks
Conclusion
References
Chapter 21: Monoclonal Gammopathies with Miscellaneous Associations
Introduction
Monoclonal Gammopathies After Tissue Transplantation
Available Data
Summarizing Remarks
Primary Immunodeficiency
Cold Agglutinin Disease
Castleman Disease
POEMS Syndrome
Definition
Epidemiology
Clinical Picture
Pathology
Pathogenesis
Diagnosis
POEMS Syndrome Versus Other Paraproteinemias
Treatment
Gaucher Disease
TEMPI Syndrome
Erythema Elevatum Diutinum
Other Associations
Conclusion
References
Part III: Experimental Therapies
Chapter 22: Novel and Experimental Clone-Directed Therapies
Introduction
A-Plasma Cell Clone and Multiple Myeloma
Agents Targeting Aberrant Plasma Cells
Experimental Monoclonal Antibodies Against Cell Surface Antigens
Targeting CD 38
Targeting CD 138
B-Cell Maturation Antigen (BCMA)
Antibody-Drug Conjugates (ADCs)
Bispecific Antibodies and Bispecific T-Cell Engagers (BiTE)
Chimeric Antigen Receptor-T Cell (CAR T) Therapy
Idecabtagene Vicleucel (Ide-Cel)
Ciltacabtagene Autoleucel (Cilta-Cel, JNJ-4528)
Orvacabtagene Autoleucel (Orva-Cel, JCAR-H125)
Other CAR-T Cell Products
Targeting Intracellular Aminopeptidases
Inhibitor of Nuclear Cytoplasmic Transport Receptors: Exportin 1
Cereblon E3 Ligase Modulators (CELMoDs)
Bruton’s Tyrosine Kinase (BTK) Inhibitors
BCL-2 Inhibitor
Immune Checkpoint Inhibitors
Anti-PD1
Anti-CD47
Cytotoxic T Lymphocyte Antigen-4 (CTLA-4)
Other Experimental Therapies
Myeloma-Developing Regimens Using Genomics (MyDRUG)
B-B-Cell Plasmacytic Clone and Waldenström Macroglobulinemia
Agents Targeting B-Cell IgM Producing Clones
Newer Anti-CD20 mABs
Newer BTK Inhibitors
BCL2 Inhibitors
Proteosome Inhibitors
PI3K Inhibitors
CXCR4 Inhibitors
Other Emerging Therapies
Conclusions
References
Chapter 23: Non-pharmacological Management of Paraproteinemia
Introduction
The Hyperviscosity Syndrome and Plasmapheresis
Cryoglobulinemia
Multiple Myeloma
Waldenström’s Macroglobulinemia
Paraproteinemia Associated with Neurological Disorders
Conclusions
References
Index
