Myeloma Therapy (eBook)

Section 1: Biologic Considerations and Myeloma


Staging and Myeloma L.T. Heffner MD


Epidemiology of Multiple Myeloma A.A Langston MD and Dixil Francis


Basic Biology of Plasma Cell Dyscrasias Kenneth Anderson MD, DFCI and Marc S. Raab


Biology Based Classification and Staging of Multiple Myeloma Peter Leif Bergsagel MD and Wee Joo Chng, MD


The importance of FISH and Cytogenetics R. Fonseca MD, Esteban Braggio and Michael Sebag


Section 2: Historical and Cytotoxic Agent based Therapies for Myeloma

Role of Autologous Stem Cell Transplantation In Multiple Myeloma J.L. Harrouseau, MD


Maintenance Therapy In Multiple Myeloma Jonathan L. Kaufman MD, Ronald Mihelic PharmD, and Sagar Lonial, MD


Therapy for Patients not Eligible for Autologous Transplant Antonio Palumbo, MD and Sara Bringhen, MD


Current Role of Anthracyclines in the Treatment of Multiple Myelma, A. Chanan-Khan, MD and Sikander Ailawadhi


Section 3: Immune Based Therapies

Allogeneic Transplantation for Multiple Myeloma Edmund K. Waller MD, PhD Fengrong Wang, MD


Immunobiology and Immunotherapy of Multiple Myeloma Madhav Dhodapkar MD


Antibody and other Immune based therapies for Myeloma N Munshi MD, DFCI


Section 4: Existing novel agents

Thalidomide In Relapsed Multiple Myeloma Patients Ashraf Badros MD


Thalidomide: Induction Therapy S. Vincent Rajkumar MD and Francis K. Baudi, MD


The Role of Bortezomib In the Treatment of Relapsed and Refractory Multiple Myeloma Paul G. Richardson MD, DFCI, Constantine S. Mitsiades, Robert Schlossman, Irene Ghobrial, Nikhil C. Munshi and Kenneth C. Anderson


Bortezomib As Induction Therapy In Multiple Myeloma Patients J San Miguel MD,PhD and M.V. Mateos, MD, PhD


Lenalidomide In Relapsed and Refractory Multiple Myeloma Donna M. Weber MD, Sheeba K. Thomas MD, Tiffany A. Richards, MS, ANP, AOCNP


Lenalidomide (Revlimid®) For Initial Therapy of Newly Diagnosed Multiple Myeloma Shaji Kumar MD


Section 5: Current and Future Targets

The Role of Heat Shock Protein 90 As A Therapeutic Target for Multiple Myeloma Constantine Mitsiades MD, DFCI, Teru Hideshima, Nikhil C. Munshi, Paul G. Richardson and Kenneth C. Anderson


The P13 Kinase/AKT Pathway As A therapeutic Target for Multiple Myeloma Donald Harvey, PharmD, Jeanine Silberman, MD and Sagar Lonial MD


The Mammalian Target of Rapamycin (mTOR) and Multiple Myeloma Patrick Frost, PhD Alan Lichtenstein, MD


CDK Inhibitors In Multiple Myeloma Yun Dai and Steven Grant MD, MCV


Fibroblast growth factor receptor 3 (FGFR3) and Multiple Myeloma (MM) Victor Hugo Jimenez-Zepeda, MD and Keith Stewart MD


Histone Deacetylase Inhibitors In Multiple Myeloma Teru Hideshima MD, PhD, DFCI


Death Receptors In Multiple Myeloma and Therapeutic Opportunities, F. Mollinedo, PhD


Proteasome Inhibitors as Therapy in Multiple Myeloma Dharminder Chauhan PhD, Ajita Singh, PhD and Kenneth Anderson, MD


Section 6: Supportive Care

Pathophysiology of Bone Disease in Multiple Myeloma Tomer M. Mark, MD and Roger N. Pearse MD, PhD


Anemia and Erythropoeitic Growth Factors in Multiple Myeloma N Raje MD, DFCI


Percutaneous Vertebroplasty and Balloon Kyphoplasty for the Treatment of Acute Painful Pathologic and Non-Pathologic Fractures Sandra Narayanan, MD and Frank Tong MD


The Role of Anatomic and

Chapter 3 Basic Biology of Plasma Cell Dyscrasias: Focus on the Role of the Tumor Microenviroment (S. 23-24)

Marc S. Raab and Kenneth C. Anderson

Introduction

B-cell development involves several mechanisms of remodeling Ig genes: VDJ recombination, somatic hypermutation, and Ig heavy chain (IgH) switch recombination. Once matured, B-cells reside in secondary lymphoid tissues. Antigen interaction induces proliferation and differentiation to lymphoblasts, leading to the generation of short-lived pregerminal center plasma cells. An antigen-activated lymphoblast entering a germinal center undergoes a unique modification of Ig genes through sequential rounds of somatic hypermutation and antigen selection, as well as by IgH switch recombination. Postgerminal center B-cells may become plasmablasts that have successfully completed somatic hypermutation and IgH switching before migrating to the bone marrow (BM), where stromal cells enable terminal differentiation into nonproliferating long-lived plasma cells. 1 , 2

Multiple myeloma (MM) is a malignant disease of terminally differentiated B-cells that may be preceded by a premalignant condition called monoclonal gammopathy of undetermined significance (MGUS). This is present in 1% of adults over the age of 25 years, the prevalence increasing with age. MGUS cells, like MM cells, secrete a monoclonal immunoglobulin and progress to malignant MM at a rate of 1% per year. Compared to MM, MGUS is characterized by a lower tumor burden (intramedullary tumor cell content less than 10%) and the absence of osteolytic lesions. Another disease related to aberrant plasma cells is amyloidosis, which shares most of the pathologic features of MGUS except that the secreted monoclonal immunoglobulin forms pathological deposits in various tissues.

Myeloma Genetics: A Brief Overview

Both MGUS and MM are characterized by the accumulation of transformed plasma cells at multiple sites in the BM. These cells show a marked karyotypic complexity with gains and losses of whole chromosomes, nonrandom chromosomal translocations causing dysregulation of genes at the breakpoints, and point mutations of genes, all contributing to disease pathogenesis. 6 , 7 In addition, small focal lesions of the MM genome as well as epigenetic changes have recently been identified 8 – 11 Briefly, MM patients can be subdivided into two groups based on the pattern of chromosomal gains and losses.

12 Approximately 55% of patients have a hyperdiploid karyotype (number of chromosomes 48–74) with trisomies of odd-numbered chromosomes including 3, 5, 7, 9, 11, 15, 19, and 21. The remaining cases (summarized as the nonhyperdiploid group) consist of patients with hypodiploid, near-diploid, pseudodiploid, or near-tetraploid chromosome numbers with less than 48 or more than 74 chromosomes.