Myeloma is a malignancy of terminally differentiated
B cells (plasma cells) that produces a complete and/or
partial (light chain) monoclonal immunoglobulin protein. Myeloma
cells induce, in the context of the extracellular matrix, critical
alterations in the marrow microenvironment, which, in turn, evoke
cell-survival signals, contributing to resistance to therapy of
this genomically complex and generally hypoproliferative tumor.
The disease causes clinical symptoms by way of tumor mass effects
(e.g., cord compression), cytokine production (e.g., anemia), bone
destruction (e.g., pain), protein deposition in visceral organs
(e.g., kidney and heart), and immunosuppression (e.g., infection).
Clinical manifestations of myeloma vary as a result of the heterogeneous
biology, spanning the entire spectrum from indolent to highly aggressive
disease with extramedullary features. Magnetic resonance imaging
has become an important tool with which to stage the disease and
to distinguish solitary plasmacytoma of bone from myeloma and, within
the latter category, to document the extent and pattern of marrow
involvement, which can be diffuse, micronodular, or macrofocal.
Fluorodeoxyglucose positron emission tomography permits functional metabolic
imaging of the entire body and, hence, detection of both intramedullary
and extramedullary myeloma lesions. Prognosis has been correlated
with serum levels of β2-microglobulin
shed from the surface of myeloma cells and C-reactive protein, reflecting
endogenous interleukin-6 activity, and with the myeloma cell labeling-index.
The molecular analysis of myeloma, using gene expression profiling and
other genetic techniques, indicates that myeloma is a heterogeneous
disorder comprising at least 7 subentities. Gene expression profiling
can identify 15 percent of patients with very aggressive myeloma
who have a poor outcome with all current therapies. The immunomodulatory
drugs, thalidomide and lenalidomide, and the proteasome inhibitor bortezomib
have demonstrated the ability to ameliorate advanced and otherwise
refractory disease, by cotargeting both myeloma and stromal cell
components, and are now used in combination with melphalan and prednisone
as initial therapy. Melphalan-based autologous hematopoietic stem
cell transplantation (auto-HSCT) in combination with novel agent
can achieve remarkable results in patients with good risk myeloma
as defined by favorable gene expression profiles. Such patients
can achieve a 10-year survival, exceeding 60 percent of patients.
The duration of complete remission in these patients has been sustained,
raising the hope that some of these patients are cured.
Acronyms and Abbreviations
Acronyms and abbreviations that
appear in this chapter include: auto-HSCT, autologous hematopoietic
stem cell transplantation; β2M, β2-microglobulin;
CT, computed tomography; del, deletion; FDG, fluorodeoxyglucose;
FISH, fluorescence insitu hybridization;
GVHD, graft-versus-host disease; GVM, graft-versus-myeloma effect;
ISS, International Staging System; LCDD, light-chain deposition
disease; MIP, macrophage inflammatory protein; MP, melphalan-prednisone;
MRI, magnetic resonance imaging; PET, positron emission tomography;
SCID, severe combined immunodeficiency; TGF-β, transforming
growth factor-β; VTE, venous thromboembolism.
Myeloma accounts for approximately 1 percent of all malignancies
and 10 percent of hematologic tumors, representing the second most
frequently occurring hematologic malignancy in the United States.1 At
any one time, 50,000 people suffer from myeloma, and approximately
15,000 cases are diagnosed ...