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CHAPTER 105 uses in patients with myeloma. The best prognostic markers in myeloma in

PLASMA CELL NEOPLASMS: order of importance are the presence of (1) specific cytogenetic abnormalities,
(2) extent of the disease by appropriate imaging techniques, such as magnetic
GENERAL CONSIDERATIONS resonance imaging and/or combined positron emission and computed tomo-
graphic imaging, (3) the serum free light-chain level and kappa-to-lambda
ratio, and (4) the use of the International Staging System. The development of
several classes of drugs over the past decade in combination with transplanta-
Guido Tricot, Siegfried Janz, Kalyan Nadiminti, Erik Wendlandt, and tion, has improved therapeutic outcomes significantly in patients achieving an
Fenghuang Zhan unequivocal complete remission. Thus, optimal techniques to assess minimal
residual disease have also become important.

SUMMARY

Plasma cell neoplasms are tumors derived from an expansion of mutated DEFINITION AND HISTORY
mature B-cells and their precursors. These neoplasms include essential mono-
clonal gammopathy (synonym: monoclonal gammopathy of unknown signif- Plasma cell neoplasms (PCNs) are clonal B-cell tumors that range from
stable disease without functional abnormalities (monoclonal gammo-
icance; Chap. 106), smoldering myeloma (Chap. 107), myeloma (Chap. 107), pathy, synonym monoclonal gammopathy of unknown significance) to
solitary and extramedullary plasmacytomas (Chap. 107), light-chain amyloi- one of slowly proliferating plasma cells (smoldering myeloma [SMM]),
dosis (Chap. 108), and Waldenström macroglobulinemia (Chap. 109). The pro- to one resulting in end-organ compromise (myeloma). PCNs are
totype of a malignant plasma cell neoplasm is myeloma, which is characterized accompanied by the synthesis and release into the plasma of a mono-
by complex genetic alterations, best assessed by metaphase cytogenetics, clonal (M) protein, and, in the case of myeloma, either diffuse oste-
fluorescence in situ hybridization analysis, and gene-expression profiling. The oporosis or osteolytic lesions. Myeloma accounts for approximately
genetic changes are more akin to solid tumors than to hematologic malignan- 1 percent of all malignant diseases and 10 percent of hematologic
cies. Interactions between myeloma cells and the marrow microenvironment malignancies.
affect the survival, proliferation, and drug resistance of myeloma cells, and the Approximately two-thirds of patients presenting with an M protein
development of osteoporosis or osteolysis, which is a hallmark of myeloma. As have (1) monoclonal gammopathy (Chap. 106), whereas approximately
in most malignancies, a cancer stem cell (e.g., myeloma stem cell) has been 15 percent have (2) myeloma (Chap. 107). Other diseases associated
with M-protein productions are (3) immunoglobulin light-chain amy-
identified and is the most likely site of drug resistance, which almost invariably loidosis (AL) (10 percent; Chap. 108) resulting from the deposition of
develops during treatment; such cells are not affected by the typical drugs one immunoglobulin (Ig) fragments in visceral organs a consequence of
extensive misfolding of these Ig fragments, (4) SMM (3 percent; Chap.
107), (5) Waldenström macroglobulinemia (3 percent; Chap. 109), (6)
lymphoproliferative disorders (2 percent; Chap. 90), (7) solitary or
Acronyms and Abbreviations: AL, light-chain amyloidosis; BAFF, B-cell activat- extramedullary plasmacytomas (1 percent; Chap. 107) and (8) miscella-
ing factor; BCR, B-cell receptor; BMSC, bone mesenchymal stem cell; BTK, Bruton neous other diseases (2 percent). 3
tyrosine kinase; CDR, complementarity determining regions of the heavy chain; CR,
complete remission; CSC, cancer stem cell; D, diversity immunoglobulin gene seg- NORMAL B-CELL DEVELOPMENT
ment; FISH, fluorescence in situ hybridization; FLC, free light chain; GFR, glomerular
filtration rate; ICAM-1, intercellular adhesion molecule 1; Ig, immunoglobulin; IGH, B-cell development is discussed in detail in Chaps. 74 and 75. In brief,
immunoglobulin heavy chain; IGF-1, insulin-like growth factor 1; IL, interleukin; B-cell lymphopoiesis occurs initially in the marrow and in lymphoid
IRAK, interleukin-1 receptor-associated kinase; JAK2/STAT3, Janus kinase 2/sig- tissues. In the marrow, the pro–B-cell, undergoes rearrangement of
nal transducers and activators of transcription; J , joining region immunoglobulin immunoglobulin heavy chain (IGH) genes and, then, is designated a
H
gene segment; M, monoclonal; MBD, myeloma bone disease; MPC, multiparameter pre–B-cell, which is characterized by the presence of cytoplasmic μ
flow cytometry; MRD, minimal residual disease; MRI, magnetic resonance imaging; chains. Subsequent rearrangement of the light chain enables the cell to
mSMART, Mayo stratification of myeloma and risk-adapted therapy; MYD, mye- express surface IgM, the immature B lymphocyte phase of development.
loid differentiation primary response gene; nCR, near complete remission; NEK2, These cells leave the marrow and upon entering the blood express sur-
a serine/threonine kinase; NF-κB, nuclear factor κB; OB, osteoblast; OC, osteoclast; face IgD, which then defines them as virgin B cells, also characterized by
OL, osteolytic lesion; OPG, osteoprotegerin; PCN, plasma cell neoplasm; PDGF, G cell-cycle arrest. Virgin B cells enter the lymphoid tissue, where they
0
platelet-derived growth factor; PET/CT, F-fluorodeoxyglucose positron emission are exposed to antigen-presenting cells, become activated when in con-
18
tomography–computed tomography; pP-7, a hyperphosphorylated protein; RAG, tact with the corresponding antigen and differentiate into short-lived,
recombinase-activating genes; RANK, receptor activator of NF-κB; RARα, retinoic low-affinity plasma cells or memory B-cells. These memory B-cells
receptor α; RB, retinoblastoma gene sCR, stringent complete remission; sIFE, serum travel from the extra-follicular area of the lymph node to the primary
immunofixation electrophoresis; SMM, smoldering myeloma; SP, side population; follicles, where if confronted with an antigen, presented by follicular
SPEP, serum protein electrophoresis; TGF-β, transforming growth factor β; TLR, toll- dendritic cells, a secondary response is induced. At this stage, primary
like receptor; TME, tumor microenvironment; TNF-α, tumor necrosis factor α; TRAF3, follicles change into secondary follicles containing germinal centers.
the adaptor molecule for toll receptor; uIFE, urine immunofixation electrophoresis; Through activation by an antigen, the memory B cells differentiate into
UPEP, urine protein electrophoresis; VCAM-1, vascular cell adhesion molecule 1; VEGF, centroblasts, resulting in Ig isotype switching and somatic mutations in
vascular endothelial growth factor; V , the variable immunoglobulin gene segment. the variable region of the immunoglobulin gene with the generation of
H
high-affinity antibodies. Centroblasts progress to the centrocyte stage

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