Page 1554 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 86

PLASMA CELL NEOPLASMS

Nikhil C. Munshi and Sundar Jagannath

Multiple myeloma (MM) is a malignancy involving terminally dif- Thomas Alexander McBean, who presented with symptoms of
ferentiated plasma cells. It includes a spectrum of plasma cell disorders fatigue, diffuse bone pain, and urinary frequency. Urinalysis showed
ranging from monoclonal gammopathy of unknown significance a urinary protein with a peculiar heat property (now called Bence Jones
(MGUS), a relatively benign condition to smoldering multiple proteins). The disease was given the name multiple myeloma by
myeloma (SMM), as well as the symptomatic malignant disorder Rustizky in 1873 following his observation of multiple bone lesions
MM, and its more aggressive form, plasma cell leukemia with circu- in a similar patient. A larger review of this disease by Kahler in 1889
lating myeloma cells in the blood (Table 86.1). Various other plasma led to its being called Kahler disease, especially in Europe. Subse-
cell disorders belong to the same group of conditions, including quently, investigative advances defined the disease further with
Castleman disease, heavy chain disease, and Waldenström macro- descriptions of plasma cell and x-ray abnormalities in 1900 by
globulinemia. MM is characterized by the presence of clonal plasma Wright, of bone marrow aspiration in 1929, of electrophoresis in
cells and production in the majority of cases of a monoclonal immu- 1937, and of immunoelectrophoresis identifying the heavy and light
noglobulin (Ig) and/or its fragment with subsequent involvement or chains in 1953, confirming the monoclonality of immunoglobulins
effects on organ function. Because there are five classes of immuno- in this disease. In recent years, recurrent chromosomal translocations
globulins, the dysfunctional plasma cells can produce any one of the have defined subgroups of patients with myeloma, and gene expres-
five immunoglobulin subtypes, including IgG, IgA, IgM, IgD, and sion profiling and proteomic studies are providing a greater molecular
IgE. Infrequently, heavy-chain components of the immunoglobulin understanding of the disease. Similarly, the influence of bone marrow
are not produced by the myeloma cells, and the disease manifests as microenvironment on myeloma cell growth and survival has been
production and secretion of κ or λ light chains only. Very rarely, explored and led to the identification of novel therapeutic targets.
myeloma fails to produce a significant amount of protein and mani- The first randomized study in myeloma compared urethane with
fests as a nonsecretory MM. With the availability of a high-sensitivity, placebo and indicated that the survival of patients receiving urethane
free light-chain assay, the frequency of true nonsecretory MM has was inferior to that observed with a placebo. Progress in myeloma
significantly decreased. therapy started with first successful use of a chemotherapeutic agent
in myeloma with racemic mixture of D- and L-phenylalanine mustards
(sarcolysine) in 1958 by Blokhin and colleagues; use of melphalan in
EPIDEMIOLOGY 1962 by Bergsagel and colleagues; use of high doses of glucocorticoids
in 1967; and subsequently use of melphalan in combination with
MM accounts for 1.8% of all malignancies and is the second most prednisone (MP), which is used even today. With the use of high-
common hematologic malignancy. The prevalence of MM was dose therapy (HDT) with melphalan by McElwain and Powles in
around 95,688 in 2013, and it was estimated that 30,330 men and 1983, complete remissions (CRs) were achieved in a proportion of
women (11,400 men and 9120 women) would be diagnosed with patients, and the identification of novel agents such as thalidomide
and 12,650 men and women would die as a result of myeloma in and its immunomodulatory analogue lenalidomide and pomalido-
2016. It is a disease involving a relatively older population with a mide, as well as the proteasome inhibitor bortezomib and carfilzomib
median age at diagnosis of 69 years and median age at death of 74 during the last 15 years targeting both myeloma cells and the bone
years (Fig. 86.1A). Less than 5% of patients at diagnosis are younger marrow microenvironment, has further improved responses and OS.
than age 40 years. Myeloma is more frequent in men than in women
and in African American than in white persons in the United States
(Fig. 86.1B). The incidence of MM in African American males is PATHOBIOLOGY
approximately 15.7 per 100,000 per year as compared with 11.5 per
100,000 per year in African American females. The corresponding MM, as with a number of other malignancies, remains a disease that
incidence rates are 7.7 and 4.5 per 100,000 in white males and is initiated and sustained by genomic changes that promote uncon-
females, respectively. A recent survey of MGUS in the US population trolled proliferative advantages to the tumor cells. Myeloma represents
showed a significantly higher prevalence of MGUS in African Ameri- the classic multistep transformation process with an initial premalig-
cans (3.7%) as compared with white (2.3%) (p = .001) or Hispanic nant stage, MGUS, demonstrating a number of recurrent cytogenetic
(1.8%) populations. Although the Asian population has a lower abnormalities as well as gene expression changes (Table 86.2). It is
incidence of myeloma than their white counterparts, ethnic groups well documented that all MM develops from MGUS, suggesting that
such as Hawaiians, female Hispanics, female American Indians from the initial event required for transformation to MGUS provides the
New Mexico, and Alaskan natives experience higher incidence rates first step in a multistep process. 1
than those of the US white population from the same geographic
regions. Although there has been an increase in the incidence of MM,
it is primarily attributed to better detection and surveillance of the Cytogenetics
disease as well as the overall aging of the population worldwide.
Moreover, there has been an improvement in the overall survival (OS) MM is characterized by a significant molecular and genomic hetero-
of patients with MM from 3 to 7 years and longer. geneity affecting tumor clones. Karyotypes in MM are usually
complex, with both number and structural chromosomal abnormali-
2
ties observed (see Chapter 56). Although chromosomal abnormali-
HISTORICAL ASPECTS ties using conventional cytogenetics in newly diagnosed patients are
detected in only 30% to 50% of patients, owing to the low prolifera-
The first published clinical description of a patient with myeloma tive activity of MM cells, in advanced stages when cells usually have
was by Dr. Henry Bence Jones in 1850. He described a patient, a higher proliferative index, a greater number of abnormalities are

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