Multiple Myeloma and Other Plasma Cell Neoplasms

Introduction

Monoclonal gammopathies, also referred to as paraproteinemias or dysproteinemias , are a group of diseases characterized by the proliferation of a clone of plasma cells. The plasma cells produce an electrophoretically and immunologically homogeneous protein usually referred to as monoclonal protein , M protein , M component , or paraprotein . The progressive proliferation of plasma cells results in marrow replacement with a resulting normochromic or slightly macrocytic anemia. Direct infiltration of the overlying bony cortex by the malignant cells causes lytic bone disease, osteoporosis, and compression fractures of the spine. In addition, the production of a monoclonal light chain in the urine can result in a severe toxic response in renal tubules, with renal failure. Differentiation of monoclonal gammopathy of undetermined significance (MGUS) from MM and solitary plasmacytoma (SPB) is important to the selection of appropriate therapy and is discussed later in this chapter.

Epidemiology and Etiology

An estimated 32,110 new cases of MM will occur in the United States in 2019, representing 1.8% of all new cases of cancer. MM accounts for 10% to 15% of all hematological malignant diseases diagnosed in the United States, 20% of all deaths resulting from hematological malignant diseases, and 2.1% of all cancer deaths. MM is an uncommon malignant disease in Pacific Rim countries.

The male-to-female ratio for the disease is 1.3 : 1.0. MM is a disease of older adults. The median age at diagnosis is 66 years; only 10% and 2% of patients are younger than 50 years and 40 years, respectively. The risk of developing MM is approximately 3.7-fold higher for persons with a first-degree relative with MM.

The average age of patients presenting with MM is approximately 63 years. In Olmsted County, Minnesota, the overall incidence of MM is 4.3 cases per 100,000 population per year.

Radiation has been linked to the pathogenesis of MM, but radiation exposure is found in only approximately 1% of patients. In the Hiroshima and Nagasaki tumor registries, there was no sign of an excess risk of MM.

Data regarding the role of antigenic stimulation are conflicting. Epidemiological studies in the United States have demonstrated associations between MM and agricultural workers. An increasing trend for the incidence of lymphohematopoietic cancers has been associated with lifetime exposure to the chemical alachlor, a commonly used pesticide. The risk for MM gave a rate ratio of 5.66 in the highest exposure category. Other occupational groups associated with the development of MM include miners, workers exposed to wood dust, and sheet metal workers.

The etiology of MM remains unknown. Cytogenetic studies in MM demonstrate no consistent chromosome break point that identifies the majority of patients. Cytogenetic abnormalities, however, are less frequent in patients with MGUS, and an increase in frequency is seen as this condition evolves into MM untreated and MM relapsed. MM probably originates from a germinal center B cell of the lymph node. Receptors allow these cells to migrate from the lymph node to the bone marrow (BM).

Myeloma plasma cells express several adhesion molecules, including the neural cell adhesion molecule (NCAM). Adhesion molecules are involved in homing of plasma cells to BM. Although MM is a neoplasm of end-stage plasma cells, most investigators believe that myeloma stem cells exist as a self-renewing population derived from an earlier compartment. The identity of the cells responsible for the initiation and maintenance of MM remains unclear. Circulating B cells clonally related to MM plasma cells have been reported in some patients with myeloma. Overexpression of BCL-2 and BCL-6 proteins has been seen in clinical myeloma and myeloma cell lines. Cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and IL-6, play an essential role in the biology of the malignancy and in mediating the bony manifestations of the disease. Both IL-6 and BCL-2 have been shown to prevent apoptosis, and IL-6 has been implicated as an essential growth factor in MM.

Pathology and Molecular Genetics

The morphology of the plasma cell in MM is relevant prognostically. Immature and plasmablastic plasma cells are associated with a poor prognosis. When 3% of the plasma cells in the BM are indistinguishable from lymphoblasts, this has been defined as plasmablastic myeloma and is associated with a higher prevalence of renal insufficiency and bone disease. Other prognostic features seen on evaluation of the BM biopsy specimen include marked dysplasia, number of mitoses per high-power field, and packing of the BM by tumor.

MM is distinct in that the BM is involved in virtually all patients ( Fig. 90.1 ), yet the peripheral blood shows large numbers of circulating cells in only a few patients. Adhesion molecules mediate both homotypical and heterotypical adhesion of tumor cells to either extracellular matrix (ECM) proteins or BM stromal cells. They play a critical role in disease progression. After class switching in the lymph node, adhesion molecules (e.g., CD44, VLA-4, VLA-5, LFA-1, CD56, syndecan-1, and MPC-1) mediate homing of MM cells to the BM stromal cells. Syndecan-1 is a multifunctional regulator of tumor cell growth and survival as well as of bone cell differentiation; elevated serum syndecan-1 correlates with increased tumor cell mass, decreased metalloproteinase-9 activity, and poor prognosis. Syndecan-1 is shed from the surface of most MM cells, induces apoptosis, and can inhibit the growth of MM cells; it also mediates decreased osteoclast and increased osteoblast differentiation. Novel agents, including thalidomide, and derivatives (IMiDs), including lenalidomide, as well as the proteasome inhibitors (PIs) can target both the tumor cell and its BM microenvironment, thereby overcoming cell adhesion-mediated (CAM) conventional drug resistance. TP53 mutations are associated with more advanced myelomas and are related to the terminal phases of the disease. Mutations of RAS are more prevalent in MM than in other lymphoid malignant diseases. In a study using genomic DNA in 128 patients, RAS mutations were far more common in patients with aggressive plasma cell leukemias (30%) than in MM patients (9%). The RAS mutations appear to represent a late molecular lesion in the process of myeloma evolution. When levels of RAS were studied in 160 patients with newly diagnosed MM, the median survival rate for patients with mutations of N- RAS was no different from that of patients with no RAS mutations. However, patients with K- RAS mutations had significantly higher tumor burdens at diagnosis and a median survival time of 2 years versus 3.7 years for those who did not have K- RAS mutations. The RAS mutations appear to have an independent impact on the median survival rate of patients with MM.

Immunoglobulin heavy chain (IgH) rearrangements can be found in 75% of patients. Dysregulation of cyclin D ₁ can be detected in 30% of MM tumors. Cell lines that overexpress cyclin D ₁ have a translocation detectable into a gamma switch region that suggests an error in VDJ recombination. V _H analysis of the clonal cells in MGUS showed much lower mutation frequencies than in MM. The clonogenic cell in MM likely originates from a preswitched but somatically mutated B cell. Genetic studies have demonstrated that the progression of MM from plateau phase to relapse does not involve a new B-cell clone, and progression beyond the plateau phase is not the result of clonal succession. Advances using molecular probes for fluorescence in situ hybridization (FISH) have demonstrated aneuploid chromosomes where conventional cytogenetics are normal. Chromosome 13 abnormalities on metaphase cytogenetics have been associated with an unfavorable prognosis in patients with myeloma. The translocation t(11;14) results in upregulation of cyclin D ₁ and is the most common translocation detected in patients with MM. Of patients with MM, 16% carry the t(11;14) and have better survival and response to therapy rates. IgH translocations are seen in 60% of patients; these translocations are more likely to be nonhyperdiploid. Patients with light-chain myeloma never display a functional IgH recombination. Most patients with light-chain myeloma have one IgH allele with a germline configuration. The second allele is usually involved in an illegitimate recombination. Light-chain myeloma may be the result of the absence of legitimate IgH rearrangement at the DNA level.

While patients with del(17p) and t(4;14) are considered to have high-risk myeloma, their outcome is not uniform, with some patients having a long survival. Analysis using high-throughput, single-nucleotide polymorphism arrays indicates that chromosome 3, when trisomic, was associated with a longer progression-free survival (PFS) and that 3 trisomies modulated overall survival (OS) in myeloma patients: trisomies 3 and 5 significantly improved OS, whereas trisomy 21 worsened OS. Trisomies 3 and/or 5 seemed to overcome the poor prognosis in patients with t(4;14).

Clinical Manifestations and Patient Evaluation