Intro to Myeloma
Intro to Myeloma
Sagar Lonial, MD
Multiple Myeloma Research Foundation

Multiple myeloma, a cancer of the plasma cell, is an incurable but treatable disease. While a myeloma diagnosis can be overwhelming, it is important to remember that there are several promising new therapies that are helping patients live longer, healthier lives. The estimated frequency of multiple myeloma is 5 to 7 new cases per 100,000 persons per year. Accordingly, in the United States, 19,920 new cases are expected to be diagnosed in 2008. There were more than 56,000 Americans living with multiple myeloma in 2005, the most current date these statistics are available.

This section is designed to serve as a fundamental resource for education about multiple myeloma. It provides a detailed overview of the disease and includes:
Causes and incidence
Classification and staging
Prognostic indicators
Myeloma bone disease
Multiple myeloma (also known as myeloma or plasma cell myeloma) is a progressive hematologic (blood) disease. It is a cancer of the plasma cell, an important part of the immune system that produces immunoglobulins (antibodies) to help fight infection and disease. Multiple myeloma is characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free monoclonal ê and ë light chains). Hypercalcemia, anemia, renal damage, increased susceptibility to bacterial infection, and impaired production of normal immunoglobulin are common clinical manifestations of multiple myeloma. It is often also characterized by diffuse osteoporosis, usually in the pelvis, spine, ribs, and skull.

Cells destined to become immune cells, like all blood cells, arise in the bone marrow from stem cells (see figure). Some stem cells develop into the small white blood cells called lymphocytes. The two major classes of lymphocytes are B cells (B lymphocytes) and T cells (T lymphocytes). Plasma cells develop from B cells.

Figure legend: Like most blood cells, plasma cells develop from stem cells in the bone marrow. Stem cells can develop into B cells (B lymphocytes), which travel to the lymph nodes, mature, and then travel throughout the body. When foreign substances (antigens) enter the body, B cells develop into plasma cells that produce immunoglobulins (antibodies) to help fight infection and disease.
Normal Plasma Cell Function in the Immune System
Plasma cells develop from B cells when foreign substances (antigens), such as bacteria, enter the body. In response to invasion by foreign substances, groups of plasma cells produce proteins called immunoglobulins (Ig), also known as antibodies that help fight disease and infection. Each plasma cell develops in response to a particular foreign substance within the body, and it produces immunoglobulins specific to that substance. Thus, there are many different immunoglobulins produced in the body.

Immunoglobulins are made up of protein chains, two long chains called heavy chains and two shorter chains known as light chains (see figure).

Figure legend: Immunoglobulins are made up of two heavy chains and two light chains.

There are five major classes of immunoglobulins. Each class has a unique type of heavy chain that is defined by use of a Greek letter: gamma (IgG), alpha (IgA), mu (IgM), epsilon (IgE), or delta (IgD). Each type has a slightly different function in the body. Normally, a plasma cell makes one of these five major classes of immunoglobulin. The immunoglobulin class normally present in the largest amounts in blood is IgG, followed by IgA and IgM. IgD and IgE are present in very small amounts in the blood. Immunoglobulin light chains are defined by use of the Greek letters kappa (ê) or lambda (l).
Development of Malignant Plasma Cells (Myeloma Cells)
It is normal for plasma cells to develop from B cells in lymph nodes as an immune response to disease or infection. Transformation of a normal B cell into a malignant plasma cell involves a multi-step process that includes multiple genetic abnormalities. Finally, the resulting plasma cells become malignant, meaning they continue to divide unchecked, generating more malignant plasma cells (see figure). These myeloma cells travel through the bloodstream and collect in the bone marrow, where they cause permanent damage to healthy tissue. We have recently learned that the interaction between the plasma cells and the bone marrow microenvironment is as important as the genetic changes in the development of these malignant cells.

Figure legend: In multiple myeloma, the B cell is damaged and gives rise to too many plasma cells (myeloma cells). These malignant cells do not function properly and their increased numbers produce excess immunoglobulins of a single type that the body does not need along with reduced amounts of normal immunoglobulins.
Normally, plasma cells make up a very small portion (less than 5%) of cells in the bone marrow. Myeloma plasma cells, however, have specific adhesion molecules on their surface allowing them to target bone marrow where they attach to structural cells called stromal cells. Once myeloma cells attach to bone marrow stromal cells, several interactions cause myeloma cells to grow (see figure):
Chemical messengers called cytokines are produced by both myeloma cells and stromal cells. These cytokines, such as interleukin 6 (IL-6), receptor for activation of NF-êB (RANK) ligand, and tumor necrosis factor (TNF), stimulate the growth of myeloma cells and inhibit (prevent) natural cell death (called apoptosis), leading to proliferation of myeloma cells and ultimately resulting in bone destruction.

Myeloma cells also produce growth factors that promote angiogenesis, the creation of new blood vessels. These new blood vessels provide the oxygen and nutrients that promote tumor growth. A growth factor called vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. Angiogenesis encourages reproduction of myeloma cells, which increase in number and begin to infiltrate the bone marrow, eventually comprising more than 10% of the cells present.

Mature myeloma cells may fail to activate the immune system and may produce substances that decrease the body's normal immune response to a foreign body. Thus, the cells can grow unchecked.

Figure legend: Bone marrow stromal cells and myeloma cells produce cytokines that help myeloma cells grow and survive. Myeloma cells also produce growth factors that stimulate new blood vessel formation through a process called angiogenesis. New blood vessels provide nutrients and oxygen to the tumor, allowing it to grow. The natural immune response that attacks myeloma cells is suppressed.

As tumors grow, they invade the hard outer part of the bone, the solid tissue. In most cases, the myeloma cells spread into the cavities of all the large bones of the body, forming multiple small lesions. This is why the disease is known as "multiple" myeloma. In some cases, collections of plasma cells arise either within bone or in soft tissues as masses or tumors. These collections are called plasmacytomas, and may represent a more aggressive form of myeloma.

Myeloma cells are identical and produce the same immunoglobulin protein, called monoclonal (M) protein or paraprotein, in large quantities. Although the specific M protein varies vary from patient to patient, it is always exactly the same in any one patient. When blood or urine is processed in a laboratory test called electrophoresis, these M proteins show up as a "spike" in the results.

Unlike normal immunoglobulin, M protein does not benefit the body. Instead, it crowds out normal, functional immunoglobulins. In addition, levels of functional immunoglobulin are depressed in individuals with myeloma. Although the process is not completely understood, it appears that the functional immunoglobulin made by existing normal plasma cells breaks down more quickly in patients with myeloma than in healthy individuals.
Myeloma Types
Myeloma is often referred to by the particular type of immunoglobulin or light chain (kappa or lambda type) produced by the cancerous plasma cell. The frequency of the various immunoglobulin types of myeloma parallels the normal serum concentrations of the immunoglobulins. The most common myeloma types are IgG and IgA. IgG myeloma accounts for about 60% to 70% of all cases of myeloma and IgA accounts for about 20% of cases. Few cases of IgD and IgE myeloma have been reported.

Although a high level of M protein in the blood is a hallmark of myeloma disease, about 15% to 20% of patients with myeloma produce incomplete immunoglobulins, containing only the light chain portion of the immunoglobulin (also known as Bence Jones proteins, after the chemist who discovered them). These patients are said to have light chain myeloma, or Bence Jones myeloma. In these patients, M protein is found primarily in the urine, rather than in the blood. These Bence Jones proteins may deposit in the kidney and clog the tiny tubules that make up the kidney's filtering system, which can eventually cause kidney damage and result in kidney failure. Bence Jones proteins will not be detected by routine urinalysis. A more complex test called immunoelectrophoresis can measure the exact amount of Bence Jones proteins in the urine.

A rare form of myeloma called nonsecretory myeloma affects about 1% of myeloma patients. In this form of the disease, plasma cells do not produce M protein or light chains.
Causes and Incidence
Multiple myeloma is the second most prevalent blood cancer after non-Hodgkin's lymphoma. It represents approximately 1% of all cancers in white US residents and 2% of cancers in black residents.

Recent statistics indicate both increasing incidence and earlier age of onset. The average age at diagnosis is 62 years for men and 61 years for women, and only 4% of cases are diagnosed in individuals under the age of 45. Approximately 56,200 Americans had myeloma in 2005 (the most current date these statistics are available) and the American Cancer Society estimates that approximately 19,920 new cases of myeloma will be diagnosed during 2008.

Multiple myeloma occurs more frequently in men than women (of the estimated 19,920 new cases referenced above, 11,190 are expected to occur in men versus 8,730 in women). African Americans have the highest reported incidence of this disease and Asians the lowest. Among African Americans, myeloma is one of the leading causes of cancer death.

Although a tremendous amount of work has gone into the search for the cause of multiple myeloma, to date no cause for this disease has been identified. However, the search for a cause has suggested possible associations between myeloma and a decline in the immune system, genetic factors, certain occupations, certain viruses, exposure to certain chemicals including Agent Orange, and exposure to radiation.

Age is the most significant risk factor for multiple myeloma, as 96% of cases are diagnosed in people over the age of 45, and more than 75% occur in people over the age of 70. Because the peak age for multiple myeloma is among the elderly it is thought that susceptibility may increase with the aging process and the consequent reduction in immune surveillance of evolving cancer, or that myeloma may result from a lifelong accumulation of toxic insults or antigenic challenges.

The higher incidence of myeloma in African Americans and the much less frequent occurrence in Asians suggest genetic factors. While it is uncommon for myeloma to develop in more than one family member, there is a slight increased risk among children and siblings of those with myeloma.

People in agricultural occupations, petroleum workers, workers in leather industries, and cosmetologists all seem to have a higher-than-average chance of developing multiple myeloma. Exposure to herbicides, insecticides, petroleum products, heavy metals, plastics, and various dusts including asbestos also appear to be risk factors for the disease. In addition, individuals exposed to large amounts of radiation, such as survivors of the atomic bomb explosions in Japan, have an increased risk for myeloma, although this accounts for a very small number of cases.

Chromosomal changes including chromosomal translocations (generally involving the Ig heavy chain gene), and chromosomal gains and losses are very frequent in myeloma. These abnormalities have an important influence on disease outcome.

It is important to remember that in most cases, individuals who develop multiple myeloma have no clear risk factors. Myeloma may be the result of several factors acting together.

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