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 4-5 new cases per 100,000 persons per year. Accordingly, in the USA 15,270 new cases are expected to be diagnosed in 2004. At present there are approximately 50,000 people in the United States living with multiple myeloma.

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:

• Definition
• Causes and incidence
• Symptoms
• Diagnosis
• Classification and staging
• Prognostic indicators
• Myeloma bone disease
• Glossary

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 _ and _ 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.

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, 2 long chains called heavy chains and 2 shorter chains known as light chains (see figure).

There are 5 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 (k) or lambda (l).

B cells develop in the lymph nodes, and plasma cells develop from B cells when they are needed to fight 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 damage 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.

Normally, plasma cells make up a very small portion (less than 1%) of cells in the bone marrow. Myeloma plasma cells, however, have specific adhesion molecules on their surface allowing them to target bone marrow. After they enter the bone marrow, these adhesion molecules allow them to 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_KB (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 necessary for tumor growth. A growth factor called vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. Angiogenesis helps the myeloma cells 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.

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, however, the myeloma cells collect in a single bone and form a tumor called a plasmacytoma.

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.

A patient's myeloma is often referred to by the 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.