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Multiple Myeloma

Multiple myeloma

Definition

Multiple myeloma is a cancer in which antibody-producing plasma cells grow in an uncontrolled and invasive (malignant) manner.

Description

Multiple myeloma, also known as plasma cell myeloma, is the second-most common cancer of the blood. It is the most common type of plasma cell neoplasm. Multiple myeloma accounts for approximately 1% of all cancers and 2% of all deaths from cancer. Multiple myeloma is a disease in which malignant plasma cells spread through the bone marrow and hard outer portions of the large bones of the body. These myeloma cells may form tumors called plasmacytomas. Eventually, multiple soft spots or holes, called osteolytic lesions, form in the bones.

Bone marrow is the spongy tissue within the bones. The breastbone, spine, ribs, skull, pelvic bones, and the long bone of the thigh all are particularly rich in marrow. Bone marrow is a very active tissue that is responsible for producing the cells that circulate in the blood. These include the red blood cells that carry oxygen, the white blood cells that develop into immune system cells, and platelets, which cause blood to clot.

Plasma cells and immunoglobulins

Plasma cells develop from B-lymphocytes or B-cells, a type of white blood cell. B-cells, like all blood cells, develop from unspecialized stem cells in the bone marrow. Each B-cell carries a specific antibody that recognizes a specific foreign substance called an antigen. Antibodies are large proteins called immunoglobulins (Igs), which recognize and destroy foreign substances and organisms such as bacteria. When a B-cell encounters its antigen, it begins to divide rapidly to form mature plasma cells. These plasma cells are all identical (monoclonal). They produce large amounts of identical antibody that are specific for the antigen.

Malignant plasma cells

Multiple myeloma begins when the genetic material (DNA) is damaged during the development of a stem cell into a B-cell in the bone marrow. This causes the cell to develop into an abnormal or malignant plasmablast, a developmentally early form of plasma cell. Plasmablasts produce adhesive molecules that allow them to bond to the inside of the bone marrow. A growth factor, called interleukin-6, promotes uncontrolled growth of these myeloma cells in the bone marrow and prevents their natural death. Whereas normal bone marrow contains less than 5% plasma cells, bone marrow of an individual with multiple myeloma contains over 10% plasma cells.

In most cases of multiple myeloma, the malignant plasma cells all make an identical Ig. Igs are made up of four protein chains that are bonded together. Two of the chains are light and two are heavy. There are five classes of heavy chains, corresponding to five types of Igs with different immune system functions. The Igs from myeloma cells are nonfunctional and are called paraproteins. All of the paraproteins from any one individual are monoclonal (identical) because the myeloma cells are identical clones of a single plasma cell. Thus, the paraprotein is a monoclonal protein or M-protein. The M-proteins crowd out the functional Igs and other components of the immune system. They also cause functional antibodies, which are produced by normal plasma cells, to rapidly break down. Thus, multiple myeloma depresses the immune system.

In about 75% of multiple myeloma cases, the malignant plasma cells also produce monoclonal light chains, or incomplete Igs. These are called Bence-Jones proteins and are secreted in the urine. Approximately 1% of multiple myelomas are called nonsecretors because they do not produce any abnormal Ig.

Osteolytic lesions

About 70% of individuals with multiple myeloma have soft spots or lesions in their bones. These lesions can vary from quite small to grapefruit-size. In part, these lesions occur because the malignant plasma cells rapidly outgrow the normal bone-forming cells. In addition, malignant myeloma cells produce factors that affect cells called osteoclasts. These are the cells that normally destroy old bone, so that new bone can be produced by cells called osteoblasts. The myeloma cell factors increase both the activation and the growth of osteoclasts. As the osteoclasts multiply and migrate, they destroy healthy bone and create lesions. Osteoporosis, or widespread bone weakness, may develop.

Demographics

There are more than 40, 000 multiple myeloma patients in the United States. The American Cancer Society predicts an additional 14, 400 new cases in 2001. About 11, 200 Americans will die of the disease in 2001. Multiple myeloma is one of the leading causes of cancer deaths among African-Americans.

In Western industrialized countries, approximately four people in 100, 000 develop multiple myeloma. The incidence of multiple myeloma among African-Americans is 9.5 per 100, 000, about twice that of Caucasians. Asians have a much lower incidence of the disease. In China, for example, the incidence of multiple myeloma is only one in 100, 000. The offspring and siblings of individuals with multiple myeloma are at a slightly increased risk for the disease.

At diagnosis, the average age of a multiple myeloma patient is 68 to 70. Although the average age at onset is decreasing, most multiple myelomas still occur in people over 40. This cancer is somewhat more prevalent in men than in women.

Causes and symptoms

Associations

The cause of multiple myeloma has not been determined. However, a number of possible associations have been identified:

  • decreased immune system function; the immune systems of older individuals may be less efficient at detecting and destroying cancer cells
  • genetic (hereditary) factors, suggested by the increased incidence in some ethnic groups and among family members
  • occupational factors, suggested by the increased incidence among agricultural, petroleum, wood, and leather workers, and cosmetologists
  • long-term exposure to herbicides, pesticides, petroleum products, heavy metals, plastics, and dusts such as asbestos
  • radiation exposure, as among Japanese atomic bomb survivors, nuclear weapons workers, and medical personnel such as radiologists
  • Kaposi's sarcoma-associated herpes virus (also called human herpes virus-8 or HHV-8), found in the blood and bone marrow cells of many multiple myeloma patients

Early symptoms

The accumulation of malignant plasma cells can result in tiny cracks or fractures in bones. Malignant plasma cells in the bone marrow can suppress the formation of red and white blood cells and platelets. About 80% of individuals with multiple myeloma are anemic due to low red blood cell formation. Low white blood cell formation results in increased susceptibility to infection, since new, functional antibodies are not produced. In addition, normal circulating antibodies are rapidly destroyed. Low platelet formation can result in poor blood clotting. It is rare, however, that insufficient white blood cell and platelet formations are presenting signs of multiple myeloma.

These factors cause the early symptoms of multiple myeloma:

  • pain in the lower back or ribs
  • fatigue and paleness due to anemia (low red blood cell count)
  • frequent and recurring infections, including bacterial pneumonia , urinary-tract and kidney infections, and shingles (herpes zoster)
  • bleeding

Bone destruction

Bone pain , particularly in the backbone, hips, and skull, is often the first symptom of multiple myeloma. As malignant plasma cells increase in the bone marrow, replacing normal marrow, they exert pressure on the bone. As overly-active osteoclasts (large cells responsible for the breakdown of bone) remove bone tissue, the bone becomes soft. Fracture and spinal cord compression may occur.

Plasmacytomas (malignant tumors of plasma cells) may weaken bones, causing fractures. Fractured bones or weak or collapsed spinal bones, in turn, may place unusual pressure on nearby nerves, resulting in nerve pain, burning, or numbness and muscle weakness. Proteins produced by myeloma cells also may damage nerves.

Calcium from the destroyed bone enters the blood and urine, causing hypercalcemia , a medical condition in which abnormally high concentrations of calcium compounds exist in the bloodstream. High calcium affects nerve cell and kidney function. The symptoms of hypercalcemia include:

  • weakness and fatigue
  • depression
  • mental confusion
  • constipation
  • increased thirst
  • increased urination
  • nausea and vomiting
  • kidney pain
  • kidney failure

Hypercalcemia affects about one-third of multiple myeloma patients.

Serum proteins

The accumulation of M-proteins in the serum (the liquid portion of the blood) may cause additional complications, such as hyperviscosity syndrome, or thickening of the blood (though rare in multiple myeloma patients). Symptoms of hyperviscosity include:

  • fatigue
  • headaches
  • shortness of breath
  • mental confusion
  • chest pain
  • kidney damage and failure
  • vision problems
  • Raynaud's phenomenon

Poor blood circulation, or Raynaud's phenomenon, can affect any part of the body, but particularly the fingers, toes, nose, and ears.

Cryoglobulinemia occurs when the protein in the blood forms particles under cold conditions. These particles can block small blood vessels and cause pain and numbness in the toes, fingers, and other extremities during cold weather.

Amyloidosis is a rare complication of multiple myeloma. It usually occurs in individuals whose plasma cells produce only Ig light chains. These Bence-Jones proteins combine with other serum proteins to form amyloid protein. This starchy substance can invade tissues, organs, and blood vessels. In particular, amyloid proteins can accumulate in the kidneys, where they block the tiny tubules that are the kidney's filtering system. Indicators of amyloidosis include:

  • carpal tunnel syndrome
  • kidney failure
  • liver failure
  • heart failure

Diagnosis

Blood and urine tests

Often, the original diagnosis of multiple myeloma is made from routine blood tests that are performed for other reasons. Blood tests may indicate:

  • anemia
  • abnormal red blood cells
  • high serum protein levels
  • low levels of normal antibody
  • high calcium levels
  • high blood urea nitrogen (BUN) levels
  • high creatinine levels

Urea and creatinine normally are excreted in the urine. High levels of urea and creatinine in the blood indicate that the kidneys are not functioning properly to eliminate these substances.

Protein electrophoresis is a laboratory technique that uses an electrical current to separate the different proteins in the blood and urine on the basis of size and charge. Since all of the multiple myeloma M-proteins in the blood and urine are identical, electrophoresis of blood and urine from a patient with multiple myeloma shows a large M-protein spike, corresponding to the high concentration of monoclonal Ig. Electrophoresis of the urine also can detect Bence-Jones proteins.

Bones

A bone marrow aspiration utilizes a very thin, long needle to remove a sample of marrow from the hip bone. Alternatively, a bone marrow biopsy with a larger needle removes solid marrow tissue. The marrow is examined under the microscope for plasma cells and tumors. If 10% to 30% of the cells are plasma cells, multiple myeloma is the usual diagnosis.

X rays are used to detect osteoporosis, osteolytic lesions, and fractures. Computed tomography (CAT or CT) scans can detect lesions in both bone and soft tissue. Magnetic resonance imaging (MRI) may give a more detailed image of a certain bone or a region of the body.

Treatment team

After the initial diagnosis, the treatment team for multiple myeloma may include a hematologist (a specialist in diseases of the blood) and an oncologist or cancer specialist. If radiation is used in treatment, a radiation oncologist may join the team. The treatment of multiple myeloma involves complex decisions, and obtaining second opinions from additional specialists may be important.

Clinical staging, treatments, and prognosis

Related disorders

Monoclonal gammopathy of undetermined significance (MGUS) is a common condition in which a monoclonal Ig is detectable. However, there are no tumors or other symptoms of multiple myeloma. MGUS occurs in about 1% of the general population and in about 3% of those over age 70. Over a period of years, about 16% to 20% of those with MGUS will develop multiple myeloma or a related cancer called malignant lymphoma .

Occasionally, only a single plasmacytoma develops, either in the bone marrow (isolated plasmacytoma of the bone) or other tissues or organs (extramedullary plasmacytoma). Some individuals with solitary plasmacytoma may develop multiple myeloma.

Clinical stages

The Durie-Salmon system is used to stage multiple myeloma. Stage I multiple myeloma requires all of the following (1 gram = approx. 0.02 pints, 1 deciliter = approx. 0.33 fluid ounces):

  • hemoglobin (the oxygen-transporting molecule of red blood cells) above 10 grams/deciliter (g/dl)
  • serum calcium below 12 mg/dl
  • normal bone structure or only isolated plasmacytoma
  • low M-protein, based on established guideline levels of Ig protein chains

Approximately 5% of multiple myeloma cases are not progressing at diagnosis, and may not progress for months or years. This is called smoldering myeloma. These patients have stage I blood chemistry but no symptoms.

Stage II multiple myeloma fits neither stage I nor stage III. Stage III multiple myeloma meets one or more the following criteria:

  • hemoglobin below 8.5 g/dl
  • serum calcium above 12 mg/dl
  • advanced bone lesions
  • high M-protein

Each stage is subclassified as A or B, based on serum creatinine indicators of normal or abnormal kidney function. Most patients have stage III multiple myeloma at diagnosis.

Prognostic indicators

Prognostic indicators for multiple myeloma may be used instead of, or in addition to, the staging system described above. Prognostic indicators are laboratory tests that help to define the stage of the disease at diagnosis, and its progression during treatment. These indicators are:

  • plasmablastic multiple myeloma (presence of plasmablasts, the precursor malignant plasma cells)
  • plasma cell labeling index (the percentage of plasma cells that are actively dividing)
  • beta 2-microglobulin, a protein secreted by B-cells that correlates with the myeloma cell mass (also indicates kidney damage)

Treatment

Since multiple myeloma often progresses slowly, and since the treatments can be toxic, the disease may not be treated until M-protein levels in the blood are quite high. In particular, MGUS and smoldering myeloma may be followed closely but not treated. Solitary plasmacytomas are treated with radiation and/or surgery and followed closely with examinations and laboratory tests.

CHEMOTHERAPY.

Chemotherapy , or treatment with anti-cancer drugs, is used for multiple myeloma. MP, a combination of the drugs melphalan and prednisone, is the standard treatment. Usually, the drugs are taken by mouth every 3 to 4 weeks for 6 to 9 months or longer, until the M-protein levels in the blood stop decreasing. MP usually results in a 50% reduction in M-protein.

Dexamethasone , a corticosteroid, sometimes is used to treat the elderly or those in poor health. It can drop the M-protein levels by 40% in untreated individuals and by 20% to 40% in patients who have not responded to previous treatment. Other chemotherapy drugs, including cyclophosphamide , carmustine , doxorubicin , vincristine , and chlorambucil , may be used as well.

Multiple myeloma usually recurs within a year after the end of chemotherapy. Although the chemotherapy can be repeated after each recurrence, it is progressively less responsive to treatment.

Side effects of chemotherapy may include:

  • anemia
  • hair loss (alopecia )
  • nausea and vomiting
  • diarrhea
  • mood swings
  • swelling
  • acne

These side effects disappear after treatment is discontinued.

OTHER DRUG TREATMENTS.

Bisphosphonates are drugs that inhibit the activity of osteoclasts. These drugs can slow the progression of bone disease, reduce pain, and help prevent bone fractures. Different types of bisphosphonates inhibit osteoclasts in different ways. They also reduce the production of interleukin-6 by bone marrow cells. Laboratory studies suggest that bisphosphonates may kill or inhibit the growth of multiple myeloma cells. Pamidronate is the most common bisphosphonate for treating multiple myeloma.

The drug thalidomide appears to have several anti-myeloma activities. Thalidomide affects the immune system in various ways and it appears to inhibit myeloma cells, both directly and indirectly. It also inhibits the growth of new blood vessels that are needed by tumors. However, if thalidomide is taken during pregnancy, it can cause severe birth defects or death of the fetus.

The drug allopurinol may be used to reduce high blood levels of uric acid that result from kidney dysfunction. Diuretics can improve kidney function. Infections require prompt treatment with antibiotics .

BONE AND PERIPHERAL BLOOD STEM CELL TRANSPLANTATION.

Bone marrow or peripheral blood stem cell transplantations (PBSCT) are used to replace the stem cells of the bone marrow following high-dosage chemotherapy. Chemotherapy destroys the bone marrow stem cells that are necessary to produce new blood cells. In an autologous transplant, the patient's bone marrow stem cells or peripheral blood stem cells (immature bone marrow cells found in the blood) are collected, treated with drugs to kill any myeloma cells, and frozen prior to chemotherapy. Growth factors are used to increase the number of peripheral stem cells prior to collection. A procedure called apheresis is used to collect the peripheral stem cells. Following high-dosage chemotherapy, the stem cells are reinjected into the individual. In an allogeneic transplant, the donor stem cells come from a genetically related individual such as a sibling.

OTHER TREATMENTS.

Blood transfusions may be required to treat severe anemia.

Plasmapheresis, or plasma exchange transfusion, may be used to thin the blood to treat hyperviscosity syndrome. In this treatment, blood is removed and passed through a machine that separates the plasma, containing the M-protein, from the red and white blood cells and platelets. The blood cells are transfused back into the patient, along with a plasma substitute or donated plasma.

Multiple myeloma may be treated with high-energy x rays directed at a specific region of the body. Radiation therapy is used for treating bone pain.

Alternative and complementary therapies

Interferon alpha, an immune-defense protein that is produced by some white blood cells and bone marrow cells, can slow the growth of myeloma cells. It usually is given to patients following chemotherapy, to prolong their remission. However, interferon may have toxic effects in older individuals with multiple myeloma.

Once multiple myeloma is in remission, calcium and vitamin D supplements can improve bone density. It is important not to take these supplements when the myeloma is active. Individuals with multiple myeloma must drink large amounts of fluid to counter the effects of hyperviscous blood.

Prognosis

The prognosis for individuals with MGUS or solitary plasmacytoma is very good. Most do not develop multiple myeloma. However, approximately 15% of all patients with multiple myeloma die within three months of diagnosis. About 60% respond to treatment and live for an average of two and a half to three years following diagnosis. Approximately 23% of patients die of other illnesses associated with advanced age.

The prognosis for a given individual may be based on the prognostic indicators described above. The median survival for those without plasmablasts, and with a low plasma cell labeling index (PCLI) and low beta 2-microglobulin, is 5.5 years. The median survival for patients with plasmablastic multiple myeloma, or with a high PCLI (1% or greater) and high beta 2-microglobulin (4 or higher), is 1.9 and 2.4 years, respectively. Many multiple myeloma patients are missing part or all of chromosome 13. The deletion of this chromosome, along with high beta 2-microglobulin, leads to a poor prognosis.

With treatment, multiple myeloma may go into complete remission. This is defined as:

  • M-protein absent from the blood and urine
  • myeloma cells not detectable in the bone marrow
  • no clinical symptoms
  • negative laboratory tests

However, with very sensitive testing, a few myeloma cells are usually detectable and eventually lead to a recurrence of the disease, in the bone or elsewhere in the body.

Coping with cancer treatment

Techniques such as biofeedback, guided imagery, and meditation may be helpful for reducing stress and relieving pain. Pain medication is usually prescribed for multiple myeloma. Back or neck braces may help relieve bone pain. Exercise, if possible, is important for retaining calcium in the bones.

Clinical trials

There are hundreds of ongoing clinical trials for the treatment of multiple myeloma. These take place throughout the United States and are sponsored by both government and industry. Clinical trials of treatments for multiple myeloma include:

  • thalidomide
  • thalidomide-like drugs that affect the immune system in various ways
  • skeletal targeted radiotherapy (STP), in which a radioactive element is attached to a drug that binds to bone
  • new anti-cancer drugs
  • new combinations of drugs
  • new chemotherapies in combination with PBSCT
  • combinations of PBSCT, interleukin-2, and interferon alpha
  • treatments for disease resulting from PBSCT (graft-versus-host disease )
  • bone marrow transplantations
  • immunotherapies, including vaccines , to destroy remaining myeloma cells after high-dosage chemotherapy and PBSCT
  • treatments for MGUS

Prevention

There are no clearly-established risk factors for multiple myeloma and it is possible that a combination of factors interact to cause the disease. Thus, there is no method for preventing multiple myeloma.

Special concerns

Since there is a high probability that multiple myeloma will recur after treatment, patients are followed carefully. Blood tests, x rays, and other imaging studies may be used to check for a recurrence.

See Also Immunoelectrophoresis; Pheresis; Protein electrophoresis; Bone marrow transplantation

Resources

BOOKS

Drum, David. Making the Chemotherapy Decision, 2nd ed. Los Angeles: Lowell House, 1996.

Holland, Jimmie C., and Sheldon Lewis. The Human Side of Cancer: Living with Hope, Coping with Uncertainty. New York: HarperCollins, 2000.

Longo, Dan L. "Plasma Cell Disorders." In Harrison's Princi ples of Internal Medicine, edited by Anthony S. Fauci, et al. New York: McGrawHill, 1998.

Malpas, James S., D. E. Bergsagel, R. A. Kyle, et al, eds. Myeloma: Biology and Management, 2nd ed. Oxford: Oxford University Press, 1998.

ORGANIZATIONS

International Myeloma Foundation. 12650 Riverside Dr., Suite 206, North Hollywood, CA 91607. (800) 452-CURE. (818) 487-7455. <http://www.myeloma.org>. Information and support for patients and families and the scientific and medical communities.

The Leukemia and Lymphoma Society. 600 Third Avenue, New York, NY 10016. (800) 955-4572. (914) 949-5213. <http://www.leukemia-lymphoma.org>. Information, sup port, and guidance for patients and health care professionals.

Multiple Myeloma Research Foundation. 11 Forest Street, New Canaan, CT 06840. (203) 972-1250. <http://www.multiplemyeloma.org>. Information and research funding.

OTHER

"About Myeloma." Multiple Myeloma Research Foundation. 16 Apr. 2001. 15 June 2001 <http://www.multiplemyeloma.org/aboutmyeloma.html>.

Complementary and Alternative Therapies for Leukemia, Lym phoma, Hodgkin's Disease and Myeloma. The Leukemia and Lymphoma Society. 27 Mar. 2001. 15 June 2001 <http://www.leukemia-lymphoma.org>.

Facts and Statistics About Leukemia, Lymphoma, Hodgkin's Disease and Myeloma. The Leukemia and Lymphoma Society. 27 Mar. 2001. 15 Mar. 2001. <http://www.leukemia-lymphoma.org>.

"Multiple Myeloma." Cancer Resource Center. American Can cer Society. 16 Apr. 2001. 15 June 2001 <http://www3.cancer.org/cancerinfo>.

"Multiple Myeloma and Other Plasma Cell Neoplasms." Can cerNet National Cancer Institute. Mar. 2001. 16 Apr. 2001. <http://cancernet.nci.nih.gov>.

Margaret Alic, Ph.D.

QUESTIONS TO ASK THE DOCTOR

  • What stage of multiple myeloma do I have and what does it mean?
  • What are my treatment options?
  • What are the side effects of treatment?
  • Are there clinical trials that may be appropriate for me?
  • How long can I expect to survive?
  • Is my cancer likely to recur?

KEY TERMS

Amyloidosis

A complication of multiple myeloma in which amyloid protein accumulates in the kidneys and other organs, tissues, and blood vessels.

Anemia

Any condition in which the red blood cell count is below normal.

Antibody

Immunoglobulin produced by immune system cells that recognizes and binds to a specific foreign substance (antigen).

Antigen

Foreign substance that is recognized by a specific antibody.

B-cell (B-lymphocyte)

Type of white blood cell that produces antibodies.

Bence-Jones protein

Light chain of an immunoglobulin that is overproduced in multiple myeloma and is excreted in the urine.

Beta 2-microglobulin

Protein produced by B-cells; high concentrations in the blood are indicative of multiple myeloma.

Cryoglobulinemia

Condition triggered by low temperatures in which protein in the blood forms particles, blocking blood vessels, leading to pain and numbness of the extremities.

Electrophoresis

Use of an electrical field to separate proteins in a mixture (such as blood or urine), on the basis of the size and electrical charge of the proteins.

Hemoglobin

Protein in red blood cells that carries oxygen.

Hypercalcemia

Abnormally high levels of calcium in the blood.

Hyperviscosity

Thick, viscous blood, caused by the accumulation of large proteins, such as immunoglobulins, in the serum.

Immunoglobulin (Ig)

Antibody; large protein produced by B-cells that recognizes and binds to a specific antigen.

M-protein

Monoclonal or myeloma protein; paraprotein; abnormal antibody found in large amounts in the blood and urine of individuals with multiple myeloma.

Malignant

A characteristic of cancer cells that grow uncontrollably and invade other tissues.

Monoclonal

Identical cells or proteins; cells (clones) derived from a single, genetically distinct cell, or proteins produced by these cells.

Monoclonal gammopathy of undetermined significance (MGUS)

Common condition in which M-protein is present, but there are no tumors or other symptoms of disease.

Neoplasm

Tumor made up of cancer cells.

Osteoblast

Bone-forming cell.

Osteoclast

Cell that absorbs bone.

Osteolytic lesion

Soft spot or hole in bone caused by cancer cells.

Osteoporosis

Condition in which the bones become weak and porous, due to loss of calcium and destruction of cells.

Paraprotein

M-protein; abnormal immunoglobulin produced in multiple myeloma.

Plasma cell

Type of white blood cell that produces antibodies; derived from an antigen-specific B-cell.

Platelet Cell that is involved in blood clotting.

Stem cell

Undifferentiated cell that retains the ability to develop into any one of numerous cell types.

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Multiple Myeloma

Multiple Myeloma

Definition

Multiple myeloma is a cancer in which antibody-producing plasma cells grow in an uncontrolled and invasive (malignant) manner.

Description

Multiple myeloma, also known as plasma cell myeloma, is the second-most common cancer of the blood. It is the most common type of plasma cell neoplasm. Multiple myeloma accounts for approximately 1% of all cancers and 2% of all deaths from cancer. Multiple myeloma is a disease in which malignant plasma cells spread through the bone marrow and hard outer portions of the large bones of the body. These myeloma cells may form tumors called plasmacytomas. Eventually, multiple soft spots or holes, called osteolytic lesions, form in the bones.

Bone marrow is the spongy tissue within the bones. The breastbone, spine, ribs, skull, pelvic bones, and the long bone of the thigh all are particularly rich in marrow. Bone marrow is a very active tissue that is responsible for producing the cells that circulate in the blood. These include the red blood cells that carry oxygen, the white blood cells that develop into immune system cells, and platelets, which cause blood to clot.

Plasma cells and immunoglobulins

Plasma cells develop from B-lymphocytes or B-cells, a type of white blood cell. B-cells, like all blood cells, develop from unspecialized stem cells in the bone marrow. Each B-cell carries a specific antibody that recognizes a specific foreign substance called an antigen. Antibodies are large proteins called immunoglobulins (Igs), which recognize and destroy foreign substances and organisms such as bacteria. When a B-cell encounters its antigen, it begins to divide rapidly to form mature plasma cells. These plasma cells are all identical (monoclonal). They produce large amounts of identical antibody that are specific for the antigen.

Malignant plasma cells

Multiple myeloma begins when the genetic material (DNA) is damaged during the development of a stem cell into a B-cell in the bone marrow. This causes the cell to develop into an abnormal or malignant plasmablast, a developmentally early form of plasma cell. Plasmablasts produce adhesive molecules that allow them to bond to the inside of the bone marrow. A growth factor, called interleukin-6, promotes uncontrolled growth of these myeloma cells in the bone marrow and prevents their natural death. Whereas normal bone marrow contains less than 5% plasma cells, bone marrow of an individual with multiple myeloma contains over 10% plasma cells.

In most cases of multiple myeloma, the malignant plasma cells all make an identical Ig. Igs are made up of four protein chains that are bonded together. Two of the chains are light and two are heavy. There are five classes of heavy chains, corresponding to five types of Igs with different immune system functions. The Igs from myeloma cells are nonfunctional and are called paraproteins. All of the paraproteins from any one individual are monoclonal (identical) because the myeloma cells are identical clones of a single plasma cell. Thus, the paraprotein is a monoclonal protein or M-protein. The M-proteins crowd out the functional Igs and other components of the immune system. They also cause functional antibodies, which are produced by normal plasma cells, to rapidly break down. Thus, multiple myeloma depresses the immune system.

In about 75% of multiple myeloma cases, the malignant plasma cells also produce monoclonal light chains, or incomplete Igs. These are called Bence-Jones proteins and are secreted in the urine. Approximately 1% of multiple myelomas are called nonsecretors because they do not produce any abnormal Ig.

Osteolytic lesions

About 70% of individuals with multiple myeloma have soft spots or lesions in their bones. These lesions can vary from quite small to grapefruit-size. In part, these lesions occur because the malignant plasma cells rapidly outgrow the normal bone-forming cells. In addition, malignant myeloma cells produce factors that affect cells called osteoclasts. These are the cells that normally destroy old bone, so that new bone can be produced by cells called osteoblasts. The myeloma cell factors increase both the activation and the growth of osteoclasts. As the osteoclasts multiply and migrate, they destroy healthy bone and create lesions. Osteoporosis, or widespread bone weakness, may develop.

There are more than 40,000 multiple myeloma patients in the United States. The American Cancer Society predicts an additional 14,400 new cases in 2001. About 11,200 Americans will die of the disease in 2001. Multiple myeloma is one of the leading causes of cancer deaths among African Americans.

In Western industrialized countries, approximately four people in 100,000 develop multiple myeloma. The incidence of multiple myeloma among African Americans is 9.5 per 100,000, about twice that of Caucasians. Asians have a much lower incidence of the disease. In China, for example, the incidence of multiple myeloma is only one in 100,000. The offspring and siblings of individuals with multiple myeloma are at a slightly increased risk for the disease.

At diagnosis, the average age of a multiple myeloma patient is 68 to 70. Although the average age at onset is decreasing, most multiple myelomas still occur in people over 40. This cancer is somewhat more prevalent in men than in women.

Causes and symptoms

Associations

The cause of multiple myeloma has not been determined. However, a number of possible associations have been identified:

  • decreased immune system function; the immune systems of older individuals may be less efficient at detecting and destroying cancer cells
  • genetic (hereditary) factors, suggested by the increased incidence in some ethnic groups and among family members
  • occupational factors, suggested by the increased incidence among agricultural, petroleum, wood, and leather workers, and cosmetologists
  • long-term exposure to herbicides, pesticides, petroleum products, heavy metals, plastics, and dusts such as asbestos
  • radiation exposure, as among Japanese atomic bomb survivors, nuclear weapons workers, and medical personnel such as radiologists
  • Kaposi's sarcoma-associated herpes virus (also called human herpes virus-8 or HHV-8), found in the blood and bone marrow cells of many multiple myeloma patients

Early symptoms

The accumulation of malignant plasma cells can result in tiny cracks or fractures in bones. Malignant plasma cells in the bone marrow can suppress the formation of red and white blood cells and platelets. About 80% of individuals with multiple myeloma are anemic due to low red blood cell formation. Low white blood cell formation results in increased susceptibility to infection, since new, functional antibodies are not produced. In addition, normal circulating antibodies are rapidly destroyed. Low platelet formation can result in poor blood clotting. It is rare, however, that insufficient white blood cell and platelet formations are presenting signs of multiple myeloma.

These factors cause the early symptoms of multiple myeloma:

  • pain in the lower back or ribs
  • fatigue and paleness due to anemia (low red blood cell count)
  • frequent and recurring infections, including bacterial pneumonia, urinary-tract and kidney infections, and shingles
  • bleeding

Bone destruction

Bone pain, particularly in the backbone, hips, and skull, is often the first symptom of multiple myeloma. As malignant plasma cells increase in the bone marrow, replacing normal marrow, they exert pressure on the bone. As overly-active osteoclasts (large cells responsible for the breakdown of bone) remove bone tissue, the bone becomes soft. Fracture and spinal cord compression may occur.

Plasmacytomas (malignant tumors of plasma cells) may weaken bones, causing fractures. Fractured bones or weak or collapsed spinal bones, in turn, may place unusual pressure on nearby nerves, resulting in nerve pain, burning, or numbness and muscle weakness. Proteins produced by myeloma cells also may damage nerves.

Calcium from the destroyed bone enters the blood and urine, causing hypercalcemia, a medical condition in which abnormally high concentrations of calcium compounds exist in the bloodstream. High calcium affects nerve cell and kidney function. The symptoms of hypercalcemia include:

  • weakness and fatigue
  • depression
  • mental confusion
  • constipation
  • increased thirst
  • icreased urination
  • nausea and vomiting
  • kidney pain
  • kidney failure

Hypercalcemia affects about one-third of multiple myeloma patients.

Serum proteins

The accumulation of M-proteins in the serum (the liquid portion of the blood) may cause additional complications, such as hyperviscosity syndrome, or thickening of the blood (though rare in multiple myeloma patients). Symptoms of hyperviscosity include:

  • fatigue
  • headaches
  • shortness of breath
  • mental confusion
  • chest pain
  • kidney damage and failure
  • vision problems
  • Raynaud's phenomenon

Poor blood circulation, or Raynaud's phenomenon, can affect any part of the body, but particularly the fingers, toes, nose, and ears.

Cryoglobulinemia occurs when the protein in the blood forms particles under cold conditions. These particles can block small blood vessels and cause pain and numbness in the toes, fingers, and other extremities during cold weather.

Amyloidosis is a rare complication of multiple myeloma. It usually occurs in individuals whose plasma cells produce only Ig light chains. These Bence-Jones proteins combine with other serum proteins to form amyloid protein. This starchy substance can invade tissues, organs, and blood vessels. In particular, amyloid proteins can accumulate in the kidneys, where they block the tiny tubules that are the kidney's filtering system. Indicators of amyloidosis include:

  • carpal tunnel syndrome
  • kidney failure
  • liver failure
  • heart failure

Diagnosis

Blood and urine tests

Often, the original diagnosis of multiple myeloma is made from routine blood tests that are performed for other reasons. Blood tests may indicate:

  • anemia
  • abnormal red blood cells
  • high serum protein levels
  • how levels of normal antibody
  • high calcium levels
  • high blood urea nitrogen (BUN) levels
  • high creatinine levels

Urea and creatinine normally are excreted in the urine. High levels of urea and creatinine in the blood indicate that the kidneys are not functioning properly to eliminate these substances.

Protein electrophoresis is a laboratory technique that uses an electrical current to separate the different proteins in the blood and urine on the basis of size and charge. Since all of the multiple myeloma M-proteins in the blood and urine are identical, electrophoresis of blood and urine from a patient with multiple myeloma shows a large M-protein spike, corresponding to the high concentration of monoclonal Ig. Electrophoresis of the urine also can detect Bence-Jones proteins.

Bones

A bone marrow aspiration utilizes a very thin, long needle to remove a sample of marrow from the hip bone. Alternatively, a bone marrow biopsy with a larger needle removes solid marrow tissue. The marrow is examined under the microscope for plasma cells and tumors. If 10% to 30% of the cells are plasma cells, multiple myeloma is the usual diagnosis.

X rays are used to detect osteoporosis, osteolytic lesions, and fractures. Computer-assisted tomography (CAT or CT) scans can detect lesions in both bone and soft tissue. Magnetic resonance imaging (MRI) may give a more detailed image of a certain bone or a region of the body.

Treatment

Related disorders

Monoclonal gammopathy of undetermined significance (MGUS) is a common condition in which a monoclonal Ig is detectable. However, there are no tumors or other symptoms of multiple myeloma. MGUS occurs in about 1% of the general population and in about 3% of those over age 70. Over a period of years, about 16% to 20% of those with MGUS will develop multiple myeloma or a related cancer called malignant lymphoma.

Occasionally, only a single plasmacytoma develops, either in the bone marrow (isolated plasmacytoma of the bone) or other tissues or organs (extramedullary plasmacytoma). Some individuals with solitary plasmacytoma may develop multiple myeloma.

Clinical stages

The Durie-Salmon system is used to stage multiple myeloma. Stage I multiple myeloma requires all of the following (1 gram = approx. 0.02 pints, 1 deciliter = approx. 0.33 ounces):

  • hemoglobin (the oxygen-transporting molecule of red blood cells) above 10 grams/deciliter (g/dl)
  • serum calcium below 12 mg/dl
  • normal bone structure or only isolated plasmacytoma
  • low M-protein, based on established guideline levels of Ig protein chains

Approximately 5% of multiple myeloma cases are not progressing at diagnosis, and may not progress for months or years. This is called smoldering myeloma. These patients have stage I blood chemistry but no symptoms.

Stage II multiple myeloma fits neither stage I nor stage III. Stage III multiple myeloma meets one or more the following criteria:

  • hemoglobin below 8.5 g/dl
  • serum calcium above 12 mg/dl
  • advanced bone lesions
  • high M-protein

Each stage is subclassified as A or B, based on serum creatinine indicators of normal or abnormal kidney function. Most patients have stage III multiple myeloma at diagnosis.

Prognostic indicators

Prognostic indicators for multiple myeloma may be used instead of, or in addition to, the staging system described above. Prognostic indicators are laboratory tests that help to define the stage of the disease at diagnosis, and its progression during treatment. These indicators are:

  • plasmablastic multiple myeloma (presence of plasmablasts, the precursor malignant plasma cells)
  • plasma cell labeling index (the percentage of plasma cells that are actively dividing)
  • beta 2-microglobulin, a protein secreted by B-cells that correlates with the myeloma cell mass (also indicates kidney damage)

Since multiple myeloma often progresses slowly, and since the treatments can be toxic, the disease may not be treated until M-protein levels in the blood are quite high. In particular, MGUS and smoldering myeloma may be followed closely but not treated. Solitary plasmacytomas are treated with radiation and/or surgery and followed closely with examinations and laboratory tests.

Chemotherapy

Chemotherapy, or treatment with anti-cancer drugs, is used for multiple myeloma. MP, a combination of the drugs melphalan and prednisone, is the standard treatment. Usually, the drugs are taken by mouth every 3 to 4 weeks for 6 to 9 months or longer, until the M-protein levels in the blood stop decreasing. MP usually results in a 50% reduction in M-protein.

Dexamethasone, a corticosteroid, sometimes is used to treat the elderly or those in poor health. It can drop the M-protein levels by 40% in untreated individuals and by 20% to 40% in patients who have not responded to previous treatment. Other chemotherapy drugs, including cyclophosphamide, carmustine, doxorubicin, vincristine, and chlorambucil, may be used as well.

Multiple myeloma usually recurs within a year after the end of chemotherapy. Although the chemotherapy can be repeated after each recurrence, it is progressively less responsive to treatment.

Side effects of chemotherapy may include:

  • anemia
  • hair loss
  • nausea
  • vomiting
  • diarrhea
  • mood swings
  • swelling
  • acne

These side effects disappear after treatment is discontinued.

Other drug treatments

Bisphosphonates are drugs that inhibit the activity of osteoclasts. These drugs can slow the progression of bone disease, reduce pain, and help prevent bone fractures. Different types of bisphosphonates inhibit osteoclasts in different ways. They also reduce the production of interleukin-6 by bone marrow cells. Laboratory studies suggest that bisphosphonates may kill or inhibit the growth of multiple myeloma cells. Pamidronate is the most common bisphosphonate for treating multiple myeloma.

The drug thalidomide appears to have several anti-myeloma activities. Thalidomide affects the immune system in various ways and it appears to inhibit myeloma cells, both directly and indirectly. It also inhibits the growth of new blood vessels that are needed by tumors. However, if thalidomide is taken during pregnancy, it an cause severe birth defects or death of the fetus.

The drug allopurinol may be used to reduce high blood levels of uric acid that result from kidney dysfunction. Diuretics can improve kidney function. Infections require prompt treatment with antibiotics.

BONE AND PERIPHERAL BLOOD STEM CELL TRANSPLANTATION. Bone marrow or peripheral blood stem cell transplantations (PBSCT) are used to replace the stem cells of the bone marrow following high-dosage chemotherapy. Chemotherapy destroys the bone marrow stem cells that are necessary to produce new blood cells. In an autologous transplant, the patient's bone marrow stem cells or peripheral blood stem cells (immature bone marrow cells found in the blood) are collected, treated with drugs to kill any myeloma cells, and frozen prior to chemotherapy. Growth factors are used to increase the number of peripheral stem cells prior to collection. A procedure called apheresis is used to collect the peripheral stem cells. Following high-dosage chemotherapy, the stem cells are reinjected into the individual. In an allogeneic transplant, the donor stem cells come from a genetically-related individual such as a sibling.

Other treatments

Blood transfusions may be required to treat severe anemia.

Plasmapheresis, or plasma exchange transfusion, may be used to thin the blood to treat hyperviscosity syndrome. In this treatment, blood is removed and passed through a machine that separates the plasma, containing the M-protein, from the red and white blood cells and platelets. The blood cells are transfused back into the patient, along with a plasma substitute or donated plasma.

Multiple myeloma may be treated with highenergy x rays directed at a specific region of the body. Radiation therapy is used for treating bone pain.

KEY TERMS

Amyloidosis A complication of multiple myeloma in which amyloid protein accumulates in the kidneys and other organs, tissues, and blood vessels.

Anemia Any condition in which the red blood cell count is below normal.

Antibody Immunoglobulin produced by immune system cells that recognizes and binds to a specific foreign substance (antigen).

Antigen Foreign substance that is recognized by a specific antibody.

B-cell (B-lymphocyte) Type of white blood cell that produces antibodies.

Bence-Jones protein Light chain of an immunoglobulin that is overproduced in multiple myeloma and is excreted in the urine.

Beta 2-microglobulin Protein produced by B-cells; high concentrations in the blood are indicative of multiple myeloma.

Cryoglobulinemia Condition in which protein in the blood forms particles in the cold, blocking blood vessels, leading to pain and numbness of the extremities.

Electrophoresis Use of an electrical field to separate proteins in a mixture (such as blood or urine), on the basis of the size and electrical charge of the proteins.

Hemoglobin Protein in red blood cells that carries oxygen.

Hypercalcemia Abnormally high levels of calcium in the blood.

Hyperviscosity Thick, viscous blood, caused by the accumulation of large proteins, such as immunoglobulins, in the serum.

Immunoglobulin (Ig) Antibody; large protein produced by B-cells that recognizes and binds to a specific antigen.

M-protein Monoclonal or myeloma protein; paraprotein; abnormal antibody found in large amounts in the blood and urine of individuals with multiple myeloma.

Malignant A characteristic of cancer cells that grow uncontrollably and invade other tissues.

Monoclonal Identical cells or proteins; cells (clones) derived from a single, genetically-distinct cell, or proteins produced by these cells.

Monoclonal gammopathy of undetermined significance (MGUS) Common condition in which M-protein is present, but there are no tumors or other symptoms of disease.

Neoplasm Tumor made up of cancer cells.

Osteoblast Bone-forming cell.

Osteoclast Cell that absorbs bone.

Osteolytic lesion Soft spot or hole in bone caused by cancer cells.

Osteoporosis Condition in which the bones become weak and porous, due to loss of calcium and destruction of cells.

Paraprotein M-protein; abnormal immunoglobulin produced in multiple myeloma.

Plasma cell Type of white blood cell that produces antibodies; derived from an antigen-specific B-cell.

Platelet Cell that is involved in blood clotting.

Stem cell Undifferentiated cell that retains the ability to develop into any one of numerous cell types.

Alternative treatment

Interferon alpha, an immune-defense protein that is produced by some white blood cells and bone marrow cells, can slow the growth of myeloma cells. It usually is given to patients following chemotherapy, to prolong their remission. However, interferon may have toxic effects in older individuals with multiple myeloma.

Once multiple myeloma is in remission, calcium and vitamin D supplements can improve bone density. It is important not to take these supplements when the myeloma is active. Individuals with multiple myeloma must drink large amounts of fluid to counter the effects of hyperviscous blood.

Prognosis

The prognosis for individuals with MGUS or solitary plasmacytoma is very good. Most do not develop multiple myeloma. However, approximately 15% of all patients with multiple myeloma die within three months of diagnosis. About 60% respond to treatment and live for an average of two and a half to three years following diagnosis. Approximately 23% of patients die of other illnesses associated with advanced age.

The prognosis for a given individual may be based on the prognostic indicators described above. The median survival for those without plasmablasts, and with a low plasma cell labeling index (PCLI) and low beta 2-microglobulin, is 5.5 years. The median survival for patients with plasmablastic multiple myeloma, or with a high PCLI (1% or greater) and high beta 2-microglobulin (4 or higher), is 1.9 and 2.4 years, respectively. Many multiple myeloma patients are missing part or all of chromosome 13. The deletion of this chromosome, along with high beta 2-microglobulin, leads to a poor prognosis.

With treatment, multiple myeloma may go into complete remission. This is defined as:

  • M-protein absent from the blood and urine
  • myeloma cells not detectable in the bone marrow
  • no clinical symptoms
  • negative laboratory tests

However, with very sensitive testing, a few myeloma cells are usually detectable and eventually lead to a recurrence of the disease, in the bone or elsewhere in the body.

Prevention

There are no clearly-established risk factors for multiple myeloma and it is possible that a combination of factors interact to cause the disease. Thus, there is no method for preventing multiple myeloma.

Resources

BOOKS

Holland, Jimmie C., and Sheldon Lewis. The Human Side of Cancer: Living with Hope, Coping with Uncertainty. New York: HarperCollins, 2000.

ORGANIZATIONS

Multiple Myeloma Research Foundation. 11 Forest Street, New Canaan, CT 06840. (203) 972-1250. http://www.multiplemyeloma.org. Information and research funding.

OTHER

"About Myeloma." Multiple Myeloma Research Foundation. April 16, 2001. [cited June 15, 2001]. http://www.multiplemyeloma.org/aboutmyeloma.html.

Complementary and Alternative Therapies for Leukemia, Lymphoma, Hodgkin's Disease and Myeloma. The Leukemia and Lymphoma Society. March 27, 2001. [cited June 15, 2001]. http://www.leukemialymphoma.org.

Facts and Statistics About Leukemia, Lymphoma, Hodgkin's Disease and Myeloma. The Leukemia and Lymphoma Society. March 15, 2001. [cited Mar27, 2001]. http://www.leukemia-lymphoma.org.

"Multiple Myeloma and Other Plasma Cell Neoplasms." CancerNet National Cancer Institute. March 2001. [cited April 16, 2001]. http://cancernet.nci.nih.gov.

"Multiple Myeloma." Cancer Resource Center. American Cancer Society. April 16, 2001. [cited June 15, 2001]. http://www3.cancer.org/cancerinfo.

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myeloma

myeloma (multiple myeloma, myelomatosis) (my-ĕ-loh-mă) n. a malignant disease of the bone marrow, characterized by two or more of the following: (1) the presence of an excess of abnormal malignant plasma cells in the bone marrow; (2) lytic deposits in the bones, giving the appearance of holes on X-ray; (3) the presence in the serum of an abnormal gammaglobulin, usually IgG. The patient may complain of tiredness due to anaemia and of bone pain and may develop pathological fractures. Treatment is usually with drugs, such as melphalan or cyclophosphamide, with local radiotherapy to particular areas of pain. See also plasmacytoma.

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myeloma

my·e·lo·ma / ˌmīəˈlōmə/ • n. (pl. -mas or -ma·ta / -mətə/ ) Med. a malignant tumor of the bone marrow.

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Myeloma

Myeloma

Definition

Cancer that arises in the bone marrow and involves plasma cells, a type of white blood cell that produces proteins called immunoglobulins.

Kate Kretschmann

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multiple myeloma

multiple myeloma (mul-ti-pŭl) n. see myeloma.

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myeloma

myeloma See cancer.

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