Multiple Myeloma

Definition

Multiple myeloma is a cancer in which plasma cells in the blood grow in an uncontrolled and invasive (malignant) manner.

Description

Normal plasma cells are an integral component of the body's immune system . When plasma cells become cancerous, the cells accumulate in the bone marrow, causing destruction of bone and eventually leading to bone marrow failure. 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. 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 are particularly rich in

marrow. Bone marrow is a very active tissue 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.

Multiple myeloma begins when the genetic material deoxyribonucleic acid (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 . Normal bone marrow contains less than 5% plasma cells, but bone marrow of an individual with multiple myeloma contains over 10% plasma cells.

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. Malignant myeloma cells also 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

The American Cancer Society estimates an additional 19,900 new cases of multiple myeloma in 2007. About 10,790 Americans will die of the disease. Multiple myeloma is one of the leading causes of cancer deaths among African-Americans.

At diagnosis, the average age of a multiple myeloma patient is 62 years for men and 61 years for women. This cancer is somewhat more prevalent in men than in women.

Causes and symptoms

Risk factors

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

• Age and gender. The greatest risk factor for multiple myeloma is increasing age. More than 50% of people who develop this type of cancer are over age 70 at the time of diagnosis. Less than 1% of multiple myeloma patients are under the age of 40. Men are more likely to be diagnosed with multiple myeloma than women.
• Race. For unknown reasons, multiple myeloma is twice as common among African Americans than among white Americans.
• Genetic (hereditary) factors. There is increased incidence in some ethnic groups and among family members. However, most patients diagnosed with multiple myeloma report no other relatives with the disease.
• Occupational factors. There is increased incidence among agricultural, petroleum, wood, and leather workers, and cosmetologists l Long-term exposure to herbicides, pesticides, petroleum products, heavy metals, plastics, and dusts such as asbestos.
• Radiation exposure. Individuals who are Japanese atomic bomb survivors, nuclear weapons workers, and medical personnel such as radiologists have an increased risk.
• Weight. Obesity may increase an individual's risk for developing multiple myeloma.

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 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. 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.

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 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 immunoglobulin. 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. A bone marrow biopsy uses a larger needle to remove solid marrow tissue. The marrow is examined under the microscope for plasma cells and tumors. If 10–30% 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 (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.

Clinical staging

Based on the clinical and laboratory testing results, patients are initially classified as having asymptomatic (smoldering) or active disease. Those classified with active disease are further categorized according to stage of disease using either the Durie-Salmon system or the International Staging System.

The Durie-Salmon System is based on four factors.

• Amount of abnormal antibodies in the blood or urine; large amounts indicate there are many cancerous plasma cells.
• Amount of calcium in the blood; high levels of calcium in the blood are indicative of advanced bone damage.
• Degree of bone damage as seen on x rays; more numerous areas of damage indicate more advanced disease.
• Amount of hemoglobin in the blood; low hemoglobin levels in the blood mean that myeloma cells are occupying more space in the bone marrow than normal cells, which make red blood cells.

Prognostic indicators

Prognostic indicators for multiple myeloma may be used instead of, or in addition to, the staging system. 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

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, smoldering myeloma and MGUS (monoclonal gammopathy of undetermined significance), a condition in which there are no signs or symptoms of disease other than high levels of M-proteins in the blood, may be followed closely but not treated. Solitary plasmacytomas are treated initially with radiation and are followed closely with examinations and laboratory tests.

KEY TERMS

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.

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 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.

As of 2008 there are five active treatment strategies to treat multiple myeloma:

• high dose corticosteroids
• anti-angiogenic agents such as thalidomide or lenalidomide
• the proteasome inhibitor, bortezomib
• conventional-dose chemotherapy
• autologous or allogeneic peripheral stem cell transplantation

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.

QUESTIONS TO ASK YOUR 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?

Clinical trials

Over 300 ongoing clinical trials for the treatment of multiple myeloma were underway as of 2008. These trials take place throughout the United States and are sponsored by both government and industry.

Alternative and complementary therapies

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

Although multiple myeloma is highly treatable in many cases, it is rarely curable. The extent or stage of disease at time of diagnosis is a strong predictor of survival. The prognosis for individuals with MGUS or solitary plasmacytoma is very good. Most do not develop multiple myeloma. Prior to the advent of chemotherapy to treat multiple myeloma, the median survival was seven months. With the use of chemotherapy, prognosis has improved considerably with a median survival of 24 to 30 months and a 10-year survival rate of 3% as of 2008.

Prevention

There are no clearly established risk factors for multiple myeloma. It is possible that a combination of factors interact to cause the disease. There is no method for preventing multiple myeloma.

Caregiver concerns

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.

Resources

books

Holland, Jimmie C., and Sheldon Lewis. The Human Side of Cancer: Living with Hope, Coping with Uncertainty. New York: HarperCollins, 2001.

organizations

International Myeloma Foundation. 12650 Riverside Dr., Suite 206, North Hollywood, CA 91607. (800) 452-CURE. (818) 487-7455. http://www.myeloma.org.

The Leukemia and Lymphoma Society. Home Office. 1311 Mamaroneck Ave., White Plains, NY 10605. (800) 955-4572. (914) 949-5213. http://www.leukemialymphoma.org.

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

other

About Myeloma. Multiple Myeloma Research Foundation. September 5, 2005 [cited March 23, 2008]. http://www.multiplemyeloma.org/about_myeloma/index.php.

Multiple Myeloma and Other Plasma Cell Neoplasms Treatment (PDQ). National Cancer Institute (NCI). February 22, 2008 [cited March 23, 2008]. http://www.cancer.gov/cancertopics/pdq/treatment/myeloma/patient.

Multiple Myeloma/Other Plasma Cell Neoplasms. National Cancer Institute. Cited March 23, 2008. http://www.cancer.gov/cancertopics/types/myeloma.

Myeloma. The Leukemia and Lymphoma Society. August 24, 2007 [cited March 23, 2008]. http://www.leukemialymphoma.org/all_page?item_id=7032.

Myeloma Facts and Statistics. The Leukemia and Lymphoma Society. July 9, 2007 [cited March 23, 2008]. http://www.leukemialymphoma.org/all_page?item_id=6989.

Practice Guidelines in Oncology Multiple Myeloma v.1.2008. National Comprehensive Cancer Network. August 15, 2007 [cited March 23, 2008]. http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf.

What is Multiple Myeloma? American Cancer Society (ACS). September 8, 2005 [cited March 23, 2008]. http://www.cancer.org/docroot/CRI/content/CRI_2_2_1x_What_Is_Multiple_Myeloma.asp?sitearea=.

Margaret Alic Ph.D.

Melinda Oberleitner R.N., D.N.S.