Results for multiple myeloma
On this page:
 
Medical Encyclopedia:

Multiple Myeloma

Definition

Multiple myeloma is a cancer in which antibodyproducing 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 anti-body 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.

— Margaret Alic, Ph.D.


 
 
Dictionary: multiple myeloma

n.

A malignant proliferation of plasma cells in bone marrow causing numerous tumors and characterized by the presence of abnormal proteins in the blood.


 
Oncology Encyclopedia: Multiple Myeloma

Key Terms: Amyloidosis, Anemia, Antibody, Antigen, B cell, Bence-Jones protein, Beta 2-microglobulin, Cryoglobulinemia, Electrophoresis, Hemoglobin, Hypercalcemia, Hyperviscosity, Immunoglobulin, M-protein, Malignant, Monoclonal, Monoclonal gammopathy of undetermined significance, Neoplasm, Osteoblast, Osteoclast, Osteolytic lesion, Osteoporosis, Paraprotein, Plasma cell, Platelet.

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 disease (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:

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 (graftversus-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

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?

carefully. Blood tests, x rays, and other imaging studies may be used to check for a recurrence.

Resources

Books

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

Organizations

International Myeloma Foundation. 12650 Riverside Dr., Suite 206, North Hollywood, CA 91607. (800) 452-CURE. (818) 487-7455. . 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. . Information, support, and guidance for patients and health care professionals.

Multiple Myeloma Research Foundation. 11 Forest Street, New Canaan, CT 06840. (203) 972-1250. . Information and research funding.

Other

"About Myeloma." Multiple Myeloma Research Foundation. [cited June 15, 2005]. .

Complementary and Alternative Therapies for Leukemia, Lymphoma, Hodgkin's Disease and Myeloma. The Leukemia and Lymphoma Society. [cited June 15, 2005]. .

Facts and Statistics About Leukemia, Lymphoma, Hodgkin's Disease and Myeloma. The Leukemia and Lymphoma Society. [cited March 15, 2005]. .

"Multiple Myeloma and Other Plasma Cell Neoplasms." CancerNet. National Cancer Institute. [cited April 16, 2005]. .

"Multiple Myeloma." Cancer Resource Center. American Cancer Society. [cited June 15, 2005]. .

—Margaret Alic, Ph.D.

 
Dental Dictionary: multiple myeloma

n

A primary malignant neoplasm of bone marrow characterized by proliferation of cells resembling plasma cells. Circumscribed radiolucencies are seen within the bones, and Bence Jones protein is usually found in the urine.

Multiple myeloma. (Regezi, Sciubba, Jordan, 2003)

Multiple myeloma. (Regezi, Sciubba, Jordan, 2003)

 
Britannica Concise Encyclopedia: multiple myeloma

A malignant proliferation of abnormal plasma cells that populate the marrow-containing bones of the body. The affected plasma cells produce myeloma protein, a monoclonal antibody that replaces normal antibodies in the blood, thereby increasing susceptibility to infection and renal failure. Symptoms include pain, anemia, weakness, infection, a tendency to hemorrhage, shortness of breath, kidney insufficiency, bone fractures, and neurological symptoms. It is considered a progressive and incurable disease; treatments with thalidomide, bone-marrow transplantation, and high-dose chemotherapy may extend life span, although success rates are variable.

For more information on multiple myeloma, visit Britannica.com.

 
Wikipedia: multiple myeloma
Multiple myeloma
Classification & external resources
ICD-10 C90.0
ICD-9 203.0
ICD-O: M9732/3
OMIM 254500
DiseasesDB 8628
MedlinePlus 000583
eMedicine med/1521 
MeSH D009101

Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease after Otto Kahler) is a type of cancer of plasma cells which are immune system cells in bone marrow that produce antibodies. Its prognosis, despite therapy, is generally poor, and treatment may involve chemotherapy and stem cell transplant. It is part of the broad group of diseases called hematological malignancies.

Clinical features

Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember the common tetrad of multiple myeloma is CRAB - C = Calcium (elevated), R =Renal failure, A = Anemia, B = Bone lesions.[1] Myeloma has many possible symptoms, and all symptoms may be due to other causes. They are presented here in decreasing order of incidence.

Bone pain

Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent localized pain may indicate a pathological fracture. Involvement of the vertebrae may lead to spinal cord compression. Myeloma bone disease is due to proliferation of tumor cells and release of IL-6, also known as osteoclast activating factor (OAF), which stimulates osteoclasts to break down bone. These bone lesions are lytic in nature and are best seen in plain radiographs, which may show a "punched-out" resorptive lesions. The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms.

Infection

The most common infections are pneumonias and pyelonephritis. Common pneumonia pathogens include S pneumoniae, S aureus, and K pneumoniae, while common pathogens causing pyelonephritis include E coli and other gram-negative organisms. The increased risk of infection is due to immune deficiency resulting from diffuse hypogammaglobulinemia, which is due to decreased production and increased destruction of normal antibodies.

Renal failure

Renal failure may develop both acutely and chronically. It is commonly due to hypercalcemia (see above). It may also be due to tubular damage from excretion of light chains, also called Bence Jones proteins, which can manifest as the Fanconi syndrome (type II renal tubular acidosis). Other causes include glomerular deposition of amyloid, hyperuricemia, recurrent infections (pyelonephritis), and local infiltration of tumor cells.

Anemia

The anemia found in myeloma is usually normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.

Neurological symptoms

Common problems are weakness, confusion and fatigue due to hypercalcemia. Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, there may be radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome and other neuropathies (due to infiltration of peripheral nerves by amyloid). It may give rise to paraplegia in late presenting cases.

Diagnosis

Investigations

The presence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate (ESR) and a high serum protein (especially raised immunoglobulin) may prompt further testing. A doctor will request protein electrophoresis of the blood and urine, which might show the presence of a paraprotein (monoclonal protein, or M protein) band, with or without reduction of the other (normal) immunoglobulins (known as immune paresis). One type of paraprotein is the Bence Jones protein which is a urinary paraprotein composed of free light chains (see below). Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease. The paraprotein is an abnormal immunoglobulin produced by the tumor clone. Very rarely, the myeloma is nonsecretory (not producing immunoglobulins).

In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM. IgD and IgE myeloma are very rare. In addition, light and or heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains).

Additional findings include: a raised calcium (when osteoclasts are breaking down bone, releasing calcium into the bloodstream), raised serum creatinine due to reduced renal function, which may be due to paraprotein deposition in the kidney.

Workup

The workup of suspected multiple myeloma includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton and proximal long bones. Myeloma activity sometimes appear as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull X-ray as "punched-out lesions" (pepper pot skull). Magnetic resonance imaging (MRI) is more sensitive than simple X-ray in the detection of lytic lesions, and may supersede skeletal survey, especially when vertebral disease is suspected. Occasionally a CT scan is performed to measure the size of soft tissue plasmacytomas.

A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for myeloma. Immunohistochemistry (staining particular cell types using antibodies against surface proteins) can detect plasma cells which express immunoglobulin in the cytoplasm but usually not on the surface; myeloma cells are typically CD56, CD38, CD138 positive and CD19 and CD45 negative.[1] Cytogenetics may also be performed in myeloma for prognostic purposes.

Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM (immunoglobulins) to look for immune paresis, and β2-microglobulin which provides prognostic information. On peripheral blood smear the rouleaux formation of red blood cells is commonly seen.

The recent introduction of a commercial immunoassay for measurement of free light chains potentially offers an improvement in monitoring disease progression and response to treatment, particularly where the paraprotein is difficult to measure accurately by electrophoresis (for example in light chain myeloma, or where the paraprotein level is very low). Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma.[citation needed]

Diagnostic criteria

In 2003, the International Myeloma Working Group[1] agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma and MGUS (monoclonal gammopathy of undetermined significance):

  • Symptomatic myeloma:
    1. Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)
    2. A monoclonal protein (paraprotein) in either serum or urine
    3. Evidence of end-organ damage (related organ or tissue impairment, ROTI):
  • Asymptomatic myeloma:
    1. Serum paraprotein >30 g/L AND/OR
    2. Clonal plasma cells >10% on bone marrow biopsy AND
    3. NO myeloma-related organ or tissue impairment
  • Monoclonal gammopathy of undetermined significance (MGUS):
    1. Serum paraprotein <30 g/L AND/OR
    2. Clonal plasma cells <10% on bone marrow biopsy AND
    3. NO myeloma-related organ or tissue impairment

Related conditions include solitary plasmacytoma (a single tumor of plasma cells, typically treated with irradiation), plasma cell dyscrasia (where only the antibodies produce symptoms, e.g. AL amyloidosis), and POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes).

Staging

International Staging System

The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group in 2003 [2]:

  • Stage I: β2-microglobulin (β2M) < 3.5 mg/L, albumin >= 3.5 g/dL
  • Stage II: β2M < 3.5 and albumin < 3.5; or β2M between 3.5 and 5.5
  • Stage III: β2M > 5.5
Durie-Salmon staging system

First published in 1975, the Durie-Salmon staging system [3] is still in use, but has largely been superseded by the simpler ISS:

  • stage 1: all of
    • Hb > 10g/dL
    • normal calcium
    • Skeletal survey: normal or single plasmacytoma or osteoporosis
    • Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgA
    • Urinary light chain excretion < 4 g/24h
  • stage 2: fulfilling the criteria of neither 1 nor 3
  • stage 3: one or more of
    • Hb < 8.5g/dL
    • high calcium > 12mg/dL
    • Skeletal survey: 3 or more lytic bone lesions
    • Serum paraprotein >7g/dL if IgG, > 5 g/dL if IgA
    • Urinary light chain excretion > 12g/24h

Stages 1, 2 and 3 of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine:

  • A: serum creatinine < 2mg/dL (< 177 umol/L)
  • B: serum creatinine > 2mg/dL (> 177 umol/L)

Pathophysiology

Multiple myeloma develops in post-germinal center B lymphocytes.

A chromosomal translocation between the immunoglobulin heavy chain gene (on the fourteenth chromosome, locus 14q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11[4]) is frequently observed in patients with multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma. The result is proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. The chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) the thirteenth chromosome is also observed in about 50% of cases.

Production of cytokines (especially IL-6) by the plasma cells causes much of their localised damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the attraction of new blood vessels) is increased.

The produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy and various other myeloma-associated symptoms.

Epidemiology

There are approximately 45,000 people in the United States living with multiple myeloma, and the American Cancer Society estimates that approximately 14,600 new cases of myeloma are diagnosed each year in the United States. It follows from here that the average survival at diagnosis is about three years.

Multiple myeloma is the second most prevalent blood cancer (10%) after non-Hodgkin's lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 65 to 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset.

Multiple myeloma affects slightly more men than women. African Americans and Native Pacific Islanders have the highest reported incidence of this disease in the United States and Asians the lowest. Results of a recent study found the incidence of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. Among African Americans, myeloma is one of the top 10 leading causes of cancer death.

Treatment

Treatment for multiple myeloma is focused on disease containment and suppression. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), treatment may be deferred.

Although allogeneic stem cell transplant might cure the cancer, it is considered investigational given the high treatment-related mortality of 5-10% associated with the procedure. In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate or zoledronic acid) are routinely administered to prevent fractures and erythropoietin to treat anemia.

Initial therapy

Initial treatment is aimed at treating symptoms and reducing disease burden. Commonly used induction regimens include dexamethasone with or without thalidomide and cyclophosphamide, and VAD (vincristine, adriamycin, and dexamethasone). Low-dose therapy with melphalan combined with prednisone can be used to palliate symptoms in patients who cannot tolerate aggressive therapy. Plasmapheresis can be used to treat symptomatic protein proliferation (hyperviscosity syndrome).

In younger patients, therapy may include high-dose chemotherapy, melphalan, and autologous stem cell transplantation. This can be given in tandem fashion, i.e. an autologous transplant followed by a second transplant. Nonmyeloablative (or "mini") allogeneic stem cell transplantation is being investigated as an alternative to autologous stem cell transplant, or as part of a tandem transplant following an autologous transplant (also known as an "auto-mini" tandem transplant).

A 2007 trial indicated that the addition of thalidomide to reduced-intensity chemotherapy (melphalan and prednisone, MP) in patients between 65-75 led to a marked prolongation (median 51 versus 33 months) in survival. Reduced intensity melphalan followed by a stem cell transplant was inferior to the MP-thalidomide regimen (median survival 38 months).[5]

Relapse

The natural history of myeloma is of relapse following treatment. Depending on the patient's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant.

Later in the course of the disease, "treatment resistance" occurs. This may be a reversible effect,[4] and some new treatment modalities may re-sensitize the tumor to standard therapy. For patients with relapsed disease, bortezomib (or Velcade®) is a recent addition to the therapeutic arsenal, especially as second line therapy. Bortezomib is a proteasome inhibitor. Finally, lenalidomide (or Revlimid®), a less toxic thalidomide analog, is showing promise for treating myeloma.

Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve dialysis.

Prognosis

The International Staging System can help to predict survival, with a median survival of 62 months for stage 1 disease, 45 months for stage 2 disease, and 29 months for stage 3 disease.[2]

Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.

Prognostic markers such as these are always generated by retrospective analyses, and it is likely that new treatment developments will improve the outlook for those with traditionally 'poor-risk' disease.

See also

References

  1. ^ a b c International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749-57. PMID 12780789.
  2. ^ a b Greipp PR, San Miguel J, Fonseca R, Avet-Loiseau H, Jacobson JL, Rasmussen E, Crowley J, Durie BMG. Development of an international prognostic index (IPI) for myeloma: report of the international myeloma working group. Hematology Journal 2003;4:S42. NLM ID 100965523.
  3. ^ Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer 1975;36:842–854. PMID 1182674.
  4. ^ a b Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;351:1860-73. PMID 15509819.
  5. ^ Facon T, Mary JY, Hulin C et al (2007). "Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial". Lancet 370: 1209-1218. 

External links

Pathology: hematology (primarily C81-C96/200-208, D45-D47, D50-D77/280-289)
WBCs hematological malignancy (Lymphoma, leukemia)
-cytosis (Agranulocytosis, Leukocytosis, Lymphocytosis, Monocytosis) • -penia (Lymphopenia, Neutropenia)
RBCs/anemia/
hemoglobinopathy		 nutritional anemia: Iron deficiency anemia, Plummer-Vinson syndrome, Megaloblastic anemia (Pernicious anemia)
hereditary hemolytic anemia: G6PD Deficiency, Thalassemia, Sickle-cell disease/trait, Hereditary spherocytosis, Hereditary elliptocytosis, Hereditary stomatocytosis
acquired hemolytic anemia: Warm autoimmune hemolytic anemia, HUS, MAHA, PNH
aplastic anemia: Acquired PRCA, Diamond-Blackfan anemia, Fanconi anemia • Sideroblastic anemia • Hemochromatosis
Coagulation/platelets coagulopathy: DIC • Hemophilia (A, B, C, XIII) • Von Willebrand disease
Purpura: Henoch-Schönlein, ITP, TTP
primary hypercoagulable state: Protein C deficiency - Protein S deficiency - Antithrombin III deficiency
other hemorrhagic conditions: Bernard-Soulier syndrome - Glanzmann's thrombasthenia - Grey platelet syndrome
Histiocytosis WHO-I Langerhans cell histiocytosis - non-Langerhans-cell histiocytosis/WHO-II (Juvenile xanthogranuloma, Hemophagocytic lymphohistiocytosis) - malignant histiocytic disorders/WHO-III (Acute monocytic leukemia, Malignant histiocytosis, Erdheim-Chester disease)
Other Asplenia/hyposplenism - Methemoglobinemia
Hematological malignancy histology (ICD-O 9590-9989)
Lymphomas (9590-9759) Hodgkin's lymphoma vs.