Multiple Myeloma – Causes, Signs and symptoms

Multiple Myeloma

Also called: Plasma Cell Myeloma, Myeloma Bone Disease, Kahler’s Disease, Myelomatosis, Multiple Myeloma Cancer

Reviewed By:
Martin E. Liebling, M.D., FACP

Summary

Multiple myeloma is cancer of the plasma cells in the bone marrow. Although it may affect the bone, the disease is considered a type of blood cancer.

Cancers of the plasma cells are known as plasma cell neoplasms. Plasma cells are part of the immune system, a network of specialized cells and organs throughout the body designed to recognize foreign substances, such as  toxins, viruses, bacteria and parasites.

The main type of immune system cell is the lymphocyte. The two types of lymphocytes are B lymphocytes (B-cells) and T lymphocytes (T-cells). When B-cells react to an infection, they mature and become plasma cells. When these cells grow uncontrollably, they can produce a tumor. Usually, these tumors develop in the bone marrow. Bone marrow is the soft, inner component of bone. It produces all forms of blood cells, including:

  • White blood cells. Cells that fight infection.
  • Red blood cells. Cells that carry oxygen to tissues all over the body.
  • Platelets. Cells that help develop blood clots and control bleeding.

When only one tumor develops, it is known as a solitary plasmacytoma. More often, there are numerous tumors spread throughout the body or diffuse penetration of the bone marrow by plasma cells. This disorder is known as multiple myeloma. The overgrowth of plasma cells can make it difficult for bone marrow to produce adequate numbers of normal blood cells. Eventually this can result in a shortage of white blood cells (leukopenia), red blood cells (anemia), and platelets (thrombocytopenia). Shortages in these types of cells can lead to a decreased ability to fight off infection, fatigue and excessive bleeding.

The exact cause of multiple myeloma has not been identified. Researchers, however, have gained a greater understanding of how specific changes in DNA can cause plasma cells to become cancerous. A number of risk factors have been identified, including age and having other plasma cell diseases. 

Symptoms of multiple myeloma vary based on the extent of the disease. Common signs and symptoms include bone pain, fatigue, weakness and recurrent infection.

Multiple myeloma may be first detected in routine blood tests. However, additional tests, including bone marrow tests, may be necessary to verify the diagnosis. The treatment and prognosis for multiple myeloma depends on the stage of the disease as well as other factors including the patient’s age and general health. Treatment may include bone marrow/stem cell transplantation, chemotherapy and radiation therapy. In many case, patients may receive a combination of these therapies.

According to the American Cancer Society (ACS), almost 20,000 new cases of multiple myeloma will be diagnosed in the United States in 2007. Of these new cases, approximately 10,900 will occur in men and 8,900 in women. The disease is also about twice as common among African Americans as it is among white Americans.

About multiple myeloma (MM)

Multiple myeloma is cancer of the plasma cells in bone marrow. Diseases in which plasma cells become cancerous are known as plasma cell neoplasms. Plasma cells are part of the immune system, a network of specialized cells that make proteins (antibodies) that attack and destroy foreign substances. These substances include viruses, bacteria, fungi and parasites.

The cells of the immune system work together to defend the body from infections and other diseases. The main type of immune system cell is the lymphocyte. The two types of lymphocytes are:

  • B lymphocytes (B-cells). B-cells defend the body from invading bacteria and other harmful substances by changing into plasma cells, which produce antibodies. The antibodies then mark the foreign substances for destruction.
  • T lymphocytes (T-cells). T-cells recognize the infected cells and destroy them directly.

When B-cells react to an infection, they mature and transform into plasma cells. Mainly located in the bone marrow (the soft, inner component of bone), plasma cells manufacture and release antibodies, also known as immunoglobulins. When these cells grow uncontrollably, they can produce a tumor, which typically develop in the bone marrow. When only one tumor develops, it is known as a solitary plasmacytoma. More frequently, there are numerous tumors or extensive cellular infiltration spread throughout the bone marrow in many bones of the body. This disorder is known as multiple myeloma.

All forms of blood cells are produced in the bone marrow, including:

  • White blood cells (WBCs or leukocytes). Cells that fight infection, which include plasma cells.
  • Red blood cells (RBCs orerythrocytes). Cells that carry oxygen to tissues throughout the body.
  • Platelets (thrombocytes). Cells that help develop blood clots and control bleeding.

In patients with multiple myeloma, the overgrowth of plasma cells can interfere with the bone marrow’s ability to produce adequate numbers of normal cells. Over time, this can result in a shortage of white blood cells (leukopenia), red blood cells (anemia), and platelets (thrombocytopenia). Shortages in these types of cells can lead to a decreased ability to fight off infection, fatigue and excessive bleeding.  Although many plasma cells are being produced in patients with multiple myeloma, the cells are abnormal. As a result, the antibodies they produce are not useful in fighting infections.

The American Cancer Society (ACS) predicts that in 2007 there will be nearly 20,000 new cases of multiple myeloma in the United States. The disease is more common in men than women, with about 10,900 cases occurring in males and 8,900 occurring in females. In 2007, about 10,800 Americans are expected to die of multiple myeloma.

The five-year survival rate for multiple myeloma is estimated at 33 percent by the ACS. Younger patients tend to have a better chance of survival than elderly people. In addition, the five-year survival rate is based on patients who were diagnosed and treated for the disease more than five years ago. Treatment advances may result in a better prognosis for recently diagnosed patients.

Potential causes and risk factors of MM

The exact cause of multiple myeloma has not been identified. Researchers, however, have gained a greater understanding of how specific changes in DNA can cause plasma cells to become cancerous.

Some forms of cancer are caused by DNA mutations that “turn on” oncogenes (genes that speed up cell division) or “turn off” tumor suppressor genes (genes that slow down cell division or cause cells to die at the right time). Researchers have determined that irregularities of some oncogenes develop early in the course of plasma cell tumors. Mutations in other oncogenes are more likely to be discovered in myeloma after bone marrow relapse. Mutations in tumor suppressor genes are associated with spread to other organs. 

Myeloma cells also have irregularities in their chromosomes, which are pieces of DNA and protein that regulate cell growth and metabolism. Normal human cells contain 46 chromosomes. Many myeloma cells, however, have parts of chromosome 13 missing. Known as a deletion, this abnormality appears to make the myeloma more aggressive and resistant to treatment.  

Another form of DNA abnormality is atranslocation. A translocation is the transfer of DNA from one chromosome to another. This abnormality can turn on oncogenes, which causes rapid cell division. Approximately 50 percent of all people with myeloma have abnormally translocated chromosomes in their cancer cells.

Researchers have also determined that patients with plasma cell tumors have irregularities in other bone marrow cells known as dendritic cells. These irregularities may also trigger excess plasma cell growth. Dendritic cells release a hormone known as interleukin–6 (IL-6), which stimulates plasma cell growth. In excess, IL-6 seems to be an important factor in the development of plasma cell tumors.

In addition, researchers have identified a number of factors that may make a person more likely to develop multiple myeloma. These risk factors include:

  • Age. A person’s age is the most significant risk factor for multiple myeloma. The average age at diagnosis is 68, and only 1 percent of cases are diagnosed in people under the age of 40.
  • Gender. Men are more likely to develop multiple myeloma than women.
  • Race. Multiple myeloma is approximately twice as common among African Americans as it is among white Americans.
  • Exposure to radiation. People exposed to radioactivity from atomic blasts (such as those in Japan during World War II) and nuclear accidents have an increased risk of developing multiple myeloma.
  • Family history. Although most patients have no affected relatives, multiple myeloma seems to be more common in some families.
  • Working in a petroleum industry. Some research has suggested that workers in certain petroleum–related industries have an increased risk of developing the disease.
  • Being overweight or obese. People who are overweight or obese have an increased risk of developing myeloma. 
  • Having other plasma cell diseases. In some patients, multiple myeloma is preceded by another condition known as monoclonal gammopathy of undetermined significance (MGUS). Like multiple myeloma, MGUS is a disorder of excessive plasma cell growth. Over time, many people who have MGUS develop multiple myeloma or lymphoma.

Solitary plasmacytomais another condition that increases a person’s risk of developing the disease. Unlike multiple myeloma, which involves numerous tumors, solitary plasmacytoma involves one tumor produced by uncontrollably growing plasma cells. Many patients with this disease eventually develop multiple myeloma as well.

Signs and symptoms of multiple myeloma

Multiple myeloma can have a variety of indicators. Many signs and symptoms may develop from the reduction of normal red blood cells, white blood cells and platelets caused by the disease. Anemia, a common sign of blood cancers, causes the body to get insufficient oxygen and nutrients. As a result, an anemic person will often experience fatigue, headaches, weakness and shortness of breath.

The decrease in the amount of normal white blood cells weakens the patient’s defense against infection. As a result, recurrent infection may be a sign of the disease. People with multiple myeloma are 15 times more likely to develop an infection. Pneumonia is the most common and serious of these infections. Others include urinary tract infections and shingles.

Thrombocytopenia (an abnormally low amount of platelets) can lower a patient’s ability to repair holes in damaged blood vessels. Signs of thrombocytopenia include easy bruising and excessive bleeding.

Myeloma can damage the kidneys and cause kidney failure.  Signs and symptoms of kidney failure include weakness and swelling in the legs. In some cases, myeloma can cause large amounts of calcium to be released into the blood. Known as hypercalcemia, this disorder can cause kidney failure. Signs and symptoms of high blood calcium include:

  • Dry mouth and excessive thirst
  • Excessive urination
  • Loss of appetite
  • Digestive problems, including constipation, nausea and vomiting
  • Drowsiness or sleepiness
  • Mental confusion
  • Restlessness

The disease can also cause bone damage and weakening of the bones. This can result in significant bone pain and unexplained bone fractures in patients. In addition, multiple myeloma can cause spinal bones to weaken and collapse, possibly putting pressure on the spinal cord and spinal nerves. When these bones compress these areas a variety of signs and symptoms may occur, including severe pain, numbness and muscle weakness.

Multiple myeloma can cause the blood to thicken. Known as hyperviscosity, this condition can also cause slow circulation to the brain, resulting in:

  • Confusion
  • Dizziness
  • Shortness of breath
  • Stroke-like symptoms

Patients experiencing signs and symptoms of nerve compression or hyperviscosity or hypercalcemia should contact their physician immediately. These conditions are medical emergencies and require immediate treatment.

Amyloidosis is a rare complication of multiple myeloma. In this condition, proteins are deposited in various tissues and organs, impairing their function. Common signs and symptoms of amyloidosis include:

  • Numbness in the hands and feet
  • Weak hand grip
  • Swelling of the extremities
  • Difficulty swallowing

Another possible complication of multiple myeloma is cryoglobulinemia. In this condition, abnormal proteins in the bloodstream thicken when exposed to cold temperatures. Signs and symptoms of cryoglobulinemia include pain or numbness in the fingers and toes in cold weather.

Many patients may not experience symptoms of myeloma until after the disease has reached an advanced stage. As a result, the disease may be diagnosed during a routine blood test. The discovery of abnormal antibodies in the blood may be a sign of multiple myeloma because protein can be produced by myeloma cells.

In other patients symptoms may be overlooked because they resemble symptoms of more common illnesses. Patients are encouraged to contact their physician when they experience any symptom of myeloma. The earlier the disease is diagnosed, the earlier treatment may begin.

Diagnosis methods for multiple myeloma

A physician who suspects that a patient may have multiple myeloma will first take the patient’s medical history and perform a physical examination. To diagnose and determine the extent of the disease, a variety of tests may be ordered, including:

  • Electrophoresis. Serum protein electrophoresis (SPEP) is a procedure used to examine the blood for the presence of abnormal antibody known as monoclonal immunoglobulin. Urine may also be examined for this protein with a urine protein electrophoresis (UPEP). These tests may be used to diagnose multiple myeloma because finding the abnormal immunoglobulin in the blood and/or urine can indicate the presence of a plasma cell tumor.
  • Beta-2-microglobulin test. High levels of the protein beta-2-microglobulin in the blood may also indicate myeloma, although it is also elevated in other diseases, such as lymphoma.  
  • A complete blood count (CBC) may also be ordered. A CBC is a blood test that measures the number of red blood cells, white blood cells and platelets in a sample of blood, as well as the amount of hemoglobin in the red blood cells and additional factors.
  • Blood chemistry tests. These tests measure the level of calcium and other chemicals in the blood. They are used to monitor changes in liver or kidney function caused by myeloma or treatment with certain chemotherapy drugs.
  • 24-hour urine test. This test measures the amount of certain substances in urine collected for 24 hours. An abnormally high amount of protein may indicate multiple myeloma.
  • Bone marrow biopsy and aspiration. Usually performed at the same time, these procedures may be ordered to confirm a diagnosis of multiple myeloma. A bone marrow aspiration involves using a thin needle to collect a small sample of liquid bone marrow. A bone marrow biopsy uses a larger needle to remove a piece of bone marrow. 
  • Bone x-rays. This test uses low doses of radiation to produce images of bone on film or fluorescent screens. It can reveal signs of bone destruction caused by the cancer cells and the hormones they release.
  • CAT scan (computed axial tomography). This test allows for multiple x-rays to be taken from different angles around the patient. In multiple myeloma patients, CAT scans (also called CT scans) can detect bone damaged caused by the disease. CAT scans may also be used to guide a biopsy needle into a suspected area. This procedure is known as a CAT-guided needle biopsy.
  • MRI (magnetic resonance imaging). This test uses a powerful magnetic field to create images of structures and organs within the body allowing a computer to produce clear cross-sectional or three-dimensional images. It may be ordered to determine if the disease has caused bone destruction. As with CAT scans, a contrast material may be injected in the patient to improve the quality of the images.
  • Cytogenetics. This test may be ordered to determine if the cells have too many chromosomes, or if the chromosomes have any translocations (the transfer of DNA from one chromosome to another), deletions (the loss of part of a chromosome), inversions (the rearrangement of DNA in part of a chromosome) or additions (all or part of a chromosome is duplicated and too many copies are found in a cell).
  • PET scan (positron emission tomography). In this procedure, the patient receives an injection of glucose (sugar) containing a small amount of radioactive material. Once in the body, the radioactive glucose is absorbed by the cancer cells. A camera then scans the patient and detects where the radioactive glucose was absorbed. Areas of cancer cells appear as hot spots on the images. This test is typically used to determine if and where cancer has spread in the body.
  • Bone density test. This procedure uses a special type of x-ray to measure bone loss.

Multiple myeloma cannot be diagnosed with any one test, according to the ACS. Instead, a physician will consider a number of factors including symptoms, findings from the physical examination, and results of blood, bone marrow, urine and imaging tests. To be diagnosed with the disease a patient must have the appropriate symptoms and at least one major criterion or at least three minor criteria.

Major criteria for the diagnosis of multiple myeloma:

  • A biopsy reveals a plasma cell tumor.
  • More than 30 percent of cells in the sample of bone marrow are plasma cells.
  • The monoclonal immunoglobulin in the blood or urine is above a certain amount.

Minor criteria for the diagnosis of multiple myeloma include:

  • Between 10 and 30 percent of cells in the bone marrow sample are plasma cells.
  • Imaging tests have detected holes in bones (osteolytic lesions) due to tumor growth.
  • There is insufficient normal antibody in the blood.
  • Monoclonal immunoglobulin is detected, but not enough to fulfill a major criterion.

Treatment and prevention for MM

After multiple myeloma has been diagnosed and staged, a treatment plan will be established for the patient. As with all cancers, treatment for multiple myeloma is usually coordinated by a cancer care team, headed by a primary care physician and/or hematologist or oncologist.

There are a variety of methods used to treat multiple myeloma. The National Cancer Institute (NCI) describes this disease as highly treatable but rarely curable. The treatment method chosen for each patient depends on the stage of the disease as well as other factors including the patient’s age (survival is higher in younger patients) and overall health. Common treatment methods for multiple myeloma include:

  • Bone marrow/stem cell transplant. This method allows a patient to receive high levels of chemotherapy. Although high-dose chemotherapy destroys the myeloma cells, it also destroys normal blood cells in the bone marrow. After the treatment, the patient receives an infusion of healthy stem cells through a vein. The stem cells may come from a matched donor or from the patients themselves. As a result, new blood cells begin to develop from the transplanted cells. This procedure is the standard treatment for young myeloma patients in otherwise good health, and many centers are also using it for patients up to age 70.

  • Chemotherapy. This treatment method uses powerful drugs to destroy cancer cells. It may also be used to prevent the cancer from spreading. For multiple myeloma, a combination of drugs is usually used in treatment.

  • Radiation therapy. Radiation therapy uses high-energy rays to destroy cancer cells and shrink tumors. It may be ordered to treat areas of bone damaged by myeloma that have not responded to chemotherapy and are producing pain. It is also the most common treatment for solitary plasmacytomas.

  • Biological therapy or immunotherapy. This method uses substances naturally produced by the immune system to kill myeloma cells, slow the growth of the cancer cells or activate the patient’s immune system to more successfully fight the disease.

In addition to cancer treatments, patients may receive treatment with medications to control their symptoms. Multiple myeloma can cause bone to dissolve, resulting in weakness and fractures. Bisphosphonates may be prescribed to slow this process. In some cases the drug is given in combination with chemotherapy. Diuretics, which are drugs that increase urination, may be prescribed to help the kidney remove excess fluid, salts and pain relievers from the body. Erythropoietin may also be prescribed to improve anemia and its symptoms.

Plasmapheresis may be recommended to relieve some symptoms of multiple myeloma. This procedure involves removing blood from a patient’s vein and separating the blood cells from the blood plasma (the liquid component of blood). The plasma is discarded because it contains the abnormal protein (monoclonal immunoglobulin) produced by the myeloma cells. The plasma is replaced with a salt solution and blood proteins from donors and the remaining components are returned to the patient through another vein. This treatment may be recommended when the buildup of myeloma proteins causes blood to thicken and interfere with circulation.

Following treatment, patients typically require regular visits to their physicians. Frequent checkups enable their physician to detect any changes in health and treat them immediately. Checkups may include a physical examination, blood tests, x-rays and other imaging tests.

Patients are encouraged to report the development of any new symptoms to their physician. They may be a sign of recurrent multiple myeloma (myeloma that has come back after treatment) or side effects of treatment. If a relapse occurs, it can occur in the bone or in another part of the body.

According to the American Cancer Society (ACS), the five-year relative survival rate for multiple myeloma is approximately 33 percent. Younger individuals diagnosed with the disease have a better chance of survival than the elderly.

There are no established prevention methods for multiple myeloma because there are no known avoidable risk factors.

Ongoing research regarding multiple myeloma

There is a great deal of research being conducted in multiple myeloma, including clinical trials and scientific studies. Areas of research for multiple myeloma include:

  • Transplants. Researchers are studying ways to improve the survival rate of patients following high-dose chemotherapy and bone marrow transplantation. Many studies are being conducted to explore the benefits of following an autologous (using the patient’s own cells) transplant with an allogenic one (using cells from donors). In addition, a new radioactive drug is being studied for use prior to stem cell transplant. This drug targets the bone and bone marrow that is to be treated. 
  • Interleukin-6 (IL-6). Produced by bone marrow-support tissue, the tumor growth factorIL-6 encourages the development of myeloma cells and eventually causes bone destruction. Researchers are trying to develop ways to block IL-6.
  • RANKL. Produced in the bone marrow, the tumor growth factor RANKL stimulates the cells responsible for dissolving bone. People with multiple myeloma have abnormally high amounts of RANKL. Scientists are looking for ways to block RANKL. One method being studied is the use of a natural substance known as osteoprotegerin.
  • Many new drugs are being tested for use in the treatment of multiple myeloma, including immunomodulatory agents (ImiDs), arsenic trioxide, radioactive drugs and thalidomide.

    In addition, a new drug that blocks blood vessel growth is being studied to treat multiple myeloma. Other drugs that block or attack molecules associated with tumor growth are also being evaluated in research studies. Two of the drugs, known as farnesyl transferase inhibitors (FTI), are being studied in clinical trials of multiple myeloma patients.
  • Diagnostic tests. A new test called gene expression profiling has been developed in recent years. This test can help determine which patients will need to receive intensive treatment. This test is experimental and needs additional research before it is used routinely for patients.

Staging multiple myeloma

Staging is the process of determining how far the cancer has spread. It is necessary for a physician to plan treatment and determine the patient’s prognosis. The Durie-Salmon system may be used to stage multiple myeloma. The system is based on four factors:

  • The quantity of abnormal monoclonal immunoglobulin in the patient’s blood or urine. The presence of large amounts of monoclonal immunoglobulin suggests that many malignant (cancerous) plasma cells are present and are producing that abnormal protein.

  • The level of calcium in the patient’s blood. High levels of calcium in the blood indicate advanced bone damage.

  • The severity of the patient’s bone damage based on x-rays. Multiple areas of bone damage suggest an advanced stage of multiple myeloma.

  • The level of hemoglobin in the patient’s blood. Hemoglobin is the substance in red blood cells that transports oxygen. Low levels suggest that the cancer cells occupy a large amount of the bone marrow and that there is not enough space for the normal red blood cell-producing marrow cells.

These factors are combined to estimate the amount of myeloma cells in the body. The cancer is then assigned a stage based on the extent of the disease. The stages of multiple myeloma include:

  • Stage I. In this stage a small amount of myeloma cells are found. Multiple myeloma is considered in stage I when all of the following features are present:

    • The level of hemoglobin is only slightly below normal (above 10 grams per deciliter [g/dl]).

    • Bone x-rays appear normal or detect only one area of bone damage.

    • The level of calcium in the blood is normal (less than 12 milligrams per deciliter [mg/dl]).

    • There is only a small amount of monoclonal immunoglobulin in the blood or urine.

    The term smoldering myeloma may be used to describe the disease in stage I.

  • Stage II. In this stage, a moderate amount of myeloma cells are found. Multiple myeloma is considered in stage II when the patient’s features are between those of stage I and stage III.

  • Stage III. In this stage, a large amount of myeloma cells are found. Multiple myeloma is considered to be at stage III when one or more of the following features are present:

    • The level of hemoglobin is low (below 8.5 g/dl).

    • The level of calcium in the blood is high (above 12 mg/dl).

    • There are three or more areas of bone damage.

    • There is a large amount of monoclonal immunoglobulin in the blood or urine.

According to the American Cancer Society (ACS), the median survival times for patients in the different stages of multiple myeloma include:

StageMedian survival time
I62 months (just over 5 years)
IIAbout 44 months (nearly 4 years)
IIIAbout 29 months (nearly 2 1/2 years)

Questions for your doctor about myeloma

Preparing questions in advance can help patients have more meaningful discussions with their physicians regarding their conditions. Patients may wish to ask their doctor or healthcare professional the following questions about multiple myeloma:

  1. What symptoms suggest that I may have multiple myeloma?
  2. What tests will be used to diagnose my condition?
  3. Where are the myelomas located in my body?
  4. What type of specialists will I need for this cancer?
  5. What are my treatment options?
  6. What are the risks with the treatments?
  7. Will I need a bone marrow transplant?
  8. Can I donate my own bone marrow or do I need another donor?
  9. How will you determine an appropriate donor?
  10. How will my condition be monitored after treatment?
  11. Am I a candidate for any clinical trials?
  12. What is my prognosis with this cancer?
  13. Can you refer me to an appropriate support group?
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