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Multiple Myeloma

The Merck Manual Home Edition
"Multiple myeloma is a cancer of plasma cells in which abnormal plasma cells multiply uncontrollably in the bone marrow and occasionally in other parts of the body.

*People often have bone pain and fractures, and they may also have kidney problems, immuno-compromise, weakness, and confusion.
*Diagnosis is made by measuring the amounts of different types of antibodies in blood and urine and confirmed by a bone marrow biopsy.
*Chemotherapy drugs and corticosteroids are often used for treatment.

Typically, multiple myeloma occurs in people at least 60 years of age. Although its cause is not certain, the increased occurrence of multiple myeloma among close relatives indicates that heredity plays a role. Exposure to radiation is thought to be a possible cause, as is exposure to benzene and other solvents.

Normally, plasma cells make up less than 1% of the cells in the bone marrow. In multiple myeloma, typically the majority of bone marrow elements are cancerous plasma cells. The overabundance of these cancerous plasma cells in the bone marrow leads to the increased production of proteins that suppress the development of other normal bone marrow elements, including white blood cells, red blood cells, and platelets (cell-like particles that help the body form blood clots). In addition, the abnormal plasma cells almost always produce a large amount of a single type of antibody accompanied by a markedly reduced amount of all other types of normal antibodies.

Often, collections of cancerous plasma cells develop into tumors that lead to loss of bone, most commonly in the pelvic bones, spine, ribs, and skull. Infrequently, these tumors develop in areas other than bone, particularly in the lungs, liver, and kidneys.

Because plasma cell tumors often invade bone, bone pain, often in the back, ribs, and hips, may occur. Other symptoms result from the complications.

Fractures may occur if loss of bone density (osteoporosis) from plasma cell tumors weakens bones.

In addition, calcium released from the bones may result in abnormally high levels of calcium in the blood, possibly causing constipation, increased frequency of urination, kidney problems, weakness, and confusion.

The reduced production of red blood cells often leads to anemia, which causes fatigue, weakness, and pallor and may lead to heart problems. Decreased production of white blood cells leads to repeated infections, which may cause fever and chills. Decreased platelet production impairs the blood's ability to clot and results in easy bruising or bleeding.

Pieces of monoclonal antibodies, known as light chains, frequently end up in the collecting system of the kidneys, sometimes permanently damaging them by interfering with their filtering function and leading to kidney failure. The light chain pieces of the antibody in the urine (or blood) are called Bence Jones proteins. The increased number of growing cancerous cells can lead to the overproduction and excretion of uric acid in the urine, which can lead to kidney stones. Deposits of certain types of antibody pieces in the kidneys or other organs can lead to amyloidosis, another serious disorder found in a small number of people with multiplemyeloma.

In rare instances, multiple myeloma interferes with blood flow to the skin, fingers, toes, nose, kidneys, and brain because the blood thickens (hyper-viscosity syndrome—see see Symptoms and Complications).

Multiple myeloma may be discovered even before people have symptoms, when laboratory tests done for another reason show elevated protein levels in the blood or protein in the urine, or an x-ray done for another reason shows specific areas of bone loss. Bone loss may be widespread or more often appear as isolated punched-out areas in bones.

Multiple myeloma is sometimes suspected because of symptoms, such as back pain or bone pain in other sites, fatigue, fevers, and bruising. Blood tests done to investigate such symptoms may reveal that a person has anemia, a decreased white blood cell count, a decreased platelet count, or kidney failure.

The most useful laboratory tests are blood and urine protein electrophoresis and immunoelectrophoresis. They detect and identify an overabundance of a single type of antibody found in most people who have multiple myeloma. Doctors also measure the different types of antibodies, especially IgG, IgA, and IgM.

Calcium levels are usually measured as well. A urine specimen collected over a 24-hour period is analyzed for the amount and types of protein in it. Bence Jones proteins are found in the urine of half of the people who have multiple myeloma.

A bone marrow aspirate and biopsy are done to confirm the diagnosis. In people with multiplmyeloma, these specimens show a large number of plasma cells abnormally arranged in sheets and clusters. Individual cells also may appear abnormal.

In addition, other blood tests are useful in determining the overall outlook for the person. Higher levels of beta2-microglobulin and lower levels of albumin in the person's blood when the disease is diagnosed usually indicate the likelihood of a shortened survival and are likely to affect treatment decisions.

Treatment and Prognosis:
Multiple myeloma remains incurable despite recent remarkable advances in therapy. Treatment is aimed at preventing or relieving symptoms and complications, destroying abnormal plasma cells, and slowing progression of the disorder.

The most consistently helpful group of drugs for multiple myeloma is corticosteroids, such as prednisone, methylprednisolone, or dexamethasone, although many new drugs are showing great promise. In addition, chemotherapy slows the progression of multiple myeloma by killing the abnormal plasma cells. Because chemotherapy kills normal cells as well as abnormal ones, the blood cells are monitored and the dose is adjusted if the number of normal white blood cells and platelets decreases too much. Melphalan, and less often cyclophosphamide, are the chemotherapy drugs most often added to corticosteroids. Doxorubicin and newer chemically related drugs are also effective. Nearly one third of people respond to treatment with thalidomide or bortezomib, but giving these drugs together with chemotherapy drugs or corticosteroids increases their effectiveness. A newer drug that is related to thalidomide, lenalidomide, also is effective in treating multiplemyeloma, especially in people in whom myeloma is difficult to treat or recurs. Combining lenalidomide with corticosteroids improves its effectiveness.

Because multiple myeloma is such a serious disorder, doctors use thalidomide, even though it can cause birth defects, but very strict precautions are needed.

Many new combinations of treatment are being used. One involves several months of conventional chemotherapy followed by high-dose chemotherapy. Because this high-dose treatment is also toxic to normal blood cells made in the bone marrow, stem cells (unspecialized cells that transform into immature blood cells, which eventually mature to become red blood cells, white blood cells, and platelets) are collected from the person's blood before the high-dose chemotherapy is administered. These stem cells are then returned (transplanted) to the person after the high-dose treatment. Generally, this procedure is reserved for people who are younger than 70.

Strong analgesics and radiation therapy directed at the affected bones can help relieve bone pain, which can be severe. Radiation therapy may also prevent the development of fractures. However, radiation therapy may damage bone marrow function, which can impact the ability of the patient to be treated with anti-myeloma drugs. Monthly intravenous administration of pamidronate (a bisphosphonate—a drug that slows loss of bone density) and the more potent drug zoledronic acid can reduce the development of bony complications, and most people with multiple myeloma receive these drugs as part of their treatment forever. People are encouraged to take calcium and vitamin D supplements as long as they do not have high levels of calcium in their blood, and doctors encourage them to stay active because these actions help prevent bone loss. Prolonged bed rest tends to accelerate bone loss and makes the bones more vulnerable to fractures. Most people can enjoy a normal lifestyle that includes most activities. Drinking plenty of fluids dilutes the urine and helps prevent dehydration, which can make kidney failure more likely.

People who have signs of infection—fever, chills, cough productive of sputum, or reddened areas of the skin—should seek medical attention promptly because they may need antibiotics. People also may be at risk of infections with the herpes zoster virus, especially when they are treated with specific anti-myeloma drugs such as bortezomib. An oral antiviral drug called acyclovir taken long-term may help prevent herpes infections. People who have severe anemia may need transfusions of red blood cells. Erythropoietin or darbepoietin, drugs that stimulate red blood cell formation, may adequately treat the anemia in some people. High levels of calcium in the blood can be treated with intravenous fluids and often require intravenous bisphosphonates. People who have high levels of uric acid in the blood or widespread disease may benefit from allopurinol, a drug that blocks the body's production of uric acid.

Currently, no cure is available for multiple myeloma, but most people respond to treatment. Recently, the number of effective treatments has increased, and as a result, the average survival has nearly doubled. But survival time varies widely depending on certain features, such as kidney problems, blood levels of certain proteins including beta2-microglobulin and serum albumin, and genetic characteristics, at the time of diagnosis and the response to treatment. Importantly, bisphosphonates to reduce bony complications, substances that stimulate the production of blood cells (growth factors) to increase the number of red and white blood cells, and better pain relievers have also greatly improved the quality of life. Occasionally, people who survive for many years after successful treatment of multiple myeloma develop leukemia or irreversible loss of bone marrow function. These late complications may result from chemotherapy and often lead to severe anemia and an increased susceptibility to infections and bleeding.

Because multiple myeloma is ultimately fatal, people with multiple myeloma are likely to benefit from discussions of end-of-life care that involve their doctors and appropriate family and friends. Points for discussion may include advance directives, the use of feeding tubes, and pain relief."

Medications Used in Treatment:
1. Thalidomides: Revlimid®/lenalidomide,Pomalyst®/pomalidomide, Thanlomid®/thalidomide
2. Alkylating Drugs: cyclophosphamide, alkeran
3. Bisphonates: Zometav/zoledronic acid
4. Anthracyclines: Doxil®/liposoomal doxorubicin
5. Proteasome Inhibitor: Velcade®/bortezomib
6. HDAC Inhibitors: Farydak®.

Suggested Links:
*N.H.S. Choices (with Video)
*Multiple Myeloma Societies and Foundations

*The European Myeloma Network recommendations on the treatment of newly diagnosed patients with multiple myeloma lists thalidomid as a possible treatment.

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