Multiple Myeloma

  • Dana-Farber/Brigham and Women's Cancer Care

    Multiple myeloma is a type of cancer that begins in plasma cells, white blood cells that produce antibodies. It is also called Kahler's disease, myelomatosis or plasma cell myeloma. Learn about multiple myeloma and find information on how we support and care for people with multiple myeloma before, during, and after treatment.

Treatment 

The Hematologic Oncology Center provides specialized care for all types of cancers of the blood, including leukemia, lymphoma, multiple myeloma and Waldenström’s macroglobulinemia.

The center also includes the hematopoietic stem cell transplantation program, which is one of the largest and most experienced in the world.

To make sure your care is as seamless as possible, a dedicated team of clinicians, who are highly specialized experts in your type of blood cancer, will care for you throughout the treatment process, from diagnosis though long-term follow-up.

Your care team will include oncologists, surgeons, hematologists, physician assistants, nurses, and clinical social workers who are committed to delivering safe, high-quality patient care.  

We develop personalized, comprehensive treatment plans for all our patients, offering the latest therapies and supportive resources and taking your individual needs into account.

In addition to conventional treatment approaches, you may have the opportunity to participate in clinical trials that offer access to new, innovative treatments for your type of cancer.

A variety of services and programs also support your care, including nutrition services, emotional support and counseling, pain management, donor services for stem cell transplantation, and support for cancer survivors.

Learn more about treatment and care in the Hematologic Oncology Center 

Contact us 

New patients: See Center page for phone numbers by treatment program

All other inquiries: 617-632-6140 

Fax: 617-632-3730 

Information for: Patients | Healthcare Professionals

General Information About Multiple Myeloma and Other Plasma Cell Neoplasms

Multiple myeloma and other plasma cell neoplasms are diseases in which the body makes too many plasma cells.

Plasma cells develop from B lymphocytes (B cells), a type of white blood cell that is made in the bone marrow. Normally, when bacteria or viruses enter the body, some of the B cells will change into plasma cells. The plasma cells make a different antibody to fight each type of bacteria or virus that enters the body, to stop infection and disease.

Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B lymphocyte, T lymphocyte, or natural killer cell. A B lymphocyte may become a plasma cell.
Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

Plasma cell neoplasms are diseases in which there are too many plasma cells, or myeloma cells, that are unable to do their usual work in the bone marrow. When this happens there is less room for healthy red blood cells, white blood cells, and platelets. This condition may cause anemia or easy bleeding, or make it easier to get an infection. The abnormal plasma cells often form tumors in bones or soft tissues of the body. The plasma cells also make an antibody protein, called M protein, that is not needed by the body and does not help fight infection. These antibody proteins build up in the bone marrow and can cause the blood to thicken or can damage the kidneys.

Plasma cell neoplasms can be benign (not cancer) or malignant (cancer).

There are different types of plasma cell neoplasms and not all of them are cancer. The following types of plasma cell neoplasms are cancer:

  • Multiple myeloma.
  • Plasmacytoma.
  • Macroglobulinemia.

Monoclonal gammopathy of undetermined significance (MGUS) is not cancer but can become cancer.

There are several types of plasma cell neoplasms.

Plasma cell neoplasms include the following:

Multiple myeloma

In multiple myeloma, abnormalplasma cells (myelomacells) build up in the bone marrow, forming tumors in many bones of the body. These tumors may prevent the bone marrow from making enough healthy blood cells. Normally, the bone marrow produces stem cells (immature cells) that develop into three types of mature blood cells:

  • Red blood cells that carry oxygen and other materials to all tissues of the body.
  • White blood cells that fight infection and disease.
  • Platelets that help prevent bleeding by causing blood clots to form.

As the number of myeloma cells increases, fewer red blood cells, white blood cells, and platelets are made. The myeloma cells also damage and weaken the hard parts of the bones. Sometimes multiple myeloma does not cause any symptoms. The following symptoms may be caused by multiple myeloma or other conditions. A doctor should be consulted if any of the following problems occur:

  • Bone pain, often in the back or ribs.
  • Bones that break easily.
  • Fever for no known reason or frequent infections.
  • Easy bruising or bleeding.
  • Trouble breathing.
  • Weakness of the arms or legs.
  • Feeling very tired.

A tumor can damage the bone and cause hypercalcemia (a condition in which there is too much calcium in the blood). This can affect many organs in the body, including the kidneys, nerves, heart, muscles, and digestive tract, and cause serious health problems.

Hypercalcemia may cause the following symptoms:

  • Loss of appetite.
  • Nausea or vomiting.
  • Feeling thirsty.
  • Frequent urination.
  • Constipation.
  • Feeling very tired.
  • Muscle weakness.
  • Restlessness.
  • Mental confusion or trouble thinking.

Plasmacytoma

In this type of plasma cellneoplasm, the abnormal plasma cells (myelomacells) collect in one location and form a single tumor, called a plasmacytoma. A plasmacytoma may form in bone marrow or may be extramedullary (in soft tissues outside of the bone marrow). Plasmacytoma of the bone often becomes multiple myeloma. Extramedullary plasmacytomas commonly form in tissues of the throat and sinuses; these usually can be cured.

Symptoms depend on where the tumor is.

  • In bone, the plasmacytoma may cause pain or broken bones.
  • In soft tissue, the tumor may press on nearby areas, causing pain or other problems. A plasmacytoma in the throat, for example, can make it difficult to swallow.

Macroglobulinemia

In macroglobulinemia, abnormalplasma cells build up in the bone marrow, lymph nodes, and spleen. They make too much M protein, which causes the blood to become thick. The lymph nodes, liver, and spleen may become swollen. The thickened blood may cause problems with blood flow in small blood vessels.

Symptoms of macroglobulinemia depend on the part of the body affected. Most patients with macroglobulinemia have no symptoms. A doctor should be consulted if any of the following problems occur:

  • Feeling very tired.
  • Headache.
  • Nosebleeds.
  • Vision changes such as blurred vision or bulging eyes.
  • Dizziness.
  • Pain, tingling, or numbness in the hands, feet, fingers, toes, or other parts of the body.
  • Trouble walking.
  • Confusion.
  • Pain or a feeling of fullness below the ribs on the left side.
  • Painless lumps in the neck, underarm, stomach, or groin.

Monoclonal gammopathy of undetermined significance (MGUS)

In this type of plasma cellneoplasm, there are abnormal plasma cells in the bone marrow but there is no cancer. The abnormal plasma cells produce M protein that may be found during a routine blood or urine test. In most patients, the amount of M protein stays the same and there are no symptoms or problems. In some patients, MGUS may later become a more serious condition or cancer, such as multiple myeloma or lymphoma.

Multiple myeloma and other plasma cell neoplasms may cause a condition called amyloidosis.

In rare cases, multiple myeloma can cause organs to fail. This may be caused by a condition called amyloidosis. Antibodyproteins build up and may bind together and collect in organs, such as the kidney and heart. This can cause the organs to become stiff and unable to work the way they should.

Age can affect the risk of developing plasma cell neoplasms.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn't mean that you will not get cancer. People who think they may be at risk should discuss this with their doctor.

Plasma cell neoplasms are found most often in people who are middle aged or older. For multiple myeloma and plasmacytoma, other risk factors include the following:

  • Being black.
  • Being male.
  • Having a brother or sister who has multiple myeloma.
  • Being exposed to atomic bomb radiation.

Tests that examine the blood, bone marrow, and urine are used to detect (find) and diagnose multiple myeloma and other plasma cell neoplasms.

The following tests and procedures may be used:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Biopsy: The removal of bone cells, lymph nodes, or tissues so they can be viewed under a microscope by a pathologist to check for abnormal cells or signs of cancer.
  • Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for abnormal cells.
    Bone marrow aspiration and biopsy; drawing shows a patient lying face down on a table and a Jamshidi needle (a long, hollow needle) being inserted into the hip bone. Inset shows the Jamshidi needle being inserted through the skin into the bone marrow of the hip bone.
    Bone marrow aspiration and biopsy. After a small area of skin is numbed, a Jamshidi needle (a long, hollow needle) is inserted into the patient’s hip bone. Samples of blood, bone, and bone marrow are removed for examination under a microscope.
  • X-ray: An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body. The x-rays are used to find areas where the bone is damaged.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI). An MRI may be used to find areas where the bone is damaged.
  • Complete blood count (CBC) with differential: A procedure in which a sample of blood is drawn and checked for the following:
    • The number of red blood cells and platelets.
    • The number and type of white blood cells.
    • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
    • The portion of the blood sample made up of red blood cells.
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances, such as calcium or albumin, released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it.
  • Blood or urineimmunoglobulin studies: A procedure in which a blood or urine sample is checked to measure the amounts of certain antibodies (immunoglobulins). For multiple myeloma, beta-2-microglobulin, M protein, and other proteins made by the myeloma cells are measured. A higher-than-normal amount of these substances can be a sign of disease.
  • Twenty-four-hour urine test: A test in which urine is collected for 24 hours to measure the amounts of certain substances. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. A higher than normal amount of protein may be a sign of multiple myeloma.
  • Electrophoresis: A test in which a blood or urine sample is checked for M proteins and the amount of M proteins is measured.
  • Cytogenetic analysis: A test in which cells in a sample of blood or bone marrow are viewed under a microscope to look for certain changes in the chromosomes.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) depends on the following:

  • The type of plasma cell neoplasm.
  • The stage of the disease.
  • Whether a certain immunoglobulin (antibody) is present.
  • Whether there are certain genetic changes.
  • Whether the kidney is damaged.
  • Whether the cancer responds to initial treatment or recurs (comes back).

Treatment options depend on the following:

  • The type of plasma cell neoplasm.
  • The age and general health of the patient.
  • Whether there are health problems related to the disease.
  • Whether the cancer responds to initial treatment or recurs (comes back).

Stages of Multiple Myeloma and Other Plasma Cell Neoplasms

After multiple myeloma and other plasma cell neoplasms have been diagnosed, tests are done to find out the amount of cancer in the body.

The process used to find out the amount of cancer in the body is called staging. It is important to know the stage in order to plan treatment. The following tests and procedures may be used in the staging process:

  • X-ray: An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body such as the bone marrow. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • PET scan (positron emission tomography scan): A procedure to find malignanttumorcells in the body. A small amount of radionuclide glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • Bone densitometry: A procedure that uses a special type of x-ray to measure bone loss.

Certain tests may be repeated to see how well the treatment is working.

The stage of multiple myeloma is based on the levels of beta-2-microglobulin and albumin in the blood.

Beta-2-microglobulin and albumin are found in the blood. Beta-2-microglobulin is a protein found on the surface of plasma cells. Albumin makes up the biggest part of the blood plasma. It keeps fluid from leaking out of blood vessels, brings nutrients to tissues, and carries hormones, vitamins, drugs, and other substances, such as calcium, throughout the body. The amount of beta-2-microglobulin is increased and the amount of albumin is decreased in the blood of patients with multiple myeloma.

The following stages are used for multiple myeloma:

Stage I multiple myeloma

In stage I multiple myeloma, the blood levels are as follows:

  • beta-2-microglobulin level is lower than 3.5 g/mL; and
  • albumin level is 3.5 g/dL or higher.

Stage II multiple myeloma

In stage II multiple myeloma, the blood levels are as follows:

  • beta-2-microglobulin level is lower than 3.5 g/mL and the albumin level is lower than 3.5 g/dL; or
  • beta-2-microglobulin level is as high as 3.5 g/mL but lower than 5.5 g/mL.

Stage III multiple myeloma

In stage III multiple myeloma, the blood level of beta-2-microglobulin is 5.5 g/mL or higher.

The stages of other plasma cell neoplasms are different from the stages of multiple myeloma.

Isolated plasmacytoma of bone

In isolated plasmacytoma of bone, one plasma cell tumor is found in the bone, less than 5% of the bone marrow is made up of plasma cells, and there are no other signs of cancer.

Extramedullary plasmacytoma

One plasma cell tumor is found in the soft tissue but not in the bone or the bone marrow.

Macroglobulinemia

There is no standard staging system for macroglobulinemia.

Monoclonal Gammopathy of Undetermined Significance

In monoclonal gammopathy of undetermined significance (MGUS), less than 10% of the bone marrow is made up of plasma cells, there is M protein in the blood, and there are no signs of cancer.

Refractory Multiple Myeloma and Other Plasma Cell Neoplasms

Multiple myeloma and other plasma cellneoplasms are called refractory when the number of plasma cells continues to increase even though treatment is given.

Treatment Option Overview

There are different types of treatment for patients with multiple myeloma and other plasma cell neoplasms.

Different types of treatments are available for patients with multiple myeloma and other plasma cellneoplasms. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Ten types of standard treatment are used:

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

Other drug therapy

Corticosteroid therapy

Corticosteroids are steroids that have antitumor effects in lymphomas and lymphoidleukemias.

Thalidomide and lenalidomide

Thalidomide and lenalidomide are drugs called angiogenesis inhibitors that prevent the growth of new blood vessels into a solid tumor.

Targeted therapy

Targeted therapy is a treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Proteasome inhibitor therapy and monoclonal antibody therapy are two types of targeted therapy used in the treatment of multiple myeloma and other plasma cell neoplasms.

  • Bortezomib is a proteasome inhibitor, which blocks the action of proteasomes in cancer cells and may prevent the growth of tumors.
  • Rituximab is a monoclonal antibody. Monoclonal antibody therapy uses antibodies made in the laboratory, from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.

High-dose chemotherapy with stem cell transplant

This treatment is a way of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.

Biologic therapy

Biologic therapy is a treatment that uses the patient's immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body's natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

Surgery

Surgery to remove the tumor may be done, usually followed by radiation therapy. Treatment given after the surgery, to increase the chances of a cure, is called adjuvant therapy.

Watchful waiting

Watchful waiting is closely monitoring a patient’s condition without giving any treatment until symptoms appear or change.

Plasmapheresis

Plasmapheresis is a procedure in which blood is removed from the patient and sent through a machine that separates the plasma (the liquid part of the blood) from the blood cells. The patient's plasma contains the unneeded antibodies and is not returned to the patient. The normal blood cells are returned to the bloodstream along with donated plasma or a plasma replacement. Plasmapheresis does not prevent new antibodies from forming.

Supportive care

This therapy controls problems or side effects caused by the disease or its treatment, and improves quality of life. Supportive care is given to treat bone problems or amyloidosis related to multiple myeloma and other plasma cell neoplasms.

New types of treatment are being tested in clinical trials.

This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI Web site.

New combinations of therapies

Clinical trials are studying different combinations of biologic therapy, chemotherapy, steroid therapy, and drugs such as thalidomide or lenalidomide.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's clinical trials database.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

Treatment Options for Multiple Myeloma and Other Plasma Cell Neoplasms

A link to a list of current clinical trials is included for each treatment section. For some types or stages of cancer, there may not be any trials listed. Check with your doctor for clinical trials that are not listed here but may be right for you.

Multiple Myeloma

Patients without symptoms may not need treatment. When symptoms appear, the treatment of multiple myeloma may be done in phases:

  • Induction therapy: This is the first phase of treatment. Its purpose is to reduce the amount of disease, and may include one or more of the following:
    • Corticosteroidtherapy.
    • Thalidomide or lenalidomide therapy.
    • Targeted therapy with a proteasome inhibitor (bortezomib).
    • Chemotherapy.
    Clinical trials of different combinations of treatment should be considered.
  • Consolidation chemotherapy: This is a type of high-dose chemotherapy often given as the second phase of treatment, and may include either:
    • autologous stem cell transplant, in which the patient's own stem cells are used; or
    • allogeneic stem cell transplant, in which the patient receives stem cells from a donor.
  • Maintenance therapy: After the initial treatment, maintenance therapy is often given to help keep the disease in remission for a longer time. Several types of treatment are being studied for this use, including:
    • Chemotherapy.
    • Biologic therapy.
    • Corticosteroid therapy.
    • Thalidomide therapy.

Supportive care to treat bone problems and amyloidosis may include:

  • Bisphosphonate therapy to slow bone loss and reduce bone pain. See the following PDQ summaries for more information about bisphosphonates and problems related to their use:
    • Pain
    • Oral Complications of Chemotherapy and Head/Neck Radiation
  • Radiation therapy for tumors of the spine.
  • Chemotherapy to reduce back pain from osteoporosis or compression fractures of the spine.
  • Chemotherapy and corticosteroid therapy to treat amyloidosis.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with multiple myeloma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Isolated Plasmacytoma of Bone

Standard treatment of isolated plasmacytoma of bone is usually radiation therapy.

Supportive care to treat amyloidosis may include chemotherapy and corticosteroidtherapy.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with isolated plasmacytoma of bone. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Extramedullary Plasmacytoma

Standard treatment of extramedullary plasmacytoma may include the following:

  • Radiation therapy to the tumor and nearby lymph nodes.
  • Surgery, usually followed by radiation therapy.
  • Watchful waiting after initial treatment, followed by radiation therapy, surgery, or chemotherapy if the tumor grows or causes symptoms.

Supportive care to treat amyloidosis may include chemotherapy and corticosteroidtherapy.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with extramedullary plasmacytoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma)

Treatment of Waldenström macroglobulinemia may include the following:

  • Plasmapheresis and chemotherapy.
  • Chemotherapy with one or more drugs.
  • Watchful waiting.
  • Targeted therapy with a monoclonal antibody (rituximab).
  • Biologic therapy.
  • A clinical trial of stem cell transplant.

Supportive care to treat amyloidosis may include chemotherapy and corticosteroidtherapy.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with Waldenstrom macroglobulinemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Monoclonal Gammopathy of Undetermined Significance

Treatment of monoclonal gammopathy of undetermined significance (MGUS) is usually watchful waiting, which will include regular blood tests to check the level of M protein in the blood.

Supportive care to treat amyloidosis may include chemotherapy and corticosteroidtherapy.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with monoclonal gammopathy of undetermined significance. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Refractory Plasma Cell Neoplasms

Treatment of refractoryplasma cellneoplasms may include the following:

  • Watchful waiting for patients whose disease is stable.
  • A different treatment than previously given. (See Multiple Myeloma treatment options.)

Supportive care to treat amyloidosis may include chemotherapy and corticosteroidtherapy.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with refractory multiple myeloma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

To Learn More About Multiple Myeloma and Other Plasma Cell Neoplasms

For more information from the National Cancer Institute about multiple myeloma and other plasma cell neoplasms, see the following:

For general cancer information and other resources from the National Cancer Institute, see the following:


This information is provided by the National Cancer Institute.

This information was last updated on November 18, 2009.


Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of multiple myeloma and other plasma cell neoplasms. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Diagnosis.
  • Cellular classification.
  • Staging.
  • Treatment options for different types of disorders.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less-technical language, and in Spanish.

General Information

Note: Estimated new cases and deaths from multiple myeloma in the United States in 2009:[1]

  • New cases: 20,580.
  • Deaths: 10,580.

Multiple myeloma is a systemic malignancy of plasma cells that is highly treatable but rarely curable. It is potentially curable when it presents as a solitary plasmacytoma of bone or as an extramedullary plasmacytoma. The median survival in the prechemotherapy era was about 7 months. After the introduction of chemotherapy, prognosis improved significantly with a median survival of 24 months to 30 months and a 10-year survival of 3%. Even further improvements in prognosis have occurred because of the introduction of newer therapies such as pulse corticosteroids, thalidomide, bortezomib, and autologous and allogeneic stem cell transplantation, with median survivals of 45 months to 60 months.[2][3][4] The disease is staged by estimating the myeloma tumor cell mass on the basis of the amount of monoclonal (or myeloma) protein (M protein) in the serum and/or urine, along with various clinical parameters, such as the hemoglobin and serum calcium concentrations, the number of lytic bone lesions, and the presence or absence of renal failure. The stage of the disease at presentation is a strong determinant of survival, but it has little influence on the choice of therapy since almost all patients, except for rare patients with solitary bone tumors or extramedullary plasmacytomas, have generalized disease. Treatment selection is influenced by the age and general health of the patient, prior therapy, and the presence of complications of the disease.[5]

The initial approach to the patient is to evaluate the following parameters:

  1. Detection of an M protein in the serum or urine.
  2. Detection of greater than 10% of plasma cells on a bone marrow examination.
  3. Detection of lytic bone lesions or generalized osteoporosis in skeletal x-rays.
  4. Presence of soft tissue plasmacytomas.
  5. Serum albumin and beta-2-microglobulin levels.
  6. Detection of free kappa and lambda serum immunoglobulin light chain.[6]

References:

  1. American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.

  2. Kumar SK, Rajkumar SV, Dispenzieri A, et al.: Improved survival in multiple myeloma and the impact of novel therapies. Blood 111 (5): 2516-20, 2008.

  3. Ludwig H, Durie BG, Bolejack V, et al.: Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group. Blood 111 (8): 4039-47, 2008.

  4. Brenner H, Gondos A, Pulte D: Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 111 (5): 2521-6, 2008.

  5. Rajkumar SV, Kyle RA: Multiple myeloma: diagnosis and treatment. Mayo Clin Proc 80 (10): 1371-82, 2005.

  6. Dispenzieri A, Kyle R, Merlini G, et al.: International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 23 (2): 215-24, 2009.

Cellular Classification

Diseases associated with a monoclonal (or myeloma) protein (M protein) included in this presentation are:

  1. Asymptomatic plasma cell neoplasia with minimal evidence of disease aside from the presence of an M protein (monoclonal gammopathy of undetermined significance [MGUS]).[1] (Usually IgG kappa or lambda, IgA kappa or lambda.)
  2. Symptomatic plasma cell neoplasia. (Usually IgG kappa or gamma, IgA kappa or gamma.)
    1. Primarily affecting bones:
      1. Multiple myeloma (94%).
      2. Solitary plasmacytoma (3%).
    2. Extramedullary plasmacytoma (3%).

      These usually occur in the nasopharynx, tonsils, or paranasal sinuses.[2]

  3. Macroglobulinemia.

    Patients often have lymphadenopathy and hepatosplenomegaly; less than 5% of patients have lytic bone lesions. (Usually IgM kappa or gamma.)

    1. Asymptomatic.
    2. Symptomatic.[3]

    This entity is called lymphoplasmacytic lymphoma or Waldenström macroglobulinemia. (Refer to the PDQ summary on Adult Non Hodgkin Lymphoma Treatment for more information.)

References:

  1. Kyle RA, Rajkumar SV: Monoclonal gammopathy of undetermined significance and smouldering multiple myeloma: emphasis on risk factors for progression. Br J Haematol 139 (5): 730-43, 2007.

  2. Knowling MA, Harwood AR, Bergsagel DE: Comparison of extramedullary plasmacytomas with solitary and multiple plasma cell tumors of bone. J Clin Oncol 1 (4): 255-62, 1983.

  3. Kyle RA, Garton JP: The spectrum of IgM monoclonal gammopathy in 430 cases. Mayo Clin Proc 62 (8): 719-31, 1987.

Stage Information

Multiple Myeloma

The International Myeloma Working Group studied 11,171 patients, of whom 2,901 received high-dose therapy and 8,270 received only standard-dose therapy.[1] An International Staging System was derived as follows:

Stage I multiple myeloma: Beta-2-microglobulin less than 3.5 and albumin greater than or equal to 3.5 (median survival of 62 mo).

Stage II multiple myeloma: Beta-2-microglobulin less than 3.5 and albumin less than 3.5 or beta-2-microglobulin 3.5 to less than 5.5 (median survival of 44 mo).

Stage III multiple myeloma: Beta-2-microglobulin greater than or equal to 5.5 (median survival of 29 mo).

Impaired renal function worsens prognosis regardless of stage. Genetic aberrations detected by interphase fluorescence in situ hybridization (FISH) may define prognostic groups in retrospective and prospective analyses.[2][3] Short survival and shorter duration of response to therapy have been reported with t(4;14)(p16;q32), t(14;16)(q32;q23), cytogenetic deletion of 13q-14, and deletion of 17p13 (p53 locus).[2][3][4][5][6] Whether choice of therapy based on FISH analysis can influence outcome must await further prospective trials.

Newer clinical investigations are stratifying patients with multiple myeloma into a so-called standard-risk group, which accounts for 75% of patients, with a median survival of 3 to 6 years, and a high-risk group, which has a median survival of less than 3 years.[2][3][4][5][6][7] This stratification, based on cytogenetic findings, has been derived from retrospective analyses and requires prospective validation.[7] Bone marrow samples are sent for cytogenetic and FISH analysis.

Standard risk is defined as any one of the following cytogenetic findings:

  • No adverse FISH or cytogenetics.
  • Hyperdiploidy.
  • t (11;14) by FISH.
  • t (6;14) by FISH.

These patients most often have disease that expresses IgG kappa monoclonal gammopathies, and they present with lytic bone lesions.

High risk is defined as any one of the following cytogenetic findings:

  • del 17p by FISH.
  • t (4;14) by FISH.
  • t (14;16) by FISH.
  • Cytogenetic del 13.
  • Hypodiploidy.

These patients often have disease that expresses IgA lambda monoclonal gammopathies and less often have skeletal-related complications.

Isolated Plasmacytoma of Bone

If a solitary lytic lesion of plasma cells is found on skeletal survey in an otherwise asymptomatic patient, and a bone marrow examination from an uninvolved site contains less than 5% to 10% plasma cells, the patient has an isolated plasmacytoma of bone.[8][9][10] About 25% of patients have a serum and/or urine M protein; this should disappear following adequate radiation of the lytic lesion. When clinically indicated, magnetic resonance imaging may reveal unsuspected bony lesions that were undetected on standard radiographs.

Extramedullary Plasmacytoma

Patients with isolated plasma cell tumors of soft tissues, most commonly occurring in the tonsils, nasopharynx, or paranasal sinuses, should have skeletal x-rays and bone marrow biopsy.[11][12][13] If these tests are negative, the patient has extramedullary plasmacytoma. About 25% of patients have serum and/or urine M protein; this should disappear following adequate radiation.

Macroglobulinemia

Macroglobulinemia is a proliferation of plasmacytoid lymphocytes secreting an IgM M protein. Patients often have lymphadenopathy and hepatosplenomegaly, but bony lesions are uncommon. No generally accepted staging system exists.

The term macroglobulinemia describes an increase in the serum concentration of a monoclonal IgM.[14] Most patients are asymptomatic and do not require treatment. The most common symptoms and signs are fatigue, manifestations of hyperviscosity (e.g., headache, epistaxis, and visual disturbances), and neurologic abnormalities. (Refer to the PDQ summary on Fatigue for more information.) Serum or plasma viscosity (relative to water) measures the risk of symptoms. The normal viscosity level is 1.7 to 2.1; symptoms may rarely appear between 3.0 and 4.0 but more commonly appear above 4.0. Emergent therapy (i.e., plasmapheresis and chemotherapy) is usually required above a viscosity level of 4.0. Lymphadenopathy and splenomegaly are found in about 33% of patients. The increased intravascular concentration of high molecular weight IgM leads to an expansion of the plasma volume, a dilutional anemia, and in extreme cases, congestive heart failure. Sludging of the blood can be seen in conjunctival and retinal veins with dilatation and segmentation of vessels (i.e., a link of sausage appearance), retinal hemorrhages, and papilledema. Similar problems with the circulation of blood in the central nervous system can cause ataxia, nystagmus, vertigo, confusion, and disturbances of consciousness.

The various disorders associated with the appearance of a monoclonal IgM include:

  1. Monoclonal Gammopathy of Undetermined Significance (MGUS). Patients are asymptomatic, the M protein is stable, and no lymphadenopathy, splenomegaly, or bony lesions are present.
  2. Waldenström Macroglobulinemia (WM). This entity is called lymphoplasmacytic lymphoma in the World Health Organization/Revised European-American Lymphoma classification system. Patients are symptomatic, have lymphoplasmacytic marrow infiltration, and a rising serum IgM concentration, and may have lymphadenopathy or splenomegaly. Rarely, patients with WM have lytic bone lesions. (Refer to the PDQ summary on Adult Non Hodgkin Lymphoma Treatment for more information.)
  3. Absolute lymphocyte count exceeding 5,000 cells/mm3. The patient may be classified as having chronic lymphocytic leukemia (CLL) if the lymphocytes are of the small, well-differentiated variety. CLL must be differentiated from the lymphoplasmacytosis that may occur as a peripheral blood manifestation of WM. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
  4. Chronic cold agglutinin disease. Patients have a high cold agglutinin titer and no morphologic evidence of neoplasia. These patients often have a hemolytic anemia that is aggravated by cold exposure. The IgM has kappa light chains in more than 90% of these types of patients.

Monoclonal Gammopathy of Undetermined Significance

Patients with MGUS have an M protein in the serum without findings of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma, and with less than 10% of plasma cells in the bone marrow.[14][15][16] These types of patients are asymptomatic and should not be treated. They must, however, be followed carefully since about 1% to 2% per year will progress to develop one of the symptomatic B-cell neoplasms and may then require therapy.[17][18] Risk factors predicting progression include an abnormal serum-free light chain ratio, non-IgG class MGUS, and a high serum M protein level (≥15 g/L).[19] Virtually all cases of multiple myeloma are preceded by a gradually rising level of MGUS.[20][21][22]

References:

  1. Greipp PR, San Miguel J, Durie BG, et al.: International staging system for multiple myeloma. J Clin Oncol 23 (15): 3412-20, 2005.

  2. Fonseca R, Blood E, Rue M, et al.: Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101 (11): 4569-75, 2003.

  3. Avet-Loiseau H, Attal M, Moreau P, et al.: Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood 109 (8): 3489-95, 2007.

  4. Gertz MA, Lacy MQ, Dispenzieri A, et al.: Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood 106 (8): 2837-40, 2005.

  5. Gutiérrez NC, Castellanos MV, Martín ML, et al.: Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 21 (1): 143-50, 2007.

  6. Sagaster V, Ludwig H, Kaufmann H, et al.: Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion. Leukemia 21 (1): 164-8, 2007.

  7. Dispenzieri A, Rajkumar SV, Gertz MA, et al.: Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc 82 (3): 323-41, 2007.

  8. Ozsahin M, Tsang RW, Poortmans P, et al.: Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients. Int J Radiat Oncol Biol Phys 64 (1): 210-7, 2006.

  9. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000.

  10. Dimopoulos MA, Hamilos G: Solitary bone plasmacytoma and extramedullary plasmacytoma. Curr Treat Options Oncol 3 (3): 255-9, 2002.

  11. Tournier-Rangeard L, Lapeyre M, Graff-Caillaud P, et al.: Radiotherapy for solitary extramedullary plasmacytoma in the head-and-neck region: A dose greater than 45 Gy to the target volume improves the local control. Int J Radiat Oncol Biol Phys 64 (4): 1013-7, 2006.

  12. Michalaki VJ, Hall J, Henk JM, et al.: Definitive radiotherapy for extramedullary plasmacytomas of the head and neck. Br J Radiol 76 (910): 738-41, 2003.

  13. Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999.

  14. Kyle RA, Rajkumar SV: Monoclonal gammopathy of undetermined significance and smouldering multiple myeloma: emphasis on risk factors for progression. Br J Haematol 139 (5): 730-43, 2007.

  15. Kyle RA, Therneau TM, Rajkumar SV, et al.: Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 354 (13): 1362-9, 2006.

  16. 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 121 (5): 749-57, 2003.

  17. Attal M, Harousseau JL, Stoppa AM, et al.: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med 335 (2): 91-7, 1996.

  18. Kyle RA, Therneau TM, Rajkumar SV, et al.: A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 346 (8): 564-9, 2002.

  19. Rajkumar SV, Kyle RA, Therneau TM, et al.: Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 106 (3): 812-7, 2005.

  20. Weiss BM, Abadie J, Verma P, et al.: A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 113 (22): 5418-22, 2009.

  21. Landgren O, Kyle RA, Pfeiffer RM, et al.: Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 113 (22): 5412-7, 2009.

  22. Bladé J, Rosiñol L, Cibeira MT: Are all myelomas preceded by MGUS? Blood 113 (22): 5370, 2009.

Treatment Option Overview

Monoclonal gammopathy of undetermined significance or smoldering myeloma must be distinguished from progressive myeloma. Asymptomatic patients with multiple myeloma who have no lytic bone lesions and normal renal function may be initially observed safely outside the context of a clinical trial.[1][2][3] Treatment should be given to patients with symptomatic advanced disease. Treatment should be directed at reducing the tumor cell burden and reversing any complications of disease, such as renal failure, infection, hyperviscosity, or hypercalcemia with appropriate medical management. (Refer to the PDQ summary on Hypercalcemia for more information.) Response criteria have been developed for patients on clinical trials.[4]

References:

  1. He Y, Wheatley K, Clark O, et al.: Early versus deferred treatment for early stage multiple myeloma. Cochrane Database Syst Rev (1): CD004023, 2003.

  2. Riccardi A, Mora O, Tinelli C, et al.: Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer 82 (7): 1254-60, 2000.

  3. Hjorth M, Hellquist L, Holmberg E, et al.: Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol 50 (2): 95-102, 1993.

  4. Durie BG, Harousseau JL, Miguel JS, et al.: International uniform response criteria for multiple myeloma. Leukemia 20 (9): 1467-73, 2006.

Amyloidosis

Primary amyloidosis can result in severe organ dysfunction especially in the kidney, heart, or peripheral nerves. Two randomized trials showed prolonged overall survival (OS) with the use of oral chemotherapy with melphalan with or without colchicine versus colchicine alone.[1][2][Level of evidence: 1iiA] A randomized prospective study of 100 patients with immunoglobulin amyloidosis light chain (AL) compared melphalan plus high-dose dexamethasone with high-dose melphalan plus autologous stem-cell rescue.[3] After a median follow-up of 3 years, median OS favored the nontransplant arm (56.9 mo vs. 22.2 mo; P = .04).[3][Level of evidence: 1iiA] The 24% transplant-related mortality in this series and others reflects the difficulties involved with high-dose chemotherapy in older patients with organ dysfunction.[3][4][5][6] A randomized trial confirming the benefit of autologous transplantation is not anticipated.[7] As is true for all plasma cell dyscrasias, anecdotal responses for amyloidosis have been reported, as in the Southwest Oncology Group's (SWOG-9628) trial, for dexamethasone alone and in combination with thalidomide and cyclophosphamide or lenalidomide.[8][9][10][11] An anecdotal series describes full-intensity and reduced-intensity allogeneic stem cell transplantation.[12]

Elevated serum levels of cardiac troponins and brain natriuretic peptide are poor prognostic factors. A proposed staging system for primary systemic amyloidosis based on these serum levels requires independent and prospective confirmation.[13]

References:

  1. Kyle RA, Gertz MA, Greipp PR, et al.: A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 336 (17): 1202-7, 1997.

  2. Skinner M, Anderson J, Simms R, et al.: Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med 100 (3): 290-8, 1996.

  3. Jaccard A, Moreau P, Leblond V, et al.: High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 357 (11): 1083-93, 2007.

  4. Dispenzieri A, Kyle RA, Lacy MQ, et al.: Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study. Blood 103 (10): 3960-3, 2004.

  5. Skinner M, Sanchorawala V, Seldin DC, et al.: High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med 140 (2): 85-93, 2004.

  6. Leung N, Leung TR, Cha SS, et al.: Excessive fluid accumulation during stem cell mobilization: a novel prognostic factor of first-year survival after stem cell transplantation in AL amyloidosis patients. Blood 106 (10): 3353-7, 2005.

  7. Mehta J, Gerta MA, Dispenzieri A: High-dose therapy for amyloidosis: the end of the beginning? Blood 103 (10): 3612-3, 2004.

  8. Dhodapkar MV, Hussein MA, Rasmussen E, et al.: Clinical efficacy of high-dose dexamethasone with maintenance dexamethasone/alpha interferon in patients with primary systemic amyloidosis: results of United States Intergroup Trial Southwest Oncology Group (SWOG) S9628. Blood 104 (12): 3520-6, 2004.

  9. Wechalekar AD, Goodman HJ, Lachmann HJ, et al.: Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood 109 (2): 457-64, 2007.

  10. Dispenzieri A, Lacy MQ, Zeldenrust SR, et al.: The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood 109 (2): 465-70, 2007.

  11. Sanchorawala V, Wright DG, Rosenzweig M, et al.: Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood 109 (2): 492-6, 2007.

  12. Schönland SO, Lokhorst H, Buzyn A, et al.: Allogeneic and syngeneic hematopoietic cell transplantation in patients with amyloid light-chain amyloidosis: a report from the European Group for Blood and Marrow Transplantation. Blood 107 (6): 2578-84, 2006.

  13. Dispenzieri A, Gertz MA, Kyle RA, et al.: Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 22 (18): 3751-7, 2004.

Multiple Myeloma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Idiotypic myeloma cells can be found in the blood of myeloma patients in all stages of the disease.[1][2] For this reason, when treatment is indicated, systemic treatment must be considered for all patients with symptomatic plasma cell neoplasms. Patients with monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic, smoldering myeloma do not require immediate treatment but must be followed carefully for signs of disease progression.

Patients with a monoclonal (or myeloma) protein (M protein) in the serum and/or urine are evaluated as follows:

  1. Measure and follow the serum M protein by serum electrophoresis or by specific immunoglobulin assays; however, specific immunoglobulin quantification always overestimates the M protein because normal immunoglobulins are included in the result. For this reason, baseline and follow-up measurements of the M protein should be done by the same method.[3] Quantitative serum-free light chains may be helpful to follow response if an M protein is not apparent.
  2. Measure and follow the amount of M protein light chains excreted in the urine per 24 hours. Measure the total amount of protein excreted per 24 hours and multiply this value by the percentage of urine protein that is M protein as determined by electrophoresis of concentrated urine protein. An easier, but less accurate, method uses a spot-urine protein electrophoresis.
  3. Identify the heavy- and light-chain of the M protein by immunofixation electrophoresis.
  4. Measure the hemoglobin, leukocyte, platelet, and differential counts.
  5. Determine the percentage of marrow plasma cells. Be aware that marrow plasma cell distribution may vary in different sites.
  6. Measure serum free kappa and lambda light chain. This is especially useful in cases of oligosecretory plasma cell dyscrasia or following cases of light chain amyloidosis.[4]
  7. Take needle aspirates of a solitary lytic bone lesion, extramedullary tumor(s), or enlarged lymph node(s) to determine whether these are plasmacytomas.
  8. Evaluate renal function with serum creatinine and a creatinine clearance. Electrophoresis of concentrated urine protein is very helpful in differentiating glomerular lesions from tubular lesions. Glomerular lesions, such as those resulting from glomerular deposits of amyloid or light chain deposition disease, result in the nonselective leakage of all serum proteins into the urine; the electrophoresis pattern of this urine resembles the serum pattern with a preponderance of albumin. In most myeloma patients, the glomeruli function normally allowing only the small molecular weight proteins, such as light chains, to filter into the urine. The concentration of protein in the tubules increases as water is reabsorbed. This leads to precipitation of proteins and the formation of tubular casts, which may injure the tubular cells. With tubular lesions, the typical electrophoresis pattern shows a small albumin peak and a larger light chain peak in the globulin region; this tubular pattern is the usual pattern found in myeloma patients.
  9. Measure serum levels of calcium, alkaline phosphatase, lactic dehydrogenase, and, when indicated by clinical symptoms, cryoglobulins, and serum viscosity.
  10. Obtain radiographs of the skull, ribs, vertebrae, pelvis, shoulder girdle, and long bones. Whole-body, low-dose, nonenhanced multidetector computed tomography (CT) and magnetic resonance imaging (MRI) are being evaluated as measures for therapy response monitoring.[5][6] MRI of the spine or long bones is more sensitive in detecting lytic lesions, but any prognostic or therapeutic value for this information remains to be determined.[6]
  11. Perform MRI if a paraspinal mass is detected or if symptoms suggest spinal cord or nerve root compression.
  12. If amyloidosis is suspected, do a needle aspiration of subcutaneous abdominal fat and stain the bone marrow biopsy for amyloid as the easiest and safest way to confirm the diagnosis.[7]
  13. Measure serum albumin and beta-2-microglobulin as independent prognostic factors.[8][9]
  14. A high plasma cell labeling index (≥3%) and the presence of circulating myeloma cells are considered poor prognostic factors.[10]

These initial studies should be compared with subsequent values at a later time, when it is necessary to decide whether the disease is stable or progressive, responding to treatment, or getting worse. The major challenge is to separate the stable asymptomatic group of patients who do not require treatment from patients with progressive, symptomatic myeloma who should be treated immediately.[11][12]

Patients with MGUS have an M protein in the serum and/or urine and less than 10% plasma cells in the marrow but no other signs or symptoms of disease. The patients with smoldering myeloma have similar characteristics but may have greater than 10% of marrow plasma cells. Since 1% to 2% of MGUS patients per year will progress to develop myeloma (most commonly), amyloidosis, a lymphoma, or chronic lymphocytic leukemia, these types of patients must be followed carefully.[13] Treatment is delayed until the disease progresses to the stage that symptoms or signs appear. Patients with MGUS or smoldering myeloma do not respond more frequently, achieve longer remissions, or have improved survival if chemotherapy is started early while they are still asymptomatic as opposed to waiting for progression before treatment is initiated.[11][12][14][15]

Current therapy for patients with symptomatic myeloma can be divided into categories of induction therapies, consolidation therapies (which are less applicable for the very elderly), maintenance therapies, and supportive care (such as bisphosphonates). (For more information on supportive care therapies such as bisphosphonates, refer to the Pain summary.) The choice of induction therapy is unclear at the present time; however, the current basic categories include the use of steroids, thalidomide, and lenalidomide, as seen in the text below. Several questions are raised when therapy is being chosen for a patient with symptomatic myeloma at first presentation:

  • Is the patient eligible for a clinical trial? The sequence and combinations of new and older therapies can only be determined by prospective clinical trials.
  • Is autologous stem cell transplantation a possible consolidation option for this patient? If so, alkylating agents should be avoided during induction therapy to avoid compromise of stem cell collection and to lessen leukemogenic risk.
  • Does the patient have comorbidities? Age, organ dysfunction, and risk of cardiovascular and thrombotic complications would influence the choice of induction therapies as well as the choice of whether to consider consolidation therapies.

Induction Therapy

Multiple therapeutic agents are available for induction therapy, either alone or in combinations [16] and include:

  • Steroids (dexamethasone, prednisone).
  • Thalidomide.
  • Lenalidomide.
  • Bortezomib.
  • Alkylating agents (melphalan, cyclophosphamide).
  • Other cytotoxic drugs (vincristine, doxorubicin, liposomal doxorubicin).

Clinical trials are needed to establish the regimens with the best efficacy and least long-term toxicity. Current trials are listed in the section on Combination therapy. Until results become available, outside the context of a clinical trial, clinicians may choose induction therapy based on the following considerations:

  1. In patients younger than age 70, alkylators are avoided up front to avoid stem cell toxicity with subsequent risks for cytopenias, secondary malignancies, or poor stem cell harvesting if transplantation is considered for consolidation.[17]
  2. Bortezomib or lenalidomide is combined with dexamethasone for at least 8 months or until best response if consolidation therapy is planned.[18][19] (See sections on Lenalidomide and Bortezomib.)
  3. The choice of bortezomib or lenalidomide is based on side-effect profile and route of administration. Bortezomib is given in frequent intravenous doses and can have significant neuropathic toxicities.[19][20][21] Lenalidomide is given orally and has increased risk for deep venous thrombosis, requiring additional prophylactic medication.[14][18] Bortezomib is preferred for patients with renal impairment.[22]
  4. Patients with a standard risk, as defined in the section on Stage Information, might receive induction therapy alone followed by careful observation after best response.[23] Patients with a high risk might receive induction therapy until best response, followed by consolidation therapy with allogeneic or autologous stem cell transplantations.[23]

These considerations require validation by ongoing clinical trials and participation in these studies is the preferred choice when possible.

Corticosteroids

Since the mid-1980s, dexamethasone has been administered at a dose of 40 mg orally for 4 consecutive days in the same schedule as administered with the vincristine plus doxorubicin plus dexamethasone (VAD) regimen.[24] Response rates of 60% to 70% in previously untreated patients appeared as high as those in patients treated with VAD.[24][25][Level of evidence: 3iiiDiv] A prospective trial randomly assigned 488 patients older than 65 years to receive dexamethasone alone, melphalan plus dexamethasone, dexamethasone plus interferon-alpha, and melphalan plus prednisone; with a median follow-up of 7.1 years, no difference was observed in overall survival (OS) (median survival times were 32 to 40 mo).[26][Level of evidence: 1iiA] The patients on the dexamethasone-based arms had significantly more infections, glucose intolerance, gastrointestinal symptoms, and psychiatric complaints. (For more information on gastrointestinal symptoms, refer to the Gastrointestinal Complications summary.)

There has never been a randomized trial comparing single-agent oral dexamethasone at a traditional high dose (40 mg a day for 4 days, repeated after 4 days off) versus a lower dose (40 mg or less weekly). This issue of dexamethasone dose has been evaluated in two prospective randomized trials, one in the context of melphalan from the National Cancer Institute of Canada (CAN-NCIC-MY7), and the other in the context of lenalidomide from the Eastern Cooperative Oncology Group (ECOG-E4A03) and published only in abstract form.[18][27] High-dose dexamethasone was associated with an increased risk of infection in the melphalan trial, but with no difference in efficacy compared to standard dose steroids.[27] The lenalidomide study questioned the safety and efficacy of high-dose dexamethasone (refer to the Lenalidomide section of this summary for more information).[18] Almost all ongoing clinical trials in the United States and Europe have implemented the low-dose dexamethasone schedule with or without other therapeutic agents.

Thalidomide

Nine randomized prospective studies (including E-E1A00 and HOVON 50) involving more than 3,500 patients have been published in final or preliminary abstract form examining the introduction of thalidomide as induction therapy for previously untreated symptomatic patients with multiple myeloma.[28][29][30][31][32][33][34][35][36] All of the trials reported improved response rates with the introduction of thalidomide and no hematopoietic damage, allowing adequate stem cell collection when applicable or allowing combinations with other myelosuppressive agents. Only three of the nine randomized studies reported a survival advantage using thalidomide. In both trials, the patients older than 65 years at the 2-year follow-ups showed 44-month to 56-month median overall survival (OS) for melphalan plus prednisone plus thalidomide (MPT) versus 28-month to 30-month median OS for melphalan plus prednisone (MP) (P < .03 in all three studies).[33][37][Level of evidence: 1iiA] A possible explanation is that these two trials used a lower dose of thalidomide than the other studies (100 mg vs. 200 mg or higher), a lower dose of steroids (60 mg of prednisone vs. high-dose dexamethasone), and involved the use of alkylating agents. As previously described in the section on corticosteroids, high-dose dexamethasone can complicate interpretation of clinical trials by worsening cardiopulmonary toxicity and deaths, especially in the context of thalidomide or lenalidomide, both of which are thrombogenic agents.

Factors that have been implicated to worsen the risk of deep venous thrombosis (DVT) include:

  • High-dose dexamethasone.
  • Concomitant erythropoietic growth factors.
  • Concomitant use of doxorubicin, liposomal doxorubicin, or alkylating agents.[38]

Personal cardiovascular risk factors can also influence the rate of DVT. Various clinical trials have included different DVT prophylaxis measures, including aspirin (81 mg–100 mg a day), warfarin, or low-molecular-weight heparin, but the validity of these measures has not been studied prospectively in a randomized study.[33][34][39][40][41][42][43] Prospective electrophysiologic monitoring provides no clear benefit versus clinical evaluation for the development of clinically significant neuropathy while on thalidomide.

Lenalidomide

A prospective randomized study of 351 relapsed patients compared lenalidomide, an analogue of thalidomide, plus high-dose dexamethasone to high-dose dexamethasone plus placebo.[44] The lenalidomide combination showed a significantly higher time-to-tumor-progression (11.3 mo vs. 4.7 mo, P < .001) with a 16-month median follow-up, and median OS had not been reached, versus 20.6 months in the placebo group (hazard ratio [HR] = 0.66, 95% confidence interval, 0.45–0.96, P = .03).[Level of evidence: 1iiDiii][44][Level of evidence: 1iA] The lenalidomide-containing arm had more DVT (11.4% vs. 4.6%).[44] Similarly, another randomized prospective trial NCT00179647 of 353 previously treated patients favors the lenalidomide plus high-dose dexamethasone arm versus dexamethasone plus placebo; at a median follow-up of 26 months, the median time-to-progression was 11.1 months versus 4.7 months (P < .001) and the median OS was 29.6 versus 20.2 months (P < .001).[45][Level of evidence: 1iA] A prospective randomized study (ECOG-E4A03) of 445 untreated symptomatic patients, published in abstract form only, compared lenalidomide and high-dose dexamethasone (40 mg D1–4, 9–12, 17–20 every 28 days) to lenalidomide and low-dose dexamethasone (40 mg D1, 8, 15, 22 every 28 days).[18] With a median follow-up of 25 months, this trial showed improved OS for patients in the low-dose dexamethasone arm (87% vs. 75% at 2 years, P = .006), despite no difference in progression-free survival.[18][Level of evidence: 1iiA] The extra deaths on the high-dose dexamethasone arm were attributed to cardiopulmonary toxicity and faster progression with subsequent therapies. DVTs were also more frequent in the high-dose arm (25% vs. 9%). OS favored the low-dose arm with a 2-year survival of 87% (low-dose) versus 75% (high-dose) (P = .006.)[18][Level of evidence: 1iiA] The low-dose dexamethasone arm with lenalidomide had less than 5% DVT with aspirin alone. Lenalidomide has substantially greater myelosuppression but less neuropathy than seen with thalidomide, but both have the same tendency for DVT.[18][44][45] DVT prophylaxis with 81 mg of aspirin has been proposed, but randomized clinical trials have not confirmed any benefit for this recommendation.[43]

Bortezomib

A prospective randomized trial (VISTA) of 682 previously untreated symptomatic patients who were not candidates for stem cell transplantation because of age (one third of patients >75 years) compared bortezomib combined with melphalan and prednisone versus melphalan and prednisone alone.[19] With a median follow-up of 26 months, the OS favored the bortezomib arm in the 3-year OS rates (72% vs. 59%, P = .03).[19][Level of evidence: 1iiA]

A prospective randomized study of 669 patients with relapsing myeloma, who had been treated previously with steroids, compared intravenous bortezomib with high-dose oral dexamethasone; with a median follow-up of 22 months, the median OS was 29.8 months for bortezomib versus 23.7 months for dexamethasone (HR = 0.77, P = .027), despite 62% of dexamethasone patients crossing over to receive bortezomib.[20][Level of evidence: 1iiA] Bortezomib-associated peripheral neuropathy is reversible in most patients after dose reduction or discontinuation.[21][46][47][48]

A prospective randomized trial (NCT00103506) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.[49] With a median follow-up of 7 months, the combination was better in both median time to progression (9.3 mo vs. 6.5 mo, P < .001) and in OS (82% vs. 75%, P = .05).[49][Level of evidence: 1iiA]

Patients with unfavorable molecular cytogenetics did not show any difference in progression-free or OS compared with patients with more favorable risk factors when bortezomib was incorporated with induction therapy. The benefit from bortezomib appears to be maintained across risk groups.[50][51][52][53][Level of evidence: 3iiiD]

Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment.[22]

Conventional-dose chemotherapy

The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.[54][55][56][57][Level of evidence: 3iiiDiv] No randomized studies support the widespread use of this regimen in untreated patients. This regimen avoids early exposure to alkylating agents, thereby minimizing any problems with stem cell collection (if needed) and any future risks for myelodysplasia or secondary leukemia. Disadvantages include the logistics for a 96-hour infusion of doxorubicin and a low complete response rate. An alternative version of VAD substitutes pegylated liposomal doxorubicin for doxorubicin, eliminates the need for an infusion, and provides comparable response rates.[58][59]Level of evidence: 3iiiDiv]

Evidence is not strong that any alkylating agent is superior to any other. All standard doses and schedules produce equivalent results.[60] The two most common regimens historically have been oral MP and oral cyclophosphamide plus prednisone.[60][61][62]

Combinations such as those used in EST-2479, of alkylating agents and prednisone, administered simultaneously or alternately, have not proven to be superior to therapy with MP.[63][64][65][66][Level of evidence: 1iiA] A meta-analysis of studies comparing melphalan plus prednisone with drug combinations concluded that both forms of treatment were equally effective.[60][Level of evidence: 1iiA] Patients who relapsed after initial therapy with cyclophosphamide and prednisone had no difference in OS (median 17 mo) when randomly assigned to receive vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisone (VBMCP) or VAD.[67]

Combination therapy

Several national and international trials have been implemented to define the optimal combination regimens. Participation in these trials should be the preferred approach, when feasible. The combination regimens in these trials represent the most successful from numerous phase II reports during the last several years:

  • ECOG-E1A05: bortezomib + dexamethasone versus lenalidomide + bortezomib + dexamethasone.[68]
  • SWOG-SO777: lenalidomide + dexamethasone versus lenalidomide + bortezomib + dexamethasone.
  • EVOLUTION trial: bortezomib + lenalidomide + dexamethasone versus bortezomib + cyclophosphamide + dexamethasone versus bortezomib + lenalidomide + cyclophosphamide + dexamethasone.
  • US Intergroup/IFM trial: lenalidomide + bortezomib + dexamethasone for three cycles, then responders randomized to five more cycles versus high-dose melphalan + stem cell transplantation.

Options for combination regimens:

  1. Bortezomib + dexamethasone (as demonstrated in ECOG-E1A05).[50][68]
  2. Lenalidomide + dexamethasone (as demonstrated in SWOG-SO777).[18][44][45]
  3. Bortezomib + lenalidomide + dexamethasone (as demonstrated in ECOG-E1A05, SWOG-SO777, EVOLUTION trial, and US Intergroup/IFM trial).[50][68][69]
  4. Bortezomib + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[70][71]
  5. Bortezomib + lenalidomide + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[72]
  6. Lenalidomide + cyclophosphamide + dexamethasone.[73]
  7. Bortezomib + melphalan + prednisone.[19]
  8. Bortezomib + liposomal doxorubicin.[49]
  9. Melphalan + prednisone + thalidomide.[30][37]
  10. Melphalan + prednisone.[30][37]

Consolidation Chemotherapy

High-dose chemotherapy: Autologous bone marrow or peripheral stem cell transplantation

The failure of conventional therapy to cure the disease has led investigators to test the effectiveness of much higher doses of drugs such as melphalan. The development of techniques for harvesting hemopoietic stem cells, from marrow aspirates or the peripheral blood of the patient, and infusing these cells to promote hemopoietic recovery made it possible for investigators to test very large doses of chemotherapy. From the experience with thousands of patients treated in this way, it is possible to draw a few conclusions. The risk of early death caused by treatment-related toxic effects has been reduced to less than 3% in highly selected populations.[74] Chemotherapy patients can now be treated as outpatients. Extensive prior chemotherapy, especially with alkylating agents, compromises marrow hemopoiesis and may make the harvesting of adequate numbers of hemopoietic stem cells impossible.[17] Younger patients in good health tolerate high-dose therapy better than patients with poor performance status.[75][76][77]

Single autologous bone marrow or peripheral stem cell transplantation

While some prospective randomized trials such as the U.S. Intergroup trial SWOG-9321, have shown improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone,[13][78][79][Level of evidence: 1iiA] other trials have not shown any survival advantage.[80][81][82][83][Level of evidence: 1iiA] Two meta-analyses of almost 3,000 patients showed no survival advantage.[84][85][Level of evidence: 1iiA] Even the trials suggesting improved survival showed no signs of a slowing in the relapse rate or a plateau to suggest that any of these patients had been cured.[13][78][79][86]

Tandem autologous bone marrow or stem cell transplantation

Another approach to high-dose therapy has been the use of two sequential episodes of high-dose therapy with stem cell support (tandem transplants).[87][88][89][90][91]

A meta-analysis of six randomized clinical trials enrolling 1,803 patients compared single versus tandem autologous hematopoietic cell transplantation; there was no difference in OS (HR = .94; 95% CI, 0.77–1.14) or in event-free survival (HR = .86; 95% CI, 0.70–1.05).[92][Level of evidence: 1A]

In a trial of 194 previously untreated patients aged 50 to 70 years, the patients were randomly assigned to conventional oral melphalan and prednisone versus VAD for two cycles followed by two sequential episodes of high-dose therapy (melphalan 100 mg/m2) with stem cell support.[79] With a median follow-up of greater than 3 years, the double transplant group had superior EFS (37% vs. 16% at 3 years, P < .001) and OS (77% vs. 62%, P < .001).[79][Level of evidence: 1iiA]

Three different groups have compared two tandem autologous transplants versus one autologous transplant followed by a reduced-intensity conditioning allograft from an HLA-identical sibling; the results have been discordant for survival in these nonrandomized trials. One study showed a survival advantage for the two tandem autologous transplants, one study showed a survival advantage for the autologous followed by allograft arm, and one study showed no difference in OS.[93][94][95][96][Level of evidence: 3iiiA] (assignment was based on the presence or absence of an HLA-identical sibling); with a median follow-up of 45 months, the median OS was 54 months for the tandem autologous grafts versus 80 months for the allogeneic arm (P = .01).[93][Level of evidence: 3iiA]

A trial of 195 patients younger than 60 years with newly diagnosed myeloma randomly compared two tandem transplants with a single autologous stem cell transplant followed by 6 months of maintenance therapy with thalidomide. With a median follow-up of 33 months, the thalidomide maintenance arm showed a benefit in PFS (85% vs. 57% at 3 years, P = .02) and OS (85% vs. 65% at 3 years, P = .04).[97][Level of evidence: 1iiA]

Interferon maintenance after stem cell transplantation

Maintenance therapy with interferon showed a benefit in progression-free survival (PFS) (46 vs. 27 mo, P < .025) and OS (75% vs. 50%, P < .01) in a randomized study of 84 patients following autologous bone marrow transplantation.[98][Level of evidence: 1iiA] A larger randomized trial of 805 patients showed no difference in PFS or OS with interferon applied after peripheral stem cell transplantation or conventional chemotherapy.[99][Level of evidence: 1iiA]

High-dose chemotherapy: Allogeneic bone marrow or peripheral stem cell transplantation

In a registry of 162 patients who underwent allogeneic matched sibling-donor transplants, the actuarial OS rate was 28% at 7 years.[100][Level of evidence: 3iiiA] Favorable prognostic features included low tumor burden, responsive disease before transplant, and application of transplantation after first-line therapy. Many patients are not young enough or healthy enough to undergo these intensive approaches. A definite graft-versus-myeloma effect has been demonstrated, including regression of myeloma relapses following the infusion of donor lymphocytes.[101][102][103][104] Allogeneic marrow transplants have significant toxic effects (15%–40% mortality), but the possibility of a potent and possibly curative graft-versus-myeloma reaction makes this procedure attractive.[104][105] Further research is required to make allogeneic transplants less dangerous and to find methods for initiating an autoimmune response to the myeloma cells. Nonmyeloablative allogeneic stem cell transplant is under development.[106][107][108] Such strategies aim to maintain efficacy (so called graft-versus-tumor-effective) while reducing transplant-related mortality.[109][110]

Maintenance Therapy

Myeloma patients who respond to treatment show a progressive fall in the M protein until a plateau is reached; subsequent treatment with conventional doses does not result in any further improvement. This has led investigators to question how long treatment should be continued. In a single study,[111] it was observed that maintenance therapy with MP prolonged the initial remission duration (31 mo) compared to no maintenance treatment (23 mo). No effect on OS was found because the majority of patients who relapsed in the no maintenance arm responded again to MP, while those on maintenance MP did not respond to further treatment. The Canadian group [111] suggests that induction chemotherapy be continued as long as the M protein continues to fall; therapy can be discontinued after the M protein reaches a plateau that remains stable for 4 months.

Maintenance interferon-alpha therapy has been reported in several studies to prolong initial remission duration.[112][113][114][115] While the impact of interferon maintenance on disease-free survival and OS has significantly varied among trials, a meta-analysis of 1,543 patients treated on 12 trials randomizing between interferon maintenance and observation indicated that interferon maintenance was associated with improved relapse-free survival (27% vs. 19% at 3 years, P < .001) and OS (12% odds reduction, P = .04).[116] Toxic effects in this population may be substantial and must be balanced against the potential benefits in response duration.[117]

A study of 125 responding patients with first-line VAD induction who were randomly assigned to maintenance corticosteroids at 10 mg or 50 mg on alternate days showed improved PFS (14 mo vs. 5 mo, P = .003) and OS (36 mo vs. 26 mo, P = .05) for the patients receiving the higher-dose corticosteroids.[118][Level of evidence: 1iiA] In a larger trial by the National Cancer Institute of Canada (CAN-NCIC-MY7) of 585 patients treated with first-line MP, 292 patients were randomly assigned to pulse dexamethasone (40 mg a day for 4 days monthly) versus no maintenance; PFS favored the dexamethasone maintenance (2.8 vs. 2.1 years, P = .002), but there was no difference in OS (4.1 years vs. 3.8 years, P = .4).[27][Level of evidence: 1iiDiii]

Two months after autologous transplantation, 597 patients younger than 65 years were randomly assigned to no maintenance, pamidronate, or pamidronate plus thalidomide; the thalidomide arm was favored by EFS (36% vs. 37% vs. 52%, P < .009) and OS at 4 years (77% vs. 74% vs. 87%, P < .04), while no differences were seen for skeletal events.[119][Level of evidence: 1iiA] After autologous transplantation, 129 patients were randomly assigned to indefinite prednisone versus indefinite prednisone with 12 months of thalidomide; with a median follow-up of 3 years, the thalidomide arm was favored by PFS (42% vs. 23%, P < .001) and by OS at 3 years (86% vs. 75%, P = .004).[120][Level of evidence: 1iiA]

Bisphosphonate therapy

A randomized, double-blind study of patients with stage III myeloma showed that monthly intravenous pamidronate significantly reduces pathologic fractures, bone pain, spinal cord compression, and the need for bone radiation therapy (38% skeletal-related events were reported in the treated group vs. 51% in the placebo group after 21 mo of therapy, P = .015).[121][Level of evidence: 1iDiii] (For more information on bisphosphonate therapy, refer to the Pain summary.)

A randomized comparison of pamidronate versus zoledronic acid in 518 patients with multiple myeloma showed equivalent efficacy in regard to skeletal-related complications.[122][Level of evidence: 1iDiii] However, bisphosphonates are associated with infrequent long-term complications (in 3%–5% of patients) including osteonecrosis of the jaw and avascular necrosis of the hip.[123][124] (For more information on osteonecrosis of the jaw, refer to the Oral Complications of Chemotherapy and Head/Neck Radiation summary.) These side effects must be balanced against the potential benefits of bisphosphonates when bone metastases are evident.[125]

Bone lesions

Lytic lesions of the spine should be radiated if they are associated with an extramedullary (paraspinal) plasmacytoma, if a painful destruction of a vertebral body occurred, or if CT or MRI scans present evidence of spinal cord compression.[126]

Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy. (For more information on back pain, refer to the PDQ summary on Pain.) Extensive radiation of the spine or long bones for diffuse osteoporosis may lead to prolonged suppression of hemopoiesis and is rarely indicated.[127] Bisphosphonates are useful for slowing or reversing the osteopenia that is common in myeloma patients.[121]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with multiple myeloma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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  59. Rifkin RM, Gregory SA, Mohrbacher A, et al.: Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III multicenter randomized trial. Cancer 106 (4): 848-58, 2006.

  60. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group. J Clin Oncol 16 (12): 3832-42, 1998.

  61. Gregory WM, Richards MA, Malpas JS: Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials. J Clin Oncol 10 (2): 334-42, 1992.

  62. Bergsagel DE, Stewart AK: Conventional-dose chemotherapy of myeloma. In: Malpas JS, Bergsagel DE, Kyle RA, et al.: Myeloma: Biology and Management. 3rd ed. Philadelphia, Pa: WB Saunders Co, 2004, pp 203-17.

  63. Pavlovsky S, Corrado C, Santarelli MT, et al.: An update of two randomized trials in previously untreated multiple myeloma comparing melphalan and prednisone versus three- and five-drug combinations: an Argentine Group for the Treatment of Acute Leukemia Study. J Clin Oncol 6 (5): 769-75, 1988.

  64. Bladé J, San Miguel JF, Alcalá A, et al.: Alternating combination VCMP/VBAP chemotherapy versus melphalan/prednisone in the treatment of multiple myeloma: a randomized multicentric study of 487 patients. J Clin Oncol 11 (6): 1165-71, 1993.

  65. Oken MM, Harrington DP, Abramson N, et al.: Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer 79 (8): 1561-7, 1997.

  66. Gertz MA, Lacy MQ, Lust JA, et al.: Prospective randomized trial of melphalan and prednisone versus vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of primary systemic amyloidosis. J Clin Oncol 17 (1): 262-7, 1999.

  67. Mineur P, Ménard JF, Le Loët X, et al.: VAD or VMBCP in multiple myeloma refractory to or relapsing after cyclophosphamide-prednisone therapy (protocol MY 85). Br J Haematol 103 (2): 512-7, 1998.

  68. Fonseca R, Rajkumar SV: Consolidation therapy with bortezomib/lenalidomide/ dexamethasone versus bortezomib/dexamethasone after a dexamethasone-based induction regimen in patients with multiple myeloma: a randomized phase III trial. Clin Lymphoma Myeloma 8 (5): 315-7, 2008.

  69. Richardson P, Lonial S, Jakubowiak A, et al.: Lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma: encouraging efficacy in high risk groups with updated results of a phaseI/II study. [Abstract] Blood 112 (11): A-92, 2008.

  70. Reece DE, Rodriguez GP, Chen C, et al.: Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin Oncol 26 (29): 4777-83, 2008.

  71. Knop S, Liebisch H, Wandt H, et al.: Bortezomib, IV cyclophosphamide, and dexamethasone (VelCD) as induction therapy in newly diagnosed multiple myeloma: results of an interim analysis of the German DSMM Xia trial. [Abstract] J Clin Oncol 27 (Suppl 15): A-8516, 2009.

  72. Kumar S, Flinn IW, Noga SJ, et al.: Safety and efficacy of novel combination therapy with bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in newly diagnosed multiple myeloma: initial results from the phase I/II multi-center EVOLUTION study. [Abstract] Blood 112 (11): A-93, 2008.

  73. Kumar S, Hayman S, Buadi F, et al.: Phase II trial of lenalidomide (Revlimid™) with cyclophosphamide and dexamethasone (RCd) for newly diagnosed myeloma. [Abstract] Blood 112 (11): A-91, 2008.

  74. Bladé J, Vesole DH, Gertz Morie: High-dose therapy in multiple myeloma. Blood 102 (10): 3469-70, 2003.

  75. Siegel DS, Desikan KR, Mehta J, et al.: Age is not a prognostic variable with autotransplants for multiple myeloma. Blood 93 (1): 51-4, 1999.

  76. Badros A, Barlogie B, Siegel E, et al.: Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol 114 (3): 600-7, 2001.

  77. Lenhoff S, Hjorth M, Westin J, et al.: Impact of age on survival after intensive therapy for multiple myeloma: a population-based study by the Nordic Myeloma Study Group. Br J Haematol 133 (4): 389-96, 2006.

  78. Child JA, Morgan GJ, Davies FE, et al.: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348 (19): 1875-83, 2003.

  79. Palumbo A, Bringhen S, Petrucci MT, et al.: Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood 104 (10): 3052-7, 2004.

  80. Segeren CM, Sonneveld P, van der Holt B, et al.: Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study. Blood 101 (6): 2144-51, 2003.

  81. Fermand JP, Katsahian S, Divine M, et al.: High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol 23 (36): 9227-33, 2005.

  82. Bladé J, Rosiñol L, Sureda A, et al.: High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 106 (12): 3755-9, 2005.

  83. Barlogie B, Kyle RA, Anderson KC, et al.: Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 24 (6): 929-36, 2006.

  84. Lévy V, Katsahian S, Fermand JP, et al.: A meta-analysis on data from 575 patients with multiple myeloma randomly assigned to either high-dose therapy or conventional therapy. Medicine (Baltimore) 84 (4): 250-60, 2005.

  85. Koreth J, Cutler CS, Djulbegovic B, et al.: High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant 13 (2): 183-96, 2007.

  86. Pineda-Roman M, Barlogie B, Anaissie E, et al.: High-dose melphalan-based autotransplants for multiple myeloma: the Arkansas experience since 1989 in 3077 patients. Cancer 112 (8): 1754-64, 2008.

  87. Barlogie B, Tricot GJ, van Rhee F, et al.: Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 135 (2): 158-64, 2006.

  88. Barlogie B, Tricot G, Rasmussen E, et al.: Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies. Blood 107 (7): 2633-8, 2006.

  89. Barlogie B, Zangari M, Bolejack V, et al.: Superior 12-year survival after at least 4-year continuous remission with tandem transplantations for multiple myeloma. Clin Lymphoma Myeloma 6 (6): 469-74, 2006.

  90. Bruno B, Rotta M, Patriarca F, et al.: Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood 113 (14): 3375-82, 2009.

  91. Rotta M, Storer BE, Sahebi F, et al.: Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood 113 (14): 3383-91, 2009.

  92. Kumar A, Kharfan-Dabaja MA, Glasmacher A, et al.: Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst 101 (2): 100-6, 2009.

  93. Bruno B, Rotta M, Patriarca F, et al.: A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 356 (11): 1110-20, 2007.

  94. Garban F, Attal M, Michallet M, et al.: Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 107 (9): 3474-80, 2006.

  95. Moreau P, Garban F, Attal M, et al.: Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood 112 (9): 3914-5, 2008.

  96. Rosiñol L, Pérez-Simón JA, Sureda A, et al.: A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 112 (9): 3591-3, 2008.

  97. Abdelkefi A, Ladeb S, Torjman L, et al.: Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood 111 (4): 1805-10, 2008.

  98. Cunningham D, Powles R, Malpas J, et al.: A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results. Br J Haematol 102 (2): 495-502, 1998.

  99. Barlogie B, Kyle R, Anderson K, et al.: Comparable survival in multiple myeloma (MM) with high dose therapy (HDT) employing MEL 140 mg/m2 + TBI 12 Gy autotransplants versus standard dose therapy with VBMCP and no benefit from interferon (IFN) maintenance: results of Intergroup Trial S9321. [Abstract] Blood 102 (11): A-135, 2003.

  100. Gahrton G, Tura S, Ljungman P, et al.: Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 13 (6): 1312-22, 1995.

  101. Tricot G, Vesole DH, Jagannath S, et al.: Graft-versus-myeloma effect: proof of principle. Blood 87 (3): 1196-8, 1996.

  102. Verdonck LF, Lokhorst HM, Dekker AW, et al.: Graft-versus-myeloma effect in two cases. Lancet 347 (9004): 800-1, 1996.

  103. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al.: Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol 18 (16): 3031-7, 2000.

  104. Reynolds C, Ratanatharathorn V, Adams P, et al.: Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 27 (8): 801-7, 2001.

  105. Arora M, McGlave PB, Burns LJ, et al.: Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma. Bone Marrow Transplant 35 (12): 1133-40, 2005.

  106. Einsele H, Schäfer HJ, Hebart H, et al.: Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. Br J Haematol 121 (3): 411-8, 2003.

  107. Maloney DG, Molina AJ, Sahebi F, et al.: Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102 (9): 3447-54, 2003.

  108. Badros A, Barlogie B, Morris C, et al.: High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. Blood 97 (9): 2574-9, 2001.

  109. Crawley C, Lalancette M, Szydlo R, et al.: Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT. Blood 105 (11): 4532-9, 2005.

  110. Badros A, Barlogie B, Siegel E, et al.: Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 20 (5): 1295-303, 2002.

  111. Belch A, Shelley W, Bergsagel D, et al.: A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 57 (1): 94-9, 1988.

  112. Mandelli F, Avvisati G, Amadori S, et al.: Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med 322 (20): 1430-4, 1990.

  113. Westin J, Rödjer S, Turesson I, et al.: Interferon alfa-2b versus no maintenance therapy during the plateau phase in multiple myeloma: a randomized study. Cooperative Study Group. Br J Haematol 89 (3): 561-8, 1995.

  114. Osterborg A, Björkholm M, Björeman M, et al.: Natural interferon-alpha in combination with melphalan/prednisone versus melphalan/prednisone in the treatment of multiple myeloma stages II and III: a randomized study from the Myeloma Group of Central Sweden. Blood 81 (6): 1428-34, 1993.

  115. Browman GP, Bergsagel D, Sicheri D, et al.: Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 13 (9): 2354-60, 1995.

  116. The Myeloma Trialists' Collaborative Group.: Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 113 (4): 1020-34, 2001.

  117. Zee B, Cole B, Li T, et al.: Quality-adjusted time without symptoms or toxicity analysis of interferon maintenance in multiple myeloma. J Clin Oncol 16 (8): 2834-9, 1998.

  118. Berenson JR, Crowley JJ, Grogan TM, et al.: Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 99 (9): 3163-8, 2002.

  119. Attal M, Harousseau JL, Leyvraz S, et al.: Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 108 (10): 3289-94, 2006.

  120. Spencer A, Prince HM, Roberts AW, et al.: Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol 27 (11): 1788-93, 2009.

  121. Berenson JR, Lichtenstein A, Porter L, et al.: Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 16 (2): 593-602, 1998.

  122. Rosen LS, Gordon D, Kaminski M, et al.: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98 (8): 1735-44, 2003.

  123. Badros A, Weikel D, Salama A, et al.: Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24 (6): 945-52, 2006.

  124. Kademani D, Koka S, Lacy MQ, et al.: Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy. Mayo Clin Proc 81 (8): 1100-3, 2006.

  125. Lacy MQ, Dispenzieri A, Gertz MA, et al.: Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 81 (8): 1047-53, 2006.

  126. Rades D, Hoskin PJ, Stalpers LJ, et al.: Short-course radiotherapy is not optimal for spinal cord compression due to myeloma. Int J Radiat Oncol Biol Phys 64 (5): 1452-7, 2006.

  127. Catell D, Kogen Z, Donahue B, et al.: Multiple myeloma of an extremity: must the entire bone be treated? Int J Radiat Oncol Biol Phys 40 (1): 117-9, 1998.

Isolated Plasmacytoma of Bone

If a solitary lytic lesion of plasma cells is found on skeletal survey in an otherwise asymptomatic patient, and a bone marrow examination from an uninvolved site contains less than 5% of plasma cells, the patient may have an isolated plasmacytoma of bone.[1] Magnetic resonance imaging scans of the total spine may identify other bony lesions.[2] The survival rate of patients with isolated plasmacytoma of bone treated with radiation of the lesion is greater than 50% at 10 years, which is much better than the survival with disseminated multiple myeloma.[3] Most patients will eventually develop disseminated disease and require chemotherapy; almost 50% will do so within 2 years of diagnosis;[1][2] however, patients with serum paraprotein or Bence Jones protein who have complete disappearance of these proteins after radiation therapy may be expected to remain free of disease for prolonged periods.[2][4] Patients who progress to multiple myeloma tend to have good responses to chemotherapy with a median survival of 63 months after progression.[2][4]

Standard treatment options:

  1. Radiation of the lesion.
  2. If the monoclonal (or myeloma) protein (M protein) increases and other evidence of symptomatic multiple myeloma occurs, chemotherapy is required.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with isolated plasmacytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000.

  2. Liebross RH, Ha CS, Cox JD, et al.: Solitary bone plasmacytoma: outcome and prognostic factors following radiotherapy. Int J Radiat Oncol Biol Phys 41 (5): 1063-7, 1998.

  3. Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Solitary plasmacytoma treated with radiotherapy: impact of tumor size on outcome. Int J Radiat Oncol Biol Phys 50 (1): 113-20, 2001.

  4. Dimopoulos MA, Goldstein J, Fuller L, et al.: Curability of solitary bone plasmacytoma. J Clin Oncol 10 (4): 587-90, 1992.

Extramedullary Plasmacytoma

Patients with isolated plasma cell tumors of soft tissues, most commonly occurring in the tonsils, nasopharynx, or paranasal sinuses, should have skeletal x-rays and bone marrow biopsy (both of which should be negative), and evaluation for a monoclonal (or myeloma) protein (M protein) in serum and urine.[1][2][3][4]

Extramedullary plasmacytoma is a highly curable disease with progression-free survival ranging from 70% to 87% at 10 to 14 years using radiation therapy (with or without previous resection).[2][4][5]

Standard treatment options:

  1. Radiation therapy to the isolated lesion with fields that cover the regional lymph nodes, if possible.[2][4]
  2. In some cases, surgical resection may be considered, but it is usually followed by radiation therapy.[4]
  3. If the monoclonal (or myeloma) protein (M protein) persists or reappears, the patient may need further radiation therapy. In some patients, the plasmacytoma may shrink, but not disappear, and the M protein persists. These types of patients should be followed closely. Surgery should be performed if the plasmacytoma is in a site where it can be removed easily, e.g., in the tonsil; the M protein may disappear from the blood or urine. In other cases, persistence or an increasing M protein may herald progression to multiple myeloma.
  4. Chemotherapy is required if the disease progresses and causes symptoms.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with extramedullary plasmacytoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Meis JM, Butler JJ, Osborne BM, et al.: Solitary plasmacytomas of bone and extramedullary plasmacytomas. A clinicopathologic and immunohistochemical study. Cancer 59 (8): 1475-85, 1987.

  2. Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Solitary plasmacytoma treated with radiotherapy: impact of tumor size on outcome. Int J Radiat Oncol Biol Phys 50 (1): 113-20, 2001.

  3. Soesan M, Paccagnella A, Chiarion-Sileni V, et al.: Extramedullary plasmacytoma: clinical behaviour and response to treatment. Ann Oncol 3 (1): 51-7, 1992.

  4. Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999.

  5. Strojan P, Soba E, Lamovec J, et al.: Extramedullary plasmacytoma: clinical and histopathologic study. Int J Radiat Oncol Biol Phys 53 (3): 692-701, 2002.

Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma)

Refer to the Waldenström macroglobulinemia section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.

Monoclonal Gammopathy of Undetermined Significance

Patients with monoclonal gammopathy of undetermined significance (MGUS) have a monoclonal (or myeloma) protein (M protein) in the serum without symptoms or findings of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma and with less than 10% of plasma cells in the bone marrow.[1][2] Multiple myeloma, other plasma cell dyscrasia, or lymphoma will develop in 12% of patients by 10 years, 25% by 20 years, and 30% by 25 years. Unfortunately, patients who will eventually develop plasma cell malignancy or lymphoma cannot be identified on the basis of the level of M protein, peripheral blood count, type of monoclonal immunoglobulin, percentage of plasma cells in the bone marrow, or levels of normal immunoglobulins. Therefore, all patients with MGUS must be kept under observation to detect increases in M protein levels and development of one of the above malignancies; however, higher levels of initial M protein levels correlate with increased risk of progression to multiple myeloma.[2] In a large retrospective report, the risk of progression at 20 years was 14% for an initial monoclonal protein level of 0.5 g/dL or less, 25% for a level of 1.5 g/dL, 41% for a level of 2.0 g/dL, 49% for a level of 2.5 g/dL, and 64% for a level of 3.0 g/dL.[2]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with monoclonal gammopathy of undetermined significance. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Kyle RA, Rajkumar SV: Monoclonal gammopathy of undetermined significance and smouldering multiple myeloma: emphasis on risk factors for progression. Br J Haematol 139 (5): 730-43, 2007.

  2. Kyle RA, Therneau TM, Rajkumar SV, et al.: A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 346 (8): 564-9, 2002.

Refractory Plasma Cell Neoplasm

There are two main types of refractory myeloma patients:

  • Primary refractory patients who never achieve a response and progress while still on induction chemotherapy.
  • Secondary refractory patients who do respond to induction chemotherapy but do not respond to treatment after relapse.

A subgroup of patients who do not achieve a response to induction chemotherapy have stable disease and enjoy a survival prognosis that is as good as that for responding patients.[1][2] When the stable nature of the disease becomes established, these types of patients can discontinue therapy until the myeloma begins to progress again. Others with primary refractory myeloma and progressive disease require a change in therapy; the options appear in the previous section on Multiple Myeloma Treatment Options.

The myeloma growth rate, as measured by the monoclonal (or myeloma) protein-doubling time, for patients who respond to their initial therapy, increases progressively with each subsequent relapse and remission durations become shorter and shorter. Marrow function becomes increasingly compromised as patients develop pancytopenia and enter a refractory phase; occasionally the myeloma cells dedifferentiate and extramedullary plasmacytomas develop. The myeloma cells may still be sensitive to chemotherapy, but the regrowth rate during relapse is so rapid that progressive improvement is not observed.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with refractory multiple myeloma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Riccardi A, Mora O, Tinelli C, et al.: Response to first-line chemotherapy and long-term survival in patients with multiple myeloma: results of the MM87 prospective randomised protocol. Eur J Cancer 39 (1): 31-7, 2003.

  2. Durie BG, Jacobson J, Barlogie B, et al.: Magnitude of response with myeloma frontline therapy does not predict outcome: importance of time to progression in southwest oncology group chemotherapy trials. J Clin Oncol 22 (10): 1857-63, 2004.

More Information

About PDQ

Additional PDQ Summaries

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).


This information is provided by the National Cancer Institute.

This information was last updated on December 11, 2009.

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