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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.
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
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.
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.
There are different types of plasma cell neoplasms and not all of them are cancer. The following types of plasma cell neoplasms are cancer:
Monoclonal gammopathy of undetermined significance (MGUS) is not cancer but can become cancer.
Plasma cell neoplasms include the following:
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:
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:
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:
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 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:
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.
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.
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:
The following tests and procedures may be used:
The prognosis (chance of recovery) depends on the following:
Treatment options depend on the following:
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:
Certain tests may be repeated to see how well the treatment is working.
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.
In stage I multiple myeloma, the blood levels are as follows:
In stage II multiple myeloma, the blood levels are as follows:
In stage III multiple myeloma, the blood level of beta-2-microglobulin is 5.5 g/mL or higher.
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.
One plasma cell tumor is found in the soft tissue but not in the bone or the bone marrow.
There is no standard staging system for macroglobulinemia.
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.
Multiple myeloma and other plasma cellneoplasms are called refractory when the number of plasma cells continues to increase even though treatment is given.
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.
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.
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 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.
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 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 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 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 is closely monitoring a patient's condition without giving any treatment until symptoms appear or change.
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.
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.
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.
Clinical trials are studying different combinations of biologic therapy, chemotherapy, steroid therapy, and drugs such as thalidomide or lenalidomide.
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.
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.
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.
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.
Patients without symptoms may not need treatment. When symptoms appear, the treatment of multiple myeloma may be done in phases:
Supportive care to treat bone problems and amyloidosis may include:
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.
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.
Standard treatment of extramedullary plasmacytoma may include the following:
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.
Treatment of Waldenström macroglobulinemia may include the following:
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.
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.
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.
Treatment of refractoryplasma cellneoplasms may include the following:
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.
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.
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:
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.
Note: Estimated new cases and deaths from multiple myeloma in the United States in 2009:[1]
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:
American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.
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.
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.
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.
Rajkumar SV, Kyle RA: Multiple myeloma: diagnosis and treatment. Mayo Clin Proc 80 (10): 1371-82, 2005.
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.
Diseases associated with a monoclonal (or myeloma) protein (M protein) included in this presentation are:
These usually occur in the nasopharynx, tonsils, or paranasal
Patients often have lymphadenopathy and
hepatosplenomegaly; less than 5% of patients have lytic bone lesions. (Usually IgM kappa or gamma.)
This entity is called lymphoplasmacytic lymphoma or Waldenström macroglobulinemia. (Refer to the PDQ summary on Adult Non Hodgkin Lymphoma Treatment for more information.)
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.
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.
Kyle RA, Garton JP: The spectrum of IgM monoclonal gammopathy in 430 cases. Mayo Clin Proc 62 (8): 719-31, 1987.
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.
These patients most often have disease that expresses IgG kappa monoclonal gammopathies, and they present with lytic bone lesions.
These patients often have disease that expresses IgA lambda monoclonal gammopathies and less often have skeletal-related complications.
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.
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 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
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]
Greipp PR, San Miguel J, Durie BG, et al.: International staging system for multiple myeloma. J Clin Oncol 23 (15): 3412-20, 2005.
Fonseca R, Blood E, Rue M, et al.: Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101 (11): 4569-75, 2003.
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.
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.
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.
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.
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.
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.
Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000.
Dimopoulos MA, Hamilos G: Solitary bone plasmacytoma and extramedullary plasmacytoma. Curr Treat Options Oncol 3 (3): 255-9, 2002.
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.
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.
Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999.
Kyle RA, Therneau TM, Rajkumar SV, et al.: Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 354 (13): 1362-9, 2006.
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.
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.
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.
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.
Weiss BM, Abadie J, Verma P, et al.: A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 113 (22): 5418-22, 2009.
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.
Bladé J, Rosiñol L, Cibeira MT: Are all myelomas preceded by MGUS? Blood 113 (22): 5370, 2009.
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]
He Y, Wheatley K, Clark O, et al.: Early versus deferred treatment for early stage multiple myeloma. Cochrane Database Syst Rev (1): CD004023, 2003.
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.
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.
Durie BG, Harousseau JL, Miguel JS, et al.: International uniform response criteria for multiple myeloma. Leukemia 20 (9): 1467-73, 2006.
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]
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.
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.
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.
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.
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.
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.
Mehta J, Gerta MA, Dispenzieri A: High-dose therapy for amyloidosis: the end of the beginning? Blood 103 (10): 3612-3, 2004.
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.
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.
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.
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.
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.
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.
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
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
Patients with a monoclonal (or myeloma) protein (M protein) in the serum and/or urine are evaluated as follows:
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:
Multiple therapeutic agents are available for induction therapy, either alone or in combinations [16] and include:
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:
These considerations require validation by ongoing clinical trials and participation in these studies is the preferred choice when possible.
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.
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:
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.
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]
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]
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]
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:
Options for combination regimens:
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]
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]
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]
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]
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
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]
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]
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]
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.
Zandecki M, Facon T, Preudhomme C, et al.: Significance of circulating plasma cells in multiple myeloma. Leuk Lymphoma 14 (5-6): 491-6, 1994.
Billadeau D, Van Ness B, Kimlinger T, et al.: Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma. Blood 88 (1): 289-96, 1996.
Riches PG, Sheldon J, Smith AM, et al.: Overestimation of monoclonal immunoglobulin by immunochemical methods. Ann Clin Biochem 28 ( Pt 3): 253-9, 1991.
Horger M, Kanz L, Denecke B, et al.: The benefit of using whole-body, low-dose, nonenhanced, multidetector computed tomography for follow-up and therapy response monitoring in patients with multiple myeloma. Cancer 109 (8): 1617-26, 2007.
Walker R, Barlogie B, Haessler J, et al.: Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol 25 (9): 1121-8, 2007.
Gertz MA, Li CY, Shirahama T, et al.: Utility of subcutaneous fat aspiration for the diagnosis of systemic amyloidosis (immunoglobulin light chain). Arch Intern Med 148 (4): 929-33, 1988.
Greipp PR: Advances in the diagnosis and management of myeloma. Semin Hematol 29 (3 Suppl 2): 24-45, 1992.
Durie BG, Stock-Novack D, Salmon SE, et al.: Prognostic value of pretreatment serum beta 2 microglobulin in myeloma: a Southwest Oncology Group Study. Blood 75 (4): 823-30, 1990.
Greipp PR, Witzig T: Biology and treatment of myeloma. Curr Opin Oncol 8 (1): 20-7, 1996.
Kyle RA, Remstein ED, Therneau TM, et al.: Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 356 (25): 2582-90, 2007.
Palumbo A, Rajkumar SV: Treatment of newly diagnosed myeloma. Leukemia 23 (3): 449-56, 2009.
Goldschmidt H, Hegenbart U, Wallmeier M, et al.: Factors influencing collection of peripheral blood progenitor cells following high-dose cyclophosphamide and granulocyte colony-stimulating factor in patients with multiple myeloma. Br J Haematol 98 (3): 736-44, 1997.
Rajkumar SV, Jacobus S, Callander N, et al.: A randomized trial of lenalidomide plus high-dose dexamethasone (RD) versus lenalidomide plus low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. [Abstract] Blood 110 (11): A-74, 2007.
San Miguel JF, Schlag R, Khuageva NK, et al.: Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359 (9): 906-17, 2008.
Richardson PG, Sonneveld P, Schuster M, et al.: Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 110 (10): 3557-60, 2007.
Richardson PG, Briemberg H, Jagannath S, et al.: Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24 (19): 3113-20, 2006.
San-Miguel JF, Richardson PG, Sonneveld P, et al.: Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. Leukemia 22 (4): 842-9, 2008.
Alexanian R, Dimopoulos MA, Delasalle K, et al.: Primary dexamethasone treatment of multiple myeloma. Blood 80 (4): 887-90, 1992.
Kumar S, Lacy MQ, Dispenzieri A, et al.: Single agent dexamethasone for pre-stem cell transplant induction therapy for multiple myeloma. Bone Marrow Transplant 34 (6): 485-90, 2004.
Facon T, Mary JY, Pégourie B, et al.: Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood 107 (4): 1292-8, 2006.
Shustik C, Belch A, Robinson S, et al.: A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol 136 (2): 203-11, 2007.
Rajkumar SV, Rosiñol L, Hussein M, et al.: Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol 26 (13): 2171-7, 2008.
Barlogie B, Tricot G, Anaissie E, et al.: Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 354 (10): 1021-30, 2006.
Palumbo A, Bringhen S, Liberati AM, et al.: Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood 112 (8): 3107-14, 2008.
Goldschmidt H, Sonneveld P, Breitkreuz I, et al.: HOVON 50/GMMG-HD3-trial: phase III study on the effect of thalidomide combined with high dose melphalan in myeloma patients up to 65 years. [Abstract] Blood 106 (11): A-424, 2005.
Facon T, Mary J, Harousseau J, et al.: Superiority of melphalan-prednisone (MP) + thalidomide (THAL) over MP and autologous stem cell transplantation in the treatment of newly diagnosed elderly patients with multiple myeloma. [Abstract] J Clin Oncol 24 (Suppl 18): A-1, 2006.
Hulin C, Facon T, Rodon P, et al.: Melphalan-prednisone-thalidomide (MP-T) demonstrates a significant survival advantage in elderly patients 75 years with multiple myeloma compared with melphalan-prednisone (MP) in a randomized, double-blind, placebo-controlled trial, IFM 01/01. [Abstract] Blood 110 (11): A-75, 2007.
Waage A, Gimsing P, Juliusson G, et al.: Melphalan-prednisone-thalidomide to newly diagnosed patients with multiple myeloma: a placebo controlled randomised phase 3 trial. [Abstract] Blood 110 (11): A-78, 2007.
Ludwig H, Hajek R, Tóthová E, et al.: Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood 113 (15): 3435-42, 2009.
Hulin C, Facon T, Rodon P, et al.: Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 27 (22): 3664-70, 2009.
Facon T, Mary JY, Hulin C, et al.: Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 370 (9594): 1209-18, 2007.
Palumbo A, Facon T, Sonneveld P, et al.: Thalidomide for treatment of multiple myeloma: 10 years later. Blood 111 (8): 3968-77, 2008.
Weber D, Rankin K, Gavino M, et al.: Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21 (1): 16-9, 2003.
Palumbo A, Bringhen S, Caravita T, et al.: Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 367 (9513): 825-31, 2006.
Zangari M, Barlogie B, Thertulien R, et al.: Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival. Clin Lymphoma 4 (1): 32-5, 2003.
Baz R, Li L, Kottke-Marchant K, et al.: The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 80 (12): 1568-74, 2005.
Niesvizky R, Martínez-Baños D, Jalbrzikowski J, et al.: Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma. Leuk Lymphoma 48 (12): 2330-7, 2007.
Dimopoulos M, Spencer A, Attal M, et al.: Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357 (21): 2123-32, 2007.
Weber DM, Chen C, Niesvizky R, et al.: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357 (21): 2133-42, 2007.
Mitchell BS: The proteasome--an emerging therapeutic target in cancer. N Engl J Med 348 (26): 2597-8, 2003.
Argyriou AA, Iconomou G, Kalofonos HP: Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood 112 (5): 1593-9, 2008.
Richardson PG, Xie W, Mitsiades C, et al.: Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol 27 (21): 3518-25, 2009.
Orlowski RZ, Nagler A, Sonneveld P, et al.: Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 25 (25): 3892-901, 2007.
Richardson PG, Sonneveld P, Schuster MW, et al.: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352 (24): 2487-98, 2005.
Jagannath S, Richardson PG, Sonneveld P, et al.: Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 21 (1): 151-7, 2007.
Chang H, Trieu Y, Qi X, et al.: Bortezomib therapy response is independent of cytogenetic abnormalities in relapsed/refractory multiple myeloma. Leuk Res 31 (6): 779-82, 2007.
Alexanian R, Barlogie B, Tucker S: VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol 33 (2): 86-9, 1990.
Segeren CM, Sonneveld P, van der Holt B, et al.: Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol 105 (1): 127-30, 1999.
Anderson H, Scarffe JH, Ranson M, et al.: VAD chemotherapy as remission induction for multiple myeloma. Br J Cancer 71 (2): 326-30, 1995.
Browman GP, Belch A, Skillings J, et al.: Modified adriamycin-vincristine-dexamethasone (m-VAD) in primary refractory and relapsed plasma cell myeloma: an NCI (Canada) pilot study. The National Cancer Institute of Canada Clinical Trials Group. Br J Haematol 82 (3): 555-9, 1992.
Dimopoulos MA, Pouli A, Zervas K, et al.: Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol 14 (7): 1039-44, 2003.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Bladé J, Vesole DH, Gertz Morie: High-dose therapy in multiple myeloma. Blood 102 (10): 3469-70, 2003.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Tricot G, Vesole DH, Jagannath S, et al.: Graft-versus-myeloma effect: proof of principle. Blood 87 (3): 1196-8, 1996.
Verdonck LF, Lokhorst HM, Dekker AW, et al.: Graft-versus-myeloma effect in two cases. Lancet 347 (9004): 800-1, 1996.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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:
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.
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.
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.
Dimopoulos MA, Goldstein J, Fuller L, et al.: Curability of solitary bone plasmacytoma. J Clin Oncol 10 (4): 587-90, 1992.
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:
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.
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.
Soesan M, Paccagnella A, Chiarion-Sileni V, et al.: Extramedullary plasmacytoma: clinical behaviour and response to treatment. Ann Oncol 3 (1): 51-7, 1992.
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.
Refer to the Waldenström macroglobulinemia section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.
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]
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.
There are two main types of refractory myeloma patients:
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.
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.
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.
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.
About PDQ
Additional PDQ Summaries
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 was last updated on December 11, 2009.
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Find practical tips and suggestions for individuals caring for a family member or friend with cancer, including creating a caregiving plan, finding community resources, and looking after your own well-being.
Friends' Place provides personal consultations to help cancer patients of all ages cope with changes in physical appearance that result from cancer treatment. Our experienced, compassionate team provides fittings for compression garments or breast prostheses, helps with wigs and other head coverings, and offers make-up and skincare advice.
The Friends' Corner Gift Shop, located on the first floor of the Yawkey Center for Cancer Care, offers a wide selection of unique gifts and everyday items for patients, families and staff.
Dana-Farber offers several services to help you and your family manage the financial side of cancer treatment. From creating bill payment schedules and estate planning advice to debt management and resource assistance for patients in need, our team is here for you.
Every year, thousands of patients with cancer from around the world come to Dana-Farber for their care. We provide a wide array of logistical and other services for individuals who live outside the United States.
Dana-Farber provides interpreting services for patients whose first language is not English. Interpreters may be requested for any activity, including registration, booking appointments, attending treatments and exams, support groups, and meetings with doctors and other members of your health care team.
Our nutritionists are registered dietitians who can assist you in planning an optimal diet during any stage of your cancer journey, cope with any side effects you may experience, and answer your questions about the latest findings on cancer and nutrition.
The Eleanor and Maxwell Blum Patient and Family Resource Center and its satellite resource rooms are staffed by health care professionals and provide computer stations, books, brochures, videos, and CDs to help you find information and support on a variety of issues about cancer treatment and care.
Patients websites help friends and family members stay up-to-date on their loved ones' condition and write messages of support and encouragement.
The Dana-Farber pharmacy fills prescriptions for all pediatric and adult patients. Our pharmacists are an extension of the patient care team and work closely with your physicians to provide seamless, convenient, safe care.
More than 1,200 Dana-Farber patients and their families have enjoyed free trips to baseball games, theater shows, museums, and other attractions this year through the Recreational Resources program.
The Sexual Health Program provides education, consultation and personalized rehabilitation for patients and their partners who have experienced changes in sexual health during and after cancer treatment.
Through all stages of cancer treatment and survivorship, our Spiritual Care staff is available 24 hours a day to provide emotional and spiritual support for adults and pediatric patients and family members.
Young adults with cancer face very different challenges than patients who were diagnosed earlier in childhood or later in adulthood. The Young Adult Program can help you to find the resources and expertise available at Dana-Farber to help support your cancer experience.
Integrative therapies, also known as complementary therapies, range from acupuncture and massage to nutritional guidance and music therapy. Patients treated at the Zakim Center credit its services with easing nausea, improving circulation, and reducing pain, stress, and anxiety associated with cancer treatment.
In this video, Dr. Corey Cutler talks about his work in the Hematologic Oncology Treatment Center at Dana-Farber/Brigham and Women's Cancer Center.