Medically reviewed by Dr. C.H. Weaver M.D. 1/2022
Multiple myeloma is a cancer of plasma cells. Plasma cells are a special type of white blood cell that are part of the body’s immune system. Plasma cells normally live in the bone marrow and make proteins, called antibodies, that circulate in the blood and help fight certain types of infections. Plasma cells also play a role in the maintenance of bone, by secretion of a hormone, called osteoclast activating factor, which causes the breakdown of bone. Patients with multiple myeloma have increased numbers of abnormal plasma cells that may produce increased quantities of dysfunctional antibodies detectable in the blood and/or urine. These abnormal antibodies are referred to as paraproteins or monoclonal proteins in the blood (M proteins) or urine (Bence Jones protein).
In multiple myeloma, plasma cells infiltrate the bone marrow, spreading into the cavities of all the large bones of the body. In a majority of patients with multiple myeloma the bones develop multiple holes, referred to as osteolytic lesions, that cause the bones to be fragile and subject to fracture. Osteolytic lesions are caused by the rapid growth of myeloma cells, which push aside normal bone-forming cells, preventing them from repairing general wear and tear of the bones. Multiple myeloma also causes the secretion of osteoclast-activating factor, a substance that contributes to bone destruction.(1)
Other complications of multiple myeloma include kidney problems and decreased bone marrow blood cell production. Kidney problems develop when abnormal proteins produced by the myeloma cells are deposited in the kidneys, clogging the tubules. Decreased bone marrow blood cell production results from the replacement of normal bone marrow cells with abnormal plasma cells, and can lead to problems such as anemia. Patients with multiple myeloma may also have decreased quantities of normal antibodies necessary to fight certain types of infection.
Symptoms & Signs of Multiple Myeloma
- Bone pain (often in the back or ribs)
- Unexplained bone fractures (usually in the spine)
- Recurrent infections, fevers.
- Shortness of breath.
- Pain in the upper or middle abdomen and back.
- Weight loss for no known reason.
- Loss of appetite.
Having these symptoms does not necessarily mean a person has multiple myeloma. Anyone with these symptoms however should see a doctor so that the problem can be caught early.
Cause of Multiple Myeloma
Cancer begins when healthy cells acquire a genetic change (mutation) that causes them to turn into abnormal cells. The exact cause of most multiple myeloma is unknown and about 5-10 percent are thought to be hereditary.
Risk factors for Multiple Myeloma
A risk factor is anything that increases a person’s chance of developing cancer. Risk factors can influence the development of cancer but most do not directly cause cancer. Many individuals with risk factors will never develop cancer and others with no known risk factors will. Most pancreatic cancers develop sporadically, which means for no known reason. Multiple myeloma may be preceded by two precancerous conditions:
- Monoclonal gamopathy of undetermined significance (MGUS)
- Smoldering multiple myeloma.
These conditions do not cause symptoms but can eventually progress to multiple myeloma. The rate of progression of MGUS to multiple myeloma is roughly 1% per year. Smoldering multiple myeloma carries a higher risk of progression.2
Diagnosis & Tests for Multiple Myeloma
20,000 individuals will be diagnosed with multiple myeloma each year in the United States3 half of these new diagnoses will occur among individuals over the age of 70 years.4 When multiple myeloma is diagnosed, approximately 70% of patients will have bone involvement with their cancer and one-third will have impaired kidney function. In order to understand the best treatment options available for the treatment of multiple myeloma, it is important to first determine the amount of cancer in the body. Determining the amount, or the stage, of the cancer requires a number of tests. These tests may include the following:5
- Measurement of beta-2 microglobulin in the blood. This provides information about tumor mass.
- Serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (SIFE) to measure the amount and type of abnormal myeloma protein in the blood.
- Urine protein electrophoresis (UPEP) and urine immunofixation electrophoresis (UIFE) to measure the amount and type of abnormal myeloma protein in the urine.
- A skeletal survey (a series of x-rays) to detect bone damage.
- Bone marrow aspiration and biopsy. A sample of cells is removed from the bone marrow in order to determine the percentage of myeloma cells in the marrow. The sample also allows doctors to assess specific characteristics of the myeloma cells (such as chromosomal abnormalities) that may influence prognosis.
- A complete blood count (CBC) to identify problems such as anemia.
- Blood tests to measure kidney function.
- Measurement of blood calcium levels. An estimated 15 to 20% of patients with multiple myeloma have hypercalcemia (high levels of calcium in the blood) at the time of diagnosis, due at least in part to myeloma-related bone destruction.(1) If left untreated, hypercalcemia can cause excessive thirst, frequent urination, dehydration, constipation, and even coma.
The results of these tests will determine the stage of the disease. In order to learn more about the treatment of myeloma, select the appropriate stage.
Stages of Multiple Myeloma
Stage I: Tests indicate a low tumor amount. Lab values will fall in the following range: M protein IgG less than 5.0 gm/100 ml serum; IgA less than 3.0 gm/100 ml serum or urine Bence Jones protein less than 4 gm in 24 hours; normal serum calcium, normal bones and hemoglobin over 10.0 gm/100 ml serum.
Stage II: An intermediate tumor mass. Lab values are between Stage I and Stage III
Stage III: Tests indicate a high tumor amount. Lab values fall in the following range: M protein IgG greater than 7.0 gm/100 ml serum; IgA greater than 5.0 gm/100 ml serum; urine Bence Jones protein over 12.0 gm in 24 hours; advanced bone lesions; hemoglobin less than 8.5 gm/100 ml serum or calcium over 12 gm/100 ml serum.
Recurrent/Relapsed: The multiple myeloma has persisted or returned (recurred/relapsed) following treatment.
Within each stage, patients may be furthered classified according to the presence or absence of kidney problems.(6) The sub classification “A” refers to patients with normal kidney function; “B” refers to patients with abnormal kidney function. Kidney function is assessed by blood tests.
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
Useful Definitions and Diagnostic Tests
Diagnostic testing for multiple myeloma utilizes unique blood, urine, and bone marrow tests in addition to a variety of standard medical tests. Tests specific to multiple myeloma include the following:
Immunoglobulin’s: Immunoglobulin’s (antibodies) are produced by multiple myeloma cells and the production of these abnormal immunoglobulin’s offer no benefit to the body and ultimately lead to the detrimental health effects suffered by myeloma patients including kidney impairment, interference with blood cell production and an impaired immune system.
Each immunoglobulin is made up of four protein chains: two long chains (called heavy chains) and two shorter chains (called light chains). Immunoglobulin’s are classified according to the heavy chain and are identified by use of a Greek letter: gamma (IgG), alpha (IgA), mu (IgM), epsilon (IgE), or delta (IgD). Normally, a plasma cell makes one of these five major classes of immunoglobulin, and each type of immunoglobulin has a slightly different function in the body. The abnormal immunoglobulin made in multiple myeloma is called the M or (monoclonal) protein.
Immunoglobulin light chains are defined by use of the Greek letters kappa or lambda. In 75% of patients, the plasma cells also produce monoclonal incomplete immunoglobulins, called light chains. These are excreted in the urine and are the so-called Bence Jones proteins. Bence Jones proteins are named after a British physician, Henry Bence Jones (1813-1873), who first discovered them. Bence Jones proteins may deposit in the kidney, clogging the tubules. In some cases, the plasma cells may produce incomplete immunoglobulin (light chain myeloma), or they may not secrete them at all (non-secretory myeloma).
Serum protein electrophoresis (SPEP): Detects the presence and level of various proteins, including the immunoglobulin protein made by myeloma cells. The SPEP can detect and measure the unique Monoclonal or M protein; higher levels indicate more extensive disease.
Immunofixation electrophoresis (IFE; also called immunoelectrophoresis): Identifies the type of abnormal antibody proteins in the blood.
Freelite™ serum free light chain assay: Measures antibody light chains made by myeloma cells called kappa or lambda. Abnormal levels and/or ratio suggest the presence of multiple myeloma or a related disease.
Urine protein level: (performed on a 24-hour specimen of urine) Measures the presence and level of Bence Jones proteins (otherwise known as myeloma light chains). Presence indicates multiple myeloma, and higher levels indicate more extensive disease.
Urine protein electrophoresis(UPEP): Determines the presence and levels of specific proteins in the urine, including M protein and Bence Jones protein. Presence of M protein or Bence Jones protein indicates multiple myeloma.
Beta2-microglobulin (ß2-M) level: Determines the level of a protein in the blood that indicates the presence/extent of multiple myeloma and kidney function. Higher levels indicate more extensive disease; aids in staging of disease.
Imaging studies: Bone [skeletal] survey, X-ray, magnetic resonance imaging,(MRI) computerized tomography(CT), positron emission tomography(PET). Assess changes in the bone structure and determine the number and size of tumors in the bone. Higher levels of bone changes suggest the presence of multiple myeloma.
Bone Marrow Biopsy: Determine the number and percentage of normal and cancerous plasma cells in the bone marrow. Presence of myeloma cells confirms the diagnosis. A higher percentage of myeloma cells indicate more extensive disease.
Cytogenetics is the study of chromosomes, the long strands of bundles of coded instructions for making and controlling cells. Cytogenetics involves examining a sample of cells with a microscope to look for changes in the cells’ chromosomes. This type of test is used to detect abnormal chromosomes and measure the number of cells that have them. The pathologist will use a microscope to examine a “map” of the chromosomes, called a karyotype. The pathologist will assess the size, shape, number, arrangement, and structure of the chromosomes on the karyotype to look for any abnormal changes. Cytogenetics is used to identify the presence of DNA alterations. Certain DNA alterations may indicate how aggressive the disease is and can also be used to monitor how well treatment is working. Cytogenetic testing can be performed on cells from the peripheral blood or bone marrow.
Fluorescence in situ hybridization (FISH) is another test used to detect the Philadelphia chromosome and the BCR-ABL fusion gene. This test may be used on a peripheral blood sample if a bone marrow sample can’t be collected. FISH uses color “probes” to find the BCR gene and the ABL gene in chromosomes. The BCR-ABL fusion gene, located on the Philadelphia chromosome, is shown by the overlapping colors of the two probes. FISH analysis of peripheral blood may be used to diagnose CML when bone marrow cytogenetics isn’t possible. But, FISH is not currently recommended for monitoring the response to treatment.
Human leukocyte antigens (HLA): are special proteins on the surface of white blood cells that help the body to identify its own cells from foreign cells. An individuals HLA type: is their unique set of HLA proteins on their white blood cells. HLA types differ among people just like blood types differ among people. HLA testing is used to determine a person’s HLA type in order to determine the role of allogeneic stem cell transplant. It’s very important that donor and patient HLA types are a near-perfect match. The better the match, the better the outcome from treatment.
Calcium: Hypercalcemia: Many multiple myeloma patients develop hypercalcemia, which is an increased level of calcium in the bloodstream. Hypercalcemia results from the destruction of bone from osteolytic lesions or sometimes from the development of generalized osteoporosis, in which all the bones are soft and porous and have lost calcium. Hypercalcemia in patients with multiple myeloma causes fatigue, lethargy and other symptoms. Severe hypercalcemia is a medical emergency requiring immediate treatment.
Kidney Dysfunction: In 75% of patients, the plasma cells also produce monoclonal incomplete immunoglobulins, called light chains. These are excreted in the urine and are the so-called Bence Jones proteins. Bence Jones proteins are named after a British physician, Henry Bence Jones (1813-1873), who first discovered them. Bence Jones proteins may deposit in the kidney, clogging the tubules. Ultimately, this damages the kidney and can cause renal failure. Hypercalcemia may exacerbate kidney problems because excess calcium in the bloodstream causes excessive fluid loss and dehydration. Because the abnormal proteins produced by the plasma cells are eliminated from the body through the urine, they may accumulate in the kidneys and cause kidney dysfunction. In addition to treating the underlying cancer, it is important for patients to maintain adequate oral intake of fluids to help avoid kidney failure and avoid using over-the-counter medications such as non-steroidal anti-inflammatory drugs that can worsen kidney function.
- Blade J, Rosinol L. Complications of multiple myeloma. Hematology/Oncology Clinics of North America. 2007; 21(6):1231-1246.
- Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined
significance and smoldering multiple myeloma. Hematology/Oncology Clinics of North America. 2007; 21(6):1093-113.
- American Cancer Society. Cancer Facts & Figures 2008. Available at: cancer.org/docroot/stt/stt_0.asp (Accessed March 12, 2019).
- Ries LAG, Harkins D, Krapcho M, Mariotto A, Miller BA, Feuer EJ, Clegg L, Eisner MP, Horner MJ, Howlader N, Hayat M, Hankey BF, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2004, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2004/, based on November 2006 SEER data submission, posted to the SEER web site 2007.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. © National Comprehensive Cancer Network, Inc. NCCN and NATIONAL COMPREHENSIVE CANCER NETWORK are registered trademarks of National Comprehensive Cancer Network, Inc.
- Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller, DG et al. AJCC CancerStaging Manual. 6th ed. New York (NY): Springer-Verlag; 2002.