Posted: September 15, 2013 in Multiple Myeloma Research


Multiple myeloma, also known as myeloma, is a hematologic cancer, or cancer of the blood. It is the second most common blood cancer, after non-Hodgkin’s lymphoma, and represents approximately 1% of all cancers in white individuals and 2% of all cancers in black individuals.

The American Cancer Society estimates that 22,350 new cases of multiple myeloma will be diagnosed in 2013. The number of cases of myeloma reported at a particular time (the prevalence) varies according to gender, age, and race/ethnicity. Multiple myeloma is more common among men than women and occurs more frequently with increasing age.

As with any cancer diagnosis, hearing that you have myeloma can be overwhelming. But new treatments continue to be evaluated in research studies, and substantial improvements in treatment have been made over the past few years. Multiple myeloma cannot be cured, but it can be treated, allowing many individuals to live longer, healthier lives with the disease.

This section is designed to serve as a fundamental resource for education about multiple myeloma. It provides an overview of the disease, including the following:

Definition and development of myeloma
Causes and risk factors
Effect of myeloma on the body
Diagnosis and classification
Prognostic indicators


Multiple myeloma is a hematologic (blood) cancer that develops in the bone marrow, the soft, spongy center of most bones. VIEW FIGURE. Myeloma typically occurs in bone marrow with the most activity, which is the marrow in the spine, pelvic bones, ribs, and area of the shoulders and hips. Many blood cells are produced in the bone marrow; myeloma affects plasma cells, cells that produceimmunogobulins (antibodies) that help fight infection and disease. In multiple myeloma, normal plasma cells transform into malignant myeloma cells and produce large quantities of an abnormal immunoglobulin called monoclonal (M) protein. The malignant cells also crowd out and inhibit the production of normal blood cells and antibodies in the bone marrow. In addition, groups of myeloma cells cause other cells in the bone marrow to remove the solid part of the bone and cause soft spots in the bone. These soft spots, also called osteolytic lesions, and other signs of bone loss are common, although they do not occur in all individuals with myeloma.

Development of Myeloma

Myeloma cells are transformed from normal plasma cells, which are an important part of the immune system. Before learning how myeloma develops, you may want to learn more about how normal plasma cells develop.

The transformation of a normal plasma cell into a malignant plasma cell, or myeloma cell, is a multistep process. Learn more about this complex process.

When plasma cells become malignant, they grow out of control by dividing rapidly. Soon, there are too many malignant cells, and they begin to crowd out normal cells in the bone marrow. Malignant cells may invade the hard outer part of the bone and then spread into the cavities of the large bones in the body and form a tumor. When only one tumor is formed, it is called a solitary plasmacytoma. When multiple small tumors are formed, the disease is multiple myeloma. VIEW X-RAY

A high level of M protein in the blood is the hallmark characteristic of myeloma. All myeloma cells are identical to each other and produce large quantities of the same specific M protein (for example, IgG or IgA). This abnormal immunoglobulin has no benefit in the body, and as the amount of M protein increases, it crowds out normally functioning immunoglobulins. As a result, the level of normal immunoglobulins is lower in individuals with multiple myeloma. Learn more about the types of myeloma according to the type of immunoglobulin.


Multiple myeloma occurs more frequently in men than women (of the estimated 22,350 new cases expected in 2013, 12,440 will be diagnosed in men and 9,910 in women). The highest incidence of myeloma has been found for the non-Hispanic black (African American) population; some studies have shown that the incidence is nearly twice as high for that population compared with the white population. The lowest incidence of myeloma has been found among Asian individuals.

Causes and Risk Factors

To date, no cause for myeloma has been identified. Some research has suggested possible associations with a decline in the immune system, specific occupations, exposure to certain chemicals, and exposure to radiation. For example, the likelihood of multiple myeloma is higher than average among people in agricultural occupations, petroleum workers, workers in leather industries, and cosmetologists. Exposure to herbicides, insecticides, petroleum products, heavy metals, plastics, and various dusts including asbestos also appear to be risk factors for the disease. However, none of these associations is strong, and in most cases, multiple myeloma develops in individuals who have no known risk factors. Genetic factors may also be involved in the development of multiple myeloma. Learn more about genetic abnormalities in multiple myeloma. Researchers believe that multiple myeloma is most likely the result of several factors acting together.

The most significant risk factor for multiple myeloma is age, as 96% of cases are diagnosed in people older than 45 years, and more than 63% are diagnosed in people older than 65 years. Thus, it is thought that susceptibility to myeloma may increase with the aging process.

It is uncommon for myeloma to develop in more than one member of a family. This means that if you have myeloma, you probably do not need to worry about the disease developing in another family member. There is a slightly increased risk of myeloma occurring in children or siblings of individuals who have the disease.

Effect of Myeloma on the Body

The primary effect of multiple myeloma is on the bone. The blood and the kidneys are also affected.


Damage caused by myeloma cells leads to bone loss in two ways. First, the cells gather to form masses in the bone marrow that may disrupt the normal structure of the surrounding bone. Second, myeloma cells secrete substances that interfere with the normal process of bone repair and growth. In most individuals with myeloma, damage to the bone structure results as soft spots, or osteolytic lesions. These soft spots appear as “holes” on a standard bone x-ray. VIEW X-RAY

Osteolytic lesions weaken the bone, causing pain and increasing the risk of fracture. The most commonly affected bones are the spine, pelvis, and rib cage. Learn more about how myeloma causes damage to bone.

Bone destruction can cause the level of calcium in the bloodstream to rise, a condition called hypercalcemia. This condition can cause additional symptoms, as discussed in the section on symptoms.


The growing number of myeloma cells can interfere with the production of all types of blood cells. A reduction in the number of white blood cells, a condition known as leukopenia, can increase the risk of infection, whereas decreased red blood cell production can result in anemia. A reduction in platelets, known as thrombocytopenia, can prevent normal blood clotting, which may cause an individual to bruise easily. In addition, high levels of M protein and light chains (Bence Jones proteins) crowd out normal functioning immunoglobulins and may “thicken” the blood, causing additional symptoms.


Excess M protein and calcium in the blood overwork the kidneys as they filter blood. The amount of urine produced can increase, and the kidneys fail to function normally.


There are often no symptoms in the early stages of myeloma. When present, symptoms may be vague and similar to those of other conditions. Some symptoms are more common than others, and less common symptoms may be the result of complications that may occur. Remember that not all individuals with myeloma will have symptoms and that it is unusual for any one individual to have all of these symptoms. In addition, advances in treatment allow for symptoms to be prevented and managed.

Symptoms Associated with Multiple Myeloma and Their Causes

Cause /Complication

Most Common Symptoms

Bone pain

Tiny fractures in the bone made by accumulation of plasma cells; weakened bone structure

Fatigue (extreme tiredness)

Low levels of red blood cells in the blood (anemia) or high level of calcium in the blood (hypercalcemia)

Loss of appetite, increased thirst, increased urination, restlessness, difficulty in thinking or confusion, nausea and vomiting

High level of calcium in the blood

Infection (pneumonia, urinary tract infection, shingles)

Low levels of white blood cells (which fight infection) resulting from an increasing number of myeloma cells (which crowd out healthy blood cells, such white blood cells)

Less Common Symptoms

Shortness of breath, chest pain, confusion

Hyperviscosity syndrome: a high level of protein in the blood makes the blood very thick and sticky

Pain and numbness in the fingers and toes in cold weather

Cryoglobulinemia: abnormal proteins become gel-like when the body is exposed to cold temperatures, and the gelled proteins may block small blood vessels

Neuropathy (numbness, tingling, and/or pain, especially in the hands and feet)*

Amyloidosis: a rare complication that occurs more often in patients who have light chain (Bence Jones) myeloma; the light chains can combine with other proteins to produce amyloid protein (a starch-like substance) that may be deposited in various tissues and organs and disrupt their normal functions

*Amyloidosis may also involve low blood pressure and may result in kidney, heart, or liver failure.

Diagnosis and Classification

Because symptoms do not usually occur with myeloma in the early stages, a diagnosis of myeloma is often made incidentally during routine blood tests for other conditions. For example, evaluation of a blood sample may show a low number of red blood cells (anemia) and a high level of serum protein, which may prompt further testing to determine if myeloma is present.

If myeloma is suspected, a specialist experienced in treating myeloma should be consulted to further evaluate the disease and help develop a treatment plan. The MMRF can help you locate a National Cancer Institute (NCI)-designated cancer center or a myeloma specialist in your area. Individuals with myeloma are usually treated by a hematologist/oncologist and sometimes a radiation oncologist is involved in treatment.

Criteria for Diagnosis

A diagnosis of multiple myeloma is difficult to make on the basis of any single laboratory test result. To obtain an accurate diagnosis, several additional factors must be considered, including the findings on physical examination and a thorough history and evaluation of symptoms.

Standards for diagnosis currently require confirmation of one major and one minor criteria or three minor criteria in an individual who has signs or symptoms of myeloma.

Major Criteria

Plasmacytoma (as demonstrated on evaluation of biopsy specimen)
30% plasma cells in a bone marrow sample
Elevated levels of M protein in the blood or urine
Minor Criteria

10% to 30% plasma cells in a bone marrow sample
Minor elevations in the level of M protein in the blood or urine
Osteolytic lesions (as demonstrated on imaging studies)
Low levels of antibodies (not produced by the cancer cells) in the blood
Tests can be done on specimens of blood, urine, bone, and bone marrow to determine if these criteria are present. These tests are done not only to determine if myeloma is present but also to assess the extent of disease. Thus, the tests are also valuable for classifying and staging the disease (discussed later).

Diagnostic Tests on Blood

Complete blood count (CBC) is done to measure the number of red blood cells, white blood cells, and platelets in the blood, as well as the number or relative proportion of the different types of white blood cells present. The results of this test indicate the degree to which myeloma is affecting the production of normal blood cells. Learn more about a CBC and normal values.

A chemistry profile provides levels of such substances as albumin, blood urea nitrogen (BUN), calcium, creatinine, and lactate dehydrogenase (LDH). These levels help provide an assessment of the general health status and the extent of disease. Abnormal levels may indicate decreased kidney function and increased size and/or number of tumors.

The beta-2 microglobulin (ß2-M) level is considered to be a standard measure of tumor burden (the extent of disease).

The C-reactive protein level reflects the level of interleukin (IL)-6, a growth factor involved in the development of myeloma cells. As such, the level is an indirect measurement of the number of myeloma cells and/or size of the tumor(s).

Quantitive immunoglobulin (QIG) testing provides measurements of the levels of the different types of immunoglobulins (antibodies)—that is, IgG, IgA, and IgM—that are produced by myeloma cells.

Serum protein electrophoresis (SPEP) detects the presence and level of various proteins in the blood, including M protein. Higher levels of M protein indicate more extensive disease. Learn more about electrophoresis.

Immunofixation electrophoresis (IFE) or immunoelectrophoresis provides more specific information than SPEP regarding the type of abnormal immunoglobulins (IgG, IgA, or IgM).

Freelite™ testing can detect and quantify free light chains (those not associated with intact immunoglobulin). Evidence suggests that this test may be a more sensitive test and detect the presence of M protein or light chains in individuals with nonsecretory myeloma.
Diagnostic Tests on Urine

Urinalysis is done to assess kidney function.

The measurement of the amount of Bence Jones protein in a 24-hour specimen of urine is done to determine the presence of disease; higher levels represent more extensive disease.

Urine protein electrophoresis (UPEP) is done to determine the presence and levels of specific proteins in the urine, including M protein and Bence Jones protein, both of which are indicators of myeloma.
Diagnostic Tests on Bone/Bone Marrow

A skeletal survey, a series of x-rays of the spine, arms, ribs, pelvis, and legs can demonstrate bone lesions and changes in bone structure.

Other imaging studies, such as magnetic resonance imaging (MRI), computerized tomography (CT), and positron emission tomography (PET), are additional tests that can assess changes in the bone structure and determine the number and size of tumors in the bone.

Evaluation of a biopsy specimen taken from either bone tissue or bone marrow can determine the number and percentage of normal and malignant plasma cells in the bone marrow. The diagnosis of myeloma is probable if 10% or more of the cells in the bone marrow sample are plasma cells.

Plasma cell labeling index (PCLI) defines the relative percentage of plasma cells that are actively growing.

Cytogenetic analysis (fluorescence in situ hybridization [FISH]) is done to evaluate the number and normalcy of chromosomes and identify the presence of chromosome translocations (a type of abnormality).
Classification of Myeloma

Myeloma is classified into one of three categories: monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma (further subdivided into smoldering or indolent myeloma), and symptomatic myeloma. The classification is important because immediate disease-directed treatment is needed only for symptomatic myeloma. Delaying treatment can help avoid unnecessary side effects associated with chemotherapy. Even though treatment directed at the myeloma is postponed for most types of the disease, supportive care is given to prevent and/or manage symptoms and complications.

Monoclonal Gammopathy of Undetermined Significance (MGUS).

MGUS involves an excess of M protein, but the plasma cells have not formed a tumor or multiple lesions, no symptoms have occurred, and other criteria for a myeloma diagnosis are absent. MGUS occurs in about 1% of the general population and in about 3% of healthy individuals older than 70 years.

The Characteristics of MGUS Include the Following:

Serum M protein level, < 3 g/dL
Percentage of plasma cells in the bone marrow, 30%

Mild anemia or a few small osteolytic lesions

Lack of symptoms
Individuals with asymptomatic multiple myeloma have close follow-up (also called observation), with visits to the physician and/or testing approximately every 3 months. Treatment with bisphosphonates is started for individuals who have osteolytic lesions, osteoporosis, or osteopenia. Treatment directed at myeloma is started once the disease has progressed to symptomatic myeloma. Participation in a clinical trial is also encouraged. Read about clinical trials.

Symptomatic Multiple Myeloma

The characteristics of symptomatic multiple myeloma are the following:

Elevated level of M protein in the serum and/or urine
Percentage of plasma cells in bone marrow, >30%
Anemia, renal failure, hypercalcemia, or osteolytic lesions
There are a variety of treatment options for symptomatic multiple myeloma and your physician will consider many factors when deciding which option to choose. Your preferences are an important consideration. You should learn all you can about the treatment options in order to participate in the decision-making process. Read about treatment options.

Staging of Myeloma

The process of staging myeloma is crucial to developing an effective treatment plan. The staging system that has been most widely used since 1975 is the Durie-Salmon system. According to this system, multiple myeloma is defined as stage I, II, or III on the basis of four measurements: the level of M protein, the number of osteolytic bone lesions, the hemoglobin level, and the serum calcium level. Each stage is further classified as A or B, depending on kidney function.

A newer, simpler, more cost-effective alternative staging system that is being used more often is the International Staging System (ISS). The ISS is based on the assessment of two blood test results, beta 2-microglobulin (ß2-M) and albumin. ß2-M is a protein that indicates the extent of disease and albumin in an indicator of overall general health. The ISS has been shown to better discriminate between the stages of myeloma than the Durie-Salmon System. The three stages in the ISS indicate different levels of predicted survival, which helps in treatment decision-making.

Staging of Multiple Myeloma


Criteria for Durie-Salmon System*

Criteria for ISS


All of the following:

Hemoglobin level, >10 g/dL
Serum calcium value, normal or <12 mg/dL
Bone x-ray, normal bone structure or solitary bone plasmacytoma only
Low M protein production rate (IgG level, <5 g/dL; IgA value, ❤ g/dL, Bence Jones protein, <4 g/24 h)
ß2-M level, < 3.5 mg/mL
and albumin level, ≥3.5 g/dL


Neither stage I nor stage III

ß2-M level, <3.5 mg/mL and albumin level, <3.5 g/dL or
ß2-M level, 3.5-5.5 mg/dL


On or more of the following:

Hemoglobin level, 12 mg/dL
Advanced osteolytic lesions
High M protein production rate (IgG level, >7 g/dL; IgA level, >5 g/dL; Bence Jones protein, >12 g/24 hr.
ß2-M level, >5.5 mg/mL

*Myeloma is further classified as A (relatively normal kidney function [serum creatinine level, < 2.0 mg/dL]) or B (abnormal kidney function [serum creatinine value, ≥ 2.0 mg/dL]).

Prognostic Indicators

The prognosis is the predicted or likely outcome of a disease. Prognosis is usually based on the existence of different signs, symptoms, and circumstances. Several clinical and laboratory findings provide important prognostic information in myeloma. These prognostic indicators help determine how fast the tumor is growing, the extent of disease, the biologic make-up of the tumor, the response to therapy, and the overall health status of the individual. Prognostic indicators may also help determine when treatment should begin, and what treatment is best according to a person’s individual risk for relapse.

Determining the levels of these prognostic tests early in the course of the disease is important, as it provides a baseline against which disease progression and response to therapy can be measured. Many tests can be performed routinely in any laboratory, whereas others are performed only in specialized laboratories or a research setting.

Prognostic Indicators in Myeloma



Values Indicating a More Favorable Prognosis

Beta 2-microglobulin (ß2-microglobulin orß2-M)

Higher levels reflect more extensive disease and poor kidney function

60 yrs.: 110-210 U/L

Freelite™ serum free light chain assay

Abnormal results may indicate poor prognosis (also indicates risk of progression of MGUS or asymptomatic myeloma to symptomatic myeloma)

Free light chain ratio
MGUS: 0.26-1.65
Asymptomatic myeloma: 0.125-8.0
Symptomatic myeloma: 0.03-32

Chromosome analysis (cytogenetic testing by either karyotyping or FISH)

Presence of specific abnormalities may indicate poor prognosis

Absence of abnormalities

Gene expression profiling

Presence of specific group of genes can predict low or high risk of early relapse.