CANCER > MULTIPLE MYELOMA - Early Detection, Diagnosis, and Staging

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Can multiple myeloma be found early?

It is difficult to diagnose multiple myeloma early. Often, multiple myeloma causes no symptoms until it reaches an advanced stage. Sometimes, it might cause vague symptoms that at first seem to be caused by other diseases. Rarely, multiple myeloma is found early when a routine blood test shows an abnormally high amount of protein in the blood.

How is multiple myeloma diagnosed?

Signs and symptoms of multiple myeloma

Although some patients with multiple myeloma have no symptoms at all, the following are the most common symptoms of this disease:

Bone problems

Normally, the 2 major kinds of bone cells work together to keep bones healthy and strong. The cells that lay down new bone are called osteoblasts. The cells that break down old bone are called osteoclasts. Myeloma cells make a substance that tells the osteoclasts to speed up the dissolving of bone. The osteoblasts do not get a signal to put down new bone, so old bone is being broken down without new bone to replace it. This can cause areas of bone weakness that are painful. Any bone can be affected, but pain in the bones in the back, the hips, and skull is particularly common with this disease. Multiple myeloma can also weaken bones all over (osteoporosis). Any of these changes increase the chance that the bones will break (fracture). Sometimes bones break from only a minor stress or injury.

Low blood counts

When myeloma cells replace normal blood-forming marrow cells, shortages of red blood cells, white blood cells, and blood platelets result. A reduced number of red blood cells, a condition called anemia, causes weakness, reduced ability to exercise, shortness of breath, and dizziness. Too few white blood cells (a condition called leukopenia) lowers resistance to infections such as pneumonia. When blood platelet counts are low (a condition calledthrombocytopenia), even minor scrapes, cuts, or bruises may cause serious bleeding.

High blood calcium

When the myeloma cells dissolve bone, calcium is released. This can lead to high levels of calcium in the blood (called hypercalcemia). Symptoms include feeling very thirsty, drinking a lot of fluids, and urinating (peeing) a lot. This can cause dehydration and even kidney failure. High calcium can also cause severe constipation, abdominal (belly) pain, and loss of appetite. It can make people feel weak, drowsy, and confused. If the level of calcium gets high enough, it can even cause you to lapse into a coma.

Nervous system symptoms

If myeloma weakens the bones in the spine, they can collapse and press on spinal nerves. This can cause sudden severe back pain, numbness, and/or muscle weakness. This, called spinal cord compression, is a medical emergency and you should contact your doctor right away or go to the emergency room.

Sometimes, the abnormal proteins produced by myeloma cells can be toxic to the nerves. This damage can lead to weakness and numbness.

In some patients, large amounts of myeloma protein can cause the blood to "thicken." This thickening is calledhyperviscosity. It can slow blood flow to the brain and cause confusion, dizziness, and stroke-like symptoms. Patients with these symptoms should call their doctor. Removing the protein from the blood using a procedure calledplasmapheresis can rapidly reverse this problem (this is not something that can be treated with drugs known as “blood thinners”).

Kidney problems

Myeloma protein can damage the kidneys. Early on, this doesn't cause any symptoms, but signs of kidney damage can be seen on a blood test. As the kidneys start to fail, they lose the ability to dispose of excess salt, fluid, and body waste products. This can lead to symptoms like weakness, shortness of breath, itching, and leg swelling.

Infections

Myeloma patients are much more likely to get infections. This happens because the body is unable to make the proper antibodies that help fight infection. When someone with myeloma gets an infection, they may be slow to respond to treatment. That person may stay sick for a long time. Pneumonia is a common and serious infection seen in myeloma patients.

Laboratory tests

If symptoms suggest that a person might have multiple myeloma, lab tests on blood and/or urine, x-rays of the bones, and a bone marrow biopsy are usually done.

Blood counts

The complete blood count (CBC) is a test that measures the levels of red cells, white cells, and platelets in the blood. If myeloma cells occupy too much of the bone marrow, levels of some of these blood cells will be low. The most common finding is a low red blood cell count (anemia).

Quantitative immunoglobulins

This test measures the blood levels of the different antibodies. There are several different types of antibodies in the blood: IgA, IgD, IgE, IgG, and IgM. The levels of these immunoglobulins are measured to see if any are abnormally high or low. In multiple myeloma, the level of one type may be high while the others are low.

Electrophoresis

The immunoglobulin produced by myeloma cells is abnormal because it is monoclonal (all the exact same antibody).Serum protein electrophoresis (SPEP) is a test that measures the immunoglobulins in the blood and can find a monoclonal immunoglobulin. Then, another test, such as immunofixation or immunoelectrophoresis, is used to determine the exact type of abnormal antibody (IgG or some other type). Finding a monoclonal immunoglobulin in the blood may be the first step in diagnosing multiple myeloma. This abnormal protein is known by several different names, including monoclonal immunoglobulin, M protein, M spike, and paraprotein.

Immunoglobulins are made up of protein chains: 2 long (heavy) chains and 2 shorter (light) chains. Sometimes the kidneys excrete pieces of the M protein into the urine. This urine protein is the part of the immunoglobulin called thelight chain. It is also known as Bence-Jones protein. The tests used for finding a monoclonal immunoglobulin in urine are called urine protein electrophoresis (UPEP) and urine immunofixation. These are most often done on urine that has been collected over 24 hours.

Free light chains

This test measures the amount of light chains in the blood. This is most helpful in the rare cases of myeloma in which no M protein is found by SPEP. Since the SPEP measures the levels of intact (whole) immunoglobulins, it cannot measure the amount of light chains.

Beta-2 microglobulin

This is another protein produced by the malignant cells. Although this protein itself doesn't cause problems, it can be a useful indicator of a patient's prognosis (outlook). High levels indicate more advanced disease and maybe a worse prognosis.

Blood chemistry tests

Levels of blood urea nitrogen (BUN) and creatinine, albumin, calcium, and other electrolytes will be checked

• BUN and creatinine (Cr) levels show how well your kidneys are working. Higher levels mean that kidney function is impaired. This is common in people with myeloma.
• Albumin is a protein found in the blood. Low levels can be a sign of more advanced myeloma.
• Calcium levels may be higher in people with advanced myeloma. High calcium levels can cause severe symptoms of fatigue, weakness, and confusion.
• Levels of electrolytes such as sodium and potassium may be affected as well.

Bone marrow biopsy

People with multiple myeloma have too many plasma cells in their bone marrow. The procedure to check the bone marrow is called a bone marrow biopsy and aspiration. It can be either done at the doctor's office or at the hospital.

In this procedure, the back of the pelvic bone is numbed with local anesthetic. Then, to do the bone marrow aspiration, a needle is inserted into the bone, and a syringe is used to remove a small amount of liquid bone marrow. This causes a brief sharp pain. Then for the biopsy, a needle is used to remove a tiny sliver of bone and marrow, about 1/16-inch across and 1-inch long. Patients may feel some pressure during the biopsy, but it usually isn’t painful. There is some soreness in the biopsy area when the numbing medicine wears off. Most patients can go home immediately after the procedure.

A doctor will use a microscope to look at the bone marrow tissue to see the appearance, size, and shape of the cells, how the cells are arranged and to determine if there are myeloma cells in the bone marrow and, if so, how many. The aspirate may also be sent for other tests, including immunohistochemistry and flow cytometry, and chromosome analyses, including karyotype and fluorescent in situ hybridization (also known as FISH).

Immunohistochemistry

In this test, a part of the biopsy sample is treated with special antibodies (man-made versions of immune system proteins) that attach only to specific molecules on the cell surface. These antibodies cause color changes, which can be seen under a microscope. This test may be helpful in telling different types of cells apart and in finding myeloma cells.

Flow cytometry

Like the immunohistochemistry test, the flow cytometry test looks for certain substances on the outside surface of cells that help identify what types of cells they are. But this test can look at many more cells than immunohistochemistry.

For this test, a sample of cells is treated with special antibodies that stick to the cells only if certain substances are present on their surfaces. The cells are then passed in front of a laser beam. If the cells now have antibodies attached to them, the laser will cause them to give off light, which can be measured and analyzed by a computer. Groups of cells can be separated and counted by these methods.

This is the most commonly used test for immunophenotyping — classifying cells according to the substances (antigens) on their surfaces. Different cells and cell types have different antigens on their surface. These antigens may also change as each cell matures.

Flow cytometry can help determine if there are abnormal cells in the bone marrow and if they are myeloma cells, lymphoma cells, some other cancer, or a non-cancerous disease.

Cytogenetics

This technique lets doctors evaluate the chromosomes (long strands of DNA) in normal bone marrow cells and myeloma cells. Some myeloma cells may have too many chromosomes, too few chromosomes, or other chromosome abnormalities. The cells are looked at under a microscope to see if the chromosomes have any changes, such as translocations (where part of one chromosome has broken off and is now attached to another chromosome) or deletions (where part or all of a chromosome is missing), as can happen in some cases of multiple myeloma. Finding these changes can sometimes help in predicting a person’s prognosis.

Cytogenetic testing usually takes about 2 to 3 weeks because the cells must grow in lab dishes for a couple of weeks before their chromosomes are ready to be seen under the microscope.

Fluorescent in situ hybridization

Fluorescent in situ hybridization (FISH) is similar to cytogenetic testing. It uses special fluorescent dyes that only attach to specific parts of chromosomes. FISH can find most chromosome changes (such as translocations and deletions) that can be seen under a microscope in standard cytogenetic tests, as well as some changes too small to be seen with usual cytogenetic testing.

FISH can be used to look for specific changes in chromosomes. It can be used on regular blood as well as bone marrow samples. It is very accurate and because the cells don’t have to grow in a dish first, results are often available within a couple of days.

Other biopsy tests

If an area looks abnormal on an x-ray, a biopsy may be needed to confirm that it is a plasmacytoma. Most often, a needle biopsy is used.

Fine needle aspiration biopsy

Fine needle aspiration (FNA) uses a very thin needle and an ordinary syringe to withdraw a small amount of tissue from a tumor or lymph node. The doctor can aim the needle while feeling an enlarged node near the surface of the body. If the abnormal area (tumor) is deep inside the body, the needle can be guided while it is viewed on a computed tomography (CT) scan (see discussion of imaging tests later in this section). The main advantage of FNA is that it does not require surgery. The disadvantage is that in some cases the thin needle cannot remove enough tissue for a definite diagnosis. FNA can be useful in diagnosing cancers that have spread to nodes from other organs.

Core needle biopsy

This test is similar to FNA, but a larger needle is used and a larger tissue sample is removed.

Imaging studies

Bone x-rays

Bone destruction caused by the myeloma cells can be detected with x-rays. Often doctors will do a series of x-rays that includes most of the bones. This is called a bone survey or skeletal survey.

Computed tomography scans

The computed tomography (CT) scan (also known as a CAT scan) is an x-ray procedure that produces detailed cross-sectional images of your body. Instead of taking one picture, like a conventional x-ray, a CT scanner takes many pictures of the part of your body being studied as it rotates around you. A computer then combines these pictures into an image of a slice of your body. Sometimes, this test can help tell if your bones have been damaged by myeloma.

A CT scanner has been described as a large donut, with a narrow table in the middle opening. You will need to lie still on the table while the scan is being done. CT scans take longer than regular x-rays, and you might feel a bit confined by the ring while the pictures are being taken.

You might be asked to drink 1 to 2 pints of a solution of contrast material before the test. This helps outline the intestine so that it is not mistaken for tumors. You might also receive an intravenous (IV; in the vein) line through which a different contrast dye is injected. This helps better outline structures in your body. The injection can cause a feeling of warmth throughout the body (flushing). Some people are allergic to the IV contrast and get hives. Rarely, more serious reactions like trouble breathing and low blood pressure can occur. Medicine can be given to prevent and treat allergic reactions. Be sure to tell the doctor if you have ever had a reaction to any contrast material used for x-rays. If IV contrast is being used, it is important you tell the radiology people that you have myeloma. Some of these contrast agents can damage the kidneys of people with myeloma.

CT scans can also be used to guide a biopsy needle precisely into a suspected tumor. For this procedure, called aCT-guided needle biopsy, the patient remains on the CT scanning table while a radiologist advances a biopsy needle toward the location of the tumor. CT scans are repeated until the doctors are confident that the needle is within the mass. A fine needle biopsy sample (tiny fragment of tissue) or a core needle biopsy sample (a thin cylinder of tissue about ½-inch long and less than 1/8 inch in diameter) is removed and examined under a microscope.

Magnetic resonance imaging scans

MRI scans use radio waves and strong magnets instead of x-rays. The energy from the radio waves is absorbed and then released in a pattern formed by the type of tissue and by certain diseases. A computer translates the pattern of radio waves given off by the tissues into a very detailed image of parts of the body. Not only does this produce cross-sectional slices of the body like a CT scanner, it can also produce slices that are parallel with the length of your body. A dye (contrast material) might be injected just as with CT scans but is used less often.

MRI scans are very helpful in looking at bones, the brain, and the spinal cord. They might be able to find plasmacytomas that cannot be seen on regular x-rays. MRI can also be used to look at the bone marrow in patients with multiple myeloma. MRI scans are a little more uncomfortable than CT scans. First, they can take an hour or longer. Also, you have to be placed inside tunnel-like equipment, which is confining and can upset some people. The machine also makes a thumping noise that could be disturbing. Some places provide headphones with music to block this out.

Positron emission tomography scans

In this test, which is also called a PET scan, radioactive glucose (sugar) is injected into the patient's vein to look for cancer cells. Because cancers use glucose (sugar) at a higher rate than normal tissues, the radioactivity will tend to concentrate in the cancer. A scanner is used to spot radioactive deposits. When a patient appears to have a solitary plasmacytoma, a PET scan may be used to look for other plasmacytomas.

Interpreting test results

Results of any single test are not enough to diagnose multiple myeloma. Diagnosis is based on a combination of factors, including the patient's description of symptoms, the doctor's physical examination of the patient, and the results of blood tests and x-rays. The diagnosis of multiple myeloma requires either:

• A plasma cell tumor (proven by biopsy)

OR

• At least 10% of the cells in the bone marrow are plasma cells.

AND one of the following:

• M protein is over a certain level in the blood (3g/dL)

OR

• M protein in the urine is over a certain level (1g/dL)

OR

• Holes in bones due to tumor growth or weak bones (osteoporosis) found on imaging studies.

Smoldering myeloma

This term used to mean early myeloma that is not causing any symptoms or problems. People with smoldering myeloma have normal blood counts, normal calcium levels, normal kidney function, and no bone or organ damage. Smoldering myeloma does not need to be treated right away.

How is multiple myeloma staged?

Staging is the process of finding out how much the cancer has advanced. It is important for treatment options and prognosis. Prognosis is a prediction of the course of disease — the outlook for survival. Knowing all you can about staging lets you take a more active role in making informed decisions about your treatment.

Multiple myeloma may be staged using the Durie-Salmon system. Although some doctors use this system, its value is becoming limited because of newer diagnostic methods. Recently, a new staging system called the International Staging System for Multiple Myeloma has been developed. It relies mainly on levels of albumin and beta-2-microglobulin in the blood. Other factors that may be important are kidney function, platelet count and the patient's age.

The Durie-Salmon staging system

This system is based on 4 factors:

• The amount of abnormal monoclonal immunoglobulin in the blood or urine: Large amounts of monoclonal immunoglobulin indicate that many malignant plasma cells are present and are producing that abnormal protein.
• The amount of calcium in the blood: High blood calcium levels can be related to advanced bone damage. Because bone normally contains lots of calcium, bone destruction releases calcium into the blood.
• The severity of bone damage based on x-rays: Multiple areas of bone damage seen on x-rays indicate an advanced stage of multiple myeloma.
• The amount of hemoglobin in the blood: Hemoglobin carries oxygen in red blood cells. Low hemoglobin levels mean you are anemic and can indicate that the myeloma cells occupy much of the bone marrow and that not enough space is left for the normal marrow cells to make enough red blood cells.

This system uses these factors to divide myeloma into 3 stages. Stage I indicates the smallest amount of tumor, and stage III indicates the largest amount of tumor:

Stage I

A relatively small number of myeloma cells are found. All of the following features must be present:

• Hemoglobin level is only slightly below normal (still above 10 g/dL)
• Bone x-rays appear normal or show only 1 area of bone damage
• Calcium levels in the blood are normal (less than 12 mg/dL)
• Only a relatively small amount of monoclonal immunoglobulin is in blood or urine

Stage II

A moderate number of myeloma cells are present. Features are between stage I and stage III.

Stage III

A large number of myeloma cells are found. One or more of the following features must be present:

• Low hemoglobin level (below 8.5 g/dL)
• High blood calcium level (above 12 mg/dL)
• 3 or more areas of bone destroyed by the cancer
• Large amount of monoclonal immunoglobulin in blood or urine

The International Staging System

This system divides myeloma into 3 stages based only on the serum beta-2 microglobulin and serum albumin levels.

Stage I

Serum beta-2 microglobulin is less than 3.5 (mg/L) and the albumin level is above 3.5 (g/L)

Stage II

Neither stage I or III, meaning that either:

• The beta-2 microglobulin level is between 3.5 and 5.5 (with any albumin level),

OR

• The albumin is below 3.5 while the beta-2 microglobulin is less than 3.5

Stage III

Serum beta-2 microglobulin is greater than 5.5.

Factors other than stage that affect survival

Kidney function

The blood creatinine (Cr) level shows how healthy the kidneys are. Kidneys eliminate this chemical from the body. When they are damaged by the monoclonal immunoglobulin, blood creatinine levels rise, predicting a worse outlook.

Age

Age is also important. In the studies of the international staging system, older people with myeloma do not live as long.

Labeling index

The myeloma cell labeling index, sometimes called the plasma cell labeling index, indicates how fast the cancer cells are growing. This test is done in specialized labs, using myeloma cells from bone marrow samples. A high labeling index can predict a more rapid accumulation of cancer cells and a worse outlook.

Chromosome studies

The bone marrow may be sent for tests to look at the chromosomes in the malignant cells. Certain chromosome changes can indicate a poorer outlook. For example, changes in chromosome 13 will lower a person’s chances for survival. Another genetic abnormality that predicts a poor outcome is an exchange of material from chromosomes 4 and 14. This is called a translocation.

Survival rates by stage for multiple myeloma

Survival rates are often used by doctors as a standard way of discussing a person's prognosis (outlook). Some patients with cancer may want to know the survival statistics for people in similar situations, while others may not find the numbers helpful, or may even not want to know them. If you decide that you don’t want to know them, stop reading here and skip to the next section.

Median survival refers to the time it took for half of the patients in that group to die. By definition, half the patients lived longer than the median survival. It is important to remember that the median is just a kind of average used by researchers. No one is "average" and many people have much better outcomes than the median.

Survival rates are often based on previous outcomes of large numbers of people who had the disease, but they cannot predict what will happen in any particular person's case. Many other factors can affect your outlook, such as your age and general health, the treatment you received, and how well your cancer responds to treatment. Your doctor can tell you how the numbers below may apply to you, as he or she is familiar with your situation.

The numbers below are the approximate overall median survival for the International Staging System stages. These times are measured from the point that treatment, such as chemotherapy, first started. Many patients, such as those with indolent or smoldering myeloma, have a good deal of time after diagnosis before treatment is started. Also, these patients were treated anywhere from 5 to 25 years ago. Treatment since then has improved considerably and modern results are likely to be better.

International Staging System Stage	Median Survival
Stage I	62 months
Stage II	44 months
Stage III	29 months

Last Medical Review: 01/15/2013
Last Revised: 02/12/2013