Multiple Myeloma? What Causes Multiple Myeloma?

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Multiple myeloma, also known as myeloma orplasma cell myeloma, iscancer of the plasma cells - a kind of white blood cell which is present in the bone marrow. Plasma cells make antibodies called immunoglobulin which help fight off infections.

A group of abnormal cells - myeloma cells - multiplies, elevating the number of plasma cells too high, which in turn results in excessively high levels of immunoglobulin. Multiple myeloma affects the bones, immune system, kidneys and red blood cell count.

According to the American Cancer Society (ACS), multiple myeloma is a relatively uncommon cancer, with a lifetime risk of 1 in 161, or 0.61%. The ACS estimates that over 20,000 new cases will have been diagnosed by the end of 2009. According to Cancer Research UK, just under 4,000 people are diagnosed with multiple myeloma each year in the UK. It represents 1% of all UK cancers. According to the Multiple Myeloma Research Foundation, USA, it represents about 1% of all cancers in white US residents and 2% of cancers in black residents.

What are the symptoms of multiple myeloma?

The signs and symptoms of multiple myeloma can vary, depending on its stage and certain aspects of the patient's general health. It is not uncommon that patients experience no symptoms during the disease's early stage. Often the first the patient knows about it is after a routine blood or urine test.

• Abnormal proteins - these are usually detected in blood or urine. The proteins are called monoclonal proteins (M proteins). If M proteins are detected during a routine exam they may indicate multiple myeloma, as well as other conditions.
• Bone pain - more commonly in the back, pelvis, ribs and skull.
• High calcium blood levels (hypercalcaemia) - this occurs because calcium in the affected bones dissolves into the blood. The following symptoms are common if blood calcium levels are high:
  
  
  • Excessive thirst
  • Frequent urination
  • Confusion
  • Constipation
  • Loss of appetite
  • Nausea
  • Vomiting
  • Abdominal pain
• Red and white blood cell and platelet levels - if the patient's normal production of red and white blood cells, as well as platelets is reduced, he/she may experience:
  
  
  • Fatigue, tiredness
  • Lethargy
  • Breathlessness
  • Repeated infections
  • Easily bruised skin
  • Nosebleeds, bleeding gums, or other unusual bleeding
• Kidney damage - if the paraproteins (monoclonal proteins, or M proteins) which are produced by the cancerous plasma cause kidney damage, the following symptoms are possible:
  
  
  • Excessive thirst
  • Excessive urination
  • Excessively reduced urination, or no urination
  • Swollen ankles
  • Breathlessness
  • Loss of appetite
  • Nausea
  • Vomiting
• Cord compression - sometimes there may be damage to the spine, causing it to press against nerves that run through the spinal column. The following symptoms are possible:
  
  
  • Tingling in the legs and feet
  • Numbness in the legs and feet
  • Weakness in the legs and feet
  • Urinary incontinence
  • Bowel incontinence
  • Problems passing urine
  • Problems passing stools

When to see the doctor

If you experience any of the symptoms below you should see your GP (general practitioner, primary care physician) - most likely it (they are) is a symptom of something else, but should be checked anyway:

• Persistent tiredness which cannot be explained
• Persistent bone pain
• Unexpected weight loss
• Excessive urination
• Excessive thirst
• Numbness, tingling or weakness in your legs

What are the causes of multiple myeloma?

Multiple myeloma is a type of cancer. Cancer starts when the structure of the DNA in a cell is altered - a genetic mutation. The DNA (deoxyribonucleic acid) consists of a set of instructions for a cell, telling it when to grow, divide, die, etc. When there is a mutation in the DNA the instructions change, sometimes accelerating cell growth and stopping cells from dying. If new cells are created but the mature ones don't die, for example, an excess of mutated cells starts to build up.

The result is an uncontrollable reproduction of cells, which in the case of multiple myeloma leads to too many plasma cells inside the bone marrow - the soft, blood-producing tissue that fills in the center of most of our bones. Less than 5% of healthy bone marrow consists of plasma cells. For people with multiple myeloma more than 10% of the bone marrow consists of plasma cells.

Unlike most other types of cancer, multiple myeloma is thought to spread through the bloodstream. Mutated cells may start off in the bone marrow of the spine, get into the bloodstream and travel to another part of the body, such as the hips or skull, and affect the bone marrow there. The disease is called multiple myeloma because it can rapidly spread to multiple parts of the body.

Multiple myeloma's ability to rapidly move from one part of the body to another makes it very hard to find a complete cure.

What are the possible risk factors linked to multiple myeloma?

Scientists are not sure what exactly causes the DNA within plasma cells to mutate and become cancerous. Experts say the following factors may raise a person's risk of developing multiple myeloma:

• Age - 96% of cases are diagnosed in people over 45 years of age. 75% are diagnosed in people over 70 years of age.
• Genetic inheritance - people who have a close relative with multiple myeloma have a higher risk of developing it.
• Obesity - obesity is a risk factor for many cancers, including multiple myeloma.
• Diet - some studies have indicated that a diet low in fish and/or green vegetables may be linked to a higher multiple myeloma risk.
• HIV/AIDS
• Certain occupations - people who work in agriculture, the leather industries, cosmetology, and petroleum workers have a higher incidence of multiple myeloma compared to the rest of the population.
• Exposure to certain chemicals and products - people who have been exposed to heavy metals, some hair dyes, plastics, various dusts including wood dust, asbestos, herbicides, insecticides, petroleum products, have a higher risk of developing multiple myeloma.
• Radiation exposure - survivors of the Hiroshima and Nagasaki atomic bomb explosions have a significantly higher incidence of multiple myeloma.
• Some autoimmune disorders, such as rheumatoid arthritis
• A history of monoclonal gammopathy (MGUS) - 1% of people with MGUS in the USA develop multiple myeloma each year. MGUS, like multiple myeloma, has the hallmark M proteins which are produced by abnormal plasma cells in the blood. However, in MGUS, there is no damage to the body.

How is multiple myeloma diagnosed?

The GP will ask the patient about his/her medical history, symptoms, family history, and possibly some other questions regarding employment history. The following tests will probably be ordered:

• Blood tests
  
  
  A blood test can be used to identify..
  ..the presence of abnormal paraproteins (M proteins) ..higher than normal blood calcium levels ..levels of red and white blood cells, as well as platelets ..beta2-microglobulin, another protein produced by myeloma cells
• Urine test
  
  A urine test can help the doctor find out whether there is any underlying kidney damage. Bence Jones proteins, parts of M proteins, may also be detected in the urine.
• X-rays
  
  A series of X-rays are taken to find out whether there is any bone damage. Any sign of bone damage will appear as dark areas in X-ray pictures. If the doctor requires more detailed images an MRI (magnetic resonance imaging) or CT (computerized tomography) scan may be ordered.
• Biopsy
  
  A needle is inserted into the bone and a small sample of bone marrow, often from the hip, is taken. This will be done under local anesthetic and is not painful. The sample is examined under a microscope to check for myeloma cells.

Staging and classification of multiple myeloma

A staging system is used by the medical profession to describe how advanced the myeloma is, and how it is affecting the body. A common staging system is called the Durie-Salmon system.

The four factors of the Durie-Salmon system:

• What is the red blood cell count?
• How much calcium is in the blood?
• How much paraproteins (monoclonal proteins, or M proteins) is in the blood?
• The general state of the patient's bones.

Stage one (Durie-Salmon system)

• Blood calcium levels are normal
• Red blood cell levels are either normal or slightly below normal
• Low levels of paraproteins (monoclonal proteins, or M proteins) in the blood
• Bones are either undamaged or slightly damaged
• Most patients have no symptoms

Stage two (Durie-Salmon system)

• Red blood cell levels still relatively normal
• Calcium blood levels still relatively normal
• Levels of paraproteins (monoclonal proteins, or M proteins) still low
• Damage is present in one or two bones

Stage three (Durie-Salmon system)

• Red blood cell levels have fallen. Symptoms of anemia are probably present.
• Blood calcium levels have risen. Symptoms of hypercalcemia are likely.
• High levels of paraproteins (monoclonal proteins, or M proteins) in the blood.
• Damage to three or more bones.

The Durie-Salmon system also has a system to indicate the health or deterioration of the kidneys:

• A - kidneys are either undamaged or only slightly damaged.
• B - kidneys are damaged, kidney function is abnormal.

Kidney damage is more likely during stages two or three, but can also occur in stage one.

What are the treatment options for multiple myeloma?

Doctors will usually adopt a policy of watchful waiting for patients in stage one. The patient will most likely receive no immediate treatment, but will be monitored carefully in case the cancer advances.

Patients in stages two and three will usually receive chemotherapy, as well as treatment to help control symptoms.

The treatment of multiple myeloma has 4 aims:

• Bringing the cancer under control - this usually involves removing the cancerous cells from the bone marrow.
• Maintenance therapy - after the cancer cells have either all been removed, or greatly reduced, the aim is to stop cancerous cells from returning for as long as possible.
• Symptomatic treatment - treating symptoms and complications linked to multiple myeloma, such as back pain, kidney damage, anemia, etc.
• Relapse therapy - treatment for recurrences.

Bringing the cancer under control

• Chemotherapy - these are medications which kill myeloma cells. They are either taken orally or intravenously. Treatment is usually given in cycles over a period of months, with rest intervals. Sometimes, if the patient's M protein levels remain stable, treatment is discontinued, and resumed if levels start to rise. Examples include melphalan (Alkeran), cyclophosphamide (Cytoxan), vincristine (Oncovin), doxorubicin (Adriamycin) and liposomal doxorubicin (Doxil).
  
  The type of initial treatment for multiple myeloma depends on whether the patient is considered a candidate for stem cell transplantation. If you are not considered a suitable stem cell transplantation candidate your therapy will likely include a combination of MPT (melphalan, prednisone and thalidomide) or MPV (melphalan, predisone and bortezomib). If side effects are too severe the patient may be switched to MP (melphalan plus prednisone).
  
  Side effects from chemotherapy may include:
  
  
  • Nausea
  • Diarrhea
  • Vomiting
  • Loss of appetite
  • Tiredness, fatigue
  • Skin rashes
  • Infertility
  • Hair loss
  
  These side effects should disappear once treatment is over. If there is hair loss, it will return within 3-6 months after treatment is finished.
• Stem cell transplantation - the patient receives a high-dose chemotherapy, usually melphalan. Then he/she receives a transfusion of stem cells (immature blood cells). These stem cells may either come from the patient or a donor.
  
  Whether or not you are deemed a suitable candidate for stem cell transplantation depends on the risk of disease progression, your age and general state of health.
  
  If doctors think you are a candidate for stem cell transplantation, therapy will initially exclude melphalan, as it can damage the stem cells and there will not be enough of them to collect later on. You will probably start on lenalidomide or bortezomib together with low-dose dexamethasone. Your stem cells will most probably be collected after three to four months of initial treatment with these agents. Stem cell transplantation will probably occur soon after the stem cells are collected - if there is a relapse this may be delayed. After the stem cell transplantation most patients will start a new course with a combination of bortezomib and melphalan.

Maintenance therapy

• Corticosteroids - commonly used for multiple myeloma treatment. Usually administered orally, a daily tablet with breakfast. Examples include prednisone and dexamethasone. Steroids are synthetic versions of naturally occurring hormones. Experts believe dexamethasone encourages the immune system to stop new cancerous cells from growing in the bone marrow - however, they are not sure how it works.
  
  The following side effects are possible:
  
  
  • Heartburn
  • Difficulty falling asleep
  • Higher risk of infection
  • Indigestion
  • Raised appetite
  • Swelling of the hands and feet
  • Weight gain
• Thalidomide (Thalomid) - despite being used in the 1950s for the treatment of morning sickness during pregnancy and causing severe birth defects, it was approved in 1998 for the treatment of leprosy, and later for the treatment of multiple myeloma. This is an oral medication, usually taken in the evening with food.
  
  Research has demonstrated that thalidomide targets the blood vessels that cancerous cells need to multiply and grow - effectively preventing the recurrence of cancerous cells.
  
  Because of the birth defect risk, both in men and women - thalidomide also affects sperm quality - it is important to use effective and reliable contraception while taking thalidomide.
  
  In the UK and many other countries, the patient will have to sign a document stating that he/she is aware of the risks of birth defects linked to thalidomide, and the precautions that have to be taken.
  
  Thalidomide may have the following side effects:
  
  
  • Loss of appetite
  • Sleepiness
  • Headaches
  • Skin rashes
  • Numbness/tingling in hands and feet
  • Constipation
  • Vomiting
  • Nausea
  • Blood clot - there is a very small risk of this. The patient may be givenwarfarin, a blood thinner, to prevent blood clots.
• Interferon alpha - works by stimulating the body's immune system to attack any cancer cells that may remain in the bone marrow. It is administered by injection. Most patients require three injections per week. Most patients are taught how to inject themselves so that it can be administered at home. Patients on interferon alpha require close monitoring and will have to undergo regular urine and blood tests.
  
  The following side effects are possible:
  
  
  • Fatigue
  • Flu-like symptoms (chills, fever and joint pain)
  
  Initially, side effects can be severe, but in the vast majority of cases they improve after each dose.
  
  These less common side effects are also possible and should be reported to your medical team if they occur because most of them are treatable:
  
  • Vomiting
  • Depression
  • Dizziness
  • Moodiness
  • Nausea
  • Pins and needles in hands or toes
  • Skin irritation around where injection occurred
  • Temporary hair loss
  • Infertility - in very rare cases this could become permanent
  • Susceptibility to infection
  • Changing blood pressure
  • Changing heart rhythm

Treatment for relapsed myeloma

If cancer cells return the patient will undergo another course of chemotherapy, perhaps in combination with a stem cell transplantation. Additional medications which can make the chemotherapy more effective may be included; usually lenalidomide and bortezomib.

• Bortezomib (Velcade) - this drug is a proteasome inhibitor and is administered intravenously. It encourages cancer cells to die by blocking the action of proteasomes.
  
  Side effects may include:
  
  
  • Fatigue
  • Nausea
  • Diarrhea
  • Numbness and tingling in hands and feet
  
  These side effects usually go away as soon as treatment is completed.
• Lenalidomide (Revlimid) - a similar chemical to thalidomide, it blocks the blood supply that cancer cells need to grow and multiply. As this drug can lower the number of white blood cells the patient will be more susceptible to infection. Lenalidomide also reduces the number of platelets in the blood, so the patient may bruise more easily.

Treating other symptoms and multiple myeloma complications

• Radiotherapy - high-energy waves are directed at cancer cells, which damage them and halt their growth - commonly used in many cancers. Radiotherapy is more commonly used to treat symptoms of bone pain in patients with multiple myeloma - it gives the bone a chance to repair itself. Most patients require one or two sessions to reduce symptoms of pain.
• Back pain - some patients are given pain medication while others obtain relief if they wear a back brace.
• Kidney problems - standard treatment for kidney complications may be necessary, including dialysis.
• Infections - when white blood cell counts are low the patient is more susceptible to infection. The doctor may prescribe antibiotics to treat current infections, and also to reduce the risk of becoming infected.
• Bone loss - such medications as bisphosphonates bind to the surface of the bones and help prevent bone loss. Examples include pamidronate (Aredia) or zoledronic acid (Zometa). It is important to check with your doctor before going to the dentist if you are on these medications.
• Anemia - erythropoietin injections may be required if the anemia is persistent. Erythropoietin stimulates the production of red blood cells. It is important to monitor patients receiving erythropoietin injections for blood clots.

What are the complications of multiple myeloma?

• Kidney failure - kidneys can become damaged from high blood levels of calcium and paraproteins (monoclonal proteins, or M proteins). In the majority of cases the damage is temporary and the kidneys recover. In some cases, unfortunately, there may be kidney failure - the kidneys lose some or all of their function. Patients with kidney failure will need dialysis.
• Susceptibility to infections - as myeloma inhibits the production of antibodies required for normal immunity, patients have a higher risk of developing infections, such as sinusitis, bladder or kidney infections, skin infections, shingles and pneumonia.
• Bone problems - the patient may have erosion of bone mass and fractures. There may also be compression of the spinal cord.
• Anemia - the cancerous cells can multiply and occupy space otherwise used by red blood cells - as these are pushed out by the cancerous cells, the patient develops anemia.

Written by Christian Nordqvist