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Multiple myeloma

 

Myeloma is a cancer of the plasma cells in the bone marrow. Overall, it is a relatively uncommon cancer accounting for approximately 2% of all cancers, but it is the 2nd most common form of bone marrow cancer in adults. Plasma cells are a type of white blood cell that live in the bone marrow which is found in large bones in the centre of the body. The main role of plasma cells is to make antibodies (also called immunoglobulins) which play an important role in fighting infection. In myeloma, the cancerous plasma cells make just one type of antibody and this antibody is called a “paraprotein” or “M-protein”. The finding of a paraprotein is a hallmark of myeloma.

Who is affected?

The average at which myeloma is diagnosed is 65-70 years. Myeloma is slightly more common in men and afro-caribbeans. It is much rarer in younger adults, with just 2% of cases occurring in those <40 years. It is estimated that there are 200-250 new cases of myeloma each year in Ireland.

Some patients have no symptoms at diagnosis when the disease may be detected during blood tests for other reasons. However, the most common symptoms and presenting features are:

 

·        Bone pain occasionally causing fractures

·        Fatigue

·        Infections

·        Anaemia

·        High blood calcium level

·        Kidney impairment

Outlook

Overall myeloma is still regarded as an incurable disease in the vast majority of cases, however nearly all patients will respond to treatment and the disease can now be controlled for several years. In fact the outlook for myeloma patients has improved markedly in the last 10-15 years because of the availability of much improved treatments such as autologous stem cell transplantation and new medications: Bortezomib, lenalidomide and thalidomide (For more information, see Multiple Myeloma - Treatment).

How cancerous plasma cells cause damage

Normally, plasma cells produce special antibodies to fight infection. When the plasma cells become cancerous, they:

  • Quickly multiply, damaging the bone and causing bone weakness and pain.
  • Interfere with the production of red blood cells. Red blood cells carry oxygen around the body, so a lack of these cells means the body does not get enough oxygen, making you feel very tired and out of breath (this is known as anaemia).
  • Interfere with the production of white blood cells. White blood cells help to fight infection, so a lack of these cells would make you more vulnerable to infections.
  • Interfere with the production of platelets. Platelets help to form clots and stop bleeding, so a lack of these cells means you are at risk of excessive bleeding.
  • Cause the bone marrow to produce abnormal antibodies, which can damage the kidneys (see below).

Bone damage

Bone pain is the most common and obvious symptom of bone damage caused by multiple myeloma. The pain can sometimes be severe.

In most cases the pain starts in the back, but it can spread to other parts of the body.

Over time, bones may become thinner and become more vulnerable to fracture.

The bones may eventually start to break down, and small particles of calcium that make up bones are passed into the blood. Having too much calcium in your blood is known as hypercalcaemia, and this can cause:

  • loss of appetite
  • frequent need to urinate
  • excessive thirst
  • nausea
  • vomiting
  • tiredness
  • mental confusion
  • constipation
  • abdominal pain
  • weight loss

Lack of blood cells

If the normal production of red blood cells, white blood cells and platelets is reduced, you will experience:

  • tiredness
  • shortness of breath 
  • repeated infections, such as colds, coughs, chest infections and bladder infections
  • easily bruised skin
  • unusual bleeding, such as nosebleeds or bleeding gums

Severe late-stage symptoms

In some cases of multiple myeloma, the release of abnormal antibodies into the blood can damage the kidneys. Kidney damage can result in a range of different symptoms, including excessive thirst, loss of appetite and swollen ankles.

In most cases, kidney damage is only temporary and the kidneys recover. However, in a small number of cases the damage to the kidneys is so severe that the kidneys lose some or all of their function. This is known as kidney failure.

In cases where kidney failure is severe you may require a period of dialysis. In many cases this may be a temporary requirement, but in some cases it may be required for a longer period. Dialysis involves using a machine to copy the main function of the kidneys, which is to filter waste products out of your blood. 

Multiple myeloma can also cause the bones of the spine to press down on the nearby nerves (known as cord compression). This can cause 'pins and needles', numbness and weakness in your legs and feet, and sometimes problems passing urine and stools.

Antibodies

Antibodies and immunoglobins are proteins in the blood. They are produced by the immune system to fight against bacteria, viruses and disease.

Immune system

The immune system is the body's defence system, which helps protect it from disease, bacteria and viruses.

Kidney

Kidneys are a pair of bean-shaped organs located at the back of the abdomen, which remove waste and extra fluid from the blood and pass them out of the body as urine.

It is not known exactly what causes the plasma cells inside the bone marrow to become cancerous. Certain studies have suggested that the factors listed below may increase your chance of developing multiple myeloma:

  • Family history: Having a close relative (parent, sibling or child) with myeloma increases the risk of developing myeloma approximately 3-fold, but it should be remembered that the overall risk of developing myeloma remains low and family screening is not recommended.
  • Viral infections such as HIV or hepatitis
  • Exposure to hair dyes
  • Occupation: Working as a farmer, working with meat, sheet metals, in the petroleum industry, working with benzene, with radiation or having a job that exposes you to wood dust may increase the risk of developing myeloma.
  • History of autoimmune disorders.

 

If your GP suspects myeloma, he/she will ask about your recent medical history and your symptoms. They will examine you to check for bruising, bleeding, signs of infection and any other clues that you may have multiple myeloma.

They will also take blood and urine tests.

Blood tests are useful for several reasons:

  • they can determine whether you have abnormal protein (paraprotein) in your blood or urine
  • they can find out whether your calcium levels are higher than usual
  • they can find out whether your kidneys are working normal
  • they can count how many red and white blood cells and platelets you have (this is known as a full blood count) and tell you if you are anaemic or not
  • A urine test can determine whether you are making an abnormal protein (paraprotein) and how much protein there is.

If your GP suspects you may have mutiple myeloma, they will refer you to see a haematologist (a specialist in blood diseases) for further tests.

Further tests

The haematologist will carry out the same assessment and may order more specialised tests including:

·        A 24 hour collection of urine to accurately measure the quantity of paraprotein being excreted

·        Serum free light chain assay – this test can detect small amounts of abnormal protein and is particularly useful for monitoring a certain type of myeloma called “light chain myeloma”

·        Bone marrow aspirate and biopsy: This test is performed to count the % of abnormal plasma cells in the bone marrow. In a patient with myeloma, the % of plasma cells is typically >10%, although in some cases of myeloma the % of plasma cells can be quite small, but the plasma cells may be very abnormal. This test takes about 15 minutes and involves the haematologist taking a small sample of bone marrow from the hip bone and the test is usually performed with the patient lying on their side. Before the sample is taken, the patient is given local anaesthetic to “numb” the area of the hip from where the sample is being taken. Patients usually feel some discomfort during the procedure, but it is usually over very quickly. Complications from this procedure are very rare, but patients should inform their doctor if they are allergic to any medications or bandages and also if they are taken any medication which may make bleeding more likely (e.g. aspirin, warfarin, clopidogrel).

·  A skeletal survey: This is a series of X-rays which will determine if there is any bony disease related to myeloma. The skull, chest, pelvis, femora, humeri and lumbar spine are all x-rayed as part of this test. Under certain circumstances, the haematologist may recommend an MRI scan which may provide a more detailed assessment of a particular area.

 

If you have multiple myeloma, you will be cared for by a team of healthcare professionals with expertise in treating multiple myeloma. Your haematologist will discuss treatment options with you and recommend what they think is the best treatment option for you (including not having any treatment). Before visiting the hospital to discuss your treatment options, you may find it useful to write a list of questions that you would like to ask the Haematologist. For example, you may want to find out what advantages and disadvantages a particular treatment has and what the potential side-effects of a particular treatment may be.

Staging system 

Haematologists use 2staging systems to describe how far multiple myeloma has advanced and how it is affecting the body. One widely used staging system is known as the Durie-Salmon system, which is based on four factors:

  • how many red blood cells are in your blood
  • how much calcium is in your blood
  • the amount of abnormal antibodies in your blood
  • the overall state of your bones.

The three stages of the Durie-Salmon system are outlined below.

Stage one

The cancer is still in an early stage of development. Levels of calcium are normal, levels of red blood cells are normal (or slightly below normal), and there are only low levels of abnormal antibodies in the blood.

Your bones will not be damaged, or only be slightly damaged. Most people do not have any symptoms during this phase.

In this early stage, you will probably not receive any treatment but your health will be carefully monitored in case the cancer progresses.

Stage two

The level of red blood cells, abnormal antibodies and calcium in the blood are still relatively normal but one or two bones may have become damaged.

In this stage and the next stage of multiple myeloma, chemotherapy treatment is usually recommended.

Stage three

The cancer has now reached an advanced state. Levels of red blood cells have dropped, and it is likely you will have anaemia.

Also, your levels of calcium will have risen and it is likely that you will have symptoms of hypercalcaemia (too much calcium in the blood).

There will be high levels of abnormal antibodies in your blood and damage will have occurred to three or more bones.

The Durie-Salmon system also uses a lettering system to describe the state of the kidneys:

  • A: the kidneys are undamaged or only minimally damaged
  • B: the kidneys have been damaged and kidney function is abnormal.

Kidney damage can occur at any stage, although it usually only happens during stage two or three.

A 2nd staging system is called the international staging system (ISS) and is based on the results of 2 blood tests – albumin and beta-2-microglobulin. Myeloma patients with a low albumin (<35g/l) and high beta-2-microglobulin (>5.5) have stage III disease whilst those with beta-2-microglobulin <3.5 and albumin >35g/l have stage I disease. Patients with values in between have stage II disease.

 

Goals of treatment

The overall aim of anti-myeloma treatment is to remove as much of the myeloma as possible and keep it away for a long period of time whilst at the same time improving quality of life and minimising treatment-related side-effects. The initial treatment that a myeloma patient will receive depends on a number of factors:

·        Age/fitness: Typically patients <65 years (or older patients who are fit and without other health problems) are treated aggressively with the aim of eradicating as much of the myeloma as possible. Such patients who respond to this treatment may then undergo a procedure called “High-dose chemotherapy and peripheral blood stem cell transplant (see separate section below)”, to improve and consolidate the response to the first treatment. Older patients are usually treated with chemotherapy alone (see below for details). If patients have pre-existing health problems (e.g. diabetes, heart failure, respiratory disease) it is often necessary to modify the treatment schedule to take these factors into account

·        Myeloma-related complications: Occasionally myeloma patients have kidney damage at the time of diagnosis. In this situation, treatment is usually started very quickly in an effort to prevent any further complications. Uncommonly, myeloma patients may also present with a bone fracture. In this situation, it is usually necessary to either fix the fracture (by surgery) before treatment with radiotherapy or sometimes by radiotherapy alone.

 

 

Myeloma Therapy

Treatment for myeloma can be divided in to “specific” myeloma treatments and “supportive” myeloma treatments

Specific myeloma treatments

These treatments are aimed “killing” the myeloma cells and significantly reducing the disease level. Currently, myeloma patients receive a combination of 2 or 3 classes of drugs. One of these drugs is a steroid drug (dexamethasone or prednisolone), the second drug is usually one of bortezomib (trade name Velcade), lenalidomide (trade name Revlimid) or thalidomide (see below for details) and the third drug may be a tablet chemotherapy drug (melphalan or cyclophosphamide). Used in this way, upwards of 70% of myeloma patients will respond to one or other of these combinations. Treatments are given in “cycles” which vary in length, from 3 weeks to 6 weeks and usually several cycles of treatment are necessary to get the best response (4 to 12). The response to treatment is usually assessed by measuring levels of the paraprotein. If the myeloma is responding to treatment then the paraprotein will reduce gradually. After a number of cycles of treatment the paraprotein will have fallen to a level, but will not fall any further with repeated cycles. This phase is termed “plateau” and at this point your haematologist may recommend stopping treatment and monitoring the disease. In certain situations, depending on treatment type and disease characteristics, your haematologist may wish to continue with some form of treatment.

Anti-Myeloma Drugs

Below are the main drugs used to treat myeloma:

1.      Bortezomib (Velcade) – Bortezomib causes myeloma cells to die rapidly by interfering with the way myeloma cells metabolise proteins. This drug is given either intravenously or subcutaneously (beneath the skin) either once or twice a week. The main side effects are neuropathy, low platelets, stomach upset, diarrhoea, increased risk of viral infections. The nurses and doctors looking after you will carefully monitor you for these side effects

2.      Lenalidomide and Thalidomide – these drugs are thought to work by stimulating the body’s immune system to attack the myeloma cells, although there are likely to several ways in which these drugs work. Lenalidomide is a more potent derivative of thalidomide with less side effects. Thalidomide may cause neuropathy, constipation, sleepiness, rash, a slow heart rate and an increased risk of “blood clots”. Lenalidomide only very rarely causes neuropathy but does increase the risk of clotting, cause rashes and can cause low blood counts (increasing the risk of infection). Because of the risk of blood clots, patients taking lenalidomide or thalidomide are usually prescribed a “blood thinner” in the form of aspirin or a daily injection of heparin. It is very important that you tell your doctor about any previous history of clotting if you are prescribed lenalidomide or thalidomide. NB: Both thalidomide and lenalidomide are harmful to babies developing in utero. Your doctor will talk to you about the necessary precautions if you are prescribed one of these drugs

3.      Cyclophosphamide and Melphalan – These drugs are more “old-fashioned” chemotherapy drugs that have been used to treat myeloma for many years. They are usually given in tablet form and are usually very well tolerated but may cause nausea, vomiting, hair loss, reduced fertility, low blood counts (e.g. anaemia and a low white cell count increasing the risk of infection)

4.      Steroids: Dexamethasone or Prednisolone – Steroids are a very important part of myeloma treatment. Again, they are given in tablet form in varying doses. They are usually well tolerated but may cause mood disturbance, high blood pressure, increased blood glucose, stomach upset, increased risk of infection and fluid retention.

Supportive Care

Bone disease: Bone disease is a common complication of myeloma and bisphosphonate drugs (“bone strengtheners”) are routinely prescribed for all myeloma patients. Bisphosphonates (e.g. Pamidronate, Zoledronate, Clodronate) have been shown to reduce the number of fractures in MM patients and may also help with bony pain as well as possibly prolonging survival. Prolonged bisphosphonate use in myeloma patients has been associated with the development of a dental complication called “osteonecrosis of the jaw” (ONJ for short). However the overall risk is low and ONJ develops in only a small minority of patients. It is preferable that you visit your dentist for a check-up before you start bisphosphonate treatment and discuss your treatment schedule with your doctor.

Anaemia: Occasionally myeloma may be complicated by anaemia (low haemoglobin). If the haemoglobin is quite low, you may require a blood transfusion. Alternatively, your doctor may prescribe an injection of a hormone called erythropoietin which may boost the blood count and reduce the requirement for blood transfusions

Infection: As myeloma patients may not make normal amounts of antibodies, the risk of infection is increased. Therefore, you should report symptoms of infection early to your doctor and discuss vaccination (e.g. influenza) with him/her. Patients receiving bortezomib are at increased risk of developing shingles and your doctor will prescribe an antiviral medication to reduce the risk of this happening.

Radiotherapy: This can be a very useful from of treatment for healing bone fractures and can also be very effective for treating bony pain, particularly if the pain is localised to one area. Radiotherapy can also be very helpful in treating collections of myeloma cells (also called “plasmacytomas”) which may uncommonly form lumps in different areas of the body but predominantly the bones (e.g. spine).

Stem-Cell Transplant

This form of treatment is usually offered to younger myeloma patients (<65-70 years) who have responded to their myeloma treatment. In most cases, this can be done as an outpatient procedure and you will not need to stay in hospital. Simply put, this treatment is really a way of giving a really high dose of chemotherapy but with manageable side-effects. The first step is to harvest the stem cells: This is done using a combination of chemotherapy (cyclophosphamide) which is given intravenously for one day. This is then followed by a daily injection of “white cell growth factor (gCSF)” which stimulates the bone marrow to produce “stem cells”. Usually by 7-10 days of the growth factor, the stem cells appear in the patient’s blood and are recognisable by the presence of a protein called CD34 on the cell surface. When there are adequate numbers of stem cells in the blood, these are collected using an “apheresis” machine. The stem cells are then preserved in liquid nitrogen until such time as they are needed.

Once the stem cells have been collected, then a date is usually arranged for the “transplant”, which is nearly always performed as an inpatient. The first step is to give a high dose of chemotherapy (melphalan) over 1-2 days. This can cause nausea and you will be given medication to counteract this. Then 1-2 days later the stem cells will thawed and given back to you through a vein, a bit like a blood transfusion. Although they are your own “stem cells”, this bit is the “transplant”. Over the next 10-14 days your blood counts will drop meaning that you will need blood and maybe platelet transfusions. Your white cell count will also become low making it likely that you will need intravenous antibiotics to treat infections. One of the main side effects of the melphalan is “mucositis”, which is inflammation of the lining of the gut. This will affect the entire length of the gut with the most common symptoms being sore mouth and throat, nausea/vomiting, abdominal pain and diarrhoea. During this period, you will lose your appetite and not be able to eat much food, so you will likely need intravenous fluid and advice from a dietitian. You will also receive “white cell boosting” injections and these will speed the recovery of the blood counts. Your blood counts will usually start to recover between 10-14 days after the stem cell reinfusion. With the recovery in the white cells, patients usually start the feel better and the mucositis will start to improve, making food easier to tolerate. Infections will usually resolve at this time also. Realistically, you can expect to be discharged within about 3 weeks of receiving the chemotherapy. Importantly, you will be prone to infection for about 6 months after the transplant and your doctor will prescribe medication to reduce the risk of infection.

Controlling the cancer

Using high doses of is the most effective way to control multiple myeloma. Chemotherapy medication (taken as tablets or an injection) will kill the cancerous cells, but will unfortunately also kill healthy bone marrow cells.

Therefore once the chemotherapy is finished, a sample of your stem cells will be injected into the damaged bone marrow, to help repair the bone marrow and encourage new blood cells to be produced. This part of the treatment is known as a stem cell transplant.

As this form of treatment can place a great strain on the human body, it is not usually recommended for people aged over 65, although exceptions can be made if you are in good health.

If you are not suitable for high-dose chemotherapy with stem cell transplants, you can still be given chemotherapy at a lower dose.

A course of chemotherapy is usually given over several months. Chemotherapy is usually given in cycles, where you receive treatment over the course of one or two days, followed by a rest period lasting one or two weeks.

Side effects from chemotherapy are common. They can include diarrhoea, vomiting and hair loss. The side effects should go away once your treatment has finished. Following treatment, your hair should take three to six months to grow back.

For more information about this treatment, see Health A-Z chemotherapy

Maintenance therapy

  • In certain circumstances, your Haematologist may recommend a form of “maintenance treatment”, but this is not currently a standard treatment for all myeloma patients. Maintenance treatment is treatment that continues even though the myeloma is stable with aim of preventing the myeloma returning for as long as possible. Thalidomide, lenalidomide and interferon are three drugs that are sometimes used as maintenance treatments.

Steroids

Steroid medication is similar to a type of hormone found naturally in the body. Dexamethasone is a steroid often used to treat multiple myeloma.

Exactly how dexamethasone works is unclear, but it seems to encourage the immune system to stop new cancer cells from growing in bone marrow.

You will usually need to take one tablet daily with breakfast. Side effects of dexamethasone include heartburn, indigestion and problems falling asleep.

Thalidomide

Thalidomide is a medication that was introduced in the 1950s to treat morning sickness, and it was later found to cause birth defects.

However, research has shown that thalidomide can be effective in preventing the return of cancerous cells.

Thalidomide tablets are usually taken during the evening with food. Because of the risk of causing birth defects, it's important to use reliable contraception, such as a condom, while taking thalidomide.

It is likely you will have to sign a confirmation form stating that you are aware of the risks of birth defects and of the precautions that you need to take.

Side effects of thalidomide include:

  • nausea
  • vomiting
  • sleepiness
  • constipation
  • loss of appetite
  • headaches
  • skin rashes
  • numbness or tingling in the hands and feet.

There is also a small but potentially serious risk that you will develop a blood clot when taking thalidomide. You may therefore be given a medication called warfarin , which helps to prevent blood clots.

Treating the symptoms of multiple myeloma

Radiotherapy

Radiotherapy can be used to help relieve bone pain. Radiotherapy involves directing high-energy waves of radiation at bones that have been weakened and damaged by cancerous cells.

The radiation reduces the number of cancerous cells in the bone, giving the bone a chance to repair itself.

You should only need one or two sessions of radiotherapy to reduce the pain.

Nausea and vomiting are the most common side effects of radiotherapy given in this way. However, these should quickly pass once the course of radiotherapy has ended.

Bisphosphonates

Bisphosphonate medication can be used to prevent bone damage and reduce the levels of calcium in your blood.

Normally, bone goes through a continuous cycle of repair, where the body removes old bone cells and replaces these with new ones.

In multiple myeloma, cancerous plasma cells disrupt this process, causing the bones to weaken. Bisphosphonates help to stop this from happening, and eventually returns the bone repair process to normal.

Bisphosphonates are usually given by injection. The most common side effects include stomach pain, nausea, vomiting and diarrhoea. Speak to your cancer team if any of these side effects are bothering you.

You will also be encouraged to drink plenty of water to flush out any excess calcium from your blood.

Treatments for anaemia

If you have anaemia as a result of having a low number of red blood cells, blood transfusions can be used to increase your red blood cell count.

You may also be given a medication called erythropoietin, which encourages new red blood cells to be produced.

Surgery

In some cases, surgery may be needed to repair or strengthen damaged bones, usually in the spine.In an operation called balloon kyphoplasty a tiny balloon is inserted into the affected bone, inflated, and then filled with cement.

Relapse therapy

If cancerous cells return, you will be given an additional course of chemotherapy (possibly in combination with a stem cell transplant) to try and get the cancer back under control.

You may also be given additional medications that can sometimes make the chemotherapy more effective.

Clinical trials

As multiple myeloma is an uncommon condition, you may be asked to take part in a clinical trial.

Most clinical trials involve comparing a new treatment with an existing treatment to determine whether the new treatment is more or less effective.

It's important to remember that if you receive a new treatment, there is no guarantee that it will be more effective than an existing one.

Cancer treatment team

You may be treated by a team of different health professionals, including:

  • a specialist cancer nurse (who will serve as the first point of contact between you and members of the treatment team)
  • a haemato-oncologist (specialist in the non-surgical treatment of cancer using techniques such as chemotherapy)
  • a haemato-pathologist (specialist in the study of cancerous blood cells)
  • a pharmacist
  • a social worker
  • a transplant specialist
  • a microbiologist (specialist in infectious diseases)
  • a psychologist
  • a counsellor
  • haematologist

Content provided by NHS Choices www.nhs.uk and adapted for Ireland by the Health A-Z.