Treatment to control myeloma

* Chemotherapy
* Side effects of chemotherapy
* Stem cell transplants
* Side effects with stem cell treatment
* Thalidomide
* Side effects of thalidomide
* Steroid therapy
* Bisphosphonates

Chemotherapy

Chemotherapy is the use of anti-cancer (cytotoxic) drugs and is one of the main treatments used to control myeloma. Chemotherapy drugs circulate in the blood, and can reach myeloma cells all over the body.

One or more chemotherapy drugs are given for a few days every 3–4 weeks, followed by a rest period during which you will have regular blood tests to check the effect of the drugs. The dose of the drugs may be altered according to the results of your blood tests.

Chemotherapy may be given to you as an outpatient, but sometimes it may mean having to spend a few days in hospital.

Some drugs for myeloma are given as tablets or capsules (orally), others by injection into a vein (intravenously). The drugs melphalan and cyclophosphamide are commonly used to treat myeloma and are usually given as tablets or capsules, but can also be given into a vein. They are most often given with steroid tablets (prednisolone). When given as tablets, these drugs have fewer side effects. This makes them more suitable for people who are not able to have stronger treatments.

Some people may be offered a combination of chemotherapy drugs given by injection or infusion (drip) into a vein over a few days, again often with steroids. Two commonly used chemotherapy regimes are VAD and C-VAMP.

* VAD involves the drugs vincristine, doxorubicin and the steroid dexamethasone
* C-VAMP is a combination of the drugs cyclophosphamide, vincristine, doxorubicin and the steroid methylprednisolone

These treatments tend to have more side effects than tablets or capsules, and will often make your hair fall out. In view of this, they are usually given only to younger people who are fit enough.

A newer combination treatment for myeloma which is given as tablets is CTD. This is a combination of the chemotherapy drug cyclophosphamide, the drug thalidomide and the steroid, dexamethasone. This treatment may form part of a research trial.

If you are going to have your treatment by drip, your doctor may suggest that you have a plastic tube (such as a central line or PICC line) put into a vein in your chest or the crook of your arm.

A central line
A central line

The PICC line is threaded through a vein until the end is near to your heart
The PICC line is threaded through a vein until the end is near to your heart

The line can stay in place throughout your treatment. Your nurses will show you how to care for the line when you are at home. A tube with an injectable port just under the skin may sometimes be used. This is known as an implantable port.

The length of treatment will depend on the stage of the myeloma and how well it is responding to the drugs, but usually the course of treatment will take four–six months to complete. On average, two out of three patients will go into remission during treatment.

back to top
Side effects of chemotherapy

Everyone reacts to chemotherapy in different ways. Not all drugs cause the same side effects and some people may have very few side effects. Your doctor will tell you about any problems that your treatment may cause.

Chemotherapy tablets for myeloma may cause fewer side effects than chemotherapy by injection or infusion into a vein.

We have further information about individual drugs and their side effects. We also have detailed information about all of the side effects mentioned in this section.
Lowered resistance to infection

Chemotherapy can reduce the production of white blood cells by the bone marrow, making you more prone to infection. This effect can begin about seven days after treatment has been given and your resistance to infection usually reaches its lowest point 10–14 days after chemotherapy. Your blood cells will then increase steadily and will usually have returned to normal before your next course of chemotherapy is due.

Contact your doctor or the hospital straightaway if:

* your temperature goes above 38ºC (100.5ºF)
* you suddenly feel unwell (even with a normal temperature).

You will have a blood test before having more chemotherapy, to make sure that your cells have recovered. Occasionally it may be necessary to delay treatment if your blood count is still low.
Bruising or bleeding

The chemotherapy can also reduce the production of platelets, which help the blood to clot. Let your doctor know if you have any unexplained bruising or bleeding, such as nosebleeds, blood spots or rashes on the skin, or bleeding gums.
Feeling sick

Chemotherapy tablets usually cause very mild feelings of sickness (nausea). With some of the injected drugs this may be more of a problem, and these may even cause vomiting. There are now very effective anti-sickness drugs to prevent or greatly reduce these effects. If nausea occurs, it may begin a few hours after the treatment is given and last for up to a day. If it is not controlled, or continues, tell your doctor. They can prescribe other drugs which may be more effective.
Sore mouth

Chemotherapy drugs can make your mouth sore, so regular mouthwashes are important; the nurse will show you how to do these properly. If you don't feel like eating at any time during your treatment, you could replace some meals with nutritious drinks or a soft diet. It might be helpful to speak to the hospital dietitian.
Anaemia (low number of red blood cells)

While having chemotherapy you may become anaemic. This may make you feel tired and breathless.
Hair loss

Hair loss is more common with chemotherapy given into a vein than it is with chemotherapy tablets. If your hair falls out, it usually grows back within three months after treatment.
Tiredness (fatigue)

Chemotherapy affects people in different ways. Some are able to lead a fairly normal life during their treatment, while others find they become very tired and have to take things more slowly. Just do as much as you feel like and try not to overdo it. For some people, the fatigue continues for quite some time after their treatment has ended.

back to top
Stem cell transplants

If they go into remission after the initial chemotherapy, some people can go on to have high-dose chemotherapy to try to destroy any remaining myeloma cells.

The high doses of chemotherapy will destroy the bone marrow as well as the myeloma, so the bone marrow will need to be replaced with a transplant of stem cells. The stem cells are collected before the treatment, stored and then given by drip into a vein afterwards. This is known as an autologous transplant.

As this is a very intensive treatment with a lot of side effects, it is usually only suitable for people under 65–70, although your general health rather than your age is the main deciding factor.

It may also be possible to have a stem cell transplant as part of a research trial, using donated stem cells, either from your brother or sister, or from an unknown donor. When the stem cells are donated by a brother or sister, this is called an allogeneic transplant. The risks of this treatment are greater than if you use your own stem cells and, as a result, it is usually only available to people under 50.

A matched unrelated donor (MUD) transplant, where the donor is not related to the patient, has more side effects than one using cells from a relative. MUD transplants are rarely used to treat people with myeloma.

Our section stem cell and bone marrow transplants explains this treatment in more detail.

Other treatments involving the use of stem cells are being researched in some hospitals. These include mini-transplants (which involve less intense chemotherapy), and tandem transplants (in which a second transplant is given straight after the first). It is not yet known how effective these methods will be.

back to top
Side effects with stem cell treatment

If high doses of chemotherapy with stem cell (or bone marrow) support are used, the side effects of the chemotherapy can be more severe and you will need to stay in hospital for about four weeks. This is because the treatment will make the number of blood cells and platelets in your blood drop to very low levels for a few weeks. During this time, people often need to be given antibiotics to prevent infections, as well as blood transfusions and transfusions of platelets to prevent any bleeding.


back to top
Thalidomide

Thalidomide is a drug that has been shown to be effective in treating myeloma. It may be given to treat myeloma that has relapsed (come back). Research trials are also looking into its use as a maintenance treatment for myeloma, especially after high dose treatment, and also its use as an initial treatment given with chemotherapy.

It is thought that thalidomide can stop cancers from developing new blood vessels, and may be able to stop the cancer getting a supply of oxygen and nutrients. It is hoped that this will stop the cancer growing or make it shrink.

Thalidomide is taken daily, usually in the evening, as a tablet.

back to top
Side effects of thalidomide

These include constipation; drowsiness; an increased risk of developing blood clots in the veins in the legs (known as deep vein thrombosis or DVT); and damage to particular nerves, which can cause tingling in the hands and feet (peripheral neuropathy). You may be given medicines to thin your blood because of the risk of blood clots.

Peripheral neuropathy is a common side effect of thalidomide. It usually starts with tingling and numbness in the feet which then spreads to the hands. It's important to tell your doctor if you have any symptoms so they can adjust the dose if appropriate. The degree of neuropathy may depend on the dose and how long you take thalidomide for. People who have had chemotherapy which causes peripheral neuropathy may be more at risk.

Thalidomide can cause birth defects, so its use is strictly controlled. It should not be given to pregnant women, and people taking thalidomide who are sexually active should use a barrier form of contraception.

Occasionally the side effects outweigh any benefit, and the dose of thalidomide will be reduced or stopped.

back to top
Steroid therapy

Steroids are drugs which are often used in the treatment of myeloma. They may be taken on their own or with chemotherapy. The steroids are usually taken as tablets.

Steroids for myeloma are usually taken only for a few days at a time. Depending on the dose prescribed, they may have some side effects. These can include feeling irritable, increased appetite, feeling more energetic, heartburn, indigestion and difficulty sleeping.

If you are taking steroids for some time, you may have other temporary side effects including water-retention, high blood pressure and a slightly greater risk of getting infections. You may also develop an increased level of sugar in the blood. If this happens to you, your doctor will prescribe daily tablets or injections to bring your blood sugar level back to normal.

You may need to do a simple daily test to check for sugar in your urine. Your nurses will show you how to do this.

It is unusual for people with myeloma to have to take steroids for a long time but if you do you, may notice that you put on weight, especially on your face, waist and shoulders.

These side effects may seem hard to bear at the time, but it is important to remember that they are all temporary and will disappear as the steroid dose is reduced.

back to top
Bisphosphonates

Bisphosphonate drugs can be given to reduce the symptoms of myeloma. They may be used to reduce the amount of excess calcium in the blood and to help strengthen weakened bones. They are also be given to people in remission, as they have been shown to help delay bone damage, and to prevent bone pain, raised calcium levels and fractures.

Research has suggested that bisphosphonates may help treat myeloma. Trials are investigating this further.

Bisphosphonates can be given in two ways. They can be given as a drip (infusion) into a vein once a month. This takes between 15 minutes and four hours, depending upon which drug is used. Bisphosphonates are also available as tablets.

Side effects are generally mild and include indigestion and nausea. A very rare side effect of bisphosphonates is osteonecrosis of the jaw. This condition involves damage and decay of the jaw bone. It is more likely if a person has had dental treatment just before or during treatment with bisphosphonates. It is important that your dentist knows if you are on bisphosphonates and that your doctors know if you need dental treatment.

myeloma · plante medicinale · remedii babesti · remedii naturiste · Retete naturiste · sanatateverde · terapii naturiste · Treatment to control myeloma

Treatment to control myeloma 2

Treatment to control myeloma

* Chemotherapy
* Side effects of chemotherapy
* Stem cell transplants
* Side effects with stem cell treatment
* Thalidomide
* Side effects of thalidomide
* Steroid therapy
* Bisphosphonates

Chemotherapy

Chemotherapy is the use of anti-cancer (cytotoxic) drugs and is one of the main treatments used to control myeloma. Chemotherapy drugs circulate in the blood, and can reach myeloma cells all over the body.

One or more chemotherapy drugs are given for a few days every 3–4 weeks, followed by a rest period during which you will have regular blood tests to check the effect of the drugs. The dose of the drugs may be altered according to the results of your blood tests.

Chemotherapy may be given to you as an outpatient, but sometimes it may mean having to spend a few days in hospital.

Some drugs for myeloma are given as tablets or capsules (orally), others by injection into a vein (intravenously). The drugs melphalan and cyclophosphamide are commonly used to treat myeloma and are usually given as tablets or capsules, but can also be given into a vein. They are most often given with steroid tablets (prednisolone). When given as tablets, these drugs have fewer side effects. This makes them more suitable for people who are not able to have stronger treatments.

Some people may be offered a combination of chemotherapy drugs given by injection or infusion (drip) into a vein over a few days, again often with steroids. Two commonly used chemotherapy regimes are VAD and C-VAMP.

* VAD involves the drugs vincristine, doxorubicin and the steroid dexamethasone
* C-VAMP is a combination of the drugs cyclophosphamide, vincristine, doxorubicin and the steroid methylprednisolone

These treatments tend to have more side effects than tablets or capsules, and will often make your hair fall out. In view of this, they are usually given only to younger people who are fit enough.

A newer combination treatment for myeloma which is given as tablets is CTD. This is a combination of the chemotherapy drug cyclophosphamide, the drug thalidomide and the steroid, dexamethasone. This treatment may form part of a research trial.

If you are going to have your treatment by drip, your doctor may suggest that you have a plastic tube (such as a central line or PICC line) put into a vein in your chest or the crook of your arm.

A central line
A central line

The PICC line is threaded through a vein until the end is near to your heart
The PICC line is threaded through a vein until the end is near to your heart

The line can stay in place throughout your treatment. Your nurses will show you how to care for the line when you are at home. A tube with an injectable port just under the skin may sometimes be used. This is known as an implantable port.

The length of treatment will depend on the stage of the myeloma and how well it is responding to the drugs, but usually the course of treatment will take four–six months to complete. On average, two out of three patients will go into remission during treatment.

back to top
Side effects of chemotherapy

Everyone reacts to chemotherapy in different ways. Not all drugs cause the same side effects and some people may have very few side effects. Your doctor will tell you about any problems that your treatment may cause.

Chemotherapy tablets for myeloma may cause fewer side effects than chemotherapy by injection or infusion into a vein.

We have further information about individual drugs and their side effects. We also have detailed information about all of the side effects mentioned in this section.
Lowered resistance to infection

Chemotherapy can reduce the production of white blood cells by the bone marrow, making you more prone to infection. This effect can begin about seven days after treatment has been given and your resistance to infection usually reaches its lowest point 10–14 days after chemotherapy. Your blood cells will then increase steadily and will usually have returned to normal before your next course of chemotherapy is due.

Contact your doctor or the hospital straightaway if:

* your temperature goes above 38ºC (100.5ºF)
* you suddenly feel unwell (even with a normal temperature).

You will have a blood test before having more chemotherapy, to make sure that your cells have recovered. Occasionally it may be necessary to delay treatment if your blood count is still low.
Bruising or bleeding

The chemotherapy can also reduce the production of platelets, which help the blood to clot. Let your doctor know if you have any unexplained bruising or bleeding, such as nosebleeds, blood spots or rashes on the skin, or bleeding gums.
Feeling sick

Chemotherapy tablets usually cause very mild feelings of sickness (nausea). With some of the injected drugs this may be more of a problem, and these may even cause vomiting. There are now very effective anti-sickness drugs to prevent or greatly reduce these effects. If nausea occurs, it may begin a few hours after the treatment is given and last for up to a day. If it is not controlled, or continues, tell your doctor. They can prescribe other drugs which may be more effective.
Sore mouth

Chemotherapy drugs can make your mouth sore, so regular mouthwashes are important; the nurse will show you how to do these properly. If you don't feel like eating at any time during your treatment, you could replace some meals with nutritious drinks or a soft diet. It might be helpful to speak to the hospital dietitian.
Anaemia (low number of red blood cells)

While having chemotherapy you may become anaemic. This may make you feel tired and breathless.
Hair loss

Hair loss is more common with chemotherapy given into a vein than it is with chemotherapy tablets. If your hair falls out, it usually grows back within three months after treatment.
Tiredness (fatigue)

Chemotherapy affects people in different ways. Some are able to lead a fairly normal life during their treatment, while others find they become very tired and have to take things more slowly. Just do as much as you feel like and try not to overdo it. For some people, the fatigue continues for quite some time after their treatment has ended.

back to top
Stem cell transplants

If they go into remission after the initial chemotherapy, some people can go on to have high-dose chemotherapy to try to destroy any remaining myeloma cells.

The high doses of chemotherapy will destroy the bone marrow as well as the myeloma, so the bone marrow will need to be replaced with a transplant of stem cells. The stem cells are collected before the treatment, stored and then given by drip into a vein afterwards. This is known as an autologous transplant.

As this is a very intensive treatment with a lot of side effects, it is usually only suitable for people under 65–70, although your general health rather than your age is the main deciding factor.

It may also be possible to have a stem cell transplant as part of a research trial, using donated stem cells, either from your brother or sister, or from an unknown donor. When the stem cells are donated by a brother or sister, this is called an allogeneic transplant. The risks of this treatment are greater than if you use your own stem cells and, as a result, it is usually only available to people under 50.

A matched unrelated donor (MUD) transplant, where the donor is not related to the patient, has more side effects than one using cells from a relative. MUD transplants are rarely used to treat people with myeloma.

Our section stem cell and bone marrow transplants explains this treatment in more detail.

Other treatments involving the use of stem cells are being researched in some hospitals. These include mini-transplants (which involve less intense chemotherapy), and tandem transplants (in which a second transplant is given straight after the first). It is not yet known how effective these methods will be.

back to top
Side effects with stem cell treatment

If high doses of chemotherapy with stem cell (or bone marrow) support are used, the side effects of the chemotherapy can be more severe and you will need to stay in hospital for about four weeks. This is because the treatment will make the number of blood cells and platelets in your blood drop to very low levels for a few weeks. During this time, people often need to be given antibiotics to prevent infections, as well as blood transfusions and transfusions of platelets to prevent any bleeding.


back to top
Thalidomide

Thalidomide is a drug that has been shown to be effective in treating myeloma. It may be given to treat myeloma that has relapsed (come back). Research trials are also looking into its use as a maintenance treatment for myeloma, especially after high dose treatment, and also its use as an initial treatment given with chemotherapy.

It is thought that thalidomide can stop cancers from developing new blood vessels, and may be able to stop the cancer getting a supply of oxygen and nutrients. It is hoped that this will stop the cancer growing or make it shrink.

Thalidomide is taken daily, usually in the evening, as a tablet.

back to top
Side effects of thalidomide

These include constipation; drowsiness; an increased risk of developing blood clots in the veins in the legs (known as deep vein thrombosis or DVT); and damage to particular nerves, which can cause tingling in the hands and feet (peripheral neuropathy). You may be given medicines to thin your blood because of the risk of blood clots.

Peripheral neuropathy is a common side effect of thalidomide. It usually starts with tingling and numbness in the feet which then spreads to the hands. It's important to tell your doctor if you have any symptoms so they can adjust the dose if appropriate. The degree of neuropathy may depend on the dose and how long you take thalidomide for. People who have had chemotherapy which causes peripheral neuropathy may be more at risk.

Thalidomide can cause birth defects, so its use is strictly controlled. It should not be given to pregnant women, and people taking thalidomide who are sexually active should use a barrier form of contraception.

Occasionally the side effects outweigh any benefit, and the dose of thalidomide will be reduced or stopped.

back to top
Steroid therapy

Steroids are drugs which are often used in the treatment of myeloma. They may be taken on their own or with chemotherapy. The steroids are usually taken as tablets.

Steroids for myeloma are usually taken only for a few days at a time. Depending on the dose prescribed, they may have some side effects. These can include feeling irritable, increased appetite, feeling more energetic, heartburn, indigestion and difficulty sleeping.

If you are taking steroids for some time, you may have other temporary side effects including water-retention, high blood pressure and a slightly greater risk of getting infections. You may also develop an increased level of sugar in the blood. If this happens to you, your doctor will prescribe daily tablets or injections to bring your blood sugar level back to normal.

You may need to do a simple daily test to check for sugar in your urine. Your nurses will show you how to do this.

It is unusual for people with myeloma to have to take steroids for a long time but if you do you, may notice that you put on weight, especially on your face, waist and shoulders.

These side effects may seem hard to bear at the time, but it is important to remember that they are all temporary and will disappear as the steroid dose is reduced.

back to top
Bisphosphonates

Bisphosphonate drugs can be given to reduce the symptoms of myeloma. They may be used to reduce the amount of excess calcium in the blood and to help strengthen weakened bones. They are also be given to people in remission, as they have been shown to help delay bone damage, and to prevent bone pain, raised calcium levels and fractures.

Research has suggested that bisphosphonates may help treat myeloma. Trials are investigating this further.

Bisphosphonates can be given in two ways. They can be given as a drip (infusion) into a vein once a month. This takes between 15 minutes and four hours, depending upon which drug is used. Bisphosphonates are also available as tablets.

Side effects are generally mild and include indigestion and nausea. A very rare side effect of bisphosphonates is osteonecrosis of the jaw. This condition involves damage and decay of the jaw bone. It is more likely if a person has had dental treatment just before or during treatment with bisphosphonates. It is important that your dentist knows if you are on bisphosphonates and that your doctors know if you need dental treatment.

Treatment for myeloma

Once the doctors know the stage of the myeloma they will be able to plan the most appropriate treatment.

* When treatment is given
* Why treatment is given
* What treatments are used
* Multidisciplinary team
* Second opinion
* Giving your consent
* Benefits and disadvantages of treatment

When treatment is given

Myeloma is rarely curable, but it is treatable. Treatment can be very effective at controlling symptoms and stopping the development of the disease. Myeloma can develop very slowly and so some people with myeloma who have no symptoms will not initially need any treatment. Usually they will see the doctor and have blood and urine samples every few months. This is known as active monitoring. Treatment will be started if the myeloma begins to get worse or if symptoms occur.

back to top
Why treatment is given

Treatment may be given:

* To control the myeloma so it goes into remission (remission is when treatment gets rid of the abnormal myeloma cells and they cannot be detected in the blood or bone marrow and normal bone marrow has developed again).
* As maintenance treatment once the myeloma is controlled, to prolong the remission.
* If the disease comes back (relapses).
* To control symptoms and any problems that the myeloma may be causing.


back to top
What treatments are used

Chemotherapy, usually combined with steroids, is the main treatment for myeloma. Some studies are using chemotherapy together with other drugs including bisphosphonates and thalidomide.

Some people may benefit from high-dose chemotherapy. For this treatment, some of the blood stem-cells are removed before the high-dose chemotherapy and are given back through a drip after the treatment. This is known as high dose treatment with stem cell support (stem-cell transplant) and can help some people to stay in remission, but it is an intensive treatment that is not suitable for everyone.

After chemotherapy, interferon or steroids may be used to help keep the myeloma in remission – this is known as maintenance treatment.

Thalidomide has recently been found to be effective in controlling myeloma that has come back after chemotherapy. Thalidomide is also being tested as an initial treatment and as maintenance treatment.

Other drugs that may be used to treat people whose myeloma has come back after initial treatment, are bortezomib (Velcade®) and lenalidomide (Revlimid®).

Drugs known as bisphosphonates are commonly used to reduce bone damage caused by the myeloma and to help bones to heal. They are also very helpful in lowering raised calcium levels in the blood. They can be given alongside chemotherapy or after chemotherapy has finished. They may also be given to help prevent bone damage from occurring.

Radiotherapy may be used to strengthen the bone and reduce pain in the affected areas.

Surgery may also occasionally be used to strengthen weakened bones, to prevent fractures or, rarely, to remove areas of myeloma that are pressing on parts of the body such as the spinal cord.

Other treatments may be needed, such as:

* painkillers to treat bone pain
* blood transfusions, if you are anaemic
* kidney dialysis, if your kidneys are not working properly.

The treatments used will vary from person to person. If you have any questions about your own treatment, don't be afraid to ask your doctor or nurse. It often helps to take a close friend or relative with you to appointments.

back to top
Multidisciplinary team

In most hospitals, a team of cancer specialists will discuss with you the treatment that they feel is best for your situation. This multidisciplinary team (MDT) will often include a doctor who specialises in treating blood disorders (haematologist), chemotherapy and radiotherapy specialists (oncologists) and may include a number of other healthcare professionals such as a:

* nurse specialist
* pathologist (a doctor who specialises in how disease affects the body)
* radiologist (a doctor who specialises in x-rays and scans)
* dietitian
* physiotherapist
* occupational therapist
* psychologist or counsellor.

Together the doctors will be able to advise you on the best course of action taking into account a number of factors. These include your age, general health, and how the myeloma is affecting you.

Occasionally your doctors may offer you a choice of treatments. Sometimes people find it very hard to make a decision. If you are asked to make a choice, make sure that you have enough information about the different treatment options, what is involved and the side effects you might experience, so that you can decide what is the right treatment for you.

Remember to ask questions about any aspects that you do not understand or feel worried about. You may find it helpful to discuss the benefits and disadvantages of each option with your cancer specialist, nurse specialist or with the nurses in our cancer support service.

If you have any questions about your own treatment, don't be afraid to ask your doctor or nurse. It often helps to make a list of questions and to take a close friend or relative with you.

back to top
Second opinion

Even though a number of cancer specialists work as a team to decide on the most suitable treatment, you may want to have another medical opinion. Most doctors will be willing to refer you to another specialist for a second opinion if you feel that it will be helpful. The second opinion may take some time to organise and may cause a delay in the start of your treatment, so you and your doctor need to be confident that it will be helpful.

If you do go for a second opinion, it may be a good idea to take a friend or relative with you, and to have a list of questions so you can make sure your concerns are covered during the discussion.

back to top
Giving your consent

Before you have any treatment your doctor will explain its aims to you and you will usually be asked to sign a form saying that you give your permission (consent) for the hospital staff to give you the treatment. No medical treatment can be given without your consent, and before you are asked to sign the form you should have been given full information about:

* the type and extent of the treatment you are advised to have
* the advantages and disadvantages of the treatment
* any other treatments that may be available
* any significant risks or side effects of the treatment.

If you do not understand what you have been told, let the staff know straight away so that they can explain again. Some myeloma treatments are complex, so it is not unusual for people to need their treatment to be explained more than once.

Patients often feel that hospital staff are too busy to answer their questions, but it is important for you to be aware of how the treatment is likely to affect you and the staff should be willing to make time for you to ask questions.

You can always ask for more time to decide about the treatment, if you feel that you can't make a decision when it is first explained to you. You are also free to choose not to have the treatment, and the staff can explain what may happen if you do not have it.

back to top
Benefits and disadvantages of treatment

Many people are frightened of having cancer treatments, and of the side effects that may occur. Some people ask what would happen if they did not have any treatment.

Although many of the treatments can cause side effects, these can often be well controlled with medicines.

Treatment can be given for different reasons and the possible benefits will vary depending upon the individual situation. Myeloma is rarely curable and treatment is usually only able to control it, leading to an reduction of symptoms and a better quality of life.

The treatments for myeloma can vary, and some involve far more side effects and risks than others. For some people, the treatment will help to control the myeloma and the side effects of the treatment will be mild. However, for others treatment will have no effect upon the cancer and they will get the side effects with little benefit.

Making decisions about whether to have treatment in these circumstances is always difficult, and you may need to discuss in detail with your doctor whether you wish to have treatment. If you choose not to have treatment, you can still be given medicines to control any symptoms that you have. This is known as supportive care (or palliative care).

It is important to tell a doctor, or the nurse in charge, so that they can record your decision in your medical notes. You do not have to give a reason for not wanting to have treatment, but it can be helpful to let the staff know your concerns so that they can give you the best advice.

myeloma · plante medicinale · remedii babesti · remedii naturiste · Retete naturiste · sanatateverde · terapii naturiste · Treatment for myeloma

Treatment for myeloma

Treatment for myeloma

Once the doctors know the stage of the myeloma they will be able to plan the most appropriate treatment.

* When treatment is given
* Why treatment is given
* What treatments are used
* Multidisciplinary team
* Second opinion
* Giving your consent
* Benefits and disadvantages of treatment

When treatment is given

Myeloma is rarely curable, but it is treatable. Treatment can be very effective at controlling symptoms and stopping the development of the disease. Myeloma can develop very slowly and so some people with myeloma who have no symptoms will not initially need any treatment. Usually they will see the doctor and have blood and urine samples every few months. This is known as active monitoring. Treatment will be started if the myeloma begins to get worse or if symptoms occur.

back to top
Why treatment is given

Treatment may be given:

* To control the myeloma so it goes into remission (remission is when treatment gets rid of the abnormal myeloma cells and they cannot be detected in the blood or bone marrow and normal bone marrow has developed again).
* As maintenance treatment once the myeloma is controlled, to prolong the remission.
* If the disease comes back (relapses).
* To control symptoms and any problems that the myeloma may be causing.


back to top
What treatments are used

Chemotherapy, usually combined with steroids, is the main treatment for myeloma. Some studies are using chemotherapy together with other drugs including bisphosphonates and thalidomide.

Some people may benefit from high-dose chemotherapy. For this treatment, some of the blood stem-cells are removed before the high-dose chemotherapy and are given back through a drip after the treatment. This is known as high dose treatment with stem cell support (stem-cell transplant) and can help some people to stay in remission, but it is an intensive treatment that is not suitable for everyone.

After chemotherapy, interferon or steroids may be used to help keep the myeloma in remission – this is known as maintenance treatment.

Thalidomide has recently been found to be effective in controlling myeloma that has come back after chemotherapy. Thalidomide is also being tested as an initial treatment and as maintenance treatment.

Other drugs that may be used to treat people whose myeloma has come back after initial treatment, are bortezomib (Velcade®) and lenalidomide (Revlimid®).

Drugs known as bisphosphonates are commonly used to reduce bone damage caused by the myeloma and to help bones to heal. They are also very helpful in lowering raised calcium levels in the blood. They can be given alongside chemotherapy or after chemotherapy has finished. They may also be given to help prevent bone damage from occurring.

Radiotherapy may be used to strengthen the bone and reduce pain in the affected areas.

Surgery may also occasionally be used to strengthen weakened bones, to prevent fractures or, rarely, to remove areas of myeloma that are pressing on parts of the body such as the spinal cord.

Other treatments may be needed, such as:

* painkillers to treat bone pain
* blood transfusions, if you are anaemic
* kidney dialysis, if your kidneys are not working properly.

The treatments used will vary from person to person. If you have any questions about your own treatment, don't be afraid to ask your doctor or nurse. It often helps to take a close friend or relative with you to appointments.

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Multidisciplinary team

In most hospitals, a team of cancer specialists will discuss with you the treatment that they feel is best for your situation. This multidisciplinary team (MDT) will often include a doctor who specialises in treating blood disorders (haematologist), chemotherapy and radiotherapy specialists (oncologists) and may include a number of other healthcare professionals such as a:

* nurse specialist
* pathologist (a doctor who specialises in how disease affects the body)
* radiologist (a doctor who specialises in x-rays and scans)
* dietitian
* physiotherapist
* occupational therapist
* psychologist or counsellor.

Together the doctors will be able to advise you on the best course of action taking into account a number of factors. These include your age, general health, and how the myeloma is affecting you.

Occasionally your doctors may offer you a choice of treatments. Sometimes people find it very hard to make a decision. If you are asked to make a choice, make sure that you have enough information about the different treatment options, what is involved and the side effects you might experience, so that you can decide what is the right treatment for you.

Remember to ask questions about any aspects that you do not understand or feel worried about. You may find it helpful to discuss the benefits and disadvantages of each option with your cancer specialist, nurse specialist or with the nurses in our cancer support service.

If you have any questions about your own treatment, don't be afraid to ask your doctor or nurse. It often helps to make a list of questions and to take a close friend or relative with you.

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Second opinion

Even though a number of cancer specialists work as a team to decide on the most suitable treatment, you may want to have another medical opinion. Most doctors will be willing to refer you to another specialist for a second opinion if you feel that it will be helpful. The second opinion may take some time to organise and may cause a delay in the start of your treatment, so you and your doctor need to be confident that it will be helpful.

If you do go for a second opinion, it may be a good idea to take a friend or relative with you, and to have a list of questions so you can make sure your concerns are covered during the discussion.

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Giving your consent

Before you have any treatment your doctor will explain its aims to you and you will usually be asked to sign a form saying that you give your permission (consent) for the hospital staff to give you the treatment. No medical treatment can be given without your consent, and before you are asked to sign the form you should have been given full information about:

* the type and extent of the treatment you are advised to have
* the advantages and disadvantages of the treatment
* any other treatments that may be available
* any significant risks or side effects of the treatment.

If you do not understand what you have been told, let the staff know straight away so that they can explain again. Some myeloma treatments are complex, so it is not unusual for people to need their treatment to be explained more than once.

Patients often feel that hospital staff are too busy to answer their questions, but it is important for you to be aware of how the treatment is likely to affect you and the staff should be willing to make time for you to ask questions.

You can always ask for more time to decide about the treatment, if you feel that you can't make a decision when it is first explained to you. You are also free to choose not to have the treatment, and the staff can explain what may happen if you do not have it.

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Benefits and disadvantages of treatment

Many people are frightened of having cancer treatments, and of the side effects that may occur. Some people ask what would happen if they did not have any treatment.

Although many of the treatments can cause side effects, these can often be well controlled with medicines.

Treatment can be given for different reasons and the possible benefits will vary depending upon the individual situation. Myeloma is rarely curable and treatment is usually only able to control it, leading to an reduction of symptoms and a better quality of life.

The treatments for myeloma can vary, and some involve far more side effects and risks than others. For some people, the treatment will help to control the myeloma and the side effects of the treatment will be mild. However, for others treatment will have no effect upon the cancer and they will get the side effects with little benefit.

Making decisions about whether to have treatment in these circumstances is always difficult, and you may need to discuss in detail with your doctor whether you wish to have treatment. If you choose not to have treatment, you can still be given medicines to control any symptoms that you have. This is known as supportive care (or palliative care).

It is important to tell a doctor, or the nurse in charge, so that they can record your decision in your medical notes. You do not have to give a reason for not wanting to have treatment, but it can be helpful to let the staff know your concerns so that they can give you the best advice.

Symptoms of myeloma

Myeloma commonly affects the bones of the spine (vertebrae), so its most common symptom is back pain. Some people also become shorter. Other bones may also be affected such as the ribs, skull or pelvis. Other symptoms may include any of the following:

* Excessive tiredness and lethargy due to a lack of red blood cells (anaemia).
* Kidney problems caused by the paraproteins produced by the myeloma cells. Kidney damage can cause tiredness and anaemia.
* Repeated colds, coughs and other infections (particularly chest infections) because of a shortage of normal antibodies.
* Weakening of the bones by the myeloma cells, which may increase the risk of fractures.
* Loss of appetite, feeling sick, constipation, depression and drowsiness caused by too much calcium in the blood (hypercalcaemia). The excess calcium is released into the blood from the damaged bones.
* Unexplained bruising and abnormal bleeding (for example, nosebleeds or bleeding gums) because the number of platelets in the blood has decreased.
* Pins and needles, numbness, tingling or weakness in the feet or legs; or difficulty passing urine or opening the bowels. Any of these symptoms could mean that a myeloma tumour is pressing on the spinal cord (known as cord compression). Contact your doctor immediately if you think that this may be happening to you.

If you have any of the symptoms in this list, it is important to see your doctor as soon as possible. But remember, many of these symptoms can occur in other conditions. Most people with the above symptoms will not have myeloma.

Occasionally myeloma will be found by a blood test done for another reason, when the person has no symptoms.

myeloma · plante medicinale · remedii babesti · remedii naturiste · Retete naturiste · sanatateverde · Symptoms of myeloma · terapii naturiste

Symptoms of myeloma

Symptoms of myeloma

Myeloma commonly affects the bones of the spine (vertebrae), so its most common symptom is back pain. Some people also become shorter. Other bones may also be affected such as the ribs, skull or pelvis. Other symptoms may include any of the following:

* Excessive tiredness and lethargy due to a lack of red blood cells (anaemia).
* Kidney problems caused by the paraproteins produced by the myeloma cells. Kidney damage can cause tiredness and anaemia.
* Repeated colds, coughs and other infections (particularly chest infections) because of a shortage of normal antibodies.
* Weakening of the bones by the myeloma cells, which may increase the risk of fractures.
* Loss of appetite, feeling sick, constipation, depression and drowsiness caused by too much calcium in the blood (hypercalcaemia). The excess calcium is released into the blood from the damaged bones.
* Unexplained bruising and abnormal bleeding (for example, nosebleeds or bleeding gums) because the number of platelets in the blood has decreased.
* Pins and needles, numbness, tingling or weakness in the feet or legs; or difficulty passing urine or opening the bowels. Any of these symptoms could mean that a myeloma tumour is pressing on the spinal cord (known as cord compression). Contact your doctor immediately if you think that this may be happening to you.

If you have any of the symptoms in this list, it is important to see your doctor as soon as possible. But remember, many of these symptoms can occur in other conditions. Most people with the above symptoms will not have myeloma.

Occasionally myeloma will be found by a blood test done for another reason, when the person has no symptoms.

Multiple myeloma, a cancer of the plasma cell, is an incurable but treatable disease. While a myeloma diagnosis can be overwhelming, it is important to remember that there are several promising new therapies that are helping patients live longer, healthier lives. The estimated frequency of multiple myeloma is 5 to 7 new cases per 100,000 persons per year. Accordingly, in the United States, 19,920 new cases are expected to be diagnosed in 2008. There were more than 56,000 Americans living with multiple myeloma in 2005, the most current date these statistics are available.

This section is designed to serve as a fundamental resource for education about multiple myeloma. It provides a detailed overview of the disease and includes:

*
Definition
*
Causes and incidence
*
Symptoms
*
Diagnosis
*
Classification and staging
*
Prognostic indicators
*
Myeloma bone disease
*
Glossary

Definition
Multiple myeloma (also known as myeloma or plasma cell myeloma) is a progressive hematologic (blood) disease. It is a cancer of the plasma cell, an important part of the immune system that produces immunoglobulins (antibodies) to help fight infection and disease. Multiple myeloma is characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free monoclonal κ and λ light chains). Hypercalcemia, anemia, renal damage, increased susceptibility to bacterial infection, and impaired production of normal immunoglobulin are common clinical manifestations of multiple myeloma. It is often also characterized by diffuse osteoporosis, usually in the pelvis, spine, ribs, and skull.

Cells destined to become immune cells, like all blood cells, arise in the bone marrow from stem cells (see figure). Some stem cells develop into the small white blood cells called lymphocytes. The two major classes of lymphocytes are B cells (B lymphocytes) and T cells (T lymphocytes). Plasma cells develop from B cells.


illustration
Figure legend: Like most blood cells, plasma cells develop from stem cells in the bone marrow. Stem cells can develop into B cells (B lymphocytes), which travel to the lymph nodes, mature, and then travel throughout the body. When foreign substances (antigens) enter the body, B cells develop into plasma cells that produce immunoglobulins (antibodies) to help fight infection and disease.
Normal Plasma Cell Function in the Immune System
Plasma cells develop from B cells when foreign substances (antigens), such as bacteria, enter the body. In response to invasion by foreign substances, groups of plasma cells produce proteins called immunoglobulins (Ig), also known as antibodies that help fight disease and infection. Each plasma cell develops in response to a particular foreign substance within the body, and it produces immunoglobulins specific to that substance. Thus, there are many different immunoglobulins produced in the body.

Immunoglobulins are made up of protein chains, two long chains called heavy chains and two shorter chains known as light chains (see figure).


illustration
Figure legend: Immunoglobulins are made up of two heavy chains and two light chains.


There are five major classes of immunoglobulins. Each class has a unique type of heavy chain that is defined by use of a Greek letter: gamma (IgG), alpha (IgA), mu (IgM), epsilon (IgE), or delta (IgD). Each type has a slightly different function in the body. Normally, a plasma cell makes one of these five major classes of immunoglobulin. The immunoglobulin class normally present in the largest amounts in blood is IgG, followed by IgA and IgM. IgD and IgE are present in very small amounts in the blood. Immunoglobulin light chains are defined by use of the Greek letters kappa (κ) or lambda (l).
Development of Malignant Plasma Cells (Myeloma Cells)
It is normal for plasma cells to develop from B cells in lymph nodes as an immune response to disease or infection. Transformation of a normal B cell into a malignant plasma cell involves a multi-step process that includes multiple genetic abnormalities. Finally, the resulting plasma cells become malignant, meaning they continue to divide unchecked, generating more malignant plasma cells (see figure). These myeloma cells travel through the bloodstream and collect in the bone marrow, where they cause permanent damage to healthy tissue. We have recently learned that the interaction between the plasma cells and the bone marrow microenvironment is as important as the genetic changes in the development of these malignant cells.


illustration
Figure legend: In multiple myeloma, the B cell is damaged and gives rise to too many plasma cells (myeloma cells). These malignant cells do not function properly and their increased numbers produce excess immunoglobulins of a single type that the body does not need along with reduced amounts of normal immunoglobulins.
Normally, plasma cells make up a very small portion (less than 5%) of cells in the bone marrow. Myeloma plasma cells, however, have specific adhesion molecules on their surface allowing them to target bone marrow where they attach to structural cells called stromal cells. Once myeloma cells attach to bone marrow stromal cells, several interactions cause myeloma cells to grow (see figure):

*
Chemical messengers called cytokines are produced by both myeloma cells and stromal cells. These cytokines, such as interleukin 6 (IL-6), receptor for activation of NF-κB (RANK) ligand, and tumor necrosis factor (TNF), stimulate the growth of myeloma cells and inhibit (prevent) natural cell death (called apoptosis), leading to proliferation of myeloma cells and ultimately resulting in bone destruction.

*
Myeloma cells also produce growth factors that promote angiogenesis, the creation of new blood vessels. These new blood vessels provide the oxygen and nutrients that promote tumor growth. A growth factor called vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. Angiogenesis encourages reproduction of myeloma cells, which increase in number and begin to infiltrate the bone marrow, eventually comprising more than 10% of the cells present.

*
Mature myeloma cells may fail to activate the immune system and may produce substances that decrease the body's normal immune response to a foreign body. Thus, the cells can grow unchecked.



illustration
Figure legend: Bone marrow stromal cells and myeloma cells produce cytokines that help myeloma cells grow and survive. Myeloma cells also produce growth factors that stimulate new blood vessel formation through a process called angiogenesis. New blood vessels provide nutrients and oxygen to the tumor, allowing it to grow. The natural immune response that attacks myeloma cells is suppressed.


As tumors grow, they invade the hard outer part of the bone, the solid tissue. In most cases, the myeloma cells spread into the cavities of all the large bones of the body, forming multiple small lesions. This is why the disease is known as "multiple" myeloma. In some cases, collections of plasma cells arise either within bone or in soft tissues as masses or tumors. These collections are called plasmacytomas, and may represent a more aggressive form of myeloma.

Myeloma cells are identical and produce the same immunoglobulin protein, called monoclonal (M) protein or paraprotein, in large quantities. Although the specific M protein varies vary from patient to patient, it is always exactly the same in any one patient. When blood or urine is processed in a laboratory test called electrophoresis, these M proteins show up as a "spike" in the results.

Unlike normal immunoglobulin, M protein does not benefit the body. Instead, it crowds out normal, functional immunoglobulins. In addition, levels of functional immunoglobulin are depressed in individuals with myeloma. Although the process is not completely understood, it appears that the functional immunoglobulin made by existing normal plasma cells breaks down more quickly in patients with myeloma than in healthy individuals.
Myeloma Types
Myeloma is often referred to by the particular type of immunoglobulin or light chain (kappa or lambda type) produced by the cancerous plasma cell. The frequency of the various immunoglobulin types of myeloma parallels the normal serum concentrations of the immunoglobulins. The most common myeloma types are IgG and IgA. IgG myeloma accounts for about 60% to 70% of all cases of myeloma and IgA accounts for about 20% of cases. Few cases of IgD and IgE myeloma have been reported.

Although a high level of M protein in the blood is a hallmark of myeloma disease, about 15% to 20% of patients with myeloma produce incomplete immunoglobulins, containing only the light chain portion of the immunoglobulin (also known as Bence Jones proteins, after the chemist who discovered them). These patients are said to have light chain myeloma, or Bence Jones myeloma. In these patients, M protein is found primarily in the urine, rather than in the blood. These Bence Jones proteins may deposit in the kidney and clog the tiny tubules that make up the kidney's filtering system, which can eventually cause kidney damage and result in kidney failure. Bence Jones proteins will not be detected by routine urinalysis. A more complex test called immunoelectrophoresis can measure the exact amount of Bence Jones proteins in the urine.

A rare form of myeloma called nonsecretory myeloma affects about 1% of myeloma patients. In this form of the disease, plasma cells do not produce M protein or light chains.
Causes and Incidence
Multiple myeloma is the second most prevalent blood cancer after non-Hodgkin's lymphoma. It represents approximately 1% of all cancers in white US residents and 2% of cancers in black residents.

Recent statistics indicate both increasing incidence and earlier age of onset. The average age at diagnosis is 62 years for men and 61 years for women, and only 4% of cases are diagnosed in individuals under the age of 45. Approximately 56,200 Americans had myeloma in 2005 (the most current date these statistics are available) and the American Cancer Society estimates that approximately 19,920 new cases of myeloma will be diagnosed during 2008.

Multiple myeloma occurs more frequently in men than women (of the estimated 19,920 new cases referenced above, 11,190 are expected to occur in men versus 8,730 in women). African Americans have the highest reported incidence of this disease and Asians the lowest. Among African Americans, myeloma is one of the leading causes of cancer death.

Although a tremendous amount of work has gone into the search for the cause of multiple myeloma, to date no cause for this disease has been identified. However, the search for a cause has suggested possible associations between myeloma and a decline in the immune system, genetic factors, certain occupations, certain viruses, exposure to certain chemicals including Agent Orange, and exposure to radiation.

Age is the most significant risk factor for multiple myeloma, as 96% of cases are diagnosed in people over the age of 45, and more than 75% occur in people over the age of 70. Because the peak age for multiple myeloma is among the elderly it is thought that susceptibility may increase with the aging process and the consequent reduction in immune surveillance of evolving cancer, or that myeloma may result from a lifelong accumulation of toxic insults or antigenic challenges.

The higher incidence of myeloma in African Americans and the much less frequent occurrence in Asians suggest genetic factors. While it is uncommon for myeloma to develop in more than one family member, there is a slight increased risk among children and siblings of those with myeloma.

People in agricultural occupations, petroleum workers, workers in leather industries, and cosmetologists all seem to have a higher-than-average chance of developing multiple myeloma. Exposure to herbicides, insecticides, petroleum products, heavy metals, plastics, and various dusts including asbestos also appear to be risk factors for the disease. In addition, individuals exposed to large amounts of radiation, such as survivors of the atomic bomb explosions in Japan, have an increased risk for myeloma, although this accounts for a very small number of cases.

Chromosomal changes including chromosomal translocations (generally involving the Ig heavy chain gene), and chromosomal gains and losses are very frequent in myeloma. These abnormalities have an important influence on disease outcome.

It is important to remember that in most cases, individuals who develop multiple myeloma have no clear risk factors. Myeloma may be the result of several factors acting together.

Multiple myeloma · myeloma · plante medicinale · remedii babesti · remedii naturiste · Retete naturiste · sanatateverde · terapii naturiste · What is myeloma

Multiple myeloma - details about Multiple myeloma

Multiple myeloma, a cancer of the plasma cell, is an incurable but treatable disease. While a myeloma diagnosis can be overwhelming, it is important to remember that there are several promising new therapies that are helping patients live longer, healthier lives. The estimated frequency of multiple myeloma is 5 to 7 new cases per 100,000 persons per year. Accordingly, in the United States, 19,920 new cases are expected to be diagnosed in 2008. There were more than 56,000 Americans living with multiple myeloma in 2005, the most current date these statistics are available.

This section is designed to serve as a fundamental resource for education about multiple myeloma. It provides a detailed overview of the disease and includes:

*
Definition
*
Causes and incidence
*
Symptoms
*
Diagnosis
*
Classification and staging
*
Prognostic indicators
*
Myeloma bone disease
*
Glossary

Definition
Multiple myeloma (also known as myeloma or plasma cell myeloma) is a progressive hematologic (blood) disease. It is a cancer of the plasma cell, an important part of the immune system that produces immunoglobulins (antibodies) to help fight infection and disease. Multiple myeloma is characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free monoclonal κ and λ light chains). Hypercalcemia, anemia, renal damage, increased susceptibility to bacterial infection, and impaired production of normal immunoglobulin are common clinical manifestations of multiple myeloma. It is often also characterized by diffuse osteoporosis, usually in the pelvis, spine, ribs, and skull.

Cells destined to become immune cells, like all blood cells, arise in the bone marrow from stem cells (see figure). Some stem cells develop into the small white blood cells called lymphocytes. The two major classes of lymphocytes are B cells (B lymphocytes) and T cells (T lymphocytes). Plasma cells develop from B cells.


illustration
Figure legend: Like most blood cells, plasma cells develop from stem cells in the bone marrow. Stem cells can develop into B cells (B lymphocytes), which travel to the lymph nodes, mature, and then travel throughout the body. When foreign substances (antigens) enter the body, B cells develop into plasma cells that produce immunoglobulins (antibodies) to help fight infection and disease.
Normal Plasma Cell Function in the Immune System
Plasma cells develop from B cells when foreign substances (antigens), such as bacteria, enter the body. In response to invasion by foreign substances, groups of plasma cells produce proteins called immunoglobulins (Ig), also known as antibodies that help fight disease and infection. Each plasma cell develops in response to a particular foreign substance within the body, and it produces immunoglobulins specific to that substance. Thus, there are many different immunoglobulins produced in the body.

Immunoglobulins are made up of protein chains, two long chains called heavy chains and two shorter chains known as light chains (see figure).


illustration
Figure legend: Immunoglobulins are made up of two heavy chains and two light chains.


There are five major classes of immunoglobulins. Each class has a unique type of heavy chain that is defined by use of a Greek letter: gamma (IgG), alpha (IgA), mu (IgM), epsilon (IgE), or delta (IgD). Each type has a slightly different function in the body. Normally, a plasma cell makes one of these five major classes of immunoglobulin. The immunoglobulin class normally present in the largest amounts in blood is IgG, followed by IgA and IgM. IgD and IgE are present in very small amounts in the blood. Immunoglobulin light chains are defined by use of the Greek letters kappa (κ) or lambda (l).
Development of Malignant Plasma Cells (Myeloma Cells)
It is normal for plasma cells to develop from B cells in lymph nodes as an immune response to disease or infection. Transformation of a normal B cell into a malignant plasma cell involves a multi-step process that includes multiple genetic abnormalities. Finally, the resulting plasma cells become malignant, meaning they continue to divide unchecked, generating more malignant plasma cells (see figure). These myeloma cells travel through the bloodstream and collect in the bone marrow, where they cause permanent damage to healthy tissue. We have recently learned that the interaction between the plasma cells and the bone marrow microenvironment is as important as the genetic changes in the development of these malignant cells.


illustration
Figure legend: In multiple myeloma, the B cell is damaged and gives rise to too many plasma cells (myeloma cells). These malignant cells do not function properly and their increased numbers produce excess immunoglobulins of a single type that the body does not need along with reduced amounts of normal immunoglobulins.
Normally, plasma cells make up a very small portion (less than 5%) of cells in the bone marrow. Myeloma plasma cells, however, have specific adhesion molecules on their surface allowing them to target bone marrow where they attach to structural cells called stromal cells. Once myeloma cells attach to bone marrow stromal cells, several interactions cause myeloma cells to grow (see figure):

*
Chemical messengers called cytokines are produced by both myeloma cells and stromal cells. These cytokines, such as interleukin 6 (IL-6), receptor for activation of NF-κB (RANK) ligand, and tumor necrosis factor (TNF), stimulate the growth of myeloma cells and inhibit (prevent) natural cell death (called apoptosis), leading to proliferation of myeloma cells and ultimately resulting in bone destruction.

*
Myeloma cells also produce growth factors that promote angiogenesis, the creation of new blood vessels. These new blood vessels provide the oxygen and nutrients that promote tumor growth. A growth factor called vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. Angiogenesis encourages reproduction of myeloma cells, which increase in number and begin to infiltrate the bone marrow, eventually comprising more than 10% of the cells present.

*
Mature myeloma cells may fail to activate the immune system and may produce substances that decrease the body's normal immune response to a foreign body. Thus, the cells can grow unchecked.



illustration
Figure legend: Bone marrow stromal cells and myeloma cells produce cytokines that help myeloma cells grow and survive. Myeloma cells also produce growth factors that stimulate new blood vessel formation through a process called angiogenesis. New blood vessels provide nutrients and oxygen to the tumor, allowing it to grow. The natural immune response that attacks myeloma cells is suppressed.


As tumors grow, they invade the hard outer part of the bone, the solid tissue. In most cases, the myeloma cells spread into the cavities of all the large bones of the body, forming multiple small lesions. This is why the disease is known as "multiple" myeloma. In some cases, collections of plasma cells arise either within bone or in soft tissues as masses or tumors. These collections are called plasmacytomas, and may represent a more aggressive form of myeloma.

Myeloma cells are identical and produce the same immunoglobulin protein, called monoclonal (M) protein or paraprotein, in large quantities. Although the specific M protein varies vary from patient to patient, it is always exactly the same in any one patient. When blood or urine is processed in a laboratory test called electrophoresis, these M proteins show up as a "spike" in the results.

Unlike normal immunoglobulin, M protein does not benefit the body. Instead, it crowds out normal, functional immunoglobulins. In addition, levels of functional immunoglobulin are depressed in individuals with myeloma. Although the process is not completely understood, it appears that the functional immunoglobulin made by existing normal plasma cells breaks down more quickly in patients with myeloma than in healthy individuals.
Myeloma Types
Myeloma is often referred to by the particular type of immunoglobulin or light chain (kappa or lambda type) produced by the cancerous plasma cell. The frequency of the various immunoglobulin types of myeloma parallels the normal serum concentrations of the immunoglobulins. The most common myeloma types are IgG and IgA. IgG myeloma accounts for about 60% to 70% of all cases of myeloma and IgA accounts for about 20% of cases. Few cases of IgD and IgE myeloma have been reported.

Although a high level of M protein in the blood is a hallmark of myeloma disease, about 15% to 20% of patients with myeloma produce incomplete immunoglobulins, containing only the light chain portion of the immunoglobulin (also known as Bence Jones proteins, after the chemist who discovered them). These patients are said to have light chain myeloma, or Bence Jones myeloma. In these patients, M protein is found primarily in the urine, rather than in the blood. These Bence Jones proteins may deposit in the kidney and clog the tiny tubules that make up the kidney's filtering system, which can eventually cause kidney damage and result in kidney failure. Bence Jones proteins will not be detected by routine urinalysis. A more complex test called immunoelectrophoresis can measure the exact amount of Bence Jones proteins in the urine.

A rare form of myeloma called nonsecretory myeloma affects about 1% of myeloma patients. In this form of the disease, plasma cells do not produce M protein or light chains.
Causes and Incidence
Multiple myeloma is the second most prevalent blood cancer after non-Hodgkin's lymphoma. It represents approximately 1% of all cancers in white US residents and 2% of cancers in black residents.

Recent statistics indicate both increasing incidence and earlier age of onset. The average age at diagnosis is 62 years for men and 61 years for women, and only 4% of cases are diagnosed in individuals under the age of 45. Approximately 56,200 Americans had myeloma in 2005 (the most current date these statistics are available) and the American Cancer Society estimates that approximately 19,920 new cases of myeloma will be diagnosed during 2008.

Multiple myeloma occurs more frequently in men than women (of the estimated 19,920 new cases referenced above, 11,190 are expected to occur in men versus 8,730 in women). African Americans have the highest reported incidence of this disease and Asians the lowest. Among African Americans, myeloma is one of the leading causes of cancer death.

Although a tremendous amount of work has gone into the search for the cause of multiple myeloma, to date no cause for this disease has been identified. However, the search for a cause has suggested possible associations between myeloma and a decline in the immune system, genetic factors, certain occupations, certain viruses, exposure to certain chemicals including Agent Orange, and exposure to radiation.

Age is the most significant risk factor for multiple myeloma, as 96% of cases are diagnosed in people over the age of 45, and more than 75% occur in people over the age of 70. Because the peak age for multiple myeloma is among the elderly it is thought that susceptibility may increase with the aging process and the consequent reduction in immune surveillance of evolving cancer, or that myeloma may result from a lifelong accumulation of toxic insults or antigenic challenges.

The higher incidence of myeloma in African Americans and the much less frequent occurrence in Asians suggest genetic factors. While it is uncommon for myeloma to develop in more than one family member, there is a slight increased risk among children and siblings of those with myeloma.

People in agricultural occupations, petroleum workers, workers in leather industries, and cosmetologists all seem to have a higher-than-average chance of developing multiple myeloma. Exposure to herbicides, insecticides, petroleum products, heavy metals, plastics, and various dusts including asbestos also appear to be risk factors for the disease. In addition, individuals exposed to large amounts of radiation, such as survivors of the atomic bomb explosions in Japan, have an increased risk for myeloma, although this accounts for a very small number of cases.

Chromosomal changes including chromosomal translocations (generally involving the Ig heavy chain gene), and chromosomal gains and losses are very frequent in myeloma. These abnormalities have an important influence on disease outcome.

It is important to remember that in most cases, individuals who develop multiple myeloma have no clear risk factors. Myeloma may be the result of several factors acting together.

What is myeloma?

Myeloma is also known as multiple myeloma or myelomatosis.

Blood cells look and work differently, but they all repair and reproduce themselves in the same way. Normally, new cells are produced to replace old, worn-out cells in an orderly, controlled way. However, in myeloma the process gets out of control and large numbers of abnormal plasma cells – myeloma cells – are produced. These fill up the bone marrow and interfere with production of normal white cells, red cells and platelets.

The myeloma cells usually produce a large amount of one type of abnormal antibody. This is known as a paraprotein or M protein. This paraprotein cannot fight infection effectively and often reduces the production of normal antibodies.

Myeloma cells have the ability to spread throughout the bone marrow and into the hard outer casing of the bone. Some, or many, areas of bone may be affected. Myeloma can cause thinning of the outer bone and bone pain.

Myeloma usually occurs in middle-aged and older people. It is unusual before the age of 50 and very rare in people younger than 40.

Myeloma is one type of disorder of the plasma cells. Some other conditions of the plasma cells can develop into myeloma but may not necessarily do so. The two most common of these are monoclonal gammopathy of uncertain significance (MGUS) and smouldering myeloma (also known as indolent or asymptomatic myeloma). If you are diagnosed with either of these conditions, you will be monitored with blood tests, but may not need to have any treatment unless the condition progresses.

Sometimes abnormal plasma cells are found in a bone in only one area of the body. This condition is known as a solitary plasmacytoma. It is treated with radiotherapy. Some people with solitary plasmacytoma may go on to develop multiple myeloma, so you will be regularly monitored with blood tests.

myeloma · plante medicinale · remedii babesti · remedii naturiste · Retete naturiste · sanatateverde · terapii naturiste · What is myeloma

What is myeloma

What is myeloma?

Myeloma is also known as multiple myeloma or myelomatosis.

Blood cells look and work differently, but they all repair and reproduce themselves in the same way. Normally, new cells are produced to replace old, worn-out cells in an orderly, controlled way. However, in myeloma the process gets out of control and large numbers of abnormal plasma cells – myeloma cells – are produced. These fill up the bone marrow and interfere with production of normal white cells, red cells and platelets.

The myeloma cells usually produce a large amount of one type of abnormal antibody. This is known as a paraprotein or M protein. This paraprotein cannot fight infection effectively and often reduces the production of normal antibodies.

Myeloma cells have the ability to spread throughout the bone marrow and into the hard outer casing of the bone. Some, or many, areas of bone may be affected. Myeloma can cause thinning of the outer bone and bone pain.

Myeloma usually occurs in middle-aged and older people. It is unusual before the age of 50 and very rare in people younger than 40.

Myeloma is one type of disorder of the plasma cells. Some other conditions of the plasma cells can develop into myeloma but may not necessarily do so. The two most common of these are monoclonal gammopathy of uncertain significance (MGUS) and smouldering myeloma (also known as indolent or asymptomatic myeloma). If you are diagnosed with either of these conditions, you will be monitored with blood tests, but may not need to have any treatment unless the condition progresses.

Sometimes abnormal plasma cells are found in a bone in only one area of the body. This condition is known as a solitary plasmacytoma. It is treated with radiotherapy. Some people with solitary plasmacytoma may go on to develop multiple myeloma, so you will be regularly monitored with blood tests.

Signs and symptoms

Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember the common tetrad of multiple myeloma is CRAB - C = Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesions.[1] Myeloma has many possible symptoms, and all symptoms may be due to other causes. They are presented here in decreasing order of incidence.

[edit] Bone pain

Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent localized pain may indicate a pathological bone fracture. Involvement of the vertebrae may lead to spinal cord compression. Myeloma bone disease is due to proliferation of tumor cells and release of Interleukin 1, IL-1, also known as osteoclast activating factor (OAF), which stimulates osteoclasts to break down bone. These bone lesions are lytic in nature and are best seen in plain radiographs, which may show "punched-out" resorptive lesions. The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms.

[edit] Infection

The most common infections are pneumonias and pyelonephritis. Common pneumonia pathogens include S. pneumoniae, S. aureus, and K. pneumoniae, while common pathogens causing pyelonephritis include E. coli and other gram-negative organisms. The greatest risk period for the occurrence of infection is in the initial few months after the start of chemotherapy.[2] The increased risk of infection is due to immune deficiency resulting from diffuse hypogammaglobulinemia, which is due to decreased production and increased destruction of normal antibodies. A selected group of patients may benefit from replacement immunoglobulin therapy to reduce the risk of infection.[3]

[edit] Renal failure

Renal failure may develop both acutely and chronically. It is commonly due to hypercalcemia (see above). It may also be due to tubular damage from excretion of light chains, also called Bence Jones proteins, which can manifest as the Fanconi syndrome (type II renal tubular acidosis). Other causes include glomerular deposition of amyloid, hyperuricemia, recurrent infections (pyelonephritis), and local infiltration of tumor cells.

[edit] Anemia

The anemia found in myeloma is usually normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.

[edit] Neurological symptoms

Common problems are weakness, confusion and fatigue due to hypercalcemia. Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, there may be radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome and other neuropathies (due to infiltration of peripheral nerves by amyloid). It may give rise to paraplegia in late presenting cases.

[edit] Diagnosis

[edit] Investigations

The presence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate (ESR) and a high serum protein (especially raised immunoglobulin) may prompt further testing. A doctor will request protein electrophoresis of the blood and urine, which might show the presence of a paraprotein (monoclonal protein, or M protein) band, with or without reduction of the other (normal) immunoglobulins (known as immune paresis). One type of paraprotein is the Bence Jones protein which is a urinary paraprotein composed of free light chains (see below). Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease. The paraprotein is an abnormal immunoglobulin produced by the tumor clone. Very rarely, the myeloma is nonsecretory (not producing immunoglobulins).

In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM. IgD and IgE myeloma are very rare. In addition, light and or heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains).

Additional findings include: a raised calcium (when osteoclasts are breaking down bone, releasing calcium into the bloodstream), raised serum creatinine due to reduced renal function, which may be due to paraprotein deposition in the kidney.

[edit] Workup

The workup of suspected multiple myeloma includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton and proximal long bones. Myeloma activity sometimes appear as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull X-ray as "punched-out lesions" (pepper pot skull). Magnetic resonance imaging (MRI) is more sensitive than simple X-ray in the detection of lytic lesions, and may supersede skeletal survey, especially when vertebral disease is suspected. Occasionally a CT scan is performed to measure the size of soft tissue plasmacytomas. Bone scans are typically not of any additional value in the workup of myeloma patients.

A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for myeloma. Immunohistochemistry (staining particular cell types using antibodies against surface proteins) can detect plasma cells which express immunoglobulin in the cytoplasm but usually not on the surface; myeloma cells are typically CD56, CD38, CD138 positive and CD19 and CD45 negative.[1] Cytogenetics may also be performed in myeloma for prognostic purposes.

Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM (immunoglobulins) to look for immune paresis, and β2-microglobulin which provides prognostic information. On peripheral blood smear the rouleaux formation of red blood cells is commonly seen.

The recent introduction of a commercial immunoassay for measurement of free light chains potentially offers an improvement in monitoring disease progression and response to treatment, particularly where the paraprotein is difficult to measure accurately by electrophoresis (for example in light chain myeloma, or where the paraprotein level is very low). Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma.[citation needed]

[edit] Diagnostic criteria

In 2003, the International Myeloma Working Group[1] agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma and MGUS (monoclonal gammopathy of undetermined significance):

* Symptomatic myeloma:
1. Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)
2. A monoclonal protein (paraprotein) in either serum or urine
3. Evidence of end-organ damage (related organ or tissue impairment, ROTI):
o Hypercalcemia (corrected calcium >2.75 mmol/L)
o Renal insufficiency attributable to myeloma
o Anemia (hemoglobin <10 g/dL)
o Bone lesions (lytic lesions or osteoporosis with compression fractures)
o Frequent severe infections (>2 a year)
o Amyloidosis of other organs
o Hyperviscosity syndrome
* Asymptomatic myeloma:
1. Serum paraprotein >30 g/L AND/OR
2. Clonal plasma cells >10% on bone marrow biopsy AND
3. NO myeloma-related organ or tissue impairment
* Monoclonal gammopathy of undetermined significance (MGUS):
1. Serum paraprotein <30 g/L AND
2. Clonal plasma cells <10% on bone marrow biopsy AND
3. NO myeloma-related organ or tissue impairment

Related conditions include solitary plasmacytoma (a single tumor of plasma cells, typically treated with irradiation), plasma cell dyscrasia (where only the antibodies produce symptoms, e.g. AL amyloidosis), and POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes).

[edit] Staging

International Staging System

The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group in 2005:[4]

* Stage I: β2-microglobulin (β2M) < 3.5 mg/L, albumin >= 3.5 g/dL
* Stage II: β2M < 3.5 and albumin < 3.5; or β2M >= 3.5 and < 5.5
* Stage III: β2M >= 5.5

Durie-Salmon staging system

First published in 1975, the Durie-Salmon staging system [5] is still in use, but has largely been superseded by the simpler ISS:

* stage 1: all of
o Hb > 10g/dL
o normal calcium
o Skeletal survey: normal or single plasmacytoma or osteoporosis
o Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgA
o Urinary light chain excretion < 4 g/24h
* stage 2: fulfilling the criteria of neither 1 nor 3
* stage 3: one or more of
o Hb < 8.5g/dL
o high calcium > 12mg/dL
o Skeletal survey: 3 or more lytic bone lesions
o Serum paraprotein >7g/dL if IgG, > 5 g/dL if IgA
o Urinary light chain excretion > 12g/24h

Stages 1, 2 and 3 of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine:

* A: serum creatinine < 2mg/dL (< 177 umol/L)
* B: serum creatinine > 2mg/dL (> 177 umol/L)

[edit] Pathophysiology

Multiple myeloma develops in post-germinal center B lymphocytes. A chromosomal translocation between the immunoglobulin heavy chain gene (on the fourteenth chromosome, locus 14q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11[6]) is frequently observed in patients with multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma. The result is proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. The chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) the thirteenth chromosome is also observed in about 50% of cases.

Production of cytokines (especially IL-6) by the plasma cells causes much of their localised damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the attraction of new blood vessels) is increased.

The produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy and various other myeloma-associated symptoms.

[edit] Treatment

Treatment for multiple myeloma is focused on disease containment and suppression. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), treatment may be deferred.

In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate or zoledronic acid) are routinely administered to prevent fractures and erythropoietin to treat anemia.

[edit] Initial therapy

Initial treatment of multiple myeloma depends on the patient’s age and comorbidities. In recent years, high-dose chemotherapy with hematopoietic stem-cell transplantation has become the preferred treatment for patients under the age of 65. Prior to stem-cell transplantation, these patients receive an initial course of induction chemotherapy. The most common induction regimens used today are thalidomide–dexamethasone, bortezomib based regimens, and lenalidomide–dexamethasone. [7] Autologous stem cell transplantation, the transplantation of a patient’s own stem cells after chemotherapy, is the most common type of stem cell transplantation for multiple myeloma. It is not curative, but does prolong overall survival. Allogeneic stem cell transplantation, the transplantation of a healthy person’s stem cells into the affected patient, has the potential for a cure, but is only available to a small percentage of patients. [6] Furthermore, there is a 5-10% treatment-associated mortality rate.

Patients over age 65 and patients with significant concurrent illness often cannot tolerate stem cell transplantation. For these patients, the standard of care has been chemotherapy with melphalan and prednisone. Recent studies among this population[8] suggest improved outcomes with new chemotherapy regimens. Treatment with bortezomib, melphalan and prednisone had an estimated overall survival of 83% at 30 months, lenalidomide plus low-dose dexamethasone an 82% survival at 2 years and melphalan, prednisone and lenalidomide had a 90% survival at 2 years. Head-to-head studies comparing these regimens have not been performed.[9]

[edit] Relapse

The natural history of myeloma is of relapse following treatment. Depending on the patient's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant.

Later in the course of the disease, "treatment resistance" occurs. This may be a reversible effect,[6] and some new treatment modalities may re-sensitize the tumor to standard therapy. For patients with relapsed disease, bortezomib (or Velcade) is a recent addition to the therapeutic arsenal, especially as second line therapy, since 2005. Bortezomib is a proteasome inhibitor. Finally, lenalidomide (or Revlimid), a less toxic thalidomide analog, is showing promise for treating myeloma.

Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve dialysis.

[edit] Prognosis

The International Staging System can help to predict survival, with a median survival of 62 months for stage 1 disease, 45 months for stage 2 disease, and 29 months for stage 3 disease.[4]

Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.

Prognostic markers such as these are always generated by retrospective analyses, and it is likely that new treatment developments will improve the outlook for those with traditionally "poor-risk" disease.

[edit] Epidemiology

There are approximately 45,000 people in the United States living with multiple myeloma, and the American Cancer Society estimates that approximately 14,600 new cases of myeloma are diagnosed each year in the United States. It follows from here that the average survival at diagnosis is about three years.

Multiple myeloma is the second most prevalent blood cancer (10%) after non-Hodgkin's lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 65 to 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset.

Multiple myeloma affects slightly more men than women. African Americans and Native Pacific Islanders have the highest reported incidence of this disease in the United States and Asians the lowest. Results of a recent study found the incidence of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. Among African Americans, myeloma is one of the top 10 leading causes of cancer death.

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Signs and symptoms myeloma

Signs and symptoms

Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember the common tetrad of multiple myeloma is CRAB - C = Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesions.[1] Myeloma has many possible symptoms, and all symptoms may be due to other causes. They are presented here in decreasing order of incidence.

[edit] Bone pain

Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent localized pain may indicate a pathological bone fracture. Involvement of the vertebrae may lead to spinal cord compression. Myeloma bone disease is due to proliferation of tumor cells and release of Interleukin 1, IL-1, also known as osteoclast activating factor (OAF), which stimulates osteoclasts to break down bone. These bone lesions are lytic in nature and are best seen in plain radiographs, which may show "punched-out" resorptive lesions. The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms.

[edit] Infection

The most common infections are pneumonias and pyelonephritis. Common pneumonia pathogens include S. pneumoniae, S. aureus, and K. pneumoniae, while common pathogens causing pyelonephritis include E. coli and other gram-negative organisms. The greatest risk period for the occurrence of infection is in the initial few months after the start of chemotherapy.[2] The increased risk of infection is due to immune deficiency resulting from diffuse hypogammaglobulinemia, which is due to decreased production and increased destruction of normal antibodies. A selected group of patients may benefit from replacement immunoglobulin therapy to reduce the risk of infection.[3]

[edit] Renal failure

Renal failure may develop both acutely and chronically. It is commonly due to hypercalcemia (see above). It may also be due to tubular damage from excretion of light chains, also called Bence Jones proteins, which can manifest as the Fanconi syndrome (type II renal tubular acidosis). Other causes include glomerular deposition of amyloid, hyperuricemia, recurrent infections (pyelonephritis), and local infiltration of tumor cells.

[edit] Anemia

The anemia found in myeloma is usually normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.

[edit] Neurological symptoms

Common problems are weakness, confusion and fatigue due to hypercalcemia. Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, there may be radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome and other neuropathies (due to infiltration of peripheral nerves by amyloid). It may give rise to paraplegia in late presenting cases.

[edit] Diagnosis

[edit] Investigations

The presence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate (ESR) and a high serum protein (especially raised immunoglobulin) may prompt further testing. A doctor will request protein electrophoresis of the blood and urine, which might show the presence of a paraprotein (monoclonal protein, or M protein) band, with or without reduction of the other (normal) immunoglobulins (known as immune paresis). One type of paraprotein is the Bence Jones protein which is a urinary paraprotein composed of free light chains (see below). Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease. The paraprotein is an abnormal immunoglobulin produced by the tumor clone. Very rarely, the myeloma is nonsecretory (not producing immunoglobulins).

In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM. IgD and IgE myeloma are very rare. In addition, light and or heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains).

Additional findings include: a raised calcium (when osteoclasts are breaking down bone, releasing calcium into the bloodstream), raised serum creatinine due to reduced renal function, which may be due to paraprotein deposition in the kidney.

[edit] Workup

The workup of suspected multiple myeloma includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton and proximal long bones. Myeloma activity sometimes appear as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull X-ray as "punched-out lesions" (pepper pot skull). Magnetic resonance imaging (MRI) is more sensitive than simple X-ray in the detection of lytic lesions, and may supersede skeletal survey, especially when vertebral disease is suspected. Occasionally a CT scan is performed to measure the size of soft tissue plasmacytomas. Bone scans are typically not of any additional value in the workup of myeloma patients.

A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for myeloma. Immunohistochemistry (staining particular cell types using antibodies against surface proteins) can detect plasma cells which express immunoglobulin in the cytoplasm but usually not on the surface; myeloma cells are typically CD56, CD38, CD138 positive and CD19 and CD45 negative.[1] Cytogenetics may also be performed in myeloma for prognostic purposes.

Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM (immunoglobulins) to look for immune paresis, and β2-microglobulin which provides prognostic information. On peripheral blood smear the rouleaux formation of red blood cells is commonly seen.

The recent introduction of a commercial immunoassay for measurement of free light chains potentially offers an improvement in monitoring disease progression and response to treatment, particularly where the paraprotein is difficult to measure accurately by electrophoresis (for example in light chain myeloma, or where the paraprotein level is very low). Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma.[citation needed]

[edit] Diagnostic criteria

In 2003, the International Myeloma Working Group[1] agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma and MGUS (monoclonal gammopathy of undetermined significance):

* Symptomatic myeloma:
1. Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)
2. A monoclonal protein (paraprotein) in either serum or urine
3. Evidence of end-organ damage (related organ or tissue impairment, ROTI):
o Hypercalcemia (corrected calcium >2.75 mmol/L)
o Renal insufficiency attributable to myeloma
o Anemia (hemoglobin <10 g/dL)
o Bone lesions (lytic lesions or osteoporosis with compression fractures)
o Frequent severe infections (>2 a year)
o Amyloidosis of other organs
o Hyperviscosity syndrome
* Asymptomatic myeloma:
1. Serum paraprotein >30 g/L AND/OR
2. Clonal plasma cells >10% on bone marrow biopsy AND
3. NO myeloma-related organ or tissue impairment
* Monoclonal gammopathy of undetermined significance (MGUS):
1. Serum paraprotein <30 g/L AND
2. Clonal plasma cells <10% on bone marrow biopsy AND
3. NO myeloma-related organ or tissue impairment

Related conditions include solitary plasmacytoma (a single tumor of plasma cells, typically treated with irradiation), plasma cell dyscrasia (where only the antibodies produce symptoms, e.g. AL amyloidosis), and POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes).

[edit] Staging

International Staging System

The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group in 2005:[4]

* Stage I: β2-microglobulin (β2M) < 3.5 mg/L, albumin >= 3.5 g/dL
* Stage II: β2M < 3.5 and albumin < 3.5; or β2M >= 3.5 and < 5.5
* Stage III: β2M >= 5.5

Durie-Salmon staging system

First published in 1975, the Durie-Salmon staging system [5] is still in use, but has largely been superseded by the simpler ISS:

* stage 1: all of
o Hb > 10g/dL
o normal calcium
o Skeletal survey: normal or single plasmacytoma or osteoporosis
o Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgA
o Urinary light chain excretion < 4 g/24h
* stage 2: fulfilling the criteria of neither 1 nor 3
* stage 3: one or more of
o Hb < 8.5g/dL
o high calcium > 12mg/dL
o Skeletal survey: 3 or more lytic bone lesions
o Serum paraprotein >7g/dL if IgG, > 5 g/dL if IgA
o Urinary light chain excretion > 12g/24h

Stages 1, 2 and 3 of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine:

* A: serum creatinine < 2mg/dL (< 177 umol/L)
* B: serum creatinine > 2mg/dL (> 177 umol/L)

[edit] Pathophysiology

Multiple myeloma develops in post-germinal center B lymphocytes. A chromosomal translocation between the immunoglobulin heavy chain gene (on the fourteenth chromosome, locus 14q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11[6]) is frequently observed in patients with multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma. The result is proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. The chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) the thirteenth chromosome is also observed in about 50% of cases.

Production of cytokines (especially IL-6) by the plasma cells causes much of their localised damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the attraction of new blood vessels) is increased.

The produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy and various other myeloma-associated symptoms.

[edit] Treatment

Treatment for multiple myeloma is focused on disease containment and suppression. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), treatment may be deferred.

In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate or zoledronic acid) are routinely administered to prevent fractures and erythropoietin to treat anemia.

[edit] Initial therapy

Initial treatment of multiple myeloma depends on the patient’s age and comorbidities. In recent years, high-dose chemotherapy with hematopoietic stem-cell transplantation has become the preferred treatment for patients under the age of 65. Prior to stem-cell transplantation, these patients receive an initial course of induction chemotherapy. The most common induction regimens used today are thalidomide–dexamethasone, bortezomib based regimens, and lenalidomide–dexamethasone. [7] Autologous stem cell transplantation, the transplantation of a patient’s own stem cells after chemotherapy, is the most common type of stem cell transplantation for multiple myeloma. It is not curative, but does prolong overall survival. Allogeneic stem cell transplantation, the transplantation of a healthy person’s stem cells into the affected patient, has the potential for a cure, but is only available to a small percentage of patients. [6] Furthermore, there is a 5-10% treatment-associated mortality rate.

Patients over age 65 and patients with significant concurrent illness often cannot tolerate stem cell transplantation. For these patients, the standard of care has been chemotherapy with melphalan and prednisone. Recent studies among this population[8] suggest improved outcomes with new chemotherapy regimens. Treatment with bortezomib, melphalan and prednisone had an estimated overall survival of 83% at 30 months, lenalidomide plus low-dose dexamethasone an 82% survival at 2 years and melphalan, prednisone and lenalidomide had a 90% survival at 2 years. Head-to-head studies comparing these regimens have not been performed.[9]

[edit] Relapse

The natural history of myeloma is of relapse following treatment. Depending on the patient's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant.

Later in the course of the disease, "treatment resistance" occurs. This may be a reversible effect,[6] and some new treatment modalities may re-sensitize the tumor to standard therapy. For patients with relapsed disease, bortezomib (or Velcade) is a recent addition to the therapeutic arsenal, especially as second line therapy, since 2005. Bortezomib is a proteasome inhibitor. Finally, lenalidomide (or Revlimid), a less toxic thalidomide analog, is showing promise for treating myeloma.

Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve dialysis.

[edit] Prognosis

The International Staging System can help to predict survival, with a median survival of 62 months for stage 1 disease, 45 months for stage 2 disease, and 29 months for stage 3 disease.[4]

Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.

Prognostic markers such as these are always generated by retrospective analyses, and it is likely that new treatment developments will improve the outlook for those with traditionally "poor-risk" disease.

[edit] Epidemiology

There are approximately 45,000 people in the United States living with multiple myeloma, and the American Cancer Society estimates that approximately 14,600 new cases of myeloma are diagnosed each year in the United States. It follows from here that the average survival at diagnosis is about three years.

Multiple myeloma is the second most prevalent blood cancer (10%) after non-Hodgkin's lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 65 to 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset.

Multiple myeloma affects slightly more men than women. African Americans and Native Pacific Islanders have the highest reported incidence of this disease in the United States and Asians the lowest. Results of a recent study found the incidence of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. Among African Americans, myeloma is one of the top 10 leading causes of cancer death.