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Multiple myeloma
Written by Dr Atul Mehta, consultant haematologist
Infection
This can occur due to a number of factors. In addition to reduced white cells, myeloma patients lack normal levels of functional antibodies in the blood, and so are less equipped to deal with antigens. Such infections are typically due to bacteria (urinary tract, skin and chest infections) or viruses (colds, flu, shingles).
The paraprotein can also interfere with the process of engulfment of bacteria by white cells (phagocytosis).
Kidney failure
If the paraprotein produced by the plasma cells is of a smaller molecular size it may get through the first part of the kidney's filtering mechanism and then silt up the rest of the fine network of tubes (tubules) within the kidney, leading to kidney failure. These small paraproteins are known as Bence Jones protein, or 'light chains'.
Most light chain production occurs alongside that of the larger molecules produced by the abnormal plasma cells, but in 20 per cent of people with myeloma, light chains only are produced. This is important because in the latter there is no abnormal paraprotein in the blood, and the diagnosis can be made only if the urine is checked for the presence of light chains.
Other causes of kidney damage in myeloma include the increased blood level of calcium (due to skeletal damage), infection and, later in the course of the disease, as a side effect of some of the drugs required to treat myeloma.
General features
Common to nearly all cancers are symptoms such as loss of appetite, weight loss and lack of energy.
About 10 per cent of myeloma patients have no symptoms, but are diagnosed incidentally either following a health screen or as a result of tests undertaken as part of investigation for unrelated conditions.
How is myeloma diagnosed?
Symptoms of myeloma are often vague and the diagnosis is often delayed, sometimes by as long as a matter of months. This probably makes no difference to the long-term outcome for those patients with early myeloma who do not need immediate treatment. However if a delay in diagnosis has led to organ damage (eg kidney failure ), then that will have a negative effect on the person's outcome.
The diagnosis will be based on blood tests, urine tests, X-rays and a bone marrow sample.
The erythrocyte sedimentation rate (ESR) is a test that is usually markedly abnormal in myeloma as a result of the presence of the abnormal protein.
Quite simply, a blood sample is left to stand vertically in a clear narrow tube, after it has been mixed with an anti-coagulant to prevent the blood from clotting.
The red cells (erythrocytes) slowly sink to the bottom of the tube, leaving a clear line between them and the straw-coloured plasma. The rate of fall is much higher in myeloma because the paraprotein causes the red cells to clump together and so fall more rapidly.
Blood tests may show elevation in serum calcium level, the changes of kidney failure, and changes in blood proteins.
Specifically, blood tests should be performed to measure the amount and exact type of paraprotein and the level of normal immunoglobulins (antibody proteins).
Other helpful blood tests are the C-reactive-protein (CRP) level and the level of b2 microglobulin. Elevation of either is associated with a poorer outlook. For b2 microglobulin a level of <4mg/l indicates a good outlook, 4-8mg/l is intermediate and above 8mg/l usually indicates a poor outlook. The level rises in patients with kidney failure.
Urine tests
Myeloma can exist in which there is no abnormal production of proteins by the malignant plasma cells. In those people both blood and urine are negative to the above tests, but this is a rare condition.
X-rays
Bone marrow sample
What else could it be?
It is best for patients to be referred to a haematologist or a cancer specialist (oncologist).
How can patients help themselves?
How is multiple myeloma treated?
Patients will be given courses at four to six weekly intervals up to a total of 8 to 10 courses. Such treatment is usually given to older patients who would be less able to tolerate more aggressive chemotherapy. However, some recent studies have shown that oral melphalan and prednisolone, if given at the highest tolerable doses, can yield very good long-term responses in all patients, including younger ones.
The overall response rate is approximately 50 to 60 per cent. It is uncommon, however, for patients to enter complete remission, ie the disappearance of all visible and measurable evidence of disease, with single agent chemotherapy.
Combination chemotherapy
There may be a marginal benefit for combination chemotherapy but this is at the expense of more complicated treatments requiring greater input from the hospital, usually involving attendance on an outpatient or day-patient basis.
Common combinations include drugs such as:
Infusion chemotherapy
The commonest is to use a vincristine/adriamcyin infusion (VAD or VAMP). This is often combined with cyclophosphamide by individual injection on days one, eight and 14 of a 21-day cycle.
The steroid element is given as dexamethasone in VAD and methylprednisolone in VAMP.
These regimens are frequently used in patients who are due to undergo stem cell (bone marrow) transplantation. They are also the treatment of choice for relapsed patients who have not previously received such treatment and who are thought to be able to tolerate it.
Other chemotherapy approaches
Stem cell transplantation
After the chemotherapy to eradicate the abnormal cells the patient is 'given back' the stem cells, which have the capability of turning into any of the blood's normal cell components.
A number of studies have compared autologous stem cell transplantation with combination chemotherapy for patients with myeloma aged less than 65.
A large French study showed a benefit for patients receiving autologous stem cell transplantation; a large British study has not yet been fully analysed.
Patients usually receive four to six courses of infusion chemotherapy (eg C-VAMP) and their stem cells are 'mobilised' using a growth promoting factor specific for early marrow cells (GCSF) combined with further chemotherapy (often high dose intravenous cyclophosphamide), the stem cells are harvested from peripheral blood (rather than the bone marrow itself), and stored until required.
High dose melphalan is commonly used beforehand, so-called 'pre-transplant conditioning'. Ill effects from this technique are reasonably low and mortality in most units is less than 2 per cent.
A large French study compared the value of giving two transplants sequentially with a single transplant and no great benefit of a dual transplant procedure was evident. However, a large centre at Little Rock, Arkansas, USA, customarily gives two transplants to myeloma patients and claims very good results particularly in patients who already have a good outlook.
Most patients relapse even after autologous transplantation although a very small number (approximately 10 per cent) do appear to survive 10 years or longer.
The average time to relapse is approximately four years. At relapse, selected patients may benefit from a repeat stem cell transplant particularly if an adequate number of previously harvested stem cells are still available.
Allogeneic stem cell transplantation
Most of the reported transplants have been performed in patients who have relapsed following some other type of treatment - however, trials are now being developed which examine the role of allogeneic stem cell transplantation in previously untreated patients.
The major problem is transplant related mortality, which in previous studies was as high as 30 per cent, but in more recent studies may be considerably lower.
There is a late relapse rate, with patients relapsing as long as 10 years after allogeneic stem cell transplantation. However, the long-term survival rate, possible equating to a long-term cure rate, is over 30 per cent in some studies, suggesting that this approach requires further investigation.
Radiotherapy (X-rays)
A myeloma deposit within the spine can result in pressure on the spinal cord, and radiotherapy is an essential part of the treatment of this. Radiotherapy is critical for the treatment of plasmacytoma (see above).
Side effects of radiotherapy include nausea, occasionally vomiting, inflammation of the lining of the digestive system (mucositis), and a fall in numbers of the blood's red cells, white cells and platelets.
Radiotherapy applied to much larger areas of the body - half or whole-body radiation - can be helpful. Radiotherapy is sometimes applied as part of the conditioning treatment prior to stem cell transplantation – although many studies have shed doubt on the value of radiotherapy in this setting.
Surgery is particularly risky in patients with myeloma but can be of value in the management of pathological bone fractures.
Other treatments
The improvement in survival was approximately six months. Interferon is poorly tolerated in some patients (fatigue, reduced appetite, fever, occasional hormone disturbance (eg thyroid abnormalities), lowering of blood counts and anaemia). Addition of Interferon to chemotherapy protocols is usually of very little value.
Thalidomide has recently been tried in a number of studies and appears to be helpful in approximately one third of patients but side effects including drowsiness and nervous system problems are also seen in approximately one third of patients.
Additional treatments
Opiate dependence is rarely a problem for a patient with terminal disease but can be a difficulty for someone taking opiates long term.
As with all painful conditions it is best to take a stepped approach, using simpler painkillers first and gradually going up in drug strength as necessary. It is, however, more important to achieve good pain control than to worry about drug dependence.
Non-steroidal anti-inflammatory drugs (NSAIDs) are useful painkillers, particularly for bone pain. Their potential disadvantages include worsening of kidney function and platelet function. These problems do not always occur but if, for example, someone already has a reduced platelet count then the NSAID might lead to significantly increased chances of bruising and bleeding.
Bisphosphonates
There are preliminary unconfirmed data suggesting that the long-term use of bisphosphonates may improve survival. These drugs clearly have an important role in controlling the bone disease in myeloma and further studies are awaited.
Physiotherapy and exercise
Myeloma patients are susceptible to infection and will frequently need antibiotic treatment. They may benefit from treatment to bolster their immunity, such as with injections of human immunoglobulin (eg Kabiglobulin)
and this can certainly be tried in patients with particularly severe infections.
There are no good data on the value of vitamin supplements or of other immune supplements.
Blood component therapy
Myeloma patients can also develop bleeding complications as a result of the paraprotein and they may in that instance benefit from plasma therapy.
Some patients require plasma exchange whereby the patient's plasma is removed on a cell separator and replaced with transfusions of human albumin or synthetic plasma.
Erythropoietin (Eprex, NeoRecormon)
is a genetically engineered preparation of the human hormone that promotes maturation of red cells in the bone marrow. It has been found to be helpful in the treatment and prevention of anaemia in myeloma patients and some studies have indicated that it leads to an improvement in quality of life in these patients.
Other treatment issues
Once a patient has entered a stable plateau phase, there is little evidence to support the use of continuing chemotherapy. It is probably better to wait until the disease shows greater activity and the patient has relapsed.
Patients typically respond less well to chemotherapy at relapse than they do at the time of initial presentation. There is increasing evidence that their disease becomes resistant to chemotherapy and the mechanisms that underlie this are under investigation.
New treatments are being developed which may get round these problems. Ultimately, however, the disease becomes unresponsive to treatment and treatment entails increasing distress for the patient. It may well become appropriate in due course to stop active treatment but this should always be done in consultation with the patient and their family.
The consequences of not treating a patient with myeloma are generally serious. The disease will progress and most patients will die within six months (often much earlier) if they are not offered treatment at the time of presentation.
What is the outlook?
Approximately one third of all patients with myeloma have a very serious disease course and die within a year of presentation. Another third have moderately active disease and die within three to five years of presentation. Finally, one third will do well with treatment in the long term, surviving more than five years and, sometimes, longer still.
What are the complications of myeloma and its treatment?
Kidney failure is a major complication and approximately 10 per cent of myeloma patients may require dialysis at some time during the course of their disease. Most of the published literature on dialysis for myeloma patients is from specialised centres and it is well recognised that the results reported from these series are often superior to those that can be expected in day-to-day practice. Nevertheless, dialysis should be considered for all myeloma patients who require it.
Anaemia is a frequent complication. It may improve with blood transfusion therapy. Increasingly, there is evidence that injections with erythropoietin can improve the degree of anaemia. Fatigue is a common consequence of anaemia, but fatigue can have many different causes. These include pain and depression, both of which may be treatable.
The paraprotein in myeloma can deposit on peripheral nerves (ie nerves outside the brain and spinal cord) and cause numbness and tingling. Other nerve complications of myeloma include compression of the spinal cord due to myeloma deposits in the back as well as trapping of nerves due to skeletal complications of myeloma. Radiotherapy, chemotherapy and sometimes surgery can be helpful for these complications. Plasma exchange is sometimes used to help in the treatment of the nerve and kidney complications of myeloma. Chemotherapy with vincristine is a frequent cause of nerve damage in myeloma patients.
Approximately 7-10 per cent of patients with myeloma ultimately develop amyloidosis, which is the laying down in many tissues of material made of immunoglobulin light chains. This can affect the skin, tongue and other parts of the digestive system as well as the liver, spleen and heart muscle. It is a very difficult complication to treat. Myeloma patients are at increased risk of infection, both as a result of the disease and its treatment. They should receive flu vaccination
as well as pneumococcal vaccination and other appropriate preventive measures.
They should have a clear idea of what action to take in the event of fever or infection and should carry with them a supply of antibiotics when travelling overseas. They should inform their doctor prior to booking holidays overseas and should consider taking out an additional insurance. They may be at increased risk of deep vein thrombosis during air travel and should discuss with their doctor the possibility of taking some aspirin 24 hours prior to the flight. They should, in any event, try to keep mobile during aircraft journeys, and they must keep well hydrated. Patients with myeloma should not smoke, should moderate their alcohol intake and remember to keep up a good intake of water.
Complications of chemotherapy
What is on the horizon?
The human genome project has provided impetus to research on the genetic changes underlying the development of cancer generally and analysis of DNA, RNA and chromosomes will become increasingly important not only in diagnosing myeloma but in assessing the disease and forecasting its behaviour in individual patients. This in turn will help in planning treatment. Drugs that block the passage of signals within cancer cells are being developed. Drugs that overcome chemotherapy resistance are under trial.
The role of allogeneic transplantation will be assessed further in trials organised by the Medical Research Council in the UK, and these trials will also examine the role of more modern (and possibly safer) transplant approaches ('mini-transplant').
Newer derivatives of thalidomide are being developed and studied. More modern bisphosphonates may have greater activity in controlling the skeletal complications of myeloma. Vaccines are being developed which may help to control the disease, when used alongside other treatments. Antibody treatments that have been found effective in other blood cancers (eg rituximab) are being developed for use in myeloma patients. The future is brighter than it has ever been before.
Conclusion
Support groups
The International Myeloma Foundation, 9 Gayfield Square, Edinburgh, EH1 3NT. Phone: 0131 557 3332. Fax: 0131 556 9720. E-mail: TheIMF@myeloma.org.uk.
Leukaemia Research Fund, 42 Great Ormond Street, London, WC1N 3JJ. Phone: 020 7405 0101. Fax: 020 7242 1488.
Cancer Link, Macmillan Cancer Relief, 89 Albert Embankment, London SE1 7UQ E-mail: cancerline@macmillan.org.uk
The urine must be checked for the presence of Bence Jones protein to detect those patients with 'light chain only' myeloma. It is best to do this with a 24-hour urine collection.
X-rays should be taken of the painful area and of the whole skeleton to detect any unsuspected bony lesions. Other radiological investigations, eg magnetic resonance imaging (MRI) are also often valuable.
This documents the level of infiltration by plasma cells. The plasma cells obtained should then be subjected to further tests, eg chromosome analysis. Some laboratories also perform a 'plasma cell labelling index', which looks at the proliferative capacity of the plasma cells. Plasma cells with a high labelling index are more likely to be associated with aggressive disease.
The following conditions are sometimes confused with multiple myeloma.
Patients with myeloma should remember that there are many things that they can do for themselves.
This has been compared with melphalan and prednisolone in a large number of clinical trials and shown to be broadly similar in terms of response rates and long-term survival.
This is the use of combinations of chemotherapy drugs given by intravenous infusion ('drip'), typically over a four-day period.
There are a number of other protocols. These include:
This involves the use stem cells harvested from a donor, usually a sibling, with a similar 'tissue type'. This should still be considered an experimental approach in myeloma although recent data indicate that it is a valuable procedure.
Radiotherapy is a very important type of treatment in multiple myeloma as it is a very effective way of treating localised tumour deposits within the tissues and bones (lytic lesions). If radiotherapy is administered to a bone lesion that has fractured ('pathological fracture'), it is important that any surgical procedure that may be contemplated should be performed prior to radiotherapy.
Interferon alfa-2a (Roferon-A) or interferon alfa-2b (Intron A, Viraferon) has shown modest benefits in overall survival and duration of the plateau phase, particularly after intensive therapy such as autologous transplantation.
These medicines help strengthen bones. They can be given either in the form of sodium clodronate (Bonefos, Loron) daily by mouth or disodium pamidronate
every three to six weeks by drip. Both have been shown to reduce the rate of progress of bone disease in myeloma patients and both probably have an important role in relieving bone pain.
Physiotherapy and exercise can and should be undertaken in myeloma patients but with care to avoid damage to the skeleton and other tissues.
Blood component therapy with red cell and platelet transfusions is often helpful.
A major issue in myeloma is when to commence treatment. Patients with stable myeloma who do not have demonstrable bony disease probably do not need treatment. However, they should attend regularly for review, have their paraprotein levels monitored and should perhaps have annual assessments of their skeleton.
The majority (more than 95 per cent) of patients diagnosed as having myeloma will ultimately die of it. Very few, if any, patients can consider themselves to be cured of myeloma. It remains true, however, that perhaps 10 per cent of patients are alive more than 10 years after diagnosis. Some of these will have had an autologous transplant whereas others will have been treated more conventionally.
Myeloma is a multiple system disorder affecting many different parts of the body. The treatment is typically intensive and can also have a large number of side effects.
Chemotherapy will damage normal cells as well as myeloma cells, and can therefore cause or aggravate low counts of red cells (anaemia), white cells (infection) and platelets (bruising/bleeding). Chemotherapy often causes nausea, vomiting and hair loss. Some forms of chemotherapy (eg melphalan) also cause damage to dividing cells lining the digestive tract, causing diarrhoea and inflammation (mucositis). Chemotherapy can cause infertility and long term may predispose to the development of new malignancies.
There have been many recent advances in our understanding of myeloma and these are being translated into new treatments.
Myeloma is a multi-system disease, a form of cancer that shortens the life of its sufferer. Most people with myeloma ultimately die of it. Treatments are available and many of them can return patients to a period of good quality life. Nevertheless, a diagnosis of myeloma will undoubtedly cause a profound change in an individual's life circumstances, and will also affect their immediate family and employment. Management of myeloma should take account of the disease, its complications, and also psychosocial issues affecting the patient and their environment. The patient and their carer should, at all times, be well informed so that they may participate in treatment decisions with the team caring for them.
Various support groups are available for myeloma patients.
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