|  | | |  | What is multiple myeloma? |
Multiple myeloma is a form of cancer which affects plasma cells in the bone marrow. These are cells which normally produce antibodies and are a specialised form of B-lymphocyte. In myeloma a single cell becomes malignant and produces a very large number of identical cells (a clone). In normal circumstances, the antibody molecules present in the blood are very varied in their structure, reflecting the large number of infections they may be required to combat. In patients with myeloma very large quantities of a single type of antibody are produced. This is called a paraprotein and it is present in the blood and/or urine in about 99% of cases. Normal antibody levels are almost always reduced in myeloma. This, combined with a slight reduction in numbers of neutrophils, leads to a susceptibility to infections which may be life-threatening.
When there is no detectable paraprotein it is called non-secretory myeloma. Detection of a paraprotein is not sufficient to give a diagnosis of multiple myeloma, as this may also occur in other conditions including lymphoma, MGUS (Monoclonal Gammopathy of Unknown Significance which is described below), amyloidosis and some inflammatory disorders.
Bone damage is often the most significant feature of multiple myeloma. The term multiple myeloma refers to the spread of the disease throughout the marrow at the time of diagnosis and the presence of multiple sites of affected bone. An altered balance between bone production and destruction leads to areas of thinning of the bone. The holes in the bone which are produced are called lytic lesions. Myeloma cells disturb the balance between cells called osteoclasts (which destroy bone) and cells called osteoblasts (which make new bone). Over a period of time this leads to local loss of bone with characteristic abnormalities on X-ray examination and a tendency for bones to break in response to very mild trauma (pathological fractures).
A potentially serious associated problem is hypercalcaemia which is the presence of higher than normal levels of calcium in the blood. Calcium is a major component of bone and the increased breakdown of bone in myeloma leads to the elevated blood levels. High blood calcium can cause dehydration and kidney damage which further raise the concentration of calcium This vicious circle can be broken by a high fluid intake, often in the range of five to six pints per day.
The diagnosis of multiple myeloma rests on finding excessive numbers of (often abnormal) plasma cells in the bone marrow, abnormal bone appearances on X-rays and the presence of a paraprotein in the blood and/or urine.
The disease can be effectively treated with drugs (chemotherapy) and most patients will respond to standard chemotherapy and achieve a state called plateau. In this state patients are free of serious disease symptoms. Plateau typically lasts for one to three years. Patients in plateau are not, however, cured as their disease will eventually return this is called relapse or progression.
| Who gets multiple myeloma? |
This disease is unknown in childhood, very uncommon in young adults and becomes increasingly common with advancing age. Only about 2% of cases in the UK occur in people under the age of 40 years.
There are about 3,000 new cases each year in the UK. The incidence is about twice as high in males as in females. Multiple myeloma is about twice as common in Black people as in Whites. The reasons for this are not understood but it does imply an underlying variation in the predisposition to develop the condition.
| What are the types of multiple myeloma? |
Myeloma may arise on a background of a clinically benign condition called Monoclonal Gammopathy of Unknown Significance (MGUS) . The hallmark of MGUS is the presence of a paraprotein but without evidence of other symptoms or features of myeloma.
The blood normally contains a large number of different proteins called the plasma proteins. About 20% of the total amount of protein in the serum is made up of antibodies produced as part of the bodys defences against infection. Collectively they are known as gamma globulins. When most of the protein being produced is one particular form of gamma globulin this is called a monoclonal gammopathy. This means that all of the abnormal protein is identical because it is produced by a population of cells which are all derived from one original cell. Such a population is called a clone, hence the term monoclonal.
A state intermediate between MGUS and myeloma, which may represent a form of pre-myeloma rather than a subtype of myeloma, is known as smouldering myeloma. In this condition there is a paraprotein but the patient remains free of symptoms. The survival of patients with MGUS or smouldering myeloma is considerably longer than for true myeloma.
When a myeloma like condition is confined to a single location, which may be in the bone or in soft tissues, it is referred to as a solitary plasmacytoma. An uncommon complication of myeloma is amyloidosis in which there is deposition of an abnormal protein (amyloid) in various tissues.
There are several different types of antibody molecule with different functions within the body. These are called IgM IgG, IgA, IgD and IgE (Ig is the abbreviation for immunoglobulin, another term for antibody molecules). In about three-quarters of all cases of myeloma the paraprotein present will all correspond to one type of antibody molecule. The disease may therefore be referred to as IgG, IgA, IgD or IgE myeloma. IgM myeloma is very rarely seen. Cases where IgM is the dominant type are usually classified as Waldenstroms Macroglobulinaemia . In the remaining cases there is no detectable paraprotein, there is a mixed Ig type, or the paraprotein molecules cannot be classified as matching any of the Ig types.
Each type of myeloma may show slightly different patterns of disease. For example patients with IgD myeloma more frequently develop an associated condition called plasma cell leukaemia and more frequently have kidney damage. If patients wish to know more about which subtype they have they should discuss this with their specialist.
| What causes multiple myeloma? |
There are no clearly defined risk factors for multiple myeloma. Among those that have been suggested are exposure to high levels of ionizing radiation and certain occupational and chemical exposures.
The incidence was initially reported to be increased among survivors of the Hiroshima and Nagasaki atomic bomb explosions. Longer-term follow up however has shown no evidence of any excess of cases among survivors.
Myeloma is not an inherited condition and there is no clear evidence of an excess of cases among the close kin of patients with myeloma or other cancers. There have, however, been reports of families with several cases. The significance of this remains unclear.
| What are the signs and symptoms of multiple myeloma? |
At the time of diagnosis about 70% of patients have pain of varying intensity associated with the presence of areas of bone destruction called lytic bone lesions. Many patients with bone lesions suffer broken bones (pathological fractures). These are breaks which may occur as a consequence of minimal trauma. The most common sites of pain are the lower back and the ribs. As back pain is very common in the general population this may lead to a delayed diagnosis.
Patients with myeloma may show:
Bone related symptoms:
 | persistent unexplained backache associated with loss of height and osteoporosis (bone thinning), especially in males and pre-menopausal women |
| symptoms suggestive of spinal cord/nerve root compression including weakness in the lower limbs and bladder problems. |
Bone marrow related signs and symptoms:
| frequent, persistent infections, in particular pneumonia and chest infections are very common in myeloma because in about three-quarters of all patients production of normal antibodies is suppressed. The risk of infection can be made worse by chemotherapy. Any patient who develops a fever may require urgent antibiotic therapy and should seek medical advice immediately. |
| anaemia: if patients are anaemic they may tire easily and may become breathless even after mild exertion. This is because there is a reduction in the number of red blood cells although the red cells appear normal under the microscope |
| low white count and/or platelet count |
Abnormal Laboratory results:
| poor kidney function |
| hypercalcaemia, that is, high blood calcium |
| persistent high ESR or plasma viscosity, ESR stands for Erythrocyte Sedimentation Rate. It is a test which is affected by levels of protein in the blood and is usually very much higher than normal in myeloma. |
| If the levels of plasma protein are very high the blood becomes very thickened (hyperviscosity) and this can reduce blood flow. |
| Patients should seek prompt medical advice if they experience any of these signs including excessive weariness, confusion, headaches, temporary disturbances of vision and any abnormal bleeding (e.g. bleeding gums when brushing teeth). |
| How is multiple myeloma diagnosed? |
Clinical presentation of myeloma is very varied. There are no definite signs or symptoms which are seen only in this disease. Some patients are free of symptoms at the time of diagnosis with the disease being detected as a result of routine blood tests.
Other patients may have areas of tenderness over a site of bony involvement, abnormal curvature of the spine or pathological fractures. These clinical signs are suggestive of myeloma but not unique to this disease. If the spinal column is involved then various neurological abnormalities may be detected including weakness and loss of sensation in the lower limbs together with bladder problems.
The diagnosis of myeloma depends on three abnormal findings:
| 1) a bone marrow containing more than 15% plasma cells. Normally no more than 4% of the cells in the bone marrow are plasma cells. |
| 2) X-rays showing generalised thinning of the bones and/or punched out lesions and |
| 3) serum and/or urine showing the presence of an abnormal protein. |
1) BONE MARROW SAMPLING
The demonstration of excessive numbers of plasma cells in the bone marrow is part of the definition of multiple myeloma. The plasma cells may also appear different to those seen in normal bone marrow. Bone marrow involvement may be patchy but it is usual to detect the presence of myeloma cells in a sample of marrow collected from a single site. If bone marrow involvement is extensive then plasma cells may be present in the blood. However this is uncommon (about 15% of cases).
2) SKELETAL FEATURES
About 70% of patients with myeloma will have readily detectable, distinctive “punched out” bone lesions which can be seen on an X-ray survey of the bones. These are areas where there has been extensive bone destruction caused by myeloma cells. In about 20% of cases there is widespread loss of bone density without distinct myeloma type lesions. The damage is similar to that seen in osteoporosis in post-menopausal women.
In 10% of patients who are considered to have myeloma the skeletal survey results are normal. MRI scans may be useful for detecting local areas of damage especially within the bones of the spinal column. MRI stands for Magnetic Resonance Imaging, this is a test similar to an X-ray but does not use radiation. It shows soft (non-bony) tissues much more clearly than X-rays. An alternative test, which is less sensitive than MRI, is called a CAT scan – this uses X-rays but shows more detail than a standard X-ray.
3) PARAPROTEINS
Antibodies are made by B-cells and are made up of two types of protein molecules called heavy chains and light chains. Two heavy chains and two light chains join together to form an antibody molecule. In the great majority of cases of myeloma both heavy and light chains are produced in excess. In a minority of cases there may be only light chain or, very rarely, only heavy chain present. An abnormal protein may also be present in the urine. This is made up of an excess of light chains and is called Bence-Jones protein. The presence of Bence-Jones protein in urine is a characteristic of multiple myeloma in about 60% of cases.
High quantities of free light chains can cause kidney damage which may be very severe. In about 25% of patients, kidney failure can occur and this may become a serious clinical problem.
Measuring the amount of paraprotein in the blood or urine is of value in the diagnosis of myeloma and in monitoring the response to treatment. The standard test is called protein electrophoresis. The presence of paraprotein is sometimes referred to as a peak or a band to distinguish it from the normal pattern. (See illustration). The sharp spike on the right of the lower plot represents the paraprotein.
OTHER INVESTIGATIONS
A number of other investigations may be of value in confirming the diagnosis, in assessing the likely prognosis and in monitoring the response to treatment. All patients with a confirmed diagnosis of myeloma will require regular monitoring of kidney function. A variety of tests of blood chemistry may be carried out including levels of calcium, uric acid and a substance called ∗2 microglobulin, the measurement of which is of value in assessing prognosis. High levels of ∗2 microglobulin (greater than 4mg/litre) have been found to be associated with a poorer response to treatment and outcome.
In most forms of leukaemia and related diseases the study of changes in the genetic structure on chromosomes has been found to be of value in predicting treatment response and likely outcome. This is known as cytogenetics. In myeloma, abnormal cytogenetic results are seen in about 70% of patients. The clinical significance of these abnormalities is not yet known but is under investigation in a number of studies including projects funded by Leukaemia Research.
A relatively new test has been introduced which detects fragments of paraprotein called free light chaines. This blood test, called the Freelite serum assay, may be particularly valuable in diagnosis of patients who have no monoclonal protein in serum or urine - light chain myeloma or non-secretory myeloma. If this test is being used, the specialist will explain the significance of any abnormal results.
| How is multiple myeloma staged? |
In most forms of cancer, some form of staging is used to assist in treatment planning and in assessing likely prognosis. Staging relates chiefly to the spread of the cancer from its original site. In multiple staging is based on the estimated number of myeloma cells and the specific properties such as how fast they divide. The most widespread staging system for myeloma is called the Durie/Salmon system. The system is described in the Appendix. This attempts to estimate the amount of disease within the body and is based on the extent of bone lesions and on the results of laboratory tests. This staging system is of very limited value in predicting the likely prognosis for individual patients but has been found to be of value in the design and interpretation of clinical trials for potential new treatments.
| How is multiple myeloma treated? |
| The treatment sections of this booklet are based on guidelines developed by the UK Myeloma Forum on behalf of the British Committee for Standards in Haematology. The UK Myeloma Forum has a website at www.ukmf.org |
PRINCIPLES OF TREATMENT
Some patients are diagnosed by chance at a time when they have no symptoms. These are called asymptomatic patients. Such patients are not normally treated unless there is evidence from laboratory tests, X-rays or scans that the disease is progressing. This is because studies have shown that there are no benefits from early treatment of these asymptomatic patients.
Asymptomatic patients will typically have measurements of serum and urine paraprotein levels at three-monthly intervals. Repeat x-ray and bone marrow examinations will be done routinely at less frequent intervals or when new signs or symptoms are seen. This is often referred to as “watch and wait”. When x-rays show evidence of bone disease patients should commence treatment immediately.
Treatment of myeloma can be divided into a) supportive measures which are aimed at controlling the effects of the disease on other tissues and organs, and b) treatment of the underlying disease which is known as definitive treatment. Supportive care of the patient includes measures to prevent problems such as kidney damage and infection. Definitive treatment of the disease may be with conventional chemotherapy or with high dose chemotherapy in association with stem cell transplantation.
Supportive treatment is aimed at achieving the best possible quality of life. Definitive treatment aims to eliminate all detectable signs of the disease, both clinically and by laboratory tests. If this can be achieved it is called a complete response. Many patients will experience a marked improvement in their condition which falls short of a complete response. This is known as a partial response. When a patients condition does not improve at all when given standard therapy this is termed refractory or resistant disease. When a patient has been in plateau phase and their disease returns this is known as relapse or progression.
Definitive treatment for myeloma may also affect production of normal blood cells by the bone marrow. This particularly affects neutrophils and platelets. Neutrophils are one type of white blood cell which play a very important part in the body’s defences against bacterial and fungal infections. Platelets are part of the clotting system and very low levels may place patients at risk of bleeding and/or bruising.
Supportive Measures
Good supportive care is crucial to maintaining quality of life in patients with myeloma regardless of the definitive treatment they are receiving.
Kidney function
The causes of kidney damage in myeloma are multiple. The abnormal paraproteins may be deposited in the kidney and block tubules in the kidney. Dehydration and high blood calcium or urea levels can contribute to kidney damage as can severe infections. All patients with myeloma must maintain a high fluid intake to prevent dehydration. The fluid intake should be at least 3 litres (5 to 6 pints) a day, more in hot weather.
Some drugs may damage the kidney, for example non-steroidal anti-inflammatory drugs (NSAID) such as aspirin and ibuprofen and also some antibiotics. It is very important that all doctors treating a patient with myeloma are aware of the need to avoid drugs which may damage the kidneys. If a patient or carer is buying over-the-counter pain treatments they must check with the pharmacist that these do not contain NSAIDs. Paracetamol and codeine based over-the-counter painkillers should be suitable but all patients should check with their specialist what, if any pain-killer, they would recommend. Many flu and cold remedies contain aspirin so caution is again necessary.
It may be advisable to obtain a MedicAlert bracelet . This is a small bracelet (also available as a necklace) which gives medical staff information on problems which may affect emergency medical treatment. It also carries a phone number which health professionals can ring to check on other relevant medical history.
Hypercalcaemia
High levels of calcium in the blood are seen in about a quarter of myeloma patients. This is chiefly a consequence of the increased bone destruction releasing calcium into the bloodstream. A high calcium level may cause nausea and vomiting. It also causes polyuria (frequent passing of excessive amounts of urine), constipation and a dry mouth. If the calcium level is very high there may be a need for a rapid reduction using intravenous saline, corticosteroid drugs and drugs called bisphosphonates. Bisphosphonates are also used in routine treatment of myeloma and are described in more detail later in the booklet.
Bone disease and pain management
A wide range of analgesic drugs are suitable for the control of pain in patients with myeloma. Caution is required in the use of non prescribed drugs by myeloma patients. This is described in the section on kidney function.
A relatively new class of drugs called bisphosphonates have been shown to help control bone disease in myeloma. As soon as patients require active treatment they should begin long-term treatment with bisphosphonates.
Orthopaedic surgery may be required to prevent or to repair pathological fractures in the long bones of the arms or legs. Radiotherapy may be given to treat severe local pain. If surgery is required then radiotherapy will be delayed to allow the surgical wounds to heal fully. In order to mimimise bone damage, patients should endeavour to remain mobile. Physiotherapy and the use of aids such as spine supports may assist with this.
Hyperviscosity
Hyperviscosity is a condition which occurs when the fluid portion of the blood (plasma) contains high amounts of paraprotein. This thickens the blood and makes it less free flowing (viscous). This may lead to circulatory problems. If there are signs or symptoms of hyperviscosity such as shortness of breath, confusion, headaches and visual disturbances, the specialist may recommend urgent treatment to lower the paraprotein levels. Treatment may include plasma exchange, which is a procedure involving the separation and removal of the plasma from the blood. The red blood cells, white blood cells and platelets are returned to the patient along with replacement fluid or new plasma. If patients with hyperviscosity require transfusions of red blood cells, this may cause further thickening of the blood leading to a stroke. To avoid this a volume of blood is removed equal to the volume of the transfusion. For example, if a patient receives a litre of packed red cells they would have a litre of blood removed. This is known as an exchange transfusion. When paraprotein levels are very high prompt chemotherapy with rapidly acting drugs or combinations of drugs is of value.
Spinal Cord Compression
Spinal cord compression is a serious complication which may arise in patients who have myeloma. Rarely, it may be present at the time of diagnosis but more frequently it develops during the course of the illness.
Spinal cord compression is an emergency and patients with the following signs or symptoms should contact their doctor or the hospital urgently:
| Pain in the back or radiating from the back. Pain can be exacerbated by coughing or movement |
| Loss of sensation in the lower part of the body |
| Inability to pass urine |
| Bowel and bladder dysfunction, incontinence |
Any patient who is thought to have spinal cord compression will be admitted to hospital immediately. An MRI scan will allow doctors to determine the site and extent of the myeloma mass. If MRI scanning is not available, or is not suitable for a given patient, then CAT scans may be used although these are less informative. It is normal to immediately commence treatment with dexamethasone in order to minimise the risk of irreversible damage to nervous tissue. The treatment of choice for spinal cord compression is local radiotherapy or combination chemotherapy. Surgery is generally indicated only if there is spinal instability as a result of bone loss.
Infections
Infection is a serious and potentially life-threatening complication of myeloma, especially when patients are on chemotherapy. All patients should have 24-hour access to specialist advice either directly or through their primary care team. Infections of the upper respiratory tract (the nose and throat) are relatively easy to treat but can easily give rise to pneumonia. It is very important that myeloma patients seek prompt medical advice if they develop any type of infection. If patients develop severe generalised infections they will need to be admitted to hospital to receive intravenous antibiotic therapy.
Annual flu vaccination should be given by the GP surgery and patients will usually be contacted and asked to arrange an appointment. Times when flu vaccination is recommended are normally publicised on TV and in the newspapers. Patients should contact their doctor if they are not called in to receive vaccination.
Anaemia
Over two-thirds of myeloma patients have anaemia at the time of diagnosis. The anaemia is not usually severe unless there are other contributing factors such as blood loss or dietary deficiencies. Mild anaemia does not usually require treatment. If the anaemia is severe enough to limit the patient’s daily activities then blood transfusions may be given. There is a need for particular caution in transfusing patients who have signs or symptoms of hyperviscosity (see above).
Anaemia usually improves on effective treatment of the underlying myeloma. It may reoccur at the time of relapse or progression of the disease or as a feature of late stage disease. If anaemia does not resolve in a patient who is responding to chemotherapy, it may be a consequence of poor kidney function. The kidneys make a substance called erythropoietin (EPO) which stimulates the bone marrow to make red blood cells. For this reason, erythropoietin infusions may improve the situation in this group. Occasionally patients with normal kidney function have persistent anaemia and erythropoietin may also be of value.
Psychological Problems
Patients with myeloma may be depressed or anxious. Such problems should be actively managed with support from a psychiatric or clinical psychology team.
TREATMENT OF PRIMARY DISEASE
There are two major options for the definitive treatment of myeloma.
1. Chemotherapy aimed at achieving a stable response (plateau) but without any attempt to eradicate the disease. This may be by the use of :
| Single drugs – usually melphalan or cyclophosphamide, each of which may be given with or without prednisolone |
| Combination chemotherapy with relatively mild drugs |
2. Alternatively, in younger and/or fitter patients it may be planned from the outset to give more intensive chemotherapy, normally followed by a bone marrow or stem cell transplant. In myeloma the majority of transplants are carried out using the patient’s own stem cells. This is termed an autologous transplant. If this is being considered it is important to avoid the use of chemotherapy drugs which may damage stem cells. Patients who are to receive a transplant typically receive initial treatment with:
| combination therapy of a type unlikely to damage stem cells |
| High dose dexamethasonE |
This is usually followed by high dose chemotherapy and a stem cell transplant (SCT).
Melphalan (with or without prednisolone)
This is usually given by mouth over four to seven days at approximately monthly intervals for up to nine months. About half of all myeloma patients will have an improvement in their condition (a response) to melphalan.
Complete responses are rare. Usually the effect of the drug is gradual and it may take months to achieve maximal response. Most patients whose condition responds to melphalan will achieve a stable state (plateau) lasting about 18 months to two years. Plateau is characterised mainly by a stable paraprotein level but also a stable blood count and clinical features. The duration of plateau phase does not appear to be increased by continuing to receive chemotherapy so most patients will stop drug treatment once they have achieved plateau.
Some centres use melphalan alone and others use it in combination with prednisolone (this is often abbreviated MP or M&P). Prednisolone can be given by injection or taken orally. This drug should be avoided if an autologous stem cell transplant is planned because it damages stem cells. Melphalan, with or without prednisolone is usually well tolerated. There may be mild nausea but hair loss is rare.
Cyclophosphamide (with or without prednisolone)
Cyclophosphamide is used in a similar way to melphalan with similar benefits but is less toxic to the bone marrow. It can be used in patients whose neutrophil or platelet counts are too low for melphalan to be given. It can be given orally or intravenously on a weekly schedule. The side effects are similar to those seen for melphalan alone or with prednisolone.
Alkylating agent based combination chemotherapy regimens
Melphalan and cyclophosphamide both belong to a group of drugs called alkylating agents. A number of combinations have been devised which include melphalan and cyclophosphamide plus two or more of the following drugs; Vincristine, Adriamycin, Prednisolone and BCNU (Carmustine). This is a combination called ABCM. Combination therapy is more complicated than single drug treatment drug treatment as it usually requires intravenous therapy but may give slightly better outcomes.
VAD and related regimens
When a patient is being considered for treatment with an autologous stem cell transplant it is very important to select drug combinations which are not likely to harm the stem cells. One of the most widely used of these is called VAD = Vincristine, doxorubicin (Adriamycin) and high dose Dexamethasone (a steroid). This is given as a four day continuous infusion. A high proportion of patients will respond to VAD and 10-25% achieve complete remission. VAD is very suitable for patients with hyperviscosity for whom a rapid response is needed to prevent organ damage. There are a number of other, similar regimens which some doctors prefer to use rather than VAD.
As well as being the treatment of choice for patients who are to undergo autologous stem cell transplants it is also suitable for patients with kidney damage as the drugs are not harmful to the kidney and no dose reduction is required. The primary disadvantages are the need to put a central venous line in place and the high incidence of steroid-related side effects (these include increased risk of infection, rise in blood pressure, peptic ulcers, diabetes mellitus, osteoporosis).
VAMP and C-VAMP –these are modifications of the VAD regimen in which high dose dexamethasone is replaced with intravenous Methyl-Prednisolone in an attempt to reduce the level of steroid-related toxicity. C-VAMP also includes weekly intravenous cyclophosphamide.
Oral Idarubicin with Dexamethasone (Z-Dex) – VAD has to be given intravenously. In an attempt to avoid this regimens have been developed which use only oral drugs. In this regimen idarubicin is given by mouth for four days per cycle along with high dose dexamethasone (HDD). There are no data on long-term outcomes for this combination but stem cell harvesting does not appear to be compromised. The addition of cyclophosphamide to this regimen makes it very similar to the widely used C-VAMP regimen.
High Dose Dexamethasone
Studies suggest that dexamethasone may be responsible for most of the benefit of the VAD regimen and some specialists prefer to use high doses of dexamethasone without other drugs. Dexamethasone alone can achieve responses in over 40% of newly diagnosed patients. The major advantages include simplicity, absence of bone marrow toxicity, safety in patients with renal failure and a rapid response. A widely used schedule is dexamethasone daily for four days every two weeks until a response is achieved and then a reduction to once a month.
High Dose Therapy followed by Autologous Stem Cell Transplant
High dose therapy usually comprises large doses of melphalan alone or with total body irradiation. This gives very effective treatment against the myeloma but will destroy the patient’s bone marrow. For this reason high dose therapy must be followed by a stem cell transplant (SCT) to repopulate the bone marrow and restore blood cell production. This is usually an autologous transplant using the patient’s stem cells which have been harvested and stored prior to high dose therapy (HDT). This approach may extend survival but is not considered curative as over 90% of all patients who receive this treatment will eventually relapse. There is a need for more trial data to determine the exact role of this approach in the treatment of myeloma.
Attempts have been made to reduce the relapse rate by sorting and selecting marrow cells in the laboratory in order to reduce the number of myeloma cells and concentrate the normal stem cells. There is currently no evidence to show that this reduces the risk of relapse. Some centres have carried out procedures in which two or more autologous transplants are carried out one after the other. These are known as tandem or double transplants. Again there is no clear evidence that this improves outcomes.
Allogeneic Stem Transplants
The role of allogeneic (donor) transplantation using a tissue-matched sibling as a donor in the treatment of myeloma is controversial, chiefly because both the transplant related mortality and the relapse rate are high. It does, however, offer a chance of a complete cure. Patients who are transplanted in first remission have an estimated 60% chance of entering complete remission and one-third of these patients remain free of disease with a very low risk of relapse. For younger patients, particularly females, the potential benefits may outweigh the risks of the procedure. Patients who have relapsed after an allogeneic transplant may benefit from a procedure called donor lymphocyte infusion . Transplants from donors other than siblings have a particularly high mortally rate and are not currently recommended. Transplants employing reduced conditioning, so-called mini-transplants, are currently being studied in clinical trials. These use less intensive pre-transplant treatment not intended to completely destroy the host’s marrow before transplanting but merely to suppress the immune system sufficiently to prevent graft rejection.
Interferons
Interferons are a family of proteins produced by white blood cells which inhibit the division and growth of virus-infected and cancer cells. The major role for interferons in the treatment of myeloma appears to be as maintenance therapy given during the plateau phase. In this context they prolong plateau phase and overall survival, although the benefit is not very large. There is no evidence that use of interferon, alone or in combination, is beneficial as an initial treatment for myeloma.
Thalidomide
This drug is currently used in clinical trials to address its possible role in the treatment of myeloma. It acts to prevent formation of new blood vessels and has shown promise against myeloma in preliminary trials. Thalidomide alone has been shown to produce a response in 30% of patients with refractory or relapsed myeloma. Many patients, however, find the side effects of thalidomide unacceptable and similar drugs are being developed which carry less severe side effects.
Bisphosphonates
Among the main causes of disability and death in myeloma are bone pain, hypercalcaemia and pathological fractures. These are caused by the interaction between myeloma cells and cells called osteoclasts and osteoblasts which are continually remodeling bone. In myeloma the balance between osteoclast and osteoblast activity is disturbed and this leads to the destruction of bone. A class of drugs called bisphosphonates can bind to the surface of bone and markedly reduce skeletal damage and thus the need for surgery and radiotherapy.
Clinical studies have clearly shown that the maximum benefit is derived when bisphosphonates are given before there is evidence of bone damage. The main bisphosphonates currently used in myeloma therapy are clodronate (which is given daily by mouth) and pamidronate (which is given by monthly infusions into a vein) . A new form of the drug called zolendronate may be even more effective but it is still in clinical trials and it is too early to assess its impact. The major benefit claimed for zolendronate is that it is more potent so a smaller dose is needed and this can be infused more quickly.
TREATMENT OF REFRACTORY OR RELAPSED DISEASE
Refractory Disease}
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