Myeloma Bone Marrow Cancer Arising From Plasma Cells Biology
Plasma CellThe myelomaUK charity describes myeloma as a bone marrow cancer arising from plasma cells which have formed from b-lymphocytes. Plasma cells are found in the bone marrow/myelium. Myeloma is a type of haematology malignancy, meaning the plasma cells produced in the bone marrow or peripheral lymphoid tissue are malignant. (Benacerraf & Unanue 1979) Depending on the age of the plasma cells sometimes the malignancy of cells can be altered or destroyed if they do not show signs of maturity. B-cells secrete antibodies which fight infection. As suggested by The Leukemia and Lymphoma Society they say that 90 percent of patients have cancer lodged in different locations.
Diagram 1: with reference to website http://www.kumed.com/healthwise
Diagram 1 shows the normal transition of stem cell maturing and differentiating into a plasma cell.
Plasma cells form part of your immune system. Normal plasma cells produce antibodies (immunoglobulin) to help fight infection. In myeloma, the abnormal plasma cells release only one type of antibody known as paraprotein M which has no useful function. It is through the measurement of this paraprotein M or M band that myeloma is diagnosed and monitored.
According to (netdoctor.co.uk) myeloma is the most common form of cancer of blood cells, accounting for 15 per cent of all blood cancers. There are about 2,500 new cases per annum in the UK, giving rise to 10,000 to 15,000 patients with the condition at any one time. The overall incidence is rising and is higher in Afro-Caribbean's and is slightly more common in males. The median age at diagnosis 71 years
Cancer derives from one single cell and divides into a mass of mutated cells known as a tumour. This is partially due to uncontrolled cell division with aid of growth-factors.
Oncogenes are converted to a mutated form called proto-oncogenes, this triggers uncontrolled cell division by constantly activating a receptor protein producing high amounts of a growth factor. Another reason for the high amount of mutated cells is due to the tumour suppressor gene. These are proteins which stop the cell cycle and destroy mutated cells. Gene mutations will not code for this protein. Telomeres are sections of DNA at the end of a chromosome which do not code for a gene. Over time these sections shorten with every cell division leading to cell death eventually. However in cancer cells they do not shorten, thus are immortal. (Toole 2004)
Red blood cell
Image based upon case study workshop PowerPoint.
2.a Shows blood screening in a normal patient 2.b. Shows blood screening in a myeloma patient
Russell bodies are immunoglobulin-containing vesicles. Often found in cells secreting high levels of immunoglobulin as seen with malignant plasma cells (plasmacytoma).
Blood screening from a myeloma patient often show Rouleaux. This is the stacking of red blood cells which stick together. Rouleaux formation is retarded by albumin proteins and is also increased with anemia. Fewer red blood cells are shown in diagram 2.b indicating anemia.
High levels of plasma cells also indicate malignant cells. Diagram 2.b shows a significant increase in plasma cells compared to diagram 2.a indicating uncontrolled plasma cell growth.
Other features of plasmacytomas not shown on the image include, large Golgi bodies and presence of nuclear-pseudo-inclusions, which indicates the malignancy of cells. The plasma cells may often have distorted nuclei also. (www.ncbi.nlm.nih.gov)
They also have abnormal chromosomes, alterations affecting chromosomes 11, 13 and 14 in particular. Research suggests this may cause the changes to oncogenes. (netdoctor.co.uk)
Specific case study:
A 70 year old female visits her GP complaining of lower back pain. She is lethargic and pale and has also been suffering from recurrent chest infections and weight loss.
The suspected disease is myeloma. This diagnosis is given due to many factors know about myelomas symptoms and that myeloma is most common in the older demographic. The re-occurring infections indicate a weakened immune system, and pale and lethargic appearance indicates anaemia. The lower back pain is possible due to lytic lesions which may have formed because of myeloma cell deposits in the bones and the weight loss can be explained because of appetite suppression.
Testing for myeloma:
There are a variety of tests which can indicate the malignancy of plasma cells and this includes radiological examination, full blood count and testing in the bone marrow.
Radiological examination such as X-rays and PET scans.
Testing for bone damage. X-rays is needed to show osteoporosis or osteopenia caused by myeloma. Lytic lesions (rounded, punched-out areas of bone) (www.clevelandclinicmeded.com), and any fracture or collapse of bone (www.myeloma.org.uk). With a PET scan (Positron emission tomography) Patients are injected with 2-fluoro-2-deoxy-glucose which shows Malignant tumour cells show up brighter in the picture because they are more active and take up more glucose than normal cells do. (www.cancer.gov)
Erythrocyte Sedimentation Rate;
Erythrocyte sedimentation rate (ESR) represents the distance that red blood cells settle in a tube of blood in one hour. Rouleaux formation increases the ESR due to or abnormal proteins in the blood that decrease the normal distance that red cells maintain between each other
The flat surface of the discoid RBC's give them a large surface area to make contact and stick to each other; thus, forming a rouleaux.
In MM the ESR is often >100 mm/hr, normal values are seen as 20-30mm/hr in females. (www.nlm.nih.gov/medlineplu)
An increased ESR rate may be due to inflammation as found with diseases such as rheumtoid arthritus, Gout, tuberculosis and anaemia, which are associated symptoms and side-effects which coincide with myeloma disease.
Performed during the investigation and monitoring of myeloma, and other plasmacytomic disease, and will automatically be performed when immunoglobulin levels are high. The blood serum is exposed to an electric current. The proteins in the serum move on the paper to form bands that show the proportion of each protein fraction (www.nlm.nih.gov/medlineplus). Serum protein electrophoresis can detect paraproteins. This shows the presence of the monoclonal myeloma protein (paraprotein)The amount of the abnormal myeloma protein as well as the normal albumin protein level are measured Shows the type of myeloma protein (i.e. heavy chain [G, A, D or E] (www.myeloma.org.uk) In some myeloma cases, the tumour secretes only Ig light chains which are rapidly cleared from plasma. They are however readily detectable in urine in which they are known as Bence Jones Protein, thus a urine test must me performed. However Paraproteins are not always associated with malignant disease. Since Benign paraproteinemias are found in around 3% of people over the age of 70, which is the common age demographic for myeloma and thus can be misleading. Routine checks to ensure malignancy doesn't form occur. High protein levels indicate multiple myeloma as well as other inflammatory disease and chronic liver disease. (www.nlm.nih.gov)
Urea and electrolytes
Assessment of renal function Tests the levels of urea, creatinine, sodium and potassium. In myeloma patients with reduced renal function is present in around on third of cases. This is due mainly to deposition of abnormal immunoglobulin fragments deposited into the renal tubules.
The myeloma cells in the bones can sometimes start to break down some of the bone cells, which release calcium into the blood. This condition is called hypercalcaemia (Macmillan.org.uk). Raised calcium levels are seen in around 45% of myeloma patients.
A small protein normally found on the surface of many cells, including lymphocytes, and in small amounts in the blood and urine
High cell turnover in myeloma results in raised serum concentrations of Î’2-microglobulin and renal dysfunction will result in serum retention contributing to higher levels.
Full blood count test and blood screening.
This is the investigation of haematological disorders and monitoring treatments. Measures red blood cells, white blood cells, platelets and associated factors
Full blood count indicates levels of red blood cells, white blood cells, platelets and haemoglobin levels. Low levels of haemoglobin and red blood cells indicate anaemia. Reduced numbers of white blood cells indicate an increase in risk to infection. Low platelet count shows the susceptibility to bruising and bleeding. A bone marrow biopsy may also be performed to test the levels of abnormal plasma cells (www.myeloma.org.uk)
More recently, another possible test is to test for CD34 on cell membranes. Since plasma cells from multiple myeloma (MM) patients do not express the stem cell marker CD34, no presence indicates malignant cells present.
Laboratory test results:
Normal results based on values given for a female aged over 50 years.
Top of Form
Bottom of Form
11.5 - 16
0.24 - 0.5
Values taken from /www.myeloma.org.uk and www.nlm.nih.gov/medlineplus
From these results myeloma is diagnosed. The results show the patient is anaemic due to the low levels of haemoglobin. The calcium levels are higher than normal indicating the breakdown of bone due to lytic lesions. The ESR is very high, indicating inflammation and roleaux in RBCs. Levels of urate are high indicating inflammation. The Protein levels are significantly higher indicating poor kidney function.
Results from the Blood film are as followed.
Results showed a normochromic, normocytic anaemia, which means there is a decrease in the level of haemoglobin levels and red blood cells count, but RBCs are of a normal size. Results also show rouleux formation and increased background staining which indicates plasmacytosis (an increase in plasma cells concentration in the blood). Within the Bone marrow if plasma cell levels are higher than 10% this indicates an excessive and uncontrollable amount.
Results from the radiological examination showed regions of lytic lesions
Serum electrophoresis showed the presence of a paraprotein which was shown to be IgG. Bence Jones protein was detected in the urine and identified as Îº in type, since this IgG is a light chain Immunoglobulin this would have only been detectable in urine sample. The M-protein produced by the malignant plasma cells is IgG occurs in about 55% which is free monoclonal Îº light chains in the urine. In 15 to 20% of patients, plasma cells secrete only Bence Jones protein. (www.merckmanuals.com)
Future treatment and outcome:
Myeloma is rarely curable, but it is treatable. During treatment blood and urine samples will be taken regularly every few months for monitoring. (www.macmillan.org.uk). There are multiple treatments which are given, to reduce or eliminate the tumours, and to relieve the side effects of myeloma.
Chemotherapy|, usually combined with steroids|, is the main treatment for myeloma. Chemotherapy is also used with other drugs including bisphosphonates| and thalidomide|.
Some people benefit from high-dose chemotherapy. For this treatment, some of the blood stem-cells are removed before the high-dose chemotherapy. This is known as high dose treatment with stem cell support|. (Macmillan.org.uk) Surgery can also be performed to remove a targeted area of myeloma, this however is very rare. Side effects to chemotherapy drugs include sickness, higher susceptibility to infection, bruising/bleeding and Anaemia. (www.myeloma.org.uk)
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. (www. macmillan.org.uk)
After chemotherapy, steroids may be used to help keep the myeloma in remission what is known as maintenance treatment. Side effects often include increased appetite, irritability and indigestion to name some. Long-term effects include high blood pressure and increase risk of infection. (www.macmillan.org.uk). 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. (Macmillan.org.uk)
Treatment of myeloma which has come back after initial treatment. Thalidomide has recently been found to be effective in controlling myeloma that has come back after chemotherapy. Other drugs that may be used to treat people whose myeloma has come back after initial treatment, are bortezomib and lenalidomide.
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. Thalidomide tablets are taken daily. Side effects include blood clotting and can lead to deep vein thrombosis. Thalidomide cannot be given to pregnant women as there is a high risk of birth defects.
Drugs which do not eliminate cancer but are effective in alleviating side-effects caused by myeloma.
Bisphosphonates are commonly used to reduce bone damage caused by the myeloma. They are lower raised calcium levels in the blood. They can be given alongside chemotherapy or after chemotherapy. 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.
Other treatments may be needed, such as: Painkillers to treat bone pain blood transfusions if you are anaemic. Erythropoietin is also an effective treatment for anaemia in multiple myeloma (www.clevelandclinicmeded.com) and kidney dialysis for kidney failure, since the myeloma proteins may prevent your kidneys from filtering waste products from your blood properly. (www.macmillan.org.uk) Myeloma makes the level of paraprotein M in the blood very high, the blood can become thicker than normal. This can cause symptoms such as headaches, dizziness, sight problems and abnormal bleeding. To help correct this problem it is sometimes possible to have plasma exchange| (plasmapheresis), a procedure which removes the excess paraproteins from the blood. (www.macmillan.org.uk)
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