H E M A T O L O G Y
C L I N I C
Multiple myeloma Introduction Myeloma is a cancer of plasma cells. Plasma cells are a specialized type of white blood cell, derived from lymphocytes, which make antibodies. In myeloma, these plasma cells exceed 10% of all marrow cells and they make an abnormal antibody (a ‘paraprotein’) which serves as a marker of the disease. Myeloma is one of the commonest types of blood cancer (4–5000 new cases each year in the UK, 1% of all malignancies, 15% of all blood cancers) and is twice as common in black people and more common in males than females. The median age at diagnosis is 70 years. Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition characterized by the presence of a low level of ‘paraprotein’ which precedes myeloma; but only approximately 5–10% of subjects with MGUS go on to develop myeloma, and then only after many years.
headaches or confusion. Patients with a light-chain paraprotein – a small molecule which can be filtered into the urine – are at an increased risk of renal failure. Many patients with myeloma have no symptoms but are diagnosed because of the discovery of a paraprotein; many of these will have evolved from MGUS. Treatment is only indicated if patients have developed one of calcium elevation, renal failure, anaemia, or bone (‘CRAB’) disease. Symptoms of nerve, heart, or kidney damage, particularly if associated with an enlarged tongue and skin infiltration, indicate amyloidosis and occur in 5% of patients. Important physical signs are anaemia, tenderness over bones which are infiltrated, or tenderness over the spine. Infection can occur anywhere but skin infections are particularly common. Patients with myeloma who have suffered complications – e.g. skeletal disease, renal failure – will have corresponding physical signs.
Cause Like all cancers, the cause is multifactorial and poorly defined. Exposure to organic chemicals, toxins, and ionizing radiation may predispose. Genetic predisposition is observed but the condition is not usually inherited. Acquired mutations in growth promoting or suppressing genes are often detected, and acquired genetic changes influence response to treatment and prognosis.
Symptoms and signs Non-specific symptoms of fatigue, loss of appetite, and weight loss are very common. Bone pain, back pain, and pathological fracture may occur; hypercalcaemia can cause abdominal pain, thirst, excessive urine loss, and kidney failure. Kidney damage is also caused directly by paraprotein deposition (called ‘cast’ nephropathy). Infection results from the generalized reduction in normal immunoglobulins and defective function of white blood cells. Declining bone marrow function causes symptoms such as tiredness, due to anaemia, infection due to reduced white cell production, and bruising/bleeding from reduced platelet production. Symptoms may relate to the abnormal protein. An IgM paraprotein is a large molecule (comprising five ordinary immunoglobulin molecules) and could cause increased blood viscosity manifesting as
58
© W. S. Maney & Son Ltd 2015 DOI 10.1179/1024533214Z.000000000333
Tests A full blood count is used to demonstrate anaemia or a reduction in any of the formed elements of the blood – red cells, white cells, and platelets. Basic biochemistry should include renal function, calcium level, and liver function tests. The level of beta-2 microglobulin gives important prognostic information (8 is guarded). Paraprotein detection and quantitation in serum and urine with a specific request for serum-free light-chain measurement is necessary; 1% of myeloma patients will have no paraprotein (‘non-secretory myeloma’). Bone marrow examination will allow plasma cell quantitation, confirmation of the diagnosis and further analysis should include cytogenetics and fluorescent in situ hybridisation (FISH) to accurately characterize additional acquired genetic aberrations. Imaging should include X-ray skeletal survey as a minimum. Skeletal MRI scan is more sensitive at detecting bone disease, CT scan will also demonstrate lesions (but involves a higher dose of radiation) and FDG PET scans are increasingly used to detect active disease.
Treatment Patients with symptomatic myeloma – i.e. CRAB – need treatment; others warrant close observation.
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delay wound healing. Other commonly used drugs include bendamustine, pomalidomide, idarubicin, adriamycin, and BCNU. Supportive care includes surgery for fractures, radiation therapy for bone lesions, infusions of bisphosphonates (e.g. zoledronic acid) with vitamin D and calcium supplements to maintain bone health, and early treatment of infection. Renal failure can be delayed by good management of the myeloma, bone disease, fluid management, and blood pressure control; and if it occurs, dialysis is needed. Pain control is important.
Outlook/prognosis Figure 1 Bone marrow aspirate from a patient with myeloma showing a large, multi-nucleated abnormal plasma cell
Patients under 70 years of age and with good performance status should receive initial combination chemotherapy (CCT) followed by an autologous haemopoietic stem cell transplant (HSCT). Choice of initial CCT includes bortezomib (a proteasome inhibitor, a totally new class of chemotherapy), steroids, and thalidomide plus/minus cyclophosphamide. Patients typically need 4–6 months of treatment and then auto HSCT with melphalan conditioning. Older patients or those with a lesser performance status receive drugs which prejudice collection of stem cells, e.g. melphalan, and this is given in combination with bortezomib and steroid or thalidomide. Lenalidomide is a thalidomide derivative typically used at first or second relapse; but trials show good activity as first-line treatment and as maintenance treatment after initial CCT or HSCT. Side effects include suppression of blood counts, nerve damage (bortezomib, thalidomide), and an increased risk of blood clots. Steroids can increase risk of infection, weight gain, mood change, osteoporosis, peptic ulceration, and they
This has improved dramatically over the last 10 years. More than 30% of myeloma sufferers live more than 10 years and 70% are alive 5 years after HSCT. Patients relapse but then respond to new treatments; new drugs include a new proteasome inhibitor (carfilzomib) which has already been licensed in the USA, and monoclonal antibody treatments (e.g. daratumumab) are showing promise in trial settings. The diagnosis of myeloma is frequently delayed; renewed effort is required to raise awareness of myeloma among general practitioners.
Additional resources Myeloma UK (http://myeloma.org.uk) offers support for patients and a vision for a cure from research and clinical trials through its own network. Dr Georgios Lyratzopoulos MD, Richard D Neal PhD, et al., Variation in number of general practitioner consultations before hospital referral for cancer: findings from the 2010 National Cancer Patient Experience Survey in England. Lancet Oncol. 2012;13(4):353–65.
Atul Mehta Department of Haematology, Royal Free Hospital, London, UK Correspondence to: Atul Mehta, Department of Haematology, Royal Free Hospital, London NW3 2QG, UK. Email: [email protected]
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NO.
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C L I N I C
Multiple myeloma Introduction Myeloma is a cancer of plasma cells. Plasma cells are a specialized type of white blood cell, derived from lymphocytes, which make antibodies. In myeloma, these plasma cells exceed 10% of all marrow cells and they make an abnormal antibody (a ‘paraprotein’) which serves as a marker of the disease. Myeloma is one of the commonest types of blood cancer (4–5000 new cases each year in the UK, 1% of all malignancies, 15% of all blood cancers) and is twice as common in black people and more common in males than females. The median age at diagnosis is 70 years. Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition characterized by the presence of a low level of ‘paraprotein’ which precedes myeloma; but only approximately 5–10% of subjects with MGUS go on to develop myeloma, and then only after many years.
headaches or confusion. Patients with a light-chain paraprotein – a small molecule which can be filtered into the urine – are at an increased risk of renal failure. Many patients with myeloma have no symptoms but are diagnosed because of the discovery of a paraprotein; many of these will have evolved from MGUS. Treatment is only indicated if patients have developed one of calcium elevation, renal failure, anaemia, or bone (‘CRAB’) disease. Symptoms of nerve, heart, or kidney damage, particularly if associated with an enlarged tongue and skin infiltration, indicate amyloidosis and occur in 5% of patients. Important physical signs are anaemia, tenderness over bones which are infiltrated, or tenderness over the spine. Infection can occur anywhere but skin infections are particularly common. Patients with myeloma who have suffered complications – e.g. skeletal disease, renal failure – will have corresponding physical signs.
Cause Like all cancers, the cause is multifactorial and poorly defined. Exposure to organic chemicals, toxins, and ionizing radiation may predispose. Genetic predisposition is observed but the condition is not usually inherited. Acquired mutations in growth promoting or suppressing genes are often detected, and acquired genetic changes influence response to treatment and prognosis.
Symptoms and signs Non-specific symptoms of fatigue, loss of appetite, and weight loss are very common. Bone pain, back pain, and pathological fracture may occur; hypercalcaemia can cause abdominal pain, thirst, excessive urine loss, and kidney failure. Kidney damage is also caused directly by paraprotein deposition (called ‘cast’ nephropathy). Infection results from the generalized reduction in normal immunoglobulins and defective function of white blood cells. Declining bone marrow function causes symptoms such as tiredness, due to anaemia, infection due to reduced white cell production, and bruising/bleeding from reduced platelet production. Symptoms may relate to the abnormal protein. An IgM paraprotein is a large molecule (comprising five ordinary immunoglobulin molecules) and could cause increased blood viscosity manifesting as
58
© W. S. Maney & Son Ltd 2015 DOI 10.1179/1024533214Z.000000000333
Tests A full blood count is used to demonstrate anaemia or a reduction in any of the formed elements of the blood – red cells, white cells, and platelets. Basic biochemistry should include renal function, calcium level, and liver function tests. The level of beta-2 microglobulin gives important prognostic information (8 is guarded). Paraprotein detection and quantitation in serum and urine with a specific request for serum-free light-chain measurement is necessary; 1% of myeloma patients will have no paraprotein (‘non-secretory myeloma’). Bone marrow examination will allow plasma cell quantitation, confirmation of the diagnosis and further analysis should include cytogenetics and fluorescent in situ hybridisation (FISH) to accurately characterize additional acquired genetic aberrations. Imaging should include X-ray skeletal survey as a minimum. Skeletal MRI scan is more sensitive at detecting bone disease, CT scan will also demonstrate lesions (but involves a higher dose of radiation) and FDG PET scans are increasingly used to detect active disease.
Treatment Patients with symptomatic myeloma – i.e. CRAB – need treatment; others warrant close observation.
Hematology
2015
VOL.
20
NO.
1
H E M A T O L O G Y
C L I N I C
delay wound healing. Other commonly used drugs include bendamustine, pomalidomide, idarubicin, adriamycin, and BCNU. Supportive care includes surgery for fractures, radiation therapy for bone lesions, infusions of bisphosphonates (e.g. zoledronic acid) with vitamin D and calcium supplements to maintain bone health, and early treatment of infection. Renal failure can be delayed by good management of the myeloma, bone disease, fluid management, and blood pressure control; and if it occurs, dialysis is needed. Pain control is important.
Outlook/prognosis Figure 1 Bone marrow aspirate from a patient with myeloma showing a large, multi-nucleated abnormal plasma cell
Patients under 70 years of age and with good performance status should receive initial combination chemotherapy (CCT) followed by an autologous haemopoietic stem cell transplant (HSCT). Choice of initial CCT includes bortezomib (a proteasome inhibitor, a totally new class of chemotherapy), steroids, and thalidomide plus/minus cyclophosphamide. Patients typically need 4–6 months of treatment and then auto HSCT with melphalan conditioning. Older patients or those with a lesser performance status receive drugs which prejudice collection of stem cells, e.g. melphalan, and this is given in combination with bortezomib and steroid or thalidomide. Lenalidomide is a thalidomide derivative typically used at first or second relapse; but trials show good activity as first-line treatment and as maintenance treatment after initial CCT or HSCT. Side effects include suppression of blood counts, nerve damage (bortezomib, thalidomide), and an increased risk of blood clots. Steroids can increase risk of infection, weight gain, mood change, osteoporosis, peptic ulceration, and they
This has improved dramatically over the last 10 years. More than 30% of myeloma sufferers live more than 10 years and 70% are alive 5 years after HSCT. Patients relapse but then respond to new treatments; new drugs include a new proteasome inhibitor (carfilzomib) which has already been licensed in the USA, and monoclonal antibody treatments (e.g. daratumumab) are showing promise in trial settings. The diagnosis of myeloma is frequently delayed; renewed effort is required to raise awareness of myeloma among general practitioners.
Additional resources Myeloma UK (http://myeloma.org.uk) offers support for patients and a vision for a cure from research and clinical trials through its own network. Dr Georgios Lyratzopoulos MD, Richard D Neal PhD, et al., Variation in number of general practitioner consultations before hospital referral for cancer: findings from the 2010 National Cancer Patient Experience Survey in England. Lancet Oncol. 2012;13(4):353–65.
Atul Mehta Department of Haematology, Royal Free Hospital, London, UK Correspondence to: Atul Mehta, Department of Haematology, Royal Free Hospital, London NW3 2QG, UK. Email: [email protected]
Hematology
2015
VOL.
20
NO.
1
59
