Paraproteinaemia
- Refers to the presence of a monoclonal Ig band in the serum
- M-band reflects the synthesis of Ig from a single clone of cells
- Diseases associated with M proteins
- Malignant
- Multiple myeloma
- Waldenstrom’s macroglobulinaemia
- Malignant lymphoma
- CLL
- Multiple myeloma
- Benign or stable disease
- Benign monoclonal gammopathy
- Solitary plasmacytoma
- AIDS
- Benign monoclonal gammopathy
- Malignant
Multiple Myeloma
- Characterised by plasma cell accumulation in the bone marrow, presence of monoclonal protein in the urine and serum and related tissue damage
- 90% of cases occur over the age of 40
- More common in patients of Afro-Caribbean origin
- Genetic changes are complex but dysregulation or increased expression of Cyclin D is an early unifying event
- Immunophenotype of the malignant plasma cell is high expression of CD38 and CD138 and low expression of CD45
- IL-6 is an important growth factor
Diagnosis
- Depends on 3 principle findings;
- Monoclonal proteins in the serum and or urine
- Increased plasma cells in the BM
- Related organ or tissue impairment such as bone disease, renal impairment, anaemia, hypercalcaemia, hyperviscosity, amyloidosis or recurrent infection
- Monoclonal proteins in the serum and or urine
Clinical features
- Bone pain
- Features of anaemia
- Recurrent infections
- Features of renal failure and/or hypercalcaemia – polydipsia, polyuria, constipation, confusion, nausea, anorexia
- Abnormal bleeding tendancy – myeloma protein may interfere with platelet function and coagulation factors
- Amyloidosis – macroglossia, diarrhoea, carpal tunnel syndrome
- Hyperviscosity syndrome – purpura, haemorrhage, visual failure, CNS symptoms, neuropathies and heart failure
Lab findings
- Presence of a paraprotein by immunoglobulin electrophoresis, IgG in 60% of cases, IgA in 10%, light chain only in the rest
- Normal Ig levels are reduced. This is called immune paresis
- The urine contains free light chains called Bence Jones proteins in 2/3 of cases
- Normocytic normochromic anaemia showing Rouleaux formation
- Neutropenia and thrombocytopenia occur in advanced disease
- High CRP and ESR
- Increased plasma cells in the bone marrow
- Serum calcium is raised in 45% of patients
- Alk phos is generally normal expect in pathological fractures
- Serum creatine can be raised due to renal failure
- In advanced disease there can be a low serum albumin
- Serum β2-microglobulin is often raised and can be used as a marker of prognosis
Radiological findings
- Bones lesions – osteolytic areas without evidence of surrounding osteoblastic reaction or sclerosis or osteoporosis
- Pathological fracture and vertebral collapse are common
- The osteolytic lesions are caused by osteoclast activity resulting from high levels of serum RANKL produced by plasma cells and the BM stroma
Treatment
- May be specific or supportive
Specific treatment
- Generally the disease is incurable apart from the very few young patients that can be cured by an allogenic stem cell transplant
- For the others intensive therapy is used for patients aged less than 65-70 and non-intensive therapy used for older patients
Intensive therapy
- Involves the combination of several courses of chemotherapy to reduce the tumour followed by stem cell collection and autologous stem cell transplant after high dose chemotherapy
- Peripheral stem cells are collected after treatment with G-CSF
- High dose melphalan with or without radiotherapy is the typical conditioning regime for autologous SCT
Non-intensive therapy
- Month courses of the oral alkylating agent melphalan sometimes in combination with prednisolone are usually effective at reducing the cancer burden
- Thalidomide may also be used as can cyclophosphamide
- Generally there is a ‘plateau phase’ where levels of paraprotein stop falling and the patient remains stable at this stage for a time
- The disease can escape from the phase and at this point it is more difficult to treat
- Radiotherapy can be used to treat the symptoms of bone pain, it can be used for bone pain and spinal compression
Prognosis
- There is an international prognostic index based on levels of β2-microglobulin and albumin levels
- Patients with a β2-microglobulin level greater than 5.5mg/Land albumin <35g/L have a poor survival
- Overall the median survival with non-intensive chemo is 3-4 years this is improved by about 1 year with an autologous stem cell transplant
Waldenström’s Macroglobulinaemia
- Uncommon. Mostly seen in men over 50 in which there is a lymphoplasmacytoid lymphoma which produces a monoclonal IgM paraprotein
- The cell of origin appears to be an IgM memory B cell
Clinical features
- Fatigue and weight loss
- Hyperviscosity syndrome – IgM paraprotein increases viscosity more than IgG or IgA
- There may be features of cyroprecipitation e.g. Raynaud’s
- Anaemia
- Bleeding tendency
- Lymphadenopathy
- Hepatosplenomegaly
Diagnosis
- Monoclonal serum IgM
- BM or lymph node infiltration with lymphoplasmacytoid cells
- Raised ESR
- Peripheral blood lymphocytosis
Monoclonal gammopathy of undetermined significance (MGUS)
- Increasingly common with age
- 1% aged over 50
- 3% aged over 70
- 1% aged over 50
- There is no bone lesions, no Bence-Jones proteinuria, the proportion of plasma cells in the BM is normal or only slightly raised
- The concentration of serum Ig is usually less than 20g/L and other serum Ig are not depressed
- Serum light chains are increased in 1/3 of patients, the greater the increase the greater the risk of malignant transformation
- No treatment is needed but patients should be routinely followed up as 1% develop overt lymphoma or myeloma each year