MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE (MGUS)
In this condition (also known as benign monoclonal gammopathy or monoclonal gammopathy unclassified (MGu)), a paraprotein is present in the blood but with no other features of myeloma, Waldenstrom macroglobulin¬aemia (see below), lymphoma or related disease. It is a common condition associated with increasing age; a para¬protein can be found in 1% aged over 50 years increasing to 5% over 80 years.
I I
I, Clinical features and investigations
Patients are usually asymptomatic, and the paraprotein is found on blood testing for other reasons. The routine blood count and biochemistry are normal, the paraprotein is usually present in small amounts with no associated immune paresis, and there are no lytic bone lesions. The bone marrow may have increased plasma cells but these usually constitute less than 10% of nucleated cells.
Prognosis
After follow-up of 20 years, only one-quarter will progress to myeloma or a related disorder. There is no way of predicting progression in an individual patient and if investigations remain stable, annual monitoring is all that is required.
I I I
I WALDENSTROM MACROGLOBULINAEMIA
This is a low-grade lymphoplasmacytoid lymphoma associated with an IgM paraprotein causing clinical features of hyperviscosity syndrome. It is a rare tumour occurring in the elderly and affects a slight excess of males.
Patients classically present with features of hyper¬viscosity such as nosebleeds, bruising, confusion and visual disturbance. However, presentation may be with anaemia, systemic symptoms, splenomegaly or lymphadenopathy. Patients are found on investigation to have an IgM para¬protein associated with a raised plasma viscosity. The bone marrow has a characteristic appearance, with infiltration of lymphoid cells and prominent mast cells.
AEMiAS
Management
Severe hyperviscosity and anaemia may necessitate plasmapheresis to remove IgM and make blood transfusion , possible. Treatment with oral agents such as chlorambucil is effective but rather slow and fludarabine may be more active in this disease. The median survival is 5 years.
MULTIPLE MYELOMA
This is a malignant proliferation of plasma cells. Normal plasma cells are derived from B cells and produce immuno¬globulins which contain heavy and light chains. Normal immunoglobulins are polyclonal, which means that a variety of heavy chains are produced and each may be of kappa or lambda light chain type. In myeloma plasma cells produce immunoglobulin of a single heavy and light chain, a mono¬clonal protein commonly referred to as a paraprotein. In some cases only light chain is produced and this appears in the urine as Bence Jones proteinuria. The frequency of different paraprotein types in myeloma is shown in Box 24.57.
24.57 CLASSIFICATION OF MULTIPLE MYELOMA
Type of paraprotein Relative frequency (%)
IgG 55
IgA 21
Light chain only 22
Others (D, E, non-secretory) 2
Pathology
Although a small number of malignant plasma cells are present in the circulation, the majority are present in the bone marrow. The malignant plasma cells produce cytokines, which stimulate osteoclasts and result in net bone absorption. The resulting lytic lesions cause bone pain, fractures and hypercalcaemia. Marrow involvement can result in anaemia or pancytopenia. The aetiology of this condition is unknown.
Clinical features
The incidence of myeloma is 4/100000 new cases per annum, with a male:female ratio of 2:1. The median age of diagnosis is 60-70 years and the disease is more common in Afro-Caribbeans. The clinical features are demonstrated in Figure 24.33.
Investigations
The diagnosis of myeloma requires two of the following criteria:
• increased malignant plasma cells in the bone marrow • serum and/or urinary paraprotein
• skeletal lesions.
Bone marrow aspiration, plasma and urinary electro¬phoresis, and a skeletal survey are thus required. Other inves¬tigations are listed in Box 24.58, and their interpretation in Box 24.59.
I 24.5$ RATIONALE FOR INVESTIGATIONS IN
I MULTIPLE MYELOMA
Problem Investigations
Presence of lytic lesions, X-rays (skeletal survey)
bone fractures
Spinal cord compression MRI spine
Presence of urine or plasma Blood and urine protein
paraprotein Electrophoresis
Type of paraprotein Blood and urine
immunoelectrophoresis
Amount of paraprotein Quantification of paraprotein
Degree of immune paresis Plasma immunoglobulins
Presence of plasma cells in Bone marrow aspiration and
bone marrow Treohinz
Degree of bone marrow failure Full blood count
Renal function Urea and electrolytes, creatinine,
Vate
Presence of hypercalcaemia Blood calcium
i
Albumin
Degree of haemostasis Bleeding time
Coagulation screen
24.59 POINTS TO NOTE 1N THE DIAGNOSIS OF MYELOMA
• Plasma alkaline phosphatase and the bone scan are normal in the absence of fractures or bone repair
• Serum (3z-microglobulin estimations may provide a useful assessment of prognosis
• Normal immunoglobulin levels, i.e. absence of immune paresis, should cast doubt on the diagnosis
v Only about 5% of patients with an ESR persis:e-:r acovs 100 mm/hr have myeloma
Management
If patients are asymptomatic, treatment ma-, not be required. Otherwise, treatment consists of the mea~ures described below.
Immediate support
• High fluid intake to treat renal impairment and hypercalcaemia.
• Analgesia for bone pain.
• Bisphosphonates for hypercalcaemia and to delay other skeletal related events (p. 11)41.
v Allopurinol to prevent urate nephropathy.
• Plasmapheresis, as necessar5•. for hyperviscosity.
Chemotherapy
In frail older patients, melphalan is an effective oral therapy, whilst in younger patients treatment with intravenous agents may improve response. Higher doses of intravenous melphalan appear to be well tolerated even in patients over 65 years and may produce better clinical responses.
Treatment is administered until paraprotein levels have stopped falling. This is termed `plateau phase and may last for weeks or years. Successive relapses respond less well to treatment.
Prognosis
The median survival of patients receiving standard treatment is approximately 40 months. Poor prognostic features include a high (3Z microglobulin, low albumin, a low haemo¬globin or a high calcium at presentation. Autotrans¬plantation improves survival and quality of life by slowing the rate of progression of bone disease. Less than 5% of patients survive longer than 10 years with standard treatment.