Introduction

Multiple myeloma is a malignant disorder in which there is an uncontrolled proliferation of clonal plasma cells in the bone marrow. Secretion of a variety of proteins by the malignant cells leads to characteristic symptoms and signs. Myeloma constitutes 10–15% of all haematological malignancies and is essentially a disease of the elderly – only 2% of cases are diagnosed in patients less than 40 years old.

Basic biology

The initial step in the development of myeloma is the appearance of a small number of clonal plasma cells (the clinical syndrome is ‘monoclonal gammopathy of uncertain significance’ (MGUS) ). Approximately 50% of patients with MGUS have translocations involving the immunoglobulin heavy chain locus on chromosome 14q32. With progression to frank myeloma, more complex genetic events occur in the neoplastic plasma cells. Changes in the bone marrow microenvironment include the induction of angiogenesis, the suppression of cell-mediated immunity and increased secretion of interleukin-6, a powerful growth factor for myeloma cells. Bone lesions result from osteoclast activation. Myeloma cells secrete a monoclonal immunoglobulin or immunoglobulin fragments (‘M-proteins’ or ‘paraproteins’) composed of a single heavy chain class and a single light chain class, kappa or lambda. Most myelomas produce IgG or IgA but light chains alone are produced in over 10% of cases. Free light chain appearing in the urine is termed Bence Jones protein. Occasionally myeloma is non-secretory with no detectable M-protein. Localised plasma cell tumours in the absence of systemic myeloma are termed ‘plasmacytomas’.

Clinical features

More than two-thirds of patients have bone pain at presentation. Pain is most common in the back and chest and may be attributed to ‘arthritis’. More advanced bone disease can lead to pathological fractures or vertebral collapse with loss of height. Infiltration of the bone marrow by plasma cells may lead to symptoms of anaemia or bleeding due to thrombocytopenia. Infections are common due to immune paresis (low level of normal immunoglobulins) and other complications which may lead to symptoms include hypercalcaemia, amyloidosis and renal failure. The major cause of the nephropathy is deposition of obstructive tubular casts composed of immunoglobulin light chains – other possible factors include dehydration, infection and amyloid.

Diagnosis and staging

Myeloma is an easy malignancy to miss as the early symptoms such as malaise and backache are common in the population. The combination of backache and a high erythrocyte sedimentation rate (ESR) should be taken seriously as it may indicate myeloma or another metastatic malignancy.

In asymptomatic (‘smouldering’) myeloma there is generally a serum monoclonal protein >30 g/L and/or bone marrow clonal plasma cells >10% but no related organ or tissue impairment (Figs 31.1 and 31.2). A diagnosis of symptomatic myeloma requires evidence of such impairment; typically increased calcium, renal insufficiency, anaemia, or bone lesions (Table 31.1 and Fig 31.3). Bony disease is increasingly assessed by MRI scanning in addition to traditional X-rays (‘skeletal survey’) (Fig 31.4). Patients who have a paraprotein in the serum but who do not meet the criteria for myeloma are diagnosed as having MGUS. They have a rate of progression to myeloma of 1% per year. Monoclonal gammopathy is associated with other diseases such as lymphoma, non-haematopoietic malignancies and connective tissue disorders but it is also quite common in healthy elderly people (approximately 5% over 70 years of age).

The prognosis of myeloma can be predicted from presenting clinical and laboratory features (Table 31.2). The combination of a high β₂-microglobulin level and a low albumin level carries a particularly poor prognosis. Cytogenetic and molecular genetic profiles of the malignant cells also predict myeloma behaviour. Hyperdiploid and t(11;14) mutations define standard risk disease while non-hyperdiploid, t(4;14), del(17p) and del(13q) mutations indicate inferior outcome.

Management and outcome

Myeloma may be diagnosed by chance on laboratory screening in patients with limited disease and no symptoms. In this group, about 20% of all patients, the disease may remain stable for several years and there is no advantage in early intervention. Where treatment is required this generally entails drug therapy, management of specific complications, and palliation.

Waldenström’s macroglobulinaemia

This disease is a form of indolent lymphoma. It is appropriately considered with myeloma as the malignant cells, which show features of lymphocytes and plasma cells, secrete an IgM paraprotein. Patients may complain only of fatigue, but high IgM levels can lead to the ‘hyperviscosity syndrome’, with confusion and neurological symptoms. In these cases retinal examination reveals engorged veins, haemorrhages, exudates (Fig 31.5) and rarely papilloedema. Other possible physical signs include lymphadenopathy and hepatosplenomegaly. Where treatment is required, options include chemotherapy (e.g. chlorambucil or fludarabine) and monoclonal antibodies (e.g. rituximab). Significant hyperviscosity requires plasmapheresis.