Myeloma

Myeloma (multiple myeloma, myelomatosis) is due to the unregulated proliferation of monoclonal plasma cells in the bone marrow. Their accumulation leads to marrow failure and, indirectly, to bone resorption resulting in osteoporosis and fracture. The cell of origin has not been conclusively identified but may be a memory B lymphocyte. The cause is unknown. An important mechanism is local production of interleukin 6, which stimulates plasma cell proliferation. Both paracrine and autocrine sources of the cytokine have been demonstrated.

The overall incidence of the disease is 4 per 100 000 in the UK, but over 30 per 100 000 in subjects over 80 years of age. It is higher amongst African-Americans and much lower in Chinese and Japanese-Asian populations. It is rare under the age of 40, the median age at presentation being 70 years.

The clonal plasma cells in myeloma synthesize, and usually secrete, a monoclonal protein (M protein, paraprotein). This is most commonly intact immunoglobulin, but may be immunoglobulin together with free light chain, or free light chain only. IgG is secreted in 60% of cases. IgA in 20%, and free light chain only in 20%. Light chains can pass through the glomerular filter and appear in the urine as Bence-Jones protein. In rare cases there is synthesis of monoclonal IgD, IgE, or IgM, or of two clonal proteins. Also uncommon are non-secretory and non-synthesizing variants of the disease.

Pathology

Monoclonal gammopathy associated pathology:

♦ Monoclonal gammopathy of uncertain significance (MGUS)

♦ Solitary plasmacytoma

♦ Waldenstrom's macroglobulinaemia

♦ Chronic lymphatic leukaemia

♦ Amyloidosis

Clinical features

These are explained by the accumulation of plasma cells in bone marrow, induction of bone resorption, and paraprotein synthesis.

Marrow infiltration

Malignant plasma cells accumulate in the red marrow of the axial skeleton and flat bones. Anaemia and thrombocytopenia are common, and frequently present at diagnosis.

Bone resorption

There is abnormal bone remodelling with increased, cytokine-driven osteoclastic bone resorption and inhibition of osteoblastic bone formation. Interleukin 6 is a major stimulus to osteoclastic activity. Bone pain is the most common presenting complaint, especially severe back pain. There may be fractures. The increased bone resorption also leads to hypercalcaemia and associated symptoms of thirst, polyuria, nausea, constipation, drowsiness, and even coma. X-ray examination typically reveals osteoporosis and lytic lesions that are often visualized on skull films.

Secretion of paraprotein

Accumulation of M protein in the plasma may result in hyperviscosity with lethargy and confusion, progressing to fits and coma. There is a characteristic retinopathy in hyperviscosity syndrome, with distension of retinal veins and irregular vessel constrictions; haemorrhages and papilloedema may be present. IgA and IgG paraproteins are especially likely to induce hyperviscosity. Bence-Jones protein is deposited in the renal tubules and may lead to renal failure. Other factors contributing to renal failures are:

♦ Hypercalcaemia

♦ Amyloid deposition

Paraproteinaemia is typically accompanied by immune paresis, which contributes to the infection risk. In non-secretory myeloma the only immunological abnormality may be immune paresis, giving rise to diagnostic confusion.

Other features

Plasmacytomas may be palpable and also cause pressure effects. Spinal cord compression is most frequent and constitutes a medical emergency with the need for urgent assessment and local radiotherapy and/or decompressive surgery. Amyloidosis is frequently present and may dominate the clinical picture: macroglossia, renal failure, peripheral neuropathy, and cardiac failure occur. A syndrome of highoutput cardiac failure is an occasional feature, unrelated to cardiac amyloid.

Very occasionally the bone lesions appear sclerotic, and this variant of the disease is often accompanied by severe progressive peripheral neuropathy. This combination of sclerotic lesions and neuropathy may also occur as part of the 'POEMS' syndrome, where plasma cell dyscrasia is accompanied by:

♦ Sensorimotor Polyneuropathy

♦ Organomegaly (principally hepatomegaly)

♦ Endocrinopathy (diabetes mellitus, amenorrhoea, gynaecomastia)

♦ Skin changes (predominantly pigmentation)

Diagnosis

The classic diagnostic triad consists of bone marrow infiltration with monoclonal plasma cells, osteolytic lesions on skeletal X-rays, and paraproteinaemia/Bence-Jones' proteinuria. The plasma cell count may be only 5-10% in marrow, but is often over 30%, usually with morphologically abnormal forms.

Cytogenetic abnormalities, most commonly on chromosomes 13 and 14, and aneuploidy, are usually present, although their demonstration is not necessary for diagnostic purposes. The myeloma cells tend to be positive for CD 19,38,56, and syndecan-1. Additional common features are:

♦ Normocytic anaemia

♦ Pancytopaenia

♦ Renal impairment (present in 20% of cases)

In approximately 30%, hypercalcaemia is present at diagnosis and, typically, the serum alkaline phosphatase concentration is normal and the isotope bone scan negative (due to suppressed osteoblastic activity). The serum albumin may be low.

The main differential diagnosis is 'monoclonal gammopathy of uncertain significance' (MGUS), defined as the presence of a serum paraprotein without the features of myeloma. Its prevalence is around 20 times higher than that of multiple myeloma and it is age-related— 3% of subjects over 80 years of age have detectable paraprotein. The serum concentration of the M protein is usually less than 30 g/l of IgG (less than 20 g/l of IgA), with no immune paresis. The blood count is normal as are skeletal X-rays. An excess of clonal plasma cells may be detected in the marrow, but these total less than 5% of nucleated cells.

In 'smouldering' myeloma there are more than 10% plasma cells in bone marrow and a serum paraprotein concentration greater than 30 g/l, but no bone symptoms, radiological skeletal abnormality, anaemia, or renal failure. It is associated with an initially stable course and relatively long survival.

In plasma cell leukaemia there are greater than 20% plasma cells in peripheral blood. It may be a presenting feature or develop late in the disease course and is typically poorly responsive to therapy.

Solitary plasmacytoma presents as a single bone lesion with normal bone marrow and absent, or only low titre, paraprotein in serum. The tumour is radio-sensitive, but myeloma subsequently develops in most cases.

Extramedullary plasmacytoma is a rare soft-tissue plasma cell tumour, most commonly affecting the head and neck areas, especially the nasopharynx, nasal sinuses, and tonsils. Again the bone marrow is normal and there is no paraprotein. The tumour is radio-sensitive. Multiple myeloma develops in up to 40% of cases.

Management

Untreated, death usually occurs within months, especially from infection and renal failure, and is often preceded by intractable bone pain. Initial therapy should include:

♦ Adequate analgesia, often necessitating the use of opiates, with radiotherapy to areas of persisting local bone pain.

♦ Rehydration and vigorous management of hypercalcaemia using intravenous bisphosphonate. Dialysis is occasionally necessary for management of renal impairment, and plasma exchange for rapid correction of hyperviscosity syndrome.

Chemotherapy

♦ Palliation to improve symptoms and reduce paraprotein

♦ Chemotherapy for 3 months is sufficient

♦ Maintenance chemotherapy is of no value

♦ Plateau phase lasts 3 months to 3 years

♦ Oral melphalan is best—4-day pulses every 4 weeks

—50% of patients achieve 50% reduction in M protein

♦ Median survival, 3 months

A more intensive regimen—VAD (vincristine and adriamycin by IV infusion and oral dexamethasone)—may produce a rapid response, but this is often poorly sustained. Combination chemotherapy (e.g. doxorubicin, BCNU, cyclophosphamide, melphalan) has improved the response rate in some trials, at the expense of greater toxicity.

Complete remission is uncommon. High-dose (marrow ablative) melphalan with autologous stem cell transplantation induces complete remission in around 20% of recipients, and prolongs survival. It can be considered in younger patients. Long-term survival has been reported after allogeneic transplantation, but treatment-related mortality is high (up to 40%).

Additional therapy

Oral clodronate appears to reduce the fracture rate, when administered continuously. Pamidromate—a more potent bisphosphonate— administered by monthly IV infusion, reduces fracture rate, pain, and hypercalcaemia and improves quality of life. Interferon-a, administered as maintenance therapy, appears to extend the duration of the plateau phase. It is unclear whether survival is meaningfully prolonged. The therapy is associated with significant side-effects and is expensive. Erythropoietin can be used to reduce transfusion requirements in a minority of cases.

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.

Get My Free Ebook


Post a comment