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multiple myeloma

Multiple Myeloma

Multiple Myeloma

Multiple Myeloma is a malignant disease of bone marrow plasma cells, accounting for 1% of all malignant disease. There is a clonal expansion of abnormal, proliferating plasma cells
producing a monoclonal paraprotein, mainly IgG (55%) or IgA (20%), and rarely IgM and IgD. The paraproteinaemia may be associated with excretion of light chains in the urine (Bence Jones protein), which are either kappa or lambda. In approximately 20%, there is no paraproteinaemia, only light chains in the urine. Rarely, patients produce no paraprotein or light chains – this is termed ‘non-secretory myeloma’ (<5%).

Clinical features

Myeloma is a disease of the elderly, the median age at presentation being over 60 years. It is rare under 40 years of age. The annual incidence is 4 per 100 000 and it is more common in males and in black Africans, but less common in Asians.

The clinical features include:

  • Bone destruction, often causing fractures of long bones or vertebral collapse (which can cause spinal cord compression) and hypercalcaemia. Soft tissue plasmacytomas also occur and they are the usual cause of spinal cord compression in myeloma.
  • Bone marrow infiltration with plasma cells, resulting in anaemia, neutropenia and thrombocytopenia, together with production of the paraprotein, which may (rarely) result in symptoms of hyperviscosity.
  • Kidney injury owing to a combination of factors: deposition of light chains in the renal tubules, hypercalcaemia, hyperuricaemia, use of NSAIDs and, rarely, the deposition of AL amyloid. 

In addition, there is a reduction in the normal immunoglobulin levels (immune paresis), contributing to the tendency for patients with myeloma to have recurrent infections, particularly of the respiratory tract.


  • Bone pain: most commonly backache, owing to vertebral involvement (60%).
  • Symptoms of anaemia.
  • Recurrent infections.
  • Symptoms of renal failure (20–30%).
  • Symptoms of hypercalcaemia.
  • Rarely, symptoms of hyperviscosity and bleeding due to thrombocytopenia.
    Patients can be asymptomatic, the diagnosis being suspected by abnormal ‘routine’ blood tests.

Life -threatening complications of Multiple Myeloma

  • Renal impairment – often a consequence of hypercalcaemia – requires urgent attention and patients may need to be referred for long-term peritoneal dialysis or haemodialysis
  • Hypercalcaemia should be treated by rehydration and use of bisphosphonates, such as pamidronate
  • Spinal cord compression due to myeloma is treated with dexamethasone, followed by radiotherapy to the lesion delineated by a magnetic resonance imaging scan
  • Hyperviscosity due to high circulating levels of paraprotein may be corrected by plasmapheresis


  • General
    • Full blood count. Haemoglobin, white blood cell count and platelet count are normal or low.
    • Erythrocyte sedimentation rate. This is often high.
    • Blood film. There may be rouleaux formation as a consequence of the paraprotein and circulating plasma cells in the aggressive plasma cell leukaemia variant of myeloma.
    • Urea and electrolytes. There may be evidence of kidney injury.
    • Serum calcium. This is normal or raised. Serum alkaline phosphatase is usually normal.
  • Immunological
    • Total protein is normal or raised.
    • Serum protein electrophoresis and immunofixation characteristically shows a monoclonal band and immune paresis. The serum free light chain assay, more sensitive than urine electrophoresis, may show an abnormal ratio and an increased total amount of free kappa or lambda chains, and is often abnormal earlier than routine electrophoresis.
    • Twenty-four-hour urine electrophoresis and immunofixation is used for assessment of light-chain excretion.
  • Radiological
    • Skeletal survey may show characteristic lytic lesions, most easily seen in the skull. CT, MRI and PET are used in plasmacytomas (bone or soft tissue deposits).
    • MRI spine is useful if there is back pain; it may show imminent compression/collapse
  • Other
    Bone marrow aspirate or trephine shows characteristic infiltration by plasma cells. Amyloid may be found.


Symptomatic myeloma (SMM) can be diagnosed if either of the following is present:

  • significant paraproteinaemia
  • increased bone marrow plasma cells (>10%)
    with evidence of end-organ failure: that is, hypercalcaemia, renal impairment, anaemia and lytic bone lesions (CRAB).

Asymptomatic myeloma (AMM; 10% of cases) has a significant paraprotein (IgG or IgA >30 g/dL or urinary light chain excretion >1 g/day) and/or a marrow plasmacytosis >10% but no end-organ damage. The median time to progression for these patients is 2–3 years. The risk is highest for those with IgA isotype and light chains in the urine.

Monoclonal gammopathy of unknown significance (MGUS) describes an isolated finding of a monoclonal paraprotein in the serum, usually in the elderly, that does not fulfil the
diagnostic criteria for SMM or AMM. Between 20% and 30% go on to develop multiple myeloma over a 25-year period. Low-risk MGUS is characterized by an IgG subtype, a paraprotein <15 g/dL and a normal serum free light chain ratio

Plasmacytoma is an isolated tumour of neoplastic plasma cells. Patients may present with a plasmacytoma and no evidence of multiple myeloma. This may be a ‘solitary plasmacytoma of bone’ within the skeleton or an ‘extramedullary plasmacytoma’ outside the marrow cavity, typically in the upper aerodigestive tract.


With good supportive care and chemotherapy, median survival is now 5 years, some patients surviving to 10 years. Young patients receiving more intensive therapy may live longer.

Supportive therapy

  • Anaemia should be corrected; blood transfusion may be required. Erythropoietin often helps. Transfusion should be undertaken slowly in patients with hyperviscosity.
  • Hypercalcaemia, kidney injury and hyperviscosity should be treated as indicated.
  • Infection should be treated promptly with antibiotics. Give pneumococcal and yearly influenza vaccinations.
  • Bone pain can be alleviated most rapidly by radiotherapy and systemic chemotherapy or highdose dexamethasone. NSAIDs are usually avoided because of the risk of acute kidney injury. Bisphosphonates, such as zoledronate, which inhibit osteoclast activity, help ensure rapid normocalcaemia and, given long-term, reduce skeletal events such as pathological fracture, cord compression and bone pain.
  • Pathological fractures may also be prevented by prompt orthopaedic surgery with pinning of lytic bone lesions at critical sites seen on the skeletal survey, such as the femoral shaft. Kyphoplasty and vertebroplasty may be useful in treating vertebral fractures. 

Specific therapy

Myeloma remains incurable. Therapy is aimed at treatment or prevention of specific complications and prolongation of overall survival. There are a plethora of agents that can be used at first line or subsequent relapse in myeloma.

Initial treatment typically consists of an alkylator (cyclophosphamide or melphalan), steroid (prednisolone or dexamethasone) and novel agent (bortezomib or thalidomide). Melphalan is avoided in those who may require stem cell mobilization subsequently. Bortezomib is preferable in those with renal impairment. Thalidomide has activity as a single agent and is widely used in first-line and relapsed settings. It is teratogenic and associated with neuropathy,  somnolence, constipation and an increased risk of venous thrombosis. Lenalidomide is a thalidomide analogue, which is also used for relapsed myeloma. It has greater potency than thalidomide with less toxicity.

In younger patients (<65–70 years), an orally active cyclophosphamide, thalidomide and dexamethasone-based induction (CTD), followed by a high-dose melphalan autograft, has a significantly higher response rate, with 40% of patients achieving a CR and median survival increasing to 6 years. A bortezomib-containing initial treatment schedule, such as bortezomib, thalidomide and dexamethasone, is also appropriate. The role of allogeneic transplantation is currently unclear but it should be considered in young patients, with a suitable donor and highrisk disease.

In older or less fit patients, melphalan and prednisolone was used, with a median survival of 29–37 months; complete remissions were rare. Recent phase III studies have suggested that these agents, combined with thalidomide as MPT, result in improved response rates and overall survival, albeit with increased toxicity. Additionally, a phase III study has shown that bortezomib plus melphalan and prednisolone (VMP) is superior to the latter two alone. Finally, the FIRST study showed superiority of lenalidomide/dexamethasone to MPT for older patients and this may come to be standard of care.

For relapsed patients, a second autograft may be considered if there was a favourable response duration to the first (>12–18 months). Choice of reinduction therapy will be tailored to the patient according to prior exposure and toxicities. New agents available or currently  under evaluation include the proteasome inhibitors ixazomib and carfilzomib; pomalidomide, bendamustine, elotuzumab (monoclonal antibody to CS1), daratumumab (monoclonal antibody to CD38), panobinostat (histone deacetylase inhibitor) and plitidepsin are in clinical trials.

(Reference : Kumar and Clark’s Clinical Medicine 9th Edition)

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