Introduction

Myeloma is a malignant disease of the plasma cells of the bone marrow.  Its name suggests that it is a disease of the myeloid stem cells, but this is not the case. All blood cells except for lymphocytes are the progeny of myeloid stem cells, but it is these lymphocytes, or plasma cells, which proliferate in this disorder, interfering with the normal production of other blood cells. The malignant plasma cells also produce aberrant antibodies which accumulate to cause hyperviscosity, amyloidosis and renal failure.

 
Quantification of immunoglobulin light chains in the urineis useful for the diagnosis of myeloma and for monitoring the response to therapy.  These light chains, either lambda or kappa, are produced by the neoplastic plasma cells, and are known as Bence-Jones proteins. 
Myeloma is regarded as incurable, but it can be brought into remission with various treatment modalities, including, steroids, chemotherapy, thalidomide and stem cell transplants.

Epidemiology

  • It accounts for 1% of all cases of malignant diseases
  • It is a disease of the elderly
  • The mean age of presentation is 60 with a slight male predominance
  • Incidence is 4 per 100 000; however, over the age of 80, this rises to 80 in 100 000
  • More common in black Africans and less common in Asians

Causes

  • Genetic – HLA Cw5 or Cw2 may play a role in the pathogenesis of multiple myeloma; defects which carry a poor prognosis are abnormalities of chromosome 13, hyperdiploidy, and p53 deletions
  • Environmental or occupational – significant exposure in agricultural, food and petrochemical industries, and long-term exposure to hair dyes
  • Monoclonal gammopathy of unknown significance (MGUS) – about 19% of individuals suffering with this form of myeloma develop multiple myeloma within 2 to 19 years
  • Radiation, e.g. survivors of the atomic bombing of Nagasaki during WWII

Pathology

There is monoclonal proliferation of certain plasma cells, i.e. mature, activated B cells, leading to the formation of abundant immunoglobulins.  Most often, these consist of IgG (55%), but IgA (25%) and IgD (rarely), are also formed.
Plasma cell levels in the blood are increased and massively raised in the bone marrow.
Dysregulation of bone remodelling results in multiple bone abnormalities.  There is increased osteoclast activity with no corresponding increase in osteoblast activity, which culminates in pathologic fractures and hypercalcaemiaThe bone abnormalities appear as lytic lesions. The mechanism of bone abnormalities is such that stromal cells, adhering to myeloma cells, stimulate the production of specific cytokines, namely RANKL, IL-6 and VEGF.  RANKL functions to stimulate osteoclast activity, and is therefore responsible for the lytic lesions.
Lytic lesions appear as “black holes” within bony structures on X-ray, MRI and CT. They typically occur in the skull and vertebrae.
This scan shows a lytic lesion in the temporal bone.  
The red arrows indicate the lesion; the green arrow indicates normal bone structure.
 
 
 
 
This image depicts bone marrow infiltration by plasma cells.
 

Clinical features

  • Bone destruction – this often leads to fracture of the long bones, and vertebral collapse. This can cause spinal cord compression, as well as hypercalcaemia.
  • Bone marrow infiltration – as the bone marrow is infiltrated with malignant plasma cells, this results in anaemia, neutropaenia, thrombocytopaenia.  These complications, along with the overproduction of Bence-Jones proteins can lead to hyperviscosity.
  • Renal impairment – this is due to a combination of factors: deposition of light chains in the renal tubules, hypercalcaemia and hyperuricaemia.  Also, in rare instances, the long term use of NSAID’s to treat the disease can result in abnormal deposition of amyloid.
  • Reduced normal immunoglobulin – the resultant reduction in antibody production leads to impaired humoral immunity, and patients have a tendency to acquire recurrent infections, particularly of the respiratory tract.

Symptoms

  • Bone pain – most commonly backache as a result of vertebral involvement in 60% of patients
  • Anaemia
  • Recurrent infections
  • Renal failure –  in 20-30% of patients
  • Hypercalcaemia
  • Hyperviscosity – rare
  • Bleeding– rare
Often patients can be asymptomatic, and the discovery of the disease is only made with routine blood tests.
Hyperviscosity syndrome results from increased circulating serum immunoglobulins in Waldenstrom macroglobulinaemia and multiple myeloma, but may also occur in hyperproliferative states such as the acute leukaemias, polycythemia and the myeloproliferative disorders in which there are increased cellular blood components. As serum proteins or cellular components rise, the blood becomes more viscous, leading to the following clinical symptoms:

Investigations

  • FBC – Hb, WCC and platelet count will be normal or low
  • ESR –almost always high
  • CRP –always raised
  • Blood film –there may be rouleaux formation due to increased paraproteins
  • U+E –may be evidence of renal failure – both will be high
  • Serum lactate dehydrogenase and serum β2-microglobulin – useful in predicting
  • prognosis
  • Serum calciumnormal or raised
  • ALP – usually normal
  • Total protein –normal or raised
  • Serum albumin –normal or low
  • Uric acid –normal or raised
  • Skeletal survey –may show characteristic lytic lesions – most commonly in the skull
  • Serum protein electrophoresis – determines the type of each protein present
  • Urine protein electrophoresis – identifies presence of Bence-Jones proteins
  • 24-hour urine immunofixation –this is useful for checking the subtype of light chains, e.g. IgA lambda
  • Bence-Jones proteins
  • Bone marrow aspirate –shows plasma cell infiltration of the bone marrow; used to calculate the percentage of plasma cells in the infiltrate; cytogenetic analysis of the aspirate may contribute prognostic information may also demonstrate amyloidosis
  • DEXA scan – this may be used as follow-up to treatment
  • β2-microglobulin – a very strong predictor of multiple myeloma outcome , with some studies suggesting it is a more powerful indicator of than disease staging. It is a surrogate marker for the overall body tumour burden. β2 microglobulin levels are increased in patients with renal insufficiency without multiple myeloma, thus making it a useful measurement for prognosis in individuals with multiple myeloma.

Diagnosis

Two of the following factors should be present:
  • Paraproteinaeamia OR Bence-Jones proteins
  • Radiologic evidence of lytic lesions, e.g. pepperpot skull
  • Increase in bone marrow plasma cells >30%
  • >1g of light chains excreted per day
  • Monoclonal band of Ig in the serum or monoclonal light chains in the urine on electrophoresis

Treatment

Treatment is aimed at preventing the main causes of death:
  • Infection
  • Renal failure
  • Haemorrhage

Bone pain is one of the major symptoms.
Median survival is 5 years; some patients may survive 10 years.
1/3 people will die within the first 3 months of diagnosis.
Younger patients tend to receive more intensive treatment, and may survive longer.

 

Supportive therapy

  • Anaemia should be corrected; this often involves blood transfusion and/or EPO.
  • Patient should have yearly flu vaccines, and all infections should be promptly treated with antibiotics.
  • Bone pain can either be treated by NSAIDS – but beware of long term use as it can cause renal impairment – or more rapidly by radiotherapy.
  • Pathological fractures can be prevented by orthopaedic surgery.  The bones affected by lytic lesions can be pinned through a procedure known as kyphoplasty.
  • Infection may be prevented with prophylactic antibiotic use, or in the case of active infection, immunoglobulin replacement therapy may be helpful.
 

Specific therapy

  • Long term use of bisphosphonates helps to reduce progression of the disease.
  • Chemotherapy can be initiated with prednisolone and melphalan.  This has a response rate of about 50%.
  • Complete remission is never attained, and patients will relapse when treatment is stopped.
  • Newer techniques have increased the duration and level of remission, even though a cure is not still possible.  This generally involves high dose melphalan, and peripheral blood stem cell rescue – this is often given alongside dexamethasone.
  • New treatments – Thalidomide – an anti-angiogenesis drug that reduces paraprotein levels, but never use in pregnancy!  

 

Life-threatening complications

  • Renal impairmentpatients may need long term peritoneal or haemodialysis
  • Hypercalcaemiashould be treated by rehydration and use of bisphosphonates,e.g. pamidronate
  • Spinal cord compressiontreated with dexamethasone followed by irradiation of the lesion, where the lesion is staged and scaled by MRI
  • Hypersensitivitydue to high circulating levels of paraprotein

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