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Multiple myeloma

Introduction and epidemiology

Multiple myeloma (MM), sometimes called plasma cell myeloma, is the most important of the plasma cell dyscrasias. It is characterised by proliferation of genetically abnormal monoclonal plasma cells in the bone marrow, which produce monoclonal paraprotein which leads to organ damage and which can be detected in blood and urine.

It’s the second most common haematological malignancy. It mostly affects elderly. Its prognosis used to be poor but nowadays the expected overall survival is >5 years. However, it is still considered incurable.

Sometimes multiple myeloma presents as a solitary tumour, in which case it’s called plasmacytoma.

Clinical features

Multiple myeloma present subacutely with:

• Anaemia
• Fatigue
• Bone pain
• Pathological fractures
• Weight loss

Diagnosis and evaluation

Multiple myeloma is diagnosed when the following criteria are met:

• >10% of the bone marrow is monoclonal plasma cells
• Presence of a myeloma-defining event (MDE) according to the CRAB SLiM criteria:
  • C – Calcium elevation (hypercalcaemia)
  • R – Renal insufficiency
  • A – Anaemia (normocytic)
  • B – Bone lesions
  • S – >60% of the bone marrow is monoclonal plasma cells
  • Li – Involved/uninvolved serum free light chain ratio elevated
  • M – MRI with >1 focal lesion of bone or bone marrow

Whole body low dose CT (WBLD-CT) is the best modality for detection of osteolytic lesions. Following diagnosis, bone marrow aspiration and biopsy is indicated for genetic testing for risk stratification.

Treatment

As MM cannot be cured, the natural history of the disease is characterised by active disease, initiation of treatment, followed by remission which will inevitably relapse at some point, and so on.

The best treatment is high dose chemotherapy followed by autologous SCT, but not all patients are eligible for this treatment. Treatment options include:

• Immunomodulatory drugs (thalidomide, lenalidomide)
• Proteosome inhibitors (bortezomib, carfilzomib)
• Chemotherapy (steroids, alkylating agents, anthracyclines)
• Targeted monoclonal antibodies (daratumumab, elotuzumab)
• HDAC inhibitor (Panobinostat, vorinostat)

Plasmacytoma is managed with surgery or radiotherapy.

Supportive treatment is also important:

• Osteolysis – bisphosphonates, radiotherapy
• Pancytopaenia – blood transfusion, G-CSF

Complications

Amyloid light-chain (AL) amyloidosis can occur due to the excessive light-chain production. This can result in cardiomyopathy or kidney disease, among others. Kidney disease can also occur due to excessive filtering of Bence-Jones proteins or due to the effects of hypercalaemia.

Infection is a major cause of death in patients with multiple myeloma, partly due to secondary immunodeficiency due to the high level of non-functional immunoglobulins and partly due to side effects of medications.

Premalignant stages of multiple myeloma

Monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of unknown significance (MGUS) is a precursor stage to multiple myeloma. MGUS can be found in 3% of healthy adults over 50. There are no symptoms or organ damage, only a laboratory abnormality (mildly elevated M-protein).

MGUS carries a 1-2% risk per year to progress to multiple myeloma. Regular follow-up allows early detection of progression.

Smouldering myeloma

Smouldering myeloma is the next precursor stage to multiple myeloma, a form of middle stage between MGUS and MM. It’s characterised by higher level of M-protein than MGUS as well as >10% of the bone marrow being occupied by plasma cells. There is still no organ damage.

As smouldering myeloma is “closer” to multiple myeloma than MGUS, the yearly risk of progression to MM is higher, 10%/year. Regular follow-up allows early detection of progression.