Multiple Myeloma

Multiple myeloma (MM) is a haematological malignancy primarily affecting the plasma cells in the bone marrow. ;

If you can recall, plasma cells originate from B lymphocytes. They are essentially a well-differentiated form of B lymphocytes that have a specific affinity to produce antibodies against a specific antigen. ;

Multiple myeloma is characterised by a clonal proliferation of abnormal plasma cells. This uncontrolled mass production originates from one singular plasma cell hence they are all genetically identical. These clones ultimately produce abnormal antibodies (mainly IgG type) that are defective and are unable to do its normal expected functions. These abnormal antibodies are referred to as paraproteins.

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Pathophysiology

• Usually there are <;5% plasma cells in bone marrow

  • Elevated in MM to >;10%

• Bone marrow stromal cells (BMSC) usually regulate haematopoeisis

• In MM, abnormally proliferated plasma cells adhere to BMSCs causing:

  • Cytokine mediated cell growth
  • Survival
  • Drug resistance
  • Migration

  (essentially helps MM cells surviving)

• Produces cytokines that promotes osteoclast activity (leading to hypercalcaemia)

  • Interleukin-3
    • Decreases production of osteoblasts
  • DKK1
    • Inhibits OPG production from osteoblasts →; increase osteoclast activity
  • MIP1a + RANKL
    • Stimulates osteoclasts directly

• Light chains in the blood stream

• If you can recall the structure of antibodies, it is made up of heavy chains and light chains
• Since MM produces abnormal paraproteins, it is not unusual for these light chains to break off on their own
• Small enough to get filtered out of the kidneys →; renal injury
• Excreted in the urine →; Bence-Jones proteins

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Presentation
Multiple myeloma typically presents at an older age (median age of 70). It is more common in men and those of Black African decent. In terms of the signs and symptoms, these can be remembered by the famous acronym: CRABB

Calcium →; Hypercalcaemia from increased osteoclast activity

• Constipation
• Nausea
• Anorexia
• Confusion
• Polyuria
• Abdominal pain

Renal →; Light chain deposition in renal tubules causes damage to the kidneys

• Renal failure
• Proteinurea (Bence-Jones proteins)
• Dehydration

Anaemia →; from bone marrow overcrowding and decreased EPO production

• Fatigue
• Pallor

Bleeding →; from bone marrow overcrowding →; thrombocytopenia

• Increased risk of bleeding
• Bruising

Bones →; Bone marrow infiltration →; increased osteoclast activity →; lytic bone lesions

• Back pain
• Fragility (pathological) fractures

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Investigations
When a diagnosis of MM is suspected after a thorough history and examination, starting with routine work-up is always a good starting point. ;

• Routine bloods (FBCs, U+Es etc.) looking for...
• Anaemia
• Paraproteinaemia
• Hypercalcaemia
• Uraemia
• ↑; Creatinine

Moving on to more specific tests, one should consider the following:

• Urine electrophoresis looking for ;Bence-Jones proteins
• Serum electrophoresis which presents as an M-spike by gamma protein region
• Bone Marrow biopsy looking for an increase in plasma cells (>;10%)
• Whole body MRI looking for bone lytic lesions

To confirm a diagnosis of myeloma, the following three points must be met:

1. CRAB symptoms (indicates end-organ damage)
2. Monoclonal plasma cells in bone marrow >;10%
3. Monoclonal antibodies (paraproteins) in serum or urine

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Management

Myeloma is a chronic relapsing and remitting condition and currently deemed incurable

• Induction of remission therapies
  • If suitable for autologous stem cell transplantation →; Bortezomib + Dexamthasone (+/- thalidomide) then transplant
  • Unsuitable to autologous stem cell transplantation →; Thalidomide + Dexamthasone + Alkylating agent
• Relapse →; Bortezomib monotherapy
• Bisphosphonates e.g. Zoledronic acid to prevent bone disease
• Don`t forget about supportive therapy as well as psychological support when needed