Myeloma

 

• Background

  Aka multiple myeloma

  

  
  

  Pathophysiology

  • Malignant proliferation of plasma cells in the bone marrow.
  • Causes bone marrow destruction via infiltration, and bone destruction via ↑RANKL activity (causing ↑osteoclast activity).
  • A single clone of plasma cells produce large amounts of identical immunoglobulin (a 'paraprotein' or 'monoclonal band'), as well as free κ or λ light chains (also a 'paraprotein', or 'Bence Jones protein' if in the urine).
  • Classified by Ig class, with prevalence reflecting prevalence in normal blood: IgG (⅔), IgA (⅓), remainder IgM or IgD.
  • Immunoglobulin classes other than that of the proliferating clone are relatively low ('immunoparesis').

  Epidemiology

  • Lifetime risk: 1/140.
  • Incidence steadily increases with age. Rare <55.
  • Slightly commoner in men.
  • 2x commoner in blacks vs. whites.

• Signs and symptoms

  • Osteolytic bone lesions → pathological fractures causing bone pain (esp. back), and ↑Ca2+.
  • Marrow infiltration → pancytopaenia → anaemia (→fatigue), infection, and bruising/bleeding.
  • Immunoparesis → infection.
  • Renal disease (50% at presentation): light chains (i.e. Bence-Jones protein) deposit in kidneys and aggregate with Tamm-Horsfall proteins in the loop of Henle, causing tubular obstruction and kidney failure in a process known as 'cast nephropathy'. Less commonly, damages kidney via monoclonal immunoglobulin deposition disease (affecting glomerular basement membrane), or light chain (AL) amyloidosis.

• DDx: Paraproteinaemia

  • Myeloma
  • Waldenström's macroglobulinaemia (aka lymphoplasmacytoid lymphoma).
  • Primary amyloidosis.
  • Monoclonal gammopathy of uncertain significance (MGUS). A diagnosis of exclusion. Relatively common.
  • Chronic lymphocytic leukaemia. Paraproteinaemia seen in a minority of CLL cases.

• Investigations

  Bloods:

  • FBC: normocytic anaemia (80%).
  • ↑ESR, ↑plasma viscosity.
  • U&E: ↑urea and creatinine.
  • Bone profile: ↑Ca2+ (30%), normal alk phos.
  • Prognostic tests: β2-microglobulin and albumin.
  • Blood film: rouleaux formation (stacked RBCs).

  Serum and urine electrophoresis:

  • May show monoclonal band and/or raised free light chains.
  • Key screening test, but may be negative in a small number.

  Imaging:

  • Used to detect bone lesions and extra-medullary plasmacytomas.
  • Whole-body MRI 1st line. 2nd line CT, 3rd line skeletal survey.

  Screening

  Serum electrophoresis and ESR on all patients aged >50 with new back pain.

  Diagnosis

  Requires both:

  1. Bone marrow aspirate and/or biopsy showing clonal plasma cells ≥10% or biopsy-proven extramedullary plasmactyoma.
  2. ≥1 of myeloma-related organ dysfunction, CRAB (↑Ca2+, Renal insufficiency, Anaemia, lytic Bone lesions) or biomarkers suggesting very high risk of progression to organ dysfunction.

• Management

  Treating symptoms and complications:

  • Bisphosphonates and analgesia for bone disease. Radiotherapy and/or surgical stabilisation if fractures occur or there is high fracture risk.
  • Transfusions and/or EPO for anaemia.
  • Fluids for kidney failure, or renal replacement therapy if severe.
  • Fluids ± bisphosphonates for ↑Ca2+.
  • Antibiotics for infections. Consider prophylactic antibiotics, antivirals, vaccines, and immunoglobulins for prevention.

  Specific treatment:

  • If suitable for autologous haematopoietic stem cell transplant (HCT): induction chemotherapy → stem cell mobilization using cyclophosphamide and/or G-CSF then harvesting via apheresis → eliminate residual disease in patient ('conditioning') with melphalan ± radiation → stem cells reinfused.
  • Chemotherapy alone if unsuitable for HCT: older (>65 is a common cut-off), severe frailty, co-morbidities.
  • Many chemo regimens available. Common 1st line is bortezomib + dexamethasone ± lenalidomide or thalidomide. In patients not suitable for HCT, regimens may include alkylating agents (melphalan, cyclophosphamide). Daratumumab is a highly effective new agent likely to become widely used in coming years.
  • Allogenic HCT may be the only truly curative treatment but has a high risk of treatment-related mortality, so is not widely used.

• Complications and prognosis

  • Hyperviscosity syndrome.
  • Spinal cord compression.
  • Median survival: 3-4 years. Death usually from infection or kidney failure.

• Hyperviscosity syndrome

  Definition

  An increase in plasma viscosity, usually due to elevated immunoglobulins/paraproteins, RBCs, or WBCs.

  Causes

  • Myeloma
  • Waldenström's macroglobulinaemia.
  • Polycythaemia vera.
  • Leukaemia
  • ↑Plasma viscosity is also a non-specific marker of inflammation (like ESR).

  Signs and symptoms

  Classic triad:

  • Neurological symptoms: impaired cognition, headache, seizures.
  • Visual changes from retinopathy.
  • Mucosal bleeding.

  Management

  Plasmapheresis.