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Myeloma and monoclonal gammopathy of undetermined significance (MGUS)

Presentation, diagnosis and treatment of myeloma and MGUS – for doctors, medical students and exams



Definition of myeloma

  • Myeloma is a cancer of plasma cells, commonly associated with a monoclonal paraprotein and bone damage.
  • Definition of active myeloma:
    • Clonal plasma cells constitute >10% of nucleated cells in a bone marrow biopsy OR biopsy-proven plasmacytoma, AND additionally at least one of:
      • Hypercalcaemia (not attributable to hyperparathyroidism or other malignancy)
      • Renal failure (not attributable to another cause)
      • Anaemia (not attributable to another cause)
      • One or more osteolytic bone lesions
      • >60% clonal plasma cells in bone marrow
      • Ratio of involved : uninvolved serum free light chains >100
      • >1 focal bone lesion on MRI >5mm
  • Definition of smoldering myeloma:
    • Clonal bone marrow plasma cells 10-60%, or serum paraprotein (IgG or IgA) ≥30g/L, or urinary paraprotein >500mg/24hrs, AND:
    • Not meeting the above criteria for active myeloma


Definition of Monoclonal Gammopathy of Undetermined Significance (MGUS)

  • A pre-malignant disorder with a 5% annual risk of progression to myeloma
  • The presence of a paraprotein or abnormal free light chain ratio not meeting criteria for smoldering myeloma or active myeloma (i.e. serum paraprotein <30g/L, clonal bone marrow plasma cells <10%, no attributable end-organ damage)
  • IgM MGUS is associated with an increased risk of progression to lymphoplasmacytic lymphoma (a.k.a. Waldenström’s macroglobulinaemia)


Definitions of related plasma cell disorders

  • A solitary plasmacytoma is a discrete soft tissue mass comprising clonal plasma cells, which may be found present in the bone marrow, or elsewhere (‘extramedullary’). It may be associated with a low level (<10%) clonal plasma cell infiltrate in the bone marrow.
  • AL amyloidosis is a disease where amyloid protein containing light chains is deposited in various organs, associated with a clonal plasma disorder.


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Epidemiology of myeloma and MGUS

  • Median age at diagnosis is 73
  • They are slightly more common in men than in women
  • MGUS is common in later life, with an annual incidence of 35 cases per 100,000 population in the over-65s, and the highest prevalence of any haematological neoplasm (due to the low mortality)
  • Myeloma has a similar incidence but a lower prevalence due to shorter survival
  • Myeloma is the second most common haematological cancer, after NHL, and makes up 1% of all cancers in the UK


Risk factors for myeloma and MGUS

  • Older age
  • In most cases no risk factors are identified
  • Ionizing radiation (e.g. prior radiotherapy) increases risk
  • There is  a modest heritable risk, though implicated gene mutations have not been identified


Pathophysiology of myeloma

  • Clonal plasma cells secrete a clonal immunoglobulin (paraprotein) which can, at high concentrations, cause hyperviscosity and deposition in renal tubules.
  • They also secrete cytokines, particularly IL-6, which activate osteoclasts, causing lytic lesions and hypercalcaemia, and the hypercalcaemia in turn can cause nephrogenic diabetes insipidus, dehydration and acute kidney injury.
  • Some plasma cell clones also secrete the light chain component of immunoglobulin without associated heavy chains. These free light chains are frequently the cause of acute kidney injury due to deposition in glomerular basement membranes (light chain deposition disease), or in renal tubules (cast nephropathy).
  • Heavy bone marrow infiltration can suppress normal haematopoiesis, leading to anaemia and more rarely neutropenia. Thrombocytopenia is uncommon because the cytokines secreted by plasma cells promote megakaryocyte proliferation and platelet production.


Video on the basics of myeloma


Presentations of myeloma

  • Short mnemonic: CRAB
    • Calcium, Renal failure, Anaemia, Bone pain
  • Fuller answer
    • Renal failure
    • Symptoms of hypercalcaemia (polydipsia, polyuria, confusion, constipation)
    • Bone pains or pathological fractures (often spinal, may cause malignant spinal cord compression)
    • Symptoms of anaemia (shortness of breath, fatigue, dizzyness)
    • Incidental finding on checking immunoglobulins
    • Recurrent infection due to hypogammaglobulinaemia
    • Rarely, hyperviscosity syndrome
    • Rarely, mass effect from extramedullary plasmacytoma
    • Very rarely, paraneoplastic neuropathy (usually sensory)


Prognostic scoring of myeloma

  • Although called ‘staging’ these are not staging systems in the conventional sense, of describing the extent of a cancer, but rather predict prognosis based on the patient’s and disease’s biology
  • The Durie-Salmon staging system was introduced in 1975, but is complex, partly subjective, and a less reliable prediction tool for survival than the International Staging System (ISS), developed in 2005:
    • Stage I – serum β2-microglobulin <3.5mg/L AND albumin >35 g/L
    • Stage II – neither stage I nor stage III
    • Stage III – serum β2-microglobulin > 5.5mg/L
  • The ISS was refined in 2015 by the addition of cytogenetic variables, to generate the Revised ISS
    • Stage I – serum β2-microglobulin <3.5mg/L AND albumin >35 g/L AND standard risk cytogenetics AND normal LDH
    • Stage II – neither R-ISS stage I nor stage III
    • Stage III – serum β2-microglobulin > 5.5mg/L AND either high risk cytogenetics or high LDH
    • High risk cytogenetic abnormalities are deletion of 17p, t(4;14) and t(14;16). All others are standard risk
  • Median survival overall is 5 years from diagnosis.
  • Survival rates at 5 years are 82% for R-ISS stage I, 62% for R-ISS stage II, and 40% for R-ISS stage III


Initial management of myeloma

Emergency management of complications
  • Hypercalcaemia
    • IV fluid (with loop diuretics e.g. furosemide 20mg od if at risk of fluid overload) with bisphosphonate e.g. zoledronate 4mg iv if severe
  • Renal failure
    • Hydration, cessation of nephrotoxic drugs, and dialysis if required
  • Spinal cord compression
    • Neurosurgical decompression or radiotherapy
  • Bone damage
    • Prophylactic surgical fixation or vertebroplasty
Investigation of presumptive myeloma
  • Bloods
    • FBC, U+E, Bone profile (note alkaline phosphatase is not raised in myeloma), LFT, Group and save, immunoglobulins, serum protein electrophoresis, serum free light chains, LDH, β2 microglobulin, HIV serology, Hepatitis B and C serology
  • Urine
    • Proteinuria, and Bence-Jones Protein (urine light chains)
  • Skeletal imaging
    • Either MRI whole body (if available), CT whole body or skeletal survey
  • Bone marrow aspirate
    • BMA with trephine, immunophenotyping and cytogenetic analysis


Early management of myeloma

  • Steroids
    • In the presence of an emergency complication where treatment must be started immediately, as soon as the bone marrow biopsy has been performed commence high dose steroids
    • e.g. dexamethasone 40mg po od for 4 days, with PPI cover
      • Dose can be reduced to 20mg or 10mg od for heart failure or frailty


Further management of myeloma

General principles
  • Myeloma is not curable, and treatment aims to induce remissions and slow or reverse end-organ damage. The disease often remains responsive to different lines of treatment for many years and so can be re-treated at relapse, though lengths of remission tend to shrink with successive lines of therapy.
  • Two new classes of drugs have dramatically improved survival in myeloma since the early 2000s: immunomodulatory drugs e.g. thalidomide, lenalidomide, pomalidomide; and proteasome inhibitors e.g. bortezomib, carfilzomib, ixazomib.
  • Several newer classes have lately been licensed e.g. histone deacetylase inhibitors, monoclonal antibodies.
  • These new agents are expensive, to the extent that many are not available to most patients.
Initial treatment
  • In patients deemed medically fit, consolidation with high dose melphalan and autologous stem cell rescue (‘autograft‘) can prolong remissions.
  • Radiotherapy to bulky plasmacytomas can help relieve symptoms and prevent future fractures
Longer term
  • The role of long-term maintenance therapy after initial treatment remains disputed.
  • At relapse, other combinations of the 5 drugs listed can be used, or combinations including newer agents such as pomalidomide, ixazomib, carfilzomib, panobinostat, daratumumab, elotuzumab, bendamustine can be used if funding is available.


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