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Editors

MarjattaSinisalo
OutiLaine

Multiple Myeloma (Mm)

Essentials

  • Affects primarily middle-aged and elderly patients.
  • Recognize complications that require prompt intervention.
  • A symptomless patient is usually not treated, whereas a symptomatic patient is actively treated.

Pathology

  • MM is a malignant clonal proliferation of mature B cells (plasma cells). Clonal plasma cells only produce one monotonous type of immunoglobulin (M component, a paraprotein).
    • The paraprotein may either be a complete immunoglobulin (including both heavy and light chains) or it may be composed of light chains only.
    • The most common paraprotein is IgG kappa/lambda, followed by IgA kappa/lambda and pure light chain paraprotein in order of frequency. IgD kappa/lambda is rare, and IgM paraprotein is almost without exception associated with Waldenström's macroglobulinaemia. IgM myeloma is extremely rare.
    • In rare cases, more than one paraprotein can be identified, and in some cases (< 3%) the tests remain negative for paraproteins.

Epidemiology

  • Approximately 5 new cases/100 000/year.
  • The disease affects middle-aged and elderly persons; the age at the time of diagnosis is 68-70 years on average. 10% of the patients are less than 50 years old, and 2% are less than 40 years old.
  • No sex differences
  • Not inheritable, but in some rare cases, different malignant B cell diseases (Waldenström's macroglobulinaemia Waldenström's Macroglobulinaemia (WM), CLL Chronic Lymphocytic Leukaemia (CLL), in addition to myeloma) are found in close relatives with higher than usual frequency.

Aetiology

  • Unknown. However, many changes typical of myeloma can be identified in the chromosomes of the bone marrow; these also affect the prognosis of the disease.

Diagnostic criteria of myeloma

  • Both of the following two criteria have to be met for a myeloma that requires treatment.
    • At least 10% clonal plasma cells on bone marrow biopsy or biopsy-confirmed extramedullary plasmacytoma
    • End-organ damage ("CRAB") attributable to myeloma
      • Hypercalcaemia (C)
      • Renal insufficiency (R)
      • Anaemia (A)
      • Lytic bone lesions (B)
  • Clonality is demonstrated either by flow cytometry or immunohistochemically.
  • Myeloma diagnosis can also be established without CRAB symptom if bone marrow clonal plasma cells are ≥ 60%, or if bone marrow plasma cells are ≥ 10% and the serum free light chain ratio is clearly abnormal (≥ 100, and the concentration of the abnormal free light chain should be at least 100 mg/l) or skeletal MRI studies show a > 5 mm focal change.

Differential diagnostics

  • Smoldering myeloma (does not require treatment)
    • Serum paraprotein ≥ 30 g/l and 10-60% plasma cells in the bone marrow, but no end-organ damage and no amyloidosis
    • Usually follow-up without treatment
  • Monoclonal gammopathy of undetermined significance (MGUS)
    • Paraprotein < 30 g/l, no end-organ damage
    • Plasma cells in bone marrow < 10%
    • Follow-up without treatment
  • Solitary plasmacytoma
    • < 10% clonal plasma cells in the bone marrow, no other bone changes, no end-organ damage
  • Waldenström's macroglobulinaemia Waldenström's Macroglobulinaemia (WM)
    • The paraprotein is IgM and the bone marrow is infiltrated by lymphocytic cells, no bone changes.
  • Lymphomas associated with a paraprotein

Clinical picture

  • Often
    • Osteolytic lesions and bone pains
    • Anaemia, hypercalcaemia, hyperuricaemia
    • Renal insufficiency
    • Plasmacytoma located in soft tissue
  • Rarely
    • Hyperviscosity syndrome (especially IgA myeloma)

Typical laboratory findings

  • Increased erythrocyte sedimentation rate (not in light-chain myeloma)
  • Paraprotein in serum and/or urine, either of the serum free light chains (kappa/lambda) elevated and their ratio abnormal
  • Decreased haemoglobin level, often also leuco- and thrombocytopenia
  • Malignant plasma cell infiltrates in the bone marrow
  • Osteolytic lesion in bone x-ray
  • Often increased plasma urate and calcium but diminished albumin concentration

Basic examinations

  • Basic blood count with platelets, plasma calcium, potassium, sodium and creatinine and ESR
  • Bone marrow examination
  • Serum protein electrophoresis and serum free light chains

Additional investigations when MM is certain or likely

  • Radiological assessment: low-dose CT, if available (without contrast medium), or plain X-rays (skull, thorax/ribs, vertebrae, scapulae, pelvis and long bones of the extremities)
  • Plasma total protein, albumin, urate and immunoglobulins (IgG, IgA, IgM, sometimes IgD), serum free light chain assay, urinary light chains
  • Paraprotein typing by immunofixation
  • Magnetic resonance imaging is more sensitive than radiography, but is seldom indicated in basic diagnosis. Scintigraphy usually does not reveal lytic changes.

Complications requiring immediate attention

  • Sepsis or pneumonia (intravenous broad-spectrum antimicrobial drug)
  • Renal insufficiency (dialysis or haemofiltration)
  • Hypercalcaemia (fluid replacement, bisphosphonates, glucocorticoids)
  • Spinal cord compression (surgical decompression, radiotherapy?)
  • Pathological fractures (pain medication, stabilization)
  • Vertebral compression (orthopaedic treatment)
  • Hyperviscosity symptoms (plasmapheresis)

Disease progression and prognosis

  • Myeloma can be classified as a low-risk, an intermediate-risk or a high-risk disease based on e.g. chromosomal changes, amount of paraprotein, haemoglobin concentration, renal damage, and concentrations of calcium, albumin and beta-2-microglobulin.
  • Risk classification has a great impact on prognosis; the median life expectancy varies from 2 years to over 10 years. The average life expectancy of a patient diagnosed with myeloma has in any case been almost doubled during the past 20 years, being now about 7-8 years.
  • Myeloma cells become gradually resistant to chemotherapy.
  • Cytopenias, Infections and renal insufficiency frequently make the disease worse.

Follow-up and treatment

  • If the patient is symptomless, no specific therapy is usually given.
  • Symptomatic patients are treated actively.
  • In follow-up, attention is paid to
    • the amount of paraprotein
    • the blood picture (reflects the degree of bone marrow infiltrates)
    • general condition and symptoms, infections and (bone) pains
    • osteolytic lesions (x-ray)
    • renal function and hypercalcaemia.
  • Follow-up of patients with MGUS (symptoms, general condition and determination of paraprotein or the immunoglobulin involved) is carried out in primary health care.

Pharmacological treatment of myeloma

  • Many myeloma drugs with new mechanisms of action have become available alongside of the traditional cytotoxic agents. This also makes the treatment choices more difficult, and therefore it is advisable that these are made by haematologists or specialists in internal medicine who are familiar with the treatment of haematological diseases.
  • Intensive therapy with the support of autologous stem cell transplantations is the first-line treatment for patients under 70(-75) years. In young patients (< 50-60 years) with a genetic profile predicting poor prognosis, also allogeneic stem cell transplantation can sometimes be considered.
  • Myeloma treatment almost always includes a glucocorticoid (usually dexamethasone) together with different combinations of the following myeloma drugs:

Supportive therapy

  • Maintenance of fluid and electrolyte balance (to prevent renal failure)
  • Treatment of hypercalcaemia
  • Treatment of infections
  • Maintenance of mobility in order to prevent osteoporosis and pathological fractures
  • If necessary, treatment of anaemia and thrombocytopenia (red blood cell and platelet transfusions, epoetin or darbepoetin)
  • Alleviation of pain with analgesics
  • Radiotherapy for local skeletal foci is quite common.
  • BisphosphonatesBisphosphonates in Multiple Myeloma and denosumab to prevent and to decelerate the progression of bony changes and to treat hypercalcaemia (generally in 2 years)
  • Pneumococcal and influenza vaccinations in patients with myeloma should be taken care of.
  • If the treatment includes a high-dose glucocorticoid, Pneumocystis jirovecii prophylaxis must be taken care of (sulpha-trimethoprim, dapsone, pentacarinat).
  • Thromboprophylaxis with either ASA or LMWH (especially in treatment with thalidomide, lenalidomide and pomalidomide)