The levels of evidence [A-D] supporting the recommendations are defined at the end of the "Major Recommendations" field.
Aim
To recognize symptoms that require early intervention
Pathology
- Multiple myeloma (MM) is a clonal bone marrow proliferation of mature B cells (plasma cells) characterized by a monoclonal immunoglobulin fraction (M component, a paraprotein) in the serum or sometimes only in urine protein electrophoresis.
- "Benign" disease forms (MGUS or monoclonal gammopathy with unknown significance) are about 100 times more common than myeloma.
Epidemiology
- Approximately 3 to 4 new cases/100,000/year
- Diagnosis is usually made at the age of 50 to 70 years, rarely before the age of 40 years.
- No sex differences
Aetiology
- Unknown.
- Ionizing radiation slightly increases the risk.
Diagnosis
- The main diagnostic difficulty is to make a distinction between early cases of MM and "benign" paraproteinaemias.
Criteria for Diagnosis of Multiple Myeloma (World Health Organization [WHO] Classification)
- The diagnosis of multiple myeloma requires one main criterion and at least one additional criterion OR three additional criteria, which include C1 and C2. In addition, the disease has to be symptomatic and progressive.
- Main criteria
- Bone marrow plasmacytosis (>30%)
- Plasmacytoma in biopsy
- M component
- Serum/plasma: Immunoglobulin G (IgG) >35 g/L, IgA >20 g/L
- Urine: >1 g/24 h
- Additional criteria
- Bone marrow plasmacytosis (10–30%)
- M component (smaller than in point B)
- Osteolytic lesions
- Decrease of polyclonal immunoglobulins in serum
- IgG <6 g/L
- IgA <1 g/L
- IgM <0.5 g/L
Differential Diagnostics
- MGUS (plasma cells in bone marrow <10%; IgG <35 g/L or IgA <20 g/L, no osteolytic foci, no symptoms). The WHO classification 2001 also includes the traditional "benign" paraproteinaemia in this group.
- Waldenström's macroglobulinaemia (See Finnish Medical Society Duodecim guideline "Waldenström's macroglobulinaemia [WM]")
- Lymphomas with an M component in some cases
- Other rare diseases where there is an M component
Clinical Picture
- Often:
- Osteolytic lesions and bone pains
- Mild anaemia, hypercalcaemia, hyperuricaemia
- Renal insufficiency
- Rarely:
- Hyperviscosity syndrome (IgA myeloma)
Typical Laboratory Findings
- Increased erythrocyte sedimentation rate (ESR) (not in light-chain myeloma)
- M component in serum and/or urine
- Decreased haemoglobin level, often also leuco- and thrombocytopenia
- Malignant plasma cell infiltrates in the bone marrow
- Osteolytic lesion in bone x-ray
- Often increased serum urate and calcium but diminished albumin concentration
Basic Examinations
- Blood picture, serum calcium, potassium, natrium and creatinine, and ESR
- Bone marrow examination
- Serum and urine protein electrophoresis (M component can be found exclusively in urine in only 10 to 20% of MM patients)
Additional Investigations when MM is Likely
- X-ray (skull, thorax/ribs, vertebrae, scapulae, pelvis, and long bones of the extremities)
- Serum/plasma total protein, albumin, potassium, sodium, calcium, ionised calcium, creatinine, urate, and immunoglobulins (IgG, IgA, IgM, sometimes IgD)
- Identification of M component heavy and light chains by immunofixation or by other means
- Magnetic resonance imaging is more sensitive than radiography, but is seldom indicated in basic diagnosis. Scintigraphy does not reveal lytic changes.
Complications Requiring Attention Preferably Within 24 Hours (Particularly in New Patients)
- Sepsis or pneumonia (intravenous broad-spectrum antibiotics)
- Renal insufficiency (dialysis or haemofiltration)
- Hyperviscosity (plasmapheresis)
- Hypercalcaemia (fluid replacement, bisphosphonates, steroids)
- Spinal cord compression (surgical decompression, radiotherapy)
- Pathological fractures (pain medication, stabilization)
- Vertebral compression (orthopaedic treatment)
Disease Progression and Prognosis
- With traditional therapies, median life expectancy at diagnosis is about 3.5 to 4 years and somewhat longer with more intensive treatments. Marked individual variation exists.
- Myeloma cells become gradually resistant to chemotherapy.
- Myeloma cell infiltrates occupy the bone marrow causing anaemia, thrombocytopenia, and leucopenia.
- Infections, haemorrhages, and renal insufficiency are frequent complications.
Follow-up and Treatment
- If the patient is symptomless, no chemotherapy is usually given, as it does not improve the patient´s well being or prolong life.
- Symptomatic patients are treated actively.
In Follow-up, Attention is Paid to:
- The amount of M component (serum and/or urine)
- 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
Pharmacological Treatment of Myeloma
- According to instructions given by a haematologist or a specialist in internal medicine who is familiar with the treatment of haematological diseases. The aim is usually intensive therapy with the support of autologous stem cell transplantations (patients under 70 years).
- Cytotoxic drugs (cyclophosphamide, melphalan, vincristine or adriamycin), often combined with corticosteroids
- Corticosteroid alone (either dexamethasone or methylprednisolone)
- Thalidomide (or lenalidomide) either alone or in combination with other drugs
- Bortezomib (proteasome inhibitor)
- Interferon in individual cases, usually in order to sustain the achieved treatment response
Supportive Therapy Includes:
- 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, erythropoietin)
- Alleviation of pain with analgesics
- Radiotherapy for local skeletal foci is quite common.
- Bisphosphonates (Djulbegovic et al., 2002) [A] to prevent and to decelerate the progression of bony changes and to treat hypercalcaemia
Stem Cell Transplantation
- Intensive treatment with the support of autologous stem cell transplantation is used increasingly and is often the first-line treatment for patients over 70 years of age (Johnson et al., 1998; DARE-989011, 2000) [C].
- Allogeneic stem cell transplantation is also used increasingly, but it is still possible only for few patients.
Related Resources
Cochrane Reviews
- Early treatment of early stage multiple myeloma appears to inhibit disease progression and reduce vertebral compression. However, early treatment may increase the risk of acute leukemia (He et al., 2003) [B].
- Bisphosphonates (clodronate and pamidronate) prevent pathological vertebral fractures and reduce pain in multiple myeloma (Djulbegovic et al., 2002) [A].
Other Evidence Summaries
- There appears to be no significant survival advantage of interferon in the maintenance treatment of multiple myeloma (Trippoli et al., 1997) [B].
- Osteonecrosis of the jaw may be associated with the use of high doses of intravenous aminobisphosphonates in patients with myeloma or metastatic cancer (Woo, Hellstein, & Kalmar, 2006) [C].
Refer to the original guideline document for other Internet resources, resources for the patient, and other literature.
Definitions:
Levels of Evidence
- Quality of Evidence: High
Further research is very unlikely to change confidence in the estimate of effect
- Several high-quality studies with consistent results
- In special cases: one large, high-quality multi-centre trial
- Quality of Evidence: Moderate
Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate.
- One high-quality study
- Several studies with some limitations
- Quality of Evidence: Low
Further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate.
- One or more studies with severe limitations
- Quality of Evidence: Very Low
Any estimate of effect is very uncertain.
- Expert opinion
- No direct research evidence
- One or more studies with very severe limitations
