Guideline:
Multiple myeloma (MM)
Bibliographic Source(s)
- Finnish Medical Society Duodecim. Multiple myeloma (MM). In: EBM Guidelines. Evidence-Based Medicine [Internet]. Helsinki Finland: Wiley Interscience. John Wiley & Sons; 2007 May 30 [Various].
Guideline Status
This is the current release of the guideline.
This guideline updates a previous version: Finnish Medical Society Duodecim. Multiple myeloma (MM). In: EBM Guidelines. Evidence-Based Medicine [Internet]. Helsinki Finland: Wiley Interscience. John Wiley & Sons; 2005 May 1 [Various].
Guideline Category
Diagnosis
Evaluation
Management
Treatment
Intended Users
Health Care Providers
Physicians
Guideline Objective(s)
Evidence-Based Medicine Guidelines collect summarize and update the core clinical knowledge essential in general practice. The guidelines also describe the scientific evidence underlying the given recommendations.
Target Population
- Patients with multiple myeloma (MM)
- Patients requiring evaluation for possible multiple myeloma
Interventions and Practices Considered
Evaluation/Diagnosis
- Use of World Health Organization (WHO) Diagnostic Criteria
- Differential diagnosis
- Laboratory tests: blood picture serum calcium potassium natrium and creatinine and erythrocyte sedimentation rate (ESR); bone marrow examination; serum and urine protein electrophoresis
- Additional investigations as indicated:
- X-ray (skull thorax/ribs backbone 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)
- Identification of M component heavy and light chains by immunofixation or by other means
- Magnetic resonance imaging as indicated
Treatment/Management
- Early treatment of complications
- Follow-up including assessment of:
- The amount of M component (serum and/or urine)
- Degree of bone marrow infiltrates
- General condition and symptoms infections and (bone) pains
- Osteolytic lesions (x-ray)
- Renal function hypercalcaemia and blood picture
- Pharmacologic treatment
- Cytotoxic drugs (vincristine melphalan cyclophosphamide adriamycin) often combined with corticosteroids
- Corticosteroids (dexamethasone or methylprednisolone)
- Thalidomide or lenalidomide
- Bortezomib
- Interferon
- Supportive therapy
- Maintenance of fluid and electrolyte balance
- Treatment of hypercalcaemia
- Treatment of infections
- Maintenance of mobility
- Treatment of anaemia and thrombocytopenia (red blood cell and platelet transfusions erythropoietin)
- Analgesia for pain relief
- Radiotherapy for focal skeletal foci
- Bisphosphonates for hypercalcemia
- Intensive treatment with the support of autologous stem cell transplantation
- Allogeneic stem cell transplantation
Major Outcomes Considered
- Survival (lifetime and progression-free)
- Mortality
- Adverse effect associated with treatment
Methods Used to Collect/Select Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods used to Collect/Select the Evidence
The evidence reviewed was collected from the Cochrane database of systematic reviews and the Database of Abstracts of Reviews of Effectiveness (DARE). In addition the Cochrane Library and medical journals were searched specifically for original publications.
Number of Source Documents
Not stated
Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence
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
Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review
Description of the Methods Used to Analyze the Evidence
Not stated
Methods Used to Formulate the Recommendations
Not stated
Rating Scheme for the Strength of the Recommendations
Not applicable
Cost Analysis
A formal cost analysis was not performed and published cost analyses were not reviewed.
Method of Guideline Validation
Peer Review
Description of Method of Guideline Validation
Not stated
Major Recommendations
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/100000/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
Clinical Algorithm(s)
None provided
References Supporting the Recommendations
- Djulbegovic B Wheatley K Ross J Clark O Bos G Goldschmidt H Cremer F Alsina M Glasmacher A. Bisphosphonates in multiple myeloma. Cochrane Database Syst Rev 2002;(4):CD003188.
- He Y Wheatley K Clark O Glasmacher A Ross H Djulbegovic B. Early versus deferred treatment for early stage multiple myeloma. Cochrane Database Syst Rev 2003;(1):CD004023. [28 references] PubMed
- Johnson PW Simnett SJ Sweetenham JW Morgan GJ Stewart LA. Bone marrow and peripheral blood stem cell transplantation for malignancy. Health Technol Assess 1998;2(8):1-187. [209 references] PubMed
- Trippoli S Becagli P Messori A Trendi E. Maintenance treatment with interferon in multiple myeloma: a survival meta-analysis. Clin Drug Invest 1997;14:392-9.
- Woo SB Hellstein JW Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006 May 16;144(10):753-61. [71 references] PubMed
Type of Evidence supporting the Recommendations
Concise summaries of scientific evidence attached to the individual guidelines are the unique feature of the Evidence-Based Medicine Guidelines. The evidence summaries allow the clinician to judge how well-founded the treatment recommendations are. The type of supporting evidence is identified and graded for select recommendations (see the "Major Recommendations" field).
Potential Benefits
Reduction of symptoms and prevention of complications through early diagnosis and treatment
Potential Harms
Osteonecrosis of the jaw may be associated with the use of high doses of intravenous aminobisphosphonates in patients with myeloma or metastatic cancer
Description of Implementation Strategy
An implementation strategy was not provided.
IOM Care Need
Living with Illness
IOM Domain
Effectiveness
Bibliographic Source(s)
- Finnish Medical Society Duodecim. Multiple myeloma (MM). In: EBM Guidelines. Evidence-Based Medicine [Internet]. Helsinki Finland: Wiley Interscience. John Wiley & Sons; 2007 May 30 [Various].
Adaptation
Not applicable: The guideline was not adapted from another source.
Source(s) of Funding
Finnish Medical Society Duodecim
Guideline Committee
Editorial Team of EBM Guidelines
Composition of Group that Authored the Guideline
Primary Authors: Petri Oivanen and Marjatta Sinisalo
Financial Disclosures/Conflicts of Interest
Not stated
Guideline Status
This is the current release of the guideline.
This guideline updates a previous version: Finnish Medical Society Duodecim. Multiple myeloma (MM). In: EBM Guidelines. Evidence-Based Medicine [Internet]. Helsinki Finland: Wiley Interscience. John Wiley & Sons; 2005 May 1 [Various].
Guideline Availability
This guideline is included in a CD-ROM titled "EBM Guidelines. Evidence-Based Medicine" available from Duodecim Medical Publications Ltd PO Box 713 00101 Helsinki Finland; e-mail: info@ebm-guidelines.com; Web site: www.ebm-guidelines.com.
Availability of Companion Documents
None available
Patient Resources
None available
NGC STATUS
This summary was completed by ECRI on December 17 2002. The information was verified by the guideline developer as of February 7 2003. This NGC summary was updated by ECRI on October 5 2004 June 24 2005 and January 3 2008. This summary was updated by ECRI Institute on March 21 2008 following the FDA advisory on Erythropoiesis Stimulating Agents. This summary was updated by ECRI Institute on August 15 2008 following the U.S. Food and Drug Administration advisory on Erythropoiesis Stimulating Agents (ESAs).
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