This article appears in the following Annals of Oncology issue: ESMO Clinical Recommendations [View the issue table of contents]
ESMO clinical recommendations |
Multiple myeloma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up
1 Department of Hematology, University Hospital Hotel-Dieu, Nantes, France
2 Department of Medicine III, University Hospital Grosshadern, LMU Munich, Germany
* Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalrecommendations{at}esmo.org
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incidence |
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 Top incidence diagnosisstaging and risk assessmenttreatmentconsolidationtreatment of relapsed/refractory...response evaluationfollow-upnotereferences |
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The incidence of multiple myeloma (MM) in Europe is 6.0/100 000/year with a median age at diagnosis of between 63 and 70 years; the mortality is 4.1/100 000/year.
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diagnosis |
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Topincidencediagnosisstaging and risk assessmenttreatmentconsolidationtreatment of relapsed/refractory...response evaluationfollow-upnotereferences |
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Diagnosis should be based on the following tests:
- Detection and evaluation of the monoclonal (M) component by serum and urine protein electrophoresis (concentrate of 24-h urine); quantification of IgG, IgA and IgM immunoglobulins; characterization of the heavy and light chains by immunofixation; serum-free light-chain measurement for identifying and monitoring non-secretory MM.
- Evaluation of bone marrow plasma cell infiltration. Bone marrow aspiration and biopsy are the standard option to detect quantitative and/or qualitative abnormalities of bone marrow plasma cells.
- Evaluation of lytic bone lesions. Full skeleton X-ray survey is recommended. Optional magnetic resonance imaging (MRI) provides greater details and is recommended if a spinal cord compression is suspected.
- Biological assessments to differentiate symptomatic and asymptomatic MM: hemoglobin (and full blood cell count), serum creatinine and calcium level (CRAB classification).
- Evaluation of bone marrow plasma cell infiltration. Bone marrow aspiration and biopsy are the standard option to detect quantitative and/or qualitative abnormalities of bone marrow plasma cells.
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staging and risk assessment |
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Topincidencediagnosisstaging and risk assessmenttreatmentconsolidationtreatment of relapsed/refractory...response evaluationfollow-upnotereferences |
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Previously, the most commonly used staging system had been the Durie–Salmon classification (Table 1).
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A number of biological parameters are of prognostic importance (β2-microglobulin, C-reactive protein, lactate dehydrogenase and serum albumin). The level of β2-microglobulin is used most commonly. Combining it with serum albumin has lead to a new International Staging System (ISS) which is a more convenient and reproducible classification (Table 2).
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Cytogenetics is a major prognostic factor and should be obtained either by conventional karyotyping or FISH analysis. The most relevant abnormalities are del(13q), t(4;14) and del(17p), which are associated with a poorer outcome.
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treatment |
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Topincidencediagnosisstaging and risk assessmenttreatmentconsolidationtreatment of relapsed/refractory...response evaluationfollow-upnotereferences |
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stage I or asymptomatic myeloma
Immediate treatment is not recommended for patients with indolent myeloma.
advanced stage or symptomatic myeloma (CRAB) (II or III)
elderly patients. Oral combination of melphalan (9 mg/m2/day for 4 days) and prednisone (30 mg/m2/day for 4 days) was previously the standard of treatment for patients ineligible for high-dose chemotherapy with stem-cell support [I, A]. Cycles are repeated every 4–6 weeks until a stable response is achieved. Multiagent chemotherapy has not been proved superior and may even be inferior in elderly patients [I, A].
Recently, two randomized studies have shown that the combination of melphalan–prednisone with thalidomide (100 mg/day) is superior to melphalan–prednisone [I, A]. Bortezomib in combination with melphalan–prednisone also achieved significantly higher survival rates [I, A]. Another novel agent (lenalidomide) is currently being tested with low-dose dexamethasone in patients >65 years of age.
younger patients (<65 years). For patients in good clinical condition, high-dose therapy with autologous stem-cell transplantation (ASCT) is the standard treatment [II, B].
Attempts to increase the complete remission rate before autologous transplantation are ongoing. Currently, the induction therapy should be dexamethasone-based in order to avoid stem-cell damage induced by alkylating agents. In randomized studies, combinations of novel agents (thalidomide or bortezomib) plus dexamethasone are superior to the classical VAD regimen (vincristine, adriamycine and high-dose dexamethasone).
Melphalan 200 mg/m2 i.v. is the preparative regimen before autologous transplantation [II, B]. Peripheral blood progenitor cells should be used as the source of stem cells, rather than bone marrow [III, B].
Double ASCT: Three randomized studies show superiority of double versus single ASCT. However, the French (IFM 94) and Italian study suggests that double ASCT does not benefit patients in complete remission after one ASCT.
Long-term administration of bisphosphonates (oral or i.v.) reduces the incidence of skeletal events and should be proposed for patients with stage III or relapsed disease receiving conventional dose chemotherapy [II, A].
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consolidation |
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Topincidencediagnosisstaging and risk assessmenttreatmentconsolidationtreatment of relapsed/refractory...response evaluationfollow-upnotereferences |
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There is no convincing evidence that post-transplantation therapy with interferon is useful, but based on three randomized studies, thalidomide maintenance increases the complete remission rate and prolongs progression-free survival and overall survival.
Although encouraging data with tandem auto/reduced intensity conditioning allotransplant have been published recently, this strategy should not be proposed for standard risk patients as first-line treatment due to a transplant-related mortality of 10%–15% and the risk of chronic GVH. In high-risk patients, upfront allogeneic transplantation should only be performed within clinical trials.
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treatment of relapsed/refractory myeloma |
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Topincidencediagnosisstaging and risk assessmenttreatmentconsolidationtreatment of relapsed/refractory...response evaluationfollow-upnotereferences |
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Regimens similar to those used initially can induce a second remission. VAD is no longer considered the standard option for patients in relapse.
Thalidomide is used mostly in combination with dexamethasone and/or chemotherapy (initial dose 100–200 mg/day) and results in an increased risk of deep vein thrombosis; therefore, at least in patients with increased risk (high tumor burden, history of thrombosis), anticoagulation prophylaxis should be administered.
Bortezomib is used either alone or in combination with dexamethasone or with chemotherapy; especially, it is also active in patients with unfavourable cytogenetics. A recently completed randomized trial shows that bortezomib in combination with pegylated liposomal doxorubicin is superior to bortezomib alone.
Lenalidomide (in combination with dexamethasone) has been shown to be superior to dexamethasone alone and seems to overcome the negative impact of unfavourable cytogenetics.
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response evaluation |
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Topincidencediagnosisstaging and risk assessmenttreatmentconsolidationtreatment of relapsed/refractory...response evaluationfollow-upnotereferences |
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Assessment of response is based on serum and urine electrophoresis.
In patients with no M-component in serum and urine, complete remission assessment requires bone marrow aspiration (<5% plasma cells) and immunofixation. Evaluation of free light chains and/or their ratio may be helpful.
Very good partial remission is now accepted as a relevant response level and is defined by disappearance of the M-component (or >90% reduction of the serum M-component) but with positive immunofixation.
Partial remission is defined by >50% reduction of M-gradient in serum and >90% reduction in 24-h urine.
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follow-up |
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Topincidencediagnosisstaging and risk assessmenttreatmentconsolidationtreatment of relapsed/refractory...response evaluationfollow-upnotereferences |
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Full blood count, serum and urine electrophoresis or/and free light-chain determination in serum or urine, creatinine, calcium and β2-microglobulin should be carried out every 3–6 months. In case of bone pain, skeletal X-ray or MRI should be performed to detect new bone lesions.
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note |
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Topincidencediagnosisstaging and risk assessmenttreatmentconsolidationtreatment of relapsed/refractory...response evaluationfollow-upnotereferences |
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Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.
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footnotes |
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Approved by the ESMO Guidelines Working Group: August 2003, last update November 2008. This publication supercedes the previously published version—Ann Oncol 2008; 19 (Suppl 2): ii55–ii57.
Conflict of interest: Prof. Harousseau has reported that he is a member of the speakers’ bureau for Ortobiotech and Celgene; Prof. Dreyling has reported no conflicts of interest.
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references |
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Topincidencediagnosisstaging and risk assessmenttreatmentconsolidationtreatment of relapsed/refractory...response evaluationfollow-upnotereferences |
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1. The International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders. Br J Haematol (2002) 121:749–757.[CrossRef][Web of Science]
2. Attal M, Harousseau JL. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med (1996) 335:91–97.
3. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem cell transplantation for multiple myeloma. N Engl J Med (2003) 349:2495–2502.
4. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in multiple myeloma patients. Blood (2006) 108:3289–3294.
5. Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood (2004) 103:20–32.
6. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med (2003) 348:1875–1883.
7. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med (2007) 357:2123–2132.
8. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia (2006) 20:1467–1473.[CrossRef][Web of Science][Medline]
9. Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomized trial. Lancet (2007) 370:1209–1218.[CrossRef][Medline]
10. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol (2005) 23:3412–3420.
11. Harousseau JL. Role of stem cell transplantation. Hematol Oncol Clin N Am (2007) 21:1157–1174.[CrossRef][Web of Science][Medline]
12. Mead GP, Carr-Smith HD, Drayson MT, et al. Serum free light chains for monitoring multiple myeloma. Br J Haematol (2004) 126:348–354.[CrossRef][Web of Science][Medline]
13. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet (2006) 367:825–831.[CrossRef][Web of Science][Medline]
14. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for multiple myeloma: 10 years later. Blood (2008) 112:3107–3114.
15. Richardson PG, Sonneveld P, Schuster MW, et al. Assessment of proteasome inhibition for extending remissions (APEX) investigators. Bortezomib or high dose dexamethasone for relapsed multiple myeloma. N Engl J Med (2005) 352:2487–2498.
16. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med (2008) 359:906–917.
17. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med (1999) 341:1565–1571.
18. Weber DM, Chen C, Nievisky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med (2007) 357:2133–2142.
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