Annals of Oncology 21 (Supplement 5): v155–v157, 2010
doi:10.1093/annonc/mdq178clinical practice guidelines
Multiple myeloma: ESMO Clinical Practice Guidelines
for diagnosis, treatment and follow-up
J.-L. Harousseau1 & M. Dreyling2
On behalf of the ESMO Guidelines Working Group*
1Rene´ Gauducheau Cancer Center Nantes, France; 2Department of Medicine III, University Hospital Grosshadern, LMU Munich, Germany
incidence
The incidence of multiple myeloma (MM) in Europe is 4.5–6.0/
100 000/year with a median age at diagnosis of between 63 and
70 years; the mortality is 4.1/100 000/year.
diagnosis
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 and oligo-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
spinal cord compression is suspected.
Biological assessments to differentiate symptomatic and
asymptomatic MM: haemoglobin (and full blood cell
count), serum creatinine and calcium level (CRAB
classification).
These tests allow the differential diagnosis between
symptomatic MM, smouldering (or indolent) MM and
monoclonal gammopathy of undetermined significance
(MGUS).
staging and risk assessment
Previously, the most commonly used staging system has been
the Durie–Salmon classification (Table 1).
A number of biological parameters are of prognostic
importance (b2-microglobulin, C-reactive protein, lactate
dehydrogenase and serum albumin). The level of
b2-microglobulin is used most commonly. Combining it with
serum albumin has led to a new International Staging System
(ISS) which is a more convenient and reproducible
classification (Table 2).
Cytogenetics is a major prognostic factor and should be
obtained either by conventional karyotyping or FISH analysis.
The most relevant abnormalities are del(13q) (karyotype),
t(4;14), t(14;16) and del(17p) (FISH), which are associated with
a poorer outcome.
treatment
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 and prednisone
has been the standard of treatment for patients ineligible for
high-dose chemotherapy with stem-cell support, including
elderly patients but should now be replaced by combinations
with novel agents. Three 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 and a complete
remission rate comparable to that achieved with high-dose
therapy plus stem-cell transplantation [I, A]. Melphalan–
prednisone plus either thalidomide or bortezomib are the new
standards in Europe. Lenalidomide combined with low-dose
dexamethasone also yields improved response and overall
survival rates, and is well tolerated even in patients >65 years of
age. The impact of this combination compared with melphalan-
containing regimens will be clarified by ongoing trials.
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].
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.
Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: clinicalrecommendations@esmo.org
Approved by the ESMO Guidelines Working Group: August 2003, last update January
2010. This publication supercedes the previously published version—Ann Oncol 2009;
20 (Suppl 4): iv97–iv99.
Conflict of interest: Dr Harousseau has reported that he has received honoraria from as
well as participated to advisory boards of Celgene, Janssen-Cilag and Novartis;
Professor Dreyling has reported no conflicts of interest.
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
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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, adriamycin and high-dose
dexamethasone). Triple combinations might be even more
effective.
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. The impact of
double ASCT in the era of novel therapies is unclear. 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].
consolidation
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. However, the optimal duration of
treatment and the respective impact of short consolidation
versus prolonged maintenance is not yet known The role of
other novel agents in this setting and of novel agents given both
before and after transplantation is currently under evaluation.
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 graft-versus-host
disease. In high-risk patients, upfront allogeneic
transplantation should only be performed within clinical trials.
treatment of relapsed/refractory
myeloma
Regimens identical to those used initially can induce a second
remission, when relapse occurs off therapy. 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 tumour burden, history of thrombosis), anticoagulation
prophylaxis should be administered.
Bortezomib is used either alone or in combination with
dexamethasone or with chemotherapy. Lenalidomide (in
combination with dexamethasone) has been shown to be
superior to dexamethasone alone. The use of novel agents at
relapse has already dramatically improved overall survival.
response evaluation
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 especially
in oligo-secretory myeloma.
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.
Table 1. Durie–Salmon classification of MM
Parameter Stage I: all of the criteria
below
Stage II: one or more of the
criteria below
Stage III: one or more of the
criteria below
Haemoglobin (g/dl) >10 8.5–10.0 <8.5
Calcium (mmol/l) <3.0 <3.0l >3.0
M-protein (g/l)
IgA <30 30–50 >50
IgG <50 50–70 >70
Urine light chain (g/24 h) <4 4–12 >12
Bone X-ray Normal – Three lytic bone lesions
Subclassification: Stage A Serum creatinine <177 lmol/l
Stage B Serum creatinine ‡177 lmol/l
Table 2. International staging system
IPI Group I b2M <3.5 mg/l and serum
albumin >3.5 g/dl
IPI Group II b2M <3.5 mg/l and serum
albumin >3.5 g/dl or b2M
3.5–5.5 mg/l
IPI Group III b2M >5.5 mg/l
clinical practice guidelines Annals of Oncology
v156 | Harousseau & Dreyling Volume 21 | Supplement 5 | May 2010
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Partial remission is defined by >50% reduction of
M-component in serum and >90% reduction in 24-h urine.
There is a statistical relationship between complete remission or
at least very good partial remission achievement and
progression-free survival or overall survival.
follow-up
Full blood count, serum and urine electrophoresis or/and
serum-free light-chain determination, creatinine and calcium
should be carried out every 3–4 months (out of a clinical trial).
In the case of bone pain, skeletal X-ray or MRI should be
performed to detect new bone lesions.
note
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.
literature
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.
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, Tricot T, Anaissie E et al. Thalidomide and hematopoietic stem cell
transplantation for multiple myeloma. N Engl J Med 2006; 35: 1021–1030.
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. Dispenzieri A, Kyle R, Merlini G et al. International Myeloma Working Group
guidelines for serum-free light chain analysis in multiple myeloma and related
disorders. Leukemia 2009; 23: 215–224.
9. Durie BG, Harousseau JL, Miguel JS et al. International uniform response criteria
for multiple myeloma. Leukemia 2006; 20: 1467–1473.
10. 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 randomised trial. Lancet 2007; 370: 1209–1218.
11. Greipp PR, San Miguel J, Durie BG et al. International staging system for multiple
myeloma. J Clin Oncol 2005; 23: 3412–3420.
12. Harousseau JL, Moreau P. Autologous stem cell transplantation for multiple
myeloma N Engl J Med 2009; 360: 41–50.
13. Harousseau JL, Attal M, Avet-Loiseau H. The role of complete remission in
multiple myeloma Blood 2009; 114: 3139–3146.
14. Hulin C, Facon T, Rodon P et al. Efficacy of melphalan and prednisone plus
thalidomide in patients older than 70 years of age: IFM 01/01 trial. J Clin Oncol
2009; 27: 3664–3670.
15. 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.
16. Palumbo A, Facon T, Sonneveld P et al. Thalidomide for multiple myeloma: 10
years later. Blood 2008; 112: 3107–3114.
17. Rajkumar SV, Jacobus S, Callander NS et al. Lenalidomide plus high-dose
dexamethasone versus lenalidomide plus low-dose dexamethasone as initial
therapy for newly diagnosed multpiple myeloma: an open randomised controlled
trial. Lancet Oncol 2010; 11: 29–37.
18. 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.
19. 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.
20. Spencer A, Prince HM, Roberts AW et al. Consolidation therapy with low-dose
thalidomide and prednisolone prolongs the survival of multiple myeloma patients
undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol
2009; 27: 1788–1793.
21. 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.
Annals of Oncology clinical practice guidelines
Volume 21 | Supplement 5 | May 2010 doi:10.1093/annonc/mdq178 | v157
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