Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Abstract

Multiple myeloma (MM) accounts for 1% of all cancers and ∼10% of all haematological malignancies. The incidence in Europe is 4.5–6.0/100 000/year with a median age at diagnosis of between 65 and 70 years; the mortality is 4.1/100 000/year. Almost all patients with MM evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a rate of 1% per year. In some patients, an intermediate asymptomatic but more advanced pre-malignant stage termed smouldering (or indolent) multiple myeloma (SMM) can be recognised. SMM progresses to myeloma at a rate of 10% per year over the first 5 years following diagnosis, 3% per year over the following 5 years and 1.5% per year thereafter [1.Kyle R.A. Rajkumar S.V. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma.Leukemia. 2009; 23: 3-9doi:10.1038/leu.2008.291Crossref PubMed Scopus (901) Google Scholar]. Diagnosis of MM should be based on the following tests: [1.Kyle R.A. Rajkumar S.V. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma.Leukemia. 2009; 23: 3-9doi:10.1038/leu.2008.291Crossref PubMed Scopus (901) Google Scholar]- Detection and evaluation of the monoclonal (M-) component by serum and/or urine protein electrophoresis (concentrate of 24 h urine collection); nephelometric quantification of IgG, IgA and IgM immunoglobulins; characterisation of the heavy and light chains by immunofixation; and serum-free light-chain (FLC) measurement;- Evaluation of bone marrow (BM) plasma cell infiltration: BM aspiration and/or biopsies are the standard options to evaluate the number and characteristics. Moreover, the BM sample should be used for cytogenetic/fluorescence in situ hybridization (FISH) studies and also has the potential for immunophenotypic and molecular investigations;- Evaluation of lytic bone lesions: a radiological skeletal bone survey, including spine, pelvis, skull, humeri and femurs is necessary. A magnetic resonance imaging (MRI) or computed tomography (CT) scan may be needed to evaluate symptomatic bony sites, even if the skeletal survey is negative and the patient has symptoms suggesting bone lesions. Moreover, MRI provides greater detail and is recommended whenever spinal cord compression is suspected. Fluorodeoxyglucose positron emission tomography is currently under evaluation but should not be systematically used;- Complete blood cell count, with differential serum creatinine and calcium level. These tests can allow for the differential diagnosis between symptomatic MM, SMM and MGUS (Table 1).Table 1Diagnostic criteria for plasma cell disordersDisorderDisease definitionMonoclonal gammopathy of undetermined significance (MGUS)All three criteria must be met:- Serum monoclonal protein <3 g/dl- Clonal BM plasma cells <10%, and- Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia and bone lesions (CRAB) that can be attributed to the plasma cell proliferative disorderSmouldering multiple myeloma (also referred to as asymptomatic multiple myeloma)Both criteria must be met:- Serum monoclonal protein (IgG or IgA) ≥3 g/dl and/or clonal BM plasma cells ≥10%, and- Absence of end-organ damage such as lytic bone lesions, anaemia, hypercalcaemia or renal failure that can be attributed to a plasma cell proliferative disorderMultiple myelomaAll criteria must be met:- Clonal BM plasma cells ≥10% or biopsy proven plasmacytoma, and- Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specificallyHypercalcaemia: serum calcium >11.5 mg/dl or Renal insufficiency: serum creatinine >1.73 µmol/l (or >2 mg/dl) or estimated creatinine clearance <40 ml/min Anaemia: normochromic, normocytic with a haemoglobin value of ≥2 g/dl below the lower limit of normal or a haemoglobin value <10 g/dl Bone lesions: lytic lesions, severe osteopenia or pathologic fractures Open table in a new tab The diagnosis of symptomatic MM requires:- ≥10% clonal plasma cells on BM examination or a biopsy proven plasmacytoma; and- evidence of end-organ damage, the so-called CRAB criteria (hypercalcaemia, renal insufficiency, anaemia or bone lesions) that is felt to be related to the underlying plasma cell disorder (Table 1). The course of MM is highly variable, and the clinical behaviour is remarkably heterogeneous. Many studies have identified prognostic factors capable of predicting this heterogeneity in survival: serum β2-microglobulin, albumin, C-reactive protein and lactate dehydrogenase. The International Staging System (ISS), a powerful and reproducible three-stage classification (Table 2), relies on the combination of serum levels of β2-microglobulin and of albumin. ISS3 is associated with the poorest outcome [2.Greipp P.R. San Miguel J. Durie B.G.M. et al.International staging system for multiple myeloma.J Clin Oncol. 2005; 23: 3412-3420doi:10.1200/JCO.2005.04.242Crossref PubMed Scopus (2042) Google Scholar].Table 2International staging system.StageCriteriaISerum β2M <3.5 mg/l and serum albumin ≥3.5 g/dlIINot stage I or IIIaThere are two possibilities for stage II: serum β2 microglobulin <3.5mg/l, but serum albumin <3.5 g/dl, and Serum β2 microglobulin 3.5–5.5mg/l irrespective of the serum albumin.IIISerum β2M ≥5.5 mg/lGreipp PR, San Miguel J, Durie BGM et al. International Staging System for Multiple Myeloma. J Clin Oncol 2005; 23: 3412–3420. Reprinted with permission. @2005 American Society of Clinical Oncology. All rights reserved.a There are two possibilities for stage II: serum β2 microglobulin <3.5 mg/l, but serum albumin <3.5 g/dl, and Serum β2 microglobulin 3.5–5.5 mg/l irrespective of the serum albumin. Open table in a new tab Greipp PR, San Miguel J, Durie BGM et al. International Staging System for Multiple Myeloma. J Clin Oncol 2005; 23: 3412–3420. Reprinted with permission. @2005 American Society of Clinical Oncology. All rights reserved. Cytogenetics, evaluated by FISH, is a major prognostic factor. Two recurrent genetic abnormalities, t(4;14) and deletion(17p), are mostly associated with a poorer outcome. Chromosome 1 abnormalities and t(14;16) are also adverse prognostic factors. It has recently been demonstrated that combining both t(4;14) and del(17p), along with the ISS stage, could significantly improve the prognostic assessment in terms of progression-free survival (PFS) and overall survival (OS) [3.Avet-Loiseau H. Durie B.G.M. Cavo M. et al.Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project.Leukemia. 2013; 27: 711-717doi:10.1038/leu.2012.282Crossref PubMed Scopus (152) Google Scholar]. Gene-expression profiling may segregate patients with standard or high-risk disease, but this is not yet established in routine practice. Immediate treatment is not recommended at the present time for patients with indolent myeloma. Treatment should be initiated in all patients with active myeloma fulfilling the CRAB criteria, (hypercalcaemia >11.0 mg/dl), creatinine >2.0 mg/ml, anaemia (Hb <10 g/dl), active bone lesions), and in those symptomatic due to the underlying disease. Oral combinations of melphalan and prednisone (MP) plus novel agents are considered as standards of care in Europe. The two following options are recommended based on data from randomised phase III trials [I, A]: melphalan/prednisone/thalidomide (MPT) [4.Fayers P.M. Palumbo A. Hulin C. et al.Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials.Blood. 2011; 118: 1239-1247doi:10.1182/blood-2011-03-341669Crossref PubMed Scopus (223) Google Scholar], or bortezomib/melphalan/prednisone (VMP) [5.San Miguel J.F. Schlag R. Khuageva N.K. et al.Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.N Engl J Med. 2008; 359: 906-917doi:10.1056/NEJMoa0801479Crossref PubMed Scopus (1607) Google Scholar]; both MPT and VMP are approved in this setting by the European Medicines Agency (EMA). Bendamustine plus prednisone is another regimen that is also approved by the EMA in patients who have clinical neuropathy at time of diagnosis precluding the use of thalidomide according to the MPT regimen or bortezomib according to the VMP regimen [6.Pönisch W. Mitrou P.S. Merkle K. et al.Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone—a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO).J Cancer Res Clin Oncol. 2006; 132: 205-212doi:10.1007/s00432-005-0074-4Crossref PubMed Scopus (161) Google Scholar]. Melphalan/prednisone/lenalidomide (MPR) has been evaluated in a prospective randomised study versus MP, but was not superior to the dual combination with a fixed number of cycles [7.Palumbo A. Hajek R. Delforge M. et al.Continuous lenalidomide treatment for newly diagnosed multiple myeloma.N Engl J Med. 2012; 366: 1759-1769doi:10.1056/NEJMoa1112704Crossref PubMed Scopus (615) Google Scholar]. This triplet combination is not approved and cannot be considered as a standard of care. Cyclophosphamide/thalidomide/dexamethasone (CTD) has also been compared with MP and is superior in terms of response rates, but does not induce a clear survival advantage over MP [8.Morgan G.J. Davies F.E. Gregory W.M. et al.Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation.Blood. 2011; 118: 1231-1238doi:10.1182/blood-2011-02-338665Crossref PubMed Scopus (160) Google Scholar]. Lenalidomide combined with low-dose dexamethasone, widely used in US centres, also yields important response and OS rates [9.Rajkumar S.V. Jacobus S. Callander N.S. et al.Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial.Lancet Oncol. 2010; 11: 29-37doi:10.1016/S1470-2045(09)70284-0Abstract Full Text Full Text PDF PubMed Scopus (782) Google Scholar] but is not approved in Europe. This regimen is currently being compared with MPT in a large randomised phase III trial. For patients in good clinical condition (e.g. fit patients), induction followed by high-dose therapy with autologous stem cell transplantation (ASCT) is the standard treatment [II, B] [10.Attal M. Harousseau J.L. Stoppa A.M. et al.A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome.N Engl J Med. 1996; 335: 91-97doi:10.1056/NEJM199607113350204Crossref PubMed Scopus (2569) Google Scholar, 11.Child J.A. Morgan G.J. Davies F.E. et al.High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.N Engl J Med. 2003; 348: 1875-1883doi:10.1056/NEJMoa022340Crossref PubMed Scopus (1574) Google Scholar]. Response rates to induction therapy have been significantly increased by the use of novel agent-based combinations. Bortezomib-dexamethasone, which is superior to the classical VAD regimen (vincristine, adriamycin and high-dose dexamethasone) [II, B] [12.Harousseau J.L. Attal M. Avet-Loiseau H. et al.Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial.J Clin Oncol. 2010; 28: 4621-4629doi:10.1200/JCO.2009.27.9158Crossref PubMed Scopus (463) Google Scholar], has become the backbone of induction therapy before ASCT. The addition of a third agent to bortezomib-dexamethasone, e.g. thalidomide (VTD), doxorubicin (DVD or PAD), lenalidomide (RVD) or cyclophosphamide (VCD), has shown higher response rates in phase II trials [13.Moreau P. Avet-Loiseau H. Harousseau J.L. Attal M. Current trends in autologous stem-cell transplantation for myeloma in the era of novel therapies.J Clin Oncol. 2011; 29: 1898-1906doi:10.1200/JCO.2010.32.5878Crossref PubMed Scopus (108) Google Scholar]. Three prospective studies have already shown that VTD is superior to TD or bortezomib-dexamethasone [14.Cavo M. Tacchetti P. Patriarca F. et al.Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.Lancet. 2010; 376: 2075-2085doi:10.1016/S0140-6736(10)61424-9Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar, 15.Moreau P. Avet-Loiseau H. Facon T. et al.Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma.Blood. 2011; 118: 5752-5758doi:10.1182/blood-2011-05-355081Crossref PubMed Scopus (240) Google Scholar, 16.Rosiñol L. Oriol A. Teruel A.I. et al.Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study.Blood. 2012; 120: 1589-1596doi:10.1182/blood-2012-02-408922Crossref PubMed Scopus (382) Google Scholar]. No data are available to assess the superiority of one combination, VTD, RVD, VCD, PAD etc., over another. Based on response rates, depth of response and PFS as surrogate markers for outcome, three-drug combinations including at least bortezomib and dexamethasone are currently the standard of care before ASCT. Three to four courses are recommended before proceeding to stem cell collection. Melphalan (200 mg/m2 i.v.) is the standard preparative regimen before ASCT [II, B] [17.Moreau P. Facon T. Attal M. et al.Comparison of 200 mg/m2 melphalan and 8Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma :final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial.Blood. 2002; 99: 731-735doi:10.1182/blood.V99.3.731Crossref PubMed Scopus (447) Google Scholar]. Peripheral blood progenitor cells are the preferred source of stem cells, rather than BM [III, B]. Tandem ASCT has been evaluated before the era of novel agents. The benefit of tandem ASCT was observed in patients that were not reaching very good partial response after the first ASCT [18.Attal M. Harousseau J.L. Facon T. et al.Single versus double autologous stem-cell transplantation for multiple myeloma.N Engl J Med. 2003; 349: 2495-2502doi:10.1056/NEJMoa032290Crossref PubMed Scopus (943) Google Scholar]. In a recent study from the Netherlands and Germany (Hovon 65-GMMG HD4 trial), in the context of bortezomib induction and maintenance treatment, OS was better in the GMMG group, which carried out tandem ASCT in contrast to HOVON (single ASCT) [19.Sonneveld P. Schmidt-Wolf I.G. van der Holt B. et al.Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial.J Clin Oncol. 2012; 30: 2946-2955doi:10.1200/JCO.2011.39.6820Crossref PubMed Scopus (644) Google Scholar]. Nevertheless, the trial was not powered to compare single versus double high-dose melphalan. Ongoing trials running both in Europe and US comparing prospectively single versus tandem ASCT in the era of novel agents will solve this important issue. Allogeneic stem cell transplantation should only be carried out in the context of a clinical trial and only in patients with good response before transplant. Thus far, in the era of novel agent-based induction therapy, there is still not enough evidence that consolidation therapy should be systematically applied. The impact of consolidation will be clarified by ongoing trials. In elderly patients following induction, three randomised trials have explored the benefit of maintenance therapy in terms of OS using either immunomodulatory drugs (IMiDs) or bortezomib: MP versus MPR versus MPR-R [7.Palumbo A. Hajek R. Delforge M. et al.Continuous lenalidomide treatment for newly diagnosed multiple myeloma.N Engl J Med. 2012; 366: 1759-1769doi:10.1056/NEJMoa1112704Crossref PubMed Scopus (615) Google Scholar], bortezomib-melphalan-prednisone-thalidomide / bortezomib-thalidomide versus VMP [20.Palumbo A. Bringhen S. Rossi D. et al.Overall survival benefit for Bortezomib-Melphalan-Prednisone-Thalidomide followed by maintenance with bortezomib-thalidomide (VMPT-VT) versus Bortezomib-Melphalan-Prednisone (VMP) in newly diagnosed multiple myeloma patients.Blood (ASH Annual Meeting Abstracts). 2012; 120: 200Google Scholar], VMP versus VTP followed by either bortezomib-prednisone (VP) or VP maintenance [21.Mateos M.V. Oriol A. Martinez-Lopez J. et al.Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial.Blood. 2012; 120: 2581-2588doi:10.1182/blood-2012-05-427815Crossref PubMed Scopus (128) Google Scholar]. Due to the trial design, the benefit in OS is not well established. These drugs are not approved by the EMA. Therefore, systematic maintenance therapy is also not recommended in elderly patients. In young patients following ASCT, phase III randomised trials have demonstrated that maintenance therapy with IMiDs, either thalidomide or lenalidomide, prolongs PFS [I, A] [22.Attal M. Lauwers-Cances V. Marit G. et al.Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.N Engl J Med. 2012; 366: 1782-1791doi:10.1056/NEJMoa1114138Crossref PubMed Scopus (874) Google Scholar, 23.McCarthy P.L. Owzar K. Hofmeister C.C. et al.Lenalidomide after stem-cell transplantation for multiple myeloma.N Engl J Med. 2012; 366: 1770-1781doi:10.1056/NEJMoa1114083Crossref PubMed Scopus (886) Google Scholar], but the OS benefit is still unclear. Bortezomib maintenance is also under evaluation [19.Sonneveld P. Schmidt-Wolf I.G. van der Holt B. et al.Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial.J Clin Oncol. 2012; 30: 2946-2955doi:10.1200/JCO.2011.39.6820Crossref PubMed Scopus (644) Google Scholar]. These three agents are not approved in this setting; therefore, systematic maintenance therapy is not recommended. The definition of response established by the International Myeloma Working Group in 2006 has recently been modified (Table 3) [24.Rajkumar S.V. Harousseau J.L. Durie B. et al.Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1.Blood. 2011; 117: 4691-4695doi:10.1182/blood-2010-10-299487Crossref PubMed Scopus (711) Google Scholar]. The quality and the depth of response have been improved over the last 5 years in the context of novel agent-based therapies allowing for introduction of novel response grades, namely stringent complete response (sCR), immunophenotypic CR and molecular CR to the definition of conventional CR.Table 3Response criteria.Response subcategoryResponse criteriaMolecular CRCR plus negative ASO-PCR, sensitivity 10-5Immunophenotypic CRStringent CR plus Absence of phenotypically aberrant PCs (clonal) in BM with a minimum of 1 million total BM cells analysed by multi-parametric flow cytometry (with >4 colours)Stringent CR (sCR)CR as defined below plusNormal FLC ratio and Absence of clonal PCs by immunohistochemistry or 2- to 4-colour flow cytometryCRNegative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and ≤5% PCs in BMVGPRSerum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hPR≥50% reduction of serum M-protein and reduction in 24 h urinary M-protein by ≥90% or to <200 mg per 24 h If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria If serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, ≥50% reduction in PCs is required in place of M-protein, provided baseline BM PC percentage was ≥30% In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is also requiredPCs, plasma cells; BM, bone marrow; CR, complete response; VGPR, very good partial response; PR, partial response; ASO-PCR, allele-specific polymerase chain reaction; FLC, free light chain.Reprinted with permission of the Americal Society of Hematology from Rajkumar SV, Harousseau JL, Durie B et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood May 5, 2011; 117: 4691-4695; permission conveyed through Copyright Clearance Center, Inc. Open table in a new tab PCs, plasma cells; BM, bone marrow; CR, complete response; VGPR, very good partial response; PR, partial response; ASO-PCR, allele-specific polymerase chain reaction; FLC, free light chain. Reprinted with permission of the Americal Society of Hematology from Rajkumar SV, Harousseau JL, Durie B et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood May 5, 2011; 117: 4691-4695; permission conveyed through Copyright Clearance Center, Inc. There is a statistical relationship between CR achievement and PFS or OS survival. Full blood count, serum and urine electrophoresis and/or serum-FLC determination, creatinine and calcium should be carried out every 2–3 months (outside the context of a clinical trial) [1.Kyle R.A. Rajkumar S.V. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma.Leukemia. 2009; 23: 3-9doi:10.1038/leu.2008.291Crossref PubMed Scopus (901) Google Scholar]. In the case of bone pain, skeletal X-ray, MRI or CT scan should be carried out to detect new bone lesions [1.Kyle R.A. Rajkumar S.V. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma.Leukemia. 2009; 23: 3-9doi:10.1038/leu.2008.291Crossref PubMed Scopus (901) Google Scholar]. The choice of therapy in the relapse setting depends on several parameters such as age, performance status, comorbidities, the type, efficacy and tolerance of the previous treatment, the number of prior treatment lines, the available remaining treatment options and the interval since the last therapy. The EMA has approved lenalidomide in combination with dexamethasone [25.Weber D.M. Chen C. Niesvizky R. et al.Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America.N Engl J Med. 2007; 357: 2133-2142doi:10.1056/NEJMoa070596Crossref PubMed Scopus (1094) Google Scholar, 26.Dimopoulos M. Spencer A. Attal M. et al.Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma.N Engl J Med. 2007; 357: 2123-2132doi:10.1056/NEJMoa070594Crossref PubMed Scopus (1250) Google Scholar] and bortezomib either alone as single agent [27.Richardson P.G. Sonneveld P. Schuster M.W. et al.Bortezomib or high-dose dexamethasone for relapsed multiple myeloma.N Engl J Med. 2005; 352: 2487-2498doi:10.1056/NEJMoa043445Crossref PubMed Scopus (2176) Google Scholar] or in combination with pegylated doxorubicin [28.Orlowski R.Z. Nagler A. Sonneveld P. et al.Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression.J Clin Oncol. 2007; 25: 3892-3901doi:10.1200/JCO.2006.10.5460Crossref PubMed Scopus (571) Google Scholar]. Nevertheless, bortezomib is mostly used in combination with dexamethasone in the relapse setting. Thalidomide and bendamustine are effective drugs, often used, but not approved [29.Moreau P. The future of therapy for relapsed/refractory multiple myeloma: emerging agents and novel treatment strategies.Semin Hematol. 2012; 49: S33-S46doi:10.1053/j.seminhematol.2012.05.004Crossref PubMed Scopus (46) Google Scholar]. Triplet combinations have proved effective in phase II trials, but only one single randomised trial has shown the superiority of VTD over TD for PFS in patients relapsing following ASCT [30.Garderet L. Iacobelli S. Moreau P. et al.Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 Randomized Phase III Trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.J Clin Oncol. 2012; 30: 2475-2482doi:10.1200/JCO.2011.37.4918Crossref PubMed Scopus (177) Google Scholar]. In young patients, a second ASCT may be considered, provided the patient responded well to the previous ASCT and had a PFS of more than 24 months [31.Lemieux E. Hulin C. Caillot D. et al.Autologous stem cell transplantation: an effective salvage therapy in multiple myeloma.Biol Blood Marrow Transplant. 2013; 19: 445-449doi:10.1016/j.bbmt.2012.11.013Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. In the relapse setting, allogeneic SCT should only be carried out in the context of a clinical trial. When possible, patients should be offered participation in clinical trials. Pomalidomide [29.Moreau P. The future of therapy for relapsed/refractory multiple myeloma: emerging agents and novel treatment strategies.Semin Hematol. 2012; 49: S33-S46doi:10.1053/j.seminhematol.2012.05.004Crossref PubMed Scopus (46) Google Scholar], the third-in-class IMiD, and carfilzomib [29.Moreau P. The future of therapy for relapsed/refractory multiple myeloma: emerging agents and novel treatment strategies.Semin Hematol. 2012; 49: S33-S46doi:10.1053/j.seminhematol.2012.05.004Crossref PubMed Scopus (46) Google Scholar], the second-in-class proteasome inhibitor, both approved in US, are not yet available in Europe outside clinical trials. Other drugs or classes of drugs such as histone-deacetylase inhibitors or monoclonal antibodies are currently under development [29.Moreau P. The future of therapy for relapsed/refractory multiple myeloma: emerging agents and novel treatment strategies.Semin Hematol. 2012; 49: S33-S46doi:10.1053/j.seminhematol.2012.05.004Crossref PubMed Scopus (46) Google Scholar]. In 2013, no prognostic factor or staging system, including ISS cytogenetics or gene-expression profiling, is used routinely to define a risk-adapted strategy. In this disease setting, more research is needed to identify molecular markers which could lead to advances in personalised medicine. Levels of evidence and grades of recommendation have been applied using the system shown in Table 4. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.Table 4Levels of evidence and grades of recommendation (adapted from the Infectious Diseases Society of America-United States Public Health Service Grading SystemaDykewicz CA. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001; 33: 139–144. By permission of the Infectious Diseases Society of America.)Levels of evidenceIEvidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneityIISmall randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneityIIIProspective cohort studiesIVRetrospective cohort studies or case–control studiesVStudies without control group, case reports, experts opinionsGrades of recommendationAStrong evidence for efficacy with a substantial clinical benefit, strongly recommendedBStrong or moderate evidence for efficacy but with a limited clinical benefit, generally recommendedCInsufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, …), optionalDModerate evidence against efficacy or for adverse outcome, generally not recommendedEStrong evidence against efficacy or for adverse outcome, never recommendeda Dykewicz CA. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001; 33: 139–144. By permission of the Infectious Diseases Society of America. Open table in a new tab Prof. Moreau has reported advisory board of Janssen, Millennium, Onyx, Celgene; speaker's honoraria from Janssen, Celgene, Mundipharma. Prof. San Miguel has reported advisory board of Millennium, Janssen, Celgene and Onyx. Prof. Mohty has reported research support and lectures honoraria from Celgene and Janssen, whose products are discussed in this manuscript. Prof. Ludwig has reported speaker's bureau honoraria from Celgene, Mundipharma, Janssen; research grants from Mundipharma, Janssen. Dr Dimopoulos has reported honoraria from Celgene, OrthoBiotech, Onyx. Prof. Dreyling has reported scientific advisory board for Celgene, Janssen, Pfizer, Roche; speaker's honoraria for Celgene, Janssen, Pfizer, Roche; research funding to the institution from Celgene, Janssen, Mundipharma, Pfizer, Roche. Prof. Schouten has declared no potential conflicts of interest.