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

2013; Elsevier BV; Volume: 24; Linguagem: Inglês

10.1093/annonc/mdt297

1569-8041

Philippe Moreau, Jesús F. San Miguel, Heinz Ludwig, Harry C. Schouten, Mohamad Mohty, Meletios Α. Dimopoulos, Martin Dreyling,

Peptidase Inhibition and Analysis

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 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 11.0 mg/dl), creatinine >2.0 mg/ml, anaemia (Hb 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.