Elsevier

The Lancet Oncology

Volume 15, Issue 12, November 2014, Pages e538-e548
The Lancet Oncology

Review
International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma

https://doi.org/10.1016/S1470-2045(14)70442-5Get rights and content

Summary

This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition.

Introduction

Multiple myeloma is a cytogenetically heterogeneous clonal plasma cell proliferative disorder1, 2 and is almost always preceded by an asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS).3, 4 MGUS is present in roughly 3–4% of the population over the age of 50 years.5, 6, 7, 8, 9 The diagnosis of MGUS requires the absence of hypercalcaemia, renal failure, anaemia, and bone lesions (referred to as CRAB features) that can be attributed to the underlying plasma cell disorder (all features must be absent; table 1).10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 About 80% of multiple myeloma originates from non-IgM immunoglobulin MGUS (non-IgM MGUS), and 20% from light-chain immunoglobulin MGUS (LC-MGUS). In the event of progression, IgM immunoglobulin MGUS (IgM MGUS) usually evolves into Waldenström macroglobulinaemia, but in rare instances IgM MGUS can progress to multiple myeloma (IgM myeloma).18, 21, 22, 23, 24 The rate of progression of MGUS to multiple myeloma is 0·5–1% per year, but the precise risk is affected by the concentration of the monoclonal protein, type of monoclonal protein, serum free light-chain ratio, bone marrow plasmacytosis, proportion of phenotypically clonal plasma cells, and presence of immunoparesis.24, 25, 26, 27, 28, 29

Smouldering multiple myeloma is an intermediate clinical stage between MGUS and multiple myeloma in which the risk of progression to malignant disease in the first 5 years after diagnosis is much higher, at about 10% per year.30 Prognostic models have been proposed to predict risk of progression, but lack concordance and need additional studies for verification.31 According to a population-based study from Scandinavia, smouldering multiple myeloma accounts for about 14% of all patients with multiple myeloma.32 As with MGUS, the diagnosis needs the absence of CRAB features attributable to the clonal plasma cell proliferative disorder, but the thresholds for monoclonal protein level and bone-marrow plasma cell (BMPC) percentage are different. Smouldering multiple myeloma is a biologically heterogeneous, clinically defined entity consisting of a subset of patients with biological premalignancy (ie, MGUS) and a subset with CRAB-negative malignancy (ie, multiple myeloma).33 It includes patients similar to those with MGUS, with a very low rate of progression, as well as patients who develop clinical symptoms and end-organ damage within the first 2 years of diagnosis.34, 35 Unfortunately, no single pathological or molecular feature can be used to distinguish patients with smouldering multiple myeloma who have only clonal premalignant plasma cells from those with clonal malignant myeloma cells. A biomarker-based definition that accurately identifies the subset of patients with smouldering multiple myeloma and biological malignancy, who are at imminent risk of developing CRAB features (and should therefore be considered for therapy), is needed.34

Section snippets

Rationale for updating of diagnostic criteria

The present disease definitions of smouldering multiple myeloma and multiple myeloma were reported by the International Myeloma Working Group (IMWG) in 2003.10 With minor clarifications,11 these criteria have been used in clinical practice as well as in research studies and trials in the past decade.36, 37 One of the major difficulties in multiple myeloma is that, unlike other malignancies, the disease definition is clinicopathological; it needs overt clinical manifestations of serious

Revised IMWG criteria for diagnosis of myeloma

The updated IMWG criteria for diagnosis of multiple myeloma are given in the panel; the supporting data for each of the changes are discussed below. The term multiple myeloma refers to multiple myeloma requiring therapy.

Future directions

The updated diagnostic criteria move multiple myeloma into line with other malignancies by removing the need for documented end-organ damage as a mandatory requirement for the definition of malignancy.34, 35, 39, 40, 41, 42, 57 They address a major drawback in terminology that prevented patients with clearcut malignancy and very high risk of developing end-organ damage from receiving therapy until such damage is clinically manifest.

Promising markers for further study are listed in table 2.93, 94

Search strategy and selection criteria

We searched PubMed for articles published in English between Jan 1, 1980, and June 30, 2014, that contained the term “smoldering myeloma” and any one of the following terms: “prognosis” or “imaging” or “biomarkers” or “risk factors” or “progression” or “therapy”. We also reviewed recent reviews on smouldering multiple myeloma. Members of the International Myeloma Working Group were then asked to identify any appropriate citation that was of interest but not detected by the search strategy.

References (100)

  • RA Kyle et al.

    Long-term follow-up of IgM monoclonal gammopathy of undetermined significance

    Blood

    (2003)
  • I Turesson et al.

    Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden

    Blood

    (2014)
  • SV Rajkumar et al.

    Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance

    Blood

    (2005)
  • E Pérez-Persona et al.

    New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells

    Blood

    (2007)
  • M Dimopoulos et al.

    Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3

    Blood

    (2011)
  • SV Rajkumar et al.

    Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1

    Blood

    (2011)
  • A Dispenzieri et al.

    Smoldering multiple myeloma requiring treatment: time for a new definition?

    Blood

    (2013)
  • O Landgren et al.

    Development of early treatment strategies for high-risk myeloma precursor disease in the future

    Semin Hematol

    (2011)
  • O Landgren

    Multiple myeloma precursor disease: current clinical dilemma and future opportunities

    Semin Hematol

    (2011)
  • A Dispenzieri et al.

    Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma

    Blood

    (2008)
  • SV Rajkumar 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)
  • PG Richardson et al.

    Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma

    Blood

    (2010)
  • AJ Jakubowiak et al.

    A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma

    Blood

    (2012)
  • AR Bradwell et al.

    Serum test for assessment of patients with Bence Jones myeloma

    Lancet

    (2003)
  • D Dingli et al.

    Immunoglobulin free light chains and solitary plasmacytoma of bone

    Blood

    (2006)
  • MA Dimopoulos et al.

    Risk of disease progression in asymptomatic multiple myeloma

    Am J Med

    (1993)
  • TB Bartel et al.

    F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma

    Blood

    (2009)
  • N Leung et al.

    Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant

    Blood

    (2012)
  • RA Kyle et al.

    Review of 1027 patients with newly diagnosed multiple myeloma

    Mayo Clin Proc

    (2003)
  • A Dispenzieri

    How I treat POEMS syndrome

    Blood

    (2012)
  • S Sethi et al.

    Monoclonal gammopathy-associated proliferative glomerulonephritis

    Mayo Clin Proc

    (2013)
  • E Nobile-Orazio

    Neuropathy and monoclonal gammopathy

    Handb Clin Neurol

    (2013)
  • S Madan et al.

    Plasma cell labeling index in the evaluation of smoldering (asymptomatic) multiple myeloma

    Mayo Clin Proc

    (2010)
  • MV Dhodapkar et al.

    Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120)

    Blood

    (2014)
  • A Palumbo et al.

    Multiple myeloma

    N Engl J Med

    (2011)
  • SV Rajkumar

    Treatment of multiple myeloma

    Nat Rev Clin Oncol

    (2011)
  • RA Kyle et al.

    Prevalence of monoclonal gammopathy of undetermined significance

    N Engl J Med

    (2006)
  • O Landgren et al.

    Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12,482 persons from the National Health and Nutritional Examination Survey

    Leukemia

    (2014)
  • J Bladé

    Monoclonal gammopathy of undetermined significance

    N Engl J Med

    (2006)
  • G Merlini et al.

    Differential diagnosis of monoclonal gammopathy of undetermined significance

    Hematology (Am Soc Hematol Educ Program)

    (2012)
  • Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group

    Br J Haematol

    (2003)
  • RA Kyle et al.

    Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma

    Leukemia

    (2009)
  • R Warsame et al.

    Trends and outcomes of modern staging of solitary plasmacytoma of bone

    Am J Hematol

    (2012)
  • RA Kyle et al.

    Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management

    Leukemia

    (2010)
  • O Landgren

    Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: biological insights and early treatment strategies

    Hematology (Am Soc Hematol Educ Program)

    (2013)
  • SR Schuster et al.

    IgM multiple myeloma: disease definition, prognosis, and differentiation from Waldenstrom's macroglobulinemia

    Am J Hematol

    (2010)
  • RA Kyle et al.

    A long-term study of prognosis in monoclonal gammopathy of undetermined significance

    N Engl J Med

    (2002)
  • C Cesana et al.

    Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma

    J Clin Oncol

    (2002)
  • JA Katzmann et al.

    Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS

    Leukemia

    (2013)
  • RA Kyle et al.

    Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma

    N Engl J Med

    (2007)
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