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.
ReviewInternational Myeloma Working Group updated criteria for the diagnosis of multiple myeloma
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
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