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• W2961582605 abstract "Waldenström macroglobulinaemia (WM) is a rare eponymous haematological malignancy characterized by the presence of a lymphoplasmacytic infiltrate in the bone marrow and circulating monoclonal immunoglobulin M (IgM) (Kapoor et al, 2017). Its antecedent condition, monoclonal gammopathy of undetermined significance (MGUS) of the IgM class, comprising approximately 15% of MGUS, afflicts a much larger population that is at risk of progression to WM or a similar lymphoproliferative disorder (Kyle et al, 2018). Not surprisingly, the identification of factors that predict evolution of IgM MGUS to WM has been an area of considerable interest for quite some time, but it is the recent discovery of novel molecular somatic mutations, including clonal MYD88 (myeloid differentiation primary response protein) mutations and subclonal CXCR4 (C-X-C chemokine receptor type 4) mutations in WM —and interestingly, even at the precursor MGUS stage—that has piqued researchers’ interests (Treon et al 2012; Xu et al, 2016; Hunter et al, 2017). Typically, the risk of progression among patients with IgM MGUS varies over time; 2% per year in the first 10 years following the diagnosis and 1% per year, thereafter (Kyle et al, 2018). The risk is, however, not uniform, with a subset of patients exhibiting a lower rate of progression —and therefore not requiring close monitoring— and another subset displaying a much higher risk, and therein lies the challenge for clinicians with respect to counselling patients regarding their prognosis and formulating a plan for active surveillance. A widely applicable model takes the serum monoclonal protein size (≥15 g/l) and serum free light chain ratio (abnormal versus normal) into account to determine the risk of progression of IgM MGUS (Blade & Rosinol, 2006; Kyle et al, 2018). It is in this context that Varettoni et al (2019) from Italy have attempted to answer a pertinent clinical question regarding the impact of MYD88L265P mutation status in 176 patients with IgM MGUS that were followed for a median of 84 months (1214 person years). Although 54% patients exhibited the MYD88L265P genotype, a subset of patients (24%) with an increased risk of progression to WM or a related lymphoproliferative disorder was identified. These investigators have proposed a pragmatic risk-stratification model based on the size of the serum monoclonal protein and the detection of MYD88L265P mutation in the B-cell clone infiltrating the marrow. In this Italian model, derived from a bivariate analysis of 173 patients, both the size of the serum monoclonal protein (≥10 g/l) and the presence of MYD88L265P were deemed independent markers of progression. When death was considered a competing event, the estimated cumulative incidence of progression was 11·6% at 5 years and 38% at 10 years for the patients harbouring MYD88L265P mutant clonal lymphoplasmacytic cell population in the marrow and concurrently displaying a circulating monoclonal protein of at least 10 g/l. That the size of the monoclonal protein dictates the risk of progression in IgM MGUS has been known for a considerable period of time (Kyle et al, 2003). In the current study, by substantially increasing the cohort size, Varettoni et al (2019) build upon their previous preliminary finding that the presence of MYD88L265P mutation in IgM MGUS at diagnosis is associated with a higher incidence of Bence Jones proteinuria, a higher concentration of serum IgM, a higher rate of concomitant immunoparesis and, importantly, an increased risk of malignant evolution (Varettoni et al, 2013). MYD88 is an adaptor protein that plays a prominent role in the Toll-like receptor signalling pathway by coordinating the assembly of a multi-subunit signalling complex, with downstream activation of multiple transcription factors, including nuclear factor-κB (Treon et al, 2012). The MYD88 gene is somatically mutated in 50–80% of patients with IgM MGUS, and this alteration represents an early oncogenic event, with acquisition of a gain-of-function (Hunter et al, 2017). The major recurrent hot-spot mutation, L265P, in the MYD88 gene, although not pathognomonic of IgM monoclonal gammopathies, is a salient contributor to enhanced cell growth and survival, and is encountered in even a higher proportion (upto 95%) of patients with WM (Poulain et al, 2013). Therefore, its role in the malignant evolution of MGUS cells comes as no surprise. However, despite its relevance to clinical practice, the Italian model was derived in the setting of limitations that are hard to overlook. Rather than using the current World Health Organization (WHO) definition of IgM MGUS (Swerdlow et al, 2017), the study relies on the 2002 consensus criteria (Owen et al, 2003), which classify patients as having IgM MGUS if there is presence of IgM monoclonal gammopathy of any size but no morphological evidence of bone marrow infiltration by lymphoma. By 2002 consensus criteria, any unequivocal evidence of lymphoplasmacytic bone marrow infiltration in the setting of circulating monoclonal IgM leads to a diagnosis of WM. Using these criteria, WM would inadvertently become one of the most frequently encountered haematological malignancies (Rajkumar, 2015). However, in a series of elegant studies integrating phenotypic, molecular and genomic approaches, Paiva et al (2014; 2015) have inarguably established that clonal lymphoplasmacytic cells infiltrate the marrow of patients even at IgM MGUS stage and bear a molecular and phenotypic signature similar to that observed in patients with smouldering WM and active WM. Additionally, the evolution to malignancy seems to be a multi-step process, with accumulation of light-chain-isotype positive B cells and acquisition of specific copy number abnormalities that progressively increase from IgM MGUS to smouldering and symptomatic (active) WM (Paiva et al, 2014; 2015). The current WHO definition of IgM MGUS is supported by this solid evidence and classifies patients as IgM MGUS if their bone marrow clonal lymphoplasmacytic infiltration is lower than 10% in the presence of monoclonal protein of <30 g/l (Swerdlow et al, 2017). Therefore, in the absence of additional data regarding the proportion of patients with a marrow infiltration of <10% vs. ≥10%, it is conceivable that a subset that would otherwise have been classified as IgM MGUS by the WHO criteria has been miscategorised as WM in the study accompanying this editorial (Varettoni et al 2019), and that the true rate of progression may have been incorrectly estimated. Furthermore, the patients' CXCR4 mutation related data were absent and the MYD88 mutation status was not assessed uniformly with a single methodology across all patients, and a more sensitive CD19 cell-sorting technique was utilized only for the marrow samples collected after 2012 (Varettoni et al, 2013; Varettoni et al, 2019). Moreover, the IgM cut off level of 10 g/l, chosen in the Italian model, is arbitrary, and low number of events and the lack of data in many subjects, pertaining to the other risk factors for progression that were significant on univariate analysis, including serum free light chain ratio (abnormal versus normal), lactate dehydrogenase above the upper limit of normal, Bence Jones proteinuria (detectable versus undetectable) precluded a multivariate analysis. As such, MYD88L265P mutation could not be established unequivocally as an independent risk factor for progression to WM, and the incremental benefit of using MYD88L265P status to risk stratify patients remains unknown. Further muddying the waters, is the recent observation of MYD88WT genotype (rather than mutant MYD88) as an independent risk factor for progression to overt WM in patients with smouldering (asymptomatic) WM (Bustoros et al, 2019). In light of these issues, the results of the current study, while interesting, need to be validated externally prior to consideration of their universal adoption in routine clinical practice." @default.
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• W2961582605 date "2019-07-12" @default.
• W2961582605 modified "2023-09-26" @default.
• W2961582605 title "The MYD88 L265P conundrum in IgM monoclonal gammopathy of undetermined significance" @default.
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• W2961582605 doi "https://doi.org/10.1111/bjh.16085" @default.
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