In the 1960s, Dr Jan Waldenström argued that patients who had monoclonal proteins without any symptoms or evidence of end-organ damage represented a benign monoclonal gammopathy. In 1978, Dr Robert ...Kyle introduced the concept of "monoclonal gammopathy of undetermined significance" (MGUS) given that, at diagnosis, it was not possible with available methods (ie, serum protein electrophoresis to define the concentration of M-proteins and microscopy to determine the plasma cell percentage in bone marrow aspirates) to determine which patients would ultimately progress to multiple myeloma. The application of low-input whole-genome sequencing (WGS) technology has circumvented previous problems related to volume of clonal plasma cells and contamination by normal plasma cells and allowed for the interrogation of the WGS landscape of MGUS. As discussed in this chapter, the distribution of genetic events reveals striking differences and the existence of 2 biologically and clinically distinct entities of asymptomatic monoclonal gammopathies. Thus, we already have genomic tools to identify "myeloma-defining genomic events," and consequently, it is reasonable to consider updating our preferred terminologies. When the clinical field is ready to move forward, we should be able to consolidate current terminologies-from current 7 clinical categories: low-risk MGUS, intermediate-risk MGUS, high-risk MGUS, low-risk smoldering myeloma, intermediate-risk smoldering myeloma, high-risk smoldering myeloma, and multiple myeloma-to future 3 genomic-based categories: monoclonal gammopathy, early detection of multiple myeloma (in which myeloma-defining genomic events already have been acquired), and multiple myeloma (patients who are already progressing and clinically defined cases). Ongoing investigations will continue to advance the field.
After decades of virtually no progress, multiple myeloma survival has improved significantly in the past 10 years. Indeed, multiple myeloma has perhaps seen more remarkable progress in treatment and ...patient outcomes than any other cancer during the last decade. Recent data show that multiple myeloma is consistently preceded by a precursor state (monoclonal gammopathy of undetermined significance MGUS/smoldering multiple myeloma SMM). This observation provides a framework for prospective studies focusing on transformation from precursor disease to multiple myeloma and for the development of treatment strategies targeting "early myeloma." This review discusses current biological insights in MGUS/SMM, provides an update on clinical management, and discusses how the integration of novel biological markers, molecular imaging, and clinical monitoring of MGUS/SMM could facilitate the development of early treatment strategies for high-risk SMM (early myeloma) patients in the future.
Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to ...multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an ≥80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM.
Infections are a major cause of morbidity and mortality in patients with multiple myeloma. To estimate the risk of bacterial and viral infections in multiple myeloma patients, we used ...population-based data from Sweden to identify all multiple myeloma patients (n=9253) diagnosed from 1988 to 2004 with follow up to 2007 and 34,931 matched controls. Cox proportional hazard models were used to estimate the risk of infections. Overall, multiple myeloma patients had a 7-fold (hazard ratio =7.1; 95% confidence interval = 6.8-7.4) risk of developing any infection compared to matched controls. The increased risk of developing a bacterial infection was 7-fold (7.1; 6.8-7.4), and for viral infections 10-fold (10.0; 8.9-11.4). Multiple myeloma patients diagnosed in the more recent calendar periods had significantly higher risk of infections compared to controls (P<0.001). At one year of follow up, infection was the underlying cause in 22% of deaths in multiple myeloma patients. Mortality due to infections remained constant during the study period. Our findings confirm that infections represent a major threat to multiple myeloma patients. The effect on infectious complications due to novel drugs introduced in the treatment of multiple myeloma needs to be established and trials on prophylactic measures are needed.
The introduction of whole genome and exome sequencing partnered with advanced bioinformatic pipelines has allowed the comprehensive characterization of mutational processes (i.e., mutational ...signatures) in individual cancer patients. Studies focusing on multiple myeloma have defined several mutational processes, including a recently identified mutational signature (called "SBS-MM1") directly caused by exposure to high-dose melphalan (i.e., autologous stem cell transplant). High-dose melphalan exposure increases both the overall and nonsynonymous mutational burden detected between diagnosis and relapse by ~10-20%. Nevertheless, most of these mutations are acquired within the heterochromatin and late-replicating regions, rarely involving key myeloma driver genes. In this review, we summarize key studies that made this discovery possible, and we discuss potential clinical implications.
Acknowledging the increasingly important role of whole-body MRI for directing patient care in myeloma, a multidisciplinary, international, and expert panel of radiologists, medical physicists, and ...hematologists with specific expertise in whole-body MRI in myeloma convened to discuss the technical performance standards, merits, and limitations of currently available imaging methods. Following guidance from the International Myeloma Working Group and the National Institute for Clinical Excellence in the United Kingdom, the Myeloma Response Assessment and Diagnosis System (or MY-RADS) imaging recommendations are designed to promote standardization and diminish variations in the acquisition, interpretation, and reporting of whole-body MRI in myeloma and allow response assessment. This consensus proposes a core clinical protocol for whole-body MRI and an extended protocol for advanced assessments. Published under a CC BY 4.0 license. Online supplemental material is available for this article.
MYD88 L265P Somatic Mutation in IgM MGUS Landgren, Ola; Staudt, Louis; Treon, Steven P ...
The New England journal of medicine,
12/2012, Letnik:
367, Številka:
23
Journal Article
Recenzirano
To the Editor:
Treon et al. (Aug. 30 issue)
1
report that MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia, an IgM-secretory lymphoplasmacytic lymphoma ...(LPL). Indeed, 49 of 54 patients (91%) with Waldenström's macroglobulinemia and 3 of 3 patients (100%) with non–IgM-secreting LPL had MYD88 L265P expression on the basis of whole-genome sequencing, as confirmed on Sanger sequencing. In contrast, MYD88 L265P was absent in 10 patients with multiple myeloma (including 2 with IgM multiple myeloma) and was expressed in only 3 of 46 patients (7%) with marginal-zone lymphoma,
1
two entities in the differential diagnosis of Waldenström's . . .
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