Exome sequencing in tracking clonal evolution in multiple myeloma following therapy
ABSTRACT Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
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ABSTRACT: Introduction: Multiple myeloma is a fatal malignant proliferation of clonal bone marrow Ig-secreting plasma cells, characterized by wide clinical, biological, and molecular heterogeneity. Areas covered: Herein, global gene and microRNA expression, genome-wide DNA profilings, and next-generation sequencing technology used to investigate the genomic alterations underlying the bio-clinical heterogeneity in multiple myeloma are discussed. Expert opinion: High-throughput technologies have undoubtedly allowed a better comprehension of the molecular basis of the disease, a fine stratification, and early identification of high-risk patients, and have provided insights toward targeted therapy studies. However, such technologies are at risk of being affected by laboratory- or cohort-specific biases, and are moreover influenced by high number of expected false positives. This aspect has a major weight in myeloma, which is characterized by large molecular heterogeneity. Therefore, meta-analysis as well as multiple approaches are desirable if not mandatory to validate the results obtained, in line with commonly accepted recommendation for tumor diagnostic/prognostic biomarker studies.Expert opinion on biological therapy 04/2013; 13(S1). DOI:10.1517/14712598.2013.793305 · 3.65 Impact Factor
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ABSTRACT: Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into an MGUS-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly-diagnosed symptomatic MM patients (N=698), cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after HDT/ASCT versus other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (~60% at 10-years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) versus cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, HR:5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.Leukemia accepted article preview online, 7 June 2013; doi:10.1038/leu.2013.166.Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2013; 27. DOI:10.1038/leu.2013.166 · 9.38 Impact Factor
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ABSTRACT: The mechanisms involved in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole genome sequencing on a series of MGUS (n=4), high risk (HR)-SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors which drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.Leukemia accepted article preview online, 2 July 2013; doi:10.1038/leu.2013.199.Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2013; 28(2). DOI:10.1038/leu.2013.199 · 9.38 Impact Factor