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Multiple myeloma (MM) is an acquired malignant plasma cell disorder that develops late in life. Although progression free and overall survival has improved across all age, race, and ethnic groups, a subset of patients have suboptimal outcomes and are labeled as having high risk disease. A uniform approach to risk in NDMM remains elusive despite several validated risk stratification systems in clinical use. While we attempt to capture risk at diagnosis, the reality is that many important prognostic characteristics remain ill-defined as some patients relapse early who were defined as low risk based on their genomic profile at diagnosis. It is critical to establish a definition of high risk disease in order to move towards risk-adapted treatment approaches. Defining risk at diagnosis is important to both effectively design future clinical trials and guide which clinical data is needed in routine practice. The goal of this review paper is to summarize and compare the various established risk stratification systems, go beyond the R-ISS and international myeloma working group risk stratifications to evaluate specific molecular and cytogenetic abnormalities and how they impact prognosis independently. In addition, we explore the wealth of new genomic information from recent whole genome/exome sequencing as well as gene expression data and review known clinical factors affecting outcome such as disease burden and early relapse as well as patient related factors such as race. Finally, we provide an outlook on developing a new high risk model system and how we might make sense of co-occurrences, oncogenic dependencies, and mutually exclusive mutations.
There is significant heterogeneity in the various risk-stratification systems currently utilized as outlined in Table 1. While we attempt to capture risk at diagnosis, the reality is that many important prognostic characteristics remain ill-defined as some patients relapse early who were defined as low risk based on their genomic profile at diagnosis. The goal of this review paper is to summarize and compare the various established risk-stratification systems and go beyond the R-ISS and international myeloma working group (IMWG) risk stratifications to evaluate specific molecular and cytogenetic abnormalities and how they impact prognosis independently. We explore the wealth of new genomic information from recent whole-genome/-exome sequencing as well as gene-expression profile data and review known clinical factors impacting outcome such as disease burden and early relapse as well as patient-related factors. Finally, we provide an outlook on developing a new high-risk model system and how we might make sense of co-occurrences, oncogenic dependencies, and mutually exclusive mutations.
The IMWG consensus statement describes clinical iFISH as the standard approach for detecting CAs and the R-ISS staging system followed the same methodology. However, within the R-ISS inconsistencies existed in defining positive cytogenetic abnormalities and the cutoff levels were not identical ranging from 8 to 20% for numerical aberrations and from 10 to 15% for immunoglobulin heavy-chain translocations. Further, in routine clinical practice, more heterogeneity exists with some labs not performing the required purification or dual staining and as with the R-ISS data the detection limits and positivity thresholds vary between institutions. This heterogeneity may limit the utility of the R-ISS and IMWG staging systems particularly when applied after collaborating data from multiple institutions. More recently, extensive collections of MM genomic data are being utilized to further elucidate risk in NDMM patients but they too have not escaped this challenge. For example, the CoMMpass study (NCT01454297) has provided an unprecedented platform for genomics and outcomes research in MM but one of the few critiques stems from the heterogeneity in cytogenetic analysis. In an audit of the top ten recruiting sites, significant discordance was found between the local data extraction and their central audit with variability in the FISH probes utilized, number of cells counted, and sorting techniques [24]. Of note, traditional FISH studies are quite expensive further motivating the field to move beyond traditional FISH studies toward next-generation sequencing tools.
Despite growing evidence of its prognostic value, the application to routine clinical care remains challenging. There is no consensus on a universal adaptation and none are validated by the FDA. Chng et al. attempted to evaluate the optimal GEP for MM by examining patients from three publically available GEP datasets [35]. They evaluated nine GEP profiles looking at all non-redundant combinations and constructed all possible combinations of multiple signatures up to nine full signatures and performed survival analysis for each combination. They demonstrated reproducibility across the nine systems, thus GEP can capture core biology that is not a result of random methodological artifact. They showed that the EMC92+HZDCD combination provides highly improved performance compared with other signatures or combinations. Others have shown that the SYK92 [36] or a combination of the EMC92 and the ISS (referred to as the EMC92-ISS) may be the optimal system [37]. With a rapidly changing therapeutic landscape, re-validation will be necessary. Capturing clonal content and evolution remains a challenge and newer high-throughput technologies are needed along with newer bioinformatics methodologies to identify meaning from the large amount of data being generated. Many unanswered questions still exist such as different GEP mutual relationships, the utilization of multiple systems, and the possibility of outperforming combinations. Nevertheless, targeted NGS approaches allow the assessment of all copy number variations, IGH translocations, and recurrent mutations in one technique. Thus, likely this technology has significant advantages in the long term [35,36,37].
The myeloma research community has amassed a vast expanse of genomic data from NDMM patients over the last decade. This has led to significant advances in our understanding of the genomic changes that portend to poor outcomes in NDMM patients. Unfortunately, our success in elucidating high-risk genomic features in NDMM patients has not translated into tailored therapeutics and improved outcomes in these patients. An up-to-date uniform consensus on high-risk features is overdue and expected soon from the IMWG. Table 5 outlines our current stance on high-risk features in NDMM patients. Certain features, such as GEP, whole-genome sequencing, and PCLI may not be applicable in routine clinical practice but nonetheless have been consistently shown to drive poor outcomes. More comprehensive and routinely obtained genomic profiling beyond traditional FISH is needed to advance risk stratification in NDMM. We would consider any NDMM patient that meets any of the criteria listed in the high-risk column as being a high-risk patient and strongly encourage enrollment onto clinical trials for these patients.
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Unlike contemporary thrillers that portray killers as inhuman two-dimensional monsters, Hughes portrays Dix Steele as a human being gone horribly wrong. We see how his actions arise from feelings that most people experience as difficult and uncomfortable but that he experiences as intolerable, torturing, and unresolvable.The novels of Jim Thompson and Patricia Highsmith are obvious descendants of this one. All three writers have insight and descriptive power that allow you to see, feel and inhabit some disturbing forms of human psychopathology. Hughes' female characters are strong, clear-eyed, and wise. They're the drivers of the story, not the victims. All her characters are fully drawn, and the tension builds consistently throughout. It's a hard book to put down, and you continue to feel it even after you've finished it.
The perfect read for Hallowe'en, this new hardback volume of Jackson's finest stories reveals the queen of American gothic at her unsettling, mesmerising bestThere's something nasty in suburbia. In these deliciously dark tales, the daily commute turns into a nightmarish game of hide and seek, the loving wife hides homicidal thoughts and the concerned citizen might just be an infamous serial killer. In the haunting world of Shirley Jackson, nothing is as it seems and nowhere is safe, from the city streets to the country manor, and from the small-town apartment to the dark, dark woods...ExploreSimilar booksBook lists with this bookWhy do people like this book?TopicsWitchcraftSerial killersBuddhaGenresComing soon...PreviewBookshop.orgAmazonThe Curse She WoreByJordan Dane,
When Jack begins to investigate the phenomenon of police suicides, a disturbing pattern emerges and he soon suspects that a serial killer is at work, one who sets up his victims and leaves "suicide" notes drawn from the dark poems of Edgar Allan Poe.ExploreSimilar booksBook lists with this bookWhy do people like this book?TopicsJournalistsSerial killersThe FBIGenresComing soon...PreviewBookshop.orgAmazonRed DragonByThomas Harris,
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