Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression

PURPOSE: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models

Regression-Based Utilization Prediction Algorithms: An Empirical Investigation

Abstract � Predicting future behavior reliably and efficiently is vital for systems that manage virtual services; such systems must be able to balance loads within a cloud environment to ensure that service level agreements (SLAs) are met at a reasonable expense. These virtual services while often comparatively idle are occasionally heavily utilized. Standard approaches to modeling system behavior (by analyzing the totality of the observed data, such as regression based approaches) tend to predict average rather than exceptional system behavior and may ignore important patterns of change over time. Consequently, such approaches are of limited use in providing warnings of future peak utilization within a cloud environment. Skewing predictions to better fit peak utilizations, results in poor fitting to low utilizations, which compromises the ability to accurately predict peak utilizations, due to false positives. In this paper, we present an adaptive approach that estimates, at run time, the best prediction value based on the performance of the previously seen predictions. This algorithm has wide applicability. We applied this adaptive technique to two large-scale real world case studies. In both studies, the results show that the adaptive approach is able to predict low, medium, and high utilizations accurately, at low cost, by adapting to changing patterns within the input time series. This facilitates better proactive management and placement of systems running within a cloud. Copyright � 2013 Ian Davis et al. Permission to copy is hereby granted provided the original copyright notice is reproduced in copies made