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Funder: E.P. is a Josie Robertson Investigator and is supported by the European Hematology Association, American Society of Hematology, Gabrielle’s Angels Foundation, V Foundation and The Geoffrey Beene Foundation and is a Damon Runyon Rachleff Innovator fellow. Work in the BJPH lab is funded by Cancer Research UK (C18680/A25508), the European Research Council (647685), MRC (MR-R009708-1), the Kay Kendall Leukaemia Fund (KKL1243), the Wellcome Trust (205254/Z/16/Z) and the Cancer Research UK Cambridge Major Centre (C49940/A25117). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), and was funded in part, by the Wellcome Trust who supported the Wellcome - MRC Cambridge Stem Cell Institute (203151/Z/16/Z). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. L.B., H.D. and B.J.P.H. are supported by the HARMONY Alliance (IMI Project No. 116026; https://www.harmony-alliance.eu/). The UK-NCRI AML working group trials were supported with research grants from the Medical Research Council (MRC), Cancer Research UK (CRUK), Blood Cancer UK and Cardiff University. We would like to thank all patients and investigators for their participation in the trials and the study., Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in

Recent genomic research efforts in multiple myeloma have revealed clinically relevant molecular subgroups beyond conventional cytogenetic classifications. Implementing these advances in clinical trial design and in routine patient care requires a new generation of molecular diagnostic tools. Here, we present a custom capture next-generation sequencing (NGS) panel designed to identify rearrangements involving the IGH locus, arm level, and focal copy number aberrations, as well as frequently mutated genes in multiple myeloma in a single assay. We sequenced 154 patients with plasma cell disorders and performed a head-to-head comparison with the results from conventional clinical assays, i.e., fluorescent in situ hybridization (FISH) and single-nucleotide polymorphism (SNP) microarray. Our custom capture NGS panel had high sensitivity (>99%) and specificity (>99%) for detection of IGH translocations and relevant chromosomal gains and losses in multiple myeloma. In addition, the assay was able to capture novel genomic markers associated with poor outcome such as bi-allelic events involving TP53. In summary, we show that a multiple myeloma designed custom capture NGS panel can detect IGH translocations and CNAs with very high concordance in relation to FISH and SNP microarrays and importantly captures the most relevant and recurrent somatic mutations in multiple myeloma rendering this approach highly suitable for clinical application in the modern era.