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While the past decade has seen meaningful improvements in clinical outcomes for multiple myeloma patients, a subset of patients do not benefit from current therapeutics for unclear reasons. Many gene expression-based models of risk have been developed, but each model uses a different combination of genes and often involve assaying many genes making them difficult to implement. We organized the Multiple Myeloma DREAM Challenge, a crowdsourced effort to develop models of rapid progression in newly diagnosed myeloma patients and to benchmark these against previously published models. This effort lead to more robust predictors and found that incorporating specific demographic and clinical features improved gene expression-based models of high risk. Furthermore, post challenge analysis identified a novel expression-based risk marker and histone modifier,PHF19, which featured prominently in several independent models. Lastly, we show that a simple four feature predictor composed of age, International Staging System stage (ISS), and expression ofPHF19andMMSETperforms similarly to more complex models with many more gene expression features included.Key pointsMost comprehensive and unbiased assessment of prognostic biomarkers in MM resulting in a robust and parsimonious model.Identification ofPHF19as the expression based biomarker most strongly associated with rapid progression in MM patients.

Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.

Thalidomide and the IMiD immunomodulatory drugs, lenalidomide and pomalidomide, are widely used in the treatment of multiple myeloma (MM), del(5q) myelodysplastic syndromes and other hematologic malignancies, including mantle cell lymphoma. Ito et al.1 recently identified cereblon as a key target of thalidomide. Subsequent studies confirmed cereblon to be a common target for lenalidomide and pomalidomide, and established its essential role in mediating anticancer and immunomodulatory effects of these drugs.2, 3 Cereblon is encoded by the CRBN gene on chromosome 3 containing 11 exons, and the fully spliced transcript produces a 51-kDa protein. Cereblon is a component of the cullin ring E3 ubiquitin ligase complex (CRL4CRBN) that also contains DNA damage-binding protein 1 (DDB1), cullin (Cul) 4a and regulator of cullins (Roc) 1.1 E3 ligases attach ubiquitin moieties to specific substrate proteins in the cell that can mark them for proteasomal degradation. The putative role of cereblon within the E3 ligase complex is that of a substrate receptor.