Faculty Bibliography

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 R²â€‰= 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.

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R_g = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.

Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal TP53 deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; P = .01). Clonal, but not subclonal, TP53 deletions were associated with clinical markers of advanced disease, specifically lower platelet counts (P < .001) and increased lactate dehydrogenase (P < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) (P = .002) or del(1p) (P = .006). Biallelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies.

Chromosomal rearrangements that result in oncogenic kinase activation are present in many solid and hematological malignancies, but none have been reported in multiple myeloma (MM). Here we analyzed 1421 samples from 958 myeloma patients using a targeted assay and detected fusion genes in 1.5% of patients. These fusion genes were in-frame and the majority of them contained kinase domains from either receptor tyrosine kinases (ALK, ROS1, NTRK3, and FGFR1) or cytoplasmic kinases (BRAF, MAP3K14, and MAPK14), which would result in the activation of MEK/ERK, NF-κB, or inflammatory signaling pathways. Fusion genes were present in smoldering MM, newly diagnosed MM, and relapse patient samples indicating they are not solely late events. Most fusion genes were subclonal in nature, but one EML4-ALK fusion was clonal indicating it is a driver of disease pathogenesis. Samples with fusions of receptor tyrosine kinases were not found in conjunction with clonal Ras/Raf mutations indicating a parallel mechanism of MEK/ERK pathway activation. Fusion genes involving MAP3K14 (NIK), which regulates the NF-κB pathway, were detected as were t(14;17) rearrangements involving NIK in 2% of MM samples. Activation of kinases in myeloma through rearrangements presents an opportunity to use treatments existing in other cancers.

Importance/UNASSIGNED:Several trials demonstrated the impact of novel agent-based maintenance in newly diagnosed multiple myeloma (NDMM), but there is no current evidence demonstrating the superiority of one regimen over the other, owing to the lack of direct/indirect comparisons. Objective/UNASSIGNED:To analyze and compare the effectiveness of different maintenance regimens in NDMM via a network meta-analysis. Data Sources/UNASSIGNED:We performed 2 independent searches in PubMed and Cochrane databases, and then we identified all the records registered after 1999 and on or before November 20, 2017. Study Selection/UNASSIGNED:By blinded review, we identified prospective phase 3 randomized trials evaluating novel agent-based maintenance in patients with NDMM; the included studies compared at least 2 maintenance approaches; comparators included placebo and no maintenance. From 364 screened records, 11 studies were included. Data Extraction and Synthesis/UNASSIGNED:We followed (independent extraction) the guidelines provided by the PRISMA Report and the EQUATOR Network. The evidence was synthesized using a network meta-analysis (NMA). To allow comparison of all treatments, no maintenance was selected as common comparator and the effect of placebo was assumed to be the same as no treatment. The best option was identified by a Bayesian consistency model based on hazard ratio (HR), 95% credible interval (CrI), probability of being the best treatment (PbBT), and median ranking distribution (MedR). Main Outcomes and Measures/UNASSIGNED:Outcomes of interest were progression-free survival (PFS) and overall survival (OS). Results/UNASSIGNED:Eleven trials and 8 treatments including a total of 5073 participants were included. By PFS analysis, lenalidomide-based regimens (lenalidomide-prednisone, lenalidomide alone) were identified as the most effective options (HR, 0.39 [95% CrI, 0.28-0.53] and 0.47 [95% CrI, 0.39-0.55], respectively; MedR, 1 and 2; overall PbBT, 74%). Four treatments (thalidomide-interferon, thalidomide-bortezomib, bortezomib-prednisone, thalidomide alone) showed an HR in favor of maintenance. By OS analysis, lenalidomide alone was identified as the best option (HR, 0.76; 95% CrI, 0.51-1.16; MedR, 2; PbBT, 38%), followed by bortezomib-thalidomide and bortezomib-prednisone. Similar features were noticed in the restricted network including transplant trials, in the sensitivity analysis, and in most of the prognostic subgroups. Conclusions and Relevance/UNASSIGNED:Based on PFS and OS results of this NMA, lenalidomide maintenance appears to be the best treatment option, by synthesizing the available evidence of novel agent-based maintenance in the past 20 years.