A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis

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

The apobec mutational activity in multiple myeloma: from diagnosis to cell lines

Next generation sequencing (NGS) studies have highlighted the role of aberrant activity of APOBEC DNA deaminases in generating the mu- tational repertoire of multiple myeloma (MM). However, the contribu- tion of this mutational process across the landscape of plasma cell dyscrasias, or its prognostic role, has never been investigated in detail. To answer these unexplored aspects of MM biology, we used published NGS data from our own work as well as others, including the large CoMMpass trial for a total of 1153 whole-exomes of MM. Furthermore, we investigated 5 MGUS, 6 primary plasma cell leukemias (pPCL) and 18 MM cell lines (MMCL). Overall, we identified signatures of two mu- tational processes, one related to spontaneous deamination of methy- lated cytosines (30% of variants, range 0-100%) and one attributed to aberrant APOBEC activity (70% of variants, range 0-100%). APOBEC contribution was extremely heterogeneous among MM patients, but was correlated with a higher mutational burden (r=0.71, p=<0.0001) and with MAF gene translocations t(14;16) and t(14;20). The activity of APOBEC increased from MGUS to MM to pPCL, both in terms of ab- solute number of mutations and as percentage contribution. In MMCL we instead observed a bi-modal distribution whereby 8 cell lines showed the highest numbers of mutations caused by APOBEC (5/8 car- ried MAF translocations), while 10 where virtually devoid of APOBEC mutations (0/10 carried MAF translocations). The contribution of APOBEC to the total mutational repertoire in MM had a clear prognos- tic impact. MM patients with APOBEC mutations in the lowest quartile had a survival advantage over patients with APOBEC mutations in the highest quartile both in terms of progression-free survival (3-y PFS 46% vs 67% months, p=<0.0001) and overall survival (3-y OS 52% vs 83%, p=0.0084). This association was retained in a multivariate model that included age, gender, cytogenetic class, ISS, and quartiles of mutational load both in PFS [p=0.02, HR 2.06 (95IC 1.11-3.81] and OS [p=0.02, HR 2.88 (95IC 1.17-7.09)]. Interestingly we found that APOBEC mutations in the 4th quartile retained its independent prognostic respect to high mutational load and presence of MAF translocations. Overall, our data suggest that APOBEC-mediated mutagenesis is strongly involved in MM pathogenesis and its activity persists during different phases of evolution, playing a critical role in MM genomic complexity, and im- pacting prognosis of the patients

SSX cancer testis antigens are expressed in most multiple myeloma patients: co-expression of SSX1, 2, 4, and 5 correlates with adverse prognosis and high frequencies of SSX-positive PCs.

Contains fulltext : 48545.pdf (publisher's version ) (Closed access)Cancer testis antigens (CTAs) are tumor-specific antigens that may be useful targets for cancer vaccines. Here, CTA expression was examined in multiple myeloma (MM), a B-cell cancer characterized by malignant plasma cells (PCs) in the bone marrow (BM), and monoclonal gammopathy of undetermined significance (MGUS), a condition that can progress to MM. We screened a panel of patient BMs at different stages of malignancy for CTA expression by reverse transcription polymerase chain reaction RT-PCR. Here, SSX (synovial sarcoma, X chromosome) emerged as a promising candidate for an MM vaccine, having a profile similar to currently studied CTA, NY-ESO-1, and MAGE. SSX1, 2, 4, and 5 expression was studied further in 114 MM (total SSX, 61% of patients; SSX1, 42%; SSX2, 23%; SSX4, 38%; SSX5, 35%), 45 MGUS (total SSX, 24% of patients; SSX1, 9%; SSX4, 20%), and 12 control (0/12, 0%) subjects. Several expression patterns were observed, the most predominant being co-expression of SSX1, 2, 4, and 5 (called group A expression, in 20% of MM), which correlated with reduced survival (P=0.0006). Of the four genes, SSX2 had the strongest association with reduced survival (P=0.0001). SSX protein expression ranged from 13.5% of PCs in an SSX1/SSX4 co-expressor to as high as 88% of PCs in group A expressor, exceeding reported frequencies of NY-ESO-1 and MAGE in MM. In single PCs from group A patients, we detected variable degrees of SSX co-expression, emphasizing the heterogeneity of CTA expression within tumor cell populations. These results demonstrate that SSX is a frequently expressed CTA in MM and highlight its potential as an MM vaccine candidate

Correlation between array-comparative genomic hybridization-defined genomic gains and losses and survival: Identification of 1p31-32 deletion as a prognostic factor in myeloma

10.1038/leu.2010.21Leukemia244833-84

Early Relapse Risk in Newly Diagnosed Multiple Myeloma Patients Characterized by Next-Generation Sequencing

Purpose: Duration of first remission is important for the survival of patients with multiple myeloma. Experimental design: From the CoMMpass study (NCT01454297), 926 patients with newly diagnosed multiple myeloma, characterized by next-generation sequencing, were analyzed to evaluate those who experienced early progressive disease (PD; time to progression, TTP 6418 months). Results: After a median follow-up of 39 months, early PD was detected in 191/926 (20.6%) patients, 228/926 (24.6%) patients had late PD (TTP &gt;18 months), while 507/926 (54.8%) did not have PD at the current follow-up. Compared with patients with late PD, patients with early PD had a lower at least very good partial response rate (47% vs. 82%, P &lt; 0.001) and more frequently acquired double refractoriness to immunomodulatory drugs (IMiD) and proteasome inhibitors (PI; 21% vs. 8%, P &lt; 0.001). Patients with early PD were at higher risk of death compared with patients with late PD and no PD (HR, 3.65; 95% CI, 2.7-4.93; P &lt; 0.001), showing a dismal median overall survival (32.8 months). In a multivariate logistic regression model, independent factors increasing the early PD risk were TP53 mutation (OR, 3.78, P &lt; 0.001), high lactate dehydrogenase levels (OR, 3.15, P = 0.006), \u3bb-chain translocation (OR, 2.25, P = 0.033), and IGLL5 mutation (OR, 2.15, P = 0.007). Carfilzomib-based induction (OR, 0.15, P = 0.014), autologous stem-cell transplantation (OR, 0.27, P &lt; 0.001), and continuous therapy with PIs and IMiDs (OR, 0.34, P = 0.024) mitigated the risk of early PD. Conclusions: Early PD identifies a high-risk multiple myeloma population. Further research is needed to better identify baseline features predicting early PD and the optimal treatment approaches for patients at risk