A Risk Stratification System in Myeloma Patients with Autologous Stem Cell Transplantation.

Autologous stem cell transplantation (ASCT) has been a mainstay in myeloma treatment for over three decades, but patient prognosis post-ASCT varies significantly. In a retrospective study of 5259 patients with multiple myeloma (MM) at the University of Arkansas for Medical Sciences undergoing ASCT with a median 57-month follow-up, we divided the dataset into training (70%) and validation (30%) subsets. Employing univariable and multivariable Cox analyses, we systematically assessed 29 clinical variables, identifying crucial adverse prognostic factors, such as extended duration between MM diagnosis and ASCT, elevated serum ferritin, and reduced transferrin levels. These factors could enhance existing prognostic models. Additionally, we pinpointed significant poor prognosis markers like high serum calcium and low platelet counts, though they are applicable to a smaller patient population. Utilizing seven easily accessible high-risk variables, we devised a four-stage system (ATM4S) with primary stage borders determined through K-adaptive partitioning. This staging system underwent validation in both the training dataset and an independent cohort of 514 ASCT-treated MM patients from the University of Iowa. We also explored cytogenetic risk factors within this staging system, emphasizing its potential clinical utility for refining prognostic assessments and guiding personalized treatment approaches.

A gene signature can predict risk of MGUS progressing to multiple myeloma.

Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS). Serum markers are currently used to stratify MGUS patients into clinical risk groups. A molecular signature predicting MGUS progression has not been produced. We have explored the use of gene expression profiling to risk-stratify MGUS and developed an optimized signature based on large samples with long-term follow-up. Microarrays of plasma cell mRNA from 334 MGUS with stable disease and 40 MGUS that progressed to MM within 10 years, was used to define a molecular signature of MGUS risk. After a three-fold cross-validation analysis, the top thirty-six genes that appeared in each validation and maximized the concordance between risk score and MGUS progression were included in the gene signature (GS36). The GS36 accurately predicted MGUS progression (C-statistic is 0.928). An optimal cut-point for risk of progression by the GS36 score was found to be 0.7, which identified a subset of 61 patients with a 10-year progression probability of 54.1%. The remainder of the 313 patients had a probability of progression of only 2.2%. The sensitivity and specificity were 82.5% and 91.6%. Furthermore, combination of GS36, free light chain ratio and immunoparesis identified a subset of MGUS patients with 82.4% risk of progression to MM within 10 years. A gene expression signature combined with serum markers created a highly robust model for predicting risk of MGUS progression. These findings strongly support the inclusion of genomic analysis in the management of MGUS to identify patients who may benefit from more frequent monitoring.

Concomitant deletion of the short arm (del(1p13.3)) and amplification or gain (1q21) of chromosome 1 by fluorescence in situ hybridization are associated with a poor clinical outcome in multiple myeloma.

BACKGROUND: Chromosome 1 abnormalities in multiple myeloma (MM) are increasingly recognized as high risk-defining features. The authors report the prognostic value of del(1p13.3) by fluorescence in situ hybridization (FISH) at enrollment in subjects treated on total therapy clinical trials 2-6. METHODS: FISH probes were generated from specific BAC DNA clones for the AHCYL1 gene locus (1p13.3) and the CKS1B locus (1q21). RESULTS: A total of 1133 patients were included in this analysis. Although del(1p13.3) was detected in 220 (19.4%) patients, 1q21gain or 1q21amp were observed in 300 (26.5%) and 150 (13.2%) patients, respectively. Concomitant del(1p13.3) with 1q21 gain or amp was observed in 65 (5.7%) and 29 (2.5%) patients, respectively. There was enrichment of high-risk features such as International Staging System (ISS) stage 3 disease and gene expression profiling (GEP)70 high risk (HR) in the group with del(1p13.3). Presence of del(1p13.3) confers inferior progression-free survival (PFS) and overall survival (OS). On multivariate analysis, the presence of ISS stage 3 disease, GEP70 HR, 1q21gain, and 1q21amp were independent predictors of PFS or OS. CONCLUSIONS: The PFS and OS of patients with combined abnormalities of del (1p13.3)/1q21gain or amp was significantly worse compared to del(1p13.3) alone and 1q21gain or 1q21 amp alone, which identifies a subset of patients with poor clinical outcomes.

TRIP13 modulates protein deubiquitination and accelerates tumor development and progression of B cell malignancies.

Multiple myeloma (MM), a terminally differentiated B cell malignancy, remains difficult to cure. Understanding the molecular mechanisms underlying the progression of MM may identify therapeutic targets and lead to a fundamental shift in treatment of the disease. Deubiquitination, like ubiquitination, is a highly regulated process, implicated in almost every cellular process. Multiple deubiquitinating enzymes (DUBs) have been identified, but their regulation is poorly defined. Here, we determined that TRIP13 increases cellular deubiquitination. Overexpression of TRIP13 in mice and cultured cells resulted in excess cellular deubiquitination by enhancing the association of the DUB USP7 with its substrates. We show that TRIP13 is an oncogenic protein because it accelerates B cell tumor development in transgenic mice. TRIP13-induced resistance to proteasome inhibition can be overcome by a USP7 inhibitor in vitro and in vivo. These findings suggest that TRIP13 expression plays a critical role in B cell lymphoma and MM by regulating deubiquitination of critical oncogenic (NEK2) and tumor suppressor (PTEN, p53) proteins. High TRIP13 identifies a high-risk patient group amenable to adjuvant anti-USP7 therapy.