A Network Analysis of Multiple Myeloma Related Gene Signatures

Multiple myeloma (MM) is the second most prevalent hematological cancer. MM is a complex and heterogeneous disease, and thus, it is essential to leverage omics data from large MM cohorts to understand the molecular mechanisms underlying MM tumorigenesis, progression, and drug responses, which may aid in the development of better treatments. In this study, we analyzed gene expression, copy number variation, and clinical data from the Multiple Myeloma Research Consortium (MMRC) dataset and constructed a multiple myeloma molecular causal network (M3CN). The M3CN was used to unify eight prognostic gene signatures in the literature that shared very few genes between them, resulting in a prognostic subnetwork of the M3CN, consisting of 178 genes that were enriched for genes involved in cell cycle (fold enrichment = 8.4, p value = 6.1 × 10−26). The M3CN was further used to characterize immunomodulators and proteasome inhibitors for MM, demonstrating the pleiotropic effects of these drugs, with drug-response signature genes enriched across multiple M3CN subnetworks. Network analyses indicated potential links between these drug-response subnetworks and the prognostic subnetwork. To elucidate the structure of these important MM subnetworks, we identified putative key regulators predicted to modulate the state of these subnetworks. Finally, to assess the predictive power of our network-based models, we stratified MM patients in an independent cohort, the MMRF-CoMMpass study, based on the prognostic subnetwork, and compared the performance of this subnetwork against other signatures in the literature. We show that the M3CN-derived prognostic subnetwork achieved the best separation between different risk groups in terms of log-rank test p-values and hazard ratios. In summary, this work demonstrates the power of a probabilistic causal network approach to understanding molecular mechanisms underlying the different MM signatures.

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A 13-Glycosylation Gene Signature in Multiple Myeloma Can Predicts Survival and Identifies Candidates for Targeted Therapy (GiMM13)

Blood ◽

10.1182/blood.v128.22.4423.4423 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4423-4423 ◽

Cited By ~ 2

Author(s):

Caoilfhionn Connolly ◽

Alokkumar Jha ◽

Alessandro Natoni ◽

Michael E O'Dwyer

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

High Risk ◽

Research Funding ◽

Gene Signature ◽

Gene Set Enrichment Analysis ◽

Rank Test ◽

P Value ◽

Log Rank Test ◽

Novel Approach

Abstract Introduction Advances in genomics have highlighted the potential for individualized prognostication and therapy in multiple myeloma (MM). Previously developed gene expression signatures have identified patients with high risk (Kuiper et al, Blood 2016) however, they provide few insights into underlying disease biology thereby limiting their use in informing treatment decisions. Glycosylation is deregulated in MM (Glavey et al), and potential consequences include altered cell adhesion, signaling, immune evasion and drug resistance. In this study we have utilized RNA sequencing data from the IA7 CoMMpass cohort to characterize the expression profile of genes involved in glycosylation. This represents a novel approach to identify a distinct molecular pathway related to outcome, which is potentially actionable. Methods A pathway based approach was adopted to evaluate genes implicated in glycosylation, including the generation of selectin ligands. A literature review and KEGG pathway analysis of pathways relating to O-glycans, N-glycans, sialic acid metabolism, glycolipid synthesis and metabolism was completed. RNA Cufflinks-gene level FPKM expression of 458 patients enrolled in the IA7 cohort of the Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) were analysed as derivation cohort. We developed expression cut-offs using a novel approach of adjusted existing linear regression model to define the gene expression cut-off by applying 3rd Quartile data (q1+q2/2-qmin). The analysis of overall survival (OS) was completed using adjusted 'kpas' R-package according to our cut-off model. Association between individual transcripts and OS was analyzed with log-rank test. Genes with p-value <0.2 were used in subsequent prioritization analysis. This cut-off methodology was employed to define the nearest neighbor for a gene for Gene Set Enrichment Analysis (GSEA). As far as 4th neighbor above and below the cut off was used to have centrally driven gene selection method for prioritization. The gene signature was validated in GSE2658 (Shaughnessy et al) dataset. Results Initial analysis yielded 184 prospective genes. 147 were significant on univariate analysis. Following further prioritization of these genes, we identified thirteen genes that had significant impact upon outcomes (GiMM13). Figure 1 reveals that GiMM13 signature has a significant correlation with inferior OS (HR 4.66 p-value 0.022). The prognostic impact of stratifying GiMM13 positive (High risk) or GiMM13 negative (Low risk) by ISS stage was evaluated. In Table 1. Kaplan Meier estimates generated for GiMM13 (High) or GiMM13 (Low) stratified by ISS are compared statistically using the log rank test. The prognostic ability of GiMM13 to synthesize distinct subgroups relative to each ISS stage is shown in Figure 2. ISS1-Low is the the lowest risk group with best prognosis. Hazard ratios relative to the ISS1-Low group were 1.8, p-value 0.029 (ISS2-Low), 2.1, p-value 0.031 (ISS3-Low), 4.3, p-value 0.04 (ISS1-HR), 5.9, p-value 0.039 (ISS2-HR) and 3.1, p-value 0.001 (ISS3-HR). The GiMM13 signature enhances the prognostic ability of ISS to identify patients with inferior or superior outcomes respectively. Conclusion While the therapeutic armamentarium for MM has expanded considerably, the significant molecular heterogeneity in the disease still poses a significant challenge. Our data suggests aberrant transcription of glycosylation genes, involved predominantly in selectin ligand synthesis, is associated with inferior survival outcomes and may help identify patients likely to benefit from treatment with agents targeting aberrant glycosylation, e.g. E-selectin inhibitor. Consistent with recent findings in chemoresistant minimal residual disease (MRD) (Paiva et al, Blood 2016), it would appear that O-glycosylation, rather than N-glycosylation is most significantly implicated in this biological processes conferring inferior outcomes. In conclusion, using a novel pathway-based approach to identify a 13-gene signature (GiMM13), we have developed a robust tool that can refine patient prognosis and inform clinical decision-making. Acknowledgment These data were generated as part of the Multiple Myeloma Research Foundation Personalized Medicine Initiatives (https://research.themmrf.org and www.themmrf.org). Disclosures O'Dwyer: Glycomimetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

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Analysis of Immune-Related Signatures Related to CD4+ T Cell Infiltration With Gene Co-Expression Network in Pancreatic Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.674897 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhen Tan ◽

Yubin Lei ◽

Bo Zhang ◽

Si Shi ◽

Jiang Liu ◽

...

Keyword(s):

Overall Survival ◽

Molecular Mechanisms ◽

Cox Regression ◽

Risk Groups ◽

Gene Signature ◽

Gene Expression Omnibus ◽

Ductal Adenocarcinoma ◽

Rank Test ◽

Cancer Center ◽

Cox Regression Analysis

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most invasive solid malignancies. Immunotherapy and targeted therapy confirmed an existing certain curative effect in treating PDAC. The aim of this study was to develop an immune-related molecular marker to enhance the ability to predict Stages III and IV PDAC patients.MethodIn this study, weighted gene co-expression network (WGCNA) analysis and a deconvolution algorithm (CIBERSORT) that evaluated the cellular constituent of immune cells were used to evaluate PDAC expression data from the GEO (Gene Expression Omnibus) datasets, and identify modules related to CD4+ T cells. LASSO Cox regression analysis and Kaplan–Meier curve were applied to select and build prognostic multi-gene signature in TCGA Stages III and IV PDAC patients (N = 126). This was followed by independent Stages III and IV validation of the gene signature in the International Cancer Genome Consortium (ICGC, N = 62) and the Fudan University Shanghai Cancer Center (FUSCC, N = 42) cohort. Inherited germline mutations and tumor immunity exploration were applied to elucidate the molecular mechanisms in PDAC. Univariate and Multivariate Cox regression analyses were applied to verify the independent prognostic factors. Finally, a prognostic nomogram was created according to the TCGA-PDAC dataset.ResultsA four-gene signature comprising NAPSB, ZNF831, CXCL9 and PYHIN1 was established to predict overall survival of PDAC. This signature also robustly predicted survival in two independent validation cohorts. The four-gene signature could divide patients into high and low-risk groups with disparity overall survival verified by a Log-rank test. Expression of four genes positively correlated with immunosuppression activity (PD-L1 and PD1). Immune-related genes nomogram and corresponding calibration curves showed significant performance for predicting 3-year survival in TCGA-PDAC dataset.ConclusionWe constructed a novel four-gene signature to predict the prognosis of Stages III and IV PDAC patients by applying WGCNA and CIBERSORT algorithm scoring to transcriptome data different from traditional methods of filtrating for differential genes in cancer and healthy tissues. The findings may provide reference to predict survival and was beneficial to individualized management for advanced PDAC patients.

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Increase of Mitochondrial Activity Contributes to the Bortezomib-Relapsed in Multiple Myeloma, a Novel Therapeutic Opportunity

Blood ◽

10.1182/blood-2019-123950 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4408-4408

Author(s):

Alejandra Ortiz-Ruiz ◽

Yanira Ruiz-Heredia ◽

Mehmet Samur ◽

Pedro Aguilar-Garrido ◽

Maria Luz Morales ◽

...

Keyword(s):

Multiple Myeloma ◽

Protein Expression ◽

Mitochondrial Function ◽

Molecular Mechanisms ◽

Mitochondrial Activity ◽

P Value ◽

Myeloma Cells ◽

Bortezomib Treatment

Introduction Mitochondria controls crucial biological pathways such as proliferation, apoptosis and cell growth. However, the implication of mitochondrial activity in the pathogenesis of Multiple Myeloma (MM) still remains unknown and only a few studies connect the mitochondrial status and MM. We planned to decipher the role of the mitochondria in the MM mechanism of resistance and the potential exploitation of mitochondrial activity as a functional target in the MM therapy. Methods In order to understand the role of mitochondria in MM and its therapeutic exploitation, firstly we explored factors involved in the mitochondrial function (c-Myc, HNRNPK, TFAM, NRF1 and EF-Tu) from 770 MM patients RNAseq CoMMpass℠ data. Furthermore, we performed different studies in our MM 77 patients set: gene expression validation by RT-PCR (n=40), protein expression (COXII) by IHC (n=28); and mitochondrial activity (COX activity) by histoenzymatic-HE assay (n=11). Additionally, we analyzed the impact of bortezomib in the mitochondria regulator CD38 in 50 samples (n=30 RVD, n=20 RD regimens), at diagnosis and 6/9 months follow-up MM patients. We have tested the effect of tigecycline, a mitochondrial inhibitor, in three regimens: monotherapy, pre-treament of tigecycline (48h) with consecutive bortezomib treatment, and in combination with bortezomib in the MM cell lines JJN3, L363 and NCI-H929. To characterize the molecular mechanisms underlying the cytotoxic effect of tigecycline we analysed mitochondria load and activity (MitoTracker green and red) OXPHOS expression by WB and COX2 activity by HE assay. Finally, we followed an in vivo experiment in NSG mice (n=40) engrafted with the JJN3-GFP cell line (1x106) via tail vein and treated by 4 weeks. Analysis of the in vivo imaging and survival curve were obtained. Results The higher expression of factors involved in the mitochondrial function such as: c-Myc, HNRNPK, NRF1 and EF-Tu predict MM poor outcomes (Fig.1A). Furthermore, mitochondrial representative gene and protein expression and activity were found increased in MM relapse stage patients. We showed overexpression of C-Myc, TFAM and EF-Tu on the MM relapsed group (Fig. 1B). Moreover, IHC reveals overexpression of mitochondrial COXII protein in relapse MM patients (p-value ** < 0.001) (Fig. 1C). By functional assays we have demonstrated that gene/protein overexpression drives to an increase of activity (COX HE) in MM at relapse (p-value ***< 0.0001). (Fig. 1D). Moreover, we observed an increase of CD38 expression in patients with RVD regimen, but not without bortezomib (RD regimen) (Fig. 1E). Together these results suggest elevation of mitochondrial activity plays a role in the mechanism of resistance to treatment and/or progression of MM and the consequent relapse of the patients. In vitro studies with tigecyline and bortezomib showed cytotoxic effects in three MM cell lines (IC50 JJN3 11,91 µM; IC50 L363 10,21 µM and NCI-H929 26,37 µM, p-value *< 0.05). Moreover, bortezomib and tigecyline showed high levels of synergism (CI 0,19) (Fig. 1F). In fact, the "conditioning" treatment with tigecyline revert the resistance to bortezomib. The cells treated with tigecycline reflect diminishing in the mitochondria respiration by MitoTracker assays, decrease of COX activity and respiratory chain complexes, suggesting a reduction of mitochondrial activity (Fig. 1G). These molecular effects are exacerbated by the tigecycline and bortezomib combination. However, bortezomib monotherapy not decrease or inclusive, increase, all the molecular mechanisms of mitochondria studied. Finally, mice groups treated with tigecycline alone or in combination with bortezomib reported a better survival and lower JJN3-GFP infiltration (p-value *< 0.05) (Fig. 1H). Conclusion To sum up, these findings highlight new vulnerabilities in myeloma cells, suggesting a potential therapeutic target in the treatment of the disease. The metabolic activation of myeloma cells with the collaboration of CD38 and/or c-Myc overexpression or his regulators (e.g. HNRNPK) in response to bortezomib treatment lead an increase of mitochondria respiration. These data confirm the important role of mitochondria in the loss of efficacy in inhibitors of proteasome treatment. Thus, mitochondrial respiration emerges as a novel target in bortezomib relapsed MM patients, and, potentially, in multiple c-Myc, HNRNPK and CD38 overexpression neoplasms. Disclosures Munshi: Adaptive: Consultancy; Oncopep: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Abbvie: Consultancy.

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The Prognostic Value of Whole-Blood PSMB5, CXCR4, POMP and RPL5 mRNA Expression in Patients with Multiple Myeloma Treated with Bortezomib

10.20944/preprints202012.0287.v2 ◽

2021 ◽

Author(s):

Paweł Robak ◽

Dariusz Jarych ◽

Damian Mikulski ◽

Izabela Dróżdż ◽

Edyta Węgłowska ◽

...

Keyword(s):

Multiple Myeloma ◽

Mrna Expression ◽

Molecular Mechanisms ◽

Multiple Drug Resistance ◽

Mrna Level ◽

Proteasome Inhibitors ◽

Progression Free Survival ◽

High Expression ◽

Multiple Drug ◽

Healthy Controls

Proteasome inhibitors, like bortezomib, play a key role in the treatment of multiple myeloma (MM); however, most patients eventually relapse and eventually show multiple drug resistance, and the molecular mechanisms of this resistance remain unclear. The present study examines the expression of previously-described genes that may influence resistance to bortezomib treatment at the mRNA level (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN and XBP1). mRNA expression was determined in 73 MM patients treated with bortezomib-based regimens (30 bortzomib-sensitive and 43 bortezomib-refractory patients) and 11 healthy controls. RPL5 was significantly down-regulated in multiple myeloma patients as compared with healthy controls. Moreover, POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. In multivariate analysis, high expression of PSMB5 and CXCR and autologous stem cell transplantation were independent predictors of progression-free survival, and high expression of POMP and RPL5 was associated with shorter overall survival.

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Associations between Microrna Expression, Disease Progression and Ex Vivo Drug Response in Multiple Myeloma

Blood ◽

10.1182/blood-2019-128181 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3069-3069

Author(s):

Romika Kumari ◽

Ashwini Kumar ◽

Alun Parsons ◽

Minna Suvela ◽

Juha Lievonen ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Mirna Expression ◽

Research Funding ◽

Drug Response ◽

Drug Sensitivity ◽

Mtor Inhibitors ◽

P Value ◽

Diagnosis And Prognosis

Targeted drug treatment strategies have significantly prolonged the overall survival rate among multiple myeloma (MM) patients. However, high relapse rates and multiple drug resistance still pose major challenges. Although, the underlying molecular features of the disease have been explored both at the genomic and transcriptomic levels, the functional role of microRNAs (miRNA) in MM disease progression and prognosis is yet to be investigated at a personalized level. In earlier studies, microRNAs have been implicated to regulate gene expression and were determined to play crucial roles in the biology of MM by acting as oncogenes or tumor suppressors. Nevertheless, considering the heterogeneity of MM, little is known about the roles of miRNAs in controlling MM disease progression and drug response at an individualized systems level. We collected bone marrow aspirates from MM patients at diagnosis (n=20) and relapse (n=25) after informed consent and following approved protocols in accordance with the Declaration of Helsinki. CD138+ plasma cells were enriched from the bone marrow samples and used for miRNA-sequencing and drug sensitivity and resistance testing (DSRT). The miRNA was prepared from the CD138+ cells and subjected to sequencing using Illumina compatible technologies. DSRT was performed and responses to 83 clinically approved drugs and investigational compounds were measured as drug sensitivity scores (DSS) as described previously (Majumder et al., Oncotarget 2017). The pairwise comparative analysis of miRNA expression and drug responses was performed using Spearman's rank-order correlations, to elucidate significant associations of miRNA expression with drug sensitivity and resistance. Additionally, using DEseq2 the differential miRNA expression was determined for the newly diagnosed and relapse samples to deconvolute the role of miRNAs in MM disease progression. The comparative analysis of the miRNA expression and drug sensitivity scores revealed statistically significant associations between miRNA expression and drug sensitivity measures with the Spearman coefficient (r) ranging from -0.71 to 0.64 (adjusted p-value ≤ 0.05) (Figure 1A). Negative associations were more prevalent, with 40 miRNAs negatively associated with ≥1 drug response from the total of 30 predicted drugs. miR-486, which is known to be an effective biomarker in diagnosis and prognosis of multiple cancer types (Jiang et al., Oncotarget 2018), was found to have significant negative correlation (r= -0.71 to -0.52, p-value ≤ 0.01) with the responses of 14 drugs. Similarly, negative correlation was observed for miR-144 with 12 drugs and miR-584 with 9 drugs. We observed that PI3K/mTOR inhibitors and HDAC inhibitors were common amongst all the significant negative correlations predicted. Specifically, the PI3K/mTOR inhibitors apitosilib, omipalisib and buparlisib were found to be negatively associated with the expression of 18, 14 and 7 miRNAs respectively. These observations can lead to the understanding of miRNA mediated regulation of molecular pathways involved in drug resistance. Differential miRNA expression analysis between newly diagnosed and relapse MM samples revealed the involvement of miRNAs in disease progression. The analysis resulted in total of 31 significant differentially expressed miRNAs with fold change ≥2 and adjusted p-value ≤ 0.1 (Figure 1B). Several miRNAs known to play crucial roles in cancer diagnosis and prognosis were found to be significantly upregulated in the relapse samples. In particular, 25 miRNAs were upregulated, including following miR-17/92 cluster members: miR-18b, miR-20a, miR-92b and miR-106a, which are known to have an oncogenic role in various cancer types (Mogilyansky & Rigoutsos, Cell Death and Differentiation 2013). Interestingly, 12/31 differentially regulated miRNAs were located on chromosome X. Although cytogenetic alteration data predicted that chromosome 1q gain is significantly prominent in the relapse samples (p-value = 0.009), only 3/31 differentially regulated miRNAs were located on chromosome 1. These results demonstrate the role of miRNAs in regulating drug response and disease progression in multiple myeloma. Monitoring miRNA expression profiles in MM patients can facilitate the assessment of treatment outcome and prognosis, and miRNAs could potentially be useful prognostic and treatment biomarkers for MM. Disclosures Silvennoinen: Amgen: Research Funding; Bristol-Myers Squibb (BMS): Research Funding; Takeda: Research Funding; Celgene: Research Funding. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding.

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Increased expression of miR-27 predicts poor prognosis and promotes tumorigenesis in human multiple myeloma

Bioscience Reports ◽

10.1042/bsr20182502 ◽

2019 ◽

Vol 39 (4) ◽

Cited By ~ 8

Author(s):

Feifei Che ◽

Chunqian Wan ◽

Jingying Dai ◽

Jiao Chen

Keyword(s):

Cell Cycle ◽

Multiple Myeloma ◽

Bone Marrow ◽

Cell Proliferation ◽

Cell Cycle Progression ◽

Molecular Mechanisms ◽

Plasma Cells ◽

Biological Role ◽

Migration And Invasion ◽

Rank Test

Abstract Multiple myeloma (MM) is an incurable hematological malignancy characterized by abnormal infiltration of plasma cells in the bone marrow. MicroRNAs (miRNAs) have emerged as crucial regulators in human tumorigenesis and tumor progression. miR-27, a novel cancer-related miRNA, has been confirmed to be implicated in multiple types of human tumors; however, its biological role in MM remains largely unknown. The present study aimed to characterize the biological role of miR-27 in MM and elucidate the potential molecular mechanisms. Here we found that miR-27 was significantly up-regulated in MM samples compared with normal bone marrow samples from healthy donors. Moreover, the log-rank test and Kaplan–Meier survival analysis displayed that MM patients with high miR-27 expression experienced a significantly shorter overall survival than those with low miR-27 expression. In the current study, we transfected MM cells with miR-27 mimics or miR-27 inhibitor to manipulate its expression. Functional studies demonstrated that miR-27 overexpression promoted MM cell proliferation, facilitated cell cycle progression, and expedited cell migration and invasion; whereas miR-27 knockdown inhibited cell proliferation, induced cell cycle arrest, and slowed down cell motility. Mechanistic studies revealed that Sprouty homolog 2 (SPRY2) was a direct target of miR-27 and that rescuing SPRY2 expression reversed the promoting effects of miR-27 on MM cell proliferation, migration, and invasion. Besides, miR-27 ablation suppressed tumorigenecity of MM cells in mouse xenograft models. Collectively, our data indicate that miR-27 exerts its oncogenic functions in MM by targetting SPRY2 and that miR-27 may be used as a promising candidate target in MM treatment.

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Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects

Cancers ◽

10.3390/cancers12092540 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2540 ◽

Cited By ~ 1

Author(s):

Elia Pancheri ◽

Valeria Guglielmi ◽

Grzegorz M. Wilczynski ◽

Manuela Malatesta ◽

Paola Tonin ◽

...

Keyword(s):

Skeletal Muscle ◽

Multiple Myeloma ◽

Adverse Effects ◽

Molecular Mechanisms ◽

Proteasome Inhibitors ◽

Hematologic Toxicity ◽

Negative Effects ◽

Early Discontinuation ◽

Cardiovascular Side Effects

The overall approach to the treatment of multiple myeloma (MM) has undergone several changes during the past decade. and proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have considerably improved the outcomes in affected patients. The first-in-class selective PI bortezomib has been initially approved for the refractory forms of the disease but has now become, in combination with other drugs, the backbone of the frontline therapy for newly diagnosed MM patients, as well as in the maintenance therapy and relapsed/refractory setting. Despite being among the most widely used and highly effective agents for MM, bortezomib can induce adverse events that potentially lead to early discontinuation of the therapy with negative effects on the quality of life and outcome of the patients. Although peripheral neuropathy and myelosuppression have been recognized as the most relevant bortezomib-related adverse effects, cardiac and skeletal muscle toxicities are relatively common in MM treated patients, but they have received much less attention. Here we review the neuromuscular and cardiovascular side effects of bortezomib. focusing on the molecular mechanisms underlying its toxicity. We also discuss our preliminary data on the effects of bortezomib on skeletal muscle tissue in mice receiving the drug.

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A multicenter, randomized, double-blind, placebo-controlled trial of thalidomide plus dexamethasone versus dexamethasone alone as initial therapy for newly diagnosed multiple myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7517 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7517-7517 ◽

Cited By ~ 5

Author(s):

S. V. Rajkumar ◽

M. Hussein ◽

J. Catalano ◽

W. Jedrzejcak ◽

S. Sirkovich ◽

...

Keyword(s):

Multiple Myeloma ◽

Primary Endpoint ◽

Interim Analysis ◽

Controlled Trial ◽

Data Monitoring Committee ◽

Rank Test ◽

P Value ◽

Primary Therapy ◽

Double Blind ◽

Significance Level

7517 Background: Thalidomide plus dexamethasone (Thal/Dex) yields superior response rates versus dexamethasone (Dex) but its impact as primary therapy for multiple myeloma (MM) is unknown. Methods: Patients (pts) with previously untreated, symptomatic MM were eligible and were randomized in this double-blind trial to Thal/Dex (Arm A) or placebo plus Dex (Arm B). Pts in Arm A received Thal 50 mg PO daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2; Dex 40 mg PO was given on days 1–4, 9–12, and 17–20. Pts in Arm B received placebo instead of Thal, and Dex as in Arm A. Cycles were 28 days long, repeated until progression or undue toxicity. The primary endpoint was time to progression (TTP) defined using EBMT criteria. All analyses were intent to treat. Planned sample size was 218 eligible pts in each arm. Full information for one-sided log rank test with significance level of 0.025 (allowing for 1interim analysis) to have 80% power to detect a 40% improvement in TTP (16.8 mo in Arm A vs. 12 mo in Arm B) would be achieved when 282 pts have progressed. A pre-planned interim analysis of the primary endpoint and safety was performed by an independent Data Monitoring Committee (DMC). P value < 0.0015 at this interim analysis would indicate that Arm A is superior to Arm B based on an alpha-spending function of the O’Brien-Fleming type. The DMC recommended release of results. Results: 470 pts were enrolled: 235 randomized to Thal/Dex and 235 to placebo/Dex. Median follow-up was 25 months. Median age was 65 yrs. TTP was significantly superior with Thal/Dex vs placebo/Dex, median TTP 17.4 months (95% CI: 8.1 months-NE) vs 6.4 months (95% CI: 5.6–7.4 months), respectively, P < 0.000065, crossing the upper boundary for superiority. DVT was higher with Thal/Dex vs placebo/Dex, 15.4% vs 4.3%, respectively. Median survival was not reached in either arm. Conclusions: Thal/Dex is significantly superior to Dex alone as first-line therapy for multiple myeloma. [Table: see text] [Table: see text]

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Bortezomib, Lenalidomide and Dexamethasone Vs. Lenalidomide and Dexamethasone in Patients (Pts) with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Transplant (ASCT): Results of the Randomized Phase III Trial SWOG S0777

Blood ◽

10.1182/blood.v126.23.25.25 ◽

2015 ◽

Vol 126 (23) ◽

pp. 25-25 ◽

Cited By ~ 37

Author(s):

Brian Durie ◽

Antje Hoering ◽

S. Vincent Rajkumar ◽

Muneer H. Abidi ◽

Joshua Epstein ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Rank Test ◽

P Value ◽

Advisory Committees ◽

Significance Level ◽

Grade 3

Abstract Background: Lenalidomide with dexamethasone (Rd) is a standard of care for patients with previously untreated multiple myeloma. SWOG S0777, a randomized phase III trial, has compared Rd with bortezomib, lenalidomide and dexamethasone (VRd). The primary end point is progression-free survival (PFS) using a pre-specified one-sided stratified log rank test at a significance level of 0.02. The stratification factors are International Staging System (ISS) stage (I, II or III) and intent to transplant (yes or no), a total of 6 strata. Overall response rate (ORR), overall survival (OS) and safety are secondary end points. Methods: This analysis includes 474 patients evaluable for survival endpoints: 232 patients were randomized to Rd and 242 patients to VRd. Rd patients received lenalidomide 25 mg/day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. VRd patients received lenalidomide 25 mg/day on days 1-14 and dexamethasone 20/mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12 plus bortezomib 1.3 mg/m2 IV push on days 1, 4, 8 and 11 of a 21-day cycle. All patients received aspirin 325 mg/day and VRd patients received HSV prophylaxis per institutional standard. Induction was six 28-day cycles of Rd and eight 21-day cycles of VRd followed by Rd maintenance for all patients until progression, unacceptable toxicity or withdrawal of consent. Initial analyses utilized the pre-specified one-sided stratified log rank test. Results: Data are presented for VRd followed by Rd throughout. Between 2008 and 2012, 525 patients from 48 institutions were randomized. Fifty-one patients, 29 randomized to Rd and 22 randomized to RVd, were ineligible for the following reasons: missing, insufficient or early or late baseline labs (40); not meeting requirements of measurable disease (6); inadequate marrow function (1); inadequate creatinine clearance (1); prior malignancy (1); prior therapy (1); and more than 2 weeks of prior steroid therapy (1). The pre-specified significance level of 0.02 was reached in the log rank testing. The stratified hazard ratio (HR) was 0.742 (96% Wald confidence interval: 0.579, 0.951), and the one-sided stratified log rank p-value for PFS (VRd vs. Rd) was 0.0066. The OS was improved for VRd vs. Rd with HR = 0.666; two-sided log-rank p-value = 0.0114. The PFS and OS survival charts are displayed below. Median PFS was 43 months (VRd) versus 31 months (Rd). Median OS was not reached (VRd) versus 63 months (Rd). Patient characteristics were well-matched between VRd and Rd with the exception of fewer women (37% vs. 47%: P = 0.033) and fewer older patients (≥ 65 years 38% vs. 48%: P = 0.042) receiving VRd. With univariate Cox regression analysis correlates of better PFS/OS were: use of VRd (HR 0.72/0.65; P = 0.006); hemogoblin ≥10 g/dl (HR 1.17/1.43; P = 0.2/0.026) and lower ISS disease stage (HR 1.35/1.98; P = 0.014/< 0.001). The ORR for VRd was 71.07% versus 63.79% for Rd. The adverse events by CTC category and toxicity category were fairly well balanced. The most common hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were low hemoglobin (RVd=13%; Rd=16%), leukopenia (RVd=14%; Rd=16%), lymphopenia (RVd=23%; Rd=18%), neutropenia (RVd=19%; Rd=21%), and thrombocytopenia (RVd=18%; Rd=14%). The most common non-hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were: fatigue (RVd=16%; Rd=14%), sensory neuropathy (RVd=23%; Rd=3%), hyperglycemia (RVd=7%; Rd=11%), thrombosis/embolism (RVd=8%; Rd=9%), hypokalemia (RVd=9%; Rd=6%), muscle weakness (RVd=7%; Rd=4%), diarrhea (RVd=8%; Rd=2%), and dehydration (RVd=8%; Rd=2%). As expected ≥ Grade 3 neuropathy was more frequent with VRd (24% vs. 5%: P < 0.0001). Sixteen patients experienced a second primary malignancy, 7 (3%) on VRd and 9 (4%) on Rd. Conclusion: The addition of bortezomib to lenalidomide dexamethasone for induction therapy in previously untreated myeloma results in a statistically significant and clinically meaningful improvement in PFS as well as better OS. VRd had an acceptable safety and tolerability profile despite increased neurotoxicity and represents a potential new standard of care. Support: NIH/NCI/NCTN grants CA180888, CA180819, CA180821, CA180820; and in part by Millennium Pharmaceuticals, Inc., The Takeda Oncology Company, for provision of study drug. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Durie: Johnson & Johnson: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Celgene: Consultancy. Abidi:Millennium: Research Funding. Epstein:University of Arkansas for Medical Sciences: Employment. Reu:Takeda/Millennium: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Orlowski:BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Forma Therapeutics: Consultancy; Array BioPharma: Consultancy, Research Funding. Barlogie:Dana Farber Cancer Institute: Other: Travel Stipend; International Workshop on Waldenström's Macroglobulinemia: Other: Travel Stipend; ComtecMed- World Congress on Controversies in Hematology: Other: Travel Stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: Travel Stipend; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Myeloma Health, LLC: Patents & Royalties: Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; Multiple Myeloma Research Foundation: Other: Travel Stipend.

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Identifying age-specific gene signatures of the human cerebral cortex with joint analysis of transcriptomes and functional connectomes

Briefings in Bioinformatics ◽

10.1093/bib/bbaa388 ◽

2020 ◽

Author(s):

Xingzhong Zhao ◽

Jingqi Chen ◽

Peipei Xiao ◽

Jianfeng Feng ◽

Qing Nie ◽

...

Keyword(s):

Cerebral Cortex ◽

Molecular Mechanisms ◽

Magnetic Resonance Images ◽

Joint Analysis ◽

P Value ◽

Specific Gene ◽

Human Cerebral Cortex ◽

Gene Signatures ◽

Brain Functions ◽

Age Related

Abstract The human cerebral cortex undergoes profound structural and functional dynamic variations across the lifespan, whereas the underlying molecular mechanisms remain unclear. Here, with a novel method transcriptome-connectome correlation analysis (TCA), which integrates the brain functional magnetic resonance images and region-specific transcriptomes, we identify age-specific cortex (ASC) gene signatures for adolescence, early adulthood and late adulthood. The ASC gene signatures are significantly correlated with the cortical thickness (P-value <2.00e-3) and myelination (P-value <1.00e-3), two key brain structural features that vary in accordance with brain development. In addition to the molecular underpinning of age-related brain functions, the ASC gene signatures allow delineation of the molecular mechanisms of neuropsychiatric disorders, such as the regulation between ARNT2 and its target gene ETF1 involved in Schizophrenia. We further validate the ASC gene signatures with published gene sets associated with the adult cortex, and confirm the robustness of TCA on other brain image datasets. Availability: All scripts are written in R. Scripts for the TCA method and related statistics result can be freely accessed at https://github.com/Soulnature/TCA. Additional data related to this paper may be requested from the authors.

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