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  • 1
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    A miRNA Risk Score for the Prediction of Response to Rituximab-CHOP Therapy and Survival of Patients with Diffuse Large B-Cell Lymphoma
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 324-324
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 324-324
    Abstract: Abstract 324 Background: Diffuse large B-cell lymphoma (DLBCL) may be curable with current immuno-chemotherapy, however nearly 30% of patients fail to benefit from this therapeutic approach. Gene expression profiling studies identified lymphocyte as well as stroma-based mRNA signatures that are predictive of response to R-CHOP; however the need for optimally cryopreserved samples has limited their clinical applicability. MicroRNAs (miRNA) are highly preserved non-coding RNAs that act post-transcriptionally to regulate gene expression by binding to the 3′UTR of mRNAs. To date multiple studies have reported selective miRNAs expression at different lymphocyte differentiation stages, distinct expression in mRNA-defined DLBCL subgroups and have correlated the expression of “selected” miRNAs with disease outcomes. Herein, we have conducted a comprehensive profiling of miRNA expression in R-CHOP treated DLBCL patients and established a miRNA-based risk score that is predictive of response to therapy. Methods and results: We have postulated that a miRNA signature in DLBCL is predictive of survival post R-CHOP chemotherapy. To test this hypothesis, we analyzed the miRNA and mRNA signatures of R-CHOP sensitive “S” and resistant “R” DLBCLs (n=20). miRNAs were hybridized to the miRNA Affymetrix gene-chip (847 hsa-miRNA probes) and raw miRNA expression values were log2 transformed and normalized (miRNA-QC tool, Affymetrix). Comparison of normalized miRNAs expression in “S” versus “R” patients (Anova testing) identified 59 differentially expressed miRNAs (Fold change 〈 -1.5 or 〉 1.5 with a p value and FDR 〈 0.05). In order to establish a risk score based on the expression of these 59 miRNAs, column-dendrogram branches were then sorted left to right based on each patient's difference between the average log2-scale expression of the 37 up-regulated and the 12 down-regulated miRNAs: this difference is interpreted as an up-/down-regulated mean ratio (ie, geometric mean) on the log2 scale [Log2 Geometric mean ratio [GMR] up-/down-regulated miRNA = Log2 [(2^Σupr egulatedümiRNA/ni)/(2^ΣdownregulatedümiRNA/nii)] where ni and nii represent the number of up-regulated and down-regulated miRNAs. This univariate summary (ie, GMR) of the 59-miRNA expression profiles for each patient enabled accurate prediction of all S versus R patients. Patients with log2 GMR 〉 0 had a 6-years PFS rate of 100%, while all patients with log2 GMR 〈 0 relapsed (HR=0.293 [95% CI 0.132–0.647]). Cox regression was then used to model relapse free survival times from treatment as a function of miRNA expression. Separate regression models were also built looking at fit measures, proportionality assumption, and discrimination ability (Harrell C statistics) and only miRNA with a discrimination ability (Harrell C) of 〉 85% (n=12 miRNA) were used to calculate the log2 GMR of up-/down-regulated miRNAs. A simplified model based on 12 miRNAs (Sensitive vs Resistant: upregulated: hsa-let-7i; hsa-miR-130a; hsa-miR-199a-3p; hsa-199b-3p; hsa-miR-223; hsa-miR22; hsa-miR-24; hsa-miR-26b; hsa-miR-27a; hsa-miR-331-5p; downregulated: hsa-miR-1288) accurately predicted sensitivity or resistance to R-CHOP. With this 12 miRNAs model, only 1 patient in each group (S and R) was misclassified (Fig 1). In addition we have validated the differential expression of these miRNA by short-stem loop RT-PCR and found a strong correlation between the gene-chip and qRT-PCR results (correlation coefficient 0.717). mRNA profiling (U133A Plus2 array chip) was also performed on the whole lymph node sections; 176 genes were identified as differentially expressed between S and R patients with many of these genes belonging to the “stroma-1 and -2” DLBCL signature. Using the TargetScan miRNA target mRNA prediction tool, combinatory analysis of miRNA and mRNA expression profiles of DLBCL patients identified positive and negative correlations (P 〈 0.05) between differentially expressed miRNA and mRNAs. Lastly in a multivariate Cox regression analysis that included the IPI and the 12 miRNA based GMR risk score, both variables were independent predictors of survival post R-CHOP therapy. Conclusion: We believe that this log2 GMR score based on the 12 identified miRNA provides a robust method of predicting sensitivity to R-CHOP in DLBCL patients and it is currently being tested in a larger independent validation cohort. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.324.324
    RVK:
    XA 33000
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 2
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    Bortezomib Induced BRCAness Sensitizes Multiple Myeloma Cells to PARP Inhibitors
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 789-789
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 789-789
    Abstract: Abstract 789 Background: Poly-ADP-ribose-polymerase (PARP) inhibitors are cytotoxic to tumor cells with impaired DNA damage repair machinery (DRR), in particular those with a deficient homology directed repair (HR) of DNA double stranded breaks (DSB). Multiple Myeloma (MM) cells are characterized by a highly unstable genome and while the exact mechanisms for this karyotypic instability is largely unknown, their DDR machinery is thought to be highly stressed. The ubiquitin-proteasome system (UPS) is involved in the regulation of several cellular functions including DDR and in particular HR. In addition proteasome inhibitors are reported to induce an unfolded protein response (UPR) in MM cells resulting in their apoptotic death. We have postulated that inhibition of the 26S proteasome also alters the DNA-DSB repair machinery leading to a BRCAness state in MM cells, sensitizing them to PARP inhibitors. Methods and results: In order to biochemically inhibit PARP in MM cells, we used a novel selective inhibitor of PARP1 and PARP2, 2-(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide or ABT-888. We first demonstrated inhibition of PARP activity as measured by a reduction in poly-ADP-ribose (PAR) polymer levels (western blotting) in human MM cell lines (MM1S, U266, H929, RPMI8226, KMS-11, OPM2, INA-6) treated with ABT-888 (5 μM). PARP inhibition and the reduction of PAR levels resulted in DNA damage as evidenced by ATM phosphorylation and induced DNA-DSBs with increased γH2AX (phospho-Ser139-H2AX) levels within 6–12 hours of MM cells treatment with ABT-888. Increased γH2AX foci formation was also detected by immunofluorescent staining within 6–12 hours of ABT-888 treatment and nearly fully resolved by 24 hours, consistent with repair of resultant DNA-DSBs. As expected treatment with ABT-888 alone had no effect on the viability of MM cells consistent with their ability to repair DNA-DSBs resulting from PARP inhibition. We then examined the effect of bortezomib on HR-mediated repair of DNA-DSBs, in particular on the BRCA/FA pathway. A significant reduction of MM cells' FANCD2, BRCA1, BRCA2 and RAD51 mRNA levels (qRT-PCR) was observed within 6–12 hours of bortezomib treatment (10 nM). Similar results were observed at the protein level indicating that bortezomib impedes homology-directed DNA-DSBs repair and results in an operational BRCAness state in MM cells. Therefore, we next tested whether this bortezomib-induced BRCAness was sufficient to sensitize MM cells to PARP inhibition with ABT-888. Consistent with our hypothesis, we observed that co-treatment of MM cell lines with bortezomib and ABT-888 lead to persistent and increased γH2AX foci at 24 hours compared to treatment with ABT-888 alone. Co-treatment also significantly potentiated cell death (Annexin V/PI staining) compared to treatment with bortezomib alone. Similar results were observed in CD138+ primary MM cells (n=8) with strong synergistic effect (CI 〈 1) between bortezomib and ABT-888. Importantly, no impaired viability (Annexin/PI staining) or function (colony forming unit assay) was noted for CD138− cells or CD34+ peripheral blood stem cells after bortezomib and ABT-888 co-treatment. Mechanistic studies have also shown that apoptotic events (caspase 3, caspase 8 and PARP cleavage) are markedly enhanced by this combination. Based on our in vitro data, we evaluated in vivo the activity of ABT-888 in combination with bortezomib in a Scid murine xenograft model of human MM. Significant inhibition of tumour growth (p 〈 0.005) was noted in mice treated with the combination of bortezomib and ABT-888 compared to bortezomib alone or control-treated mice. This tumour growth inhibition also resulted in a significant increase in survival (p 〈 0.05) of the animals. No toxicity (e.g. weight loss, ruffled coats, paralysis, etc.) was observed in mice treated with the combination. Induction of DNA-DSBs was also confirmed in vivo as shown by an increase in 53BP1 and γH2AX foci formation in tumors of mice treated with the combination compared to bortezomib alone. Conclusion: Our studies indicate that bortezomib induces a BRCAness state in MM cells by impairing HR-mediated repair of DNA-DSBs and results in a contextual synthetic lethality when combined with the PARP inhibitor ABT-888. These data provide the scientific basis for the future clinical testing of PARP inhibitors in combination with proteasome inhibitors for the treatment of MM. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.789.789
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
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    Ikaros-Dependent Downregulation of MYC with IMiDs in Myeloma (MM) Cells Is Mediated through the Depletion of the Acetylated Chromatin Reader BRD4 at Super-Enhancer Loci
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 4175-4175
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4175-4175
    Abstract: Background: IMiDs are now recognized to promote the proteasomal degradation of IKZF1/3 and the transcriptional repression of MYC and IRF4. MYC locus rearrangement is a recurrent somatic event in MM and results in MYC repositioning near superenhancers (such as IGH@, IGL@ and others). The mechanisms of IMiDs-mediated downregulation of MYC in MM cells is not well understood, in particular it is unclear how IMiDs alter the activity of the super-enhancers driving MYC transcription. Methods and results: Transcriptome analysis (RNAseq) of MM cells (OPM2 and MM1S) treated with lenalidomide or upon the silencing of IKZF3 (lentiviral delivery of dox-inducible IKZF3 shRNA) confirmed the downregulation of MYC, IRF4 and among others the upregulation of other genes of interest such as CD38, DKK1, PDL1, FOXO3 and a host of genes involved in interferon response. Gene set enrichment analysis (GSEA) confirmed the enrichment of genes signatures associated with MYC as well as the interferon response. Notably, in t(4;14) MM cell lines we observed a significant downregulation of FGFR3 while the expression of WHSC1 was not affected. This finding was confirmed in a library of t(4;14) MM cell lines by qRT-PCR analysis. As FGFR3 is driven by the 3' IGH enhancer while WHSC1 is under the control of the intronic Em enhancer in t(4;14) MM cells, and in view of the known role of IKZF1/3 in class switch recombination, we postulated that IKZF1/3 regulate the 3' IGH enhancer activity and MYC expression in cells harbouring a MYC-IGH rearrangement. To validate this hypothesis we established the genome-wide distribution of IKZF1 in OPM2 and MM1S cells (both cell lines harbour an IGH-MYC rearrangement) by ChIP-Seq. Ikaros bound to 17660 loci of which 43% were associated with gene targets. Ikaros-binding motifs and other motifs such as STAT1, E2A, RUNX1 were also identified (MEME Tomtom and Jasper motif analysis) in the vicinity of Ikaros enrichment peaks. Importantly IKZF1 peaks also mapped to the IGH 3' enhancer loci and these results were confirmed by ChIP-PCR analysis. Of interest while no Ikaros peaks mapped to MYC (within 5 kb of TSS) by ChIP-seq, modest enrichment of Ikaros at MYC promoter was identified by ChIP-PCR in MM1S and KMS11 cells, and this enrichment was significantly attenuated by lenalidomide treatment. Since inhibition of MYC occurs as a consequence of depletion of the acetylated chromatin reader BRD4 at enhancers that drive MYC expression (Delmore et al., 2011), we examined the interaction between BRD4, IKZF1 and IMiDs treatment. Chip-Seq analysis revealed that BRD4 and IKZF1 are associated with most active enhancers and promoters in MM1S tumor cells. In particular, BRD4 and IKZF1 were enriched at the IGH 3'α2 enhancer locus. Importantly, treatment with lenalidomide (10μM, 4 hours), dramatically depleted IKZF1 and BRD4 enrichment at the 3' IGH enhancers (ChIP-PCR analysis). In contrast, treatment with the bromodomain inhibitor JQ1 depleted BRD4, but not IKZF1 from the IGH 3' enhancer locus. These findings suggest that IKZF1 regulates BRD4 binding to the 3' IGH enhancers and explain the selective effect of IMiDs on MYC transcription in transformed cells harboring a MYC rearrangement. In addition, these results suggest that IMiDs will affect MYC expression only in cells were MYC is driven by an IKZF1/IKZF3 responsive enhancer. Lastly we sought to explain how IKZF1 may regulate BRD4 enrichment at H3K27Ac marks in super-enhancer loci. Since Ikaros is a known integral component of the NuRD (nucleosome remodelling and histone deacetylase) complex, we examined whether lenalidomide treatment and the ensuing Ikaros depletion lead to local gain of NuRD at MYC TSS and depletion of H3K27 acetylation. CHD4 (helicase subunit of the NURD complex) and H3K27Ac ChIP-PCR analysis revealed significant accumulation of the NuRD complex at MYC TSS as well as reduced H3K27Ac at 3'IGH enhancers after IMiDs exposure in MM1S and OPM2 cells. Importantly, CHD4 silencing abrogated lenalidomide induced MYC transcriptional repression and cell death. Conclusion: In summary, our studies suggest that Ikaros drives MYC expression in MM cells harbouring an IGH-MYC rearrangement by regulating the accumulation of the acetylated chromatin reader BRD4 at the IGH 3' enhancer and preventing the NURD complex mediated depletion of H3K27Ac marks at these enhancers. Our findings also explain the IKZF1/3 dependent mechanism of IMiDs-mediated MYC transcriptional repression. Disclosures Neri: Celgene: Research Funding. Duggan:Jansen: Honoraria; Celgene: Honoraria. Keats:Translational Genomic Research Institute: Employment. Bahlis:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Consultancy; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Research Funding; Amgen: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.4175.4175
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 4
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    Validation of a Novel Tissue Array Based Classification of Multiple Myeloma (MM).
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 1671-1671
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1671-1671
    Abstract: Background: Gene expression profiling molecular classification of MM was proven to be an independent predictor of survival post autologous stem cell transplant (ASCT); however it had limited clinical applicability due to its complex methodology and high costs. We have previously reported the results of a protein-array based classification of MM in an initial testing cohort and concluded that positive immunoperoxidase staining for FGFR3, Cyclin B2 or Integrin beta7 correlates with a shortened survival post ASCT (Bahlis et al. Blood2007:110:449a). We now report on the results of this TMA classification in a larger and independent validation cohort. Methods: Immunoperoxidase staining for Cyclins B1, B2, D1, D2 and D3, FGFR3, PAX5 and Integrin beta 7 were previously validated in our initial testing cohort (n=52). Further analysis of our initial testing cohort identified 3 risk groups: positive expression of FGFR3 or Integrin beta 7 defined as “High risk”, positive Cyclin B2 (in the absence of FGFR3 or Integrin beta 7) as “Intermediate risk” and the lack of expression of any of these biomarkers defined as “Low risk”. In order to confirm the predictive value of our proposed protein-array classification, these immunohistochemical (IHC) stains were performed on the bone marrow biopsies of a larger and independent validation cohort of 79 newly diagnosed MM patients uniformly treated with a dexamethasone based regimen followed by ASCT. The clinical parameters, response criteria and survival outcomes (TTP and OS) of this validation cohort were defined according to the international uniform response criteria. For IHC analysis two pathologists who were blinded with regards to the clinical outcome of these patients scored the cases independently as positive or negative. Discordance in their scoring was seen in 20/79 (25.7%) with a consensus scoring reassigned to all of these cases. The Kaplan-Meier method was used to estimate OS and TTP. Multivariate analysis was performed using the Cox regression method. Figure Figure Results: 79 patients were included in this validation cohort, the median age was 54.4 yrs (27.9–71), 23.7% had ISS stage III, median beta 2-microglobulin was 3.29 mg/L (1.16–37.5). Del13q and t(4;14) were detected by FISH in 35.6% and 13.6% of patients, respectively. Post ASCT, 68% achieved a CR or VGPR with an overall median TTP and OS of 2.29 years (CI 1.84–2.73) and 5.74 years (CI 4.98–6.51) respectively. Expression of FGFR3 was detected in 7.6% of the patients, cyclin B2 in 58.2% and integrin-beta7 in 17.7%. In univariate analysis expression of FGFR3 was associated with a significantly shorter TTP (P=0.011) but not OS (P=0.114). Similarly integrin-beta7 predicted for a shorter TTP (P=0.008) but not OS (P=0.570). Cyclin B2 also predicted for worse TTP (P=0.047) but not OS (P=0.098), whereas the expression of cyclins D1, D2, D3 and PAX5 did not affect survival. Based on our testing cohort definition of risk groups, 18/79 (22.8%) were considered as “High risk” with significantly shorter TTP 0.93 years (CI 0.74–1.12) compared to 2.29 years (CI 1.88–2.69) and 3.35 years (CI 2.51–4.19) for the “Intermediate” (34/79; 43%) and “Low” (27/79; 34.2%) risk groups respectively (P=0.002). The 5-years estimates for OS was 57.1% for the High-risk group compared to 66.3% and 71.6% for the Intermediate and Low risk group respectively (P=0.258). Multivariate analysis was performed using ISS, del13q and the TMA risk group classification as variables. The TMA classification and del 13q were the only independent predictors of TTP with the high-risk group having 3.4 fold greater risk of relapse (P=0.001). Conclusion: We have validated our protein array based classification of Multiple Myeloma and confirmed its survival predictive value post ASCT. MM patients with the High-risk signature should be spared the toxicity of ASCT and considered instead for other frontline novel therapeutic agents.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.1671.1671
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 5
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    Bortezomib and High Dose Melphalan (Bor-HDM) Compared to HDM Conditioning for the Treatment of Transplant Eligible Multiple Myeloma: Report from a Single Center
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 3189-3189
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3189-3189
    Abstract: Introduction Preclinical and clinical data suggest that bortezomib in combination with high-dose melphalan (Bor-HDM) provides with a synergistic effect able to improve the quality of response for MM patients undergoing auto-SCT. In the present study, we aimed to assess the impact of Bor-HDM conditioning on ORR, and MRD negativity for MM patients undergoing single auto-SCT at our Institution. Methods All consecutive patients who underwent single auto-SCT at Tom Baker Cancer Center (TBCC) from 01/2004 to 06/2015 using Bor-HDM or HDM as conditioning regimen were evaluated. Definitions of response and progression were used according to the EBMT modified criteria and a category of very good partial response (VGPR) was added. MRD negativity was assessed by multiparameter flow cytometry. All patients received induction chemotherapy before undergoing auto-SCT. Bortezomib was administered intravenously at 1-1.3 mg/m2 on days −5, −2, 1, and 4, while melphalan was given at 200 mg/m2 on day −1. A p value of 〈 0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Results Two-hundred and fifty-eight consecutive patients receiving Bor-HDM or HDM alone were evaluated. A total of 85 patients received Bor-HDM conditioning and 173 received HDM. Clinical characteristics and chemotherapy induction regimens are listed in Table 1. At day-100 post auto-SCT a ³VGPR was seen in 83.3% in the Bor-HDM group compared to 67.6% for HDM patients. The CR/nCR rate was higher in the Bor-HDM group (47.6% vs 23.6%) as well as MRD negativity assessed by flow cytometry (30.9% vs 9.7%, p=0.0001). Median OS in the Bor-HDM group was NR compared to 95 months for HDM alone (p=0.572), while median PFS was 39.3 months for Bor-HDM compared to 27 months for HDM (p=0.1). Median OS was shorter in the HR cytogenetic group regardless of the type of conditioning regimen employed (39 months vs NR for SR cytogenetics). In addition, patients who achieved MRD negativity, exhibited a longer OS (NR vs 78 months, p=0.007). Transplant-related mortality (TRM) was similar between both groups (p0.5). In conclusion, Bor-HDM is a safe and efficacious conditioning regimen able to increase the nCR/CR and MRD negativity rates compared to HDM. Further studies are warranted to explore this regimen, especially when other upfront therapies are employed, with special view on the high-risk MM patients where response rates are good but sustainability remains an issue. Table 1. Clinical Characteristics Characteristic Bor/HDM, N=85 HDM alone, N=173 Age (median) 58 59 GenderMaleFemale 51 (60%)34 (40%) 113 (65.3%)60 (34.7%) Hb (g/L) 112 117 Calcium (µmol/L) 2.25 2.29 Creatinine (µmol/L) 85 80 B2microglobulin (µmol/L) 3.3 2.79 Albumin (g/L) 31 35 Stage IStage IIStage III 154723 617333 M-spike (g/L) 34 30 LDH (IU/L) 194 180 BMPC (%) 40 33 Heavy chain:IgGIgAIgDFLC onlyBiclonalIgM 491811511 1142403210 Light chain:KappaLambdaBiclonal 50351 124471 High riskStandard risk 2263 36135 InductionCyBorDVDDexamethasoneRVD 4524016 16544315 Figure 1. Overall Survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 1. Overall Survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 2. Progression-Free survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 2. Progression-Free survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 3. Overall Survival for patients with MM undergoing single auto-SCT according to MRD negativity assessed by flow cytometry Figure 3. Overall Survival for patients with MM undergoing single auto-SCT according to MRD negativity assessed by flow cytometry Disclosures Jimenez-Zepeda: Celgene: Honoraria; J & J: Honoraria; Amgen: Honoraria. Duggan:Jansen: Honoraria; Celgene: Honoraria. Neri:Celgene: Research Funding. Bahlis:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.3189.3189
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 6
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    Bortezomib-Containing Regimens (BCR) for the Treatment of Non-Transplant Eligible Multiple Myeloma
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1846-1846
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1846-1846
    Abstract: Introduction In patients not eligible for transplant due to age and/or co-morbidities, the selection of up-front therapy needs to balance efficacy and toxicity. Recently, regimens with bortezomib, a proteasome inhibitor proven to be efficacious in myeloma, have been reported. Based on these findings, we aimed to evaluate the impact of different bortezomib combinations for the treatment of non transplant-eligible MM. Methods All- consecutive patients treated with bortezomib-containing regimens (BCR) at Tom Baker Cancer Center (TBCC) from 01/2006 to June/2015 were evaluated. Definitions of response and progression were used according to the EBMT modified criteria and a category of very good partial response (VGPR) was added. Two-sided Fisher exact test was used to test for differences between categorical variables. A p value of 〈 0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Results 113 consecutive patients with MM received BCR. Thirty-three patients were treated with cyclophosphamide, bortezomib and dexamethasone (CyBorD), 41 with bortezomib, melphalan and prednisone (VMP) and 39 with bortezomib and dexamethasone (VD). Clinical characteristics are shown in Table 1. At the time of analysis, 20, 17 and 18 patients in the CyBorD, VMP and VD groups are still alive and 14, 33 and 30 have already progressed, respectively. ORR and VGPR rates were 93.9%/75.7%, 80%/53% and 76%/48% (p=0.001) for patients treated with CyBorD, VMP and VD, respectively. Median OS was NR for CyBorD, compared to 41months and 37 months for VMP and VD patients (p=0.6). Median PFS was 16.7 months for CyBorD compared to 17.5 months and 11 months for VMP and VD (P=0.6), respectively. The rate of treatment discontinuation and median number of cycles were: 9%, 26% and 12.8% and 6, 7.5 and 4 cycles for CyBorD, VMP and VD patients, respectively. Patients were to receive 6-9 cycles of treatment and the regimen could be continued to a maximum of 2 years at the discretion of the treating hematologist based on tolerability and response. Nine patients (27%) in the CyBorD group and 17 (41.4%) and 4 (10%) in the VMP and VD group received maintenance treatment. Median OS and PFS was longer for the group receiving maintenance (62 months vs 32 months and 23 months vs 10 months, p=0.007). In conclusion, bortezomib containing regimens are efficacious in the treatment of non-transplant eligible MM. Patients receiving maintenance appeared to exhibit longer PFS and OS. Very elderly patients should be subjected to frailty and comorbidity indexes aiming to decrease toxicity and prolong survival. Table 1. Clinical Characteristics Characteristic CyBorD, n=33 VMP, n=41 VD, n=39 Age (median) 58 58 58 GenderMaleFemale 20 (60.6%)13 (39.4%) 22 (53.6%)19 (46.4%) 26 (66.6%)13 (33.4%) Hb (g/L) 107 110 103 Calcium (µmol/L) 2.4 2.35 2.31 Creatinine (µmol/L) 115.5 103 108 B2microglobulin (µmol/L) 4.1 3.42 5.9 Albumin (g/L) 31 31 30 Stage IStage IIStage III 6 (12.1%)14 (42.4%)13 (45.5%) 9 (21.9%)19 (46.3%)13 (31.8%) 4 (10.2%)16 (41%)18 (48.8%) LDH (IU/L) 185 179 174 BMPC (%) 31 30 33.5 Heavy chain:IgGIgAFLC onlyIgDIgMBiclonal 2247000 19148000 21107010 Light chain:KappaLambdaBiclonal 16170 29120 24150 High riskStandard risk 5 (15%) 28 6 (14.6%)35 8 (20%)31 Ab: BMPC: Bone marrow plasma cells. Figure 1. Overall survival for patients receiving CyBorD, VMP and VD Figure 1. Overall survival for patients receiving CyBorD, VMP and VD Figure 2. Progression-Free survival for patients receiving CyBorD, VMP and VD Figure 2. Progression-Free survival for patients receiving CyBorD, VMP and VD Figure 3. OS for patients receiving CyBorD, VMP and VD maintenance Figure 3. OS for patients receiving CyBorD, VMP and VD maintenance Disclosures Jimenez-Zepeda: Celgene: Honoraria; Amgen: Honoraria; J & J: Honoraria. Duggan:Jansen: Honoraria; Celgene: Honoraria. Neri:Celgene: Research Funding. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1846.1846
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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    Integrated Epigenetic and Transcriptional Single-Cell Analysis of t(11;14) Multiple Myeloma and Its BCL2 Dependency
    American Society of Hematology ; 2023
    In:  Blood Journal ( 2023-09-20)
    Details
    In: Blood Journal, American Society of Hematology, ( 2023-09-20)
    Abstract: The translocation t(11;14) occurs in 20% of multiple myeloma (MM) patients and results in the upregulation of CCND1. Nearly two-thirds of t(11;14) MM cells are BCL2 primed and highly responsive to the oral BCL2 inhibitor venetoclax. While it is evident that this unique sensitivity to venetoclax depends on the BH3-proapoptotic protein priming of BCL2, the biology underlying t(11;14) MM dependency on BCL2 is poorly defined. Importantly, the epigenetic regulation of t(11;14) transcriptomes and its impact on gene regulation and clinical response to venetoclax remains elusive. In this study, by integrating ATACseq and RNAseq at the single-cell level in primary MM samples, we have defined the epigenetic regulome and transcriptome associated with t(11;14) MM. A "B cell-like" epigenetic signature was enriched in t(11;14) MM, confirming its phylogeny link to B cell rather than plasma cell biology. Of note, a loss of a "B cell-like" epigenetic signature with a gain of canonical plasma cell transcription factors was observed at the time of resistance to venetoclax. In addition, MCL1 and BCL2L1 copy number gains and structural rearrangements were linked to venetoclax resistance in t(11;14) MM patients. To date, this is the first study in which both scATAC-seq and scRNA-seq analysis are integrated into primary MM cells to obtain a deeper resolution of the epigenetic regulome and transcriptome associated with t(11;14) MM biology and venetoclax resistance.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2023020276
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
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  • 8
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    Integrin β7-Mediated Regulation of Multiple Myeloma Cell Adhesion, Migration and Survival.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 949-949
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 949-949
    Abstract: Abstract 949 Background: Integrin β7 (ITGB7) mRNA is detected in primary myeloma (MM) cells and its presence was correlated with maf gene activation. However, little is known about the role ITGB7 plays in MM. Methods and results: We have determined the expression of ITGB7 by flow cytometry in a large library of human MM cell lines and found it to be universily expressed, albeit at different levels. Similarly ITGB7 mRNA was detected by qRT-PCR in 25/27 samples of primary MM CD138+ cells. In order to better investigate the role of ITGB7 in MM adhesion, migration and survival we performed a loss-of-function analysis using the shRNA lentivirus system. Lentiviral transduction particles with validated ITGB7 shRNA, were transduced into three different MM cell lines (MM1S, INA-6 and H929) establishing stable clones with silenced ITGB7. Using adhesion assays we have demonstrated that ITGB7silenced cells are 40-50% less adherent to fibronectin (FN), E-cadherin (E-CDH) and BMSCs coated plates when compared to ITGB7positive cells (scrambeled shRNA), confirming the role ITGB7 in MM cell adhesion to stromal elements. In a transwell migration assay, ITGB7 silencing abrogated MM cells migration in response to SDF-1 gradient implicating ITGB7 in MM cells migration. Next, we investigated whether ITGB7 conferred a survival benefit to MM cells. By MTT assay ITGB7silenced cell are more sensitive to the cytotoxic effect of Bortezomib and Melphalan when cultured on regular plate and/or in the presence of FN and E-CDH, suggesting a role for ITGB7 in conferring drug resistance to MM cells through cell-adhesion dependent and independent mechanisms. Mechanistic studies have shown that ITGB7silenced cells have reduced NF-kB activity with reduced NFkB-p65 binding to the related consensus sequence and decreased nuclear phospho-p65 translocation was confirmed by immunofluorescence staining. In ELISA based assay ITGB7silenced cells co-cultured with BMSCs produced less cytokines and growth factors (VEGF, IL-6, TNF, IL-1, SDF1α) compared to ITGB7positive/BMSCs co-cultures confirming the role of ITGB7 in mediating MM cells intereaction with BMSCs altering the cytokines and growth factors produced by stromal cells. In order to investigate the signalling pathways downstream of ITGB7, ITGB7positive and ITGB7silenced INA-6 and MM1S cells were added into human FN coated plates and total RNA extracted and submitted to gene array profiling using the U133 Plus 2.0 Array. Several NF-kB regulated genes (TNF-α2, syndecan 4, IL-6, IL-8, CDK-6, Max) were downregulated and pathway analysis (Ingenuity Systems Software) identified several MM relevant pathways to be modulated by ITGB7 silencing; among them p53, integrin, IGF-1, IL-6 and VEGF signaling as well as cell cycle, apoptosis and the Wnt/β-catenin signalling pathways. Based on the in vitro data, we next investigated in vivo the effect of ITGB7 silencing on engraftment and homing of MM to bone marrow (BM), using a human plasmacytoma xenograft scid mouse model. ITGB7silenced cells grew mainly locally at the subcutaneous implantation site with delayed engraftment into the BM while ITGB7positive cells homed mostly into the BM, as indicated by the number of human CD138+ cells counted on femoral BM sections (14% in ITGB7positive vs. 4% in ITGB7silenced). In addition, tumor vessels density within the xenografted tumors, as assessed by CD31 staining, was significantly reduced in ITGB7silenced compared to ITGB7positive tumors (CD31 target area %: 4.1 vs 7.7 respectively). Lastly using myeloma tissue microarray (TMA) we have correlated ITGB7 expression with a significantly worse survival outcomes post high dose therapy and stem cell transplantation with a mTTP of 0.9 years in ITGB7 positive patients versus 2.6 years in negative cases (p 〈 0.005). Conclusions: Taken together our results support a role for ITGB7 in MM cells migration, homing and survival and pave the way for a novel therapeutic approach targeting this molecule. Disclosures: Bahlis: Celgene: Honoraria, Speakers Bureau; OrthoBiotech: Honoraria, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.949.949
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 9
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    Real-world Outcomes With Cumulative Bortezomib Dose and Efficacy in the Treatment of Transplant-ineligible Multiple Myeloma With Cyclophosphamide, Bortezomib, and Dexamethasone
    Elsevier BV ; 2023
    In:  Clinical Lymphoma Myeloma and Leukemia Vol. 23, No. 2 ( 2023-02), p. 104-111
    Details
    In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 23, No. 2 ( 2023-02), p. 104-111
    Type of Medium: Online Resource
    ISSN: 2152-2650
    URL: Article
    DOI: 10.1016/j.clml.2022.10.005
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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    detail.hit.zdb_id: 2193618-3
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    Panobinostat for the treatment of multiple myeloma
    Informa UK Limited ; 2012
    In:  Expert Opinion on Investigational Drugs Vol. 21, No. 5 ( 2012-05), p. 733-747
    Details
    In: Expert Opinion on Investigational Drugs, Informa UK Limited, Vol. 21, No. 5 ( 2012-05), p. 733-747
    Type of Medium: Online Resource
    ISSN: 1354-3784 , 1744-7658
    URL: Article
    DOI: 10.1517/13543784.2012.668883
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2012
    detail.hit.zdb_id: 2030114-5
    SSG: 15,3
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