MAGE-A Inhibits Apoptosis In Proliferating Multiple Myeloma Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 785-785
Author(s):  
Tricia Nardiello ◽  
Achim A Jungbluth ◽  
Anna Mei ◽  
Maurizio DiLiberto ◽  
Xiangao Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Conflicts Of Interest ◽  
Independent Set ◽  
Cell Cycle Checkpoints ◽  
Type I ◽  
Newly Diagnosed ◽  
Ki 67 ◽  
Myeloma Cells ◽  
Apoptosis Protein ◽  
The Impact

Abstract Abstract 785 The type I Melanoma Antigen GEne (MAGE) MAGE-A3 is commonly present in primary multiple myeloma cells and its expression is correlated with advanced disease and proliferation. MAGE-A3 belongs to the Cancer-Testis antigen (CTAg) family of tumor-associated proteins, which are present in many cancers, but their normal expression is limited to developing germ cells and placental trophoblast. This unique expression pattern fuels speculation on a role for CTAg in oncogenesis; however, very little is known about their function. In gene expression analyses of primary myeloma cells, CTAg were associated with proliferative gene signatures and poor clinical outcome, suggesting they contribute to the pathogenesis or progression of this disease through effects on survival and/or proliferation of myeloma cells. To investigate this, we examined the impact of MAGE-A on disease progression, proliferation, and apoptosis in primary myeloma specimens and human myeloma cell lines (HMCL). MAGE-A3 protein expression was examined by immunohistochemistry in a new, independent set of myeloma bone marrow specimens from two critical clinical milestones, newly diagnosed, untreated patients and patients who relapsed after chemotherapy. MAGE-A3 was detected in a higher percentage of tumor specimens from relapsed patients (77%) compared to those from newly diagnosed patients (36%, p=0.0003). The percentage of proliferating myeloma cells, as measured by staining for the proliferation marker Ki-67, was significantly higher in relapsed specimens (19.0 ± 3.5%) compared to newly diagnosed (6.9 ± 1.3%, p=0.0002), demonstrating a correlation between MAGE-A3, progression of disease and proliferation. The mechanisms for MAGE-A3 activity were investigated by silencing this gene in primary myeloma cells and HMCL by shRNA interference. Targeted lentiviral shRNA transduction efficiently knocked down MAGE-A3 mRNA and protein in MM.1r (p53+/+) and ARP-1 (p53−/−) HMCL and in primary myeloma cells by 48 hours, and this effect was maintained up to 96 hours. Silencing of MAGE-A did not affect cell cycling, as this intervention did not affect the phosphorylation of the Retinoblastoma gene product (Rb) that is required for progression through the G1 cell cycle checkpoints and entry into S phase. In contrast, MAGE-A was required for survival of proliferating myeloma cells. Silencing of MAGE-A led to a precipitous loss of viable cells within 48–72 hrs compared to controls. This was due to activation of intrinsic apoptosis, as demonstrated by increased annexin V staining, loss of mitochondrial membrane polarization, and cleavage/activation of caspase-9. These effects of MAGE-A knock-down were completely reversed by the pan-caspase inhibitor Quinoline-Val-Asp-CH2-OPh. Apoptosis after MAGE-A silencing appeared to be mediated by at least two distinct mechanisms; p53-dependent activation of pro-apoptotic Bax and Bak expression and reduced expression of the Inhibitor of Apoptosis Protein survivin through both p53-dependent and independent mechanisms. These results demonstrate that MAGE-A plays a role in the survival of proliferating multiple myeloma cells through the regulation of two critical apoptotic mechanisms. Disclosures: No relevant conflicts of interest to declare.

TIMP-1 and TIMP-2 Levels Are Directly Correlated with Neoangiogenesis and Are Prognostic Factors in Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4866-4866
Author(s):  
Luciana Correa Oliveira de Oliveira ◽  
Juliana Alves Uzuelli ◽  
Ana Paula Alencar de Lima Lange ◽  
Barbara Amelia Aparecida Santana-Lemos ◽  
Marcia Sueli Baggio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Bone Disease ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4866 Background Multiple myeloma (MM) is an incurable malignant disease, characterized by increased angiogenesis in the bone marrow (BM) microenvironment and aberrant BM metabolism. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases implicated in tumour progression, invasion, metastasis and angiogenesis, via proteolytic degradation of extracellular matrix. MMPs are inhibited by tissue inhibitors of metalloproteinase (TIMP). Although recent studies have implicated MMP 9 in MM bone disease, little is known about the role of the TIMPs. Objectives a) to compare levels of sRANKL, OPG, MMP-2, MMP-9, TIMP-1, TIMP-2, VEGF, bFGF, microvessel density (MVD) between newly diagnosed MM patients and healthy controls; b) to determine the association of these molecules with disease progression, bone disease and neoangiogenesis and c) to evaluate the impact of these variables on survival. Patients and Methods As of July 2009 38 newly diagnosed and untreated multiple myeloma patients were enrolled in the study. The median age was 61years-old (range 39-91) with 24 (63%) males. Patients were diagnosed and categorized according The International Myeloma Working Group criteria and ISS, respectively. Bone involvement was graded according to standard X-ray: patients with no lesions, or with one/ two bones involved or diffuse osteoporosis were classified as low score, whereas patients with lesions in more than two bones or presence of bone fracture were classified as high score. MMP-2 and MMP-9 were determined by PAGE gelatin zymography from plasma as previously described. MMP-9, TIMP-1 and TIMP-2, OPG and sRANKL concentrations were measured by ELISA. The levels of VEGF, bFGF were obtained using cytometric bead array. Ten healthy volunteers were used as controls. Bone marrow MVD measured in hotspots was evaluated in 26 out of 38 patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Comparisons among groups were analyzed by ANOVA and the correlation by the Spearman's correlation coefficient. Cox regression were performed for overall survival (OS) analysis. Results Patients with MM had elevated TIMP-1, TIMP-2 and OPG values compared with controls. No significant difference was found between plasma sRANKL, pro-MMP2, pro-MMP9 and MMP-9 levels. We found that plasma TIMP-1 levels correlated positively with bFGF, VEGF, MVD, beta-2 microglobulin (B2M) and OPG (r: 0.514, p=0,001, r: 0.350, p=0,031; r: 0.610, p<0.0001; r: 0.760, p<0.0001 and r: 0.701, p<0.0001, respectively) and TIMP-2 levels with bFGF, DMV, B2M and OPG (r: 0.512, p=0.002; r: 0.595, p<0.0001; r: 0.587, p<0.0001 and r: 0.552, p<0.0001, respectively). TIMP-1 and TIMP-2 levels correlated with the ISS stage (p<0.0001, p=0.006, respectively). The only variables that correlated with clinical bone disease staging were hemoglobin, B2M and albumin levels, whereas TIMP-1, TIMP-2, bFGF, VEGF and OPG correlated with DMV. On the univariate analyses, age, gender, proMMP2, TIMP-1, TIMP-2, creatinine, B2M and MVD were significantly associated with overall survival. In Cox regression model, TIMP-1, TIMP-2 and B2M levels remained to be significantly associated with OS. In conclusion, our results suggest that TIMP-1 and TIMP-2 levels are strongly associated with neoangiogenesis and are independent prognostic factors in MM. Disclosures No relevant conflicts of interest to declare.

The Expression Of CD200 As a Prognostic Factor In Newly Diagnosed Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3082-3082
Author(s):  
Yi Li ◽  
Wenjun Wu ◽  
Jingsong He ◽  
Xiaoyan Han ◽  
Gaofeng Zheng ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Staging System ◽  
Newly Diagnosed ◽  
New Approach ◽  
Myeloma Cells ◽  
Targeting Therapy ◽  
Molecular Therapeutic

Abstract Introduction multiple myeloma (MM) is currently an incurable hematological malignancy. Discovering molecular therapeutic targets is a new approach to improve the outcome in the treatment of the malignant disease. As CD200 is a type Ⅰmembrane glycoprotein expressed on myeloma cells, we asked if the expression of CD200 could serve as a prognostic marker for MM patients. Our data indicated that the expression level of CD200 is indeed correlated with the prognosis of the MM patients. Methods bone marrow samples from 96 newly diagnosed MM patients from April 2011 to July 2013 were evaluated by flow cytometry, using PE-conjugated anti-CD200 mAb, FITC-conjugated anti-CD138 mAb, and PE-Cy7-conjugated anti-CD45 mAb. PE-or FITC-conjugated normal mouse IgG was used as isotype-matched controls. Results 96 MM patients were investigated in the present study, including 60 men and 36 women, with a median age of 63 years (range 34–86 years). 81/96(84%) MM patients were CD200 positive with a median Mean Fluorescence Intensity (MFI) of 127 as analyzed by flow cytometry, which was consistent with the previous studies. While in 15 of 96 patients, CD200 expression was undetectable. Among the CD200 positive ones 7.40% patients were classified as stage Ⅰ, 12.35% were stage Ⅱ, and 80.25% were stage Ⅲ according to Durie–Salmon staging criteria. 40.74% patients were stageⅠ, 22.22% were stage Ⅱ, and 37.04% were stage Ⅲ, according to the International Staging System (ISS). Analysis of the CD200 positive patients revealed the MFI<127 group had a better progression free survival (PFS) (p=0.046) (Fig 1A) and overall survival (OS) (p=0.069) compared to those with MFI≥127. In the patients with age ≥65 years old, PFS (p=0.023) (Fig 1B) and OS (p=0.044) (Fig 1C) were much shorter in the MFI≥127 group, compared to the MFI<127 ones. Conclusions Our study demonstrated that the expression and MFI of CD200 on primary multiple myeloma cells is correlated with the prognosis of the MM patients. The better PFS and OS were observed in the MFI<127 group compared to the patients with MFI≥127, especially in the patients with age≥65 years old. Improved PFS in CD200 positive ones is likely due to the immune suppression mediated by CD200. Our study suggests that targeting therapy against CD200 may become a new approach to the treatment of MM in clinical practice. Disclosures: No relevant conflicts of interest to declare.

MAGE-A3 Inhibits p53 and Promotes Proliferation and Survival in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1795-1795
Author(s):  
Hearn J. Cho ◽  
Anna Mei ◽  
Tricia Nardiello ◽  
Maurizio DiLiberto ◽  
Xiangao Huang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Research Funding ◽  
Myeloma Cell ◽  
Type I ◽  
Newly Diagnosed ◽  
Apoptosis Pathway ◽  
Myeloma Cells ◽  
Intrinsic Apoptosis Pathway

Abstract Abstract 1795 Poster Board I-821 The type I Melanoma Antigen GEne (MAGE) proteins MAGE-A3 and CT7 (MAGE-C1) were commonly detected in primary tumor cells from multiple myeloma patients and their expression was correlated with advanced disease and proliferation. They belong to the Cancer-Testis antigen (CTAg) family of tumor-associated proteins. In gene expression analyses of primary myeloma cells, CTAg were associated with proliferative gene signatures and poor clinical outcome. These findings suggest that type I MAGE may play a pathogenic role in proliferation or survival in multiple myeloma cells. To test this hypothesis, we examined MAGE expression, proliferation, and apoptosis in primary myeloma specimens and human myeloma cell lines (HMCL). First, we examined CTAg expression and proliferation in vivo at two critical clinical milestones, in newly diagnosed, untreated patients and patients who relapsed after chemotherapy. MAGE-A3 was detected in a higher percentage of tumor specimens from relapsed patients (77%) compared to those from newly diagnosed patients (36%, p=0.0003), whereas CT7 was detected in about 75% of both patient populations. The percentage of proliferating myeloma cells, as measured by staining for the proliferation marker Ki-67, was significantly higher in relapsed specimens (19.0 ± 3.5%) compared to newly diagnosed (6.9 ± 1.3%, p=0.0002), demonstrating an association between MAGE-A3, progression of disease and proliferation. Second, we investigated the functional role of MAGE-A3 by silencing this gene in HMCL by shRNA interference. Targeted lentiviral shRNA transduction efficiently knocked down MAGE-A3 mRNA (≥90% compared to controls) and protein in MM.1r and Arp-1 HMCL by 48 hours and this effect was maintained up to 96 hours. Pulse labeling of HMCL with bromodeoxyuridine for 30 minutes revealed that silencing of MAGE-A3 led to cell cycle arrest, as evidenced by the complete loss of cells in S phase and accumulation of cells in both G1 and G2. This was accompanied by increased expression of the tumor suppressor p53 and the endogenous cyclin-dependent kinase (CDK) inhibitor p21Cip1, a p53 target that inhibits CDKs in both late G1 and G2. However, CDK4/6-specific phosphorylation of the retinoblastoma gene product (Rb) was unimpaired, indicating that control of the mid-G1 cell cycle checkpoints by Rb remained intact and suggesting that MAGE-A3 acted in part to promote G1-S progression. Within 24 hours of cell cycle arrest, 70-80% of MAGE-A3-silenced cells underwent apoptosis as measured by Annexin V staining, compared to '20% in cells transduced with a non-target control lentivirus or untreated. Furthermore, this apoptosis was caspase-dependent, as it was completely prevented by the pan-caspase inhibitor Quinoline-Val-Asp-CH2-OPh, and was triggered by the loss of mitochondrial outer membrane potential in the activation of the intrinsic apoptosis pathway. Taken together, the in vivo and in vitro results suggest that MAGE-A3 promoted myeloma cell proliferation by inhibiting p53-dependent expression of p21, and loss of this activity leads to growth arrest and cell cycle-coupled apoptosis via activation of the intrinsic apoptosis pathway. Understanding the biochemical mechanism of MAGE-A3 in cell cycle regulation and survival may identify novel therapeutic strategies for multiple myeloma. Proof of principle in this disease may lead to broader application of these strategies in other cancers that express MAGE-A3. Disclosures Niesvizky: Proteolix: Research Funding, data monitoring committee; Seattle Genetics, Inc: Research Funding; Celgene: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau.

Myeloma Cells Induce Osteoblast Suppression through Sclerostin Secretion

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2961-2961 ◽  
Author(s):  
Silvia Colucci ◽  
Giacomina Brunetti ◽  
Angela Oranger ◽  
Giorgio Mori ◽  
Francesca Sardone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Formation ◽  
Bone Disease ◽  
Culture System ◽  
Conflicts Of Interest ◽  
Negative Regulator ◽  
Type I ◽  
Myeloma Cells ◽  
Myeloma Bone Disease ◽  
Osteoblast Activity

Abstract Abstract 2961 Reduced osteoblast activity contributes to the development of multiple myeloma-bone disease. Wingless-type (Wnt) signalling pathway is critical in osteoblastogenesis, and it is negatively regulated by molecules such as frizzled-related proteins (sFRPs), Dickkopf proteins (DKKs) and sclerostin. Myeloma cells are known to induce inhibition of osteoblastogenesis through Wnt antagonists such as DKK-1 and sFRP-2 and -3 whereas the role of sclerostin, an osteocyte-expressed negative regulator of bone formation, has not been yet investigated. We provide novel evidence showing sclerostin expression by myeloma cells from patients with multiple myeloma-bone disease and human myeloma cell lines (HMCLs). By means of a co-culture system of bone marrow stromal cells (BMSCs) and HMCLs, we demonstrated that sclerostin expression by myeloma cells and HMCLs is responsible for reduced expression of major osteoblastic specific proteins namely bone-specific alkaline phosphatase, collagen-type I, bone sialoprotein II and osteocalcin as well as decreased mineralized nodule formation and attenuated expression of member of the AP-1 transcription factor family (i.e. Fra-1, Fra-2 and Jun-D). The addition of a neutralizing anti-sclerostin antibody to our co-culture system can restore the above parameters, through the intranuclear accumulation of β-catenin in BMSCs. On the other hand, we demonstrated that sclerostin is also involved in inducing increased receptor activator of nuclear factor-k B ligand (RANKL) and decreased osteoprotegerin (OPG) expression in osteoblasts, contributing to the enhanced osteoclast activity occurring in patients with multiple myeloma-bone disease. Our data suggest that myeloma cells contribute to the suppression of bone formation through sclerostin secretion. Disclosures: No relevant conflicts of interest to declare.

Multi-Organ Involvement of Multiple Myeloma Cells In the Cases of Recent 10 Years: A Clinicopathologic Study of 81 Consecutively Autopsied Cases

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5004-5004
Author(s):  
Shotaro Hagiwara ◽  
Makoto Mochizuki ◽  
Hisako Endo ◽  
Risen Hirai ◽  
Akira Tanimura ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conflicts Of Interest ◽  
High Dose ◽  
Clinicopathological Feature ◽  
Pathological Feature ◽  
Myeloma Cells ◽  
The Impact

Abstract Abstract 5004 Background: Despite recent progress in treatment, multiple myeloma is still uncurable disease. The impact of modern therapy on the causes of death and pathological feature of end-stage myeloma is not fully understood. Methods: We studied autopsied cases with multiple myeloma between 1979 and 2009 at National Medical Center of Global Health and Medicine, Tokyo, Japan. We compared the clinicopathological feature of the autopsied cases in recent 10 years with the cases before 2000. Statistical analysis was performed using student's t-test and chi-square test. Results: There were 81 autopsied cases between 1979 and 2009. 31 cases were autopsied in recent 10 years and the older 50 cases were before 2000. Mean age at death was 59.2 and 65.1 years old, and the mean duration of illness was 46.1 and 31.9 months, respectively. Stem cell transplantation was performed in 13 (12 autologous, 1 allogeneic) of recent cases and 3 (2 autologous and 1 allogeneic) of older cases. In recent cases, five patients were treated with bortezomib, 2 were with thalidomide and 2 were with both. Extramedullary infiltration of myeloma cells were observed in both groups. The frequent sites of involvement were spleen, liver, kidney, lymph nodes, lung, pancreas, adrenal gland and perioneum. The infiltration in liver and lung was significantly frequent in the recent cases than in the older cases (58.1% vs. 28.0%, p=0.007, and 38.7% vs. 18%, p=0.039). Infection as a cause of death was noted more frequently in the recent cases than in the older cases (41.9% vs. 18.0%, p=0.019). Amyloid deposition was detected in 16.1% and 22.0% (ns.), and myeloma kidney was noted in 48.4% and 60% (ns.). Conclusion: High dose chemotherapy with stem cell support and novel agents have been contributed to improving the survival. However, the increase in resistant bacterial and fungal infection is serious problem. Also, extramedullary relapse after autologous and allogeneic stem cell transplantation is not rare, and extramedullary progression under thalidomide has been reported. In our recent autopsied cases, the incidence of fatal infection and extramedullary involvement of myeloma cells was significantly higher than in the older cases. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Reversibility of Renal Insufficiency in Patients with Newly Diagnosed Multiple Myeloma and the Role of different induction Regimens

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5749-5749
Author(s):  
Li Bao ◽  
Jin Lu ◽  
Xiaojun Huang
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Median Survival ◽  
Conflicts Of Interest ◽  
Complete Recovery ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Renal Response ◽  
The Impact

Abstract We retrospectively compared the impact of treatments based on thalidomide, bortezomib or tranditional regimen (VAD) on renal function recovery in a consecutive, unselected population of newly diagnosed myeloma patients presenting with renal failure. Between May 2005 and February 2014, 130 (24.3%) patients with newly diagnosed multiple myeloma and RI were treated upfront with VAD or a novel agent containing regimen and all received a similar supportive care in our single center. A complete recovery of renal function(renal complete response )was observed in 56.1% of patients treated with bortezomib, in 38.9% with thalidomide and in 28.6% with VAD (P=0.033), a significant improvement of renal function (≥renalPR (renal partial response)) was observed in 63.6% of patients treated with bortezomib, in 66.1% with thalidomide and in 42.9% with VAD (P=0.162). There has a significantly difference in the rates and quality of renal response among patients with different quality of myeloma response: renal CR rates for patients who achieved ≥VGPR, PR, MR or NR were 63.1% vs 46.8% vs 35.7% vs 25.8%, P<0.05, respectively. eGFR ≥30 ml/min and myeloma response higher than PR were independently associated with a higher probability of major renal response in the multivariate analysis. The median follow-up for all patients was 36.5 months and the median survival was 74 months. The median survival for patients of groups B,T and VAD was79 months,71 months and 39 months, respectively (P=0.007). Patients died within the first 2 months from initiation of therapy and the corresponding frequencies in groups B, T and VAD were 0%, 2.8% and 17.9%, respectively (P<0.05). In multivariate analyses on survival, myeloma response higher than PR and new agents-based therapy are identified independent prognostic factors. For newly diagnosed myeloma patients with RI, bortezomib or thalidomide based regimen should be selected promptly to achieve rapid effective myeloma rate and high rates of renal recovery. Disclosures No relevant conflicts of interest to declare.

YM155, a Survivin Suppressant, Induces Cell Death Via Suppression Of c-Myc Expression In Multiple Myeloma Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1667-1667
Author(s):  
Shigeki Ito ◽  
Maki Asahi ◽  
Ryousei Sasaki ◽  
Tatsuo Oyake ◽  
Hideto Tamura ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Conflicts Of Interest ◽  
Mrna Level ◽  
Inhibitor Of Apoptosis ◽  
Dependent Manner ◽  
Myeloma Cells ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein

Abstract Survivin is a member of the inhibitor of apoptosis protein (IAP) family with its dual roles in mitosis and apoptosis, and emerges as an attractive target for cancer therapy. Recent reports have demonstrated that survivin overexpression is associated with drug resistance and poor outcome in hematological malignancy including multiple myeloma (MM). YM155, a novel molecular targeted agent, suppresses survivin through the inhibition of transcription. However, the effect of this agent on MM cells has not been elucidated. In this study, we investigated the effect of YM155 on proliferation and survival of five human MM cell lines. YM155 inhibited the proliferation of these cells in a dose- and time-dependent manner (IC50 = 10 nM in 3 and 100 nM in 2 cell lines, respectively). Annexin V assay showed that YM155 induced apoptosis in these cells. To better understand these effects of YM155 on MM cells, we evaluated the intracellular signaling and apoptosis-associated protein status. Immunoblot analyses showed that YM155 reduced not only survivin but also myeloid cell leukemia sequence 1 (Mcl-1) and X-linked inhibitor of apoptosis protein (XIAP) expression. We also observed the activation of caspase-3 and poly(ADP-ribose) polymerase in YM155-treated cells, indicating that YM155 induces caspase-dependent apoptosis. YM155 did not affect phosphorylation status of Erk1/2 and STAT3. Interestingly, we found that YM155 suppressed c-Myc and interferon regulatory factor 4 (IRF4) expression, both of which are recognized as an important oncogene in the pathogenesis of MM. In addition, c-Myc and IRF4 protein levels were reduced at 6 and 12 hours after treatment with YM155, respectively. As IRF4 and c-Myc form a positive feedback loop in myeloma cells, this observation indicates that c-Myc inhibition by YM155 treatment might lead to subsequent inhibition of IRF4 expression, and thus raises the possibility of YM155 target for c-Myc rather than IRF4. We next examined the mechanism of downregulation of c-Myc in RPMI8226 cells. Real-time quantitative RT-PCR assay showed that YM155 treatment reduced c-Myc mRNA level. On the other hand, proteasome inhibitor did not prevent the suppression of c-Myc expression by YM155 treatment. These Results suggest that YM155 transcriptionally at least in part represses c-Myc in RPMI8226 cells. In conclusion, YM155 suppresses cell proliferation and survival in MM cells in part via not only inhibiting anti-apoptotic proteins such as survivin, Mcl-1 and XIAP but also repressing c-Myc oncogene. Further study is needed to clarify the molecular mechanism of downregulation of c-Myc induced by YM155. Our Results may provide a platform for clinical trials of YM155 in MM. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficacy of Modified Vrd-Lite for Transplant Ineligible Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Mizuki Ogura ◽  
Tadao Ishida ◽  
Moe Nomura ◽  
Hirofumi Irita ◽  
Junichiro Nashimoto ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Multiple Myeloma ◽  
Cardiac Amyloidosis ◽  
Staging System ◽  
Treatment Interruption ◽  
Cardiac Complications ◽  
High Dose ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
The Impact

BACKGROUND: High dose chemotherapy followed by autologous peripheral blood stem cell transplantation is an effective treatment for multiple myeloma. However, many patients with newly diagnosed multiple myeloma are transplant-ineligible because of their age and complications, result in a poorer prognosis than transplant-eligible patients. Furthermore, many of them cannot complete normal chemotherapy because of low tolerability. Here, we investigated the efficacy and safety of modified bortezomib with lenalidomide and dexamethasone (mVRD-lite) for transplant-ineligible patients with newly diagnosed multiple myeloma. STUDY DESIGN: A retrospective observational analysis was performed on patients who received mVRd-lite for the first line chemotherapy between Jan. 2016 and Mar. 2020 in our hospital. Patients who received high dose dexamethasone to reduce tumor burden, and patients who received bortezomib with dexamethasone or lenalidomide with dexamethasone as a reduction regimen of mVRd-lite were also included. We evaluated ORR, OS, PFS and adverse effect. mVRD-lite at first was administered over a 28-day cycle. Bortezomib 1.3 mg/m2 weekly was administered subcutaneously on days 1, 8, 15 and 22. Lenalidomide 15 mg was given orally 18 days, omitted on days 1, 8, 15, which are the days of bortezomib administration. Dexamethasone 20 mg was given orally on days 1, 2, 8, 9, 15, 16, 22, which are the day of and day after bortezomib. We also reviewed patients background, especially complication of light-chain amyloidosis and considered the impact of cardiac amyloidosis on patient prognosis. This study was conducted with the permission of the Ethics Review Board in our hospital. RESULTS: The subjects analyzed totaled 40 transplant-ineligible patients. 11(27.5%) patients were AL amyloidosis associated with multiple myeloma and 8(20%) patients had cardiac amyloidosis. Median age at diagnosis was 73 (range 48-86) and Male:Female=1:1. Most of them were judged inadequate to transplantation due to their age, general condition, or complication. One patient was ruled unfit to transplantation, because of his refusion. The Revised International Staging System (R-ISS) were I in 5 (12.5%), II in 25 (62.5%) and III in 8 (20%). 5(25%) patients switched to maintenance therapy. 17(42.5%) patients discontinued treatment, because of adverse effect (cardiac failure 4 ; two of them combined with cardiac amyloidosis, rash 4, peripheral neuropathy 3, infection 3, etc). 2(5%) patients died during treatment by mVRd-lite, because of Grade 4 adverse effect, such as pneumonia. 11(27.5%) patients died during observation period and causes of death were primary disease and TRM. 1(2.5%) patient was died of heart failure associated with cardiac amyloidosis. The overall response rate(ORR) during treatment period of mVRd-lite was obtained in 34(85%), including sCR in 5 (12.5%), VGPR in 13 (32.5%) and PR in 14(30%). 2(5%) patients achieved MRD negative. SD were observed in 3(7.5%) patients. 3(7.5%) patients were not evaluated efficacy because of treatment interruption by adverse effect. Overall survival rate at two year is 64.3%, median OS was not reached, at a median follow-up of 20 months. CONCLUSIONS: Transplant-ineligible multiple myeloma patients are associated with poor prognosis. Modified RVD-lite is one of the appropriate therapeutic options, in the transplant-ineligible multiple myeloma patients. Twenty-five percent of patients with cardiac amyloidosis had treatment discontinued due to cardiac complications. Further study is needed for treatment of patients with multiple myeloma complicated with cardiac amyloidosis. Disclosures Ishida: Janssen: Speakers Bureau; Celgene: Speakers Bureau; Ono pharmaceutical co: Speakers Bureau; Takeda pharmaceutical co: Speakers Bureau. Nashimoto:Janssen: Speakers Bureau; Celgene: Speakers Bureau. Tsukada:Takeda pharmaceutical co: Speakers Bureau. Suzuki:Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria; Bristol-Myers Squibb, Celgene and Amgen: Research Funding.

scholarly journals Outcomes with early response to first-line treatment in patients with newly diagnosed multiple myeloma

2019 ◽  
Vol 3 (5) ◽  
pp. 744-750 ◽  
Author(s):  
Nidhi Tandon ◽  
Surbhi Sidana ◽  
S. Vincent Rajkumar ◽  
Morie A. Gertz ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Light Chain ◽  
Progression Free Survival ◽  
Early Response ◽  
Stage Iii ◽  
Newly Diagnosed ◽  
Best Response ◽  
Light Chain Disease ◽  
The Impact

Abstract We evaluated the impact of achieving a rapid response in 840 newly diagnosed multiple myeloma patients from 2004 to 2015. Rates of very good partial response (VGPR) or better were 29% (240/840) after 2 cycles of treatment, 42% (350/840) after 4 cycles of treatment, and 66% (552/840) as best response. Early responders after 2 cycles of treatment had higher rates of light chain disease, anemia, renal failure, International Staging System (ISS) stage III disease, and high-risk cytogenetics, especially t(4;14), and were more likely to have received triplet therapy and undergo transplant. Median progression-free survival (PFS) and overall survival (OS) were not different among patients with ≥VGPR and &lt;VGPR after 2 cycles (PFS, 28 vs 30 months, P = .6; OS, 78 vs 96 months, P = .1) and 4 cycles (PFS, 31 vs 29 months; OS, 89 vs 91 months, P = .9), although both were improved, with ≥VGPR as best response (PFS, 33 vs 22 months, P &lt; .001; OS, 102 vs 77 months, P = .003). On multivariate analysis stratified by transplant status, achievement of ≥VGPR after 2 cycles was not associated with improved PFS (hazard ratio [95% confidence interval]; transplant cohort, 1.1 [0.7-1.6]; nontransplant cohort, 1.2 [0.8-1.7]) or OS (transplant cohort, 1.6 [0.9-2.9]; nontransplant cohort, 1.5 [1.0-2.4]). Covariates in the model included high-risk cytogenetics, ISS stage III, triplet therapy, creatinine ≥2 mg/dL, light chain disease, and age. Although patients with high-risk disease are more likely to achieve early response, a rapid achievement of a deep response by itself does not affect long-term outcomes.

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