共查询到20条相似文献,搜索用时 31 毫秒
1.
Kihyun Kim Sun‐Young Kong Mariateresa Fulciniti Xianfeng Li Weihua Song Sabikun Nahar Peter Burger Mathew J. Rumizen Klaus Podar Dharminder Chauhan Teru Hideshima Nikhil C. Munshi Paul Richardson Ann Clark Janet Ogden Andreas Goutopoulos Luca Rastelli Kenneth C. Anderson Yu‐Tzu Tai 《British journal of haematology》2010,149(4):537-549
This study investigated the cytotoxicity and mechanism of action of AS703026, a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026 inhibited growth and survival of MM cells and cytokine‐induced osteoclast differentiation more potently (9‐ to 10‐fold) than AZD6244. Inhibition of proliferation induced by AS703026 was mediated by G0‐G1 cell cycle arrest and was accompanied by reduction of MAF oncogene expression. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). Importantly, AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti‐MM therapies. Significant tumour growth reduction in AS703026‐ vs. vehicle‐treated mice bearing H929 MM xenograft tumours correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. Moreover, AS703026 (<200 nmol/l) was cytotoxic against the majority of tumour cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC‐induced viability of MM patient cells was similarly blocked within the same dose range. Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti‐MM agents, to improve patient outcome. 相似文献
2.
Overall survival of relapsed and refractory multiple myeloma patients after adjusting for crossover in the MM‐003 trial for pomalidomide plus low‐dose dexamethasone
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Gareth Morgan Antonio Palumbo Sujith Dhanasiri Dawn Lee Katja Weisel Thierry Facon Michel Delforge Albert Oriol Mohamed Zaki Xin Yu Lars Sternas Christian Jacques Ron Akehurst Fritz Offner Meletios A. Dimopoulos 《British journal of haematology》2015,168(6):820-823
In the phase III MM‐003 trial, pomalidomide plus low‐dose dexamethasone (POM+LoDEX) improved overall survival (OS) versus high‐dose dexamethasone (HiDEX) in 455 patients with relapsed and refractory multiple myeloma (RRMM) after treatment with bortezomib and lenalidomide. Here, a two‐stage Weibull method was used to adjust for the crossover of patients in the HiDEX arm to pomalidomide‐based therapy. The adjusted difference in median OS between patients in the POM+LoDEX and HiDEX arms was 7·0 months (12·7 vs. 5·7 months, respectively). These findings provide important evidence for understanding the clinical efficacy of pomalidomide on OS benefits seen in RRMM patients. 相似文献
3.
Phase I study of carfilzomib,lenalidomide, vorinostat,and dexamethasone in patients with relapsed and/or refractory multiple myeloma
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David H. Vesole Elizabeth Bilotti Joshua R. Richter Ann McNeill Laura McBride Laura Raucci Palka Anand Urszula Bednarz Kristin Ivanovski Judith Smith Veena Batra Adolfo Aleman Taliah Sims Laura Guerrero Anthony Mato David S. Siegel 《British journal of haematology》2015,171(1):52-59
Research has shown that proteasome inhibitors (e.g., carfilzomib), immunomodulatory agents (e.g., lenalidomide), histone deacetylase inhibitors (e.g., vorinostat) and corticosteroids (e.g., dexamethasone) have synergistic anti‐multiple myeloma (MM) activity. This phase I dose‐escalation study evaluated a regimen combining carfilzomib, lenalidomide, vorinostat and dexamethasone (QUAD) in patients with relapsed and/or refractory MM. Seventeen patients received carfilzomib (15, 20, or 20/27 mg/m2; 30‐min infusion; days 1, 2, 8, 9, 15, 16), lenalidomide (15 or 25 mg; days 1–21), vorinostat (300 or 400 mg; days 1–7, 15–21), and dexamethasone (40 mg; days 1, 8, 15, 22) in 28‐d cycles. No dose‐limiting toxicities were observed; the maximum tolerated dose was not reached. The maximum administered dose was carfilzomib 20/27 mg/m2, lenalidomide 25 mg, vorinostat 400 mg, and dexamethasone 40 mg. Common grade ≥3 adverse events included neutropenia (53%), thrombocytopenia (53%) and anaemia (41%). The overall response rate was 53%: 12% of patients achieved a very good partial response (PR) and 41% of patients achieved a PR. At a median follow‐up of 10 months, median progression‐free survival was 12 months and median overall survival was not reached. Treatment with QUAD was feasible and had encouraging activity in patients with relapsed and/or refractory MM. 相似文献
4.
Efficacy and safety of low‐dose lenalidomide plus dexamethasone in patients with relapsed or refractory POEMS syndrome
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Qian‐Qian Cai Chen Wang Xin‐Xin Cao Hao Cai Dao‐Bin Zhou Jian Li 《European journal of haematology》2015,95(4):325-330
Although autologous stem cell transplantation or melphalan‐based chemotherapy has significantly improved the prognosis of POEMS syndrome, a few patients will relapse or be refractory to primary therapy, and there is a lack of studies regarding these patients. In this study, we used low‐dose lenalidomide (10 mg daily) and dexamethasone (40 mg, once weekly) to treat twelve patients with relapsed (n = 8) or refractory (n = 4) POEMS syndrome. After a median follow‐up time of 20 months, the overall hematologic response rate was 77% with 44% having a complete response. Eight (67%) patients had neurological response, and the median overall neuropathy limitation scale score was reduced from 3 (range, 1–9) to 2 (range, 0–6). Serum vascular endothelial growth factor response rate was 91% and 46% of patients had normal serum VEGF levels. One patient had progression of the disease 3 months after the end of treatment and subsequently died from the disease. Therefore, the estimated 2 year overall survival and progression‐free survival were 92%. The low‐dose lenalidomide and dexamethasone regimen was well tolerated, with no treatment‐related death or any grade 3 or 4 toxicity. In conclusion, low‐dose lenalidomide plus dexamethasone therapy is an effective and safe regimen for patients with relapsed or refractory POEMS syndrome. 相似文献
5.
《British journal of haematology》2017,177(3):441-448
The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression‐free survival (PFS) and overall survival (OS) were 8·9 (6·9–11·5) and 30·5 (20·0–36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard‐dose lenalidomide (25 mg) and high‐dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3–4 toxicities were reduced with low‐dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at‐risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes. 相似文献
6.
《British journal of haematology》2017,176(3):440-447
Clinical trials of vorinostat, a Class I/II histone deacetylase inhibitor, in combination with proteasome inhibitors and immunomodulatory agents have shown activity in relapsed/refractory multiple myeloma. This phase IIb, open‐label, single‐institution study evaluated the efficacy of vorinostat in combination with lenalidomide and dexamethasone in lenalidomide‐refractory patients. Patients were considered lenalidomide‐refractory if they had no clinical response (<minimal response) on a previous lenalidomide‐containing regimen (lenalidomide non‐responsive) or if they had progressive disease on or within 60 days of discontinuing a previous lenalidomide‐containing regimen (lenalidomide relapsed/refractory). Patients received oral vorinostat 400 mg days 1–7 and 15–21, lenalidomide 25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15 and 22 in 28‐day cycles. Twenty‐five patients were enrolled, median age was 65 years and patients had received a median of 5 prior regimens. The overall response rate was 24% (6 partial responses) and clinical benefit rate (≥stable disease) was 80%. Median time to a partial response was 1·9 months and median duration of response was 3·3 months. Median progression‐free survival was 5·3 months. Most common grade 3/4 adverse events were neutropenia (48%), thrombocytopenia (32%), anaemia (20%) and gastrointestinal toxicities (16%). In this heavily pre‐treated population, vorinostat in combination with lenalidomide and dexamethasone was active in lenalidomide‐refractory patients. 相似文献
7.
Long‐term disease control in patients with newly diagnosed multiple myeloma after suspension of lenalidomide therapy
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Taxiarchis V. Kourelis Shaji K. Kumar Geetika Srivastava Morie A. Gertz Martha Q. Lacy Francis K. Buadi Suzanne R. Hayman Steven R. Zeldenrust Nelson Leung Robert A. Kyle Stephen J. Russell David Dingli John A. Lust Yi Lin Prashant Kapoor Ronald Go S. Vincent Rajkumar Angela Dispenzieri 《American journal of hematology》2014,89(3):302-305
There are no systematic data regarding nonmaintained induction for those patients with multiple myeloma (MM) who do not receive consolidative autologous stem cell transplantation. Of 173 patients with newly diagnosed MM treated with lenalidomide and dexamethasone (LenDex) as primary therapy, 31 patients had their lenalidomide discontinued for reasons other than progression or alternate therapy. Median progression free survival (PFS) from the time of discontinuing lenalidomide was longer in patients who received lenalidomide ≥1 year (39 vs. 13 months, P < 0.05); there was no difference in PFS for those treated for 1–2 years as compared to ≥2 years. Among those taking lenalidomide for ≥1 year PFS was superior in patients who were in very good partial response (VGPR) or better as compared to those with partial response (48.4 versus 14.8 months, P < 0.05). All patients who progressed and were rechallenged with LenDex responded. These analyses illustrate that discontinuation of lenalidomide after 1 year among those patients achieving a ≥VGPR can result in long‐term disease control. Am. J. Hematol. 89:302–305, 2014. © 2013 Wiley Periodicals, Inc. 相似文献
8.
S. Vincent Rajkumar 《American journal of hematology》2014,89(10):998-1009
Disease overview : Multiple myeloma accounts for approximately 10% of hematologic malignancies. Diagnosis : The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end‐organ damage. If end‐organ damage is not present, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma. Risk stratification : In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high‐risk myeloma. Patients with t(4;14) translocation are considered intermediate‐risk. All others are considered as standard‐risk. Risk‐adapted intial therapy : Standard‐risk patients can be treated with lenalidomide plus low‐dose dexamethasone (Rd), or a bortezomib‐containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate‐risk and high‐risk patients require a bortezomib‐based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients who are not candidates for transplant, initial therapy is given for approximately 12 to 18 months. Maintenance therapy : After initial therapy, lenalidomide maintenance is considered for standard risk patients who are not in very good partial response or better, while maintenance with a bortezomib‐based regimen should be considered in patients with intermediate or high risk myeloma. Management of refractory disease : Patients with indolent relapse can be treated first with 2‐drug or 3‐drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 89:998–1009, 2014. © 2014 Wiley Periodicals, Inc. 相似文献
9.
Ulrike Heider Martin Kaiser Maren Mieth Britta Lamottke Jessica Rademacher Christian Jakob Edgar Braendle David Stover Orhan Sezer 《European journal of haematology》2009,82(1):31-38
Lytic bone destruction is a hallmark of multiple myeloma (MM) and is because of an uncoupling of bone remodeling. Secretion of Dickkopf (DKK)‐1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. In this study, the effect of different treatment regimens for MM on serum DKK‐1 was evaluated and correlated with the response to treatment in 101 myeloma patients receiving bortezomib, thalidomide, lenalidomide, adriamycin and dexamethasone (AD) or high‐dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT). At baseline, myeloma patients had increased serum DKK‐1 as compared with patients with MGUS (mean 3786 pg/mL vs. 1993 pg/mL). There was no difference between previously untreated MM patients and patients at relapse. A significant decrease of DKK‐1 after therapy was seen in the following groups: Bortezomib (4059 pg/mL vs. 1862 pg/mL, P = 0.016), lenalidomide (11837 pg/mL vs. 4374 pg/mL, P = 0.039), AD (1668 pg/mL vs. 1241 pg/mL, P = 0.016), and AD + HDCT + ASCT (2446 pg/mL vs. 1082 pg/mL, P = 0.001). Thalidomide led to a non‐significant decrease in DKK‐1 (1705 pg/mL vs. 1269 pg/mL, P = 0.081). Within all groups, a significant decrease of DKK‐1 was only seen in responders (i.e. patients achieving complete remission or partial remission), but not in non‐responders. We show for the first time that serum DKK‐1 levels decrease in myeloma patients responding to treatment, irrespective of the regimen chosen. These data suggest that myeloma cells are the main source of circulating DKK‐1 protein and provide a framework for clinical trials on anti‐DKK‐1 treatment in MM. 相似文献
10.
MDX‐1097 induces antibody‐dependent cellular cytotoxicity against kappa multiple myeloma cells and its activity is augmented by lenalidomide
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Parisa Asvadi Andrew Cuddihy Rosanne D. Dunn Vivien Jiang Mae X. Wong Darren R. Jones Tiffany Khong Andrew Spencer 《British journal of haematology》2015,169(3):333-343
MDX‐1097 is an antibody specific for a unique B cell antigen called kappa myeloma antigen (KMA) that consists of cell membrane‐associated free kappa light chain (κFLC). KMA was detected on kappa human multiple myeloma cell lines (κHMCLs), on plasma cells (PCs) from kappa multiple myeloma (κMM) patients and on κPC dyscrasia tissue cryosections. In primary κMM samples, KMA was present on CD38+ cells that were CD138 and CD45 positive and/or negative. MDX‐1097 exhibited a higher affinity for KMA compared to κFLC and the latter did not abrogate binding to KMA. MDX‐1097‐mediated antibody‐dependent cellular cytotoxicity (ADCC) and in vitro exposure of target cells to the immunomodulatory drug lenalidomide resulted in increased KMA expression and ADCC. Also, in vitro exposure of peripheral blood mononuclear cells (PBMCs) to lenalidomide enhanced MDX‐1097‐mediated ADCC. PBMCs obtained from myeloma patients after lenalidomide therapy elicited significantly higher levels of MDX‐1097‐mediated ADCC than cells obtained prior to lenalidomide treatment. These data establish KMA as a relevant cell surface antigen on MM cells that can be targeted by MDX‐1097. The ADCC‐inducing capacity of MDX‐1097 and its potentiation by lenalidomide provide a powerful rationale for clinical evaluation of MDX‐1097 alone and in combination with lenalidomide. 相似文献
11.
《British journal of haematology》2017,178(6):896-905
The randomized phase III ELOQUENT‐2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3‐year follow‐up data. Endpoints included progression‐free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post‐hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M‐protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd (P = 0·0257); 1‐, 2‐ and 3‐year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ≥ median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0·47). Serum M‐protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity. 相似文献
12.
Rachel Rosovsky Fangxin Hong Deanna Tocco Brendan Connell Constantine Mitsiades Robert Schlossman Irene Ghobrial Leslie Lockridge Diane Warren Gary Bradwin Mary Doyle Nikhil Munshi Robert J. Soiffer Kenneth C. Anderson Edie Weller Paul Richardson 《British journal of haematology》2013,160(3):351-358
In this prospective study of patients with relapsed or relapsed and refractory multiple myeloma (MM) treated with lenalidomide and dexamethasone, relationships between markers of endothelial stress and drug administration and incidence of venous thromboembolism (VTE) were assessed. Of 33 enrolled patients, laboratory and treatment data were available for 32 patients. Of these, 23 received pulsed dexamethasone (40 mg/day on days 1–4, 9–12 and 17–21 of each 28‐day cycle) and 9 received weekly dexamethasone (40 mg/day on days 1, 8, 15 and 21 of each cycle). The overall incidence of VTE was 9%. A decreasing trend in markers values was observed with intercellular adhesion molecule (P = 0·05), fibrinogen (P = 0·008), plasminogen activator inhibitor‐1 (P < 0·001), homocysteine (P = 0·002) and P–selectin (P < 0·001) during therapy. Compared with weekly dexamethasone, pulsed dexamethasone was associated with significantly greater variation in mean adjusted relative values of fibrinogen, P‐selectin and vascular endothelial growth factor (P < 0·001 for all comparisons), although there was no apparent association with VTE incidence. Lenalidomide plus dexamethasone affects endothelial stress marker levels in patients with advanced MM. The higher variation seen with pulsed dexamethasone suggests greater endothelial stress with this approach. 相似文献
13.
A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells
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Arghya Ray Deepika S. Das Yan Song Eva Nordström Joachim Gullbo Paul G. Richardson Dharminder Chauhan Kenneth C. Anderson 《British journal of haematology》2016,174(3):397-409
Our prior study utilized both in vitro and in vivo multiple myeloma (MM) xenograft models to show that a novel alkylator melphalan‐flufenamide (Melflufen) is a more potent anti‐MM agent than melphalan and overcomes conventional drug resistance. Here we examined whether this potent anti‐MM activity of melflufen versus melphalan is due to their differential effect on DNA damage and repair signalling pathways via γ‐H2AX/ATR/CHK1/Ku80. Melflufen‐induced apoptosis was associated with dose‐ and time‐dependent rapid phosphorylation of γ‐H2AX. Melflufen induces γ‐H2AX, ATR, and CHK1 as early as after 2 h exposure in both melphalan‐sensitive and –resistant cells. However, melphalan induces γ‐H2AX in melphalan‐sensitive cells at 6 h and 24 h; no γ‐H2AX induction was observed in melphalan‐resistant cells even after 24 h exposure. Similar kinetics was observed for ATR and CHK1 in meflufen‐ versus melphalan‐treated cells. DNA repair is linked to melphalan‐resistance; and importantly, we found that melphalan, but not melflufen, upregulates Ku80 that repairs DNA double‐strand breaks. Washout experiments showed that a brief (2 h) exposure of MM cells to melflufen is sufficient to initiate an irreversible DNA damage and cytotoxicity. Our data therefore suggest that melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan‐resistance in MM cells. 相似文献
14.
《British journal of haematology》2018,180(2):224-235
In the mantle cell lymphoma (MCL)‐002 study, lenalidomide demonstrated significantly improved median progression‐free survival (PFS) compared with investigator's choice (IC) in patients with relapsed/refractory MCL. Here we present the long‐term follow‐up data and results of preplanned subgroup exploratory analyses from MCL‐002 to evaluate the potential impact of demographic factors, baseline clinical characteristics and prior therapies on PFS. In MCL‐002, patients with relapsed/refractory MCL were randomized 2:1 to receive lenalidomide (25 mg/day orally on days 1–21; 28‐day cycles) or single‐agent IC therapy (rituximab, gemcitabine, fludarabine, chlorambucil or cytarabine). The intent‐to‐treat population comprised 254 patients (lenalidomide, n = 170; IC, n = 84). Subgroup analyses of PFS favoured lenalidomide over IC across most characteristics, including risk factors, such as high MCL International Prognostic Index score, age ≥65 years, high lactate dehydrogenase (LDH), stage III/IV disease, high tumour burden, and refractoriness to last prior therapy. By multivariate Cox regression analysis, factors associated with significantly longer PFS (other than lenalidomide treatment) included normal LDH levels (P < 0·001), nonbulky disease (P = 0·045), <3 prior antilymphoma treatments (P = 0·005), and ≥6 months since last prior treatment (P = 0·032). Overall, lenalidomide improved PFS versus single‐agent IC therapy in patients with relapsed/refractory MCL, irrespective of many demographic factors, disease characteristics and prior treatment history. 相似文献
15.
《British journal of haematology》2017,177(3):457-466
Multiple myeloma (MM ) is a disease with known immune dysregulation. Natural killer (NK ) cells have shown preclinical activity in MM . We conducted a first‐in‐human study of umbilical cord blood‐derived (CB) NK cells for MM patients undergoing high dose chemotherapy and autologous haematopoietic stem cell transplantation (auto‐HCT). Patients received lenalidomide (10 mg) on days −8 to −2, melphalan 200 mg/m2 on day −7, CB‐NK cells on day −5 and auto‐HCT on day 0. Twelve patients were enrolled, three on each of four CB‐NK cell dose levels: 5 × 106, 1 × 107, 5 × 107 and 1 × 108 CB‐NK cells/kg. Ten patients had either high‐risk chromosomal changes or a history of relapsed/progressed disease. There were no infusional toxicities and no graft‐versus‐host disease. One patient failed to engraft due to poor autologous graft quality and was rescued with a back‐up autologous graft. Overall, 10 patients achieved at least a very good partial response as their best response, including eight with near complete response or better. With a median follow‐up of 21 months, four patients have progressed or relapsed, two of whom have died. CB‐NK cells were detected in vivo in six patients, with an activated phenotype (NKG2D+/NKp30+). These data warrant further development of this novel cellular therapy. 相似文献
16.
Wenjing Yang Yoshiyuki Wakabayashi Louis DePalma Young‐Tae Chang Weiqun Peng Jun Zhu Robert G. Hawley 《American journal of hematology》2013,88(4):265-272
Multiple myeloma (MM) is characterized by the malignant expansion of differentiated plasma cells. Although many chemotherapeutic agents display cytotoxic activity toward MM cells, patients inevitably succumb to their disease because the tumor cells become resistant to the anticancer drugs. The cancer stem cell hypothesis postulates that a small subpopulation of chemotherapy‐resistant cancer cells is responsible for propagation of the tumor. Herein we report that efflux of the pluripotent stem cell dye CDy1 identifies a subpopulation in MM cell lines characterized by increased expression of P‐glycoprotein, a member of the ABC (ATP‐binding cassette) superfamily of transporters encoded by ABCB1. We also demonstrate that ABCB1‐overexpressing MM cells are resistant to the second‐generation proteasome inhibitor carfilzomib that recently received accelerated approval for the treatment of therapy‐refractive MM by the U.S. Food and Drug Administration. Moreover, increased resistance to carfilzomib in sensitive MM cells following drug selection was associated with upregulation of ABCB1 cell‐surface expression which correlated with increased transporter activity as measured by CDy1 efflux. We further show that chemosensitization of MM cells to carfilzomib could be achieved in vitro by cotreatment with vismodegib, a hedgehog pathway antagonist which is currently in MM clinical trials. CDy1 efflux may therefore be a useful assay to determine whether high expression of ABCB1 is predictive of poor clinical responses in MM patients treated with carfilzomib. Our data also suggest that inclusion of vismodegib might be a potential strategy to reverse ABCB1‐mediated drug resistance should it occur. Am. J. Hematol. 88:265–272, 2013. © 2013 Wiley Periodicals, Inc. 相似文献
17.
A CD138‐independent strategy to detect minimal residual disease and circulating tumour cells in multiple myeloma
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Barbara Muz Pilar de la Puente Feda Azab Micah John Luderer Justin King Ravi Vij Abdel Kareem Azab 《British journal of haematology》2016,173(1):70-81
CD138 (also termed SDC1) has been the gold‐standard surface marker to detect multiple myeloma (MM) cells for decades; however, drug‐resistant residual and circulating MM cells were shown to have lower expression of this marker. In this study, we have shown that residual MM cells following bortezomib treatment are hypoxic. This combination of drug exposure and hypoxia down‐regulates their CD138 expression, thereby making this marker unsuitable for detecting residual or other hypoxic MM cells, such as circulating tumour cells, in MM. Hence, we developed an alternative biomarker set which detects myeloma cells independent of their hypoxic and CD138 expression status in vitro, in vivo and in primary MM patients. The new markers were able to identify a clonal CD138‐negative population as minimal residual disease in the bone marrow and peripheral blood of MM patients. Further investigation to characterize the role of this population as a prognostic marker in MM is warranted. 相似文献
18.
Mature results of MM‐011: A phase I/II trial of liposomal doxorubicin,vincristine, dexamethasone,and lenalidomide combination therapy followed by lenalidomide maintenance for relapsed/refractory multiple myeloma
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Aleksandr Lazaryan Mohamad A. Hussein Frederic J. Reu Beth Faiman Becky Habecker Mary Ann Karam Janice Reed Kimberly Hamilton Joel Waksman Kellie Bruening Gordan Srkalovic Steven Andresen Matthew Kalaycio John W. Sweetenham Ronald Sobecks Robert Dean Robert Knight Jerome B. Zeldis Rachid Baz 《American journal of hematology》2014,89(4):349-354
A previous interim report of MM‐011, the first study that combined lenalidomide with anthracycline‐based chemotherapy followed by lenalidomide maintenance for relapsed and/or refractory multiple myeloma (RRMM), showed promising safety and activity. We report the long‐term outcomes of all 76 treated patients with follow‐up ≥5 years. This single‐center phase I/II study administered lenalidomide (10 mg on days 1–21 of every 28‐day cycle), intravenous liposomal doxorubicin (40 mg/m2 on day 1), dexamethasone (40 mg on days 1–4), and intravenous vincristine (2 mg on day 1). After 4–6 planned induction cycles, lenalidomide maintenance therapy was given at the last tolerated dose until progression, with or without 50 mg prednisone every other day. The median number of previous therapies was 3 (range, 1–7); 49 (64.5%) patients had refractory disease. Forty‐three (56.6%) patients received maintenance therapy. Grade 3/4 adverse events occurred during induction and maintenance therapy in 48.7% and 25.6% of patients, respectively. Four (5.3%) treatment‐related deaths occurred during induction. Responses were seen in 53.0% (at least partial response) and 71.2% (at least minor response) of patients. Overall, median progression‐free survival and overall survival were 10.5 and 19.0 months, respectively; in patients with refractory disease these values were 7.5 and 11.3 months, respectively. Lenalidomide with anthracycline‐based chemotherapy followed by maintenance lenalidomide provided durable control in patients with RRMM ( ClinicalTrials.gov number, NCT00091624). Am. J. Hematol. 89:349–354, 2014. © 2013 Wiley Periodicals, Inc. 相似文献
19.
Cancer‐testis antigen MAGEC2 promotes proliferation and resistance to apoptosis in Multiple Myeloma
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Nesrine Lajmi Tim Luetkens Sara Yousef Julia Templin Yanran Cao York Hildebrandt Katrin Bartels Nicolaus Kröger Djordje Atanackovic 《British journal of haematology》2015,171(5):752-762
Cancer‐testis antigens belonging to the MAGE family of genes, such as MAGEC2, are commonly and specifically expressed in Multiple Myeloma (MM) and are associated with a more aggressive clinical course and chemotherapy resistance. MAGEC2 is thought to be an excellent candidate for cancer immunotherapy; however, the biological role of MAGEC2 in MM has remained unclear. We investigated the biological role of MAGEC2 in myeloma cells determining the effect of MAGEC2 knockdown on proliferation and apoptosis. Loss of MAGEC2 resulted in reduced proliferation, viability, and anchorage‐independent growth of myeloma cells irrespective of the functional status of TP53 (p53). The anti‐proliferative effect of MAGEC2 silencing was due to a decrease of cells in the S phase, cell cycle delay at both G0/G1 and/or G2/M, and an increase in the sub‐G0/G1 diploid population related to apoptotic cell death. Importantly, overexpression of short hairpin (sh)RNA‐refractory MAGEC2 rescued the anti‐proliferative effect of mRNA knockdown and protected cells from apoptotic cell death. Our findings support a TP53‐independent role of MAGEC2 in promoting the survival of myeloma cells suggesting that MAGEC2‐specific immunotherapies have the potential to eradicate the most malignant cells within the myeloma tumour bulk leading to durable clinical responses. 相似文献
20.
Polyphyllin I induces cell cycle arrest and apoptosis in human myeloma cells via modulating β‐catenin signaling pathway
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Yun Liang Xian Li Xin He Xi Qiu Xue‐li Jin Xiao‐ying Zhao Rong‐zhen Xu 《European journal of haematology》2016,97(4):371-378
Multiple myeloma (MM) is an indolent B‐cell disease characterized by clonal proliferation of malignant plasma cells. Multiple myeloma remains incurable despite new targeted drugs and development of drug resistance or intolerable toxicity emerges as a major problem. Therefore, design, identification, and validation of novel chemicals with therapeutic potential are clearly needed for MM treatment. Here, we explore polyphyllin I (PPI), a major active constituent extracted from Paris polyphyllin, its inhibitory effects and its mechanisms in MM cells in vitro. We found that PPI inhibited the proliferation of myeloma cells. The combination of PPI with dexamethasone, doxorubicin, arsenic trioxide, or bortezomib enhanced the inhibition of cell growth. As analyzed by flow cytometry, MM cells were arrested at G2/M phase and apoptotic cells increased in a time‐dependent manner. Morphological changes of cells undergoing apoptosis were observed under light microscope. To explore the mechanism of apoptosis induced by PPI, we next examined whether the Wingless‐Int (Wnt)/β‐catenin signaling pathway played a role in the PPI‐induced growth inhibition in MM cells. The canonical Wnt signaling pathway is activated in MM cells through constitutively active β‐catenin, a messenger molecule relevant to growth, survival, and migration of MM cells. Western blotting was used to measure the protein levels of β‐catenin, and PPI treatment led to downregulating the expression of β‐catenin protein and was followed by inhibition of β‐catenin nuclear localization. As a result, β‐catenin downstream targets, such as cyclin D1 and survivin, were downregulated. To the best of our knowledge, this is the first report identifying anti‐proliferative potency of PPI against myeloma cells. PPI blocks β‐catenin nuclear translocation and decreasing expression of the downstream targets of β‐catenin. Our results suggest that PPI is a novel inhibitor of β‐catenin activity with potential anti‐myeloma efficacy. 相似文献