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  • 1
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 61, No. 1 ( 1997-01-01), p. 96-105
    Abstract: In the mouse, mutations at the natural resistance-associated macrophage protein 1 (Nrampl) gene abrogate resistance to infection with antigenically unrelated intracellular parasites such as Mycobacterium, Salmonella, and Leishmania. Nrampl expression is restricted to reticuloendothelial organs and peripheral blood leukocytes, where the protein may function as a membrane transporter of an as yet to be identified substrate. To identify the human blood cell type(s) expressing NRAMPl mRNA and determine how Nrampl expression is regulated in these cells, we have examined separated populations of peripheral blood leukocytes and in vitro cell lines. We observed that polymorphonuclear leukocytes (PMN) are the major site of NRAMP1 expression, followed to a lesser degree by monocytes (MN). Migration of MN to tissues (alveolar macrophages) or maturation in vitro (long-term culture) was associated with a higher level of NRAMP1 expression compared with blood MN. Northern analyses of RNA from model cultured cells showed absence of NRAMP1 expression in transformed cell lines from either erythroid or lymphoid T or B lineages as well as progenitors of the monocyte/macrophage pathway (KG1, U937, THP1), and the HL-60 promyelocytic leukemia. Induction of differentiation of HL-60 cells toward either the monocyte/ macrophage (vitamin D3, phorbol ester) or the granulocyte pathways (DMF, DMSO), as measured by induction of IL8-Rb, c-FMS, and CD14 marker gene expression, was concomitant with a strong induction of NRAMP1 expression. These results suggest that NRAMP1 expression is specific to the myeloid lineage and is acquired during the maturation of PMN and MN. The possibility that NRAMP1 may be a component of the phagosomal/endosomal apparatus common to PMN and MN is discussed.
    Type of Medium: Online Resource
    ISSN: 0741-5400 , 1938-3673
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    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 1997
    detail.hit.zdb_id: 2026833-6
    SSG: 12
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 30 ( 2016-10-20), p. 3609-3617
    Abstract: This analysis of the FIRST trial in patients with newly diagnosed multiple myeloma (MM) ineligible for stem-cell transplantation examined updated outcomes and impact of patient age. Patients and Methods Patients with untreated symptomatic MM were randomly assigned at a one-to-one-to-one ratio to lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks), stratified by age (≤ 75 v 〉 75 years), disease stage (International Staging System stage I/II v III), and country. The primary end point was progression-free survival. Rd continuous and MPT were primary comparators. Results Between August 21, 2008, and March 7, 2011, 1,623 patients were enrolled (Rd continuous, n = 535; Rd18, n = 541; MPT, n = 547), including 567 (35%) age older than 75 years. Higher rates of advanced-stage disease and renal impairment were observed in patients older than 75 versus 75 years of age or younger. Rd continuous reduced the risk of progression or death compared with MPT by 31% (hazard ratio [HR], 0.69; 95% CI, 0.59 to 0.80; P 〈 .001) overall, 36% (HR, 0.64; 95% CI, 0.53 to 0.77; P 〈 .001) in patients age 75 years or younger, and 20% (HR, 0.80; 95% CI, 0.62 to 1.03; P = .084) in those age older than 75 years. Median overall survival was longer with Rd continuous than with MPT, including a 14-month difference in patients age older than 75 years. Progression-free survival with Rd18 was similar to that with MPT, and overall survival with Rd18 was marginally inferior to that with Rd continuous. Rates of grade 3 to 4 treatment-emergent adverse events were similar for Rd continuous–treated patients age 75 years or older and those age older than 75 years; however, older patients had more frequent lenalidomide dose reductions. Conclusion Results support Rd continuous treatment as a new standard of care for stem-cell transplantation–ineligible patients with newly diagnosed MM of all ages.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 47, No. 4 ( 2006-01), p. 697-706
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2006
    detail.hit.zdb_id: 2030637-4
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  • 4
    Online Resource
    Online Resource
    Informa UK Limited ; 2020
    In:  Leukemia & Lymphoma Vol. 61, No. 7 ( 2020-06-06), p. 1724-1727
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 61, No. 7 ( 2020-06-06), p. 1724-1727
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2020
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  • 5
    In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 366, No. 5 ( 2012-02-02), p. 399-408
    Type of Medium: Online Resource
    ISSN: 0028-4793 , 1533-4406
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    Language: English
    Publisher: Massachusetts Medical Society
    Publication Date: 2012
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  • 6
    In: Cancer Medicine, Wiley, Vol. 9, No. 23 ( 2020-12), p. 8923-8930
    Abstract: The phase 3 FIRST trial demonstrated significant improvement in progression‐free survival (PFS) and overall survival (OS) with an immune‐stimulatory agent, lenalidomide, in combination with low‐dose dexamethasone until disease progression (Rd continuous) vs melphalan +prednisone + thalidomide (MPT) in transplant‐ineligible patients with newly diagnosed multiple myeloma (NDMM). Rd continuous similarly extended PFS vs fixed‐duration Rd for 18 cycles (Rd18). Outcomes in the Canadian/US subgroup (104 patients per arm) are reported in this analysis. Rd continuous demonstrated a significant improvement in PFS vs MPT (median, 29.3 vs 20.2 months; HR, 0.69 [95% CI, 0.49‐0.97]; p  = 0.03326) and an improvement vs Rd18 (median, 21.9 months). Median OS was 56.9 vs 46.8 months with Rd continuous vs MPT ( p  = 0.15346) and 59.5 months with Rd18. The overall response rate was higher with Rd continuous and Rd18 (78.8% and 79.8%) vs MPT (65.4%). In the 49.0%, 52.9%, and 29.8% of patients with at least very good partial response in the Rd continuous, Rd18, and MPT arms, respectively, the median PFS was 56.0, 30.9, and 40.2 months, respectively. The most common grade 3/4 treatment‐emergent adverse events were neutropenia (28.4%, 30.1%, and 52.0%), anemia (23.5%, 21.4%, and 23.5%), and infections (37.3%, 30.1%, and 24.5%) with Rd continuous, Rd18, and MPT, respectively. These results were consistent with those in the intent‐to‐treat population, confirming the benefit of Rd continuous vs MPT in the Canadian/US subgroup and supporting the role of Rd continuous as a standard of care for transplant‐ineligible patients with NDMM.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2659751-2
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  • 7
    In: Blood, American Society of Hematology, Vol. 123, No. 12 ( 2014-03-20), p. 1826-1832
    Abstract: Pomalidomide plus low-dose dexamethasone significantly improved PFS vs pomalidomide alone in relapsed and refractory multiple myeloma. Pomalidomide plus low-dose dexamethasone is an important new treatment option for RRMM patients who have received multiple prior therapies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2741-2741
    Abstract: Abstract 2741 Poster Board II-717 Bortezomib (Velcade ™, PS-341, BTZ) is a boronate dipeptide that reversibly inhibits the 26S proteasome, which is essential for the breakdown of ubiquitinated proteins and the regulation of normal cellular homeostasis. The activity of BTZ in treatment of newly diagnosed and refractory/relapsed multiple myeloma may be limited by the development of chemoresistance, the mechanisms of which are poorly understood. To investigate the molecular basis of Bortezomib resistance, BTZ-resistant (BTZr) cell lines were generated by stepwise selection procedures from HeLa, CCRF-CEM, and 4 multiple myeloma cells lines (8226S, U266, H929, and MM.1S), respectively. These BTZ-selected cell lines displayed varying degrees of elevated resistance (2 to 50 fold) to clinically relevant concentrations of BTZ. In addition, while most of the BTZr cells showed cross resistance to several other proteasome inhibitors (PIs), including MG-132 and Epoxomicin, they remained as sensitive to other chemotherapeutic drugs, such as anthracyclines, vinkalkaloids and etoposide, as their parental cells. The proteasome activity profiles are distinct among the cell lines. All parental cell lines displayed varying levels of chymotrypsin-like (CT-L) activity, which is the primary target of BTZ. Most BTZr lines showed markedly decreased CT-L activity, with a few exceptions. Moreover, the observed CT-L activity in all cell lines can be inhibited directly by BTZ and other PIs. In contrast, very low levels of caspase-like or post-glutamyl peptide hydrolyzing (PGPH) proteasome activity were detected in all cell lines. BTZ resistance in HeLa/BTZ cells was closely associated with increased resistance to PI-induced apoptosis, as shown by reduced number of Annexin V-stained cells and by delayed activation/cleavage of apoptosis proteins, such as Caspase-3 and Poly(ADP-ribose) Polymerase (PARP). Furthermore, the resistance to BTZ affected the mechanisms of cell stress responses. As for the parental HeLa cells, HeLa/BTZr cells retained the ability to form, in response to PI treatment, pro-survival foci in the cytoplasm known as stress granules (SGs). However, the drug concentrations required to induce SG formation in HeLa/BTZr cells are much higher (∼4 fold) than those for the parental HeLa, suggesting the development of stress-coping mechanisms in these BTZr cells. Gene expression profiling studies are in progress to identify transcriptomes individually or generally associated with BTZ resistance in these cell lines. Further characterization of these phenotypically similar, yet mechanistically distinct BTZr cell lines may elucidate diverse mechanisms of drug resistance to Bortezomib and other proteasome inhibitors. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 9
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4201-4201
    Abstract: Background: The initial therapies for multiple myeloma have changed significantly in the recent years with routine incorporation of combinations containing IMiDs and proteasome inhibitors. However, patients with MM invariably relapse after their initial treatment and undergo successive therapies for continued control of their disease. The increasing access to new therapies for treatment of relapsed disease has led to improved survival of patients with MM. Many recent phase 3 trials have studied the impact of new agents on outcome of patients with MM who are relapsing after the initial lines of therapy for relapsed disease. However, the natural history of relapsed myeloma earlier in the course of relapsed disease has not been studied in detail. Patients and methods: We designed a global, multicenter, retrospective study to examine the current treatment approaches for initial relapses in MM and patient outcomes following application of successive treatment regimens. Patients with multiple myeloma who experience a first relapse between January 1, 2007 and December 31, 2011 were identified at participating sites. Clinical and laboratory data pertaining to the time of diagnosis and from the time of individual relapses up to and including the third relapse will be obtained from the clinical records. The first date of treatment with an anti-myeloma regimen for first disease relapse was termed time zero (T0). Results: Three hundred and fifteen patients were enrolled; median age at diagnosis was 59 years (range: 35 - 86), 59% were male. Patients were enrolled from North America (33%), Europe (35%) or Asia (32%). The patients were diagnosed between 1997 and 2011 and the median time to T0 from diagnosis was 23.9 months (range: 0.8 - 131.9 months). An IMiD (thalidomide or lenalidomide), bortezomib or alkylator (melphalan or cyclophosphamide) was part of the initial therapy in 63%, 36% and 51% of patients, respectively; 93 (33%) patients had stem cell transplantation as part of initial treatment. The median follow up from the study entry was 56 months; 117 were alive at the time of data extraction. A second line, third line and fourth line of treatment were recorded in 307, 163 and 84 patients respectively. An IMiD (thalidomide, lenalidomide, or pomalidomide), proteasome inhibitor (bortezomib or carfilzomib) or alkylator (melphalan or cyclophosphamide) was part of the therapy for first relapse in 50%, 59% and 33% of patients, respectively. The responses to the regimens after T0, the TTNT, PFS and OS to each line of therapy are provided in the Table. Conclusion: The current study provides an assessment of the current treatment approaches used for initial treatment of MM and the salvage treatment options utilized. The study again demonstrates the progressively shorter duration of disease control with each successive treatment regimen, reflecting ongoing development of drug resistance. The overall survival of over 3 years from the time of therapy for first relapse highlights the impact of the newer therapies that have been introduced for this disease. Table. Treatment outcomes after initial relapse Endpoint 2nd line therapyN=307 3rd line therapyN=163 4th line therapyN=84 Partial response or better Median in Months (95% Confidence Interval) Overall Survival 36.1 (30.2, 42.4) 18.4 (14.5, 26.8) 12.6 (10.4, 19.0) Progression-Free Survival 13.4 (11.8, 15.8) 8.3 (6.5, 11.2) 6.4 (5.0, 8.1) Time to Next Treatment 15 (12,17) 9.8 (7.4, 12.0) 6.6 (5.8, 8.7) Figure 1. Figure 1. Disclosures Kumar: Onyx: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dimopoulos:Novartis: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Onyx: Honoraria; Celgene: Honoraria. Leleu:Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; TEVA: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pierre Fabre: Honoraria; LeoPharma: Honoraria; Chugai: Honoraria. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen Cilag, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    Online Resource
    Online Resource
    SAGE Publications ; 1998
    In:  Cancer Control Vol. 5, No. 3 ( 1998-05), p. 226-234
    In: Cancer Control, SAGE Publications, Vol. 5, No. 3 ( 1998-05), p. 226-234
    Abstract: The role of interferon (IFN) in the treatment of multiple myeloma has been investigated for nearly two decades. The mechanisms underlying antitumor activity of IFN may be mediated by antiproliferative and immunomodulatory effects. The benefits of treatment remain controversial, and guidelines for the use of IFN in myeloma are needed. This review evaluates available data on the impact of IFN therapy on multiple myeloma. Methods A MEDLINE search of published prospective, randomized trials of IFN in multiple myeloma provided the data included in this review, as well as selected abstracts presented at international meetings. Results IFN has complex and pleiotropic effects on human myeloma lines and ex vivo myeloma cells. An antiproliferative effect with disruption of the IL-6-mediated growth loop may be crucial, but biologic heterogeneity in myeloma may have important clinical implications for response to IFN. IFN has demonstrable antitumor activity in multiple myeloma but appears to have a modest effect on overall survival when combined with chemotherapy during induction or when used as maintenance therapy. Most studies have shown a prolongation of the plateau phase of disease with IFN of variable duration of between four and 12 months. Conclusions A reliable estimate of the benefit of IFN in the overall population of patients with myeloma is difficult to determine with discordant results from different trials. Possible sources of heterogeneity in randomized trials need to be identified, and recognition of subsets of patients who may benefit is important. Cost-benefit analyses with integration of quality-of-life data are essential for developing guidelines for the use of IFN in myeloma.
    Type of Medium: Online Resource
    ISSN: 1073-2748 , 1073-2748
    Language: English
    Publisher: SAGE Publications
    Publication Date: 1998
    detail.hit.zdb_id: 2004182-2
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