Imperial College London

DrHolgerAuner

Faculty of MedicineDepartment of Immunology and Inflammation

Clinical Reader in Molecular Haemato-Oncology
 
 
 
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Contact

 

holger.auner04 Website

 
 
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Assistant

 

Miss Mandy Sale +44 (0)20 3313 4017

 
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Location

 

4N7ACommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

139 results found

Trasanidis N, Katsarou A, Ponnusamy K, Shen Y-A, Kostopoulos IV, Bergonia B, Keren K, Reema P, Xiao X, Szydlo RM, Sabbattini P, Roberts I, Auner HW, Naresh KN, Chaidos A, Wang T-L, Magnani L, Caputo VS, Karadimitris Aet al., 2022, Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma., Blood

Understanding the biological and clinical impact of copy number aberrations (CNA) for the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chr1q portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here, with reference to the 3D chromatin structure, we integrate MM patient multi-omics datasets with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent amongst these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional programme. Together, PBX1 and FOXM1 activate a proliferative gene signature which predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small-molecule inhibitor (T417) is selectively toxic against chr1q-amplified myeloma and solid tumour cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in multiple myeloma and other types of cancer.

Journal article

Delimpasi S, Mateos MV, Auner HW, Gavriatopoulou M, Dimopoulos MA, Quach H, Pylypenko H, Hajek R, Leleu X, Dolai TK, Sinha DK, Venner CP, Benjamin R, Garg MK, Doronin V, Levy Y, Moreau P, Chai Y, Arazy M, Shah J, Shacham S, Kauffman MG, Richardson PG, Grosicki Set al., 2021, Efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in comparison with standard twice-weekly bortezomib and dexamethasone in previously treated multiple myeloma with renal impairment: Subgroup analysis from the BOSTON study, AMERICAN JOURNAL OF HEMATOLOGY, ISSN: 0361-8609

Journal article

Klionsky DJ, 2021, Look youse guys and gals, dat just ain’t right, Autophagy, Vol: 17, Pages: 3895-3896, ISSN: 1554-8627

Journal article

Yong KL, Hinsley S, Auner HW, Bygrave C, Kaiser MF, Ramasamy K, De Tute RM, Sherratt D, Flanagan L, Garg M, Hawkins S, Williams C, Cavenagh J, Rabin NK, Croft J, Morgan G, Davies F, Owen RG, Brown SRet al., 2021, Carfilzomib or bortezomib in combination with cyclophosphamide and dexamethasone followed by carfilzomib maintenance for patients with multiple myeloma after one prior therapy: results from a multi-centre, phase II, randomized, controlled trial (MUKfive), Haematologica: the hematology journal, Vol: 106, Pages: 2694-2706, ISSN: 0390-6078

The proteasome inhibitors (PIs), carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these PIs in combination with cyclophosphamide and dexamethasone (KCd vs VCd) in second line treatment using fixed duration therapy and evaluated the efficacy of carfilzomib maintenance. MUKfive was a phase II controlled, parallel group trial that randomised patients (2:1) to KCd (201) or VCd (99); responding patients on carfilzomib were randomised to maintenance carfilzomib (69) or no further treatment (72). Primary endpoints were (i) very good partial response (VGPR, non-inferiority, OR 0.8) at 24 weeks, and (ii) progression-free survival (PFS). More participants achieved ≥VGPR with carfilzomib compared to bortezomib (40.2% vs. 31.9%, OR=1.48, 90%CI:0.95,2.31; non-inferior), with a trend for particular benefit in adverse risk disease. KCd was associated with higher overall response (≥PR, 84.0% vs. 68.1%, OR=2.72, 90%CI:1.62,4.55, p=0.001). Neuropathy (grade ≥3 or ≥2 with pain) was more common with bortezomib (19.8% vs. 1.5%, p.

Journal article

Sanchez L, Leleu X, Beaumont JL, Yu H, Hudgens S, Simonova M, Auner HW, Quach H, Delimpasi S, Špička I, Pour L, Kriachok I, Dimopoulos MA, Usenko G, Hájek R, Benjamin R, Sinha DK, Venner C, Illmer T, Garg MK, Stevens DA, Jagannath S, Levy M, Anderson LD, Bahlis NJ, Facon T, Cavo M, Chai Y, Ma X, Tang S, Leong H, Shah J, Shacham S, Kauffman M, Richardson P, Grosicki Set al., 2021, Peripheral neuropathy symptoms, pain, and functioning in previously treated multiple myeloma patients treated with selinexor, bortezomib, and dexamethasone, American Journal of Hematology, Vol: 96, Pages: E383-E386, ISSN: 0361-8609

Journal article

Karadimitris A, 2021, Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma, Nature Communications, Vol: 12, Pages: 1-16, ISSN: 2041-1723

Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct myeloma transcriptome profiles are primarily driven by myelomainitiating events (MIE) and converge into a mutually exclusive overexpression of the CCND1 and CCND2 oncogenes. Here, with reference to their normal counterparts, we find that myeloma PC enhanced chromatin accessibility combined with paired transcriptome profiling can classify MIE-defined genetic subgroups. Across and within different MM genetic subgroups, we ascribe regulation of genes and pathways critical for myeloma biology to unique or shared, developmentally activated or de novo formed candidate enhancers. Such enhancers co-opt recruitment of existing transcription factors, which although not transcriptionally deregulated per se, organise aberrant gene regulatory networks that help identify myeloma cell dependencies with prognostic impact. Finally, we identify and validate the critical super-enhancer that regulates ectopic expression of CCND2 in a subset of patients with MM and in chronic lymphocytic leukemia.

Journal article

Richard S, Chari A, Delimpasi S, Simonova M, Spicka I, Pour L, Kriachok I, Dimopoulos MA, Pylypenko H, Auner HW, Leleu X, Usenko G, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens DA, Quach H, Jagannath S, Moreau P, Levy M, Badros A, Anderson LD, Bahlis NJ, Facon T, Mateos MV, Cavo M, Chang H, Landesman Y, Chai Y, Arazy M, Shah J, Shacham S, Kauffman MG, Grosicki S, Richardson PGet al., 2021, Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 96, Pages: 1120-1130, ISSN: 0361-8609

Journal article

Mateos MV, Gavriatopoulou M, Facon T, Auner HW, Leleu X, Hajek R, Dimopoulos MA, Delimpasi S, Simonova M, Spicka I, Pour L, Kriachok I, Pylypenko H, Doronin V, Usenko G, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens DA, Quach H, Jagannath S, Moreau P, Levy M, Badros AZ, Anderson LD, Bahlis NJ, Cavo M, Chai Y, Jeha J, Arazy M, Shah J, Shacham S, Kauffman MG, Richardson PG, Grosicki Set al., 2021, Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma, Journal of Hematology and Oncology, Vol: 14, ISSN: 1756-8722

Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM.

Journal article

Leleu X, Mateos M-V, Jagannath S, Delimpasi S, Simonova M, Spicka I, Pour L, Kriachok I, Gavriatopoulou M, Dimopoulos MA, Pylypenko H, Auner HW, Reuben B, Venner CP, Garg M, DeCastro A, Shah JJ, Grosicki S, Richardson PGet al., 2021, Effects of refractory status to lenalidomide on safety and efficacy of selinexor, bortezomib, and dexamethasone (XVd) versus bortezomib and dexamethasone (Vd) in patients with previously treated multiple myeloma., Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X

Conference paper

Facon T, Auner HW, Gavriatopoulou M, Delimpasi S, Simonova M, Spicka I, Pour L, Dimopoulos MA, Kriachok I, Pylypenko H, Leleu X, Quach H, Reuben B, Dolai TK, Sinha DK, Garg M, Stevens DA, Shah JJ, Richardson PG, Grosicki Set al., 2021, Survival among older patients with previously treated multiple myeloma treated with selinexor, bortezomib, and dexamethasone (XVd) in the BOSTON study., Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X

Conference paper

Auner HW, Gavriatopoulou M, Delimpasi S, Simonova M, Spicka I, Pour L, Dimopoulos MA, Kriachok I, Pylypenko H, Leleu X, Doronin V, Usenko G, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens DA, Quach H, Jagannath S, Moreau P, Levy M, Badros A, Jr LDA, Bahlis NJ, Facon T, Victoria Mateos M, Cavo M, Chai Y, Arazy M, Shah J, Shacham S, Kauffman MG, Richardson PG, Grosicki Set al., 2021, Effect of age and frailty on the efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 96, Pages: 708-718, ISSN: 0361-8609

Journal article

Saavedra-Garcia P, Roman-Trufero M, Al-Sadah HA, Blighe K, Lopez-Jimenez E, Christoforou M, Penfold L, Capece D, Xiong X, Miao Y, Parzych K, Caputo V, Siskos AP, Encheva V, Liu Z, Thiel D, Kaiser MF, Piazza P, Chaidos A, Karadimitris A, Franzoso G, Snijder AP, Keun HC, Oyarzún DA, Barahona M, Auner Het al., 2021, Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs, Proceedings of the National Academy of Sciences of USA, Vol: 118, ISSN: 0027-8424

Cancer cells can survive chemotherapy-induced stress, but how they recover from it is not known.Using a temporal multiomics approach, we delineate the global mechanisms of proteotoxic stressresolution in multiple myeloma cells recovering from proteasome inhibition. Our observations definelayered and protracted programmes for stress resolution that encompass extensive changes acrossthe transcriptome, proteome, and metabolome. Cellular recovery from proteasome inhibitioninvolved protracted and dynamic changes of glucose and lipid metabolism and suppression ofmitochondrial function. We demonstrate that recovering cells are more vulnerable to specific insultsthan acutely stressed cells and identify the general control nonderepressable 2 (GCN2)-driven cellularresponse to amino acid scarcity as a key recovery-associated vulnerability. Using a transcriptomeanalysis pipeline, we further show that GCN2 is also a stress-independent bona fide target intranscriptional signature-defined subsets of solid cancers that share molecular characteristics. Thus,identifying cellular trade-offs tied to the resolution of chemotherapy-induced stress in tumour cellsmay reveal new therapeutic targets and routes for cancer therapy optimisation.

Journal article

Ponnusamy K, Tzioni MM, Begum M, Robinson ME, Caputo VS, Katsarou A, Trasanidis N, Xiao X, Kostopoulos IV, Iskander D, Roberts I, Trivedi P, Auner HW, Naresh K, Chaidos A, Karadimitris Aet al., 2021, The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma., Haematologica

Multiple myeloma is a malignancy of plasma cells (PC) initiated and driven by primary and secondary genetic events. Nevertheless, myeloma PC survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B cell development in both human and mouse cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma PC, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the PC lineage-defining transcription factor IRF4, and thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a non-canonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology.

Journal article

Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A, Adamopoulos IE, Adeli K, Adolph TE, Adornetto A, Aflaki E, Agam G, Agarwal A, Aggarwal BB, Agnello M, Agostinis P, Agrewala JN, Agrotis A, Aguilar P, Ahmad ST, Ahmed ZM, Ahumada-Castro U, Aits S, Aizawa S, Akkoc Y, Akoumianaki T, Akpinar HA, Al-Abd AM, Al-Akra L, Al-Gharaibeh A, Alaoui-Jamali MA, Alberti S, Alcocer-Gomez E, Alessandri C, Ali M, Al-Bari MAA, Aliwaini S, Alizadeh J, Almacellas E, Almasan A, Alonso A, Alonso GD, Altan-Bonnet N, Altieri DC, Alves S, da Costa CA, Alzaharna MM, Amadio M, Amantini C, Amaral C, Ambrosio S, Amer AO, Ammanathan V, An Z, Andersen SU, Andrabi SA, Andrade-Silva M, Andres AM, Angelini S, Ann D, Anozie UC, Ansari MY, Antas P, Antebi A, Anton Z, Anwar T, Apetoh L, Apostolova N, Araki T, Araki Y, Arasaki K, Araujo WL, Araya J, Arden C, Arevalo M-A, Arguelles S, Arias E, Arikkath J, Arimoto H, Ariosa AR, Armstrong-James D, Arnaune-Pelloquin L, Aroca A, Arroyo DS, Arsov I, Artero R, Asaro DML, Aschner M, Ashrafizadeh M, Ashur-Fabian O, Atanasov AG, Au AK, Auberger P, Auner HW, Aurelian L, Autelli R, Avagliano L, Avalos Y, Aveic S, Aveleira CA, AvinWittenberg T, Aydin Y, Ayton S, Ayyadevara S, Azzopardi M, Baba M, Backer JM, Backues SK, Bae D-H, Bae O-N, Bae SH, Baehrecke EH, Baek A, Baek S-H, Baek SH, Bagetta G, Bagniewska-Zadworna A, Bai H, Bai J, Bai X, Bai Y, Bairagi N, Baksi S, Balbi T, Baldari CT, Balduini W, Ballabio A, Ballester M, Balazadeh S, Balzan R, Bandopadhyay R, Banerjee S, Banerjee S, Bao Y, Baptista MS, Baracca A, Barbati C, Bargiela A, Barila D, Barlow PG, Barmada SJ, Barreiro E, Barreto GE, Bartek J, Bartel B, Bartolome A, Barve GR, Basagoudanavar SH, Bassham DC, Jr RCB, Basu A, Batoko H, Batten I, Baulieu EE, Baumgarner BL, Bayry J, Beale R, Beau I, Beaumatin F, Bechara LRG, Beck GR, Beers MF, Begun J, Behrends C, Behrens GMN, Bei R, Bejarano E, Bel S, Behl C, Belaid A, Belgareh-Touzeet al., 2021, Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition), Autophagy, Vol: 17, Pages: 1-382, ISSN: 1554-8627

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Journal article

Caputo VS, Trasanidis N, Xiao X, Robinson ME, Katsarou A, Ponnusamy K, Prinjha RK, Smithers N, Chaidos A, Auner HW, Karadimitris Aet al., 2021, Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro, iScience, Vol: 24, Pages: 1-31, ISSN: 2589-0042

Osteoclast development in response to RANKL is critical for bone homeostasis in health and in disease. The early and direct chromatin regulatory changes imparted by the BET chromatin readers Brd2-4 and osteoclast-affiliated transcription factors (TF) during osteoclastogenesis are not known. Here, we demonstrate that in response to RANKL, early osteoclast development entails regulation of two alternative cell fate transcriptional programmes, osteoclast vs macrophage, with repression of the latter following activation of the former. Both programmes are regulated in a non-redundant manner by increased chromatin binding of Brd2 at promoters and of Brd4 at enhancers/super-enhancers. Myc, the top RANKL-induced TF, regulates osteoclast development in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TF. These insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate pathological OC activation.

Journal article

Grosicki S, Simonova M, Spicka I, Pour L, Kriachok I, Gavriatopoulou M, Pylypenko H, Auner H, Leleu X, Doronin V, Usenko G, Bahlis NJ, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Gironella M, Jurczyszyn A, Robak P, Galli M, Wallington-Beddoe C, Radinoff A, Salogub G, Stevens DA, Basu S, Liberati AM, Quach H, St Goranova-Marinova V, Bila J, Katodritou E, Oliynyk H, Korenkova S, Kumar J, Jagannath S, Moreau P, Levy M, White D, Gatt ME, Facon T, Mateos MV, Cavo M, Reece D, Anderson LD, Saint-Martin J-R, Jeha J, Joshi AA, Chai Y, Li L, Peddagali V, Arazy M, Shah J, Shacham S, Kauffman MG, Dimopoulos MA, Richardson PG, Delimpasi Set al., 2020, Once-weekly selinexor, bortezomib, and dexamethasone versus twice-weekly bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label phase 3 trial, The Lancet, Vol: 396, Pages: 1563-1573, ISSN: 0140-6736

Background Selinexor with dexamethasone has demonstrated activity in patients with heavily pretreated multiple myeloma (MM). In a phase 1b/2 study, the combination of oral selinexor with the proteasome inhibitor (PI) bortezomib, and dexamethasone (SVd) induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. The aim of this trial was to evaluate the clinical benefit of weekly SVd versus standard bortezomib and dexamethasone (Vd) in patients with previously treated MM.Methods This phase 3, randomised, open label trial was conducted at 123 sites in 21 countries. Patients who were previously treated with one to three lines of therapy, including PIs were randomised (1:1) to selinexor (100 mg once-weekly) plus bortezomib (1·3 mg/m2 once-weekly) and dexamethasone (20 mg twice-weekly) [SVd] or bortezomib (1·3 mg/m2 twice-weekly) and dexamethasone (20 mg 4 times per week) [Vd]. Randomisation was done using interactive response technology and stratified by previous PI therapy, lines of treatment, and MM stage. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562.Findings Between June 2017 and February 2019, 402 patients were randomised: 195 to SVd and 207 to Vd. Median PFS was 13·93 (95% CI 11·73–NE) with SVd versus 9·46 months (8·11–10·78) with Vd; HR 0·70, [95% CI 0·53–0·93]; P=0.0075. Most frequent grade ≥3 adverse events (SVd vs Vd) were thrombocytopenia (77 [40%] vs 35 [17%]), fatigue (26 [13%] vs 2 [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy rates (overall, 32·3% vs 47·1%; OR 0·52, [95% CI 0·35-0·79]; P=0.0010 and grade ≥2, 21&middo

Journal article

Auner HW, Gavriatopoulou M, Delimpasi S, Simonova M, Spicka I, Pour L, Dimopoulos MA, Kryachok I, Pylypenko H, Leleu X, Doronin VA, Usenko G, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens DA, Quach H, Jagannath S, Moreau P, Levy MY, Badros AZ, Anderson LD, Bahlis NJ, Facon T, Mateos M, Cavo M, Joshi AA, Chai Y, Arazy M, Shah J, Shacham S, Kauffman MG, Richardson PG, Grosicki Set al., 2020, Once Weekly Selinexor, Bortezomib, and Dexamethasone Versus Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Age and Frailty Subgroup Analyses from the Phase 3 Boston Study, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Mateos M, Gavriatopoulou M, Facon T, Auner HW, Leleu X, Hajek R, Dimopoulos MA, Delimpasi S, Simonova M, Spicka I, Pour L, Kryachok I, Pylypenko H, Doronin VA, Usenko G, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens DA, Quach H, Jagannath S, Moreau P, Levy M, Badros AZ, Anderson LD, Bahlis NJ, Cavo M, Chai Y, Arazy M, Shah J, Shacham S, Kauffman MG, Richardson PG, Grosicki Set al., 2020, Effect of Prior Treatment with Proteasome Inhibitors on the Efficacy and Safety of Once-Weekly Selinexor, Bortezomib, and Dexamethasone in Comparison with Twice-Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Subgroup Analysis from the Boston Study, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Richard S, Chari A, Delimpasi S, Simonova M, Spicka I, Pour L, Kryachok I, Dimopoulos MA, Pylypenko H, Auner HW, Leleu X, Doronin VA, Usenko G, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens DA, Quach H, Jagannath S, Moreau P, Levy MY, Badros AZ, Anderson LD, Bahlis NJ, Facon T, Mateos M-V, Cavo M, Chang H, Landesman Y, Joshi AA, Chai Y, Arazy M, Shah J, Shacham S, Kauffman MG, Grosicki S, Richardson PGet al., 2020, Once Weekly Selinexor, Bortezomib, and Dexamethasone (SVd) Versus Twice Weekly Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma: High-Risk Cytogenetic Risk Planned Subgroup Analyses from the Phase 3 Boston Study, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Sanchez L, Leleu X, Beaumont J, Yu H, Hudgens S, Auner HW, Quach H, Delimpasi S, Spicka I, Pour L, Dimopoulos MA, Pylypenko H, Doronin VA, Usenko G, Hajek R, Benjamin R, Venner CP, Garg M, Stevens DA, Jagannath S, Moreau P, Levy M, Bahlis NJ, Facon T, Chai Y, Ma X, Tang S, Leong H, Shah JJ, Shacham S, Kauffman MG, Richardson PG, Grosicki Set al., 2020, Peripheral Neuropathy Symptoms, Pain and Functioning in Relapsed or Refractory Multiple Myeloma Patients Treated with Selinexor, Bortezomib, and Dexamethasone, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Mateos M, Jagannath S, Delimpasi S, Simonova M, Spicka I, Pour L, Kryachok I, Gavriatopoulou M, Dimopoulos MA, Pylypenko H, Auner HW, Leleu X, Doronin VA, Usenko G, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens DA, Quach H, Moreau P, Levy MY, Badros AZ, Anderson LD, Bahlis NJ, Facon T, Cavo M, Chai Y, Arazy M, Shah J, Shacham S, Kauffman MG, Richardson PG, Grosicki Set al., 2020, Impact of Prior Therapies on the Safety and Efficacy of Once Weekly Selinexor, Bortezomib, and Dexamethasone Compared with Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Results from the Boston Study, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Hinsley S, Walker K, Sherratt D, Bailey L, Reed S, Flanagan L, McKee S, Brudenell Straw F, Dawkins B, Meads D, Auner HW, Kaiser MF, Cook M, Brown S, Cook G, Myeloma UK Clinical Trials Networket al., 2020, The MUK eight protocol: A randomised phase II trial of Cyclophosphamide and Dexamethasone in combination with Ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and a proteasome inhibitor, Trials, Vol: 21, ISSN: 1745-6215

BackgroundMultiple myeloma is a plasma cell tumour with approximately 5500 new cases in the UK each year. Ixazomib is a next generation inhibitor of the 20S proteasome and is thought to be an effective treatment for those who have relapsed from bortezomib. The combination of cyclophosphamide and dexamethasone (CD) is a recognised treatment option for patients with relapsed refractory multiple myeloma (RRMM) who have relapsed after treatment with bortezomib and lenalidomide, whilst also often being combined with newer proteasome inhibitors. The most apparent combination for ixazomib is therefore with CD.MethodsMUK eight is a randomised, controlled, open, parallel group, multi-centre phase II trial that will recruit patients with RRMM who have relapsed after treatment with thalidomide, lenalidomide, and a proteasome inhibitor. The primary objective of the trial is to evaluate whether ixazomib in combination with cyclophosphamide and dexamethasone (ICD) has improved clinical activity compared to CD in terms of progression-free survival (PFS). Secondary objectives include comparing toxicity profiles and the activity and cost-effectiveness of both treatments. Since opening, the trial has been amended to allow all participants who experience disease progression (as per the IMWG criteria) on the CD arm to subsequently switch to receive ICD treatment, once progression has been confirmed with two clinical members of the Trial Management Group (TMG). This ‘switch’ phase of the study is exploratory and will assess second progression-free survival measured from randomisation to second disease progression (PFS2) and progression-free survival from the point of switching to second disease progression (PFS Switch) in participants who switch from CD to ICD treatment.DiscussionDevelopment of ixazomib offers the opportunity to further investigate the value of proteasome inhibition through oral administration in the treatment of RRMM. Previous studies investigating the safe

Journal article

Dimopoulos MA, Delimpasi S, Simonova M, Spicka I, Pour L, Kryachok I, Gavriatopoulou M, Pylypenko H, Auner HW, Leleu X, Doronin V, Kaplan P, Hajek R, Reuben B, Dolai TK, Sinha DK, Arazy M, Richardson PG, Bahlis NJ, Grosicki Set al., 2020, Weekly selinexor, bortezomib, and dexamethasone (SVd) versus twice weekly bortezomib and dexamethasone (Vd) in patients with multiple myeloma (MM) after one to three prior therapies: Initial results of the phase III BOSTON study., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X

Conference paper

Saavedra-Garcia P, Martini F, Auner HW, 2020, Proteasome inhibition in multiple myeloma: lessons for other cancers, AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, Vol: 318, Pages: C451-C462, ISSN: 0363-6143

Journal article

Morris C, Chabannon C, Masszi T, Russell N, Nahi H, Kobbe G, Krejci M, Auner H, Pohlreich D, Hayden P, Basak GW, Lenhoff S, Schaap N, van Biezen A, Knol C, Iacobelli S, Liu Q, Celanovic M, Garderet L, Kröger Net al., 2020, Results from a multi-center, non-interventional registry study for multiple myeloma patients who received stem cell mobilization regimens with and without plerixafor, Bone Marrow Transplantation, Vol: 55, Pages: 356-366, ISSN: 1476-5365

Plerixafor plus granulocyte-colony stimulating factor (G-CSF) enhances the mobilization of haematopoietic stem cells (HSCs) for collection and subsequent autologous haematopoietic stem cell transplantation (HSCT) in patients with multiple myeloma (MM).This international, multicenter, non-interventional registry study (NCT01362972), evaluated long-term outcomes for MM patients who received plerixafor versus other mobilization regimens. The comparisons were: G-CSF+plerixafor (G-CSF+P) versus G-CSF-; G-CSF+P versus G-CSF+chemotherapy (G-CSF+C); and G-CSF+P+C versus G-CSF+C. Propensity score matching was used to balance groups. Primary outcome measures were progression free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR) after transplantation. After propensity matching, 77 versus 41 patients in the G-CSF+P versus G-CSF cohorts, 129 versus 129 in the G-CSF+P versus G-CSF+C cohort and 117 versus 117 in the G-CSF+P+C versus G-CSF+C cohort, were matched, respectively. Propensity score matching resulted in a smaller sample size and imbalances were not completely overcome. For both PFS and OS, the upper limits of the hazard ratio 95% confidence intervals exceeded pre-specified boundaries; non-inferiority was not demonstrated. CIR rates were higher in the plerixafor cohorts. G-CSF+P remains an option for the mobilization of HSCs in poor-mobilizers with MM with no substantial differences in PFS, OS and CIR in comparison with other regimens.

Journal article

Graziani G, Herget G, Ihorst G, Zeissig M, Chaidos A, Auner H, Duyster J, Waesch R, Engelhardt Met al., 2020, Time from first symptom onset to the final diagnosis of Multiple Myeloma (MM) - possible risks and future solutions: retrospective and prospective ‘Deutsche Studiengruppe MM’ (DSMM) and ‘European Myeloma Network’ (EMN) analysis, Leukemia and Lymphoma, Vol: 61, Pages: 875-886, ISSN: 1026-8022

Multiple Myeloma (MM) often presents with unspecific symptoms and is challenging to diagnose. We performed this DSMM/EMN-analysis via test-(retro-) and validation (prospective) study to determine the time interval from the onset of first symptoms to the diagnosis of MM. The retrospective and prospective analyses were performed in 101 and 176 patients, respectively. The median time from first symptoms to the MM diagnosis in both cohorts was 4 and 6 months, respectively. Frequencies of MM-related pathologic bone fractures, renal and infectious complications at diagnosis occurred in 41%, 35% and 16% of patients, respectively. Our MM-questionnaire determined that 39% of patients were dissatisfied with the diagnostic process. PFS and OS proved insignificantly different with shorter (≤6) and longer (>6 months) latency periods. In conclusion, our in depth studies demonstrate that delays in diagnosis do not decrease PFS or OS, but induce MM-related complications and influence patients' satisfaction with their medical care.

Journal article

Ponnusamy K, Tzioni M-M, Begum M, Robinson ME, Caputo VS, Katsarou A, Trasanidis N, Xiao X, Kostopoulos IV, Iskander D, Roberts I, Trivedi P, Auner HW, Naresh K, Chaidos A, Karadimitris Aet al., 2019, Novel ZBP1-IRF3 Dependency in Multiple Myeloma Mediated By IRF3-Driven Regulation of Cell Cycle Genes, BLOOD, Vol: 134, ISSN: 0006-4971

Journal article

Saavedra-Garcia P, Al-Sadah HA, Penfold L, Xiong X, Lopez-Jimenez E, Parzych K, Caputo VS, Blighe K, Kaiser MF, Piazza P, Encheva V, Snijders AP, Keun HC, Oyarzun D, Thiel D, Liu Z, Barahona M, Auner HWet al., 2019, Integrated Systems Level Examination of Proteasome Inhibitor Stress Recovery in Myeloma Cells Reveals Druggable Vulnerabilities Linked to Multiple Metabolic Processes, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Trasanidis N, Alvarez-Benayas J, Katsarou A, Chaidos A, May PC, Ponnusamy K, Xiao X, Bua M, Atta M, Roberts I, Auner HW, Hatjiharissi E, Papaioannou M, Caputo VS, Sudbery I, Karadimitris Aet al., 2019, Distinct Chromatin Accessibility Changes, Aberrant Transcription Factor Networks Combined with Novel Oncogenic Enhancers Characterise Myeloma-Initiating Genetic Events, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Caputo VS, Trasanidis N, Xiao X, Robinson ME, Katsarou A, Ponnusamy K, Chaidos A, Auner HW, Roberts I, Karadimitris Aet al., 2019, Myc and Bet Proteins Orchestrate the Early Regulatory Genome Changes Required for Osteoclast Lineage Commitment, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

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