Publications
152 results found
Garderet L, Sbianchi G, van der Werf S, et al., 2018, Impact of induction regimen duration before autologous stem cell transplantation in myeloma, 44th Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: 650-651, ISSN: 0268-3369
Bringhen S, Milan A, Ferri C, et al., 2018, Cardiovascular adverse events in modern myeloma therapy - incidence and risks. A review from European Myeloma Network (EMN) and Italian Society of Arterial Hypertension (SIIA), Haematologica, Vol: 103, Pages: 1422-1432, ISSN: 0390-6078
Cardiovascular disease in myeloma patients may derive from factors unrelated to the disease (age, diabetes, dyslipidemia, obesity, prior cardiovascular diseases), related to the disease (cardiac AL-amyloidosis, hyperviscosity, high-output failure, arteriovenous shunting, anemia, renal dysfunction) and linked to antimyeloma treatment (anthracyclines, corticosteroids, alkylating agents, immunomodulatory drugs, proteasome inhibitors). An accurate knowledge of cardiovascular events, effective dose reductions, prevention and management of early and late cardiovascular side effects of chemotherapeutic agents are essential in current clinical practice. Myeloma experts are obliged to carefully balance drugs' efficacy and toxicity for each individual patient. This review summarizes current data and novel insights on cardiovascular adverse events of today's antimyeloma treatment, focusing on carfilzomib, which is the starting point to develop consensus recommendations on preventing and managing cardiovascular side effects in myeloma patients.
Auner HW, Yong KL, 2018, More convenient proteasome inhibition for improved outcomes, Lancet Oncology, Vol: 19, Pages: 856-858, ISSN: 1470-2045
Delimpasi S, Pour L, Auner HW, et al., 2018, A phase 3 randomized, controlled, open-label study of selinexor, bortezomib, and dexamethasone (SVd) versus bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM)., Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
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- Citations: 1
Larocca A, Dold SM, Zweegman S, et al., 2018, Patient-centered practice in elderly myeloma patients: an overview and consensus from the European Myeloma Network (EMN), Leukemia, Vol: 32, Pages: 1697-1712, ISSN: 1476-5551
Multiple myeloma is a disease typical of the elderly, and, because of the increase in life expectancy of the general population, its incidence is expected to grow in the future. Elderly patients represent a particular challenge due to their marked heterogeneity. Many new and highly effective drugs have been introduced in the last few years, and results from clinical trials are promising. Besides the availability of novel agents, a careful evaluation of elderly patients showed to be a key factor for the success of therapy. A geriatric assessment is a valid strategy to better stratify patients. In particular, different scores are available today to appropriately assess elderly patients and define their fitness/frailty status. The choice of treatment – transplantation, triplets, doublets, or reduced-dose therapies including novel agents – should depend on the patient’s fitness status (fit, intermediate-fit or frail). Second-generation novel agents have also been evaluated as salvage therapy in the elderly, and these new agents certainly represent a further step forward in the treatment armamentarium for elderly patients with multiple myeloma.
Gay F, Engelhardt M, Terpos E, et al., 2017, From transplant to novel cellular therapies in multiple myeloma: EMN guidelines and future perspectives., Haematologica, Vol: 103, Pages: 197-211, ISSN: 0390-6078
Survival of myeloma patients has greatly improved with the use of autologous stem cell transplantation and novel agents, such as proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. Compared to bortezomib- and lenalidomide-based regimens alone, the addition of high-dose melphalan followed by autologous transplantation significantly improves progression-free survival; although an overall survival benefit was not observed in all trials. Moreover, follow-up of recent trials is still too short to show any difference in survival. In the light of these findings, novel agent-based induction followed by autologous transplantation is considered the standard upfront treatment for eligible patients (level of evidence: 1A). Post-transplant consolidation and maintenance treatment can further improve patient outcome (1A). The availability of several novel agents has led to the development of multiple combination regimens as salvage treatment options. In this context, the role of salvage autologous transplantation and allotransplant have not been extensively evaluated. In case of prolonged remission after upfront autologous transplantation, another autologous transplantation at relapse can be considered (2B). Patients who experience early relapse and/or have high-risk features have a poor prognosis and may be considered as candidates for clinical trials that - in young and fit patients - may also include an allograft in combination with novel agents (2B). Ongoing studies are evaluating the role of novel cellular therapies, such as inclusion of antibody-based triplets and quadruplets and Chimeric Antigen Receptor-T cells: despite preliminary encouraging results, longer follow-up and larger patient numbers are needed before their clinical use can be widely recommended.
Caputo V, Goudevenou K, Trasanidis N, et al., 2017, Myeloma Cell Addiction to the Transcription Factor TCF11, 59th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Yong K, Hinsley S, Auner HW, et al., 2017, Carfilzomib, Cyclophosphamide and Dexamethasone (KCD) Versus Bortezomib, Cyclophosphamide and Dexamethasone (VCD) for Treatment of First Relapse or Primary Refractory Multiple Myeloma (MM): First Final Analysis of the Phase 2 Muk <i>Five</i> Study, 59th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
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- Citations: 6
Auner HW, Iacobelli S, Sbianchi G, et al., 2017, Melphalan 140mg/m2 or 200mg/m2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party, Haematologica, Vol: 103, Pages: 514-521, ISSN: 0390-6078
Melphalan at a dose of 200mg/m2 is standard conditioning prior to autologous haematopoietic stem cell transplantation for multiple myeloma, but a dose of 140mg/m2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine if melphalan 200 and melphalan 140 are equally effective and tolerable in clinically relevant patient subgroups we analysed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, haematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 (n=245) and melphalan 200 (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 versus melphalan 140: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favoured melphalan 140 for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 and melphalan 140 patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favour melphalan 200 or melphalan 140 for key transplant outcomes (NCT01362972).
Auner H, 2017, IMiDs, proteasome-inhibitors and antibodies as part of a transplant-package for multiple myeloma, 43rd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S119-S119, ISSN: 0268-3369
Khoder A, Palanicawandar R, Atta M, et al., 2017, The choice between stem cell mobilisation with GCSF alone or with GCSF plus chemotherapy may impact on the stem cell transplant service, 43rd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S146-S147, ISSN: 0268-3369
Auner H, Iacobelli S, Bianchi G, et al., 2017, The impact of melphalan dosage on outcomes of autologous haematopoietic cell transplantation for multiple myeloma: Results from the EBMT collaboration to collect autologous transplant outcomes in lymphoma and myeloma (CALM) study, 43rd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: SPRINGERNATURE, Pages: S473-S474, ISSN: 0268-3369
Pavlu J, Auner H, Szydlo RM, et al., 2017, Analysis of hematopoietic recovery after autologous transplantation as method of quality control for long-term progenitor cell cryopreservation., Bone Marrow Transplantation, Vol: 52, Pages: 1599-1601, ISSN: 1476-5365
Hematopoietic precursor cells (HPC) are able to restore hematopoiesis after high-dose chemotherapy and their cryopreservation is routinely employed prior to the autologous hematopoietic cell transplantation (AHCT). Although previous studies showed feasibility of long-term HPC storage, concerns remain about possible negative effects on their potency. To study the effects of long-term cryopreservation, we compared time to neutrophil and platelet recovery in 50 patients receiving two AHCT for multiple myeloma at least 2 years apart between 2006 and 2016, using HPC obtained from one mobilization and collection attempt before the first transplant. This product was divided into equivalent fractions allowing a minimum of 2 × 106 CD34+ cells/kg recipient’s weight. One fraction was used for the first transplant after median storage of 60 days (range, 17–165) and another fraction was used after median storage of 1448 days (range, 849–3510) at the second AHCT. Neutrophil recovery occurred at 14 days (median; range, 11–21) after the first and 13 days (10–20) after the second AHCT. Platelets recovered at a median of 16 days after both procedures. Considering other factors, such as disease status, conditioning and HPC dose, this single institution data demonstrated no reduction in the potency of HPC after long-term storage.
Alasiri G, Fan LY, Zona S, et al., 2017, ER stress and cancer: the FOXO forkhead transcription factor link, Molecular and Cellular Endocrinology, Vol: 462, Pages: 67-81, ISSN: 1872-8057
The endoplasmic reticulum (ER) is a cellular organelle with central roles in maintaining proteostasis due to its involvement in protein synthesis, folding, quality control, distribution and degradation. The accumulation of misfolded proteins in the ER lumen causes ‘ER stress’ and threatens overall cellular proteostasis. To restore ER homeostasis, cells evoke an evolutionarily conserved adaptive signalling and gene expression network collectively called the ‘unfolded protein response (UPR)’, a complex biological process which aims to restore proteostasis. When ER stress is overwhelming and beyond rectification, the normally pro-survival UPR can shift to induce cell termination. Emerging evidence from mammalian, fly and nematode worm systems reveals that the FOXO Forkhead proteins integrate upstream ER stress and UPR signals with the transcriptional machinery to decrease translation, promote cell survival/termination and increase the levels of ER-resident chaperones and of ER-associated degradation (ERAD) components to restore ER homeostasis. The high rates of protein synthesis/translation associated with cancer cell proliferation and metabolism, as well as mutations resulting in aberrant proteins, also induce ER stress and the UPR. While the pro-survival side of the UPR underlies its ability to sustain and promote cancers, its apoptotic functions can be exploited for cancer therapies by offering the chance to ‘flick the proteostatic switch’. To this end, further studies are required to fully reevaluate the roles and regulation of these UPR signalling molecules, including FOXO proteins and their targets, in cancer initiation and progression as well as the effects on inhibiting their functions in cancer cells. This information will help to establish these UPR signalling molecules as possible therapeutic targets and putative biomarkers in cancers.
Khoder A, Sever M, Palanicawandar R, et al., 2017, PLERIXAFOR EFFECTIVELY RESCUES BIOSIMILAR G-CSFALONE-BASED STEM CELL MOBILISATION FAILURES, Publisher: ELSEVIER SCI LTD, Pages: S55-S55, ISSN: 1465-3249
Patel A, Szydlo RM, Auner HW, et al., 2016, C-reactive protein prior to myeloablative allogeneic haematopoietic cell transplantation identifies patients at risk of early- and long-term mortality, British Journal of Haematology, Vol: 180, Pages: 889-892, ISSN: 1365-2141
Auner H, 2016, Treatment options for relapse after autograft in multiple myeloma – report from an EBMT educational meeting, Leukemia and Lymphoma, ISSN: 1026-8022
Eccersley L, Szydlo R, Muffett E, et al., 2016, The effect of body mass index and melphalan dose adjustments on outcomes in patients undergoing autologous haematopoietic cell transplantation for multiple myeloma: a single-centre retrospective study, 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation, Publisher: Nature Publishing Group, Pages: S19-S19, ISSN: 1476-5365
Khoder A, Sever M, Allwood Z, et al., 2016, The use of filgrastim alone compared with filgrastim plus etoposide, with or without plerixafor, for stem cell mobilization - a single centre experience, 42nd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation, Publisher: NATURE PUBLISHING GROUP, Pages: S130-S131, ISSN: 0268-3369
Patel A, Szydlo R, Auner H, et al., 2016, C-reactive protein (CRP) prior to myeloablative allogeneic haematopoietic stem cell transplantation is associated with early and long term survival to five years, 42nd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation, Publisher: NATURE PUBLISHING GROUP, Pages: S213-S214, ISSN: 0268-3369
Bruno B, Auner HW, Gahrton G, et al., 2016, Stem cell transplantation in multiple myeloma and other plasma cell disorders (report from an EBMT preceptorship meeting), Leukemia & Lymphoma, Vol: 57, Pages: 1256-1268, ISSN: 1042-8194
The European Society for Blood and Marrow Transplantation Chronic Malignancies Working Party held a preceptorship meeting in Turin, Italy on 25–26 September 2014, to discuss the role of stem cell transplantation (SCT) in the treatment of multiple myeloma and other plasma cell disorders. Scientists and clinicians working in the field gathered to discuss a variety of topics including the results of recent clinical trials, basic research, the concept of minimal residual disease, and immune modulation. As individual presentations revealed, important advances have occurred in our understanding of the pathophysiology of myeloma and the role that SCT, along with other forms of immunotherapy, plays in treating it. Each presentation stimulated discussion and exchange of ideas among the attendants. We decided to summarize and, importantly, to update the meeting proceedings in this review to share stimulating discussions and ideas on potentially novel treatment strategies among clinicians.
Auner H, Parzych K, Chinn TM, et al., 2015, Inadequate fine-tuning of protein synthesis and failure of amino acid homeostasis following inhibition of the ATPase VCP/p97, Cell Death & Disease, Vol: 6, ISSN: 2041-4889
The cellular mechanisms that control protein degradation may constitute a non-oncogenic cancer cell vulnerability and, therefore, a therapeutic target. Although this proposition is supported by the clinical success of proteasome inhibitors in some malignancies, most cancers are resistant to proteasome inhibition. The ATPase valosin-containing protein (VCP; p97) is an essential regulator of protein degradation in multiple pathways and has emerged as a target for cancer therapy. We found that pharmacological depletion of VCP enzymatic activity with mechanistically different inhibitors robustly induced proteotoxic stress in solid cancer and multiple myeloma cells, including cells that were insensitive, adapted, or clinically resistant to proteasome inhibition. VCP inhibition had an impact on two key regulators of protein synthesis, eukaryotic initiation factor 2α (eIF2α) and mechanistic target of rapamycin complex 1 (mTORC1), and attenuated global protein synthesis. However, a block on protein translation that was itself cytotoxic alleviated stress signaling and reduced cell death triggered by VCP inhibition. Some of the proteotoxic effects of VCP depletion depended on the eIF2α phosphatase, protein phosphatase 1 regulatory subunit 15A (PPP1R15A)/PP1c, but not on mTORC1, although there appeared to be cross-talk between them. Thus, cancer cell death following VCP inhibition was linked to inadequate fine-tuning of protein synthesis and activity of PPP1R15A/PP1c. VCP inhibitors also perturbed intracellular amino acid levels, activated eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4), and enhanced cellular dependence on amino acid supplies, consistent with a failure of amino acid homeostasis. Many of the observed effects of VCP inhibition differed from the effects triggered by proteasome inhibition or by protein misfolding. Thus, depletion of VCP enzymatic activity triggers cancer cell death in part through inadequate regulation of pro
Tornatore L, Acton G, Adams N, et al., 2015, Cancer-selective targeting of the NF-kappa B survival pathway in multiple myeloma with the GADD45 beta/MKK7 inhibitor, DTP3, 57th Annual Meeting of the American-Society-of-Hematology, Publisher: American Society of Hematology, Pages: 1-3, ISSN: 0006-4971
Auner HW, Garderet L, Kroeger N, 2015, Autologous haematopoietic cell transplantation in elderly patients with multiple myeloma, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 171, Pages: 453-462, ISSN: 0007-1048
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- Citations: 20
Parzych K, Loaiza S, Chinn TM, et al., 2015, Comprehensive failure of intracellular protein homeostasis kills myeloma and solid cancer cells following VCP/p97 inhibition, 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Johnston AC, Naresh K, Barwick T, et al., 2015, Cutaneous presentation of an aggressive plasmablastic neoplasm indiscriminate between lymphoma and myeloma, ANNALS OF HEMATOLOGY, Vol: 94, Pages: 691-692, ISSN: 0939-5555
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- Citations: 3
Auner HW, Szydlo R, Hoek J, et al., 2015, Trends in autologous hematopoietic cell transplantation for multiple myeloma in Europe: increased use and improved outcomes in elderly patients in recent years, Bone Marrow Transplantation, Vol: 50, Pages: 209-215, ISSN: 0268-3369
Autologous hematopoietic cell transplantation (AHCT) is a standard of care in multiple myeloma (MM) patients aged <65 years. To understand age-related trends in utilisation and outcome of AHCT, we analysed 53 675 MM patients who underwent a first AHCT in 31 European countries between 1991 and 2010. The number of patients undergoing AHCT increased for all age groups (<40, 40–49, 50–59, 60–64, 65–69 and ⩾70 years) throughout the observation period. The highest increase was observed for patients aged ⩾65 years, who accounted for 3% of AHCTs in 1991–1995 and for 18.8% of AHCTs in 2006–2010. Risk factors associated with survival over the entire observation period (P<0.001) were calendar period, remission status at AHCT, gender, disease duration before AHCT and age. Survival improved considerably more in older than in younger patients in recent years. In 2006–2010, median 2- and 5-year post-transplant survival ranged from 85.9 and 61.5% in patients <40 years to 80.2 and 49.7% in those ⩾70 years. All-cause day-100 mortality decreased throughout the observation period to ⩽2.4% for all age groups in 2006–2010. The results of this study demonstrate increased utilisation and safety of AHCT with improved post-transplant survival particularly in elderly MM patients in recent years in Europe.
Auner HW, Cenci S, 2015, Recent advances and future directions in targeting the secretory apparatus in multiple myeloma, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 168, Pages: 14-25, ISSN: 0007-1048
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- Citations: 31
Pitcher DS, de Mattos-Shipley K, Tzortzis K, et al., 2015, Bortezomib Amplifies Effect on Intracellular Proteasomes by Changing Proteasome Structure, EBioMedicine, Vol: 2, Pages: 642-648
The proteasome inhibitor Bortezomib is used to treat multiple myeloma (MM). Bortezomib inhibits protein degradation by inactivating proteasomes’ active-sites. MM cells are exquisitely sensitive to Bortezomib - exhibiting a low-nanomolar IC50 - suggesting that minimal inhibition of degradation suffices to kill MM cells. Instead, we report, a low Bortezomib concentration, contrary to expectation, achieves severe inhibition of proteasome activity in MM cells: the degree of inhibition exceeds what one would expect from the small proportion of active-sites that Bortezomib inhibits. Our data indicate that Bortezomib achieves this severe inhibition by triggering secondary changes in proteasome structure that further inhibit proteasome activity. Comparing MM cells to other, Bortezomib-resistant, cancer cells shows that the degree of proteasome inhibition is the greatest in MM cells and only there leads to proteasome stress, providing an explanation for why Bortezomib is effective against MM but not other cancers.
Auner HW, Szydlo R, Hoek J, et al., 2014, AGE-RELATED TRENDS IN AUTOLOGOUS HAEMATOPOIETIC CELL TRANSPLANTATION FOR MULTIPLE MYELOMA IN EUROPE 1991-2010-A STUDY BY THE EBMT CHRONIC MALIGNANCIES WORKING PARTY, 19th Congress of the European-Hematology-Association, Publisher: FERRATA STORTI FOUNDATION, Pages: 519-520, ISSN: 0390-6078
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