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1
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Kul AN, Ipek Y. Investigation of the frequency of bortezomib neuropathy in patients with multiple myeloma diagnosis with normal and abnormal genetic characteristics. J Oncol Pharm Pract 2023; 29:1652-1660. [PMID: 36237141 DOI: 10.1177/10781552221132554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Bortezomib-induced peripheral neuropathy in patients with multiple myeloma is an undesirable and sometimes severe side effect. Our study aimed to examine whether there was a difference in bortezomib-induced peripheral neuropathy between multiple myeloma patients with normal and abnormal genetic characteristics. METHODS This retrospective analysis is based on the assessment of bortezomib-induced peripheral neuropathy frequency in newly-diagnosed multiple myeloma patients with normal (n = 68) and abnormal (n = 45) genetic profiles. A total of 113 patients diagnosed with multiple myeloma according to the International Myeloma Working Group criteria, between 2016 and 2021, were included in this study. RESULTS Neuropathy was detected in 42 (37.1%) patients. The most common genetic anomalies were 13q del (in 28.9%), t(4.14) (in 22.2%), and trisomy 7 (in 20.0%). When patients with and without bortezomib-induced peripheral neuropathy were compared, the only significant differences were observed for age (p = 0.032) and genetic grouping (p = 0.001); whereas other characteristics that could be associated with bortezomib-induced peripheral neuropathy were similarly distributed in both groups. Bortezomib-induced peripheral neuropathy was significantly more frequent in multiple myeloma patients with normal genetic characteristics (p = 0.001). CONCLUSION As a result of our study, it was observed that the frequency of bortezomib neuropathy was significantly higher in patients with normal genetic features compared to those with abnormal genetic features. This result suggested that factors other than genetic factors should be investigated to clarify the etiology of bortezomib-associated neuropathy in patients with multiple myeloma.
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Affiliation(s)
- Ayse N Kul
- Department of Hematology, Istanbul Kartal Dr Lutfi Kurdar City Hospital, Istanbul, Turkey
| | - Yildiz Ipek
- Department of Hematology, Istanbul Kartal Dr Lutfi Kurdar City Hospital, Istanbul, Turkey
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2
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McCaughan GJ, Gandolfi S, Moore JJ, Richardson PG. Lenalidomide, bortezomib and dexamethasone induction therapy for the treatment of newly diagnosed multiple myeloma: a practical review. Br J Haematol 2022; 199:190-204. [PMID: 35796524 PMCID: PMC9796722 DOI: 10.1111/bjh.18295] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/10/2022] [Accepted: 05/20/2022] [Indexed: 01/07/2023]
Abstract
For patients with newly diagnosed multiple myeloma, survival outcomes continue to improve significantly: however, nearly all patients will relapse following induction treatment. Optimisation of induction therapy is essential to provide longer term disease control and the current standard of care for most patients incorporates an immunomodulatory agent and proteasome inhibitor, most commonly lenalidomide and bortezomib in combination with dexamethasone (RVD), with maintenance until progression. Historically there has been limited access to RVD as an induction strategy outside of the United States; fortunately, there is now increasing access worldwide. This review discusses the rationale for use of RVD as induction therapy and aims to provide guidance in prescribing this regimen in order to optimise efficacy while minimising the toxicities of treatment. We also highlight the increasing evidence for the utility of addition of a monoclonal antibody to the RVD backbone to deepen responses and potentially provide longer disease control.
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Affiliation(s)
- Georgia J. McCaughan
- Department of HaematologySt Vincent's HospitalSydneyAustralia
- University of New South Wales, Medicine and HealthSydneyAustralia
| | - Sara Gandolfi
- Translational Research ProgramUniversity of HelsinkiHelsinkiFinland
- Haematology Research UnitUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - John J. Moore
- Department of HaematologySt Vincent's HospitalSydneyAustralia
- University of New South Wales, Medicine and HealthSydneyAustralia
| | - Paul G. Richardson
- Dana‐Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, Department of Medical OncologyBostonMassachusettsUSA
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3
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Benvenuto M, Ciuffa S, Focaccetti C, Sbardella D, Fazi S, Scimeca M, Tundo GR, Barillari G, Segni M, Bonanno E, Manzari V, Modesti A, Masuelli L, Coletta M, Bei R. Proteasome inhibition by bortezomib parallels a reduction in head and neck cancer cells growth, and an increase in tumor-infiltrating immune cells. Sci Rep 2021; 11:19051. [PMID: 34561494 PMCID: PMC8463577 DOI: 10.1038/s41598-021-98450-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/30/2021] [Indexed: 01/18/2023] Open
Abstract
Head and neck cancer (HNC) has frequently an aggressive course for the development of resistance to standard chemotherapy. Thus, the use of innovative therapeutic drugs is being assessed. Bortezomib is a proteasome inhibitor with anticancer effects. In vitro antitumoral activity of Bortezomib was investigated employing human tongue (SCC-15, CAL-27), pharynx (FaDu), salivary gland (A-253) cancer cell lines and a murine cell line (SALTO-5) originated from a salivary gland adenocarcinoma arising in BALB-neuT male mice transgenic for the oncogene neu. Bortezomib inhibited cell proliferation, triggered apoptosis, modulated the expression and activation of pro-survival signaling transduction pathways proteins activated by ErbB receptors and inhibited proteasome activity in vitro. Intraperitoneal administration of Bortezomib delayed tumor growth of SALTO-5 cells transplanted in BALB-neuT mice, protracted mice survival and adjusted tumor microenvironment by increasing tumor-infiltrating immune cells (CD4+ and CD8+ T cells, B lymphocytes, macrophages, and Natural Killer cells) and by decreasing vessels density. In addition, Bortezomib modified the expression of proteasome structural subunits in transplanted SALTO-5 cells. Our findings further support the use of Bortezomib for the treatment of HNC and reveal its ineffectiveness in counteracting the activation of deregulated specific signaling pathways in HNC cell lines when resistance to proteasome inhibition is developed.
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Affiliation(s)
- Monica Benvenuto
- Saint Camillus International, University of Health and Medical Sciences, Via di Sant'Alessandro 8, 00131, Rome, Italy.,Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy
| | - Sara Ciuffa
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy
| | - Chiara Focaccetti
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.,Department of Human Science and Promotion of the Quality of Life, San Raffaele University Rome, Via di Val Cannuta 247, 00166, Rome, Italy
| | | | - Sara Fazi
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161, Rome, Italy
| | - Manuel Scimeca
- Saint Camillus International, University of Health and Medical Sciences, Via di Sant'Alessandro 8, 00131, Rome, Italy.,Department of Human Science and Promotion of the Quality of Life, San Raffaele University Rome, Via di Val Cannuta 247, 00166, Rome, Italy.,Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy
| | | | - Giovanni Barillari
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy
| | - Maria Segni
- Department of Maternal Infantile and Urological Sciences, University of Rome "Sapienza", Viale Regina Elena 324, 00161, Rome, Italy.,Pediatric Endocrinology Unit, Policlinico Umberto I, Viale Regina Elena 364, 00161, Rome, Italy
| | - Elena Bonanno
- Saint Camillus International, University of Health and Medical Sciences, Via di Sant'Alessandro 8, 00131, Rome, Italy.,Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.,"Diagnostica Medica" & "Villa Dei Platani", Neuromed Group, 83100, Avellino, Italy
| | - Vittorio Manzari
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy
| | - Andrea Modesti
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy
| | - Laura Masuelli
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161, Rome, Italy
| | - Massimo Coletta
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.,IRCCS-Fondazione Bietti, Rome, Italy
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.
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4
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Sorrentino VG, Thota S, Gonzalez EA, Rameshwar P, Chang VT, Etchegaray JP. Hypomethylating Chemotherapeutic Agents as Therapy for Myelodysplastic Syndromes and Prevention of Acute Myeloid Leukemia. Pharmaceuticals (Basel) 2021; 14:641. [PMID: 34358067 PMCID: PMC8308509 DOI: 10.3390/ph14070641] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 12/11/2022] Open
Abstract
Myelodysplastic Syndromes (MDSs) affect the elderly and can progress to Acute Myeloid Leukemia (AML). Epigenetic alterations including DNA methylation and chromatin modification may contribute to the initiation and progression of these malignancies. DNA hypomethylating agents such as decitabine and azacitidine are used as therapeutic treatments and have shown to promote expression of genes involved in tumor suppression, apoptosis, and immune response. Another anti-cancer drug, the proteasome inhibitor bortezomib, is used as a chemotherapeutic treatment for multiple myeloma (MM). Phase III clinical trials of decitabine and azacitidine used alone and in combination with other chemotherapeutics demonstrated their capacity to treat hematological malignancies and prolong the survival of MDS and AML patients. Although phase III clinical trials examining bortezomib's role in MDS and AML patients are limited, its underlying mechanisms in MM highlight its potential as a chemotherapeutic for such malignancies. Further research is needed to better understand how the epigenetic mechanisms mediated by these chemotherapeutic agents and their targeted gene networks are associated with the development and progression of MDS into AML. This review discusses the mechanisms by which decitabine, azacitidine, and bortezomib alter epigenetic programs and their results from phase III clinical trials.
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Affiliation(s)
- Vincent G. Sorrentino
- Department of Biological Sciences, Rutgers University—Newark, Newark, NJ 07102, USA; (V.G.S.); (S.T.); (E.A.G.)
| | - Srijan Thota
- Department of Biological Sciences, Rutgers University—Newark, Newark, NJ 07102, USA; (V.G.S.); (S.T.); (E.A.G.)
| | - Edward A. Gonzalez
- Department of Biological Sciences, Rutgers University—Newark, Newark, NJ 07102, USA; (V.G.S.); (S.T.); (E.A.G.)
| | - Pranela Rameshwar
- Department of Medicine, Division of Hematology/Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA;
| | - Victor T. Chang
- Department of Medicine, Division of Hematology/Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA;
- Veteran Affairs New Jersey Health Care System, East Orange, NJ 07018, USA;
| | - Jean-Pierre Etchegaray
- Department of Biological Sciences, Rutgers University—Newark, Newark, NJ 07102, USA; (V.G.S.); (S.T.); (E.A.G.)
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5
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Lemoine J, Bonnin A, Marjanovic Z, van de Wyngaert Z, Ikhlef S, Alsuliman T, M'Hammedi-Bouzina F, Mohty M, Malard F. Resolution of bortezomib-associated chalazia/blepharitis after switch to ixazomib: A case report. Curr Res Transl Med 2021; 69:103283. [PMID: 33639586 DOI: 10.1016/j.retram.2021.103283] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 02/08/2021] [Indexed: 01/12/2023]
Affiliation(s)
- Jean Lemoine
- Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Sorbonne Université, INSERM UMRs 938, Paris, France
| | - Agnes Bonnin
- Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Sorbonne Université, INSERM UMRs 938, Paris, France
| | - Zora Marjanovic
- Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Sorbonne Université, INSERM UMRs 938, Paris, France
| | - Zoe van de Wyngaert
- Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Sorbonne Université, INSERM UMRs 938, Paris, France
| | - Souhila Ikhlef
- Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Sorbonne Université, INSERM UMRs 938, Paris, France
| | - Tamim Alsuliman
- Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Sorbonne Université, INSERM UMRs 938, Paris, France
| | - Fella M'Hammedi-Bouzina
- Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Sorbonne Université, INSERM UMRs 938, Paris, France
| | - Mohamad Mohty
- Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Sorbonne Université, INSERM UMRs 938, Paris, France
| | - Florent Malard
- Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Sorbonne Université, INSERM UMRs 938, Paris, France.
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6
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Vaxman I, Al Saleh AS, Kumar S, Nitin M, Dispenzieri A, Buadi F, Dingli D, Lacy M, Muchtar E, Hobbs M, Fonder A, Hwa L, Visram A, Kapoor P, Siddiqui M, Lust J, Kyle R, Rajkumar V, Hayman S, Leung N, Gonsalves W, Kourelis T, Warsame R, Gertz MA. Colon perforation in multiple myeloma patients - A complication of high-dose steroid treatment. Cancer Med 2020; 9:8895-8901. [PMID: 33022868 PMCID: PMC7724303 DOI: 10.1002/cam4.3507] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/19/2020] [Accepted: 09/14/2020] [Indexed: 12/13/2022] Open
Abstract
Gastrointestinal complications of multiple myeloma (MM) treatment are common and include nausea, constipation, and diarrhea. However, acute gastrointestinal events like perforations are rare. We aimed to describe the characteristics and outcomes of patients with MM that had colonic perforations during their treatment. This is a retrospective study that included patients from all three Mayo Clinic sites who had MM and developed a colonic perforation. All patients were diagnosed with colonic perforations based on CT scans and were surgically treated. Patients diagnosed with AL amyloidosis, a perforated colon complicating neutropenic colitis during ASCT and those with perforation due to colonic cancer were excluded. A high dose of dexamethasone was defined as ≥40 mg dexamethasone once a week. Thirty patients met inclusion criteria. All patients received steroids at doses ≥10 mg once weekly prior to the perforation, while four (11%) were on high-dose dexamethasone without chemotherapy. Fourteen patients were given high doses of dexamethasone. Twenty-five patients required ostomies with all surviving surgery. Twenty-four perforations (80%) were associated with diverticulitis. Treatment with steroids was resumed in 23 patients with no further gastrointestinal complications. The median OS was 20 months following perforation (IQR 8-59). Within the same timeframe 5854 patients were treated at Mayo Clinic for MM, making the risk of bowel perforation 0.5%. Intestinal perforations in MM are rare and, in our series, always occurred with dexamethasone ≥10 mg per week. Urgent surgery is lifesaving and resumption of anti-myeloma treatment appears to be safe.
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Affiliation(s)
- Iuliana Vaxman
- Division of Hematology, Mayo Clinic, Rochester, MN, USA.,Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah-Tikva, Israel.,Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel
| | - Abdullah S Al Saleh
- Division of Hematology, Mayo Clinic, Rochester, MN, USA.,King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Shaji Kumar
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Mishra Nitin
- Division of Colon and Rectal Surgery, Mayo Clinic, Scottsda, AZ, USA
| | | | - Francis Buadi
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - David Dingli
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Martha Lacy
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Eli Muchtar
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Miriam Hobbs
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Amie Fonder
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Lisa Hwa
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Alissa Visram
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | | | - John Lust
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Robert Kyle
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | | | - Nelson Leung
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | | | - Rahma Warsame
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Morie A Gertz
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
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7
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Yıkılmaz AŞ, Akinci S, Bakanay ŞM, Dilek İ. VAD Chemotherapy versus Bortezomib Containing Regimens as Remission Induction For ASCT in Multiple Myeloma: A Single Center Experience. Int J Hematol Oncol Stem Cell Res 2020; 14:248-256. [PMID: 33603986 PMCID: PMC7876426 DOI: 10.18502/ijhoscr.v14i4.4481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Background: Complete response (CR) and very good partial response (VGPR) are targeted with pre-ASCT induction regimens in patients by diagnosed multiple myeloma (MM), who are candidates for ASCT. In this study, it was aimed to compare the response and survival evaluations of cases who underwent induction treatment by vincristine-doxorubicin-dexamethasone (VAD) protocol versus bortezomib containing regimens. Materials and Methods: The data of 96 ASCT eligible patients, retrospectively analyzed. P value> 0.05 was considered statistically significant. Results: While 66 cases had received bortezomib containing regimens as induction regimen, 30 cases had received VAD protocol. The total survival was 91.3 (st.s 6) months and 43 (st.s 7.9) months, respectively, when we compared the cases without ASCT and with ASCT (p = 0.001). The OS of patients who underwent ASCT after reaching at least VGPR was longer than the underwent ASCT without reaching VGPR (p=0.019). Post-ASCT PFS (p=0.717) and OS (p = 0.126) analyzes were performed in 74 cases undergoing ASCT treatment, there was no significant statistical difference when patients with treated by VAD protochol and treated by bortezomib containing regimens as pre-ASCT induction regimens was compared to each other. Conclusion: Whatever the type of induction regimen is, the level of response achieved before ASCT is important. The survival of the myeloma patients are much more influenced with HDT-ASCT as well as post-transplantation strategies to keep the patients in remission. Even though it is outdated, we think that the VAD protocol may be an option in patients who are not responding with the new generation of agents in the following days.
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Affiliation(s)
| | - Sema Akinci
- Department of Hematology, Ataturk Training And Research Hospital, Ankara 06010, Turkey
| | - Şule Mine Bakanay
- Department of Hematology, Yıldırım Beyazıt University, Ankara 06010, Turkey
| | - İmdat Dilek
- Department of Hematology, Yıldırım Beyazıt University, Ankara 06010, Turkey
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8
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Tundo GR, Sbardella D, Santoro AM, Coletta A, Oddone F, Grasso G, Milardi D, Lacal PM, Marini S, Purrello R, Graziani G, Coletta M. The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges. Pharmacol Ther 2020; 213:107579. [PMID: 32442437 PMCID: PMC7236745 DOI: 10.1016/j.pharmthera.2020.107579] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 05/05/2020] [Indexed: 01/10/2023]
Abstract
Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.
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Affiliation(s)
- G R Tundo
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
| | | | - A M Santoro
- CNR, Institute of Crystallography, Catania, Italy
| | - A Coletta
- Department of Chemistry, University of Aarhus, Aarhus, Denmark
| | - F Oddone
- IRCCS-Fondazione Bietti, Rome, Italy
| | - G Grasso
- Department of Chemical Sciences, University of Catania, Catania, Italy
| | - D Milardi
- CNR, Institute of Crystallography, Catania, Italy
| | - P M Lacal
- Laboratory of Molecular Oncology, IDI-IRCCS, Rome, Italy
| | - S Marini
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - R Purrello
- Department of Chemical Sciences, University of Catania, Catania, Italy
| | - G Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - M Coletta
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
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9
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Figueiredo A, Atkins H, Mallick R, Kekre N, Kew A, McCurdy A. Cyclophosphamide-bortezomib-dexamethasone compared with bortezomib-dexamethasone in transplantation-eligible patients with newly diagnosed multiple myeloma. ACTA ACUST UNITED AC 2020; 27:e81-e85. [PMID: 32489256 DOI: 10.3747/co.27.5385] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Introduction Cyclophosphamide-bortezomib-dexamethasone (CyBorD) is considered a standard induction regimen for transplant-eligible patients with newly diagnosed multiple myeloma (mm). It has not been prospectively compared with bortezomib-dexamethasone (Bor-Dex). We aimed to compare the efficacy of CyBorD and Bor-Dex induction in transplant-eligible patients. Methods In a retrospective observational study at a single tertiary centre, all patients with transplant-eligible mm who received induction with CyBorD or Bor-Dex between March 2008 and April 2016 were enrolled. Progression-free survival (pfs), response, and stem-cell collection for a first autologous stem-cell transplantation (ahsct) were compared. Results Of 155 patients enrolled, 78 (50.3%) had received CyBorD, and 77 (49.7%), Bor-Dex. The patients in the Bor-Dex cohort were younger than those in the CyBorD cohort (median: 57 years vs. 62 years; p = 0.0002) and more likely to have had treatment held, reduced, or discontinued (26% vs. 14.5%, p = 0.11). The stem-cell mobilization regimen for both cohorts was predominantly cyclophosphamide and granulocyte colony-stimulating factor (gcsf). Plerixafor was used more often for the CyBorD cohort (p = 0.009), and more collection failures occurred in the CyBorD cohort (p = 0.08). In patients receiving Bor-Dex, more cells were collected (9.9×106 cells/kg vs. 7.7×106cells/kg, p = 0.007). At day +100, a very good partial response or better was achieved in 75% of the CyBorD cohort and in 73% of the Bor-Dex cohort (p = 0.77). Median pfs was 3.2 years in the Bor-Dex cohort and 3.7 years in the CyBorD cohort (p = 0.56). Conclusions Overall efficacy was similar in our patients receiving CyBorD and Bor-Dex. After ahsct, no difference in depth of response or pfs was observed. Cyclophosphamide-gcsf seems to increase collection failures and hospitalizations in patients receiving CyBorD. Prospective studies are required to examine that relationship.
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Affiliation(s)
- A Figueiredo
- Division of Hematology, The Ottawa Hospital, Ottawa, ON
| | - H Atkins
- Division of Hematology, The Ottawa Hospital, Ottawa, ON
| | - R Mallick
- School of Epidemiology, Public Health and Preventive Medicine, The Ottawa Hospital Research Institute, Ottawa, ON
| | - N Kekre
- Division of Hematology, The Ottawa Hospital, Ottawa, ON
| | - A Kew
- Division of Hematology, The Ottawa Hospital, Ottawa, ON
| | - A McCurdy
- Division of Hematology, The Ottawa Hospital, Ottawa, ON
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10
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Moore DC, Ringley JT, Nix D, Muslimani A. Impact of Body Mass Index on the Incidence of Bortezomib-induced Peripheral Neuropathy in Patients With Newly Diagnosed Multiple Myeloma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:168-173. [DOI: 10.1016/j.clml.2019.08.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 07/08/2019] [Accepted: 08/22/2019] [Indexed: 11/30/2022]
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11
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Peripheral neuropathy following bortezomib therapy in multiple myeloma patients: association with cumulative dose, heparanase, and TNF-α. Ann Hematol 2019; 98:2793-2803. [PMID: 31650289 DOI: 10.1007/s00277-019-03816-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 10/02/2019] [Indexed: 01/01/2023]
Abstract
Multiple myeloma (MM) is a plasma cell neoplasm which constitutes about 10% of all hematologic malignancies. Despite bortezomib is a promising new generation of drugs for MM, its clinical use is limited by peripheral neurotoxicity in the vast majority of patients, which can be severe and require a reduction of dose or even treatment withdrawal. Tumor necrosis factor-α (TNF-α), as the most important inflammatory factor, could induce the inflammatory response and expression of heparanase (HPSE), which may play a crucial role in peripheral neuropathy after chemotherapy. However, the role of TNF-α in bortezomib-induced peripheral neuropathy (BIPN) has not been reported. In this study, treatment-emergent neuropathy was assessed by total neuropathy score and electrophysiological examination. The expression level of TNF-α and HPSE were evaluated by enzyme-linked immunosorbent assay. The effects of anti-TNF-α on the evolution of neuropathy were tested in rat models of neurotoxicity. The results indicated that with the augment of cumulative dose of bortezomib, the incidence of neuropathy was increased. Moreover, bortezomib administration induced the expression of TNF-α. With the increased expression of TNF-α, neuropathy was exacerbated. TNF-α-induced expression of HSPE was secondary to the development of neuropathy. Co-administration of anti-TNF-α in bortezomib therapy has a potential neuroprotective effect on BIPN in rats. TNF-α participates in the pathogenesis of BIPN, which represents an attractive target for future therapeutic intervention.
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Yao R, Hu X, Zhou S, Zhang Q, Huang H, Sun N, Guo W, Yu K, Lin Y. Once-weekly bortezomib had similar effectiveness and lower thrombocytopenia occurrence compared with twice-weekly bortezomib regimen in treating patients with newly diagnosed multiple myeloma in China. Medicine (Baltimore) 2019; 98:e17147. [PMID: 31574817 PMCID: PMC6775427 DOI: 10.1097/md.0000000000017147] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The study aims to examine the treatment effect and adverse reactions of patients with newly diagnosed MM receiving different bortezomib-based regimens.This was a retrospective study of patients with newly diagnosed MM and who were treated with bortezomib-based combined chemotherapy at the Department of Hematology of the 2 affiliated hospitals of Wenzhou Medical University between July 2009 and May 2016. Cox proportion hazard multivariate analyses were carried out to assess the differences in treatment effect and adverse events between standard (1.3 mg/m on days 1, 4, 8, 11) and weekly (1.6 mg/m on days 1, 8, 15) cohorts, as well as the differences between intravenous injection and subcutaneous injection therapy. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier method and the log-rank test.Among the 117 patients, 78 patients were treated with bortezomib standard therapy and 39 patients were treated with bortezomib weekly therapy (all with intravenous injection). In all patients, the treatment strategy was not independently associated with PFS or OS. The patients in the weekly therapy group had less thrombocytopenia events than those in the standard therapy group. The subcutaneous route had similar treatment effect as the intravenous route, but the incidence of peripheral neuropathy was lower.The once-weekly bortezomib regimen was similar in effectiveness to standard therapy in treating patients with newly diagnosed MM, but the incidence of thrombocytopenia was lower with the weekly regimen compared with the standard regimen.
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Affiliation(s)
- Rongxin Yao
- Department of Hematology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
| | - Xudong Hu
- Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou
| | - Shuping Zhou
- Department of Hematology, Ningbo Yinzhou Second Hospital, Ningbo, Zhejiang, China
| | - Qianying Zhang
- Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou
| | - He Huang
- Department of Hematology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
| | - Ni Sun
- Department of Hematology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
| | - Wenjian Guo
- Department of Hematology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
| | - Kang Yu
- Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou
| | - Ying Lin
- Department of Hematology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
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13
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Sklar BA, Gervasio KA, Leng S, Ghosh A, Chari A, Wu AY. Management and outcomes of proteasome inhibitor associated chalazia and blepharitis: a case series. BMC Ophthalmol 2019; 19:110. [PMID: 31088416 PMCID: PMC6518763 DOI: 10.1186/s12886-019-1118-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 05/02/2019] [Indexed: 11/24/2022] Open
Abstract
Background The purpose of this case series was to further characterize proteasome inhibitor associated chalazia and blepharitis, to investigate outcomes of different management strategies, and to propose a treatment algorithm for eyelid complications in this patient population. Methods This retrospective case series included sixteen patients found to have chalazia and/or blepharitis while receiving proteasome inhibitors for plasma cell disorders at Mount Sinai Hospital in New York, NY from January 2010 through January 2017. Main outcomes were complete resolution of eyelid complications and time to resolution. Student’s t-test was used to compare average values and Fisher’s exact test was used to compare proportions. Results Fourteen patients had chalazia and 10 had blepharitis. Chalazia averaged 5.4 mm, and 11 patients with chalazia experienced two or more lesions. Median follow-up time was 17 months. Average time from bortezomib exposure to onset of first eyelid complication was 3.4 months. Chalazia episodes were more likely to completely resolve than blepharitis episodes (p = 0.03). Ocular therapy alone was trialed for an average of 1.8 months before proceeding to bortezomib omission. Average time to eyelid complication resolution using ocular therapy alone was 1.8 months versus 3.1 months after bortezomib omission. In this series, the combination of ocular therapy and bortezomib omission led to complete resolution of eyelid complications more often than ocular therapy alone. Conclusion Proteasome inhibitor associated eyelid complications were identified in sixteen patients with plasma cell disorders. Eyelid complications may be treated with a 2-month trial of conservative ocular therapies alone, followed by continuation of ocular therapy in combination with bortezomib omission if eyelid signs persist.
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Affiliation(s)
- Bonnie A Sklar
- Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place Box 1183, New York, NY, 10029, USA.
| | - Kalla A Gervasio
- Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place Box 1183, New York, NY, 10029, USA.,Wills Eye Hospital, 840 Walnut Street, Philadelphia, PA, 19107, USA
| | - Siyang Leng
- Department of Medicine, Hematology, and Oncology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY, 10029, USA.,Division of Hematology/Oncology, Columbia University Medical Center, 630 West 168th St., New York, NY, 10032, USA
| | - Arnab Ghosh
- Department of Medicine, Hematology, and Oncology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY, 10029, USA.,Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Ajai Chari
- Department of Medicine, Hematology, and Oncology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY, 10029, USA
| | - Albert Y Wu
- Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place Box 1183, New York, NY, 10029, USA.,Department of Ophthalmology, Byers Eye Institute, Stanford School of Medicine, 2452 Watson Court, Palo Alto, CA, 94303, USA
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Ao N, Dai Y, Chen Q, Feng Y, Yu J, Wang C, Liu F, Li M, Liu G. Genome-Wide Profiling of the Toxic Effect of Bortezomib on Human Esophageal Carcinoma Epithelial Cells. Technol Cancer Res Treat 2019; 18:1533033819842546. [PMID: 30961474 PMCID: PMC6457034 DOI: 10.1177/1533033819842546] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Objectives: Bortezomib has been widely used to treat multiple myeloma and other hematological
malignancies. However, not much is known about its effect on solid tumors. The aim of
this study was to study the effect of Bortezomib on human esophageal cancer cell lines
and investigate the potential target pathways. Methods: Two human esophageal cancer cell lines, TE-1 and KYSE-150, were used in this study.
Cell viability, cell cycle distribution, and apoptosis after Bortezomib treatment was
detected by Cell Counting Kit-8, flow cytometry, and Annexin V/propidium iodide
staining, respectively. The genes targeted by Bortezomib were analyzed at the messenger
RNA level by microarray chips and quantitative real-time polymerase chain reaction. Results: The proliferation of human esophageal cancer cell lines was inhibited by Bortezomib in
a dose- and time-dependent manner. Bortezomib treatment led to G2/M arrest
and apoptosis. Microarray chips revealed multiple signaling pathways targeted by
Bortezomib, including proteasome, endoplasmic reticulum, Wnt-, and calcium-mediated
pathway. The expression patterns of 4 representative genes UBD, CUL3, HDAC6, and GADD45A
were verified by quantitative real-time polymerase chain reaction and showed consistency
with the microarray assay. Conclusion: Bortezomib could suppress cell viability, cause G2/M arrest, and induce
apoptosis in human esophageal cancer cells, with possible targets including UBD, CUL3,
HDAC6, and GADD45A.
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Affiliation(s)
- Nannan Ao
- 1 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu Province, People's Republic of China.,2 Department of Radiation Oncology, Zhengzhou Yihe Hospital Affiliated to Henan University, Zhengzhou, Henan Province, People's Republic of China
| | - Yingchu Dai
- 1 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu Province, People's Republic of China
| | - Qianping Chen
- 1 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu Province, People's Republic of China
| | - Yang Feng
- 1 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu Province, People's Republic of China
| | - Jingping Yu
- 3 Department of Radiation Oncology, Changzhou Second Hospital-Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People's Republic of China
| | - Chang Wang
- 1 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu Province, People's Republic of China
| | - Fenju Liu
- 1 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu Province, People's Republic of China
| | - Ming Li
- 1 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu Province, People's Republic of China
| | - Geng Liu
- 1 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu Province, People's Republic of China
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Mandıroğlu S, Çevik C, Aylı M. Acupuncture for Neuropathic Pain Due to Bortezomib in a Patient with Multiple Myeloma. Acupunct Med 2018; 32:194-6. [DOI: 10.1136/acupmed-2013-010491] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Multiple myeloma (MM) is characterised by an increase in plasma cells, particularly in the bone marrow but also in other organs and systems, and with the abnormal production of immunoglobulin. Bortezomib, a current treatment option, inhibits angiogenesis by proteasome inhibition and is known to be effective in the treatment of MM. Peripheral neuropathy (PN) is a common dose-related side effect of bortezomib in patients with MM. We describe a case of PN due to bortezomib treatment which responded dramatically to acupuncture treatment, enabling his bortezomib treatment to continue. The patient was a 74-year-old man with pain, numbness, tingling and weakness in his hands and feet after 22 days of bortezomib treatment given by the haematology clinic. His neuropathic pain score was 8/10. There were no autonomic symptoms. Electroneurophysiological testing confirmed sensorimotor PN. Acupuncture treatment was planned as his neuropathic pain continued. Acupuncture was administered bilaterally to ST36, SP6 and LI4 15 times (every other day in the first five sessions and then twice a week). The numbness, tingling and pain symptoms substantially decreased after the first two treatments. After the 15th session acupuncture treatment was continued once a month. At the end of the sixth month the neuropathic pain assessment score was 0/10. There was no side effect of acupuncture treatment. Acupuncture seems promising as a complementary medical treatment for neuropathic pain from bortezomib-induced PN. Clinical studies involving more cases and electrophysiological studies are necessary to investigate the effectiveness of acupuncture.
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Affiliation(s)
- Sibel Mandıroğlu
- Department of Physical Medicine and Rehabilitation, Ankara Physical Medicine and Rehabilitation Training and Research Hospital, Ankara, Turkey
| | - Cemal Çevik
- Medicine Faculty, Department of Biochemistry, Gazi University, Ankara, Turkey
| | - Meltem Aylı
- Medicine Faculty, Department of Hematology, Ufuk University, Ankara, Turkey
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16
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Okazuka K, Ishida T. Proteasome inhibitors for multiple myeloma. Jpn J Clin Oncol 2018; 48:785-793. [PMID: 30102324 DOI: 10.1093/jjco/hyy108] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Accepted: 07/10/2018] [Indexed: 02/06/2023] Open
Abstract
Therapeutic strategies for multiple myeloma have dramatically changed in the last two decades, especially after the introduction of proteasome inhibitors. The first-in-class proteasome inhibitor, bortezomib, was approved by the US Food and Drug Administration in 2003. Since then, it has been a backbone therapy for not only relapsed or refractory myeloma patients but also newly diagnosed multiple myeloma patients. Second-generation proteasome inhibitors, such as carfilzomib and ixazomib, have been approved, and three proteasome inhibitors were incorporated into several regimens with other cytotoxic agents, such as alkylating agents, immunomodulatory drugs and monoclonal antibodies. Because each proteasome inhibitor shows different properties with respect to adverse events, understanding and managing each adverse event of proteasome inhibitors are necessary for the continuation of therapy with minimal interruption of treatment. This review summarizes the recent advances in proteasome inhibitors used in the treatment of multiple myeloma.
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Affiliation(s)
- Kiyoshi Okazuka
- Department of Hematology, Japanese Red Cross Medical Center, Shibuya, Tokyo, Japan
| | - Tadao Ishida
- Department of Hematology, Japanese Red Cross Medical Center, Shibuya, Tokyo, Japan
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17
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Guo X, He D, Zhang E, Chen J, Chen Q, Li Y, Yang L, Yang Y, Zhao Y, Wang G, He J, Cai Z. HMGB1 knockdown increases MM cell vulnerability by regulating autophagy and DNA damage repair. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:205. [PMID: 30157958 PMCID: PMC6114506 DOI: 10.1186/s13046-018-0883-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 08/16/2018] [Indexed: 02/06/2023]
Abstract
Background With the development of novel therapeutic agents, the survival of multiple myeloma (MM) patients has much improved. However, the disease is incurable due to drug resistance. Previous studies have found that high-mobility group box 1 (HMGB1) is involved in inflammation, angiogenesis, DNA damage repair, and cancer invasion, progression, metastasis and drug resistance and that high HMGB1 expression is associated with poor MM prognosis, yet the role and mechanism of HMGB1 in MM remains unclear. Methods Through gene expression and Oncomine database analyses, we found that HMGB1 is associated with a poor prognosis in MM patients. RNA interference together with gene array analysis, cell proliferation and apoptosis assays, autophagy detection assays, western blotting, and in vivo xenograft models were employed to evaluate the effect of HMGB1 and the mechanism involved in MM drug resistance. Results MM cell lines and primary MM samples were found to express high levels of HMGB1, which was negatively associated with the 3-year survival of MM patients. HMGB1 knockdown in MM cells enhanced the inhibitory effect of chemotherapy with dexamethasone (Dex) via apoptosis induction. Furthermore, downregulation of HMGB1 activated the mTOR pathway, inhibited autophagy and increased DNA damage induced by Dex by modulating expression of related genes. In vivo, xenograft models showed that after Dex treatment, the tumor burden of HMGB1-knockdown mice was decreased compared with that of control mice. Conclusions Our research shows that HMGB1 participates in autophagy and DNA damage repair and that downregulation of HMGB1 enhances the sensitivity of MM cells to Dex, suggesting that HMGB1 may serve as a target for MM treatment.
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Affiliation(s)
- Xing Guo
- Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Donghua He
- Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Enfan Zhang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Jing Chen
- Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Qingxiao Chen
- Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Yi Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Li Yang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Yang Yang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Yi Zhao
- Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Gang Wang
- Quzhou People's Hospital, Quzhou, 324000, Zhejiang, China
| | - Jingsong He
- Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Zhen Cai
- Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.
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18
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Ly KNI, Arrillaga-Romany IC. Neurologic Complications of Systemic Anticancer Therapy. Neurol Clin 2018; 36:627-651. [DOI: 10.1016/j.ncl.2018.04.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Abstract
Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.
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Affiliation(s)
- Arjan Mofers
- Department of Medical and Health Sciences, Linköping University, SE-581 83, Linköping, Sweden
| | - Paola Pellegrini
- Department of Medical and Health Sciences, Linköping University, SE-581 83, Linköping, Sweden
| | - Stig Linder
- Department of Medical and Health Sciences, Linköping University, SE-581 83, Linköping, Sweden. .,Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, SE-171 76, Stockholm, Sweden.
| | - Pádraig D'Arcy
- Department of Medical and Health Sciences, Linköping University, SE-581 83, Linköping, Sweden.
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20
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Oyekunle A, Shumilov E, Kostrewa P, Burchert A, Trümper L, Wuchter P, Wulf G, Bacher U, Kröger N. Chemotherapy-Based Stem Cell Mobilization Does Not Result in Significant Paraprotein Reduction in Myeloma Patients in the Era of Novel Induction Regimens. Biol Blood Marrow Transplant 2018; 24:276-281. [PMID: 29037891 DOI: 10.1016/j.bbmt.2017.10.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/03/2017] [Indexed: 11/17/2022]
Abstract
Novel induction agents markedly improved remission rates in multiple myeloma (MM), and the continued use of chemotherapy for CD34+ stem cell mobilization (SCM) has been questioned. We examined the additional effect of chemotherapy in SCM regarding remission status/morbidity. We reviewed 236 consecutive MM patients (aged 36 to 75 years) with first autologous stem cell transplantation from January 2009 to March 2016 after chemotherapy-based SCM. Responses were measured by changes in intact Ig and free light chain levels before and after chemomobilization (International Myeloma Working Group [IMWG] criteria). Most patients (225/236, 95.3%) received novel induction regimens, which were bortezomib-based (n = 223) and/or lenalidomide-based (n = 19). Most patients (170/190, 89.5%) achieved at least partial remission postinduction and pre-SCM. Stem cells were mobilized with granulocyte colony-stimulating factor and cyclophosphamide-based (212/227, 93.4%) or etoposide-based (15/227, 6.6%) regimens. There were insignificant changes in serum Ig and free light chain levels before and after chemomobilization either in the whole cohort or subgroups. Significant improvements of the IMWG remission status were documented in only 7 of 236 patients (3.0%). Sixty-seven patients (28.4%) developed chemotherapy-related complications (neutropenic fever, sepsis, and others), resulting in 9 hospitalizations (3.8%). Our study suggests that although causing significant morbidity, chemotherapy-based mobilization fails to improve remission status. The value of incorporating additional chemotherapy for SCM is thus not evident.
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Affiliation(s)
- Anthony Oyekunle
- Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany; Department of Internal Medicine, University of Botswana, Botswana
| | - Evgenii Shumilov
- Department of Hematology and Medical Oncology, Medical Center University of Göttingen, Germany
| | - Philippe Kostrewa
- Department of Hematology and Oncology, University Hospital Giessen and Marburg, Germany
| | - Andreas Burchert
- Department of Hematology and Oncology, University Hospital Giessen and Marburg, Germany
| | - Lorenz Trümper
- Department of Hematology and Medical Oncology, University Medicine Göttingen (UMG), Göttingen, Germany
| | - Patrick Wuchter
- Department of Internal Medicine V, University of Heidelberg, Germany; Institute of Transfusion Medicine, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany
| | - Gerald Wulf
- Department of Hematology and Medical Oncology, Medical Center University of Göttingen, Germany
| | - Ulrike Bacher
- Department of Hematology, Inselspital Bern, Bern, Switzerland
| | - Nicolaus Kröger
- Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany.
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Roeten MSF, Cloos J, Jansen G. Positioning of proteasome inhibitors in therapy of solid malignancies. Cancer Chemother Pharmacol 2018; 81:227-243. [PMID: 29184971 PMCID: PMC5778165 DOI: 10.1007/s00280-017-3489-0] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 11/19/2017] [Indexed: 12/13/2022]
Abstract
Targeting of the protein degradation pathway, in particular, the ubiquitin-proteasome system, has emerged as an attractive novel cancer chemotherapeutic modality. Although proteasome inhibitors have been most successfully applied in the treatment of hematological malignancies, they also received continuing interest for the treatment of solid tumors. In this review, we summarize the current positioning of proteasome inhibitors in the treatment of common solid malignancies (e.g., lung, colon, pancreas, breast, and head and neck cancer), addressing topics of their mechanism(s) of action, predictive factors and molecular mechanisms of resistance.
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Affiliation(s)
- Margot S F Roeten
- Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands
| | - Jacqueline Cloos
- Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
- Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
| | - Gerrit Jansen
- Amsterdam Rheumatology and Immunology Center, Location VUmc, VU University Medical Center, Amsterdam, The Netherlands
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22
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Vandross A. Proteasome inhibitor-based therapy for treatment of newly diagnosed multiple myeloma. Semin Oncol 2018; 44:381-384. [PMID: 29935899 DOI: 10.1053/j.seminoncol.2018.01.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 01/01/2018] [Indexed: 01/09/2023]
Abstract
Multiple myeloma is a hematologic malignancy that is unable to be cured and has significant impact throughout the world. Front line treatment has shifted but ultimately has landed on a bortezomib-based combination therapy. Carfilzomib is a next-generation proteasome inhibitor shown to improve both progression-free and overall survival in relapsed and refractory multiple myeloma in combination with lenalidomide and dexamethasone (KRd). Given the favorable response rates seen in phase II trials treating newly diagnosed myeloma, this combination is listed as a viable option for upfront treatment. This systematic review compares pharmacologic properties, clinical efficacy, and toxicities of carfilzomib- and bortezomib-based regimens.
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Affiliation(s)
- Andrae Vandross
- Division of Hematology/Oncology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA.
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23
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Sahin U, Demirer T. Current strategies for the management of autologous peripheral blood stem cell mobilization failures in patients with multiple myeloma. J Clin Apher 2017; 33:357-370. [DOI: 10.1002/jca.21591] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 09/09/2017] [Accepted: 09/11/2017] [Indexed: 12/22/2022]
Affiliation(s)
- Ugur Sahin
- Department of Hematology; Ankara University Medical School; Ankara Turkey
| | - Taner Demirer
- Department of Hematology; Ankara University Medical School; Ankara Turkey
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Frinc I, Ilies P, Zaharie F, Dima D, Tanase A, Petrov L, Irimie A, Berce C, Lisencu C, Berindan-Neagoe I, Tomuleasa C, Bojan A. Transthoracic ultrasonography for the immunocompromised patient. A pilot project that introduces transthoracic ultrasonography for the follow-up of hematological patients in Romania. ACTA ACUST UNITED AC 2017; 55:103-116. [PMID: 28103204 DOI: 10.1515/rjim-2017-0006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Indexed: 11/15/2022]
Abstract
In the past decade, there has been significant progress in clinical hematology with the discovery of targeted molecules and thus the achievement of both hematologic and molecular responses. Nevertheless, chemotherapy remains the treatment of choice for many types of hematological malignancies. Aggressive chemotherapy leads to immunosuppression, accompanied by a high rate of infections and an increased rate of treatment-related mortality. Invasive fungal infections as well as more common bacterial and viral infections are frequent in immunocompromised patients as they are difficult to diagnose and treat. Pleuropulmonary infections in immunocompromised patients are diagnosed using clinical examination, imaging and laboratory tests. Many laboratory tests are run for several days before a final result is given and are expensive. Computer tomography is a reliable technique, but it is encumbered by high irradiation and high cost, and can assess lesions larger than 1 cm. Transthoracic ultrasound is a modern method, used in the diagnostic algorithm of pleuropulmonary pathology. It allows the diagnosis of small lesions, can be performed at the patients' bedside, with acceptable costs and no irradiation. A fast, informed and accurate medical decision is essential for a favorable outcome in immunosuppressed patients with an adjacent infection. In the current case series we present the implementation of a new protocol for the follow-up of immunocompromised patients using transthoracic ultrasonography, of great potential use in the clinic.
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Evaluation of Bortezomib-Induced Neuropathy Using Total Neuropathy Score (Reduced and Clinical Versions) and NCI CTCAE v4.0 in Newly Diagnosed Patients With Multiple Myeloma Receiving Bortezomib-Based Induction. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2017; 17:513-519.e1. [DOI: 10.1016/j.clml.2017.06.035] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 06/18/2017] [Accepted: 06/27/2017] [Indexed: 01/06/2023]
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Huang SY, Chang CS, Liu TC, Wang PN, Yeh SP, Ho CL, Kuo MC, Lin HY, de Jong J, Chen JY, Yang YW. Pharmacokinetic study of bortezomib administered intravenously in Taiwanese patients with multiple myeloma. Hematol Oncol 2017. [PMID: 28626947 DOI: 10.1002/hon.2432] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
This phase 4, single-arm, non-randomized, open-label, post approval commitment study evaluated the pharmacokinetics and safety of bortezomib in Taiwanese patients with multiple myeloma. Patients (≥20 years) with measurable secretory multiple myeloma (serum monoclonal IgG ≥10, IgA/IgE ≥5, IgD ≥0.5 g/L, IgM present [regardless of level], and urine M protein of ≥200 mg/24 h) received intravenous bortezomib 1.3 mg/m2 , twice weekly for 2 weeks, followed by a 10-day resting phase (days 12 to 21). Pharmacokinetics and safety were assessed at pre-specified time points. All enrolled patients (n = 18, men: 11; women: 7) completed the study. Mean (SD) Cmax (maximum observed plasma concentration) on day 11 was 266 (77.5) ng/mL, approximately 60% higher compared with non-Asian patients receiving a similar bortezomib regimen but with overlapping ranges. Because of the protracted terminal phase, half-life (t1/2 ), area under the plasma concentration-time curve from time 0 to infinity (AUC∞ ), volume of distribution (Vz ), and systemic clearance were not assessable. All patients experienced treatment-emergent adverse events (TEAEs); 78% were drug-related. Most commonly reported TEAEs were thrombocytopenia (n = 11 [61%]), neutropenia (n = 9 [50%]), leukopenia (n = 6 [33%]), and diarrhoea (n = 6 [33%]); the most common serious adverse event was pneumonia (n = 2 [11%]). One patient had a dose reduction due to a TEAE of thrombocytopenia. Overall, bortezomib exposure (AUC) in Taiwanese patients (AUClast [SD]: 230 [147] ng·h/mL) with twice weekly intravenous administration was comparable with non-Asian population (AUClast [SD]: 241 [82] ng·h/mL). Bortezomib treatment was associated with manageable toxicity profile and did not limit the continuity of therapy.
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Affiliation(s)
- Shang-Yi Huang
- Division of Hematology, College of Medicine, National Taiwan University and Hospital, Taipei, Taiwan
| | - Cheng-Shyong Chang
- Division of Hematology-Oncology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Ta-Chih Liu
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Po-Nan Wang
- Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Su-Peng Yeh
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ching-Liang Ho
- Division of Hematology/Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | | | - Hsuan-Yu Lin
- Division of Hematology-Oncology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Jan de Jong
- Janssen Research & Development, San Diego, CA, USA
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Ting KR, Henry M, Meiller J, Larkin A, Clynes M, Meleady P, Bazou D, Dowling P, O'Gorman P. Novel panel of protein biomarkers to predict response to bortezomib-containing induction regimens in multiple myeloma patients. BBA CLINICAL 2017; 8:28-34. [PMID: 28725572 PMCID: PMC5502697 DOI: 10.1016/j.bbacli.2017.05.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 05/19/2017] [Accepted: 05/19/2017] [Indexed: 01/03/2023]
Abstract
BACKGROUND Multiple myeloma (MM) is a complex heterogeneous disease. Various risk stratification models have been recommended including cytogenetic and FISH analysis to identify high-risk patients who may benefit from novel treatments, but such facilities are not widely available. The International Scoring System (ISS) using beta-2-microglobulin and albumin remains a widely used prognostic scoring system in many clinical practices; however it is not useful in predicting response to treatment in MM. The aim of this study is to identify clinically useful biomarkers to predict response to treatment containing bortezomib. METHODS 17 MM patient serum samples (9 responders/8 non-responders) were used for the discovery phase (label-free mass spectrometry) and an additional 20 MM patient serum samples were used for the ELISA-based validation phase (14 responders/6 non-responders). RESULTS CLU and ANG mean levels were higher in the responders group, while Complement C1q had lower concentrations. The combination of all standard biomarkers (albumin, beta-2-microglobulin (ß2M), paraprotein and kappa/lambda (K/L) ratio) had an AUC value of 0.71 with 65% correct classification, while an overall combination of new candidate protein biomarkers with standard biomarkers had an AUC value of 0.89 with 85.3% correct classification. CONCLUSIONS A combination of new and standard biomarkers consisting of CLU, ANG, C1Q, albumin, ß2M, paraprotein and K/L ratio may have potential as a novel panel of biomarkers to predict MM response to treatment containing bortezomib. GENERAL SIGNIFICANCE Use of this biomarker panel could facilitate a more personalized therapy approach and to minimize unnecessary side effects from ineffective drugs.
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Affiliation(s)
- Kay Reen Ting
- Mater Misericordiae University Hospital, Dublin 7, Ireland.,National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Michael Henry
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Justine Meiller
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Annemarie Larkin
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Martin Clynes
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Paula Meleady
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Despina Bazou
- Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - Paul Dowling
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.,Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Peter O'Gorman
- Mater Misericordiae University Hospital, Dublin 7, Ireland.,National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.,School of Medicine & Medical Science, University College Dublin, Dublin 4, Ireland
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Kandula T, Farrar MA, Kiernan MC, Krishnan AV, Goldstein D, Horvath L, Grimison P, Boyle F, Baron-Hay S, Park SB. Neurophysiological and clinical outcomes in chemotherapy-induced neuropathy in cancer. Clin Neurophysiol 2017; 128:1166-1175. [PMID: 28511129 DOI: 10.1016/j.clinph.2017.04.009] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 03/21/2017] [Accepted: 04/14/2017] [Indexed: 12/14/2022]
Abstract
Chemotherapy induced peripheral neuropathy (CIPN) is a significant toxicity of cancer treatment, with the potential to affect long-term function and quality of life in cancer survivors. There remains a lack of consensus around optimal assessment techniques. While current approaches to CIPN assessment are focused on clinical grading scales, it is becoming increasingly evident that a more comprehensive multimodal assessment package is necessary to accurately characterise the impact of CIPN as well as gauge the utility of neuroprotective mechanisms. Neurophysiological techniques provide objective biomarkers and may enable early detection of toxicity while patient reported outcomes are necessary to determine the significance of symptoms to individual patients. In addition to providing an objective assessment, clinical neurophysiological techniques provide important insights into the contributory pathophysiological mechanisms of CIPN with different chemotherapy agents. There is a paucity of implementation of these techniques in the clinical trial setting. The present Review aims to facilitate the use of neurophysiological studies as part of comprehensive assessment packages for the monitoring of CIPN by summarising current understanding of neurophysiological changes that underlie the development of neuropathy, clinical presentations and patient reported outcomes as well as advantages and limitations of current techniques for the neurophysiological assessment of CIPN.
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Affiliation(s)
- Tejaswi Kandula
- Discipline of Pediatrics, School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, Randwick, NSW, Australia; Department of Neurology, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Michelle A Farrar
- Discipline of Pediatrics, School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, Randwick, NSW, Australia; Department of Neurology, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Matthew C Kiernan
- Brain & Mind Centre, Sydney Medical School, University of Sydney, 94 Mallett Street, Sydney, NSW, Australia
| | - Arun V Krishnan
- Prince of Wales Clinical School, UNSW Medicine, The University of New South Wales, Randwick, NSW, Australia
| | - David Goldstein
- Prince of Wales Clinical School, UNSW Medicine, The University of New South Wales, Randwick, NSW, Australia
| | - Lisa Horvath
- Chris O'Brien Lifehouse, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, NSW, Australia; Department of Oncology, Royal Prince Alfred Hospital, NSW, Australia
| | - Peter Grimison
- Chris O'Brien Lifehouse, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, NSW, Australia
| | - Frances Boyle
- Sydney Medical School, University of Sydney, NSW, Australia; Patricia Ritchie Centre for Cancer Care and Research, The Mater Hospital, NSW, Australia
| | - Sally Baron-Hay
- Department of Oncology, Royal North Shore Hospital, NSW, Australia
| | - Susanna B Park
- Brain & Mind Centre, Sydney Medical School, University of Sydney, 94 Mallett Street, Sydney, NSW, Australia; Prince of Wales Clinical School, UNSW Medicine, The University of New South Wales, Randwick, NSW, Australia.
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Thoennissen GB, Görlich D, Bacher U, Aufenberg T, Hüsken AC, Hansmeier AA, Evers G, Mikesch JH, Fritz F, Bokemeyer C, Müller-Tidow C, Stelljes M, Mesters RM, Krug U, Kropff MH, Thoennissen NH, Berdel WE. Autologous Stem Cell Transplantation in Multiple Myeloma in the Era of Novel Drug Induction: A Retrospective Single-Center Analysis. Acta Haematol 2017; 137:163-172. [PMID: 28399522 DOI: 10.1159/000463534] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 02/12/2017] [Indexed: 12/22/2022]
Abstract
Within this retrospective single-center study, we analyzed the survival of 320 multiple myeloma (MM) patients receiving melphalan high-dose chemotherapy (HDCT) and either single (n = 286) or tandem (n = 34) autologous stem cell transplantation (ASCT) from 1996 to 2012. Additionally, the impact of novel induction regimens was assessed. Median follow-up was 67 months, median overall survival (OS) 62 months, median progression-free survival (PFS) 33 months (95% CI 27-39), and treatment-related death (TRD) 3%. Multivariate analysis revealed age ≥60 years (p = 0.03) and stage 3 according to the International Staging System (p = 0.006) as adverse risk factors regarding PFS. Median OS was significantly better in newly diagnosed MM patients receiving induction therapy with novel agents, e.g., bortezomib, thalidomide, or lenalidomide, compared with a traditional regimen (69 vs. 58 months; p = 0.01). More patients achieved at least a very good partial remission in the period from 2005 to 2012 than from 1996 to 2004 (65 vs. 30%; p < 0.001), with a longer median OS in the later period (71 vs. 52 months, p = 0.027). In conclusion, our analysis confirms HDCT-ASCT as an effective therapeutic strategy in an unselected large myeloma patient cohort with a low TRD rate and improved prognosis due to novel induction strategies.
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Affiliation(s)
- Gabriela B Thoennissen
- Department of Oncology, Hematology, and Bone Marrow Transplantation with Section of Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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García-Ávila AK, Farfán-García ED, Guevara-Salazar JA, Trujillo-Ferrara JG, Soriano-Ursúa MA. Scope of translational medicine in developing boron-containing compounds for therapeutics. World J Transl Med 2017; 6:1-9. [DOI: 10.5528/wjtm.v6.i1.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 02/23/2017] [Accepted: 03/13/2017] [Indexed: 02/06/2023] Open
Abstract
The ubiquitousness of naturally occurring boron-containing compounds (BCCs) has led to their constant contact with humankind. Recently, many synthetic BCCs have been elaborated for a broad spectrum of purposes, especially boric, boronic and borinic acids. Although BCCs were once employed primarily as antiseptics and later as antibiotics, they have become an increasingly relevant therapeutic tool. Nevertheless, this potential of BCCs has been drastically limited due to some unfortunate intra-hospital accidents in the 1940s and 1950s. The increasing use of BCCs as insecticides, antimicrobials, and other agents is providing new insights into their role in the physiology of several living species and in the pathophysiology of humans. It is becoming clear that BCCs act through a wide range of mechanisms, as do their corresponding boron-free counterparts. When comparing BCCs and similar boron-free compounds, in many cases the former show advantages in the medical field. The current mini-review focuses on how BCCs have been developed by means of translational medicine, a process connecting biomedical research with clinical applications. This process of discovery is currently in an exponential stage.
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Leucovorin Enhances the Anti-cancer Effect of Bortezomib in Colorectal Cancer Cells. Sci Rep 2017; 7:682. [PMID: 28386133 PMCID: PMC5429730 DOI: 10.1038/s41598-017-00839-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 03/15/2017] [Indexed: 01/06/2023] Open
Abstract
Colorectal cancer is a major cancer type worldwide. 5-fluorouracil, often given with leucovorin, is the most commonly used drug in colorectal cancer chemotherapy, yet development of drug resistance to 5-fluorouracil in colorectal cancer cells is the primary cause of chemotherapy failure. Most patients receiving intravenous 5-fluorouracil develop side effects. Leucovorin, due to its vitamin-like profile, has few side-effects. Drug repurposing is the application of approved drugs to treat new indications. In this study, we performed a novel drug-repurposing screening to identify Food and Drug Administration-approved chemotherapeutic compounds possessing synergistic activity with leucovorin against colorectal cancer cells. We found that the combination of bortezomib and leucovorin enhanced caspase activation and increased apoptosis in colorectal cancer cells better than either agent alone. Further, the synergistic induction of apoptosis and inhibition of tumor growth were also observed in mouse colorectal cancer xenografts. These data support leucovorin enhances the anti-cancer effect of bortezomib and present this novel combinatorial treatment against colorectal cancer.
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Sidana S, Narkhede M, Elson P, Hastings D, Faiman B, Valent J, Samaras C, Hamilton K, Liu HK, Smith MR, Reu FJ. Neuropathy and efficacy of once weekly subcutaneous bortezomib in multiple myeloma and light chain (AL) amyloidosis. PLoS One 2017; 12:e0172996. [PMID: 28278302 PMCID: PMC5344345 DOI: 10.1371/journal.pone.0172996] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 02/13/2017] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Randomized studies have shown that bortezomib (BTZ) can be given weekly via intravenous (IV) route or twice weekly via subcutaneous (SC) route with lower neuropathy risk and no loss of anti-myeloma efficacy compared to original standard IV twice weekly schedule. Weekly SC should therefore yield the best therapeutic index and is widely used but has not been compared to established administration schedules in the context of a clinical trial. METHODS Comprehensive electronic medical record review was done for disease control and neuropathy symptoms of 344 consecutive patients who received their first BTZ-containing regimen for myeloma or AL amyloidosis before or after we changed to SC weekly in December 2010. Univariate and multivariable analyses were carried out that adjusted for age, underlying disease, concurrently used anticancer agents, underlying conditions predisposing to neuropathy, and number of prior regimens compared SC weekly to other schedules. RESULTS Fifty-three patients received BTZ SC weekly, 17 SC twice weekly, 127 IV weekly and 147 IV twice weekly. Risk for neuropathy of any grade was higher with other schedules compared to SC weekly (44.3% vs. 26.9%, p = 0.001) while response rate was similar (72.1% vs. 76.6%, respectively, p = 0.15). Multivariable analyses upheld higher neuropathy risk (Odds ratio 2.45, 95% CI 1.26-4.76, p = 0.008) while the likelihood of not achieving a response (= partial response or better) was comparable (Odds ratio 1.25, 95% CI 0.58-2.71, p = 0.56) for other schedules compared to SC weekly, respectively. Lower neuropathy risk translated into longer treatment duration when BTZ was started SC weekly (p = 0.001). CONCLUSIONS Weekly SC BTZ has activity comparable to other schedules and causes low rates of neuropathy.
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Affiliation(s)
- Surbhi Sidana
- Department of Internal Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Mayur Narkhede
- Department of Internal Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Paul Elson
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Debbie Hastings
- Department of Cancer Center Research, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Beth Faiman
- Department of Hematology & Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Jason Valent
- Department of Hematology & Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Christy Samaras
- Department of Hematology & Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Kimberly Hamilton
- Department of Hematology & Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Hien K. Liu
- Department of Hematology & Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Mitchell R. Smith
- Department of Hematology & Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Frederic J. Reu
- Department of Hematology & Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
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The role of initial clinical presentation, comorbidity and treatment in multiple myeloma patients on survival: a detailed population-based cohort study. Eur J Clin Pharmacol 2017; 73:771-778. [DOI: 10.1007/s00228-017-2227-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 02/22/2017] [Indexed: 12/22/2022]
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Kaplan GS, Torcun CC, Grune T, Ozer NK, Karademir B. Proteasome inhibitors in cancer therapy: Treatment regimen and peripheral neuropathy as a side effect. Free Radic Biol Med 2017; 103:1-13. [PMID: 27940347 DOI: 10.1016/j.freeradbiomed.2016.12.007] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 10/22/2016] [Accepted: 12/04/2016] [Indexed: 01/10/2023]
Abstract
Proteasomal system plays an important role in protein turnover, which is essential for homeostasis of cells. Besides degradation of oxidized proteins, it is involved in the regulation of many different signaling pathways. These pathways include mainly cell differentiation, proliferation, apoptosis, transcriptional activation and angiogenesis. Thus, proteasomal system is a crucial target for treatment of several diseases including neurodegenerative diseases, cystic fibrosis, atherosclerosis, autoimmune diseases, diabetes and cancer. Over the last fifteen years, proteasome inhibitors have been tested to highlight their mechanisms of action and used in the clinic to treat different types of cancer. Proteasome inhibitors are mainly used in combinational therapy along with classical chemo-radiotherapy. Several studies have proved their significant effects but serious side effects such as peripheral neuropathy, limits their use in required effective doses. Recent studies focus on peripheral neuropathy as the primary side effect of proteasome inhibitors. Therefore, it is important to delineate the underlying mechanisms of peripheral neuropathy and develop new inhibitors according to obtained data. This review will detail the role of proteasome inhibition in cancer therapy and development of peripheral neuropathy as a side effect. Additionally, new approaches to prevent treatment-limiting side effects will be discussed in order to help researchers in developing effective strategies to overcome side effects of proteasome inhibitors.
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Affiliation(s)
- Gulce Sari Kaplan
- Department of Biochemistry, School of Medicine/Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, 34854 Maltepe, Istanbul, Turkey
| | - Ceyda Corek Torcun
- Department of Biochemistry, School of Medicine/Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, 34854 Maltepe, Istanbul, Turkey
| | - Tilman Grune
- Department for Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany
| | - Nesrin Kartal Ozer
- Department of Biochemistry, School of Medicine/Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, 34854 Maltepe, Istanbul, Turkey
| | - Betul Karademir
- Department of Biochemistry, School of Medicine/Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, 34854 Maltepe, Istanbul, Turkey.
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Lu J, Chen WM, Geng CY, Durie BG, Huang XJ. Efficacy and Safety of Bortezomib in Multiple Myeloma Patients with Hepatitis B: A Multicenter Retrospective Study. Chin Med J (Engl) 2017; 129:274-8. [PMID: 26831227 PMCID: PMC4799569 DOI: 10.4103/0366-6999.174508] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Background: The efficacy and safety evidence of bortezomib in multiple myeloma (MM) patients with hepatitis B is vacant. This study aimed to investigate the efficacy and safety of bortezomib in MM patients with hepatitis B in China. Methods: From 2006 to 2011, 739 newly diagnosed MM patients were screened for serum hepatitis B virus (HBV) biomarkers. HBV-infected patients were followed for HBV reactivation by monitoring of serum alanine transaminase (ALT) and HBV DNA load. The pattern of HBV reactivation in relation to bortezomib was evaluated. Seven hundred thirty-nine MM patients were included in this study. Results: The prevalence of MM patients infected with HBV was 3.4% (n = 25), of which 17 cases were treated with bortezomib. Bortezomib had no significant influence on liver function (ALT before and after treatment: 36.69 ± 8.90 U/L vs. 11.31 ± 2.74 U/L, P = 0.19) and HBV DNA of MM patients with HBV (detectable HBV DNA percentage: 5.9% vs. 11.8%, P = 0.12). Conclusions: Bortezomib can be used safely and effectively in MM patients with hepatitis B. HBV prophylaxis and surveillance are recommended during the MM treatment.
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Affiliation(s)
| | | | | | | | - Xiao-Jun Huang
- Department of Hematology, Peking University People's Hospital and Peking University Institute of Hematology, Beijing 100044, China
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Wei D, Tong Y, Bai H, Cai Q, Gao Y, Wang C. A dose increased once-weekly bortezomib-based combination therapy for multiple myeloma. Oncotarget 2016; 7:70168-70174. [PMID: 27659525 PMCID: PMC5342543 DOI: 10.18632/oncotarget.12162] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 09/14/2016] [Indexed: 11/30/2022] Open
Abstract
Background The purpose of the current study was to evaluate the efficacy and safety of a dose increased weekly Bortezomib (Bor) based combination therapy in multiple myeloma (MM) patients. Results The overall response rate (ORR) in the modified Bor group was 76.6%, composed of 40% complete response (CR), 3.3% very good partial response (VGPR) and 33.3% partial response (PR). The ORR was 82.3%, with 26.5% CR, 5.9% VGPR and 50% PR in control. A subgroup analysis showed both groups had equal efficacy in newly diagnosed MM patients (P = 1.000). The median progression free survival was 16 (11.7–20.3) months for the modified Bor group and 12 (10.5–13.5) months for the control (P = 0.503), and the median overall survival was 36 (9.4–62.6) vs 28 (21.6–34.4) months (P = 0.759). The incidences of AEs were similar except grade 1–4 peripheral neuropathy (PN) rate was 10% in modified regime group and 32.4% in control (P = 0.038). Materials and Methods This was a monocentric, prospective, non-randomized, phase IV, non-inferiority trial. Thirty MM patients were treated with modified Bor-based combination therapy (Bor 1.6 mg/m2 on day 1, 8), with 34 MM patients on conventional Bor-based combination therapy (1.3 mg/m2 on day 1, 4, 8, 11) as control. The responses and adverse events (AEs) were compared. Conclusions The increased-dose weekly Bor-based combination therapies were not inferior to conventional ones in terms of response and survival benefit, but showed lower rate of peripheral neuropathy (PN).
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Affiliation(s)
- Daolin Wei
- Department of Hematology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China
| | - Yin Tong
- Department of Hematology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China
| | - Haitao Bai
- Department of Hematology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China
| | - Qi Cai
- Department of Hematology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China
| | - Yanrong Gao
- Department of Hematology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China
| | - Chun Wang
- Department of Hematology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China
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Zhang J, Lu W, Chen Y, Jiang Q, Yang K, Li M, Wang Z, Duan X, Xu L, Tang H, Sun D, Wang J. Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs. Am J Physiol Cell Physiol 2016; 311:C482-97. [PMID: 27413173 PMCID: PMC5129762 DOI: 10.1152/ajpcell.00324.2015] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 06/27/2016] [Indexed: 01/18/2023]
Abstract
The ubiquitin-proteasome system is considered to be the key regulator of protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor approved by the US Food and Drug Administration for treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ treatment was reported to inhibit right ventricular hypertrophy and vascular remodeling in hypoxia-exposed and monocrotaline-injected rats. However, the underlying mechanisms remain poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca(2+) concentration ([Ca(2+)]i) and store-operated Ca(2+) entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) are involved in pulmonary vascular remodeling. In this study we aim to determine whether BTZ attenuates the hypoxia-induced elevation of [Ca(2+)] in PASMCs and the signaling pathway involved in this mechanism. Our results showed that 1) in hypoxia- and monocrotaline-induced rat pulmonary hypertension (PH) models, BTZ markedly attenuated the development and progression of PH, 2) BTZ inhibited the hypoxia-induced increase in cell proliferation, basal [Ca(2+)]i, and SOCE in PASMCs, and 3) BTZ significantly normalized the hypoxia-upregulated expression of hypoxia-inducible factor-1α, bone morphogenetic protein 4, canonical transient receptor potential isoforms 1 and 6, and the hypoxia-downregulated expression of peroxisome proliferator-activated receptor-γ in rat distal pulmonary arteries and PASMCs. These results indicate that BTZ exerts its protective role in the development of PH potentially by inhibiting the canonical transient receptor potential-SOCE-[Ca(2+)]i signaling axis in PASMCs.
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Affiliation(s)
- Jun Zhang
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Wenju Lu
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yuqin Chen
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Qian Jiang
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Kai Yang
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Meichan Li
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ziyi Wang
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xin Duan
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and
| | - Lei Xu
- Division of Pulmonary and Critical Care Medicine, Affiliated Hospital of Inner Mongolia Medical University, Huhhot, Inner Mongolia, China
| | - Haiyang Tang
- Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona, Tucson, Arizona
| | - Dejun Sun
- Division of Pulmonary Medicine, The People's Hospital of Inner Mongolia, Hohhot, Inner Mongolia, China
| | - Jian Wang
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona, Tucson, Arizona; Division of Pulmonary Medicine, The People's Hospital of Inner Mongolia, Hohhot, Inner Mongolia, China;
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Logan A, Zuppan C, Pi A, Zhang Z, Jaipaul N. Rare and unusual clinicopathologic presentation of renal AL amyloidosis. JRSM Open 2016; 7:2054270416640156. [PMID: 27186381 PMCID: PMC4858726 DOI: 10.1177/2054270416640156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Rarely, renal light chain (AL) amyloidosis may present without significant proteinuria owing to glomerular sparing and amyloid deposition confined to the vasculature and tubulointerstitium.
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Affiliation(s)
- Andrew Logan
- School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA
| | - Craig Zuppan
- School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA
| | - Alexander Pi
- School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA
| | - Zhiwei Zhang
- School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; VA Loma Linda Healthcare System, Loma Linda, CA 92357, USA
| | - Navin Jaipaul
- School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; VA Loma Linda Healthcare System, Loma Linda, CA 92357, USA
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Low M, Infantino S, Grigoriadis G, Tarlinton D. Targeting plasma cells: are we any closer to a panacea for diseases of antibody-secreting cells? Immunol Rev 2016; 270:78-94. [DOI: 10.1111/imr.12388] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Michael Low
- Immunology Division; Walter and Eliza Hall Institute of Medical Research; University of Melbourne; Parkville Vic. Australia
- Department of Haematology; Monash Health; Monash Hospital; Clayton Vic. Australia
- Department of Medical Biology; The University of Melbourne; Parkville Vic. Australia
| | - Simona Infantino
- Immunology Division; Walter and Eliza Hall Institute of Medical Research; University of Melbourne; Parkville Vic. Australia
- Department of Medical Biology; The University of Melbourne; Parkville Vic. Australia
| | - George Grigoriadis
- Department of Haematology; Monash Health; Monash Hospital; Clayton Vic. Australia
- School of Clinical Sciences at Monash Health; Monash University; Clayton Vic. Australia
- Centre for Cancer Research; Hudson Institute of Medical Research; Clayton Vic. Australia
- Malignant Haematology and Stem Cell Transplantation Service and Alfred Pathology Service; The Alfred; Melbourne Vic. Australia
| | - David Tarlinton
- Immunology Division; Walter and Eliza Hall Institute of Medical Research; University of Melbourne; Parkville Vic. Australia
- Department of Haematology; Monash Health; Monash Hospital; Clayton Vic. Australia
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Martino M, Recchia AG, Fedele R, Neri S, Vincelli ID, Moscato T, Gentile M, Morabito F. The role of tandem stem cell transplantation for multiple myeloma patients. Expert Opin Biol Ther 2016; 16:515-34. [PMID: 26698133 DOI: 10.1517/14712598.2016.1136285] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Autologous Stem Cell Transplantation (ASCT) represents the standard treatment in eligible "de-novo" multiple myeloma (MM) patients. AREAS COVERED ASCT may be single or tandem, and a single ASCT can be followed by an allogeneic (Allo)-SCT. A systematic review has been conducted to examine the current evidence for the efficacy of using a tandem transplant strategy in MM. EXPERT OPINION A tandem ASCT approach should be considered for all patients, although the benefit from the second ASCT in patients who are in complete remission or experience a very good partial response should be answered in a clinical trial. Recent results with the new induction regimens indicate that there is a role for tandem ASCT in the presence of adverse cytogenetic abnormalities. Planned AlloSCT after ASCT has not been found to be superior in the majority of studies and is not recommended outside of a clinical trial. However, single or tandem ASCT are both appropriate options and participation in prospective clinical trials should be encouraged to resolve the debate in the era of novel agents for MM.
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Affiliation(s)
- Massimo Martino
- a Hematology, Stem Cell Collection and Transplant Unit, Oncology and Hematology Department , Azienda Ospedaliera BMM , Reggio Calabria , Italy
| | - Anna Grazia Recchia
- b Biotechnology Research Unit , Azienda Sanitaria Provinciale di Cosenza , Aprigliano (CS) , Italy
| | - Roberta Fedele
- a Hematology, Stem Cell Collection and Transplant Unit, Oncology and Hematology Department , Azienda Ospedaliera BMM , Reggio Calabria , Italy
| | - Santo Neri
- c Hematology Unit , Azienda Ospedaliera 'Papardo' , Messina , Italy
| | | | - Tiziana Moscato
- a Hematology, Stem Cell Collection and Transplant Unit, Oncology and Hematology Department , Azienda Ospedaliera BMM , Reggio Calabria , Italy
| | - Massimo Gentile
- e Hematology Unit , Azienda Ospedaliera Cosenza , Cosenza , Italy
| | - Fortunato Morabito
- b Biotechnology Research Unit , Azienda Sanitaria Provinciale di Cosenza , Aprigliano (CS) , Italy.,e Hematology Unit , Azienda Ospedaliera Cosenza , Cosenza , Italy
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Fairfield H, Falank C, Avery L, Reagan MR. Multiple myeloma in the marrow: pathogenesis and treatments. Ann N Y Acad Sci 2016; 1364:32-51. [PMID: 27002787 PMCID: PMC4806534 DOI: 10.1111/nyas.13038] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Multiple myeloma (MM) is a B cell malignancy resulting in osteolytic lesions and fractures. In the disease state, bone healing is limited owing to increased osteoclastic and decreased osteoblastic activity, as well as an MM-induced forward-feedback cycle where bone-embedded growth factors further enhance tumor progression as bone is resorbed. Recent work on somatic mutation in MM tumors has provided insight into cytogenetic changes associated with this disease; the initiating driver mutations causing MM are diverse because of the complexity and multitude of mutations inherent in MM tumor cells. This manuscript provides an overview of MM pathogenesis by summarizing cytogenic changes related to oncogenes and tumor suppressors associated with MM, reviewing risk factors, and describing the disease progression from monoclonal gammopathy of undetermined significance to overt MM. It also highlights the importance of the bone marrow microenvironment (BMM) in the establishment and progression of MM, as well as associated MM-induced bone disease, and the relationship of the bone marrow to current and future therapeutics. This review highlights why understanding the basic biology of the healthy and diseased BMM is crucial in the quest for better treatments and work toward a cure for genetically diverse diseases such as MM.
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Affiliation(s)
| | | | | | - Michaela R Reagan
- Maine Medical Center Research Institute, Scarborough, Maine
- University of Maine, Orono, Maine
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Qiao M, Wu D, Carey M, Zhou X, Zhang L. Multi-Scale Agent-Based Multiple Myeloma Cancer Modeling and the Related Study of the Balance between Osteoclasts and Osteoblasts. PLoS One 2015; 10:e0143206. [PMID: 26659358 PMCID: PMC4676611 DOI: 10.1371/journal.pone.0143206] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 11/02/2015] [Indexed: 12/31/2022] Open
Abstract
Research Background Currently, multiple myeloma is the second most common hematological malignancy in the U.S., constituting 1% of all cancers. With conventional treatment, the median survival time is typically 3–4 years, although it can be extended to 5–7 years or longer with advanced treatments. Recent research indicated that an increase in osteoclast (OC) activity is often associated withmultiple myeloma (MM) and that a decrease inosteoblast (OB) activity contributesto the osteolytic lesions in MM. Normally, the populations of OCs and OBs are inequilibrium, and an imbalance in this statecontributes to the development of lesions. Research procedures A multi-scale agent-based multiple myeloma model was developed to simulate the proliferation, migration and death of OBs and OCs. Subsequently, this model was employed to investigate the efficacy of thethree most commonly used drugs for MM treatment under the following two premises: the reduction in the progression of MM and the re-establishment of the equilibrium between OCs and OBs. Research purposes The simulated results not only demonstrated the capacity of the model to choose optimal combinations of the drugs but also showed that the optimal use of the three drugs can restore the balance between OCs and OBs as well as kill MMs. Furthermore, the drug synergism analysis function of the model revealed that restoring the balance between OBs and OCs can significantly increase the efficacy of drugs against tumor cells.
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Affiliation(s)
- Minna Qiao
- College of Computer and Information Science, Southwest University, Chongqing, P. R. China
| | - Dan Wu
- Department of Radiology, Wake Forest University School of Medicine, Winston Salem, United States of America
| | - Michelle Carey
- Department of Biostatistics and Computational Biology, University of Rochester, Rochester, United States of America
| | - Xiaobo Zhou
- Department of Radiology, Wake Forest University School of Medicine, Winston Salem, United States of America
- * E-mail: (LZ); (XBZ)
| | - Le Zhang
- College of Computer and Information Science, Southwest University, Chongqing, P. R. China
- * E-mail: (LZ); (XBZ)
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Muñoz-Galván S, Gutierrez G, Perez M, Carnero A. MAP17 (PDZKIP1) Expression Determines Sensitivity to the Proteasomal Inhibitor Bortezomib by Preventing Cytoprotective Autophagy and NFκB Activation in Breast Cancer. Mol Cancer Ther 2015; 14:1454-65. [PMID: 25837675 DOI: 10.1158/1535-7163.mct-14-1053] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 03/24/2015] [Indexed: 11/16/2022]
Abstract
MAP17 is a small nonglycosylated membrane protein that is overexpressed in a high percentage of carcinomas. High levels of MAP17 enhance the tumorigenic properties of tumor cells by increasing oxidative stress, which is dependent on Na(+)-coupled cotransport. Here, we show that MAP17 is associated with proteins involved in protein degradation and that proteasome inhibition induces autophagy. To analyze whether MAP17 could also alter this process, we used the proteasome inhibitor bortezomib (Velcade, PS-341), which is approved for the treatment of multiple myeloma and mantle cell lymphoma, although it has a high rate of resistance emergence and poor efficacy in solid tumors. We provide evidence that bortezomib induces a cytoprotective effect by activating autophagy and NFκB nuclear translocation, responses that are repressed in the presence of high levels of MAP17 both in vitro and in vivo. Indeed, patients with multiple myeloma treated with bortezomib showed higher response rates and a longer time to progression associated with increased levels of MAP17 expression. The MAP17-induced sensitivity to bortezomib is dependent on the oxidative status of the cells and the activity of Na(+)-coupled transporters because treatment with antioxidants or the inhibitor furosemide restores the cytoprotective activity induced by bortezomib. Therefore, bortezomib induces a prosurvival response through cytoprotective autophagy and NFκB nuclear translocation, which is repressed by high levels of MAP17. We propose that the levels of MAP17 could be used as a prognostic marker to predict the response to bortezomib in hematologic malignancies and in other tissues that are not commonly responsive to the drug.
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Affiliation(s)
- Sandra Muñoz-Galván
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain
| | | | - Marco Perez
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain.
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Obrist F, Manic G, Kroemer G, Vitale I, Galluzzi L. Trial Watch: Proteasomal inhibitors for anticancer therapy. Mol Cell Oncol 2015; 2:e974463. [PMID: 27308423 PMCID: PMC4904962 DOI: 10.4161/23723556.2014.974463] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2014] [Revised: 09/15/2014] [Accepted: 09/17/2014] [Indexed: 01/12/2023]
Abstract
The so-called "ubiquitin-proteasome system" (UPS) is a multicomponent molecular apparatus that catalyzes the covalent attachment of several copies of the small protein ubiquitin to other proteins that are generally (but not always) destined to proteasomal degradation. This enzymatic cascade is crucial for the maintenance of intracellular protein homeostasis (both in physiological conditions and in the course of adaptive stress responses), and regulates a wide array of signaling pathways. In line with this notion, defects in the UPS have been associated with aging as well as with several pathological conditions including cardiac, neurodegenerative, and neoplastic disorders. As transformed cells often experience a constant state of stress (as a result of the hyperactivation of oncogenic signaling pathways and/or adverse microenvironmental conditions), their survival and proliferation are highly dependent on the integrity of the UPS. This rationale has driven an intense wave of preclinical and clinical investigation culminating in 2003 with the approval of the proteasomal inhibitor bortezomib by the US Food and Drug Administration for use in multiple myeloma patients. Another proteasomal inhibitor, carfilzomib, is now licensed by international regulatory agencies for use in multiple myeloma patients, and the approved indications for bortezomib have been extended to mantle cell lymphoma. This said, the clinical activity of bortezomib and carfilzomib is often limited by off-target effects, innate/acquired resistance, and the absence of validated predictive biomarkers. Moreover, the antineoplastic activity of proteasome inhibitors against solid tumors is poor. In this Trial Watch we discuss the contribution of the UPS to oncogenesis and tumor progression and summarize the design and/or results of recent clinical studies evaluating the therapeutic profile of proteasome inhibitors in cancer patients.
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Affiliation(s)
- Florine Obrist
- Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre, France
- INSERM, U1138; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers; Paris, France
- Gustave Roussy Cancer Campus; Villejuif, France
| | | | - Guido Kroemer
- INSERM, U1138; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers; Paris, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou; Paris, France
- Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus; Villejuif, France
| | - Ilio Vitale
- Regina Elena National Cancer Institute; Rome, Italy
- Department of Biology, University of Rome “Tor Vergata”
| | - Lorenzo Galluzzi
- INSERM, U1138; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers; Paris, France
- Gustave Roussy Cancer Campus; Villejuif, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
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Shallwani S, Dalzell MA, Sateren W, O'Brien S. Exercise compliance among patients with multiple myeloma undergoing chemotherapy: a retrospective study. Support Care Cancer 2015; 23:3081-8. [PMID: 25744289 DOI: 10.1007/s00520-015-2680-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 02/22/2015] [Indexed: 11/30/2022]
Abstract
PURPOSE Multiple myeloma (MM) is often associated with osteolytic bone disease and anemia, resulting in skeletal fragility and persistent fatigue, pain, and reduced quality of life. Exercise is considered safe and beneficial for this population. Our objectives were to evaluate the extent to which MM patients undergoing chemotherapy complied with exercise recommendations and to identify factors associated with noncompliance. METHODS This retrospective study included 41 MM patients referred to a hospital-based rehabilitation program while undergoing chemotherapy. Variables collected at baseline (T1) and follow-up (T2) included: (a) demographics and medical history, (b) exercise levels (MET-hours/week), preferences and barriers, and (c) fatigue severity scores (0-10). Statistical analyses included logistic regression to identify factors associated with exercise noncompliance and t-tests and chi-squared tests to compare outcomes between the groups according to compliance. RESULTS The mean age of the participants was 61 years; 73 % were male and 81 % had bone lesions. Overall exercise compliance at T2 was 71 %, with an observed increase in exercise levels (mean group difference: 6.5 MET-hours/week; p < 0.001) and decrease in fatigue severity scores (mean group difference -1.2; p = 0.003). Factors associated with exercise noncompliance included history of pathological fracture (odds ratio [OR] 4.7; p = 0.049), spinal cord compression (SCC) (OR 14.1; p = 0.023), and radiation (OR 28.0; p < 0.001). CONCLUSIONS In this sample of MM patients, high compliance with exercise and associated improvements in fatigue were observed. However, participants with a history of pathological fracture, SCC, or radiation are at increased risk of noncompliance and may require additional supervision to improve exercise compliance.
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Affiliation(s)
- Shirin Shallwani
- Jewish General Hospital, Hope & Cope, 3755 Cote-Ste-Catherine, E-773, Montréal, QC, H3T 1E2, Canada,
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Quach H, Joshua D, Ho J, Szer J, Spencer A, Harrison S, Mollee P, Roberts A, Horvath N, Talaulikar D, To B, Zannettino A, Brown R, Catley L, Augustson B, Jaksic W, Gibson J, Prince HM. Treatment of patients with multiple myeloma who are not eligible for stem cell transplantation: position statement of the myeloma foundation of Australia Medical and Scientific Advisory Group. Intern Med J 2015; 45:335-43. [DOI: 10.1111/imj.12688] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Accepted: 12/20/2014] [Indexed: 11/29/2022]
Affiliation(s)
- H. Quach
- Department of Haematology; St Vincent's Hospital; Melbourne Victoria Australia
- Faculty of Medicine; Dentistry and Health Sciences; The University of Melbourne; Melbourne Victoria Australia
| | - D. Joshua
- Faculty of Medicine; University of Sydney; Sydney New South Wales Australia
- Department of Haematology; Royal Prince Alfred Hospital; Sydney New South Wales Australia
| | - J. Ho
- Faculty of Medicine; University of Sydney; Sydney New South Wales Australia
- Department of Haematology; Royal Prince Alfred Hospital; Sydney New South Wales Australia
| | - J. Szer
- Department of Clinical Haematology and BMT; Royal Melbourne Hospital; Melbourne Victoria Australia
| | - A. Spencer
- Department of Haematology; The Alfred Hospital; Melbourne Victoria Australia
| | - S. Harrison
- Faculty of Medicine; Dentistry and Health Sciences; The University of Melbourne; Melbourne Victoria Australia
- Department of Haematology; Peter MacCallum Cancer Centre; Melbourne Victoria Australia
| | - P. Mollee
- Amyloidosis Centre and Department of Haematology; Princess Alexandra Hospital; Brisbane Queensland Australia
- School of Medicine; University of Queensland; Brisbane Queensland Australia
| | - A. Roberts
- Faculty of Medicine; Dentistry and Health Sciences; The University of Melbourne; Melbourne Victoria Australia
- Department of Clinical Haematology and BMT; Royal Melbourne Hospital; Melbourne Victoria Australia
| | - N. Horvath
- Department of Haematology; South Australia Pathology; Adelaide South Australia Australia
| | - D. Talaulikar
- Department of Haematology; Canberra Hospital; Canberra Australian Capital Territory Australia
- Australian National University; Canberra Australian Capital Territory Australia
| | - B. To
- Department of Haematology; South Australia Pathology; Adelaide South Australia Australia
| | - A. Zannettino
- Department of Haematology; South Australia Pathology; Adelaide South Australia Australia
| | - R. Brown
- Department of Haematology; Royal Prince Alfred Hospital; Sydney New South Wales Australia
| | - L. Catley
- School of Medicine; University of Queensland; Brisbane Queensland Australia
- Department of Haematology; Mater Public Hospital; Brisbane Queensland Australia
- Mater Medical Research Institute; Brisbane Queensland Australia
| | - B. Augustson
- Department of Haematology; Sir Charles Gairdner Hospital; Perth Western Australia Australia
| | - W. Jaksic
- Department of Haematology; Queen Elizabeth Hospital; Adelaide South Australia Australia
| | - J. Gibson
- Faculty of Medicine; University of Sydney; Sydney New South Wales Australia
- Department of Haematology; Royal Prince Alfred Hospital; Sydney New South Wales Australia
| | - H. M. Prince
- Faculty of Medicine; Dentistry and Health Sciences; The University of Melbourne; Melbourne Victoria Australia
- Department of Haematology; Peter MacCallum Cancer Centre; Melbourne Victoria Australia
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Abstract
Multiple myeloma (MM) is a plasma cell malignancy leading to significant life-expectancy shortening. Although the incorporation of the novel agents thalidomide, bortezomib, and lenalidomide in the front-line therapy has resulted in significant improvement, almost all patients relapse, making the treatment of relapse a real challenge. In the present article, when and how to treat relapsed MM is discussed. Treatment can be safely delayed in a subset of patients with asymptomatic relapse, whereas those with symptomatic relapse, advanced disease at diagnosis, or significant paraproteinemic increase require prompt rescue therapy. The benefit of retreatment and the use of a sequential approach for successive relapses considering drug synergism are highlighted. For patients with aggressive relapses and for those who have exhausted all available options, continued therapy until disease progression is recommended, particularly when using regimens with a long-term safety profile. Patients with a duration response to a first autologous stem cell transplantation (ASCT) longer than 2 years may benefit from a second ASCT. Patients with aggressive disease and/or poor cytogenetics at diagnosis relapsing within the first 2 years from ASCT should be considered for an allogeneic transplantation. Finally, a number of newer promising drugs are being actively investigated and the enrolment of patients in clinical trials is encouraged.
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48
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Quach H, Joshua D, Ho J, Szer J, Spencer A, Harrison SJ, Mollee P, Roberts AW, Horvath N, Talulikar D, To B, Zannettino A, Brown R, Catley L, Augustson B, Jaksic W, Gibson J, Prince HM. Treatment of patients with multiple myeloma who are eligible for stem cell transplantation: position statement of the Myeloma Foundation of Australia Medical and Scientific Advisory Group. Intern Med J 2015; 45:94-105. [DOI: 10.1111/imj.12640] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Accepted: 09/29/2014] [Indexed: 11/28/2022]
Affiliation(s)
- H. Quach
- Department of Haematology; St Vincent's Hospital; Melbourne Victoria Australia
- Faculty of Medicine, Dentistry and Health Sciences; University of Melbourne; Melbourne Victoria Australia
| | - D. Joshua
- Department of Haematology; Royal Prince Alfred Hospital; Sydney New South Wales Australia
- Faculty of Medicine; University of Sydney; Sydney New South Wales Australia
| | - J. Ho
- Department of Haematology; Royal Prince Alfred Hospital; Sydney New South Wales Australia
- Faculty of Medicine; University of Sydney; Sydney New South Wales Australia
| | - J. Szer
- Department of Clinical Haematology and BMT; Royal Melbourne Hospital; Melbourne Victoria Australia
| | - A. Spencer
- Department of Haematology; The Alfred Hospital; Melbourne Victoria Australia
| | - S. J. Harrison
- Faculty of Medicine, Dentistry and Health Sciences; University of Melbourne; Melbourne Victoria Australia
- Department of Haematology; Peter MacCallum Cancer Centre; Melbourne Victoria Australia
| | - P. Mollee
- Amyloidosis Centre and Department of Haematology; Princess Alexandra Hospital; Brisbane Queensland Australia
- School of Medicine; University of Queensland; Brisbane Queensland Australia
| | - A. W. Roberts
- Department of Clinical Haematology and BMT; Royal Melbourne Hospital; Melbourne Victoria Australia
| | - N. Horvath
- Department of Haematology; South Australia Pathology; Adelaide South Australia Australia
| | - D. Talulikar
- Department of Haematology; Canberra Hospital; Canberra ACT Australia
- Australian National University; Canberra ACT Australia
| | - B. To
- Department of Haematology; South Australia Pathology; Adelaide South Australia Australia
| | - A. Zannettino
- Department of Haematology; South Australia Pathology; Adelaide South Australia Australia
| | - R. Brown
- Department of Haematology; Royal Prince Alfred Hospital; Sydney New South Wales Australia
| | - L. Catley
- School of Medicine; University of Queensland; Brisbane Queensland Australia
- Department of Haematology; Mater Public Hospital; Brisbane Queensland Australia
- Mater Medical Research Institute; Brisbane Queensland Australia
| | - B. Augustson
- Department of Haematology; Sir Charles Gairdner Hospital; Perth Western Australia Australia
| | - W. Jaksic
- Department of Haematology; Queen Elizabeth Hospital; Adelaide South Australia Australia
| | - J. Gibson
- Department of Haematology; Royal Prince Alfred Hospital; Sydney New South Wales Australia
- Faculty of Medicine; University of Sydney; Sydney New South Wales Australia
| | - H. M. Prince
- Faculty of Medicine, Dentistry and Health Sciences; University of Melbourne; Melbourne Victoria Australia
- Department of Haematology; Peter MacCallum Cancer Centre; Melbourne Victoria Australia
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Wang WA, Groenendyk J, Michalak M. Endoplasmic reticulum stress associated responses in cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:2143-9. [DOI: 10.1016/j.bbamcr.2014.01.012] [Citation(s) in RCA: 143] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 01/08/2014] [Accepted: 01/10/2014] [Indexed: 11/29/2022]
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Improved response rates with bortezomib in relapsed or refractory multiple myeloma: an observational study in Chinese patients. Adv Ther 2014; 31:1082-94. [PMID: 25331616 PMCID: PMC4209095 DOI: 10.1007/s12325-014-0159-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Indexed: 11/02/2022]
Abstract
INTRODUCTION Bortezomib, a novel proteasome inhibitor, is approved for the treatment of relapsed multiple myeloma (MM). Efficacy and safety of bortezomib is well known; however, it was necessary to validate the data in patients with different ethnic backgrounds. The efficacy and safety of bortezomib was assessed in patients from China with relapsed/refractory MM in a real-world scenario. METHODS This prospective, non-interventional, observational study enrolled both male and female Chinese patients, aged ≥18 years and diagnosed with relapsed or refractory MM. Administration of intravenous bortezomib at 1.3 mg/m2 was recommended twice a week for 2 weeks (days 1, 4, 8 and 11), followed by a 10-day rest period (maximum of 8 cycles) and a follow-up every 12 weeks for 3 years. Efficacy assessments included best response, objective response rate (ORR), time to response, duration of response, and overall survival. Safety was also assessed. RESULTS A total of 517 patients were enrolled with a median age of 58.7 years. Patients predominantly had immunoglobulin G type (46.2%) and stage III (47.8%) myeloma. Overall, 202 (42.3%) patients had partial response as best response, ORR was 88.9% and the proportion of patients exhibiting complete response was 24.7%. The median time to response observed was 27 (21-40) days. Median time to progression was 415 days and median overall survival was 475 days. Thrombocytopenia (14.4%) was the most common adverse event. CONCLUSION Bortezomib demonstrated clinical response in majority of patients and was well tolerated in this observational study in Chinese patients with relapsed/refractory MM.
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