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Gundesen MT, Schjesvold F, Lund T. Treatment of myeloma bone disease: When, how often, and for how long? J Bone Oncol 2025; 52:100680. [PMID: 40242221 PMCID: PMC12002780 DOI: 10.1016/j.jbo.2025.100680] [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] [Received: 12/30/2024] [Revised: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 04/18/2025] Open
Abstract
The landscape of MM has changed dramatically in recent years. Several new and more effective treatments have been introduced that not only makes patients live longer but also brings them into a deeper remission. This makes the potential total exposure of bone protective treatment much higher but perhaps also less needed. New and more precise imagining techniques have been introduced making detection of bone disease more sensitive, and the introduction of SLiM-CRAB criteria have changed the parameters used in old clinical trials investigating treatment of MM bone disease. New data have also emerged investigating the effect of the RANKL inhibitor denosumab compared to zoledronic acid (ZOL). Randomized trials have investigated longer treatment durations, which becomes more relevant as patients now live longer. In addition in this review, data regarding interval between individual treatment, impact of remission status, new data in relation to rebound after discontinuation and of denosumab, as well as the rational for drug holidays before dental procedures will also be discussed.
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Affiliation(s)
| | - Fredrik Schjesvold
- Oslo Myeloma Center, Department of Hematology, Oslo University Hospital, Oslo, Norway
- K.G. Jebsen Centre for B-Cell Malignancies, University of Oslo, Oslo, Norway
| | - Thomas Lund
- Department of Hematology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Centre for Innovative Medical Technology, Odense University Hospital, Odense, Denmark
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2
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Deng M, Tang C, Yin L, Jiang Y, Huang Y, Feng Y, Chen C. Clinical and omics biomarkers in osteoarthritis diagnosis and treatment. J Orthop Translat 2025; 50:295-305. [PMID: 39911590 PMCID: PMC11795539 DOI: 10.1016/j.jot.2024.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 11/03/2024] [Accepted: 12/09/2024] [Indexed: 02/07/2025] Open
Abstract
Osteoarthritis (OA) is a prevalent degenerative joint disease that significantly impacts the quality of life for hundreds of millions, and is a major cause of disability. Despite this, diagnostic and therapeutic options for OA are still limited. With advances in molecular biology, an increasing number of OA biomarkers have been identified, which not only enhances our understanding of OA pathogenesis, but also offers new approaches for OA diagnosis and treatment. This review discussed the research progress on traditional OA biomarkers, and analyzed the application of various omics, including genomics, transcriptomics, proteomics, and metabolomics, in the diagnosis and treatment of OA. Furthermore, we explored how integrating multi-omics methods can reveal interactions among different biomolecules and their roles in the development of OA. This emerging interdisciplinary approach not only provides a more comprehensive understanding of the fundamental biological characteristics of OA, but also aids in identifying new integrated biomarkers, thereby allowing for more accurate predictions of disease progression and treatment responses. The identification and development of biomarkers offer new perspectives in understanding OA, enhancing the specificity and sensitivity of biological diagnostic markers, providing a basis for the design of targeted drugs, and ultimately advancing the development of precision diagnosis and treatment strategies in clinical OA. This study provides an overview of both commonly used and emerging biomarkers of OA which is beneficial for a more accurate, timely, effective clinical diagnosis and treatment for OA.
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Affiliation(s)
- Muhai Deng
- College of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
| | - Cong Tang
- College of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
| | - Li Yin
- Department of Orthopaedics, General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Yunsheng Jiang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yang Huang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Wound Infection and Drug, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Yong Feng
- Department of Orthopedic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing, 400014, China
| | - Cheng Chen
- College of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
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3
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Huang L, Zhong Y, Chen Q, He D, Zheng G, Yang Y, Han X, Wu W, Zhao Y, Li Y, Yang L, Cai Z, He J. The correlation between serum bone metabolism indexes and bone disease and survival in newly diagnosed multiple myeloma patients. Cancer Biol Ther 2024; 25:2403205. [PMID: 39295128 DOI: 10.1080/15384047.2024.2403205] [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] [Received: 05/08/2024] [Revised: 08/26/2024] [Accepted: 09/07/2024] [Indexed: 09/21/2024] Open
Abstract
Objective Myeloma-related bone disease (MBD) is one of the most common complications of multiple myeloma (MM). This study aims to investigate the correlation between serum bone metabolism indexes (BMIs), the clinical characteristics and prognosis of newly diagnosed MM (NDMM) patients. METHODS The serum BMIs of 148 patients with NDMM in a single hematological disease treatment center from April 2014 to December 2019 were analyzed retrospectively, including type I collagen amino terminal elongation peptide (PINP), β-C-terminal telopeptide of type I collagen (β-CTX) and N-terminal osteocalcin (N-MID). Other clinical indexes were simultaneously collected and the degree of bone damage in patients was evaluated. We explored the effect of serum BMIs on the prognosis and identified independent prognostic factors. Another 77 NDMM patients from April 2018 to February 2021 served as the validation cohort. RESULTS The area under the curve (AUC) predicted by β-C-terminal telopeptide of type I collagen (β-CTX), type I collagen amino terminal elongation peptide (PINP), and N-terminal osteocalcin (N-MID) for overall survival (OS) were 0.708, 0.613, and 0.538, respectively. Patients with high serum levels had shorter OS (p < .001, p = .004, p = .027, respectively). Cox multivariate analysis indicated that serum β- CTX、lactic dehydrogenase、hemoglobin and the degree of bone injury were independent prognostic factors. A COX regression model was established with a C-index of 0.782 and validated with a C-index of 0.711. CONCLUSION The serum BMIs are correlated with the patients' OS, and β- CTX can be an independent prognostic factor.
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Affiliation(s)
- Linlin Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Yi Zhong
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Qingxiao Chen
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Donghua He
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Gaofeng Zheng
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yang Yang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoyan Han
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenjun Wu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi Zhao
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Li Yang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhen Cai
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jingsong He
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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4
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Bruno T, Catena V, Corleone G, Cortile C, Cappelletto MC, Bellei B, De Nicola F, Amadio B, Gumenyuk S, Marchesi F, Annibali O, Blandino G, Fanciulli M, Di Agostino S. Che-1/miR-590-3p/TAZ axis sustains multiple myeloma disease. Leukemia 2024; 38:877-882. [PMID: 38368441 PMCID: PMC10997508 DOI: 10.1038/s41375-024-02168-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 02/01/2024] [Accepted: 02/02/2024] [Indexed: 02/19/2024]
Affiliation(s)
- Tiziana Bruno
- SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Valeria Catena
- SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Giacomo Corleone
- SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Clelia Cortile
- SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | | | - Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, IRCCS San Gallicano Dermatological Institute, Rome, Italy
| | - Francesca De Nicola
- SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Bruno Amadio
- SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Svitlana Gumenyuk
- Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Francesco Marchesi
- Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Ombretta Annibali
- Unit Of Hematology, Stem Cell Transplantation, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128, Roma, Italy
| | - Giovanni Blandino
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144, Rome, Italy
| | - Maurizio Fanciulli
- SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
| | - Silvia Di Agostino
- Department of Health Sciences, Magna Græcia University of Catanzaro, 88100, Catanzaro, Italy
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5
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Mehdi SH, Gentry AC, Lee JY, Chung CP, Yoon D. The Synthetic Collagen-Binding Peptide NIPEP-OSS Delays Mouse Myeloma Progression. Cancers (Basel) 2023; 15:2473. [PMID: 37173940 PMCID: PMC10177053 DOI: 10.3390/cancers15092473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 05/15/2023] Open
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy. It is a clonal B-cell disorder characterized by the proliferation of malignant plasma cells in the bone marrow, the presence of monoclonal serum immunoglobulin, and osteolytic lesions. An increasing amount of evidence shows that the interactions of MM cells and the bone microenvironment play a significant role, suggesting that these interactions may be good targets for therapy. The osteopontin-derived collagen-binding motif-bearing peptide NIPEP-OSS stimulates biomineralization and enhances bone remodeling dynamics. Due to its unique targeted osteogenic activity with a broad safety margin, we evaluated the potential of NIPEP-OSS for anti-myeloma activity using MM bone disease (MMBD) animal models. In a 5TGM1-engrafted NSG model, the survival rates of the control and treated groups were significantly different (p = 0.0014), with median survival times of 45 and 57 days, respectively. The bioluminescence analyses showed that myeloma slowly developed in the treated mice compared to the control mice in both models. NIPEP-OSS enhanced bone formation by increasing biomineralization in the bone. We also tested NIPEP-OSS in a well-established 5TGM1-engrafted C57BL/KaLwRij model. Similar to the previous model, the median survival times of the control and treated groups were significantly different (p = 0.0057), with 46 and 63 days, respectively. In comparison with the control, an increase in p1NP was found in the treated mice. We concluded that NIPEP-OSS delays mouse myeloma progression via bone formation in MMBD mouse models.
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Affiliation(s)
- Syed Hassan Mehdi
- Myeloma Center, The University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Austin C. Gentry
- Myeloma Center, The University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Jue-Yeon Lee
- Research Institute, NIBEC Co., Ltd., 174 Yulgok-ro, Jongno-gu, Seoul 03170, Republic of Korea
| | - Chong-Pyoung Chung
- Research Institute, NIBEC Co., Ltd., 174 Yulgok-ro, Jongno-gu, Seoul 03170, Republic of Korea
| | - Donghoon Yoon
- Myeloma Center, The University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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6
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Harmon KA, Roman S, Lancaster HD, Chowhury S, Cull E, Goodwin RL, Arce S, Fanning S. Structural and Ultrastructural Analysis of the Multiple Myeloma Cell Niche and a Patient-Specific Model of Plasma Cell Dysfunction. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2022; 28:254-264. [PMID: 34881690 DOI: 10.1017/s1431927621013805] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Multiple myeloma (MM) is a deadly, incurable malignancy in which antibody-secreting plasma cells (PCs) become neoplastic. Previous studies have shown that the PC niche plays a role cancer progression. Bone marrow (BM) cores from MM and a premalignant condition known as monoclonal gammopathy of unknown significance (MGUS) patients were analyzed with confocal and transmission electron microscopy. The BM aspirates from these patients were used to generate 3D PC cultures. These in vitro cultures were then assayed for the molecular, cellular, and ultrastructural hallmarks of dysfunctional PC at days 1 and 5. In vivo, evidence of PC endoplasmic reticulum stress was found in both MM and MGUS BM; however, evidence of PC autophagy was found only in MM BM. Analysis of in vitro cultures found that MM PC can survive and maintain a differentiated phenotype over an unprecedented 5 days, had higher levels of paraprotein production when compared to MGUS-derived cultures, and showed evidence of PC autophagy as well. Increased fibronectin deposition around PC associated with disease severity and autophagy dysregulation was also observed. 3D cultures constructed from BM aspirates from MGUS and MM patients allow for long-term culture of functional PC while maintaining their distinct morphological phenotypes.
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Affiliation(s)
| | | | - Harrison D Lancaster
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
| | - Saeeda Chowhury
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
- Department of Internal Medicine, Prisma Health System Upstate, Greenville, SC29605, USA
- Prisma Health Cancer Institute, Greenville, SC29605, USA
| | - Elizabeth Cull
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
- Department of Internal Medicine, Prisma Health System Upstate, Greenville, SC29605, USA
- Prisma Health Cancer Institute, Greenville, SC29605, USA
| | - Richard L Goodwin
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
| | - Sergio Arce
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
- Prisma Health Cancer Institute, Greenville, SC29605, USA
| | - Suzanne Fanning
- School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
- Department of Internal Medicine, Prisma Health System Upstate, Greenville, SC29605, USA
- Prisma Health Cancer Institute, Greenville, SC29605, USA
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7
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Pop V, Parvu A, Craciun A, Farcas AD, Tomoaia G, Bojan A. Modern markers for evaluating bone disease in multiple myeloma (Review). Exp Ther Med 2021; 22:1329. [PMID: 34630683 DOI: 10.3892/etm.2021.10764] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 08/20/2021] [Indexed: 12/24/2022] Open
Abstract
Multiple myeloma (MM) is a bone marrow neoplasia with increasing incidence compared to previous years. Although new therapeutic molecules have been introduced, it remains an incurable disease with severe repercussions to patients. For many patients, bone disease represents a severe problem often causing pain, pathological bone fractures, and spinal cord compression, which affects the quality of life. This article analyzes the main markers of bone destruction in MM as well as risk factors for severe bone damage. Bone complications have a negative impact on the quality of life of patients with MM, along with other associated complications (renal failure, hypogammaglobulinemia, osteolytic bone disease, hypercalcemia, anemia). The markers of bone destruction described in this article include: interleukin (IL)-6, tumor necrosis factor (TNF)-α, receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX, CTX), human bone sialoprotein (BSP) and dickkopf-1 secreted glycoprotein (DKK1). The future practical applicability of this literature review would be the large-scale determination of markers of bone destruction that correlate with the negative evolution to complications of bone disease or the implications that these markers have in regards to treatment.
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Affiliation(s)
- Vlad Pop
- Hematology Department, 'Iuliu Haţieganu' University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania.,Hematology Department, 'Prof. Dr. Ioan Chiricuta' Oncological Institute, 400015 Cluj-Napoca, Romania
| | - Andrada Parvu
- Hematology Department, 'Iuliu Haţieganu' University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania.,Hematology Department, 'Prof. Dr. Ioan Chiricuta' Oncological Institute, 400015 Cluj-Napoca, Romania
| | - Alexandra Craciun
- Medical Biochemistry Department, 'Iuliu Haţieganu' University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Anca Daniela Farcas
- Internal Medicine Department, 'Iuliu Haţieganu' University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania.,Cardiology Department, Emergency County Clinic Hospital, 400006 Cluj-Napoca, Romania
| | - Gheorghe Tomoaia
- Orthopedics and Traumatology Department, 'Iuliu Haţieganu' University of Medicine and Pharmacy, 400132 Cluj-Napoca, Romania
| | - Anca Bojan
- Hematology Department, 'Iuliu Haţieganu' University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania.,Hematology Department, 'Prof. Dr. Ioan Chiricuta' Oncological Institute, 400015 Cluj-Napoca, Romania
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8
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Wallington-Beddoe CT, Mynott RL. Prognostic and predictive biomarker developments in multiple myeloma. J Hematol Oncol 2021; 14:151. [PMID: 34556161 PMCID: PMC8461914 DOI: 10.1186/s13045-021-01162-7] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 09/07/2021] [Indexed: 12/24/2022] Open
Abstract
New approaches to stratify multiple myeloma patients based on prognosis and therapeutic decision-making, or prediction, are needed since patients are currently managed in a similar manner regardless of individual risk factors or disease characteristics. However, despite new and improved biomarkers for determining the prognosis of patients, there is currently insufficient information to utilise biomarkers to intensify, reduce or altogether change treatment, nor to target patient-specific biology in a so-called predictive manner. The ever-increasing number and complexity of drug classes to treat multiple myeloma have improved response rates and so clinically useful biomarkers will need to be relevant in the era of such novel therapies. Therefore, the field of multiple myeloma biomarker development is rapidly progressing, spurred on by new technologies and therapeutic approaches, and underpinned by a deeper understanding of tumour biology with individualised patient management the goal. In this review, we describe the main biomarker categories in multiple myeloma and relate these to diagnostic, prognostic and predictive applications. ![]()
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Affiliation(s)
- Craig T Wallington-Beddoe
- College of Medicine and Public Health, Level 4, Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, SA, 5042, Australia. .,Flinders Medical Centre, Bedford Park, SA, 5042, Australia. .,Centre for Cancer Biology, SA Pathology and The University of South Australia, Adelaide, SA, 5000, Australia. .,Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, 5000, Australia.
| | - Rachel L Mynott
- College of Medicine and Public Health, Level 4, Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, SA, 5042, Australia
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9
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Steplewski A, Fertala J, Tomlinson RE, Wang ML, Donahue A, Arnold WV, Rivlin M, Beredjiklian PK, Abboud JA, Namdari S, Fertala A. Mechanisms of reducing joint stiffness by blocking collagen fibrillogenesis in a rabbit model of posttraumatic arthrofibrosis. PLoS One 2021; 16:e0257147. [PMID: 34492074 PMCID: PMC8423260 DOI: 10.1371/journal.pone.0257147] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
Posttraumatic fibrotic scarring is a significant medical problem that alters the proper functioning of injured tissues. Current methods to reduce posttraumatic fibrosis rely on anti-inflammatory and anti-proliferative agents with broad intracellular targets. As a result, their use is not fully effective and may cause unwanted side effects. Our group previously demonstrated that extracellular collagen fibrillogenesis is a valid and specific target to reduce collagen-rich scar buildup. Our previous studies showed that a rationally designed antibody that binds the C-terminal telopeptide of the α2(I) chain involved in the aggregation of collagen molecules limits fibril assembly in vitro and reduces scar formation in vivo. Here, we have utilized a clinically relevant arthrofibrosis model to study the broad mechanisms of the anti-scarring activity of this antibody. Moreover, we analyzed the effects of targeting collagen fibril formation on the quality of healed joint tissues, including the posterior capsule, patellar tendon, and subchondral bone. Our results show that blocking collagen fibrillogenesis not only reduces collagen content in the scar, but also accelerates the remodeling of healing tissues and changes the collagen fibrils’ cross-linking. In total, this study demonstrated that targeting collagen fibrillogenesis to limit arthrofibrosis affects neither the quality of healing of the joint tissues nor disturbs vital tissues and organs.
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Affiliation(s)
- Andrzej Steplewski
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Jolanta Fertala
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Ryan E. Tomlinson
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Mark L. Wang
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- Rothman Institute of Orthopaedics, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, United States of America
| | - Allison Donahue
- College of Medicine, Drexel University, Philadelphia, Pennsylvania, United States of America
| | - William V. Arnold
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- Rothman Institute of Orthopaedics, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, United States of America
| | - Michael Rivlin
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- Rothman Institute of Orthopaedics, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, United States of America
| | - Pedro K. Beredjiklian
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- Rothman Institute of Orthopaedics, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, United States of America
| | - Joseph A. Abboud
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- Rothman Institute of Orthopaedics, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, United States of America
| | - Surena Namdari
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- Rothman Institute of Orthopaedics, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, United States of America
| | - Andrzej Fertala
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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10
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Mehdi SH, Morris CA, Lee JA, Yoon D. An Improved Animal Model of Multiple Myeloma Bone Disease. Cancers (Basel) 2021; 13:4277. [PMID: 34503090 PMCID: PMC8428359 DOI: 10.3390/cancers13174277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/17/2021] [Accepted: 08/18/2021] [Indexed: 12/05/2022] Open
Abstract
Multiple myeloma (MM) is a plasma cell malignancy that causes an accumulation of terminally differentiated monoclonal plasma cells in the bone marrow, accompanied by multiple myeloma bone disease (MMBD). MM animal models have been developed and enable to interrogate the mechanism of MM tumorigenesis. However, these models demonstrate little or no evidence of MMBD. We try to establish the MMBD model with severe bone lesions and easily accessible MM progression. 1 × 106 luciferase-expressing 5TGM1 cells were injected into 8-12 week-old NOD SCID gamma mouse (NSG) and C57BL/KaLwRij mouse via the tail vein. Myeloma progression was assessed weekly via in vivo bioluminescence (BL) imaging using IVIS-200. The spine and femur/tibia were extracted and scanned by the micro-computer tomography for bone histo-morphometric analyses at the postmortem. The median survivals were 56 days in NSG while 44.5 days in C57BL/KaLwRij agreed with the BL imaging results. Histomorphic and DEXA analyses demonstrated that NSG mice have severe bone resorption that occurred at the lumbar spine but no significance at the femur compared to C57BL/KaLwRij mice. Based on these, we conclude that the systemic 5TGM1 injected NSG mouse slowly progresses myeloma and develops more severe MMBD than the C57BL/KaLwRij model.
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Affiliation(s)
- Syed Hassan Mehdi
- Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Carol A Morris
- Graduate Program in Interdisciplinary Biomedical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Jung Ae Lee
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA 01605, USA;
| | - Donghoon Yoon
- Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
- Graduate Program in Interdisciplinary Biomedical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
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11
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Abstract
Bone turnover markers fill a clinical need that improves comprehensive care of metabolic bone health and osteoporosis. Creating a standard process for drawing them that reduces modifiable variability improves their precision and clinical usefulness. Creating a standard process for interpreting them by applying statistical significance improves their clinical applicability. Understanding what causes them to increase and decrease can help elucidate secondary causes of osteoporosis. Monitoring them can assess patient adherence to therapy for a silent disease that will progressively become louder with an aging global population.
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Affiliation(s)
- Sumeet Jain
- Division of Endocrinology and Metabolism, Department of Medicine, Rush University Medical Center, 1725 West Harrison Street, Suite 250, Chicago, IL 60612, USA.
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12
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Terpos E, Ntanasis-Stathopoulos I, Katodritou E, Kyrtsonis MC, Douka V, Spanoudakis E, Papatheodorou A, Eleutherakis-Papaiakovou E, Kanellias N, Gavriatopoulou M, Makras P, Kastritis E, Dimopoulos MA. Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study. Cancers (Basel) 2021; 13:cancers13061257. [PMID: 33809268 PMCID: PMC7998249 DOI: 10.3390/cancers13061257] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/07/2021] [Accepted: 03/11/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Carfilzomib with dexamethasone is an important therapeutic option for patients with relapsed/refractory multiple myeloma. We sought to evaluate the effect of this regimen on the bone-related outcomes, which are associated with both quality of life and survival. Among 25 patients, less than one third experienced a new skeletal-related event during treatment, even in the absence of any bone-targeted agent. Interestingly, there was a significant decrease in serum biomarkers of bone resorption, which was at least partially due to the sRANKL/OPG ratio reduction. Furthermore, Kd produced an increase in markers of bone formation. Importantly, these changes were independent of myeloma response to treatment. Therefore, the combination of carfilzomib and dexamethasone improves bone metabolism and bone health in patients with advanced multiple myeloma. Abstract Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 (p = 0.048) and of tartrate-resistant acid phosphatase-5b (p = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months (p = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months (p = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use.
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Affiliation(s)
- Evangelos Terpos
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
- Correspondence: ; Tel.: +30-2132162846
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
| | - Eirini Katodritou
- Department of Hematology, Theagenio Cancer Hospital, PS 54639 Thessaloniki, Greece;
| | - Marie-Christine Kyrtsonis
- First Department of Propedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece;
| | - Vassiliki Douka
- Department of Hematology and Bone Marrow Transplantation Unit, General Hospital “G.Papanikolaou”, PS 57010 Thessaloniki, Greece;
| | - Emmanouil Spanoudakis
- Department of Hematology, Faculty of Medicine, Democritus University of Thrace, PS 68131 Alexandroupolis, Greece;
| | - Athanasios Papatheodorou
- Department of Medical Research, 251 General Air-Force Hospital, PS 11525 Athens, Greece; (A.P.); (P.M.)
| | - Evangelos Eleutherakis-Papaiakovou
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
| | - Nikolaos Kanellias
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
| | - Polyzois Makras
- Department of Medical Research, 251 General Air-Force Hospital, PS 11525 Athens, Greece; (A.P.); (P.M.)
| | - Efstathios Kastritis
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
| | - Meletios A Dimopoulos
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
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13
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Diamond TH, Golombick T, Manoharan A, Ramakrishna R, Bryant C. Teriparatide (recombinant human parathyroid hormone 1-34) therapy in myeloma patients with severe osteoporosis and fractures despite effective anti-myeloma therapy and bisphosphonates: A pilot study. Am J Hematol 2020; 95:E272-E276. [PMID: 32602126 DOI: 10.1002/ajh.25919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 11/07/2022]
Affiliation(s)
- Terrence H Diamond
- Department of Endocrinology, St George Hospital, Sydney, New South Wales, Australia
| | - Terry Golombick
- Department of Endocrinology, St George Hospital, Sydney, New South Wales, Australia
| | - Arumugam Manoharan
- Southern Sydney Haematology, University of Wollongong, Wollongong, New South Wales, Australia
| | - Rajeev Ramakrishna
- Southern Sydney Haematology, University of Wollongong, Wollongong, New South Wales, Australia
| | - Carl Bryant
- Bryant Radiology, Kogarah, Sydney, New South Wales, Australia
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14
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Yamanaka T, Fukatsu T, Uchimuro T, Takanashi S. Cardiac calcified amorphous tumour associated with multiple myeloma. BMJ Case Rep 2020; 13:13/4/e233679. [PMID: 32350053 DOI: 10.1136/bcr-2019-233679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
We report an 86-year-old woman who was diagnosed with multiple myeloma (MM) and was receiving chemotherapy since the age of 82. A high echoic mass attached to the mitral valve was observed on transthoracic echocardiography 4 years after the treatment. The possibility of malignancy could not be ruled out, and hence, the mass was excised surgically. Pathologically, most of the mass consisted of calcified lesion without tumour tissue, and these findings were not inconsistent with calcified amorphous tumour (CAT). This case suggests that CAT may be associated with MM and has been reported after a thorough literature review.
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15
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Liu Z, Liu H, Li Y, Wang Y, Xing R, Mi F, Xiang C, Fu R. Adiponectin inhibits the differentiation and maturation of osteoclasts via the mTOR pathway in multiple myeloma. Int J Mol Med 2020; 45:1112-1120. [PMID: 31985020 PMCID: PMC7053860 DOI: 10.3892/ijmm.2020.4475] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 12/10/2019] [Indexed: 01/05/2023] Open
Abstract
The present study sought to investigate the correlation between adipose cytokines (visfatin, leptin and adiponectin) and markers of multiple myeloma bone disease, and to determine the effects and mechanism of action of adiponectin on the differentiation and maturation of osteoclasts in multiple myeloma (MM). The levels of visfatin, leptin and adiponectin were measured. Their association with the indices of myeloma tumor load and bone disease were analyzed. Reverse transcription-quantitative PCR was used to detect the expression of receptor activator of nuclear factor-κB ligand (RANKL), osteoclast associated Ig-like receptor (OSCAR), tartrate-resistant acid phosphatase (TRAP) and Cathepsin K genes. Flow cytometry was used to detect the expression of adiponectin receptor 1 (AdipoR1) and the phosphorylation of the mechanistic target of rapamycin kinase (mTOR) pathway-associated proteins mTOR and eukaryotic translation initiation factor 4E-binding protein (4EBP1). There were no significant correlations among leptin, visfatin and the indexes of myeloma tumor load and bone disease. Serum adiponectin levels were significantly lower in patients with newly diagnosed multiple myeloma compared with healthy volunteers (12.37±3.13 vs. 13.80±0.95; P<0.05). The number of mature osteoclasts in the adiponectin group was lower compared with in the control group. Adiponectin also inhibited the mRNA expression of the osteoclast-associated factors RANKL, OSCAR, TRAP and Cathepsin K. Comparison between the non-adiponectin group and the adiponectin group revealed that adiponectin increased the expression of AdipoR1 on the surface of osteoclast precursor cells (26.21±4.27% vs. 29.86±6.23%; P<0.05) and reduced the expression of phosphorylated (p-)mTOR (7.89±1.00% vs. 5.91±1.26%; P<0.05) and p-4EBP1 (26.78±5.00% vs. 22.49±4.24%; P<0.05). The p-mTOR and p-4EBP1 levels in the adiponectin + MHY1485 (an mTOR signaling pathway-specific agonist) group were significantly higher compared with those in the adiponectin group. It was revealed that adiponectin may inhibit osteoclast differentiation and maturation via the mTOR pathway. In conclusion, adiponectin inhibits the differentiation and maturation of osteoclasts by increasing the expression of AdipoR1 and reducing the phosphorylation levels of mTOR and 4EBP1 in patients with MM.
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Affiliation(s)
- Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Hui Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Yanqi Li
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Yangyang Wang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Rui Xing
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Fu Mi
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Chenhuan Xiang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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16
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Terpos E, Kastritis E, Ntanasis‐Stathopoulos I, Christoulas D, Papatheodorou A, Eleutherakis‐Papaiakovou E, Kanellias N, Fotiou D, Ziogas DC, Migkou M, Roussou M, Trougakos IP, Gavriatopoulou M, Dimopoulos MA. Consolidation therapy with the combination of bortezomib and lenalidomide (VR) without dexamethasone in multiple myeloma patients after transplant: Effects on survival and bone outcomes in the absence of bisphosphonates. Am J Hematol 2019; 94:400-407. [PMID: 30592079 DOI: 10.1002/ajh.25392] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 11/30/2018] [Accepted: 12/21/2018] [Indexed: 12/29/2022]
Abstract
Optimizing consolidation treatment in transplant-eligible newly diagnosed multiple myeloma patients in order to improve efficacy and bone-related outcomes is intriguing. We conducted an open-label, prospective study evaluating the efficacy and safety of bortezomib and lenalidomide (VR) consolidation after ASCT, in the absence of dexamethasone and bisphosphonates. Fifty-nine patients, who received bortezomib-based induction, were given 4 cycles of VR starting on day 100 post-ASCT. After ASCT, 58% of patients improved their response status, while following VR consolidation 39% further deepened their response; stringent complete response rates increased to 51% after VR from 24% post-ASCT. VR consolidation resulted in a significant reduction of soluble receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio and sclerostin circulating levels, which was more pronounced among patients achieving very good partial response or better. After a median follow-up of 62 months, no skeletal-related events (SREs) were observed, despite the lack of bisphosphonates administration. The median TTP after ASCT was 37 months, while median overall survival (OS) has not been reached yet; the probability of 4- and 5-year OS was 81% and 64%, respectively. In conclusion, VR consolidation is an effective, dexamethasone- and bisphosphonate-free approach, which offers long OS with improvements on bone metabolism and no SREs.
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Affiliation(s)
- Evangelos Terpos
- Department of Clinical Therapeutics National and Kapodistrian University of Athens, School of Medicine Athens Greece
| | - Efstathios Kastritis
- Department of Clinical Therapeutics National and Kapodistrian University of Athens, School of Medicine Athens Greece
| | - Ioannis Ntanasis‐Stathopoulos
- Department of Clinical Therapeutics National and Kapodistrian University of Athens, School of Medicine Athens Greece
| | | | | | | | - Nikolaos Kanellias
- Department of Clinical Therapeutics National and Kapodistrian University of Athens, School of Medicine Athens Greece
| | - Despina Fotiou
- Department of Clinical Therapeutics National and Kapodistrian University of Athens, School of Medicine Athens Greece
| | - Dimitrios C. Ziogas
- Department of Clinical Therapeutics National and Kapodistrian University of Athens, School of Medicine Athens Greece
| | - Magdalini Migkou
- Department of Clinical Therapeutics National and Kapodistrian University of Athens, School of Medicine Athens Greece
| | - Maria Roussou
- Department of Clinical Therapeutics National and Kapodistrian University of Athens, School of Medicine Athens Greece
| | - Ioannis P. Trougakos
- Department of Cell Biology and Biophysics, Faculty of Biology National and Kapodistrian University of Athens Athens Greece
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics National and Kapodistrian University of Athens, School of Medicine Athens Greece
| | - Meletios A. Dimopoulos
- Department of Clinical Therapeutics National and Kapodistrian University of Athens, School of Medicine Athens Greece
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17
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Myeloma Bone Disease: Update on Pathogenesis and Novel Treatment Strategies. Pharmaceutics 2018; 10:pharmaceutics10040202. [PMID: 30355994 PMCID: PMC6321035 DOI: 10.3390/pharmaceutics10040202] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/15/2018] [Accepted: 10/20/2018] [Indexed: 01/31/2023] Open
Abstract
Bone disease, including osteolytic lesions and/or osteoporosis, is a common feature of multiple myeloma (MM). The consequences of skeletal involvement are severe pain, spinal cord compressions, and bone fractures, which have a dramatic impact on patients’ quality of life and, ultimately, survival. During the past few years, several landmark studies significantly enhanced our insight into MM bone disease (MBD) by identifying molecular mechanisms leading to increased bone resorption due to osteoclast activation, and decreased bone formation by osteoblast inhibition. Bisphosphonates were the mainstay to prevent skeletal-related events in MM for almost two decades. Excitingly, the most recent approval of the receptor activator of NF-kappa B ligand (RANKL) inhibitor, denosumab, expanded treatment options for MBD, for patients with compromised renal function, in particular. In addition, several other bone-targeting agents, including bone anabolic drugs, are currently in preclinical and early clinical assessment. This review summarizes our up-to-date knowledge on the pathogenesis of MBD and discusses novel state-of-the-art treatment strategies that are likely to enter clinical practice in the near future.
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18
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Lee OL, Horvath N, Lee C, Joshua D, Ho J, Szer J, Quach H, Spencer A, Harrison S, Mollee P, Roberts AW, Talaulikar D, Brown R, Augustson B, Ling S, Jaksic W, Gibson J, Kalff A, Johnston A, Kalro A, Ward C, Prince HM, Zannettino A. Bisphosphonate guidelines for treatment and prevention of myeloma bone disease. Intern Med J 2018; 47:938-951. [PMID: 28782211 DOI: 10.1111/imj.13502] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/26/2017] [Accepted: 05/15/2017] [Indexed: 01/10/2023]
Abstract
Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells in the bone marrow. More than 80% of patients with MM display evidence of myeloma bone disease (MBD), characterised by the formation of osteolytic lesions throughout the axial and appendicular skeleton. MBD significantly increases the risk of skeletal-related events such as pathologic fracture, spinal cord compression and hypercalcaemia. MBD is the result of MM plasma cells-mediated activation of osteoclast activity and suppression of osteoblast activity. Bisphosphonates (BP), pyrophosphate analogues with high bone affinity, are the only pharmacological agents currently recommended for the treatment and prevention of MBD and remain the standard of care. Pamidronate and zoledronic acid are the most commonly used BP to treat MBD. Although generally safe, frequent high doses of BP are associated with adverse events such as renal toxicity and osteonecrosis of the jaw. As such, optimal duration and dosing of BP therapy is required in order to minimise BP-associated adverse events. The following guidelines provide currently available evidence for the adoption of a tailored approach when using BP for the management of MBD.
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Affiliation(s)
- Oi Lin Lee
- Department of Haematology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Noemi Horvath
- Department of Haematology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.,Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia
| | - Cindy Lee
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Queen Elizabeth Hospital, Adelaide, South Australia, Australia
| | - Doug Joshua
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.,Department of Cancer and Haematology, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Joy Ho
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.,Department of Cancer and Haematology, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Jeff Szer
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.,Department of Clinical Haematology and BMT, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Hang Quach
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.,Department of Haematology, St Vincent's Hospital, Melbourne, Victoria, Australia
| | - Andrew Spencer
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.,Department of Haematology, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Simon Harrison
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.,Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Peter Mollee
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.,School of Medicine, University of Queensland, Brisbane, Queensland, Australia
| | - Andrew W Roberts
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.,Department of Clinical Haematology and BMT, Royal Melbourne Hospital, Melbourne, Victoria, Australia.,Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
| | - Dipti Talaulikar
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Canberra Hospital, Canberra, Australian Capital Territory, Australia.,College of Medicine, Biology and Environment, Australian National University, Canberra, Australian Capital Territory, Australia
| | - Ross Brown
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Bradley Augustson
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Silvia Ling
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Liverpool Hospital, Sydney, New South Wales, Australia.,South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Wilfrid Jaksic
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Queen Elizabeth Hospital, Adelaide, South Australia, Australia
| | - John Gibson
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.,Department of Cancer and Haematology, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Anna Kalff
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Anna Johnston
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Royal Hobart Hospital, Hobart, Tasmania, Australia.,Faculty of Health, University of Tasmania, Hobart, Tasmania, Australia
| | - Akash Kalro
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Haematology, Royal Darwin Hospital, Darwin, Northern Territory, Australia
| | - Chris Ward
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Department of Cancer and Haematology, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.,Department of Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - H Miles Prince
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.,Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Andrew Zannettino
- Medical and Scientific Advisory Group, Myeloma Australia, Melbourne, Victoria, Australia.,Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.,Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
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19
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Terpos E, Christoulas D, Gavriatopoulou M. Biology and treatment of myeloma related bone disease. Metabolism 2018; 80:80-90. [PMID: 29175022 DOI: 10.1016/j.metabol.2017.11.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 11/16/2017] [Accepted: 11/18/2017] [Indexed: 02/08/2023]
Abstract
Myeloma bone disease (MBD) is the most common complication of multiple myeloma (MM), resulting in skeleton-related events (SREs) such as severe bone pain, pathologic fractures, vertebral collapse, hypercalcemia, and spinal cord compression that cause significant morbidity and mortality. It is due to an increased activity of osteoclasts coupled to the suppressed bone formation by osteoblasts. Novel molecules and pathways that are implicated in osteoclast activation and osteoblast inhibition have recently been described, including the receptor activator of nuclear factor-kB ligand/osteoprotegerin pathway, activin-A and the wingless-type signaling inhibitors, dickkopf-1 (DKK-1) and sclerostin. These molecules interfere with tumor growth and survival, providing possible targets for the development of novel drugs for the management of lytic disease in myeloma but also for the treatment of MM itself. Currently, bisphosphonates are the mainstay of the treatment of myeloma bone disease although several novel agents such as denosumab and sotatercept appear promising. This review focuses on recent advances in MBD pathophysiology and treatment, in addition to the established therapeutic guidelines.
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Affiliation(s)
- Evangelos Terpos
- Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece.
| | - Dimitrios Christoulas
- Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece
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20
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Vallet S, Hoyle NR, Kyle RA, Podar K, Pecherstorfer M. A role for bone turnover markers β-CrossLaps (CTX) and amino-terminal propeptide of type I collagen (PINP) as potential indicators for disease progression from MGUS to multiple myeloma. Leuk Lymphoma 2018; 59:2431-2438. [PMID: 29345175 DOI: 10.1080/10428194.2017.1421757] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Multiple myeloma (MM) is characterized by bone lesions arising due to unbalanced bone remodeling. Changes in the bone formation marker amino-terminal propeptide of type I collagen (PINP) and the bone resorption marker β-CrossLaps (CTX) reflect physiologic bone turnover. Whether PINP and CTX have a role in disease progression from monoclonal gammopathy of undetermined significance (MGUS) to MM is unknown. In this cross-sectional follow-up study, 241 patients with MM or MGUS were included. Serum levels of PINP and CTX were significantly higher in MM patients compared to MGUS. Moreover, increasing concentrations of PINP and CTX were observed in those MGUS patients progressing to MM, whereas PINP and CTX levels remained unchanged in MGUS patients with stable disease. In conclusion, these data indicate a potential role of PINP and CTX as biomarkers for the progression of MGUS to MM.
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Affiliation(s)
- Sonia Vallet
- a Department of Oncology , University Hospital Krems and Karl Landsteiner University , Krems an der Donau , Austria
| | | | - Robert A Kyle
- c Division of Hematology , Mayo Clinic , Rochester , MN , USA
| | - Klaus Podar
- a Department of Oncology , University Hospital Krems and Karl Landsteiner University , Krems an der Donau , Austria
| | - Martin Pecherstorfer
- a Department of Oncology , University Hospital Krems and Karl Landsteiner University , Krems an der Donau , Austria
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21
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Boutsikas G, Terpos E, Papatheodorou A, Tsirkinidis P, Tsirigotis P, Meletiou A, Lalou E, Telonis V, Zannou A, Kanellopoulos A, Galani Z, Stefanou A, Tsaftaridis P, Viniou NA, Panayiotidis P, Kyrtsonis MC, Meletis J, Vassilakopoulos TP, Angelopoulou MK. Study of bone metabolism and angiogenesis in patients undergoing high-dose chemotherapy/autologous hematopoietic stem cell transplantation. Eur J Haematol 2017; 100:131-139. [PMID: 29105864 DOI: 10.1111/ejh.12990] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2017] [Indexed: 11/30/2022]
Abstract
OBJECTIVES As the interaction between hematopoietic stem cells (HSCs) and endosteal and endothelial niches in HSCs homing is essential, we aimed to study bone turnover and angiogenesis in 29 patients with lymphoma/multiple myeloma undergoing hematopoietic stem cell transplantation (HSCT). METHODS Serum samples were collected before high-dose chemotherapy (HDT), at the end of HDT, after HSC infusion, at the nadir of myelotoxicity, and at engraftment. Bone metabolism (CTX, TRACP-5b, bALP, OC, DKK1, RANKL, OPG), and angiogenesis (Ang1, Ang2) markers were measured. These markers were also measured in 21 control patients before and after conventional chemotherapy. RESULTS AND CONCLUSIONS Bone resorption declined during HSCT (decrease in TRACP-5b [P < .001] and CTX [P = .006]). Bone formation declined as well (decrease in bALP and OC [P < .001 for both]). RANKL/OPG ratio, an indicator of osteoclastic activation, did not change significantly (P = .5). Ang1/Ang2 ratio, a vessel equilibrium marker, decreased significantly (P < .001) suggesting endothelial destabilization. The changes observed in the control group were similar except of bALP and RANKL/OPG ratio. Moreover, Ang1/Ang2 ratio on the day after HSC infusion strongly correlated with time to neutrophil and platelet engraftment (P < .001 for both). Conclusively, bone turnover and vessel destabilization represent important events during HSCT probably reflecting the effect of chemotherapy.
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Affiliation(s)
- Georgios Boutsikas
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Terpos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | - Panayiotis Tsirigotis
- 2nd Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Meletiou
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleni Lalou
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Athens, Greece
| | - Vasileios Telonis
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Zannou
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexander Kanellopoulos
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Athens, Greece
| | - Zacharoula Galani
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Athens, Greece
| | - Angeliki Stefanou
- 1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Panayiotis Tsaftaridis
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Athens, Greece
| | - Nora-Athina Viniou
- 1st Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Panayiotis Panayiotidis
- 1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Marie-Christine Kyrtsonis
- 1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - John Meletis
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Athens, Greece
| | - Theodoros P Vassilakopoulos
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria K Angelopoulou
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Athens, Greece
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Asimakopoulos F, Hope C, Johnson MG, Pagenkopf A, Gromek K, Nagel B. Extracellular matrix and the myeloid-in-myeloma compartment: balancing tolerogenic and immunogenic inflammation in the myeloma niche. J Leukoc Biol 2017; 102:265-275. [PMID: 28254840 DOI: 10.1189/jlb.3mr1116-468r] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 02/06/2017] [Accepted: 02/09/2017] [Indexed: 12/14/2022] Open
Abstract
The last 10-15 years have witnessed a revolution in treating multiple myeloma, an incurable cancer of Ab-producing plasma cells. Advances in myeloma therapy were ushered in by novel agents that remodel the myeloma immune microenvironment. The first generation of novel agents included immunomodulatory drugs (thalidomide analogs) and proteasome inhibitors that target crucial pathways that regulate immunity and inflammation, such as NF-κB. This paradigm continued with the recent regulatory approval of mAbs (elotuzumab, daratumumab) that impact both tumor cells and associated immune cells. Moreover, recent clinical data support checkpoint inhibition immunotherapy in myeloma. With the success of these agents has come the growing realization that the myeloid infiltrate in myeloma lesions-what we collectively call the myeloid-in-myeloma compartment-variably sustains or deters tumor cells by shaping the inflammatory milieu of the myeloma niche and by promoting or antagonizing immune-modulating therapies. The myeloid-in-myeloma compartment includes myeloma-associated macrophages and granulocytes, dendritic cells, and myeloid-derived-suppressor cells. These cell types reflect variable states of differentiation and activation of tumor-infiltrating cells derived from resident myeloid progenitors in the bone marrow-the canonical myeloma niche-or myeloid cells that seed both canonical and extramedullary, noncanonical niches. Myeloma-infiltrating myeloid cells engage in crosstalk with extracellular matrix components, stromal cells, and tumor cells. This complex regulation determines the composition, activation state, and maturation of the myeloid-in-myeloma compartment as well as the balance between immunogenic and tolerogenic inflammation in the niche. Redressing this balance may be a crucial determinant for the success of antimyeloma immunotherapies.
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Affiliation(s)
- Fotis Asimakopoulos
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA; .,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Chelsea Hope
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Michael G Johnson
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Adam Pagenkopf
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Kimberly Gromek
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Bradley Nagel
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
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Huang X, Zhang C, Wang C, Cai Q, Cao X, Cai H, Zhang L, Feng J, Zhou D, Li J. Measurement of β-isomerized C-terminal telopeptide of type I collagen in patients with POEMS syndrome: diagnostic, prognostic, and follow-up utilities. Blood Cancer J 2016; 6:e495. [PMID: 27834942 PMCID: PMC5148056 DOI: 10.1038/bcj.2016.109] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- X Huang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - C Zhang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - C Wang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Q Cai
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - X Cao
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - H Cai
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - L Zhang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - J Feng
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - D Zhou
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - J Li
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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25
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MGUS to myeloma: a mysterious gammopathy of underexplored significance. Blood 2016; 128:2599-2606. [PMID: 27737890 DOI: 10.1182/blood-2016-09-692954] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Accepted: 10/04/2016] [Indexed: 12/13/2022] Open
Abstract
All cases of multiple myeloma (MM) are preceded by precursor states termed monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). Genetic analyses of MGUS cells have provided evidence that it is a genetically advanced lesion, wherein tumor cells carry many of the genetic changes found in MM cells. Intraclonal heterogeneity is also established early during the MGUS phase. Although the genetic features of MGUS or SMM cells at baseline may predict disease risk, transition to MM involves altered growth of preexisting clones. Recent advances in mouse modeling of MGUS suggest that the clinical dormancy of the clone may be regulated in part by growth controls extrinsic to the tumor cells. Interactions of MGUS cells with immune cells, bone cells, and others in the bone marrow niche may be key regulators of malignant transformation. These interactions involve a bidirectional crosstalk leading to both growth-supporting and inhibitory signals. Because MGUS is already a genetically complex lesion, application of new tools for earlier detection should allow delineation of earlier stages, which we term as pre-MGUS Analyses of populations at increased risk of MGUS also suggest the possible existence of a polyclonal phase preceding the development of MGUS. Monoclonal gammopathy in several patients may have potential clinical significance in spite of low risk of malignancy. Understanding the entire spectrum of these disorders may have broader implications beyond prevention of clinical malignancy.
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26
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Clinical significance of osteoblast precursors and osteoclast precursors in earlier diagnosis and monitoring of myeloma bone disease. Ann Hematol 2016; 95:1099-106. [PMID: 27118542 DOI: 10.1007/s00277-016-2657-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 03/28/2016] [Indexed: 12/15/2022]
Abstract
Bone disease is the most common complication of multiple myeloma (MM). In order to diagnose and monitor the bone damages earlier, we detected circulating osteoclast precursors (OCPs) and osteoblast precursors (OBPs) by flow cytometry, comparing with special biochemical markers, such as tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), carboxy-terminal cross-linking telopeptide of type I collagen (CTX), osteocalcin (OCN), and procollagen I amino-terminal propeptide (PINP). The results showed that the circulating OBPs in the newly diagnosed MM patients significantly decreased compared with the normal controls (7.14 vs 12.82 %, P = 0.045), while circulating OCPs in the newly diagnosed patients and remission patients were significantly increased than the normal controls (2.46 vs 0.17 %, P = 0.000; 1.87 vs 0.17 %, P = 0.000, respectively). According to X-ray, newly diagnosed patients were divided into stages A and B (without and with osteolytic lesions). Compared with the normal controls, the circulating OBPs in stages A and B reduced (12.82 vs 7.47 %, P = 0.041; 12.82 vs 7.14 %, P = 0.010, respectively), while the circulating OCPs elevated (0.17 vs 2.31 %, P=0.010; 0.17 % vs 2.71 %, P=0.001, respectively). The levels of TRACP-5b and CTX in the newly diagnosed patients were higher than the normal controls (P = 0.014, P = 0.037) and remission patients (P = 0.025, P = 0.003), and they were significantly higher in stage B than the normal controls (P = 0.015, P = 0.002). However, the PINP and OCN levels had no significant changes in different stages. In conclusion, abnormal circulating OBPs and OCPs were found earlier before X-ray in MM and still existed in remission patients, indicating that they may be novel predictive markers for early diagnosing and monitoring bone disease.
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Silbermann R, Roodman GD. Current Controversies in the Management of Myeloma Bone Disease. J Cell Physiol 2016; 231:2374-9. [PMID: 26910829 DOI: 10.1002/jcp.25351] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Accepted: 02/19/2016] [Indexed: 12/22/2022]
Abstract
Recent significant advances in the treatment of multiple myeloma have resulted in an improvement in median overall survival from 4.6 years, for patients diagnosed between 2001 and 2005, to 6.1 years, for those diagnosed between 2006 and 2010 (Kumar et al., 2014). However, myeloma bone lesions persist in the absence of active disease and continue to be frequent and significant causes of patient morbidity and contribute to mortality. While bisphosphonate therapy in combination with anti-myeloma therapy remains the cornerstone of skeletal disease management in myeloma, open questions regarding the optimal management of patients with myeloma bone disease remain. This article will address when to initiate and stop bone-targeted therapy in patients with monoclonal gammopathies, duration of bisphosphonate treatment in the era of more effective anti-myeloma treatment, the role of bone resorption markers in determining the dosing schedule for anti-resorptive therapy, risks and benefits of long term anti-resorptive therapy, and whether anti-resorptive therapies should be stopped to enhance the potential anabolic effects of proteasome antagonists and other anabolic agents. J. Cell. Physiol. 231: 2374-2379, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Rebecca Silbermann
- Department of Medicine, Hematology/Oncology, Indiana University, Indianapolis, Indiana
| | - Garson David Roodman
- Department of Medicine, Hematology/Oncology, Indiana University, Indianapolis, Indiana.,Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
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28
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Vyzoukaki R, Tsirakis G, Pappa CA, Devetzoglou M, Tzardi M, Alexandrakis MG. The Impact of Mast Cell Density on the Progression of Bone Disease in Multiple Myeloma Patients. Int Arch Allergy Immunol 2016; 168:263-8. [DOI: 10.1159/000443275] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 12/09/2015] [Indexed: 11/19/2022] Open
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29
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Bhutani M, Landgren O, Usmani SZ. Multiple myeloma: is it time for biomarker-driven therapy? Am Soc Clin Oncol Educ Book 2016:e493-503. [PMID: 25993214 DOI: 10.14694/edbook_am.2015.35.e493] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Remarkable strides have been made in understanding the molecular mechanisms by which multiple myeloma develops, leading to more sophisticated classification that incorporates not only the traditional diagnostic criteria, but also immunophenotype, genetic, and molecular features. However, even with this added information, considerable heterogeneity in clinical outcomes exists within the identified subtypes. The present paradigm for myeloma treatment is built on the basic step of defining transplant eligibility versus noneligibility, as determined by age, performance status, and cumulative burden of comorbidities. An incredibly complex heterogeneous disease is, therefore, treated in a generalized way with the result that large interpatient variability exists in the outcome. As antimyeloma therapeutics continue to expand it is becoming even more crucial to personalize treatment approaches that provide the most value to a specific patient. Development of biomarkers, either individually or as larger sets or patterns and ranging from analysis of blood or bone marrow to biomedical imaging, is a major focus in the field. Biomarkers such as involved serum free light chain ratio and MRI focal lesions have been implemented in the new definition of multiple myeloma and guide clinicians to initiate treatment in otherwise asymptomatic individuals. Currently, however, there is not enough evidence to support intensifying the treatment for high-risk disease or reducing the treatment for low-risk disease. Minimal residual disease-negative status is an important biomarker that holds promise for monitoring the effectiveness of response-adapted strategies. This article sheds light on the forward landscape and rear-mirror view of biomarkers in myeloma.
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Affiliation(s)
- Manisha Bhutani
- From the Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC; Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ola Landgren
- From the Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC; Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Saad Z Usmani
- From the Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC; Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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30
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Ting KR, Brady JJ, Hameed A, Le G, Meiller J, Verburgh E, Bayers C, Benjamin D, Anderson KC, Richardson PG, Dowling P, Clynes M, Fitzgibbon MC, O'Gorman P. Clinical utility of C-terminal telopeptide of type 1 collagen in multiple myeloma. Br J Haematol 2016; 173:82-8. [DOI: 10.1111/bjh.13928] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 11/18/2015] [Indexed: 11/28/2022]
Affiliation(s)
- Kay R. Ting
- Department of Haematology; Mater Misericordiae University Hospital; Dublin 7 Ireland
- National Institute for Cellular Biotechnology; Dublin City University; Dublin 9 Ireland
| | - Jennifer J. Brady
- Department of Clinical Chemistry and Diagnostic Endocrinology; Mater Misericordiae University Hospital; Dublin 7 Ireland
| | - Abdul Hameed
- Department of Haematology; Mater Misericordiae University Hospital; Dublin 7 Ireland
- National Institute for Cellular Biotechnology; Dublin City University; Dublin 9 Ireland
| | - Giao Le
- Department of Haematology; Mater Misericordiae University Hospital; Dublin 7 Ireland
- National Institute for Cellular Biotechnology; Dublin City University; Dublin 9 Ireland
| | - Justine Meiller
- National Institute for Cellular Biotechnology; Dublin City University; Dublin 9 Ireland
| | - Estelle Verburgh
- Department of Haematology; Mater Misericordiae University Hospital; Dublin 7 Ireland
| | - Christopher Bayers
- Department of Haematology; Mater Misericordiae University Hospital; Dublin 7 Ireland
| | - Dalia Benjamin
- Department of Haematology; Mater Misericordiae University Hospital; Dublin 7 Ireland
| | - Kenneth C. Anderson
- Department of Medical Oncology; Dana-Farber Cancer Institute; Boston MA USA
- Department of Medicine; Harvard Medical School; Boston MA USA
| | - Paul G. Richardson
- Department of Medical Oncology; Dana-Farber Cancer Institute; Boston MA USA
- Department of Medicine; Harvard Medical School; Boston MA USA
| | - Paul Dowling
- National Institute for Cellular Biotechnology; Dublin City University; Dublin 9 Ireland
- Department of Biology; Maynooth University; Co. Kildare Ireland
| | - Martin Clynes
- National Institute for Cellular Biotechnology; Dublin City University; Dublin 9 Ireland
| | - Maria C. Fitzgibbon
- Department of Clinical Chemistry and Diagnostic Endocrinology; Mater Misericordiae University Hospital; Dublin 7 Ireland
| | - Peter O'Gorman
- Department of Haematology; Mater Misericordiae University Hospital; Dublin 7 Ireland
- National Institute for Cellular Biotechnology; Dublin City University; Dublin 9 Ireland
- School of Medicine & Medical Science; University College Dublin; Dublin 4 Ireland
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Affiliation(s)
- Kengo Udaka
- Department of Hematology, Tokushima Prefectural Central Hospital
| | - Shuji Ozaki
- Department of Hematology, Tokushima Prefectural Central Hospital
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Raje N, Vescio R, Montgomery CW, Badros A, Munshi N, Orlowski R, Hadala JT, Warsi G, Argonza-Aviles E, Ericson SG, Anderson KC. Bone Marker–Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Results of the Z-MARK Study. Clin Cancer Res 2015; 22:1378-84. [DOI: 10.1158/1078-0432.ccr-15-1864] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 11/15/2015] [Indexed: 11/16/2022]
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Minarik J, Hermanova Z, Petrova P, Hrbek J, Zapletalova J, Krhovska P, Flodr P, Pika T, Bacovsky J, Flodrova P, Herman M, Scudla V. Prospective study of signalling pathways in myeloma bone disease with regard to activity of the disease, extent of skeletal involvement and correlation to bone turnover markers. Eur J Haematol 2015; 97:201-7. [PMID: 26613192 DOI: 10.1111/ejh.12708] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2015] [Indexed: 12/15/2022]
Abstract
AIMS The aim of our study was to address the utility of serum levels of selected parameters of myeloma bone disease (MBD) signalling with regard to the pathogenesis of multiple myeloma (MM), activity, markers of bone turnover and extent of skeletal changes. PATIENTS AND METHODS We assessed prospectively 77 individuals with monoclonal gammopathies - 46 patients with active MM (AMM), 12 patients with smouldering MM (SMM) and 19 individuals with monoclonal gammopathy of undetermined significance (MGUS) to determine the role of HGF, MIP-1α, Syndecan-1, osteoprotegerin, Activin A, DKK1, Annexin A2 and NF-κB. RESULTS We found significant differences of most of the parameters between MGUS and AMM, and with respect to the activity of MM assessed by International Staging System. Most of the parameters of MBD signalling correlated with traditional markers of bone turnover. CONCLUSIONS All the signalling pathways were activated in MM with more pronounced osteoclastogenesis in comparison with bone formation but not in MGUS regardless of its risk category, suggesting that MBD is not activated in MGUS until the process of transformation into MM. The parameters of MBD signalling might precede the increase of conventional parameters of bone turnover suggesting their possible role in early indication of anti-resorption therapy.
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Affiliation(s)
- Jiri Minarik
- Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Zuzana Hermanova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Pavla Petrova
- Department of Clinical Biochemistry, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Jan Hrbek
- Department of Radiology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Jana Zapletalova
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Petra Krhovska
- Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Patrik Flodr
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Tomas Pika
- Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Jaroslav Bacovsky
- Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Pavla Flodrova
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Miroslav Herman
- Department of Radiology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Vlastimil Scudla
- Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
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Kassen D, Lath D, Lach A, Evans H, Chantry A, Rabin N, Croucher P, Yong KL. Myeloma impairs mature osteoblast function but causes early expansion of osteo-progenitors: temporal changes in bone physiology and gene expression in the KMS12BM model. Br J Haematol 2015; 172:64-79. [DOI: 10.1111/bjh.13790] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 07/22/2015] [Indexed: 11/29/2022]
Affiliation(s)
- Deepika Kassen
- Department of Haematology; Cancer Institute; University College London; London UK
| | - Darren Lath
- Academic Unit of Bone Biology; University of Sheffield; Sheffield UK
| | - Anna Lach
- Department of Haematology; Cancer Institute; University College London; London UK
| | - Holly Evans
- Academic Unit of Bone Biology; University of Sheffield; Sheffield UK
| | - Andy Chantry
- Academic Unit of Bone Biology; University of Sheffield; Sheffield UK
| | - Neil Rabin
- Department of Haematology; Cancer Institute; University College London; London UK
| | - Peter Croucher
- Bone Biology Division; Garvan Institute of Medical Research; Sydney NSW Australia
| | - Kwee L. Yong
- Department of Haematology; Cancer Institute; University College London; London UK
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Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling. BIOMED RESEARCH INTERNATIONAL 2015; 2015:172458. [PMID: 26579531 PMCID: PMC4633537 DOI: 10.1155/2015/172458] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 09/22/2015] [Accepted: 09/27/2015] [Indexed: 12/17/2022]
Abstract
Multiple myeloma (MM) is characterized by a high capacity to induce alterations in the bone remodeling process. The increase in osteoclastogenesis and the suppression of osteoblast formation are both involved in the pathophysiology of the bone lesions in MM. The proteasome inhibitor (PI) bortezomib is the first drug designed and approved for the treatment of MM patients by targeting the proteasome. However, recently novel PIs have been developed to overcome bortezomib resistance. Interestingly, several preclinical data indicate that the proteasome complex is involved in both osteoclast and osteoblast formation. It is also evident that bortezomib either inhibits osteoclast differentiation induced by the receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) or stimulates the osteoblast differentiation. Similarly, the new PIs including carfilzomib and ixazomib can inhibit bone resorption and stimulate the osteoblast differentiation. In a clinical setting, PIs restore the abnormal bone remodeling by normalizing the levels of bone turnover markers. In addition, a bone anabolic effect was described in responding MM patients treated with PIs, as demonstrated by the increase in the osteoblast number. This review summarizes the preclinical and clinical evidence on the effects of bortezomib and other new PIs on myeloma bone disease.
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Palma BD, Guasco D, Pedrazzoni M, Bolzoni M, Accardi F, Costa F, Sammarelli G, Craviotto L, De Filippo M, Ruffini L, Omedè P, Ria R, Aversa F, Giuliani N. Osteolytic lesions, cytogenetic features and bone marrow levels of cytokines and chemokines in multiple myeloma patients: Role of chemokine (C-C motif) ligand 20. Leukemia 2015; 30:409-16. [PMID: 26419509 DOI: 10.1038/leu.2015.259] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Revised: 09/07/2015] [Accepted: 09/10/2015] [Indexed: 01/17/2023]
Abstract
The relationship between bone marrow (BM) cytokine and chemokine levels, cytogenetic profiles and skeletal involvement in multiple myeloma (MM) patients is not yet defined. This study investigated a cohort of 455 patients including monoclonal gammopathy of uncertain significance (MGUS), smoldering MM and symptomatic MM patients. Skeletal surveys, positron emission tomography (PET)/computerized tomography (CT) and magnetic resonance imaging (MRI) were used to identify myeloma bone disease. Significantly higher median BM levels of both C-C motif Ligand (CCL)3 and CCL20 were found in MM patients with radiographic evidence of osteolytic lesions as compared with those without, and in all MM patients with positive PET/CT scans. BM levels of CCL3, CCL20, Activin-A and Dickkopf-1 (DKK-1) were significantly higher in patients with high bone disease as compared with patients with low bone disease. Moreover, CCL20 BM levels were significant predictors of osteolysis on X-rays by multivariate logistic analysis. On the other hand, DKK-1 levels were related to the presence of MRI lesions independently of the osteolysis at the X-rays. Our data define the relationship between bone disease and the BM cytokine and chemokine patterns highlighting the tight relationship between CCL20 BM levels and osteolysis in MM.
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Affiliation(s)
- B Dalla Palma
- Department of Clinical and Experimental Medicine, Myeloma Unit, University of Parma, Parma, Italy.,Hematology and BMT Center, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
| | - D Guasco
- Department of Clinical and Experimental Medicine, Myeloma Unit, University of Parma, Parma, Italy
| | - M Pedrazzoni
- Department of Clinical and Experimental Medicine, Myeloma Unit, University of Parma, Parma, Italy.,Clinica e Terapia Medica, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
| | - M Bolzoni
- Department of Clinical and Experimental Medicine, Myeloma Unit, University of Parma, Parma, Italy
| | - F Accardi
- Department of Clinical and Experimental Medicine, Myeloma Unit, University of Parma, Parma, Italy
| | - F Costa
- Department of Clinical and Experimental Medicine, Myeloma Unit, University of Parma, Parma, Italy
| | - G Sammarelli
- Department of Clinical and Experimental Medicine, Myeloma Unit, University of Parma, Parma, Italy
| | - L Craviotto
- Department of Clinical and Experimental Medicine, Myeloma Unit, University of Parma, Parma, Italy
| | - M De Filippo
- Radiology Unit, University of Parma, Parma, Italy
| | - L Ruffini
- Nuclear Medicine Unit, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
| | - P Omedè
- Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy
| | - R Ria
- Department of Biomedical Sciences and Human Oncology, Internal Medicine, University of Bari, Bari, Italy
| | - F Aversa
- Department of Clinical and Experimental Medicine, Myeloma Unit, University of Parma, Parma, Italy.,Hematology and BMT Center, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
| | - N Giuliani
- Department of Clinical and Experimental Medicine, Myeloma Unit, University of Parma, Parma, Italy.,Hematology and BMT Center, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
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Mylin AK, Goetze JP, Heickendorff L, Ahlberg L, Dahl IM, Abildgaard N, Gimsing P. N-terminal pro-C-type natriuretic peptide in serum associated with bone destruction in patients with multiple myeloma. Biomark Med 2015; 9:679-89. [DOI: 10.2217/bmm.15.35] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Aim: To examine whether N-terminal proCNP concentrations in serum is associated with bone destruction in patients with multiple myeloma. Materials & methods: N-terminal proCNP and biochemical bone markers were measured in 153 patients. Radiographic bone disease and skeletal-related events were evaluated at specific time-points. Results: N-terminal proCNP concentrations increased with age. High N-terminal proCNP concentrations were associated with high-risk disease and renal impairment. Renal function explained 22% of the variation. N-terminal proCNP concentrations correlated with serum bone ALP and serum PINP, but lacked association with bone resorption markers, radiographic bone disease and skeletal-related events. Conclusion: Serum N-terminal proCNP are associated with bone formation activity in patients with multiple myeloma, but should be interpreted with caution in patients with renal impairment.
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Affiliation(s)
- Anne K Mylin
- Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jens P Goetze
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lene Heickendorff
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Lucia Ahlberg
- Division of Hematology, Linköping University Hospital, Linköping, Sweden
| | - Inger Marie Dahl
- Section of Hematology, TromsøUniversity Hospital, Tromsø, Norway
| | - Niels Abildgaard
- Department of Hematology, Odense University Hospital, Odense, Denmark
| | - Peter Gimsing
- Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Osteoprotegerin is a significant prognostic factor for overall survival in patients with primary systemic amyloidosis independent of the Mayo staging. Blood Cancer J 2015; 5:e319. [PMID: 26047389 PMCID: PMC4648482 DOI: 10.1038/bcj.2015.45] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 03/14/2015] [Accepted: 03/26/2015] [Indexed: 01/28/2023] Open
Abstract
Bone metabolism has not been systematically studied in primary (AL) amyloidosis. Thus we prospectively evaluated bone remodeling indices in 102 patients with newly diagnosed AL amyloidosis, 35 healthy controls, 35 newly diagnosed myeloma and 40 monoclonal gammopathy of undetermined significance patients. Bone resorption markers (C-telopeptide of type-1 collagen, N-telopeptide of type-1 collagen) and osteoclast regulators (soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG)) were increased in AL patients compared with controls (P<0.01), but bone formation was unaffected. Myeloma patients had increased bone resorption and decreased bone formation compared with AL patients, while sRANKL/OPG ratio was markedly decreased in AL, due to elevated OPG in AL (P<0.001). OPG correlated with N-terminal pro-brain natriuretic peptide (P<0.001) and was higher in patients with cardiac involvement (P=0.028) and advanced Mayo stage (P=0.001). OPG levels above the upper value of healthy controls was associated with shorter survival (34 versus 91 months; P=0.026), while AL patients with OPG levels in the top quartile had very short survival (12 versus 58 months; P=0.024). In Mayo stage 1 disease, OPG identified patients with poor survival (12 versus >60 months; P=0.012). We conclude that increased OPG in AL is not only a compensation to osteoclast activation but may also reflect early cardiac damage and may identify patients at increased risk of death within those with earlier Mayo stage.
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Mylin AK, Abildgaard N, Johansen JS, Heickendorff L, Kreiner S, Waage A, Turesson I, Gimsing P. Serum YKL-40: a new independent prognostic marker for skeletal complications in patients with multiple myeloma. Leuk Lymphoma 2015; 56:2650-9. [PMID: 25573204 DOI: 10.3109/10428194.2015.1004168] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
In a time of increasing treatment options for multiple myeloma bone disease, risk factors predicting progression need to be elucidated. This study investigated the value of serum YKL-40, previously shown to be associated with radiographic progression of bone destruction, as a predictor for time to clinical progression, i.e. skeletal-related events (SREs), in 230 newly diagnosed patients with multiple myeloma receiving intravenous bisphosphonates. Serum concentrations of YKL-40 and biochemical bone markers (CTX-MMP, CTX-I, PINP) were measured at diagnosis. Patients were evaluated every third month for SRE and at 9 and 24 months for radiographic progression. Elevated serum YKL-40 was seen in 47% of patients and associated with high-risk disease (International Staging System stage III; p < 0.001), increased bone resorption (serum CTX/MMP; p < 0.001) and early radiographic progression at 9 months (p = 0.01). Serum YKL-40 together with serum CTX-MMP/PINP ratio and World Health Organization status were independent predictors of time to first SRE.
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Affiliation(s)
- Anne K Mylin
- a Department of Hematology , Rigshospitalet, University of Copenhagen , Copenhagen , Denmark
| | - Niels Abildgaard
- b Department of Hematology , Odense University Hospital , Odense , Denmark
| | - Julia S Johansen
- c Departments of Medicine and Oncology , Herlev Hospital, University of Copenhagen , Herlev , Denmark
| | - Lene Heickendorff
- d Department of Clinical Biochemistry , Aarhus University Hospital , Aarhus , Denmark
| | - Svend Kreiner
- e Department of Biostatistics , University of Copenhagen , Copenhagen , Denmark
| | - Anders Waage
- f Department of Hematology , St Olav Hospital, Norwegian University of Science and Technology , Trondheim , Norway
| | - Ingemar Turesson
- g Department of Hematology , Skane University Hospital , Malmö , Sweden
| | - Peter Gimsing
- a Department of Hematology , Rigshospitalet, University of Copenhagen , Copenhagen , Denmark
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40
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Drake MT. unveiling skeletal fragility in patients diagnosed with MGUS: no longer a condition of undetermined significance? J Bone Miner Res 2014; 29:2529-33. [PMID: 25319751 PMCID: PMC4268401 DOI: 10.1002/jbmr.2387] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 10/09/2014] [Accepted: 10/13/2014] [Indexed: 01/11/2023]
Abstract
Monoclonal gammopathy of undetermined significance (MGUS) is a common finding in clinical practice, affecting greater than 3% of adults aged 50 years and older. As originally described, the term MGUS reflected the inherent clinical uncertainty of distinguishing patients with a benign stable monoclonal plasma cell disorder from subjects destined to progress to malignancy. There is now clear epidemiologic evidence, however, that patients with MGUS suffer from a significantly increased fracture risk and that the prevalence of MGUS is increased in patients with osteoporosis. Despite this relationship, no clinical care guidelines exist for the routine evaluation or treatment of the skeletal health of patients with MGUS. Recent work has demonstrated that circulating levels of at least two cytokines (CCL3/MIP-1α and DKK1) with well-recognized roles in bone disease in the related monoclonal gammopathy multiple myeloma are also increased in patients with MGUS. Further, recent imaging studies using high-resolution peripheral quantitative CT have documented that patients with MGUS have substantial skeletal microarchitectural deterioration and deficits in biomechanical bone strength that likely underlie the increased skeletal fragility in these patients. Accordingly, this Perspective provides evidence that the "undetermined significance" portion of the MGUS acronym may be best replaced in favor of the term "monoclonal gammopathy of skeletal significance" (MGSS) in order to more accurately reflect the enhanced skeletal risks inherent in this condition.
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Affiliation(s)
- Matthew T Drake
- Division of Endocrinology, Metabolism, Nutrition and Diabetes, Department of Medicine, Mayo Clinic, Rochester, MN, USA
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41
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Dowling P, Hayes C, Ting KR, Hameed A, Meiller J, Mitsiades C, Anderson KC, Clynes M, Clarke C, Richardson P, O'Gorman P. Identification of proteins found to be significantly altered when comparing the serum proteome from Multiple Myeloma patients with varying degrees of bone disease. BMC Genomics 2014; 15:904. [PMID: 25322877 PMCID: PMC4213504 DOI: 10.1186/1471-2164-15-904] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 10/03/2014] [Indexed: 12/20/2022] Open
Abstract
Background Bone destruction is a feature of multiple myeloma, characterised by osteolytic bone destruction due to increased osteoclast activity and suppressed or absent osteoblast activity. Almost all multiple myeloma patients develop osteolytic bone lesions associated with severe and debilitating bone pain, pathologic fractures, hypercalcemia, and spinal cord compression, as well as increased mortality. Biomarkers of bone remodelling are used to identify disease characteristics that can help select the optimal management of patients. However, more accurate biomarkers are needed to effectively mirror the dynamics of bone disease activity. Results A label-free mass spectrometry-based strategy was employed for discovery phase analysis of fractionated patient serum samples associated with no or high bone disease. A number of proteins were identified which were statistically significantly correlated with bone disease, including enzymes, extracellular matrix glycoproteins, and components of the complement system. Conclusions Enzyme-linked immunosorbent assay of complement C4 and serum paraoxonase/arylesterase 1 indicated that these proteins were associated with high bone disease in a larger independent cohort of patient samples. These biomolecules may therefore be clinically useful in assessing the extent of bone disease. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-904) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Paul Dowling
- Department of Biology, National University of Ireland, Maynooth, Co, Kildare, Ireland.
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42
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Garcia-Gomez A, Sanchez-Guijo F, del Cañizo MC, San Miguel JF, Garayoa M. Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics. World J Stem Cells 2014; 6:322-343. [PMID: 25126382 PMCID: PMC4131274 DOI: 10.4252/wjsc.v6.i3.322] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 03/24/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma is a hematological malignancy in which clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic lesions due to increased osteoclast (OC) activity and suppressed osteoblast (OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells (MSCs) play a critical role in multiple myeloma pathophysiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of myeloma bone disease (MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients (pMSCs) and their healthy counterparts (dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibitory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and activity at various levels (i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncoupling ephrinB2-EphB4 signaling, and through augmented production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents (at preclinical or clinical stage) targeting those signaling pathways is commented.
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43
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Patel CG, Yee AJ, Scullen TA, Nemani N, Santo L, Richardson PG, Laubach JP, Ghobrial IM, Schlossman RL, Munshi NC, Anderson KC, Raje NS. Biomarkers of bone remodeling in multiple myeloma patients to tailor bisphosphonate therapy. Clin Cancer Res 2014; 20:3955-61. [PMID: 24958808 DOI: 10.1158/1078-0432.ccr-14-0434] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Patients with multiple myeloma may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether urinary N-telopeptide (NTX) or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling. METHODS We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 patients with multiple myeloma in remission who previously received 8 to 12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA. RESULTS All patients had continued suppression of NTX levels, except 1 patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, whereas bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients. CONCLUSION Our data show that NTX levels continue to be suppressed after aBP therapy, and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. These data provide the basis for less frequent dosing of aBPs.
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Affiliation(s)
| | - Andrew J Yee
- Massachusetts General Hospital Cancer Center; Harvard Medical School, Boston, Massachusetts
| | | | - Neeharika Nemani
- Massachusetts General Hospital Cancer Center; Harvard Medical School, Boston, Massachusetts
| | - Loredana Santo
- Massachusetts General Hospital Cancer Center; Harvard Medical School, Boston, Massachusetts
| | - Paul G Richardson
- LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts
| | - Jacob P Laubach
- LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts
| | - Irene M Ghobrial
- LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts
| | - Robert L Schlossman
- LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts
| | - Nikhil C Munshi
- LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts
| | - Kenneth C Anderson
- LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts
| | - Noopur S Raje
- Massachusetts General Hospital Cancer Center; Harvard Medical School, Boston, Massachusetts
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Gordon GW, Monge J, Channon MB, Wu Q, Skulan JL, Anbar AD, Fonseca R. Predicting multiple myeloma disease activity by analyzing natural calcium isotopic composition. Leukemia 2014; 28:2112-5. [PMID: 24919808 DOI: 10.1038/leu.2014.193] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- G W Gordon
- School of Earth and Space Exploration, Arizona State University, Tempe, AZ, USA
| | - J Monge
- Division of Hematology and Oncology, Mayo Clinic in Arizona, Scottsdale, AZ, USA
| | - M B Channon
- School of Earth and Space Exploration, Arizona State University, Tempe, AZ, USA
| | - Q Wu
- Division of Health Sciences Research, Mayo Clinic in Arizona, Scottsdale, AZ, USA
| | - J L Skulan
- Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ, USA
| | - A D Anbar
- 1] School of Earth and Space Exploration, Arizona State University, Tempe, AZ, USA [2] Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ, USA
| | - R Fonseca
- 1] Division of Hematology and Oncology, Mayo Clinic in Arizona, Scottsdale, AZ, USA [2] Department of Medicine, Mayo Clinic in Arizona, Scottsdale, AZ, USA
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Abdulkadyrov KM, Salogub GN, Khuazheva NK, Sherman ML, Laadem A, Barger R, Knight R, Srinivasan S, Terpos E. Sotatercept in patients with osteolytic lesions of multiple myeloma. Br J Haematol 2014; 165:814-23. [PMID: 24650009 PMCID: PMC4312883 DOI: 10.1111/bjh.12835] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 02/05/2014] [Indexed: 02/06/2023]
Abstract
This phase IIa study evaluated the safety and tolerability of sotatercept, and its effects on bone metabolism and haematopoiesis in newly diagnosed and relapsed multiple myeloma (MM) patients. Patients were randomized (4:1) to receive four 28-d cycles of sotatercept (0·1, 0·3, or 0·5 mg/kg) or placebo. Patients also received six cycles of combination oral melphalan, prednisolone, and thalidomide (MPT). Thirty patients were enrolled; six received placebo and 24 received sotatercept. Overall, 25% of patients received all four sotatercept doses; 71% of sotatercept-treated patients had ≥1 dose interruption mainly due to increases in haemoglobin levels. Grade ≥3 adverse events (AEs) were reported in 17% of patients receiving placebo and 58% receiving sotatercept. Grade 4 AEs in sotatercept-treated patients were neutropenia, granulocytopenia, and atrial fibrillation (one patient each). In patients without bisphosphonate use, anabolic improvements in bone mineral density and in bone formation relative to placebo occurred, whereas bone resorption was minimally affected. Increases in haemoglobin levels, versus baseline, and the duration of the increases, were higher in the sotatercept-treated patients, with a trend suggesting a dose-related effect. Multiple doses of sotatercept plus MPT appear to be safe and generally well-tolerated in MM patients.
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Affiliation(s)
- Kudrat M Abdulkadyrov
- Russian Research Institute of Haematology and Blood Transfusion, St Petersburg, Russia
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47
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Garcia-Gomez A, Quwaider D, Canavese M, Ocio EM, Tian Z, Blanco JF, Berger AJ, Ortiz-de-Solorzano C, Hernández-Iglesias T, Martens ACM, Groen RWJ, Mateo-Urdiales J, Fraile S, Galarraga M, Chauhan D, San Miguel JF, Raje N, Garayoa M. Preclinical activity of the oral proteasome inhibitor MLN9708 in Myeloma bone disease. Clin Cancer Res 2014; 20:1542-54. [PMID: 24486586 DOI: 10.1158/1078-0432.ccr-13-1657] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolic and antiresorptive effects in the myeloma setting and in comparison with bortezomib in preclinical models. EXPERIMENTAL DESIGN The in vitro effect of MLN2238 was tested on osteoclasts and osteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins. We used an in vivo model of bone marrow-disseminated human myeloma to evaluate MLN2238 antimyeloma and bone activities. RESULTS Clinically achievable concentrations of MLN2238 markedly inhibited in vitro osteoclastogenesis and osteoclast resorption; these effects involved blockade of RANKL (receptor activator of NF-κB ligand)-induced NF-κB activation, F-actin ring disruption, and diminished expression of αVβ3 integrin. A similar range of MLN2238 concentrations promoted in vitro osteoblastogenesis and osteoblast activity (even in osteoprogenitors from patients with myeloma), partly mediated by activation of TCF/β-catenin signaling and upregulation of the IRE1 component of the unfolded protein response. In a mouse model of bone marrow-disseminated human multiple myeloma, orally administered MLN2238 was equally effective as bortezomib to control tumor burden and also provided a marked benefit in associated bone disease (sustained by both bone anabolic and anticatabolic activities). CONCLUSION Given favorable data on pharmacologic properties and emerging clinical safety profile of MLN9708, it is conceivable that this proteasome inhibitor may achieve bone beneficial effects in addition to its antimyeloma activity in patients with myeloma.
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Affiliation(s)
- Antonio Garcia-Gomez
- Authors' Affiliations: Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC); Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León; Hospital Universitario de Salamanca-IBSAL, Salamanca; Laboratorio de Imagen del Cáncer, Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain; MGH Cancer Center, Massachusetts General Hospital; Dana-Farber Cancer Institute, Harvard Medical School, Boston; Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA; and Departments of Cell Biology and Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
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Terpos E, Berenson J, Raje N, Roodman GD. Management of bone disease in multiple myeloma. Expert Rev Hematol 2014; 7:113-25. [DOI: 10.1586/17474086.2013.874943] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Pochintesta L, Mangiacavalli S, Cocito F, Pompa A, Albertini R, Pascutto C, Ferretti VV, Cazzola M, Corso A. Serum C terminal telopeptide maintains its correlation with bone disease in patients with myeloma even under treatment with bisphosphonates. Leuk Lymphoma 2013; 55:1397-8. [DOI: 10.3109/10428194.2013.830305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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50
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Kristensen IB, Christensen JH, Lyng MB, Møller MB, Pedersen L, Rasmussen LM, Ditzel HJ, Abildgaard N. Expression of osteoblast and osteoclast regulatory genes in the bone marrow microenvironment in multiple myeloma: only up-regulation of Wnt inhibitors SFRP3 and DKK1 is associated with lytic bone disease. Leuk Lymphoma 2013; 55:911-9. [PMID: 23915193 DOI: 10.3109/10428194.2013.820288] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Multiple myeloma (MM) lytic bone disease (LBD) is caused by osteoclast activation and osteoblast inhibition. RANK/RANKL/OPG play central roles in osteoclast activation and Wnt inhibitor DKK1 in osteoblast inhibition. The role of other Wnt inhibitors is less clear. We evaluated gene expression of osteoclast regulators (RANK, RANKL, OPG, TRAIL, MIP1A), Wnt inhibitors (DKK1, SFRP2, SFRP3, sclerostin, WIF1) and osteoblast transcription factors (RUNX2, osterix) by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in the bone marrow (BM) microenvironment using snap-frozen BM biopsies, thereby achieving minimal post-sampling manipulation, and gene expression profiling (GEP) data, reflecting the in vivo situation. We analyzed 110 biopsies from newly diagnosed patients with MM and monoclonal gammopathy of unknown significance (MGUS) and healthy volunteers. LBD was evaluated using standard radiographs and the bone resorption marker CTX-1. Protein levels were evaluated by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Among Wnt inhibitors, only SFRP3 and DKK1 were significantly overexpressed in advanced LBD, correlating with protein levels. SFRP3 correlated with CTX-1. Our findings support osteoblast inhibition as the driving force behind MM LBD.
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