1
|
Rahmat M, Clement K, Alberge JB, Sklavenitis-Pistofidis R, Kodgule R, Fulco CP, Heilpern-Mallory D, Nilsson K, Dorfman D, Engreitz JM, Getz G, Pinello L, Ryan RJH, Ghobrial IM. Selective Enhancer Gain-of-Function Deregulates MYC Expression in Multiple Myeloma. Cancer Res 2024; 84:4173-4183. [PMID: 39312195 PMCID: PMC11649448 DOI: 10.1158/0008-5472.can-24-1440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/17/2024] [Accepted: 09/11/2024] [Indexed: 12/17/2024]
Abstract
MYC deregulation occurs in the majority of multiple myeloma cases and is associated with progression and worse prognosis. Enhanced MYC expression occurs in about 70% of patients with multiple myeloma, but it is known to be driven by translocation or amplification events in only ∼40% of myelomas. Here, we used CRISPR interference to uncover an epigenetic mechanism of MYC regulation whereby increased accessibility of a plasma cell-type-specific enhancer leads to increased MYC expression. This native enhancer activity was not associated with enhancer hijacking events but led to specific binding of cMAF, IRF4, and SPIB transcription factors that activated MYC expression in the absence of known genetic aberrations. In addition, focal amplification was another mechanism of activation of this enhancer in approximately 3.4% of patients with multiple myeloma. Together, these findings define an epigenetic mechanism of MYC deregulation in multiple myeloma beyond known translocations or amplifications and point to the importance of noncoding regulatory elements and their associated transcription factor networks as drivers of multiple myeloma progression. Significance: The discovery of a native developmental enhancer that sustains the expression of MYC in a subset of myelomas could help identify predictive biomarkers and therapeutic targets to improve the outcomes of patients with multiple myeloma.
Collapse
Affiliation(s)
- Mahshid Rahmat
- Dana-Farber Cancer Institute, Boston MA, USA
- Harvard Medical School, Boston MA, USA
| | - Kendell Clement
- Harvard Medical School, Boston MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston MA, USA
| | - Jean-Baptiste Alberge
- Dana-Farber Cancer Institute, Boston MA, USA
- Harvard Medical School, Boston MA, USA
- Broad Institute of MIT and Harvard, Cambridge MA, USA
| | - Romanos Sklavenitis-Pistofidis
- Dana-Farber Cancer Institute, Boston MA, USA
- Harvard Medical School, Boston MA, USA
- Broad Institute of MIT and Harvard, Cambridge MA, USA
| | - Rohan Kodgule
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Charles P. Fulco
- Broad Institute of MIT and Harvard, Cambridge MA, USA
- Current address: Bristol Myers Squibb, Cambridge MA, USA
| | | | - Katarina Nilsson
- Department of Biochemistry, Northeastern University, Boston MA, USA
| | - David Dorfman
- Department of Pathology, Brigham and Women's Hospital, Boston MA, USA
| | - Jesse M. Engreitz
- Broad Institute of MIT and Harvard, Cambridge MA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford CA, USA
- BASE Initiative, Betty Irene Moore Children’s Heart Center, Lucile Packard Children’s Hospital, Stanford CA, USA
| | - Gad Getz
- Harvard Medical School, Boston MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston MA, USA
- Broad Institute of MIT and Harvard, Cambridge MA, USA
- Cancer Center, Massachusetts General Hospital, Charlestown MA, USA
| | - Luca Pinello
- Harvard Medical School, Boston MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston MA, USA
- Broad Institute of MIT and Harvard, Cambridge MA, USA
| | | | - Irene M. Ghobrial
- Dana-Farber Cancer Institute, Boston MA, USA
- Harvard Medical School, Boston MA, USA
| |
Collapse
|
2
|
Vu T, Wang Y, Fowler A, Simieou A, McCarty N. TRIM44, a Novel Prognostic Marker, Supports the Survival of Proteasome-Resistant Multiple Myeloma Cells. Cells 2024; 13:1431. [PMID: 39273003 PMCID: PMC11394402 DOI: 10.3390/cells13171431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
TRIM44, a tripartite motif (TRIM) family member, is pivotal in linking the ubiquitin-proteasome system (UPS) to autophagy in multiple myeloma (MM). However, its prognostic impact and therapeutic potential remain underexplored. Here, we report that TRIM44 overexpression is associated with poor prognosis in a Multiple Myeloma Research Foundation (MMRF) cohort of 858 patients, persisting across primary and recurrent MM cases. TRIM44 expression notably increases in advanced MM stages, indicating its potential role in disease progression. Single-cell RNA sequencing across MM stages showed significant TRIM44 upregulation in smoldering MM (SMM) and MM compared to normal bone marrow, especially in patients with t(4;14) cytogenetic abnormalities. This analysis further identified high TRIM44 expression as predictive of lower responsiveness to proteasome inhibitor (PI) treatments, underscoring its critical function in the unfolded protein response (UPR) in TRIM44-high MM cells. Our findings also demonstrate that TRIM44 facilitates SQSTM1 oligomerization under oxidative stress, essential for its phosphorylation and subsequent autophagic degradation. This process supports the survival of PI-resistant MM cells by activating the NRF2 pathway, which is crucial for oxidative stress response and, potentially, other chemotherapy-induced stressors. Additionally, TRIM44 counters the TRIM21-mediated suppression of the antioxidant response, enhancing MM cell survival under oxidative stress. Collectively, our discoveries highlight TRIM44's significant role in MM progression and resistance to therapy, suggesting its potential value as a therapeutic target.
Collapse
Affiliation(s)
- Trung Vu
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, TX 77021, USA; (T.V.); (Y.W.)
| | - Yuqin Wang
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, TX 77021, USA; (T.V.); (Y.W.)
| | - Annaliese Fowler
- The Department of Biomedical Engineering, Texas A&M University, Houston, TX 77030, USA;
| | - Anton Simieou
- The Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA;
| | - Nami McCarty
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, TX 77021, USA; (T.V.); (Y.W.)
| |
Collapse
|
3
|
Rees MJ, Kumar S. High-risk multiple myeloma: Redefining genetic, clinical, and functional high-risk disease in the era of molecular medicine and immunotherapy. Am J Hematol 2024; 99:1560-1575. [PMID: 38613829 DOI: 10.1002/ajh.27327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 03/22/2024] [Accepted: 04/02/2024] [Indexed: 04/15/2024]
Abstract
Multiple myeloma (MM) exhibits significant heterogeneity in its presentation, genetics, and treatment response. Despite therapeutic advances, some patients continue to relapse early (ER, <18-months) and rapidly cycle through therapies. Myriad prognostic factors have been identified and incorporated into risk stratification models; however, these produce discordant, often three-tiered outputs that fail to identify many patients destined for ER. Treatment strategies are increasingly focused on disease biology and trials enriched for high-risk (HR)MM, but consensus on the minimum required testing and a succinct, specific, and clinically meaningful definition for HRMM remains elusive. We review the risk-factors, definitions, and future directions for HRMM.
Collapse
Affiliation(s)
- Matthew J Rees
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Shaji Kumar
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
4
|
Liu M, Zhang JY. Reduction rate of monoclonal protein as a useful prognostic factor in standard-risk group of newly diagnosed multiple myeloma. World J Clin Cases 2023; 11:5643-5652. [PMID: 37727707 PMCID: PMC10506002 DOI: 10.12998/wjcc.v11.i24.5643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 07/02/2023] [Accepted: 08/01/2023] [Indexed: 08/24/2023] Open
Abstract
BACKGROUND Multiple myeloma (MM) is a common hematologic malignancy that originates from a malignant clone of plasma cells. Solitary plasmacytoma, history of diabetes, and platelet count are considered as prognostic factors for MM. But some patients are still associated with much worse outcomes without any prognostic predictors. This study aimed to observe the reduction rate of monoclonal protein (M protein) after the first and fourth chemotherapy cycles, which is considered as a new prognostic factor for progression-free survival (PFS) in standard-risk group of newly diagnosed MM patients. AIM To investigate the reduction rate of M protein after first and fourth cycle chemotherapy as a useful prognostic factor. METHODS A total of 316 patients diagnosed with MM for the first time between 2010 and 2019 at the Lishui Municipal Central Hospital were included. All patients were diagnosed according to the National Comprehensive Cancer Network (NCCN) 2020.V1 diagnostic criteria. The risk assessment was performed by the Mayo Stratification for Macroglobulinemia and Risk-Adapted Therapy guidelines. After diagnosis, 164 patients were evaluated and underwent treatment with four to eight courses of continuous induction chemotherapy. The patients with no response after induction treatment were administered additional therapy following the NCCN 2020.V1 criteria. The following baseline data from the patients were collected: Gender, age at diagnosis, Durie-Salmon stage, glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, catabolite activator protein, albumin/globulin ratio, lactate dehydrogenase, translocation (t)(6;14), t(11;14), maintenance regimen, total cholesterol (TC), triglyceride, and phosphorous. All baseline data and the reduction rate of M protein after each chemotherapy cycle from the first to fourth were assessed by univariate analysis. The factors influencing the overall survival and PFS were then assessed by multivariate analysis. We found the first cycle (C1) reduction rate and the fourth cycle (C4) reduction rate as predictors of PFS. Then, PFS was compared between patients with a C1 reduction rate of M protein of ≥ 25% vs < 25% and ≥ 50% vs < 50%, and between patients with a C4 reduction rate of ≥ 25% vs < 25%, ≥ 50% vs < 50%, and ≥ 75% vs < 75%. RESULTS Multivariate analysis revealed age [hazard ratio (HR): 1.059, 95% confidence interval (95%CI): 1.033-1.085, P ≤ 0.001], International Staging System stage (HR: 2.136, 95%CI: 1.500-3.041, P ≤ 0.001), autotransplantion (HR: 0.201, 95%CI: 0.069-0.583, P = 0.019), TC (HR: 0.689, 95%CI: 0.533-0.891, P = 0.019), C1 reduction rate (HR: 0474, 95%CI: 0.293-0.767, P = 0.019), and C4 reduction rate (HR: 0.254, 95%CI: 0.139-0.463, P = 0.019) as predictors of PFS. The Kaplan-Meier survival analysis and the log-rank tests revealed that a higher reduction rate of M protein after first cycle (≥ 50%) and fourth cycle (≥ 75%) chemotherapy was associated with a longer PFS than the lower one. CONCLUSION Higher reduction rates of M protein after the first and fourth chemotherapy cycles can act as advantageous prognostic factors for PFS in standard-risk group of MM patients during initial diagnosis.
Collapse
Affiliation(s)
- Min Liu
- Department of Hematology, Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China
| | - Jun-Yu Zhang
- Department of Hematology, Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China
| |
Collapse
|
5
|
Morito N, Usui T, Ishibashi S, Yamagata K. Podocyte-specific Transcription Factors: Could MafB Become a Therapeutic Target for Kidney Disease? Intern Med 2023; 62:11-19. [PMID: 35249929 PMCID: PMC9876710 DOI: 10.2169/internalmedicine.9336-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The increasing number of patients with chronic kidney disease (CKD) is being recognized as an emerging global health problem. Recently, it has become clear that injury and loss of glomerular visceral epithelial cells, known as podocytes, is a common early event in many forms of CKD. Podocytes are highly specialized epithelial cells that cover the outer layer of the glomerular basement membrane. They serve as the final barrier to urinary protein loss through the formation and maintenance of specialized foot-processes and an interposed slit-diaphragm. We previously reported that the transcription factor MafB regulates the podocyte slit diaphragm protein production and transcription factor Tcf21. We showed that the forced expression of MafB was able to prevent CKD. In this review, we discuss recent advances and offer an updated overview of the functions of podocyte-specific transcription factors in kidney biology, aiming to present new perspectives on the progression of CKD and respective therapeutic strategies.
Collapse
Affiliation(s)
- Naoki Morito
- Department of Nephrology, Faculty of Medicine, University of Tsukuba, Japan
| | - Toshiaki Usui
- Department of Nephrology, Faculty of Medicine, University of Tsukuba, Japan
| | - Shun Ishibashi
- Department of Nephrology, Faculty of Medicine, University of Tsukuba, Japan
| | - Kunihiro Yamagata
- Department of Nephrology, Faculty of Medicine, University of Tsukuba, Japan
| |
Collapse
|
6
|
Szudy-Szczyrek A, Mlak R, Mielnik M, Mazurek M, Chocholska S, Podgajna M, Szczyrek M, Homa-Mlak I, Małecka-Massalska T, Hus M. Circulating Serum MiRNA-8074 as a Novel Prognostic Biomarker for Multiple Myeloma. Cells 2022; 11:cells11040752. [PMID: 35203396 PMCID: PMC8870602 DOI: 10.3390/cells11040752] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/16/2022] [Accepted: 02/17/2022] [Indexed: 02/06/2023] Open
Abstract
MiRNA-8074 is a molecule with the potential to regulate the expression of key genes related to the pathogenesis of multiple myeloma (MM), i.e., TP53, MYC, MAPK1, and KIAA. We analyzed the predictive and prognostic value of miRNA-8074 expression in MM patients. In total, 105 newly diagnosed MM patients treated with thalidomide (n = 27), bortezomib (n = 41) and bortezomib with thalidomide (n = 37) were studied. For miRNA analysis, the column method and the Real-Time PCR technique with specific TaqMan Fast Advanced Master Mix and TaqMan probes were used. Factors that were associated with a significant reduction in progression-free survival (PFS) included: ECOG > 1, ISS stage III, low hemoglobin, thrombocytopenia, hypoalbuminemia, abnormal renal function, elevated creatinine, GFR < 60 mL/min/1.73 m2, elevated LDH, del(17p), t(11;14), the use of a single drug regimen (thalidomide or bortezomib) and high miRNA-8074 expression (HR = 2.01, 95% CI: 1.16–3.49; p = 0.0233). In addition to the known prognostic factors, such as ECOG > 1, Durie–Salmon stage III, diagnosis of light chain disease or non-secreting MM, renal failure, hypoalbuminemia, hypercalcemia, high β2-microglobulin, elevated LDH, and t(14;16), a high expression of miRNA-8074 was significantly associated with a higher risk of death (HR = 4.12, 95% CI: 2.20–7.70; p = 0.0009). In summary, miRNA-8074 may be a useful diagnostic tool to assess the prognosis in MM patients.
Collapse
Affiliation(s)
- Aneta Szudy-Szczyrek
- Chair and Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-081 Lublin, Poland; (M.M.); (S.C.); (M.P.)
- Correspondence: (A.S.-S.); (M.H.)
| | - Radosław Mlak
- Department of Human Physiology, Medical University of Lublin, 20-080 Lublin, Poland; (R.M.); (M.M.); (I.H.-M.); (T.M.-M.)
| | - Michał Mielnik
- Chair and Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-081 Lublin, Poland; (M.M.); (S.C.); (M.P.)
| | - Marcin Mazurek
- Department of Human Physiology, Medical University of Lublin, 20-080 Lublin, Poland; (R.M.); (M.M.); (I.H.-M.); (T.M.-M.)
| | - Sylwia Chocholska
- Chair and Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-081 Lublin, Poland; (M.M.); (S.C.); (M.P.)
| | - Martyna Podgajna
- Chair and Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-081 Lublin, Poland; (M.M.); (S.C.); (M.P.)
| | - Michał Szczyrek
- Chair and Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-950 Lublin, Poland;
| | - Iwona Homa-Mlak
- Department of Human Physiology, Medical University of Lublin, 20-080 Lublin, Poland; (R.M.); (M.M.); (I.H.-M.); (T.M.-M.)
| | - Teresa Małecka-Massalska
- Department of Human Physiology, Medical University of Lublin, 20-080 Lublin, Poland; (R.M.); (M.M.); (I.H.-M.); (T.M.-M.)
| | - Marek Hus
- Chair and Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-081 Lublin, Poland; (M.M.); (S.C.); (M.P.)
- Correspondence: (A.S.-S.); (M.H.)
| |
Collapse
|
7
|
Jeryczynski G, Bolomsky A, Agis H, Krauth MT. Stratification for RRMM and Risk-Adapted Therapy: Sequencing of Therapies in RRMM. Cancers (Basel) 2021; 13:5886. [PMID: 34885001 PMCID: PMC8657274 DOI: 10.3390/cancers13235886] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 11/16/2022] Open
Abstract
The treatment landscape for relapsed multiple myeloma (RRMM) has experienced an unprecedented wave of innovation. Implementation of numerous new substances and drug classes with different modes of action is made possible in routine clinical practice. Next generation proteasome inhibitors, monoclonal antibodies, as well as first in class agents such as selinexor and venetoclax have widened the therapeutic spectrum. This has led to an increase in progression-free and overall survival. Consequently, new challenges for treating physicians in choosing the right treatment at the right stage of the disease have been generated. Several trials support the use of novel agents in the frontline treatment of newly diagnosed multiple myeloma. The use of lenalidomide or bortezomib as a backbone in the first-line setting, requires strategies for treatment once these patients relapse and are refractory to these drugs. Despite the variety of options, selecting the optimal treatment strategy is difficult, since multiple factors have to be considered: patient-specific factors such as age and co-morbidities, as well as myeloma/tumor specific factors such as cytogenetics and relapse kinetics. This review intends to summarize the existing data and guidelines regarding the optimal sequencing of treatments of RRMM using already approved agents as well as agents under investigation.
Collapse
Affiliation(s)
- Georg Jeryczynski
- Division of Oncology, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria;
| | - Arnold Bolomsky
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Hermine Agis
- Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, 1080 Vienna, Austria;
| | - Maria-Theresa Krauth
- Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, 1080 Vienna, Austria;
| |
Collapse
|
8
|
Clinical characteristics and treatment outcomes of newly diagnosed multiple myeloma with chromosome 1q abnormalities. Blood Adv 2021; 4:3509-3519. [PMID: 32750129 DOI: 10.1182/bloodadvances.2020002218] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/26/2020] [Indexed: 11/20/2022] Open
Abstract
A gain in chromosome 1q (+1q) is among the most common cytogenetic abnormalities in multiple myeloma (MM). It is unclear whether +1q is independently associated with decreased overall survival (OS). The objective of this study was to evaluate the impact of +1q on clinical characteristics, treatment response, and survival outcomes. We included 1376 Mayo Clinic patients diagnosed with MM from 2005 to 2018 who underwent fluorescence in situ hybridization testing at diagnosis with a panel including the +1q probe. A gain in 1q was found in 391 patients (28%) and was associated with anemia, hypercalcemia, high tumor burden, International Staging System (ISS) stage 3, high-risk (HR) translocations, and chromosome 13 abnormalities. There was no difference in overall response or deeper responses to proteasome inhibitor (PI)-, immunomodulatory drug (iMiD)-, or PI plus IMiD-based induction. Time to next treatment was shorter in patients with +1q compared with those without +1q (19.9 vs 27.7 months; P < .001). On univariate analysis, +1q was associated with increased risk of death (risk ratio [RR], 1.9; P < .001), and decreased OS was seen in all treatment groups. +1q was independently associated with decreased OS on multivariate analysis when other HR cytogenetic abnormalities, ISS stage 3, and age ≥70 years were included (RR, 1.5; P < .001). Gain of >1 copy of 1q was not associated with worse OS compared with gain of 1 copy (4.9 vs 4.3 years; P = .21). +1q was associated with high tumor burden, advanced disease stage, and HR translocations. It is independently associated with decreased OS, even in the setting of novel therapy and transplant.
Collapse
|
9
|
Huang C, Liu H, Jia L, Lu M, Hu S. Survival Disparities in Multiple Myeloma by Health Insurance Status among US Non-Elderly Adults: A SEER-Based Comparative Analysis. Acta Haematol 2021; 144:542-550. [PMID: 33784666 DOI: 10.1159/000514671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 01/22/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIM The impacts of health insurance status on survival outcomes in multiple myeloma (MM) have not been addressed in depth. The present study was conducted to identify definite relationships of cancer-specific survival (CSS) and overall survival (OS) with health insurance status in MM patients. METHODS MM patients aged 18-64 years and with complete insurance records between January 1, 2007, and December 31, 2016, were identified from 18 Surveillance, Epidemiology, and End Results (SEER) Database registries. Health insurance condition was categorized as uninsured, any Medicaid, insured, and insured (no specifics). Relationships of health insurance condition with OS/CSS were identified through Kaplan-Meier, and uni-/multivariate Cox regressions using the hazard ratio and 95% confidence interval. Potential baseline confounding was adjusted using multiple propensity score (mPS). RESULTS Totally 17,981 patients were included, including 68.3% with private insurance and only 4.9% with uninsurance. Log-rank test uncovered significant difference between health insurance status and OS/CSS among MM patients. Patients with non-insurance or Medicaid coverage in comparison with private insurance tended to present poorer OS/CSS both in multivariate Cox regression and in mPS-adjusted model (non-insurance vs. private insurance [OS/CSS]: 1.33 [1.20-1.48]/1.13 [1.00-1.28] and 1.45 [1.25-1.69]/1.18 [1.04-1.33], respectively; Medicaid coverage vs. private insurance [OS/CSS]: 1.67 [1.56-1.78]/1.25 [1.16-1.36] and 1.76 [1.62-1.90]/1.23 [1.13-1.35], respectively). CONCLUSIONS Our observational study of exposure-outcome associations suggests that insufficient or no insurance is moderately linked with OS among MM patients aged 18-64 years. Wide insurance coverage and health-care availability may strengthen some disparate outcomes. In the future, prospective cohort research is needed to further clarify concrete risks with insurance type, owing to the lack of definite division of insurance data in SEER.
Collapse
Affiliation(s)
- Congyang Huang
- Institute of Economics, Shanghai Academy of Social Sciences, Shanghai, China
- The Bureau of Jiangyin Human Resources and Social Security, Jiangyin, Jiangsu, China
| | - Hanshan Liu
- Second Department of Internal Medicine, Jiangsu Provincial Corps Hospital of Chinese People's Armed Police Forces, Yangzhou, China
| | - Li Jia
- Department of Nephrology, Ningbo Yinzhou Second Hospital, Ningbo, China
| | - Min Lu
- Department of Oncology, People's Hospital of Xuyi, Xuyi, China
| | - Suyun Hu
- Institute for Urban and Population Development, Shanghai Academy of Social Sciences, Shanghai, China
| |
Collapse
|
10
|
Abdallah N, Baughn LB, Rajkumar SV, Kapoor P, Gertz MA, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Dingli D, Go RS, Hwa YL, Fonder A, Hobbs M, Lin Y, Leung N, Kourelis T, Warsame R, Siddiqui M, Lust J, Kyle RA, Ketterling R, Bergsagel L, Greipp P, Kumar SK. Implications of MYC Rearrangements in Newly Diagnosed Multiple Myeloma. Clin Cancer Res 2020; 26:6581-6588. [PMID: 33008815 DOI: 10.1158/1078-0432.ccr-20-2283] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 08/20/2020] [Accepted: 09/29/2020] [Indexed: 12/18/2022]
Abstract
PURPOSE Rearrangements involving the MYC protooncogene are common in newly diagnosed multiple myeloma, but their prognostic significance is still unclear. The purpose of this study was to assess the impact of MYC rearrangement on clinical characteristics, treatment response, and survival in patients with newly diagnosed multiple myeloma. EXPERIMENTAL DESIGN This is a retrospective study including 1,342 patients seen in Mayo Clinic in Rochester, MN, from January 2006 to January 2018, who had cytogenetic testing by FISH at diagnosis, including MYC testing using the break apart FISH probe (8q24.1). RESULTS A rearrangement involving MYC was found in 8% of patients and was associated with elevated β2-microglobulin, ≥50% bone marrow plasma cells, IgA multiple myeloma, and the cooccurrence of trisomies. There were no differences in overall response rates between patients with and without MYC rearrangement when induction chemotherapy was proteasome inhibitor (PI)-based, immunomodulatory drug (IMiD)-based or PI + IMiD-based. Overall survival was shorter in patients with MYC rearrangement compared with patients without MYC rearrangement (5.3 vs. 8.0 years, P < 0.001). MYC rearrangement was associated with increased risk of death on multivariate analysis when high-risk cytogenetic abnormalities, ISS stage III, and ≥70 years of age were included (risk ratio: 1.5; P = 0.007). CONCLUSIONS MYC rearrangement is associated with high disease burden and is an independent adverse prognostic factor in patients with newly diagnosed multiple myeloma.
Collapse
Affiliation(s)
| | - Linda B Baughn
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | | | - Morie A Gertz
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | | | - Martha Q Lacy
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | | | | | - David Dingli
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Ronald S Go
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Yi L Hwa
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Amie Fonder
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Miriam Hobbs
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Yi Lin
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Nelson Leung
- Division of Hematology, Mayo Clinic, Rochester, Minnesota.,Division of Nephrology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Rahma Warsame
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | | | - John Lust
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Robert A Kyle
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Rhett Ketterling
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Leif Bergsagel
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona
| | - Patricia Greipp
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Shaji K Kumar
- Division of Hematology, Mayo Clinic, Rochester, Minnesota.
| |
Collapse
|
11
|
Zhang S, DuBois W, Zhang K, Simmons JK, Hughitt VK, Gorjifard S, Gaikwad S, Peat TJ, Mock BA. Mouse tumor susceptibility genes identify drug combinations for multiple myeloma. ACTA ACUST UNITED AC 2020; 6. [PMID: 32923678 PMCID: PMC7486007 DOI: 10.20517/2394-4722.2020.40] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Long-term genetic studies utilizing backcross and congenic strain analyses coupled with positional cloning strategies and functional studies identified Cdkn2a, Mtor, and Mndal as mouse plasmacytoma susceptibility/resistance genes. Tumor incidence data in congenic strains carrying the resistance alleles of Cdkn2a and Mtor led us to hypothesize that drug combinations affecting these pathways are likely to have an additive, if not synergistic effect in inhibiting tumor cell growth. Traditional and novel systems-level genomic approaches were used to assess combination activity, disease specificity, and clinical potential of a drug combination involving rapamycin/everolimus, an Mtor inhibitor, with entinostat, an histone deacetylase inhibitor. The combination synergistically repressed oncogenic MYC and activated the Cdkn2a tumor suppressor. The identification of MYC as a primary upstream regulator led to the identification of small molecule binders of the G-quadruplex structure that forms in the NHEIII region of the MYC promoter. These studies highlight the importance of identifying drug combinations which simultaneously upregulate tumor suppressors and downregulate oncogenes.
Collapse
Affiliation(s)
- Shuling Zhang
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA
| | - Wendy DuBois
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA
| | - Ke Zhang
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA
| | - John K Simmons
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA.,Personal Genome Diagnostics, Baltimore, MD 21224, USA
| | - V Keith Hughitt
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA
| | - Sayeh Gorjifard
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA.,University of Washington School of Medicine, Department of Genome Sciences, Seattle, WA 98195, USA
| | - Snehal Gaikwad
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA
| | - Tyler J Peat
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA
| | - Beverly A Mock
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA
| |
Collapse
|
12
|
Cytogenetic abnormalities in multiple myeloma: association with disease characteristics and treatment response. Blood Cancer J 2020; 10:82. [PMID: 32782240 PMCID: PMC7419564 DOI: 10.1038/s41408-020-00348-5] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/29/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023] Open
Abstract
Cytogenetic abnormalities are found in most multiple myeloma (MM) patients. Although their prognostic value has been well studied, there are limited data on the association of primary cytogenetic abnormalities with disease characteristics and treatment response. This study was designed to evaluate these associations. This is a retrospective study including 2027 Mayo Clinic patients diagnosed with MM between February 2004 and February 2018 who had cytogenetic testing by FISH at diagnosis. Translocations t(4;14), t(14;16), t(6;14), and t(14;20) were associated with anemia, beta2microglobulin >5.5 µg/ml and ≥50% bone marrow plasma cells; t(4;14) was associated with higher serum monoclonal protein and plasma cell proliferation. Overall response rate to proteasome inhibitor (PI)-based treatment was higher for IgH translocations compared to trisomies (83% vs. 71%, P = 0.002), but was higher for trisomies with immunomodulatory drug (IMiD)-based treatment (87% vs. 75%, P < 0.001). Time to next treatment was longer with trisomies than IgH translocation with IMiD-based (32.1 vs. 18.4 months, P < 0.001) and PI + IMiD-based (44.0 vs. 27.4 months, P = 0.003) treatments. Outcomes were superior with PI + IMiD combinations in all groups. Our results show that t(4;14), t(14;16), t(6;14), and t(14;20) are associated with high-risk disease characteristics, and IgH translocations and trisomies may be associated with better responses to PIs and IMiDs, respectively.
Collapse
|
13
|
CNV Radar: an improved method for somatic copy number alteration characterization in oncology. BMC Bioinformatics 2020; 21:98. [PMID: 32143562 PMCID: PMC7060549 DOI: 10.1186/s12859-020-3397-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 02/07/2020] [Indexed: 12/15/2022] Open
Abstract
Background Cancer associated copy number variation (CNV) events provide important information for identifying patient subgroups and suggesting treatment strategies. Technical and logistical issues, however, make it challenging to accurately detect abnormal copy number events in a cost-effective manner in clinical studies. Results Here we present CNV Radar, a software tool that utilizes next-generation sequencing read depth information and variant allele frequency patterns, to infer the true copy number status of genes and genomic regions from whole exome sequencing data. Evaluation of CNV Radar in a public multiple myeloma dataset demonstrated that CNV Radar was able to detect a variety of CNVs associated with risk of progression, and we observed > 70% concordance with fluorescence in situ hybridization (FISH) results. Compared to other CNV callers, CNV Radar showed high sensitivity and specificity. Similar results were observed when comparing CNV Radar calls to single nucleotide polymorphism array results from acute myeloid leukemia and prostate cancer datasets available on TCGA. More importantly, CNV Radar demonstrated its utility in the clinical trial setting: in POLLUX and CASTOR, two phase 3 studies in patients with relapsed or refractory multiple myeloma, we observed a high concordance rate with FISH for del17p, a risk defining CNV event (88% in POLLUX and 90% in CASTOR), therefore allowing for efficacy assessments in clinically relevant disease subgroups. Our case studies also showed that CNV Radar is capable of detecting abnormalities such as copy-neutral loss of heterozygosity that elude other approaches. Conclusions We demonstrated that CNV Radar is more sensitive than other CNV detection methods, accurately detects clinically important cytogenetic events, and allows for further interrogation of novel disease biology. Overall, CNV Radar exhibited high concordance with standard methods such as FISH, and its success in the POLLUX and CASTOR clinical trials demonstrated its potential utility for informing clinical and therapeutic decisions.
Collapse
|
14
|
Consensus Guidelines on the Diagnosis of Multiple Myeloma and Related Disorders: Recommendations of the Myeloma Canada Research Network Consensus Guideline Consortium. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:e352-e367. [PMID: 32249195 DOI: 10.1016/j.clml.2020.01.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 01/17/2020] [Accepted: 01/24/2020] [Indexed: 02/07/2023]
Abstract
Multiple myeloma (MM) is a plasma cell (PC) malignancy of terminally differentiated B lymphocytes that is typically associated with the secretion of partial and/or complete monoclonal immunoglobulins and a constellation of particular symptoms and signs. MM is a treatable condition, and timely diagnosis is essential to limit or avoid irreversible target-organ damage and to prolong survival. The Myeloma Canada Research Network Consensus Guideline Consortium (MCRN-CGC) proposes national consensus recommendations for the diagnosis of MM and associated PC neoplasms. The focus is on widely available tests but also highlights recent advancements that are important to include in the diagnostic paradigm. By clarifying and updating the required laboratory, radiographic, and bone marrow investigations, the MCRN-CGC hopes to address the needs of Canadian physicians and people living with MM across the country through accurate and timely diagnosis of MM, as well as appropriate initial stratification to improve treatment selection and outcomes. The MCRN-CGC will periodically review the recommendations herein and update as necessary. Recommendations on the therapeutic approaches and associated monitoring of MM will follow.
Collapse
|
15
|
Murase T, Inagaki A, Masaki A, Fujii K, Narita T, Ri M, Hanamura I, Iida S, Inagaki H. Plasma cell myeloma positive for t(14;20) with relapse in the central nervous system. J Clin Exp Hematop 2019; 59:135-139. [PMID: 31391406 PMCID: PMC6798141 DOI: 10.3960/jslrt.19011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
t(14;20)(q32;q11)/IGH-MAFB is a rare chromosomal abnormality in plasma cell myeloma (PCM), accounting for 1-2% of PCM cases. Patients with this translocation may have a poor prognosis. However, the clinicopathological features and response to novel agents have not been well clarified. We present a 63-year-old Japanese female with PCM positive for t(14;20). The tumor responded well to a proteasome inhibitor, bortezomib, and the patient achieved complete remission. Six months after remission, tumor relapse was noted in the left cerebellum and the right frontal lobe of the cerebrum. After whole brain radiation therapy, the tumor masses decreased in size. The patient was followed up with best-care support, but died of the disease 29 months after the initial PCM diagnosis. t(14;20)-positive PCM responded well to bortezomib at the time of the initial treatment. The CNS tumor involvement, which is rare in PCM, may be associated with the clinical aggressiveness of the t(14;20)-positive form of this myeloma.
Collapse
|
16
|
Bolt T, Mahlich J, Nakamura Y, Nakayama M. Hematologists' Preferences for First-line Therapy Characteristics for Multiple Myeloma in Japan: Attribute Rating and Discrete Choice Experiment. Clin Ther 2018; 40:296-308.e2. [PMID: 29358004 DOI: 10.1016/j.clinthera.2017.12.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 12/06/2017] [Accepted: 12/18/2017] [Indexed: 01/24/2023]
Abstract
PURPOSE With the progress being made in the treatment of multiple myeloma and other complex cancers, a variety of clinical research and treatment options are being pursued. This study uses a discrete choice experiment (DCE) to estimate treatment characteristic preferences of hematologists in Japan. METHODS A 2-stage process was applied within this study. The first stage is an attribute-rating exercise in which each of the full list of 21 attributes is rated on its importance by the clinicians when selecting a first-line therapy. The top 8 rated attributes from a stepwise logistic regression model are then used to develop a DCE to estimate hematologists' willingness to trade-off characteristics of the treatment options in their recommendation of a first-line treatment. A logit model was used to identify the attribute levels that were the strongest determinants of the physicians' treatment preferences. FINDINGS From among the potential treatment attributes presented, improved overall survival had the most significant impact on the treatment choice of participating Japanese hematologists. Improvement in the ability to promptly reduce M-protein is also a highly prioritized treatment characteristic, with hematologists willing to sacrifice just over 1 month extra overall survival for this. Additionally, the hematologists' value improved suitability for chromosomal abnormalities with poor prognosis, suitability of the mechanism of action in initial treatment, and promptly improving calcium-renal-anemia-bone symptoms each at roughly 0.9 months extended overall survival. The reduction of adverse events is among the other significant factors in choice of treatment, though it was not found to be as strong a determinant as those mentioned. IMPLICATIONS This study reinforces the expectation that clinical research and treatment options should continue to focus on overall survival and are key priorities in multiple myeloma treatment development. However, clinicians are willing to consider and trade off other clinical factors and markers in their choice of treatment. The potential improvements presented were also found to have a greater impact on treatment choice than aversion to the potential worse outcomes presented.
Collapse
Affiliation(s)
- Timothy Bolt
- Faculty of Economics, Saitama University, Saitama, Japan
| | - Jörg Mahlich
- Health Economics, Janssen KK, Tokyo, Japan; Düsseldorf Institute for Competition Economics, University of Düsseldorf, Düsseldorf, Germany.
| | | | | |
Collapse
|
17
|
Gaultney JG, Ng TW, Uyl-de Groot CA, Sonneveld P, van Beers EH, van Vliet MH, Redekop WK. Potential therapeutic and economic value of risk-stratified treatment as initial treatment of multiple myeloma in Europe. Pharmacogenomics 2018; 19:213-226. [DOI: 10.2217/pgs-2017-0140] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Biomarkers associated with prognosis in multiple myeloma (MM) can be used to stratify patients into risk categories. An attractive alternative to uniform treatment (UT), risk-stratified treatment (RST) is proposed where high-risk patients receive bortezomib-based regimens while standard-risk patients receive alternative less costly regimens. An early Markov-type decision analytic model evaluated the potential therapeutic and economic value of different RST strategies compared with UT in MM patients in key European countries. Results suggest RST strategies were both cheaper and more effective than UT across all countries, with the molecular marker-only strategy RST-SKY92 producing maximum health gains (0.031–0.039 QALYs). The conclusions remained consistent in the univariate sensitivity analyses. These findings should encourage stakeholders to support the adoption of RST approaches in MM.
Collapse
Affiliation(s)
| | - Therese W Ng
- IQVIA, 210 Pentonville Road, London N1 9JY, United Kingdom
| | - Carin A Uyl-de Groot
- Erasmus School of Health Policy & Management, Institute for Medical Technology Assessment, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Pieter Sonneveld
- Department of Haematology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Erik H van Beers
- SkylineDx BV, Rotterdam Science Tower, Marconistraat 16, 18th floor 3029 AK Rotterdam, The Netherlands
| | - Martin H van Vliet
- SkylineDx BV, Rotterdam Science Tower, Marconistraat 16, 18th floor 3029 AK Rotterdam, The Netherlands
| | - William K Redekop
- Erasmus School of Health Policy & Management, Institute for Medical Technology Assessment, Erasmus University Rotterdam, Rotterdam, The Netherlands
| |
Collapse
|
18
|
Krishnan A. How to Think About Risk in Myeloma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2017; 16 Suppl:S135-8. [PMID: 27521310 DOI: 10.1016/j.clml.2016.02.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 02/09/2016] [Indexed: 11/30/2022]
Abstract
An integral part of myeloma therapy is risk stratification of newly diagnosed patients. This method involves a combination of staging and genetic risk assessment. Although survival has dramatically improved for patients with genetically defined, standard-risk myeloma, those with high-risk disease remain a therapeutic challenge. Current treatment approaches might include the use of combination therapy for induction and maintenance. Future approaches are expected to involve drugs that are "risk agnostic," such as monoclonal antibodies and immunotherapy.
Collapse
Affiliation(s)
- Amrita Krishnan
- Department of Hematology and Hematopoietic Cell Transplantation, Judy and Bernard Briskin Center for Multiple Myeloma, City of Hope, Duarte, CA.
| |
Collapse
|
19
|
[Prognostic value of the revised international staging system for newly diagnosed multiple myeloma patients]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2017; 38:475-479. [PMID: 28655089 PMCID: PMC7342976 DOI: 10.3760/cma.j.issn.0253-2727.2017.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Objective: To assess the prognostic value of revised international staging system (R-ISS) for multiple myeloma (MM) in real world. Methods: A total of 202 newly diagnosis symptomatic MM patients were enrolled from May 2010 to April 2015 and the clinical data were retrospectively analyzed. All the patients received at least four courses of bortezomib-based or thalidomide-based induction therapy. Results: With a median follow-up of 31 months, the cohort included 56 cases in R-ISSⅠ, 108 in R-ISS Ⅱ, and 38 in R-ISS Ⅲ, and the median OS was not reached/61/38 months, respectively (P=0.001). According to the ISS system, 62 patients were classified in ISS-Ⅰ, 70 in ISS-Ⅱ and 70 in ISS-Ⅲ, with the median OS was 58, 52 and 40 months, respectively (P=0.001). The relative risk (HR) of R-ISS stage Ⅲ vs Ⅰ, Ⅱ vs Ⅰ were 9.606 (P=0.008) and 4.038 (P=0.029). The HR of Ⅲ vs Ⅰ, Ⅱ vs Ⅰ of ISS system were 4.127 (P=0.070) and 2.877 (P=0.005). In the subgroup analysis, R-ISS predicted survival for patients who were not transplanted (P=0.003) , receiving bortezomib-based therapy (P=0.010) , and patients younger than 65 years (P=0.001). Conclusion: R-ISS system could better predict prognosis for OS in unselected nonclinical trial myeloma patients than ISS system, especially for the younger patients, patients with bortezomib-based therapy, and patients without transplantation.
Collapse
|
20
|
Jakab S, Lázár E, Benedek I, Köpeczi JB, Pakucs A, Benedek I. New Treatment Methods in Multiple Myeloma. JOURNAL OF INTERDISCIPLINARY MEDICINE 2017. [DOI: 10.1515/jim-2017-0055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Abstract
Multiple myeloma accounts for 10% of the hematologic malignancies and is characterized by a single clone of plasma cells producing a monoclonal protein. The aim of this review is to summarize the current treatment methods of multiple myeloma. In the last 15 years, the incidence of myeloma has increased in patients younger than 65 years, thus treatment became even more important in order to obtain a long lasting remission or plateau phase. The treatment of this disease is complex and focuses not only on increasing the patients’ survival, but also improving their quality of life.
Collapse
Affiliation(s)
- Szende Jakab
- Clinic of Hematology and Bone Marrow Transplantation Unit , Tîrgu Mureș , Romania
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
| | - Erzsébet Lázár
- Clinic of Hematology and Bone Marrow Transplantation Unit , Tîrgu Mureș , Romania
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
| | - István Benedek
- Clinic of Hematology and Bone Marrow Transplantation Unit , Tîrgu Mureș , Romania
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
| | - Judit Beáta Köpeczi
- Clinic of Hematology and Bone Marrow Transplantation Unit , Tîrgu Mureș , Romania
| | - Annamária Pakucs
- Clinic of Hematology and Bone Marrow Transplantation Unit , Tîrgu Mureș , Romania
| | - István Benedek
- Clinic of Hematology and Bone Marrow Transplantation Unit , Tîrgu Mureș , Romania
- University of Medicine and Pharmacy , Tîrgu Mureș , Romania
| |
Collapse
|
21
|
Dingli D, Ailawadhi S, Bergsagel PL, Buadi FK, Dispenzieri A, Fonseca R, Gertz MA, Gonsalves WI, Hayman SR, Kapoor P, Kourelis T, Kumar SK, Kyle RA, Lacy MQ, Leung N, Lin Y, Lust JA, Mikhael JR, Reeder CB, Roy V, Russell SJ, Sher T, Stewart AK, Warsame R, Zeldenrust SR, Rajkumar SV, Chanan Khan AA. Therapy for Relapsed Multiple Myeloma: Guidelines From the Mayo Stratification for Myeloma and Risk-Adapted Therapy. Mayo Clin Proc 2017; 92:578-598. [PMID: 28291589 PMCID: PMC5554888 DOI: 10.1016/j.mayocp.2017.01.003] [Citation(s) in RCA: 118] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 12/12/2016] [Accepted: 01/04/2017] [Indexed: 12/13/2022]
Abstract
Life expectancy in patients with multiple myeloma is increasing because of the availability of an increasing number of novel agents with various mechanisms of action against the disease. However, the disease remains incurable in most patients because of the emergence of resistant clones, leading to repeated relapses of the disease. In 2015, 5 novel agents were approved for therapy for relapsed multiple myeloma. This surfeit of novel agents renders management of relapsed multiple myeloma more complex because of the occurrence of multiple relapses, the risk of cumulative and emergent toxicity from previous therapies, as well as evolution of the disease during therapy. A group of physicians at Mayo Clinic with expertise in the care of patients with multiple myeloma regularly evaluates the evolving literature on the biology and therapy for multiple myeloma and issues guidelines on the optimal care of patients with this disease. In this article, the latest recommendations on the diagnostic evaluation of relapsed multiple myeloma and decision trees on how to treat patients at various stages of their relapse (off study) are provided together with the evidence to support them.
Collapse
Affiliation(s)
- David Dingli
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN.
| | | | - P Leif Bergsagel
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ
| | - Francis K Buadi
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Angela Dispenzieri
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Rafael Fonseca
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ
| | - Morie A Gertz
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Wilson I Gonsalves
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Susan R Hayman
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Prashant Kapoor
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Taxiarchis Kourelis
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Shaji K Kumar
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Robert A Kyle
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Martha Q Lacy
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Nelson Leung
- Division of Nephrology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Yi Lin
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - John A Lust
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Joseph R Mikhael
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ
| | - Craig B Reeder
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ
| | - Vivek Roy
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL
| | - Stephen J Russell
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Taimur Sher
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL
| | - A Keith Stewart
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ
| | - Rahma Warsame
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Stephen R Zeldenrust
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - S Vincent Rajkumar
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | | |
Collapse
|
22
|
Lub S, Maes A, Maes K, De Veirman K, De Bruyne E, Menu E, Fostier K, Kassambara A, Moreaux J, Hose D, Leleu X, King RW, Vanderkerken K, Van Valckenborgh E. Inhibiting the anaphase promoting complex/cyclosome induces a metaphase arrest and cell death in multiple myeloma cells. Oncotarget 2016; 7:4062-76. [PMID: 26716651 PMCID: PMC4826190 DOI: 10.18632/oncotarget.6768] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 11/26/2015] [Indexed: 01/11/2023] Open
Abstract
The anaphase promoting complex/cyclosome (APC/C) is an ubiquitin ligase involved in cell cycle. During the metaphase-anaphase transition the APC/C is activated by Cdc20. The aim of this study is to elucidate the importance and therapeutic potential of APC/C and its co-activator Cdc20 in multiple myeloma (MM). Gene expression analysis revealed that Cdc20 was expressed at higher levels in gene expression-based high-risk MM patients. Moreover, high Cdc20 expression correlated with poor prognosis. Treatment of human myeloma cell lines with proTAME, an APC/C inhibitor, resulted in an accumulation of APC/CCdc20 substrate cyclin B1 and an accumulation of cells in metaphase. Moreover we observed a significant dose-dependent decrease in viability and increase in apoptosis in MM cells upon proTAME treatment. The induction of apoptosis was accompanied with caspase 3, 8, 9 and PARP cleavage. A similar metaphase arrest and induction of apoptosis were obtained with specific knockdown of Cdc20. In addition, we demonstrated the accumulation of Bim was partially responsible for the observed cell death. Combining proTAME with another APC/C inhibitor apcin or the alkylating agent melphalan resulted in enhanced anti-MM activity. This study suggests that the APC/C and its co-activator Cdc20 could be a new and promising target especially in high-risk MM patients.
Collapse
Affiliation(s)
- Susanne Lub
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Anke Maes
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Ken Maes
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Kim De Veirman
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Elke De Bruyne
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Eline Menu
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Karel Fostier
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Alboukadel Kassambara
- Department of Biological Hematology, CHU Montpellier, Montpellier, France.,Institute of Human Genetics, CNRS-UPR1142, Montpellier, France
| | - Jérôme Moreaux
- Department of Biological Hematology, CHU Montpellier, Montpellier, France.,Institute of Human Genetics, CNRS-UPR1142, Montpellier, France.,University of Montpellier 1, UFR de Médecine, Montpellier, France
| | - Dirk Hose
- Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany
| | - Xavier Leleu
- Service des maladies du sang, Hôpital Huriez, CHRU, Lille, France
| | - Randall W King
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA
| | - Karin Vanderkerken
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Els Van Valckenborgh
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| |
Collapse
|
23
|
Jimenez-Zepeda VH, Duggan P, Neri P, Rashid-Kolvear F, Tay J, Bahlis NJ. Revised International Staging System Applied to Real World Multiple Myeloma Patients. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2016; 16:511-518. [DOI: 10.1016/j.clml.2016.06.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 05/10/2016] [Accepted: 06/01/2016] [Indexed: 10/21/2022]
|
24
|
Thumallapally N, Yu H, Asti D, Vennepureddy A, Terjanian T. Salvage therapies in relapsed and/or refractory myeloma: what is current and what is the future? Onco Targets Ther 2016; 9:4843-58. [PMID: 27540299 PMCID: PMC4981158 DOI: 10.2147/ott.s110189] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The treatment landscape for multiple myeloma (MM) is evolving with our understanding of its pathophysiology. However, given the inevitable cohort heterogeneity in salvage therapy, response to treatment and overall prognoses tend to vary widely, making meaningful conclusions about treatment efficacy difficult to derive. Despite the hurdles in current research, progress is underway toward more targeted therapeutic approaches. Several new drugs with novel mechanism of action and less toxic profile have been developed in the past decade, with the potential for use as single agents or in synergy with other treatment modalities in MM therapy. As our discovery of these emerging therapies progresses, so too does our need to reshape our knowledge on knowing how to apply them. This review highlights some of the recent landmark changes in MM management with specific emphasis on salvage drugs available for relapsed and refractory MM and also discusses some of the upcoming cutting-edge therapies that are currently in various stages of clinical development.
Collapse
Affiliation(s)
| | - Hana Yu
- Department of Internal Medicine
| | | | | | - Terenig Terjanian
- Division of Hematology and Oncology, Staten Island University Hospital, New York, NY, USA
| |
Collapse
|
25
|
Boudreault JS, Touzeau C, Moreau P. The role of SLAMF7 in multiple myeloma: impact on therapy. Expert Rev Clin Immunol 2016; 13:67-75. [PMID: 27376202 DOI: 10.1080/1744666x.2016.1209112] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Multiple myeloma (MM), a mature B-cell neoplasm, is the second most common hematologic malignancy worldwide. Despite significant improvements in outcome with new therapies, the majority of responding patients will eventually develop resistance to treatment. Furthermore, patients swith disease refractory to both proteasome inhibitors and immunomodulatory drugs (IMiDs) have a poor prognosis. Areas covered: Several new therapeutic approaches are emerging and immunotherapeutic strategies present an important advance for the treatment of patients with relapsed or refractory MM. Among the monoclonal antibodies under development in MM, those targeting SLAMF7 and CD38 have shown the most consistent benefit in trials to date. In this review, we will specifically focus on elotuzumab (anti-SLAMF7 antibody), and provide a summary of the mechanism of action, the clinical results and the safety profile of this new drug. Expert commentary: Although elotuzumab has no single agent activity in MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when the agent is added to bortezomib-dexamethasone or lenalidomide-dexamethasone. Furthermore, this agent with its novel mechanism of action can be combined with standard therapies without a significant increase in toxicity. Elotuzumab is a highly effective therapy and future data are necessary to identify the best place for this therapy in the setting of MM.
Collapse
Affiliation(s)
| | - Cyrille Touzeau
- a Hematology Department , University Hospital Hôtel-Dieu , Nantes , France
| | - Philippe Moreau
- a Hematology Department , University Hospital Hôtel-Dieu , Nantes , France
| |
Collapse
|
26
|
Szabo AG, Gang AO, Pedersen MØ, Poulsen TS, Klausen TW, Nørgaard P. Overexpression of c-myc is associated with adverse clinical features and worse overall survival in multiple myeloma. Leuk Lymphoma 2016; 57:2526-34. [PMID: 27243588 DOI: 10.1080/10428194.2016.1187275] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The role of c-myc in multiple myeloma (MM) is controversial. We conducted a retrospective study of 117 patients with MM diagnosed between 2004 and 2010 at Herlev Hospital. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) were performed on tissue microarrays (TMAs) made from diagnostic bone marrow aspirates. Clinical data were obtained from the Danish Multiple Myeloma Database (DMMD). Overexpression of c-myc was found in 40% of patients. MYC translocation was found in 10% of patients. Overexpression of c-myc was not associated with MYC translocation. Overexpression of c-myc was associated with hypercalcemia (p = 0.02) and extramedullary myeloma (p < 0.01). Overexpression of c-myc was associated with shorter overall survival (OS) by multivariable analysis of the entire patient cohort [HR 1.92 (1.06-3.45), p = 0.03] and univariable analysis of high-dose-therapy (HDT)-ineligible patients [HR 2.01 (1.05-3.86), p = 0.04]. Further studies of c-myc overexpression in larger cohorts of patients with MM are warranted.
Collapse
Affiliation(s)
- Agoston Gyula Szabo
- a Department of Pathology , Copenhagen University Hospital Herlev , Herlev , Denmark
| | - Anne Ortved Gang
- b Department of Hematology , Copenhagen University Hospital Herlev , Herlev , Denmark
| | - Mette Ølgod Pedersen
- a Department of Pathology , Copenhagen University Hospital Herlev , Herlev , Denmark
| | - Tim Svenstrup Poulsen
- a Department of Pathology , Copenhagen University Hospital Herlev , Herlev , Denmark
| | | | - Peter Nørgaard
- a Department of Pathology , Copenhagen University Hospital Herlev , Herlev , Denmark
| |
Collapse
|
27
|
Cornell RF, Kassim AA. Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity. Bone Marrow Transplant 2016; 51:479-91. [PMID: 26726946 PMCID: PMC4827007 DOI: 10.1038/bmt.2015.307] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 10/08/2015] [Accepted: 10/22/2015] [Indexed: 12/12/2022]
Abstract
The use of modern therapies such as thalidomide, bortezomib and lenalidomide coupled with upfront high-dose therapy and autologous stem cell transplant (ASCT) has resulted in improved survival in patients with newly diagnosed multiple myeloma (MM). However, patients with relapsed/refractory multiple myeloma (RRMM) often have poorer clinical outcomes and might benefit from novel therapeutic strategies. Emerging therapies, such as deacetylase inhibitors, monoclonal antibodies and new proteasome inhibitors, appear promising and may change the therapeutic landscape in RRMM. A limited number of studies has shown a benefit with salvage ASCT in patients with RRMM, although there remains ongoing debate about its timing and effectiveness. Improvement in transplant outcomes has re-ignited a debate on the timing and possible role for salvage ASCT and allogeneic stem cell transplant in RRMM. As the treatment options for management of patients with RRMM become increasingly complex, physicians must consider both disease- and patient-related factors in choosing the appropriate therapeutic approach, with the goal of improving efficacy while minimizing toxicity.
Collapse
Affiliation(s)
- R F Cornell
- Department of Medicine, Division of Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - A A Kassim
- Department of Medicine, Division of Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA
| |
Collapse
|
28
|
Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood 2016; 127:2955-62. [PMID: 27002115 DOI: 10.1182/blood-2016-01-631200] [Citation(s) in RCA: 688] [Impact Index Per Article: 76.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 03/08/2016] [Indexed: 02/07/2023] Open
Abstract
The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification.
Collapse
|
29
|
Mlynarcikova M, Balcarkova J, Mickova P, Scudla V, Pika T, Bacovsky J, Minarik J, Janousova E, Jarosova M. Molecular Cytogenetic Analysis of Chromosome 8 Aberrations in Patients With Multiple Myeloma Examined in 2 Different Stages, at Diagnosis and at Progression/Relapse. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2016; 16:358-65. [PMID: 27052024 DOI: 10.1016/j.clml.2016.02.038] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 02/09/2016] [Accepted: 02/18/2016] [Indexed: 12/21/2022]
Abstract
BACKGROUND The genome of multiple myeloma (MM) clonal plasma cells is characterized by genetic changes of prognostic importance. Disease progression is accompanied by a number of secondary chromosomal aberrations including chromosome 8. We focused on the detection of chromosome 8 aberrations in patients with MM who were examined at 2 different phases: diagnosis and progression/relapse. PATIENTS AND METHODS A total of 62 patients with MM were examined at the time of diagnosis and at relapse/progression. The median age was 64 years (range, 39-78 years); the study included 29 males and 33 females. We analyzed bone marrow samples for detecting aberrations on chromosome 8 by the fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms (FICTION) and fluorescence in situ hybridization methods with specific probes. RESULTS Chromosome 8 aberrations were detected in 24 (38.7%) patients at diagnosis and in 29 (46.8%) patients at progression/relapse. Only 5 (8%) patients developed additional chromosome 8 changes at progression/relapse. The aberrations were heterogeneous, involving numerical and structural changes of the MYC gene. Aberrations of the short arm of chromosome 8, involving the genes TRAIL-R1/-R2, were less frequent (4 of 62 patients, 6.4%). All aberrations of chromosome 8 were accompanied with additional changes and with an advanced clinical phase of the disease. This finding significantly influenced the overall survival of patients. CONCLUSION In the current study, chromosome 8 aberrations were highly heterogeneous, were presented at diagnosis in patients with advanced clinical stage, and were associated with worse overall survival. We have not confirmed the increase of frequency aberration of chromosome 8 in disease progression. The findings demonstrate the importance of fluorescence in situ hybridization examination of chromosome 8 in newly diagnosed patients with MM.
Collapse
Affiliation(s)
| | - Jana Balcarkova
- Department of Hemato-oncology, Palacky University Hospital, Olomouc, Czech Republic
| | - Pavla Mickova
- Department of Hemato-oncology, Palacky University Hospital, Olomouc, Czech Republic
| | - Vlastimil Scudla
- Department of Hemato-oncology, Palacky University Hospital, Olomouc, Czech Republic
| | - Tomas Pika
- Department of Hemato-oncology, Palacky University Hospital, Olomouc, Czech Republic
| | - Jaroslav Bacovsky
- Department of Hemato-oncology, Palacky University Hospital, Olomouc, Czech Republic
| | - Jiri Minarik
- Department of Hemato-oncology, Palacky University Hospital, Olomouc, Czech Republic
| | - Eva Janousova
- Institute of Biostatistics and Analysis, Masaryk University, Brno, Czech Republic
| | - Marie Jarosova
- Department of Hemato-oncology, Palacky University Hospital, Olomouc, Czech Republic.
| |
Collapse
|
30
|
Kishimoto RK, de Freitas SLVV, Ratis CA, Borri D, Sitnik R, Velloso EDRP. Validation of interphase fluorescence in situ hybridization (iFISH) for multiple myeloma using CD138 positive cells. Rev Bras Hematol Hemoter 2016; 38:113-20. [PMID: 27208569 PMCID: PMC4877610 DOI: 10.1016/j.bjhh.2016.01.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 01/18/2016] [Accepted: 01/26/2016] [Indexed: 02/02/2023] Open
Abstract
Background Multiple myeloma is a plasma cell neoplasm with acquired genetic abnormalities of clinical and prognostic importance. Multiple myeloma differs from other hematologic malignancies due to a high fraction of low proliferating malignant plasma cells and the paucity of plasma cells in bone marrow aspiration samples, making cytogenetic analysis a challenge. An abnormal karyotype is found in only one-third of patients with multiple myeloma and interphase fluorescence in situ hybridization is the most useful test for studying the chromosomal abnormalities present in almost 90% of cases. However, it is necessary to study the genetic abnormalities in plasma cells after their identification or selection by morphology, immunophenotyping or sorting. Other challenges are the selection of the most informative FISH panel and determining cut-off levels for FISH probes. This study reports the validation of interphase fluorescence in situ hybridization using CD138 positive cells, according to proposed guidelines published by the European Myeloma Network (EMN) in 2012. Method Bone marrow samples from patients with multiple myeloma were used to standardize a panel of five probes [1q amplification, 13q14 deletion, 17p deletion, t(4;14), and t(14;16)] in CD138+ cells purified by magnetic cell sorting. Results This test was validated with a low turnaround time and good reproducibility. Five of six samples showed genetic abnormalities. Monosomy/deletion 13 plus t(4;14) were found in two cases. Conclusion This technique together with magnetic cell sorting is effective and can be used in the routine laboratory practice. In addition, magnetic cell sorting provides a pure plasma cell population that allows other molecular and genomic studies.
Collapse
Affiliation(s)
| | | | | | - Daniela Borri
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Roberta Sitnik
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | | |
Collapse
|
31
|
Abstract
Multiple myeloma is a disorder characterized by accumulation of malignant plasma cells in the bone marrow, hypercalcemia, monoclonal protein, and end organ damage. Recently newer generation proteosome inhibitors, monoclonal antibodies and novel agents have been approved by FDA, which is undoubtedly increasing life expectancy of the patients. However, hematopoietic stem cell transplantation still remains the cornerstone of the treatment. In this chapter, we are discussing the autologous stem cell transplant, allogeneic stem cell transplant and total therapy trials with outcomes.
Collapse
Affiliation(s)
- Yogesh S Jethava
- Stem Cell and Allogeneic Transplant, Department of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
| | - Frits van Rhee
- Stem Cell and Allogeneic Transplant, Department of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| |
Collapse
|
32
|
Rack K, Vidrequin S, Dargent JL. Genomic profiling of myeloma: the best approach, a comparison of cytogenetics, FISH and array-CGH of 112 myeloma cases. J Clin Pathol 2015; 69:82-6. [DOI: 10.1136/jclinpath-2015-203054] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 08/12/2015] [Indexed: 11/04/2022]
|
33
|
Kazmi SM, Nusrat M, Gunaydin H, Cornelison AM, Shah N, Kebriaei P, Nieto Y, Parmar S, Popat UR, Oran B, Shah JJ, Orlowski RZ, Champlin RE, Qazilbash MH, Bashir Q. Outcomes Among High-Risk and Standard-Risk Multiple Myeloma Patients Treated With High-Dose Chemotherapy and Autologous Hematopoietic Stem-Cell Transplantation. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2015; 15:687-93. [PMID: 26361647 DOI: 10.1016/j.clml.2015.07.641] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 06/29/2015] [Accepted: 07/28/2015] [Indexed: 01/23/2023]
Abstract
BACKGROUND Conventional cytogenetics and interphase fluorescence in-situ hybridization (FISH) identify a high-risk multiple myeloma population characterized by poor response and short survival. PATIENTS AND METHODS We compared outcomes between high-risk and standard-risk myeloma patients who underwent autologous hematopoietic stem-cell transplantation (auto-HCT) at our institution between January 2005 and December 2009. High-risk myeloma was defined as -13/del(13q) or hypodiploidy in at least 2 metaphases of conventional cytogenetics, or -17/del(17p), t(4;14), t(14;16), t(14;20), hypodiploidy (< 45 chromosomes excluding -Y), or chromosome 1 abnormalities (+1q, -1p, t(1;x)) on FISH or conventional cytogenetics. RESULTS Of 670 myeloma patients, 74 (11%) had high-risk myeloma. These high-risk patients had significantly lower overall response rates (74% vs. 85%; P < .01), shorter median progression-free survival (10.3 vs. 32.4 months; P < .001), and shorter overall survival (28 months vs. not reached; P < .001) than the standard-risk patients. Having only 1 high-risk cytogenetic abnormality or experiencing at least very good partial remission after auto-HCT independently predicted improved progression-free survival and overall survival (P < .05) in high-risk patients. CONCLUSION Even in an era of novel therapies, cytogenetically identified high-risk myeloma patients have worse prognoses than standard-risk myeloma patients after auto-HCT, and having more than 1 high-risk cytogenetic abnormality further reduces survival.
Collapse
Affiliation(s)
- Syed M Kazmi
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Maliha Nusrat
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX
| | - Hilal Gunaydin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Amanda M Cornelison
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Nina Shah
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Partow Kebriaei
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yago Nieto
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Simrit Parmar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Uday R Popat
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Betul Oran
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jatin J Shah
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Robert Z Orlowski
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Richard E Champlin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Muzaffar H Qazilbash
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Qaiser Bashir
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.
| |
Collapse
|
34
|
Cogbill CH, Spears MD, Vantuinen P, Harrington AM, Olteanu H, Kroft SH. Morphologic and cytogenetic variables affect the flow cytometric recovery of plasma cell myeloma cells in bone marrow aspirates. Int J Lab Hematol 2015. [DOI: 10.1111/ijlh.12411] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- C. H. Cogbill
- Department of Pathology; Medical College of Wisconsin; Milwaukee WI USA
| | - M. D. Spears
- Department of Pathology; Medical College of Wisconsin; Milwaukee WI USA
| | - P. Vantuinen
- Department of Pathology; Medical College of Wisconsin; Milwaukee WI USA
| | - A. M. Harrington
- Department of Pathology; Medical College of Wisconsin; Milwaukee WI USA
| | - H. Olteanu
- Department of Pathology; Medical College of Wisconsin; Milwaukee WI USA
| | - S. H. Kroft
- Department of Pathology; Medical College of Wisconsin; Milwaukee WI USA
| |
Collapse
|
35
|
Abstract
Plasma cell myeloma (PCM) is a hematologic malignancy that primarily affects the elderly. Approximately two-thirds of patients are aged 65 years or older at diagnosis. Major advances in testing, treatment, and supportive care have resulted in substantial improvement in overall survival in younger, standard-risk, PCM patients over the past 3 decades. However, this positive impact progressively diminishes with advancing age, with some studies showing no improvement in survival outcomes in the elderly. Slow improvement in survival for elderly PCM patients is likely multifactorial, influenced by factors such as age-related physiologic changes, increased comorbidities, decreased treatment tolerance, socioeconomic barriers, and possible differences in disease biology. The standard approach of basing treatment decisions on age and performance status does not account for this complexity, and can be insufficient to determine the risks and benefits of treatment. Comprehensive geriatric assessment (CGA) produces a more thorough iteration of the factors influencing an individual's treatment risk, and can potentially identify targets for intervention to lower risk. Ongoing studies are looking at developing and refining the tools available for risk screening and assessment. Treating elderly PCM patients with novel agent-based regimens with or without autologous stem cell transplantation has improved response rates and survival in some studies, but elderly PCM patients have benefitted less than their younger counterparts from recent advances in PCM treatment. Personalizing treatment decisions, based on predictions of risk, determined by geriatric assessment, and response, determined by precision medicine (our understanding of the genetic, molecular, and cellular pathways that drive an individual's cancer) will help maximize the benefit and minimize the risk of PCM treatment for each patient. Continued evaluation of new strategies and treatments for PCM in clinical trials specifically designed for elderly patients is needed to continue to improve outcomes for elderly PCM patients in the future.
Collapse
|
36
|
Sun JJ, Zhang C, Zhou J, Yang HL. Pooled analysis of pomalidomide for treating patients with multiple myeloma. Asian Pac J Cancer Prev 2015; 16:3163-6. [PMID: 25921115 DOI: 10.7314/apjcp.2015.16.8.3163] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Patients with refractory or relapsed multiple myeloma are considered to have a very poor prognosis, and new regimens are needed to improve this setting. Pomalidomide is a new immunomodulatory drug with high in vitro potency. Immunomodulatory drugs are hypothesized to act through multiple mechanisms. Here we performed a systemic analysis to evaluate pomalidomide-based chemotherapy (pomalidomide in combination with low-dose dexamethasone) as salvage treatment for patients with refractory and relapsed multiple myeloma. METHODS Clinical studies evaluating the efffectiveness of pomalidomide based regimens on response and safety for patients with refractory and relapsed multiple myeloma were identified using a predefined search strategy. Pooled response rate (RR) of treatment were calculated. RESULTS For pomalidomide based regimens, 4 clinical studies which including 291 patients with refractory and relapsed multiple myeloma were considered eligible for inclusion. Systemic analysis suggested that, in all patients, pooled RR was 41.2% (120/291). Major adverse effects were hematologic toxicity, including grade 1 or 2 anemia, leucopenia and thrombocytopenia with pomalidomide based treatment. No treatment related death occurred. CONCLUSION This pooled analysis suggests that pomalidomide in combination with low-dose dexamethasone is active with good tolerability in treating patients with refractory or relapsed multiple myeloma.
Collapse
Affiliation(s)
- Jia-Jia Sun
- The First Affiliated Hospital of Soochow University, Soochow, Jiangsu, China E-mail :
| | | | | | | |
Collapse
|
37
|
Galera P, Martin HC, Welch L, Sulmasy P, Cerny J, Greene M, Vauthrin M, Bailey JA, Weinstein R. Automated red blood cell exchange for acute drug removal in a patient with sirolimus toxicity. J Clin Apher 2015; 30:367-70. [DOI: 10.1002/jca.21381] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Accepted: 12/17/2014] [Indexed: 11/09/2022]
Affiliation(s)
- Pallavi Galera
- Transfusion Medicine and Apheresis Service; UMass Memorial Medical Center; Worcester Massachusetts
- Department of Pathology; University of Massachusetts Medical School; Worcester Massachusetts
| | - Hannah C. Martin
- Transfusion Medicine and Apheresis Service; UMass Memorial Medical Center; Worcester Massachusetts
- University of Massachusetts Medical School; Worcester Massachusetts
| | - Linda Welch
- Transfusion Medicine and Apheresis Service; UMass Memorial Medical Center; Worcester Massachusetts
| | - Paula Sulmasy
- Transfusion Medicine and Apheresis Service; UMass Memorial Medical Center; Worcester Massachusetts
| | - Jan Cerny
- University of Massachusetts Medical School; Worcester Massachusetts
- Division of Hematology/Oncology; UMass Memorial Medical Center; Worcester Massachusetts
- Department of Medicine; University of Massachusetts Medical School; Worcester Massachusetts
| | - Mindy Greene
- Transfusion Medicine and Apheresis Service; UMass Memorial Medical Center; Worcester Massachusetts
| | - Michelle Vauthrin
- Transfusion Medicine and Apheresis Service; UMass Memorial Medical Center; Worcester Massachusetts
| | - Jeffrey A. Bailey
- Transfusion Medicine and Apheresis Service; UMass Memorial Medical Center; Worcester Massachusetts
- Department of Pathology; University of Massachusetts Medical School; Worcester Massachusetts
- University of Massachusetts Medical School; Worcester Massachusetts
- Department of Medicine; University of Massachusetts Medical School; Worcester Massachusetts
- Division of Transfusion Medicine; UMass Memorial Medical Center; Worcester Massachusetts
| | - Robert Weinstein
- Transfusion Medicine and Apheresis Service; UMass Memorial Medical Center; Worcester Massachusetts
- Department of Pathology; University of Massachusetts Medical School; Worcester Massachusetts
- University of Massachusetts Medical School; Worcester Massachusetts
- Department of Medicine; University of Massachusetts Medical School; Worcester Massachusetts
- Division of Transfusion Medicine; UMass Memorial Medical Center; Worcester Massachusetts
| |
Collapse
|
38
|
Novel agents have a significant impact on survival of patients with multiple myeloma. Wien Klin Wochenschr 2015; 127:92-7. [DOI: 10.1007/s00508-014-0605-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 08/24/2014] [Indexed: 11/25/2022]
|
39
|
Gaultney JG, Franken MG, Uyl-de Groot CA, Redekop WK, Huijgens PC, van der Holt B, Lokhorst HM, Sonneveld P. Experience with outcomes research into the real-world effectiveness of novel therapies in Dutch daily practice from the context of conditional reimbursement. Health Policy 2014; 119:186-94. [PMID: 25476554 DOI: 10.1016/j.healthpol.2014.11.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Revised: 09/13/2014] [Accepted: 11/16/2014] [Indexed: 12/24/2022]
Abstract
Policymakers more often request outcomes research for expensive therapies to help resolve uncertainty of their health benefits and budget impact at reimbursement. Given the limitations of observational data, we assessed its usefulness in evaluating clinical outcomes for bortezomib in advanced multiple myeloma patients. Data were retrospectively collected from patients included in the pivotal Assessment of Proteasome Inhibition for Extending Remissions trial (APEX; n=333) and two groups of daily practice patients treated with bortezomib following progression from upfront therapy (n=201): real-world patients treated as of May 2009 (RW-1; n=72) and June 2012 (RW-2; n=129). Prognosis, treatment, and effectiveness were compared. Outcomes research was useful for policymakers for addressing to whom and how bortezomib was administered in daily practice. It was limited however in generating robust evidence on real-world safety and effectiveness. The quality of real-world evidence on effectiveness was low due to missing data in patient charts, existing treatment variation and the dynamics in care during the novel drug's initial market uptake period. Policymakers requesting real-world evidence on clinical outcomes for reimbursement decisions should be aware of these limitations and advised to carefully consider beforehand the type of evidence that best addresses their needs for the re-assessment phase.
Collapse
Affiliation(s)
- Jennifer G Gaultney
- Institute for Medical Technology Assessment/Department of Health Policy and Management, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands; Mapi Group, De Molen 84, 3995 AX Houten, The Netherlands.
| | - Margreet G Franken
- Institute for Medical Technology Assessment/Department of Health Policy and Management, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
| | - Carin A Uyl-de Groot
- Institute for Medical Technology Assessment/Department of Health Policy and Management, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
| | - William K Redekop
- Institute for Medical Technology Assessment/Department of Health Policy and Management, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
| | - Peter C Huijgens
- Department of Haematology, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Bronno van der Holt
- HOVON Data Centre, Erasmus MC Cancer Institute-Clinical Trial Centre, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
| | - Henk M Lokhorst
- Department of Haematology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Pieter Sonneveld
- Department of Haematology, Erasmus University Medical Centre, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
| |
Collapse
|
40
|
Abstract
Multiple myeloma (MM) is a heterogeneous disease that, over the past 15 years, has seen an increased understanding of its biology and of novel therapeutic options. Distinctive subtypes of the disease have been described, each with different outcomes and clinic-pathological features. Even though a detailed classification of MM into at least seven or eight major subtypes is possible, a more practical clinical approach can classify the disease into high-risk and non-high-risk MM. Such classification has permitted a more personalized approach to the management of the disease. Additionally, risk stratification should be included in outcome discussions with patients, as survival differs significantly by high-risk status. Nowadays, test for risk stratification are widely available and can be routinely used in the clinic. A greater understanding of the genetic abnormalities underlying the biology of MM will allow for the development of novel targeted therapies and better prognostic markers of the disease.
Collapse
Affiliation(s)
- Rafael Fonseca
- Department of Medicine, Mayo Clinic in Arizona, Scottsdale, AZ 85259-5494, USA
| | | | | |
Collapse
|
41
|
Glitza IC, Lu G, Shah R, Bashir Q, Shah N, Champlin RE, Shah J, Orlowski RZ, Qazilbash MH. Chromosome 8q24.1/c-MYC abnormality: a marker for high-risk myeloma. Leuk Lymphoma 2014; 56:602-7. [PMID: 24844357 DOI: 10.3109/10428194.2014.924116] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The proto-oncogene c-MYC is rearranged in about 15% of patients with multiple myeloma (MM). We identified 23 patients with MM and c-MYC. Primary objectives were to describe the clinical characteristics, response to therapy, progression-free survival and overall survival (OS). Twelve out of twenty-three patients presented with or progressed to either plasma cell leukemia (PCL) and/or extramedullary disease (EMD). Induction therapy consisted of an immunomodulatory, proteasome inhibitor-based or conventional chemotherapy regimen. Fifteen patients achieved a partial response and three achieved a very good partial response. Sixteen patients received an autologous and one patient an allogeneic hematopoietic stem cell transplant. Median OS from diagnosis was 20.2 months. Patients with PCL or EMD had significantly shorter OS (15.5 vs. 40.4 months, p = 0.0005). This is the first report describing the clinical characteristics of patients with MM and c-MYC. These abnormalities are associated with an aggressive form of MM, high incidence of PCL/EMD and short OS.
Collapse
Affiliation(s)
- Isabella C Glitza
- Hematology/Oncology Fellowship, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center , Houston, TX , USA
| | | | | | | | | | | | | | | | | |
Collapse
|
42
|
Dimopoulos MA, Leleu X, Palumbo A, Moreau P, Delforge M, Cavo M, Ludwig H, Morgan GJ, Davies FE, Sonneveld P, Schey SA, Zweegman S, Hansson M, Weisel K, Mateos MV, Facon T, Miguel JFS. Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. Leukemia 2014; 28:1573-85. [PMID: 24496300 PMCID: PMC4131249 DOI: 10.1038/leu.2014.60] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 01/16/2014] [Accepted: 01/21/2014] [Indexed: 11/24/2022]
Abstract
In this report, a panel of European myeloma experts discuss the role of pomalidomide in the treatment of relapsed and refractory multiple myeloma (RRMM). Based on the available evidence, the combination of pomalidomide and low-dose dexamethasone is a well-tolerated and effective treatment option for patients with RRMM who have exhausted treatment with lenalidomide and bortezomib. The optimal starting dose of pomalidomide is 4 mg given on days 1-21 of each 28-day cycle, whereas dexamethasone is administered at a dose of 40 mg weekly (reduced to 20 mg for patients aged >75 years). The treatment should continue until evidence of disease progression or unacceptable toxicity. Dose-modification schemes have been established for patients who develop neutropenia, thrombocytopaenia and other grade 3-4 adverse events during pomalidomide therapy. Guidance on the prevention and management of infections and venous thromboembolism is provided, based on the available clinical evidence and the experience of panel members. The use of pomalidomide in special populations, such as patients with advanced age, renal impairment or unfavourable cytogenetic features, is also discussed.
Collapse
Affiliation(s)
| | - X Leleu
- Service des Maladies du Sang, Hôpital Huriez, CHRU Lille, Lille, France
| | - A Palumbo
- Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliera S Giovanni Battista, Turin, Italy
| | - P Moreau
- Service d'Hematologie, CHU, Nantes, France
| | - M Delforge
- University Hospital Leuven, Leuven, Belgium
| | - M Cavo
- Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy
| | - H Ludwig
- 1st Department of Internal Medicine, Center for Oncology and Hematology, Wilhelminenhospital, Vienna, Austria
| | - G J Morgan
- Institute of Cancer Research, Royal Marsden Hospital, London, UK
| | - F E Davies
- Institute of Cancer Research, Royal Marsden Hospital, London, UK
| | - P Sonneveld
- Department of Hematology, University Hospital Rotterdam, Rotterdam, The Netherlands
| | - S A Schey
- Department of Haemato-oncology, King's College Hospital and King's College London, London, UK
| | - S Zweegman
- Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands
| | - M Hansson
- Department of Hematology, Skåne University Hospital, Lund University, Lund, Sweden
| | - K Weisel
- University of Tuebingen, Tuebingen, Germany
| | - M V Mateos
- Hospital Universitario de Salamanca, CIC, IBMCC (USAL-CSIC), Salamanca, Spain
| | - T Facon
- Service des Maladies du Sang, Hôpital Huriez, CHRU Lille, Lille, France
| | - J F S Miguel
- Clinica Universidad de Navarra, Centro Investigaciones Medicas Aplicada (CIMA), Pamplona, Spain
| |
Collapse
|
43
|
Geller MD, Pei Y, Spurgeon SE, Durum C, Leeborg NJ. Chronic lymphocytic leukemia with a FGFR3 translocation: case report and literature review of an uncommon cytogenetic event. Cancer Genet 2014; 207:340-3. [DOI: 10.1016/j.cancergen.2014.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 09/05/2014] [Accepted: 09/06/2014] [Indexed: 10/24/2022]
|
44
|
Shin SJ, Lee H, Jung G, Gil M, Park H, Park YS, Yoon DH, Suh C, Park CJ, Huh J, Park CS. Expression of CD99 in Multiple Myeloma: A Clinicopathologic and Immunohistochemical Study of 170 Cases. KOREAN JOURNAL OF PATHOLOGY 2014; 48:209-16. [PMID: 25013419 PMCID: PMC4087134 DOI: 10.4132/koreanjpathol.2014.48.3.209] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 05/12/2014] [Accepted: 05/13/2014] [Indexed: 11/25/2022]
Abstract
Background Multiple myeloma (MM) is a heterogeneous and ultimately fatal disease. Risk stratification using prognostic biomarkers is crucial to individualize treatments. We sought to investigate the role of CD99, a transmembrane protein highly expressed in many hematopoietic cells including subpopulations of normal and neoplastic plasma cells, for MM risk stratification. Methods CD99 expression was measured in paraffin samples of bone marrow and extramedullary biopsies of 170 patients with MM. Patients were divided into those with high score (moderately and strongly positive) and low score (negative and weakly positive), with all staining being cytoplasmic and/or membranous. Results High anti-CD99 immunostaining was observed in 72 of 136 (52.9%) bone marrow biopsies and 24 of 87 (27.6%) extramedullary biopsies in MM. High CD99 expression of extramedullary specimens was associated with significantly longer overall survival (OS; p=.016). High CD99 expression of extramedullary specimens was also associated with better prognosis in the nonautologous stem cell transplantation group of MM patients (p=.044). In multivariate analysis, International Staging System stage was an independent prognostic factor, whereas CD99 expression was no longer statistically significant. Conclusions Expression of CD99 in extramedullary specimens was correlated with longer OS, suggesting that CD99 may be a helpful immunohistochemical marker for risk stratification.
Collapse
Affiliation(s)
- Su-Jin Shin
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyangsin Lee
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Geunyoung Jung
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Minchan Gil
- Cell Dysfunction Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hosub Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dok Hyun Yoon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Cheolwon Suh
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chan-Jeoung Park
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jooryung Huh
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chan-Sik Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. ; Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. ; Cell Dysfunction Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| |
Collapse
|
45
|
Boneva T, Brazma D, Gancheva K, Howard-Reeves J, Raynov J, Grace C, Nacheva EP. Can genome array screening replace FISH as a front-line test in multiple myeloma? Genes Chromosomes Cancer 2014; 53:676-92. [PMID: 24757046 DOI: 10.1002/gcc.22178] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 04/05/2014] [Accepted: 04/07/2014] [Indexed: 02/03/2023] Open
Abstract
Multiple myeloma (MM) is a malignant disorder characterized by neoplastic transformation of mature B cells in the bone marrow (BM), accompanied by complex genetic changes. The disease is heterogeneous at both the clinical and genomic levels. Molecular genetics and genomic investigations have demonstrated that disease evolution is associated with an accumulation of specific aberrations, mostly genome imbalances, which not only shed light on the disease pathogenesis but also allow risk assessment and treatment monitoring. We used a catalogue version of the Agilent 8x60K oligo-array with immuno-magnetically isolated CD138(+) cells from BM samples of 50 patients with myeloma to evaluate the merit of array comparative genomic hybridization (aCGH) as a diagnostic tool. We demonstrate the ability of aCGH to detect clonal imbalances to a level well below established clinically significant thresholds. aCGH, combined with target enrichment and complemented with tests for IGH rearrangements offers a cost neutral alternative to multiprobe fluorescence in situ hybridization screening. While we recognize the limitations of the standard version of the 8x60k array we demonstrate the value of aCGH as a first tier test in the diagnostic workup of MM. The array technology enables high-risk disease stratification with the added benefit of providing whole genome data to assist in establishing clinically relevant predicative markers.
Collapse
|
46
|
Chromosome 13 deletion and hypodiploidy on conventional cytogenetics are robust prognostic factors in Korean multiple myeloma patients: web-based multicenter registry study. Ann Hematol 2014; 93:1353-61. [PMID: 24671365 DOI: 10.1007/s00277-014-2057-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 03/10/2014] [Indexed: 01/08/2023]
Abstract
This study was designed to evaluate the prevalence of chromosomal abnormalities and to identify the specific abnormalities associated with poor prognosis. A total of 2,474 patients whose conventional cytogenetics were available at the time of diagnosis were evaluated via a nationwide registry. Normal metaphase cytogenetics was observed in 2,012 patients (81.3%). Among the 462 patients with chromosomal abnormalities, there were 161 (34.8%) patients with hyperdiploidy, 197 (42.6%) with pseudodiploidy, 79 (17.1%) with hypodiploidy, and 25 (5.5%) with near-tetraploidy. Deletion 13 (Δ13) in metaphase was observed in 167 patients (6.8%). Fluorescent in situ hybridization (FISH) was carried out in 967 patients (39.1%), and 66 (13.7%) out of 482 and 63 (10.3%) out of 611 patients were positive for t(4;14) and del(17p), respectively. With a median follow-up duration of 25.1 months, the median overall survival (OS) was 51.2 months (95% confidence interval, 46.5-55.9 months). In univariate analysis, the following four chromosomal abnormalities were significantly associated with a poor survival outcome: Δ13, hypodiploidy, del(13q) in FISH, and del(17p) in FISH. In the subsequent multivariate analysis, in which del(13q) and del(17p) in FISH were excluded due to a relatively low number of patients, Δ13 and hypodiploid status were independently associated with a poor survival outcome after adjusting for important clinical factors, including age, sex, performance, beta2-microglobulin, albumin, and lactate dehydrogenase (LDH). Using conventional metaphase cytogenetics, we confirmed that both Δ13 and hypodiploid status were robust poor prognostic factors. The metaphase karyotyping should remain the primary cytogenetic tool and an essential investigation for risk stratification in newly diagnosed multiple myeloma patients.
Collapse
|
47
|
Eicher DM, Lonial S, Cavallo F, Palumbo A, Nair B, Waheed S, Hofmeister C, Rogers HJ. High-risk myeloma: when to transplant-or not. Semin Oncol 2014; 41:e1-9. [PMID: 24565588 DOI: 10.1053/j.seminoncol.2013.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
|
48
|
Huang BT, Tan Y, Zhao WH, Zeng QC, Li BS, Chen RL. How to determine bortezomib-based regimen for elderly patients with multiple myeloma: PAD versus CBd, an observational study. J Cancer Res Clin Oncol 2014; 140:303-9. [PMID: 24337419 DOI: 10.1007/s00432-013-1570-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 12/08/2013] [Indexed: 01/10/2023]
Abstract
BACKGROUND This was an open-label, observational, prospective assessment. We conducted an analysis of the impact of bortezomib-based therapy (PAD: bortezomib, doxorubicin, high-dose dexamethasone vs. CBd: cyclophosphamide bortezomib, low-dose dexamethasone) on the survival rates and adverse events in elderly patients with newly diagnosed multiple myeloma (MM). METHODS Out of 303 patients, 128 received the PAD regimen and the other 175 patients received the CBd induction therapy (age 65-89 years). Baseline patient characteristics between the two cohorts were balanced in age (P = 0.69), international staging system (ISS) prognostic stages (P = 0.90), serum calcium (P = 0.70), and serum creatinine (P = 0.52). RESULTS Overall response (OS) after the induction chemotherapy was achieved in 214 of 303 patients (70.6 %), with no significant differences observed between the two treatment groups (71.9 vs. 69.7 %, P = 0.68). Patients with ISS stage 2 reached the same 5-year OS advantages compared to patients with ISS stage 1, because they received bortezomib-based PAD or CBd treatments. Patients receiving CBd protocol gained similar satisfactory progression-free survival (PFS) results when compared to the PAD regimen group: PFS at 5 years reached 58.2 versus 58.9 % (P = 0.85). Five-year OS in the CBd arm had significant advantages compared to the PAD group, 79.9 versus 49.9 % (P < 0.05). The overall safety profiles showed that 26 of 128 (20.3 %) patients died in the PAD arm, while 13 of 175 patients died (7.4 %) in the CBd group (P < 0.01). Similarly, the PAD arm had a higher serious infection rate than that of the CBd arm (39.2 vs. 13.1 %, P < 0.01). CONCLUSIONS Bortezomib benefits elderly patients with newly diagnosed MM; they achieve satisfactory treatment responses and survival advantages. Further, patients treated with CBd have superior treatment advantages, with a predictable safety profile, when compared to the PAD regimen.
Collapse
Affiliation(s)
- Bin-Tao Huang
- Department of Hematology, The Affiliated Hospital of Inner Mongolia Medical University, 1 TongDao Avenue North, Hohhot, 010059, People's Republic of China,
| | | | | | | | | | | |
Collapse
|
49
|
|
50
|
de la Rubia J, Roig M. Bortezomib for previously untreated multiple myeloma. Expert Rev Hematol 2014; 4:381-98. [DOI: 10.1586/ehm.11.38] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
|