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Mateos MV, San-Miguel J, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Pour L, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Yoon SS, Iosava G, Fujisaki T, Garg M, Ngo M, Katz EG, Krevvata M, Bolyard K, Carson R, Borgsten F, Dimopoulos MA. Bortezomib, melphalan, and prednisone with or without daratumumab in transplant-ineligible patients with newly diagnosed multiple myeloma (ALCYONE): final analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol 2025; 26:596-608. [PMID: 40220771 DOI: 10.1016/s1470-2045(25)00018-x] [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: 05/06/2024] [Revised: 01/10/2025] [Accepted: 01/17/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND In the phase 3 ALCYONE study, the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) significantly improved outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma. Here, we present results from the final analysis of ALCYONE. METHODS ALCYONE was an international, multicentre, randomised, open-label, active-controlled, phase 3 trial in adults aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or presence of substantial comorbidities, and had an Eastern Cooperative Oncology Group performance status of 0-2. Patients were enrolled between Feb 9, 2015, and July 14, 2016, and were randomly assigned (1:1) by randomly permuted blocks using an interactive web-based randomisation system to receive bortezomib, melphalan, and prednisone (VMP) alone or D-VMP, with randomisation stratified by International Staging System disease stage, geographical region, and age. Patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area, twice per week on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9), oral melphalan (9 mg/m2, once daily on days 1-4 of each cycle), and oral prednisone (60 mg/m2, once daily on days 1-4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab at a dose of 16 mg/kg once weekly during cycle 1, once every 3 weeks in cycles 2-9, and once every 4 weeks thereafter until disease progression, unacceptably toxicity, or the end of study. The primary endpoint, progression-free survival, has been previously reported. The ALCYONE study has completed; presented here are final analyses for selected secondary endpoints related to overall survival, depth of response, subsequent therapy, and safety. The intention-to-treat population was the primary analysis population (including for overall survival), defined as all patients who were randomly assigned to study treatment. The safety population, consisting of patients who received any dose of study treatment, was used in safety analyses. This trial is registered with ClinicalTrials.gov, NCT02195479. FINDINGS In total, 706 patients were enrolled and randomly assigned to receive D-VMP (n=350) or VMP (n=356). Baseline characteristics were balanced between the two treatment groups; most participants were female (379 [54%] of 706 patients) and White (601 [85%] of 706 patients). At a median follow-up of 86·7 months (IQR 28·5-85·2), median overall survival was 83·0 months (95% CI 72·5-not estimable) with D-VMP versus 53·6 months (46·3-60·9) with VMP (hazard ratio [HR] 0·65 [95% CI 0·53-0·80]; p<0·0001). The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (140 [40%] of 346 patients in the D-VMP group vs 138 [39%] of 354 patients in the VMP group), thrombocytopenia (120 [35%] vs 134 [38%]), and anaemia (63 [18%] vs 70 [20%]). Serious treatment-related adverse events occurred in 74 (21%) of 346 patients in the D-VMP group and 56 (16%) of 354 patients in the VMP group. Deaths due to treatment-related adverse events occurred in five (1%) of 346 patients in the D-VMP group (pneumonia, acute myocardial infarction, neuroendocrine tumour, tumour lysis syndrome, and acute respiratory failure) and three (1%) of 354 patients in the VMP group (acute myeloid leukaemia, pulmonary embolism, and bacterial pneumonia). INTERPRETATION With more than 7 years of follow-up, D-VMP continued to elicit clinical benefits in transplant-ineligible patients with newly diagnosed multiple myeloma, supporting the efficacy and safety of frontline daratumumab-based therapy in this patient population. FUNDING Janssen Research & Development.
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Affiliation(s)
- Maria-Victoria Mateos
- University Hospital of Salamanca/IBSAL/Cancer Research Center-IBMCC (USAL-CSIC), Salamanca, Spain.
| | - Jesus San-Miguel
- Cancer Center Clínica Universidad de Navarra, CCUN, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBER-ONC, Pamplona, Spain
| | - Michele Cavo
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Kenshi Suzuki
- Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
| | | | - Stefan Knop
- Department of Hematology, Oncology and Stem Cell Transplantation, Nuremberg General Hospital, Paracelsus Medical School, Nuremberg, Germany
| | - Chantal Doyen
- Université Catholique de Louvain, CHU UCL Namur, Yvoir, Belgium
| | - Paulo Lucio
- Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Zsolt Nagy
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary
| | - Ludek Pour
- University Hospital and Masaryk University Brno, Brno, Czech Republic
| | - Sebastian Grosicki
- Department of Hematology and Cancer Prevention in Chorzów, Faculty of Health Sciences in Bytom, Medical University of Silesia in Katowice, Katowice, Poland
| | | | - Anna Marina Liberati
- Università degli Studi di Perugia, Azienda Ospedaliera Santa Maria, Terni, Italy
| | - Philip Campbell
- Andrew Love Cancer Centre, University Hospital Geelong, Geelong, VIC, Australia
| | - Sung-Soo Yoon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | | | | | - Mamta Garg
- Leicester Royal Infirmary - Haematology, Leicester, UK
| | - Mai Ngo
- Janssen Research & Development, LLC, Titusville, NJ, USA
| | - Eva G Katz
- Janssen Research & Development, LLC, Raritan, NJ, USA
| | - Maria Krevvata
- Janssen Research & Development, LLC, Spring House, PA, USA
| | - Kasey Bolyard
- Janssen Research & Development, LLC, Raritan, NJ, USA
| | - Robin Carson
- Janssen Research & Development, LLC, Spring House, PA, USA
| | | | - Meletios A Dimopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital, Athens, Greece
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Khan S, Bergstrom DJ, Côté J, Kotb R, LeBlanc R, Louzada ML, Mian HS, Othman I, Colasurdo G, Visram A. First Line Treatment of Newly Diagnosed Transplant Eligible Multiple Myeloma Recommendations From a Canadian Consensus Guideline Consortium. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2025; 25:e151-e172. [PMID: 39567294 DOI: 10.1016/j.clml.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 10/02/2024] [Accepted: 10/17/2024] [Indexed: 11/22/2024]
Abstract
The availability of effective therapies for multiple myeloma (MM) has sparked debate on the role of first line autologous stem cell transplantation (ASCT), particularly in standard-risk patients. However, treatment for individuals with high-risk disease continues to display suboptimal outcomes. With novel therapies used earlier, practice is changing rapidly in the field of MM. Presently, quadruplet induction therapy incorporating an anti-CD38 monoclonal antibody to a proteasome inhibitor and an immunomodulatory drug prior to ASCT followed by maintenance therapy stands as the foremost strategy for attaining deep and sustained responses in transplant eligible MM (TEMM). This Canadian Consensus Guideline Consortium (CGC) proposes consensus recommendations for the first line treatment of TEMM. To address the needs of physicians and people diagnosed with MM, this document focuses on ASCT eligibility, induction therapy, mobilization and collection, conditioning, consolidation, and maintenance therapy, as well as, high-risk populations, management of adverse events, assessment of treatment response, and monitoring for disease relapse. The CGC will periodically review the recommendations herein and update as necessary.
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Affiliation(s)
- Sahar Khan
- Windsor Regional Hospital, University of Western Ontario, Windsor, Ontario, Canada.
| | - Debra J Bergstrom
- Division of Hematology, Memorial University of Newfoundland, Newfoundland and Labrador, Canada
| | - Julie Côté
- Centre Hospitalier Universitaire de Québec, Quebec, Quebec, Canada
| | - Rami Kotb
- Department of Medical Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Richard LeBlanc
- Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, Quebec, Canada
| | - Martha L Louzada
- London Health Sciences Centre, Western University, London, Ontario, Canada
| | - Hira S Mian
- Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada
| | - Ibraheem Othman
- Allan Blair Cancer Centre, University of Saskatchewan, Regina, Saskatchewan, Canada
| | | | - Alissa Visram
- The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
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Xie D, Zhang PF. Cost-effectiveness analysis of daratumumab plus bortezomib, melphalan and prednisone versus bortezomib, melphalan and prednisone in patients with newly diagnosed multiple myeloma ineligible for stem cell transplantation. BMJ Open 2025; 15:e076914. [PMID: 39971598 PMCID: PMC11840893 DOI: 10.1136/bmjopen-2023-076914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 01/06/2025] [Indexed: 02/21/2025] Open
Abstract
OBJECTIVES The aim of this study was to investigate the cost-effectiveness of bortezomib, melphalan and prednisone with daratumumab (D-VMP) versus bortezomib, melphalan and prednisone (VMP) in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for autologous stem-cell transplantation (ASCT). METHODS A Markov model was established and three exclusive health states, progression-free survival (PFS), progressive disease (PD) and death were included. The cycle length was set at 1.5 months and the time horizon was set at 20 years. The efficacy data were derived from the ALCYONE trial, and the utility values were obtained from previously published studies. The discount rate in the model was 3% per annum, and the willingness-to-pay (WTP) threshold was set at $150 000.00/quality-adjusted life year (QALY) in the USA. Moreover, one-way and probabilistic sensitivity analyses were performed to evaluate the parameter uncertainty. RESULTS D-VMP achieved an effectiveness of 6.91 QALYs at a cost of $858 695.42, while VMP achieved an effectiveness of 4.70 QALYs at a cost of $357 387.82. The incremental effectiveness and cost of D-VMP versus VMP were 2.21 QALYs and $501 307.6, yielding an incremental cost-effectiveness ratio (ICER) of US $226 836.02/QALY. The cost of daratumumab, utility for PFS, cost of subsequent therapies in the VMP group and cost of subsequent therapies in the D-VMP group were the most influential factors, and the probabilities of D-VMP and VMP as the cost-effective option were 0% and 100% at the WTP threshold of $150 000.00/QALY, respectively. CONCLUSIONS Compared with VMP, D-VMP is unlikely to be a cost-effective regimen for patients with NDMM who are ineligible for ASCT from the US payer's perspective.
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Affiliation(s)
- Dan Xie
- Prenatal Diagnosis Center, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Peng-Fei Zhang
- Gastric Cancer Center, Division of Medical Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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Liu A, Yu H, Hou R, Zhu Z, Zhuang J, Bao L, Li Z, Liu L, Hua L, Ma Y, Gao D, Jin A, Suo X, Yang W, Bai Y, Fu R, Zheng D, Chen W. Assessment of prolonged proteasome inhibition through ixazomib-based oral regimen on newly diagnosed and first-relapsed multiple myeloma: A real-world Chinese cohort study. Cancer Med 2024; 13:e7177. [PMID: 38686615 PMCID: PMC11058688 DOI: 10.1002/cam4.7177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/20/2024] [Accepted: 03/28/2024] [Indexed: 05/02/2024] Open
Abstract
OBJECTIVE To evaluate the effectiveness, safety, and convenience of in-class transition (iCT) from intravenous bortezomib-based induction to ixazomib-based oral regimens. METHODS This retrospective real-world study was conducted in 16 Chinese hospitals between October 2017 and April 2023 and analyzed newly diagnosed (NDMM) and first-line relapsed multiple myeloma (FRMM) patients who attained at least a partial response from bortezomib-based induction therapy, followed by an ixazomib-based oral regimen for 2 year or until disease progression or intolerable toxicity. RESULTS The study enrolled 199 patients, median age: 63 years old, male 55.4%, 53% as high risk (HR), and 47% as standard risk. Cytogenetic risk stratification by metaphase fluorescence in situ hybridization (M-FISH), based on the Mayo Clinic risk stratification system. The median duration of total PI therapy was 11 months, with ixazomib-based treatment spanning 6 months. At the 20-month median follow-up, 53% of patients remained on therapy. The 24-month PFS rate was 84.3% from the initiation of bortezomib-based induction and 83.4% from the start of ixazomib-based treatment. Overall response rate (ORR) was 100% post-bortezomib induction and 90% following 6 cycles of the ixazomib-based regimen. Based on the Sankey diagrams, 89.51% of patients maintained or improved their disease response after 2 cycles of iCT, 6 cycles (90.14%), and 12 cycles (80%). The HR level of Mayo was found to be a significant independent factor in a worse remission (hazard ratio (HR) 2.55; p = 0.033). Ixazomib's safety profile aligned with previous clinical trial data, with 49% of patients experiencing at least one AE of any grade. The most common AEs included peripheral neuropathy, nausea and vomiting, diarrhea, thrombocytopenia, and granulocytopenia. CONCLUSION In the real-world Chinese MM population, NDMM and FRMM patients responded favorably to PI-based continuous therapy, demonstrating substantial response rates. The ixazomib-based iCT allows for sustained PI-based treatment, offering promising efficacy and tolerable AEs.
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Affiliation(s)
- Aijun Liu
- Department of HematologyBeijing Chaoyang Hospital, Affiliated to Capital Medical UniversityBeijingChina
| | - Hong Yu
- Department of HematologyTianjin Medical University General hospitalTianjinChina
| | - Rui Hou
- School of Public HealthCapital Medical UniversityBeijingChina
| | - Zunmin Zhu
- Department of HematologyHenan Provincial people's hospitalZhengzhouChina
| | - Jun‐ling Zhuang
- Department of HematologyPeking Union Medical HospitalBeijingChina
| | - Li Bao
- Department of HematologyBeijing Jishuitan HospitalBeijingChina
| | - Zhenling Li
- Department of HematologyChina‐Japan Friendship HospitalBeijingChina
| | - Lihong Liu
- Department of HematologyThe Fourth hospital, Affiliated to Hebei Medical UniversityShijiazhuangChina
| | - Luoming Hua
- Department of HematologyAffiliated Hospital of Hebei UniversityShijiazhuangChina
| | - Yanping Ma
- Department of HematologySecond hospital of Shanxi Medical UniversityTaiyuanChina
| | - Da Gao
- Department of HematologyThe Affiliated Hospital of Inner Mongolia Medical UniversityHohhotChina
| | - Arong Jin
- Department of HematologyInner Mongolia Autonomous Region People's HospitalHohhotChina
| | - Xiaohui Suo
- Department of HematologyHan Dan Central HospitalHandanChina
| | - Wei Yang
- Department of HematologySheng Jing Hospital of China Medical UniversityShenyangChina
| | - Yuansong Bai
- Department of HematologyChina‐Japan Union Hospital of Jilin UniversityChangchunChina
| | - Rong Fu
- Department of HematologyTianjin Medical University General hospitalTianjinChina
| | - Deqiang Zheng
- School of Public HealthCapital Medical UniversityBeijingChina
| | - Wenming Chen
- Department of HematologyBeijing Chaoyang Hospital, Affiliated to Capital Medical UniversityBeijingChina
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Fu XH, Guan RY, Huang Z, Li Y, Lu G, Mou WW, Du J. From Multiple Myeloma to Acute Myeloid Leukemia: A Case Report of a 61-year-old Woman after 8 Years of Chemotherapy and Immunotherapy. Recent Pat Anticancer Drug Discov 2024; 19:396-401. [PMID: 38214323 DOI: 10.2174/1574892818666230619093300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/28/2023] [Accepted: 05/17/2023] [Indexed: 01/13/2024]
Abstract
BACKGROUND As the second most prevalent hematologic malignancy, multiple myeloma (MM) affects plasma cells and is characterized by chromosomal abnormalities, particularly involving the immunoglobulin heavy chain switch region. MM represents a biologically and clinically heterogeneous hematological malignancy that serves as a clonal evolution model, exhibiting clonal heterogeneity throughout all stages from monoclonal gammopathy undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM. Although significant progress has been made in the treatment of MM, leading to improved patient outcomes, concerns are arising regarding disease relapse due to the presence and selection of pre-existing resistant clones or selective pressure during therapy. CASE PRESENTATION We present a case of multiple myeloma (MM) in a female patient, who underwent an 8-year course of treatment, including chemotherapy, immunomodulators, hematopoietic stem cell transplantation, CD38 monoclonal antibody, and chimeric antigen receptor T-cell (CAR-T), and was recently diagnosed with concurrent progressive MM and acute myeloid leukemia (AML). This patient has witnessed the evolution of MM treatment paradigms. CONCLUSION In this course, disease relapses occurred twice, one of which was manifested by a light chain escape (LCE). Moreover, through the course of the disease in this patient, we review the process of clonal evolution that may be relevant.
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Affiliation(s)
- Xue-Hang Fu
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Rong-Yan Guan
- Department of Hematology, Aviation General Hospital, Beijing, 100012, China
| | - Zoufang Huang
- Ganzhou Key Laboratory of Hematology, Department of Hematology, The First Affiliated Hospital of Gannan Medical University, 341000 Ganzhou, Jiangxi, China
| | - Yun Li
- Department of Hematology, Aviation General Hospital, Beijing, 100012, China
| | - Guang Lu
- Department of Hematology, Shengli Oilfield Central Hospital, Dongying, 257099, China
| | - Wei-Wei Mou
- Department of Pediatrics, Shengli Oilfield Central Hospital, Dongying, 257034, China
| | - Jun Du
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
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Rifkin RM, Girnius SK, Noga SJ, Birhiray RE, Kambhampati S, Manda S, Lyons RM, Yimer HA, Cherepanov D, Lloyd E, Whidden P, Richter J. In-class transition (iCT) of proteasome inhibitor-based therapy: a community approach to multiple myeloma management. Blood Cancer J 2023; 13:147. [PMID: 37726298 PMCID: PMC10509188 DOI: 10.1038/s41408-023-00912-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 09/21/2023] Open
Abstract
Long-term proteasome inhibitor (PI) treatment can improve multiple myeloma (MM) outcomes, but this can be difficult to achieve in clinical practice due to toxicity, comorbidities, and the burden of repeated parenteral administration. US MM-6 (NCT03173092) enrolled transplant-ineligible patients with newly diagnosed MM to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd; ≤39 cycles or until progression or toxicity) following three cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS). Key secondary/exploratory endpoints included overall response rate (ORR), overall survival (OS), safety, quality of life (QoL), treatment satisfaction, and actigraphy. At datacut, in the fully accrued cohort of 140 patients, median age was 73 years with 42% aged ≥75 and 61% deemed frail; 10% of patients were ongoing on treatment. After a median follow-up of 27 months, the 2-year PFS rate was 71% (95% confidence interval: 61-78). ORR increased from 62% at the end of induction to 80% following in-class transition (iCT) to IRd for a median of 11 months. The 2-year OS rate was 86%. The overall safety profile/actigraphy levels were consistent with previous reports; QoL/treatment satisfaction scores were stable with ongoing therapy. iCT to IRd may allow prolonged PI-based therapy with promising efficacy and a tolerable safety profile, while maintaining QoL.
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Affiliation(s)
- Robert M Rifkin
- Rocky Mountain Cancer Centers/US Oncology Research, Denver, CO, USA.
| | | | | | - Ruemu E Birhiray
- Hematology Oncology of Indiana/American Oncology Network, Indianapolis, IN, USA
| | | | - Sudhir Manda
- Arizona Oncology/US Oncology Research, Tucson, AZ, USA
| | - Roger M Lyons
- Texas Oncology/US Oncology Research, San Antonio, TX, USA
| | | | - Dasha Cherepanov
- Takeda Development Center Americas, Inc. (TDCA), Lexington, MA, USA
| | - Eric Lloyd
- Takeda Pharmaceuticals U.S.A., Inc., Bannockburn, IL, USA
| | | | - Joshua Richter
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Abe Y, Sasaki M, Takezako N, Ito S, Suzuki K, Handa H, Chou T, Yoshida T, Mori I, Shinozaki T, Suzuki K. Efficacy and Safety of Ixazomib Plus Lenalidomide and Dexamethasone Following Injectable PI-Based Therapy in Relapsed/Refractory Multiple Myeloma. Ann Hematol 2023; 102:2493-2504. [PMID: 37341778 PMCID: PMC10444638 DOI: 10.1007/s00277-023-05212-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 04/01/2023] [Indexed: 06/22/2023]
Abstract
This nationwide, multicenter, open-label, single-arm study evaluated the efficacy and safety of the oral proteasome inhibitor (PI), ixazomib plus lenalidomide (LEN) and dexamethasone (DEX) (IRd) following injectable PI-based therapy for relapsed/refractory multiple myeloma (RRMM). Of 45 patients enrolled, 36 patients received IRd after achieving at least a minor response to 3 cycles of bortezomib or carfilzomib plus LEN + DEX (VRd, n=6; KRd, n=30). At median follow-up of 20.8 months, the 12-month event-free survival rate (primary endpoint) was 49% (90% CI: 35.9-62.0), counting 11 events of progressive disease/death, 8 dropouts and 4 missing response data. The 12-month progression-free survival (PFS) rate by Kaplan-Meier analysis (dropouts as censoring) was 74% (95% CI: 56-86). Median PFS and time to next treatment (95% CI) were 29.0 (21.3-NE) and 32.3 (14.9-35.4) months, respectively; median OS was not evaluable. The overall response rate was 73%, and 42% of patients had a very good partial response or better. Frequent (≥10% incidence) grade ≥3 treatment emergent adverse events were decreased neutrophil and platelet counts (n=7 [16%] each). Two deaths occurred (one during KRd treatment and one during IRd treatment), both due to pneumonia. IRd following injectable PI-based therapy was tolerable and efficacious in RRMM patients. TRIAL REGISTRATION NUMBER: NCT03416374; Date of registration: January 31, 2018.
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Affiliation(s)
- Yu Abe
- Division of Haematology, Japanese Red Cross Medical Centre, 4 Chome-1-22 Hiroo, Shibuya City, Tokyo, 150-8935, Japan
| | - Makoto Sasaki
- Division of Haematology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoki Takezako
- Division of Haematology, Japan Association for Development of Community Medicine, Nerima Hikarigaoka Hospital, Tokyo, Japan
| | - Shigeki Ito
- Division of Haematology and Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Iwate, Japan
| | - Kazuhito Suzuki
- Division of Clinical Oncology and Haematology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Chiba, Japan
| | - Hiroshi Handa
- Department of Haematology, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Takaaki Chou
- Niigata Kenshin Plaza, General Incorporated Foundation, Health Medicine Prevention Association, Niigata, Japan
| | - Takahiro Yoshida
- Japan Medical Affairs, Japan Oncology Business Unit, Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Ikuo Mori
- Japan Medical Affairs, Japan Oncology Business Unit, Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Tomohiro Shinozaki
- Department of Information and Computer Technology, Faculty of Engineering, Tokyo University of Science, Tokyo, Japan
| | - Kenshi Suzuki
- Division of Haematology, Japanese Red Cross Medical Centre, 4 Chome-1-22 Hiroo, Shibuya City, Tokyo, 150-8935, Japan.
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Solimando AG, Krebs M, Desantis V, Marziliano D, Caradonna IC, Morizio A, Argentiero A, Shahini E, Bittrich M. Breaking through Multiple Myeloma: A Paradigm for a Comprehensive Tumor Ecosystem Targeting. Biomedicines 2023; 11:2087. [PMID: 37509726 PMCID: PMC10377041 DOI: 10.3390/biomedicines11072087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/29/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Multiple myeloma (MM) is a cancerous condition characterized by the proliferation of plasma cells within the hematopoietic marrow, resulting in multiple osteolytic lesions. MM patients typically experience bone pain, kidney damage, fatigue due to anemia, and infections. Historically, MM was an incurable disease with a life expectancy of around three years after diagnosis. However, over the past two decades, the development of novel therapeutics has significantly improved patient outcomes, including response to treatment, remission duration, quality of life, and overall survival. These advancements include thalidomide and its derivatives, lenalidomide and pomalidomide, which exhibit diverse mechanisms of action against the plasma cell clone. Additionally, proteasome inhibitors such as bortezomib, ixazomib, and carfilzomib disrupt protein degradation, proving specifically toxic to cancerous plasma cells. Recent advancements also involve monoclonal antibodies targeting surface antigens, such as elotuzumab (anti-CS1) and daratumumab (anti-CD38), bispecific t-cell engagers such as teclistamab (anti-BCMA/CD3) and Chimeric antigen receptor T (CAR-T)-based strategies, with a growing focus on drugs that exhibit increasingly targeted action against neoplastic plasma cells and relevant effects on the tumor microenvironment.
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Affiliation(s)
- Antonio G. Solimando
- Unit of Internal Medicine and Clinical Oncology “G. Baccelli”, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro Medical School, 70124 Bari, Italy;
| | - Markus Krebs
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080 Würzburg, Germany;
- Department of Urology and Pediatric Urology, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Vanessa Desantis
- Department of Precision and Regenerative Medicine and Ionian Area, Pharmacology Section, University of Bari Aldo Moro Medical School, 70124 Bari, Italy; (V.D.); (I.C.C.)
| | - Donatello Marziliano
- Unit of Internal Medicine and Clinical Oncology “G. Baccelli”, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro Medical School, 70124 Bari, Italy;
| | - Ingrid Catalina Caradonna
- Department of Precision and Regenerative Medicine and Ionian Area, Pharmacology Section, University of Bari Aldo Moro Medical School, 70124 Bari, Italy; (V.D.); (I.C.C.)
| | - Arcangelo Morizio
- Orthopedics and Traumatology Unit ASL BA-Ospedale della Murgia “Fabio Perinei”, 70022 Altamura, Italy
| | | | - Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology—IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy
| | - Max Bittrich
- Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
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9
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Costa BA, Mouhieddine TH, Ortiz RJ, Richter J. Revisiting the Role of Alkylating Agents in Multiple Myeloma: Up-to-Date Evidence and Future Perspectives. Crit Rev Oncol Hematol 2023; 187:104040. [PMID: 37244325 DOI: 10.1016/j.critrevonc.2023.104040] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/15/2023] [Accepted: 05/23/2023] [Indexed: 05/29/2023] Open
Abstract
From the 1960s to the early 2000s, alkylating agents (e.g., melphalan, cyclophosphamide, and bendamustine) remained a key component of standard therapy for newly-diagnosed or relapsed/refractory multiple myeloma (MM). Later on, their associated toxicities (including second primary malignancies) and the unprecedented efficacy of novel therapies have led clinicians to increasingly consider alkylator-free approaches. Meanwhile, new alkylating agents (e.g., melflufen) and new applications of old alkylators (e.g., lymphodepletion before chimeric antigen receptor T-cell [CAR-T] therapy) have emerged in recent years. Given the expanding use of antigen-directed modalities (e.g., monoclonal antibodies, bispecific antibodies, and CAR-T therapy), this review explores the current and future role of alkylating agents in different treatment settings (e.g., induction, consolidation, stem cell mobilization, pre-transplant conditioning, salvage, bridging, and lymphodepleting chemotherapy) to ellucidate the role of alkylator-based regimens in modern-day MM management.
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Affiliation(s)
- Bruno Almeida Costa
- Department of Medicine, Mount Sinai Morningside and West, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tarek H Mouhieddine
- Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ricardo J Ortiz
- Department of Medicine, Mount Sinai Morningside and West, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joshua Richter
- Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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10
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Park SS, Lee JC, Byun JM, Choi G, Kim KH, Lim S, Dingli D, Jeon YW, Yahng SA, Shin SH, Min CK, Koo J. ML-based sequential analysis to assist selection between VMP and RD for newly diagnosed multiple myeloma. NPJ Precis Oncol 2023; 7:46. [PMID: 37210456 DOI: 10.1038/s41698-023-00385-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 05/03/2023] [Indexed: 05/22/2023] Open
Abstract
Optimal first-line treatment that enables deeper and longer remission is crucially important for newly diagnosed multiple myeloma (NDMM). In this study, we developed the machine learning (ML) models predicting overall survival (OS) or response of the transplant-ineligible NDMM patients when treated by one of the two regimens-bortezomib plus melphalan plus prednisone (VMP) or lenalidomide plus dexamethasone (RD). Demographic and clinical characteristics obtained during diagnosis were used to train the ML models, which enabled treatment-specific risk stratification. Survival was superior when the patients were treated with the regimen to which they were low risk. The largest difference in OS was observed in the VMP-low risk & RD-high risk group, who recorded a hazard ratio of 0.15 (95% CI: 0.04-0.55) when treated with VMP vs. RD regimen. Retrospective analysis showed that the use of the ML models might have helped to improve the survival and/or response of up to 202 (39%) patients among the entire cohort (N = 514). In this manner, we believe that the ML models trained on clinical data available at diagnosis can assist the individualized selection of optimal first-line treatment for transplant-ineligible NDMM patients.
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Affiliation(s)
- Sung-Soo Park
- Catholic Research Network for Multiple Myeloma, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Jong Cheol Lee
- Department of Otorhinolaryngology, GangNeung Asan Hospital, University of Ulsan College of Medicine, Gangneung-si, Gangwon-do, 25440, Republic of Korea
| | - Ja Min Byun
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Gyucheol Choi
- ImpriMedKorea, Inc., Seoul, 08507, Republic of Korea
| | - Kwan Hyun Kim
- ImpriMedKorea, Inc., Seoul, 08507, Republic of Korea
| | - Sungwon Lim
- ImpriMedKorea, Inc., Seoul, 08507, Republic of Korea
- ImpriMed, Inc., Palo Alto, CA, 94303, USA
| | - David Dingli
- Division of Hematology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Young-Woo Jeon
- Catholic Research Network for Multiple Myeloma, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
- Department of Hematology, Yeoido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 07345, Republic of Korea
| | - Seung-Ah Yahng
- Catholic Research Network for Multiple Myeloma, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
- Department of Hematology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, 22711, Republic of Korea
| | - Seung-Hwan Shin
- Catholic Research Network for Multiple Myeloma, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
- Department of Hematology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 03312, Republic of Korea
| | - Chang-Ki Min
- Catholic Research Network for Multiple Myeloma, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
| | - Jamin Koo
- ImpriMedKorea, Inc., Seoul, 08507, Republic of Korea.
- ImpriMed, Inc., Palo Alto, CA, 94303, USA.
- Department of Chemical Engineering, Hongik University, Seoul, 04066, Republic of Korea.
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11
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Côté J, Kotb R, Bergstrom DJ, LeBlanc R, Mian HS, Othman I, Louzada ML. First Line Treatment of Newly Diagnosed Transplant Ineligible Multiple Myeloma: Recommendations from the Canadian Myeloma Research Group Consensus Guideline Consortium. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2023; 23:340-354. [PMID: 36925389 DOI: 10.1016/j.clml.2023.01.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/14/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023]
Abstract
Although the availability of effective novel treatments has positively impacted the quality of life and survival of newly diagnosed multiple myeloma (MM) patients, benefits in the transplant ineligible MM population may be limited by functional/frailty status. The Canadian Myeloma Research Group Consensus Guideline Consortium proposes consensus recommendations for the first-line treatment of transplant ineligible MM. To address the needs of physicians and people diagnosed with MM, this document further focuses on eligibility for transplant, frailty assessment, management of adverse events, assessment of treatment response, and monitoring for disease relapse. The Canadian Myeloma Research Group Consensus Guideline Consortium will periodically review the recommendations herein and update as necessary.
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Affiliation(s)
- Julie Côté
- Centre hospitalier universitaire de Québec, Quebec, QC, Canada.
| | - Rami Kotb
- CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada
| | | | - Richard LeBlanc
- Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, QC, Canada
| | - Hira S Mian
- Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada
| | - Ibraheem Othman
- Allan Blair Cancer Centre, University of Saskatchewan, Regina, SK, Canada
| | - Martha L Louzada
- London Health Sciences Centre, Western University, London, ON, Canada
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12
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Ng JH, Izard S, Murakami N, Jhaveri KD, Sharma A, Nair V. Outcomes of kidney transplantation in patients with myeloma and amyloidosis in the USA. Nephrol Dial Transplant 2022; 37:2569-2580. [PMID: 35687020 PMCID: PMC9681913 DOI: 10.1093/ndt/gfac196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Recent improvement in treatment and patient survival has opened the eligibility of kidney transplantation to patients who developed end-stage kidney disease (ESKD) from plasma cell dyscrasias (PCDs). Data on clinical outcomes in this population are lacking. METHODS We conducted a retrospective study of United Network for Organ Sharing/Organ Procurement and Transplantation Network dataset (2006-2018) to compare patient and graft outcomes of kidney transplant recipients with ESKD due to PCD versus other causes. RESULTS Among 168 369 adult first kidney transplant recipients, 0.22-0.43% per year had PCD as the cause of ESKD. The PCD group had worse survival than the non-PCD group for both living and deceased donor types {adjusted hazard ratio [aHR] 2.24 [95% confidence interval (CI) 1.67-2.99] and aHR 1.40 [95% CI 1.08-1.83], respectively}. The PCD group had worse survival than the diabetes group, but only among living donors [aHR 1.87 (95% CI 1.37-2.53) versus aHR 1.16 (95% CI 0.89-1.2)]. Graft survival in patients with PCD were worse than non-PCD in both living and deceased donors [aHR 1.72 (95% CI 1.91-2.56) and aHR 1.30 (95% CI 1.03-1.66)]. Patient and graft survival were worse in amyloidosis but not statistically different in multiple myeloma compared with the non-PCD group. CONCLUSION The study data are crucial when determining kidney transplant eligibility and when discussing transplant risks in patients with PCD.
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Affiliation(s)
- Jia H Ng
- Division of Kidney Diseases and Hypertension, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
| | - Stephanie Izard
- Center for Health Innovations and Outcomes Research, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Naoka Murakami
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kenar D Jhaveri
- Division of Kidney Diseases and Hypertension, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
| | - Amy Sharma
- Northwell Cancer Institute, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, USA
- New affiliation as of June 2022. Montefiore Medical Center, Department of Hematology and Oncology, NY, USA
| | - Vinay Nair
- Division of Kidney Diseases and Hypertension, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
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13
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Xie C, Wei M, Yang F, Liu Q, Wu F, Huang J. Efficacy and toxicity of carfilzomib- or bortezomib-based regimens for treatment of transplant-ineligible patients with newly diagnosed multiple myeloma: A meta-analysis. Medicine (Baltimore) 2022; 101:e30715. [PMID: 36181088 PMCID: PMC9524967 DOI: 10.1097/md.0000000000030715] [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: 01/05/2023] Open
Abstract
BACKGROUND Multiple myeloma is a clonal disorder of malignant plasma cells that comprises approximately 10% of hematologic malignancies. The aim of this study was to investigate the efficacy and toxicity of carfilzomib- or bortezomib-based regimens for treatment of transplant-ineligible patients with newly diagnosed multiple myeloma by performing a meta-analysis of randomized controlled trials (RCTs). METHODS Data mining was conducted in March 2022 across PubMed, EMBASE and ClinicalTrials.gov. All published RCTs which assessed efficacy and toxicity of carfilzomib-based regimens treatment for transplant-ineligible patients with newly diagnosed multiple myeloma when compared with a bortezomib-based regimens were included. RESULTS Our meta-analysis showed that the overall response rate (ORR) (Odds ratio = 1.33, 95% CI 1.05-1.69, P = .02) was significantly higher in the carfilzomib-based regimens group than in the bortezomib-based regimens group. However, the difference in ORR did not translate into improvements in progression-free survival (PFS), overall survival (OS) and complete response rate (CRR). Adverse events of grade 3 or worse that occurred with a higher incidence in the carfilzomib-based regimens group compared with the bortezomib-based regimens group were dyspnea, hypertension, acute kidney injury, and heart failure. CONCLUSIONS The carfilzomib-based regimens did not improve PFS, OS and CRR compared with the bortezomib-based regimens in transplant-ineligible patients with newly diagnosed multiple myeloma, and they showed higher toxicity.
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Affiliation(s)
- Chunhong Xie
- Department of Hematology, Affiliated Liuzhou People’s Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Min Wei
- Department of Hematology, Affiliated Liuzhou People’s Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Feiyan Yang
- Department of Hematology, Affiliated Liuzhou People’s Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Qin Liu
- Department of Hematology, Affiliated Liuzhou People’s Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Fuzhen Wu
- Department of Hematology, Affiliated Liuzhou People’s Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Jinxiong Huang
- Department of Hematology, Affiliated Liuzhou People’s Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
- *Correspondence: Jinxiong Huang, Department of Hematology, Affiliated Liuzhou People’s Hospital of Guangxi Medical University, No. 8, Wenchang Road, Liuzhou 545006, Guangxi, China (e-mail: )
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14
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Invasive Orbital Squamous Cell Carcinoma in a Patient with Multiple Myeloma. Case Rep Ophthalmol Med 2022; 2022:8585692. [PMID: 35815062 PMCID: PMC9259366 DOI: 10.1155/2022/8585692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 06/03/2022] [Accepted: 06/18/2022] [Indexed: 11/18/2022] Open
Abstract
Background Orbital squamous cell carcinoma (SCC) is a rare entity. It is often a result of local invasion of SCC originating from the skin, nasopharynx, nasal cavity, paranasal sinuses, conjunctiva, lacrimal glands, or sac or less commonly occurs through hematogenous metastasis. Herein, we report a patient with orbital SCC with a history of multiple myeloma (MM). Case presentation. A 45-year-old woman with a history of MM in the past two years presented to our clinic complaining of gradual right eye proptosis for six months. The relative afferent pupillary defect was detected in the right eye on her examination. Ocular movements of the right eye were limited in all directions. Orbital magnetic resonance imaging demonstrated an infiltrative mass in the right orbit extended from the anterior to the orbital apex and the optic canal. The patient underwent debulking, and a histopathology examination revealed SCC results. No other secondary site was found to be the origin of the tumor. Result The patient underwent chemotherapy and subsequent radiotherapy. To our knowledge, this is the first report of concomitant MM and primary orbital SCC.
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15
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Lalive d'Epinay M, Güsewell S, Graf N, Mey UJM, Driessen C, Hitz F. Outcome of older myeloma patients in relationship to comorbidities and availability of second-generation novel agents in a real-life setting. Hematol Oncol 2022; 40:716-723. [PMID: 35574642 DOI: 10.1002/hon.3024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/23/2022] [Accepted: 05/06/2022] [Indexed: 11/11/2022]
Abstract
Major improvements in outcome of older patients with multiple myeloma (MM) have been achieved with the introduction of novel agents. Their impact in real-life treatment of older patients is unclear. In this single center retrospective study, we analyzed the outcome of patients >65 years treated with first-generation (FGNA) and second-generation novel agents (SGNA) within two time periods 2012-2014 and 2015-2017. Patients were analyzed based on age, Charlson Comorbidity Index (CCI), International Staging System stage, year of diagnosis and withdrawal of agents due to toxicities. Overall 96 patients were included for analysis. Median age was 73 years (range 65-90), 55 (57%) patients were 65-75 years and 41 (43%) were >75 years old. 84 patients received a first-line therapy, whereas 45 patients had ≥2 lines of systemic therapy. 20 patients were consolidated with autologous stem cell transplantation. 12 patients had no systemic therapy at all. In 17 of 21 cases a FGNA and in 4 of 21 a SGNA was withdrawn due to toxicity. Median overall survival (OS) for all patients with systemic therapy was 4.75 years (95% CI, 3.05-NA). Borderline significant improvement of OS was observed in patients diagnosed 2015-2017 compared to 2012-2014 with HR 0.57 (95% CI, 0.31-1.02) p = 0.06. OS significantly differed for comorbid patients with low and intermediate risk CCI, HR 1.94 (95% CI, 1.07-3.54), p = 0.03 in the overall population. OS in patients treated with SGNA was not significantly different in patients with intermediate versus low risk CCI (HR 1.48 (95% CI 0.43-5.14, p = 0.54)). In conclusion, we found a trend toward improved survival for older MM patients after the introduction of novel agents during the observed time period. In patients treated with SGNA a smaller effect that comorbidity negatively affects survival was observed.
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Affiliation(s)
| | - Sabine Güsewell
- Clinical Trials Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Nicole Graf
- Clinical Trials Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Ulrich J M Mey
- Medical Oncology and Haematology, Kantonsspital Graubünden, Chur, Switzerland
| | - Christoph Driessen
- Medical Oncology and Haematology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Felicitas Hitz
- Medical Oncology and Haematology, Kantonsspital St. Gallen, St. Gallen, Switzerland
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16
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Goel U, Usmani S, Kumar S. Current approaches to management of newly diagnosed multiple myeloma. Am J Hematol 2022; 97 Suppl 1:S3-S25. [PMID: 35234302 DOI: 10.1002/ajh.26512] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 12/16/2022]
Abstract
Major developments in the treatment of multiple myeloma (MM) over the past decade have led to a continued improvement in survival. Significant progress has been made with deeper and longer remissions seen with newer treatment approaches-both for induction as well as maintenance therapy. The treatment approach to MM is guided by several factors including patient age, frailty, comorbidities, eligibility for autologous stem cell transplantation (ASCT), and risk stratification into standard-risk or high-risk MM. High-risk MM is defined by the presence of t(4;14), t(14;16), t(14;20), del (17p), TP53 mutation, or gain (1q). Transplant eligible patients should receive 4-6 cycles of induction followed by stem cell collection. Patients can then undergo ASCT, or continue induction therapy and shift to maintenance, delaying ASCT till first relapse. Transplant ineligible patients should receive induction therapy followed by maintenance. For induction therapy prior to ASCT, a proteasome inhibitor-IMiD combination remains standard with monoclonal antibody-based quadruplets preferred in high-risk patients. Among transplant ineligible patients, those with standard-risk MM should receive DRd continued until disease progression, while bortezomib containing regimens (VRd or VRd lite) can be considered for high-risk patients. Finally, standard-risk patients should receive lenalidomide maintenance after induction/ASCT, while proteasome inhibitor-IMiD combinations should be used for high-risk patients.
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Affiliation(s)
- Utkarsh Goel
- Division of Hematology, Department of Medicine Mayo Clinic Rochester Minnesota USA
| | - Saad Usmani
- Multiple Myeloma Service, Department of medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Shaji Kumar
- Division of Hematology, Department of Medicine Mayo Clinic Rochester Minnesota USA
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Vekemans MC, Doyen C, Caers J, Wu K, Kentos A, Mineur P, Michaux L, Delforge M, Meuleman N. Recommendations on the management of multiple myeloma in 2020. Acta Clin Belg 2022; 77:445-461. [PMID: 33355041 DOI: 10.1080/17843286.2020.1860411] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
With the introduction of immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies, major improvements have been achieved in the treatment of multiple myeloma (MM), with a significant impact on the outcome of this disease. Different treatment combinations are now in use and other therapies are being developed. Based on an extensive review of the recent literature, we propose practical recommendations on myeloma management, to be used by hematologists as a reference for daily practice.
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Affiliation(s)
| | - Chantal Doyen
- Centre Hospitalier Universitaire de Namur, UCL, Yvoir, Belgium
| | - Jo Caers
- Centre Hospitalier Universitaire de Liège, Ulg, Liège, Belgium
| | - Kalung Wu
- Zienkenhuis Netwerk Antwerpen, Antwerp, Belgium
| | | | | | - Lucienne Michaux
- Universitair Ziekenhuis Leuven Gasthuisberg, KUL, Leuven, Belgium
| | - Michel Delforge
- Universitair Ziekenhuis Leuven Gasthuisberg, KUL, Leuven, Belgium
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18
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Kiss S, Gede N, Soós A, Hegyi P, Nagy B, Imrei M, Czibere B, Farkas N, Hanák L, Szakács Z, Eröss B, Alizadeh H. Efficacy of first-line treatment options in transplant-ineligible multiple myeloma: A network meta-analysis. Crit Rev Oncol Hematol 2021; 168:103504. [PMID: 34673218 DOI: 10.1016/j.critrevonc.2021.103504] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 08/30/2021] [Accepted: 10/10/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Despite major therapeutic advances, the rational choice of the most appropriate first-line regimen in newly diagnosed transplant-ineligible multiple myeloma (TIE-MM) is currently undefined. AIM We aimed to identify the most effective first-line treatment for TIE-MM patients. METHODS A total of 37 articles, including 34 treatments and 16,681 patients, were included in this Bayesian network meta-analysis. The outcomes of interest were risk ratios (RR) for progression-free survival (PFS) and overall survival (OS). RESULTS Based on surface under cumulative ranking curve values, daratumumab-bortezomib-melphalan-prednisone (Dara-VMP) and daratumumab-lenalidomide-dexamethasone (Dara-Rd28) showed superiority compared to other combinations regarding 12-, 24-, 36-, and 48-month PFS. Dara-VMP also ranked first for 12-, 24-, 36-, and 48-month OS. CONCLUSION Our finding supports the incorporation of daratumumab into first-line regimens. Additionally, these results highlight the relative benefit of incorporating novel agents like monoclonal antibodies, immunomodulatory derivatives, and proteasome inhibitors in combination with the currently existing treatment options.
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Affiliation(s)
- Szabolcs Kiss
- Doctoral School of Clinical Medicine, University of Szeged, H-6720 Szeged, Korányi fasor 8-10., Szeged, Hungary; Institute for Translational Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary
| | - Noémi Gede
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary
| | - Alexandra Soós
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary; János Szentágothai Research Centre, University of Pécs, Pécs, H-7624 Pécs, Ifjúság Street 20., Hungary; First Department of Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Ifjúság Street 13., Hungary
| | - Bettina Nagy
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary
| | - Marcell Imrei
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary
| | - Bernadett Czibere
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary
| | - Nelli Farkas
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary; Institute of Bioanalysis, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary
| | - Lilla Hanák
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary
| | - Zsolt Szakács
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary; First Department of Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Ifjúság Street 13., Hungary
| | - Bálint Eröss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Szigeti Street 12. 2nd floor, Hungary; János Szentágothai Research Centre, University of Pécs, Pécs, H-7624 Pécs, Ifjúság Street 20., Hungary; First Department of Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Ifjúság Street 13., Hungary
| | - Hussain Alizadeh
- Doctoral School of Clinical Medicine, University of Szeged, H-6720 Szeged, Korányi fasor 8-10., Szeged, Hungary; Division of Haematology, First Department of Medicine, Medical School, University of Pécs, Pécs, H-7624 Pécs, Ifjúság Street 13., Hungary.
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Shen M, Zhang J, Tang R, Wang Y, Zhan X, Fan S, Huang Z, Zhong Y, Li X. Ixazomib-based maintenance therapy after bortezomib-based induction in patients with multiple myeloma not undergoing transplantation: A real-world study. Cancer Med 2021; 11:2173-2183. [PMID: 34655168 PMCID: PMC9160809 DOI: 10.1002/cam4.4313] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 08/30/2021] [Accepted: 09/15/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Maintenance therapy with proteasome inhibitors (PIs) can improve outcomes of multiple myeloma (MM) patients, however, the neurotoxicity and parenteral route of bortezomib limit its long-term use. An efficacious, tolerable, and convenient PI option is needed. METHODS In this single-center, real-world study, we retrospectively analyzed the outcome and safety profile of ixazomib-based maintenance therapy in patients who plateaued with the responses of steady disease or better after bortezomib-based induction therapy in MM patients not undergoing transplantation. RESULTS Of all the 71 patients, 37 cases (52.1%) were newly diagnosed MM (NDMM) and 34 cases (47.9%) were relapsed and/or refractory MM (RRMM). The overall response rate (ORR) was 81.7%, including 34 patients (47.9%) with a very good response rate or better (≥VGPR) after a median of nine cycles (6-14) of bortezomib-based induction therapy. Then the ORR was transformed to 74.6% including 39 patients of ≥VGPR (54.9%) after a median of six courses (2-25) of ixazomib-based maintenance therapy. Of these, 18 patients (25.4%) exhibited responses deepened. With 26.5 months median follow-up, median progression-free survival (PFS) was 28.4 and 16.5 months from the start of bortezomib and 16.2 and 10.0 months from the initiation of ixazomib in NDMM and RRMM group, respectively. Moreover, responses deepened during the maintenance phase (hazard ratio: 0.270, p = 0.007), and responses of ≥VGPR during the induction phase (hazard ratio: 0.218, p < 0.001) were confirmed to independently predict longer PFS after multivariate analyses. Severe adverse events (grade 3/4) were relatively rare. Bortezomib-emergent peripheral neuritis (PN) was significantly relived after the transition to ixazomib (p < 0.001). CONCLUSION This real-world analysis has demonstrated oral ixazomib is a favorable option of long-term administration for maintenance with efficacy and feasibility and confirmed the association between deepening responses with ixazomib and prolonged PFS.
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Affiliation(s)
- Man Shen
- Department of Hematology, Multiple Myeloma Medical Center of Beijing, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Jiajia Zhang
- Department of Hematology, Multiple Myeloma Medical Center of Beijing, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Ran Tang
- Department of Hematology, Multiple Myeloma Medical Center of Beijing, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Yuhao Wang
- Department of Hematology, Multiple Myeloma Medical Center of Beijing, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Xiaokai Zhan
- Department of Hematology, Multiple Myeloma Medical Center of Beijing, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Sibin Fan
- Department of Hematology, Multiple Myeloma Medical Center of Beijing, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Zhongxia Huang
- Department of Hematology, Multiple Myeloma Medical Center of Beijing, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Yuping Zhong
- Department of Hematology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
| | - Xin Li
- Department of Hematology, Multiple Myeloma Medical Center of Beijing, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
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20
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Tacchetti P, Rocchi S, Barbato S, Zamagni E, Pantani L, Mancuso K, Rizzello I, Cavo M. Emerging and current treatment combinations for transplant-ineligible multiple myeloma patients. Expert Rev Hematol 2021; 14:1085-1098. [PMID: 34602012 DOI: 10.1080/17474086.2021.1983426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Availability of new classes of novel agents has led to a radical switch in treatment paradigms for newly diagnosed transplant-ineligible multiple myeloma (NDTIMM) patients, providing an opportunity to significantly enhance the depth of response and extend survival outcomes. AREAS COVERED Treatment regimens including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and/or monoclonal antibodies (mAbs), have achieved recent regulatory approval for NDTIMM, while novel combinations and newer agents are currently being explored. This review discusses the current landscape and possible treatment development of NDTIMM. EXPERT OPINION Bortezomib-lenalidomide-dexamethasone (VRd), daratumumab-bortezomib-melphalan-prednisone (DaraVMP) and daratumumab-lenalidomide-dexamethasone (DaraRd) represent new standard of care (SOC) treatments for NDTIMM patients, based on phase III trials showing their superior efficacy as compared with previous SOCs. The possibility of improving results by incorporating second generation PIs or using quadruple regimens has also been explored and different trials are still ongoing. Newer agents and innovative immunotherapies targeting B-cell maturation antigen have the potential to change the therapeutic landscape in coming years. Personalized approaches based on frailty-adapted, risk-based and minimal residual disease driven paradigms are under investigation.
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Affiliation(s)
- Paola Tacchetti
- Irccs Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Serena Rocchi
- Irccs Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.,Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
| | - Simona Barbato
- Irccs Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Elena Zamagni
- Irccs Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.,Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
| | - Lucia Pantani
- Irccs Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Katia Mancuso
- Irccs Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.,Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
| | - Ilaria Rizzello
- Irccs Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.,Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
| | - Michele Cavo
- Irccs Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.,Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
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21
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Buda G, Del Giudice ML, Antonioli E, Ghio F, Orciuolo E, Morganti R, Martini F, Staderini M, Galimberti S, Petrini M. Real-Life Experience With First-Line Therapy Bortezomib Plus Melphalan and Prednisone in Elderly Patients With Newly Diagnosed Multiple Myeloma Ineligible for High Dose Chemotherapy With Autologous Stem-Cell Transplantation. Front Med (Lausanne) 2021; 8:712070. [PMID: 34513878 PMCID: PMC8429780 DOI: 10.3389/fmed.2021.712070] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/02/2021] [Indexed: 12/22/2022] Open
Abstract
Introduction: Currently, the regimen with bortezomib plus melphalan and prednisone (VMP) is a standard treatment for multiple myeloma and it is recommended as the first-line therapy for patients with multiple myeloma (MM) ineligible for high-dose chemotherapy with autologous stem-cell transplantation. Objectives: Participants of the clinical trial are highly selected populations; therefore, the aim of this study was to present observations from real practice that can provide important information for practitioners and to investigate clinical outcomes of VMP regimen in elderly patients with newly diagnosed MM. Patients and Methods: We retrospectively analyzed the data on the efficacy and survival parameters, such as overall survival (OS) and event-free survival (EFS), with attention to the effect of gender, age and International Staging System (ISS) stage, of VMP regimen in 164 patients with newly diagnosed MM not eligible for high-dose chemotherapy with autologous stem-cell transplantation (median age, 75 years; range, 60–86 years). Results: Patients aged 75 years or older constituted 50.6% of the study cohort. Frail patients were 10.36%, according to the clinical frailty scale of geriatric assessment (GA). A total of 1203 courses of VMP regimen (mainly VMP 1–29, 99.16 %) were administered. The median cumulative delivered dose of bortezomib was 46.8 mg/m2. The overall response rate (ORR), including all patients with a partial response or better, was 81.7% and the complete response rate (CRR) was 10.36 %. After a median 38.51 months of follow-up, the median overall survival (OS) was 34.33 months; the median event-free survival (EFS) after VMP and second-line therapy (mainly Rd, 56.31%) were 18.51 and 10.75 months, respectively. In the subgroup of patients with 75 years or older the median OS was 29.76 months; the median EFS after first and second-line therapy were 17.76 and 8.93 months, respectively. The hazard ratio for OS was 2.276 (p-value 0.046) and for EFS was 1.507 (p-value 0.055) for the ISS stage II and III group. Age and gender were not negative predictors of survival. Conclusions: VMP treatment is highly effective in the first-line therapy of elderly patients with multiple myeloma ineligible for HDT with auto-SCT.
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Affiliation(s)
- Gabriele Buda
- Department of Experimental and Clinical Medicine, UO Hematology, AOUP University of Pisa, Pisa, Italy
| | - Maria Livia Del Giudice
- Department of Experimental and Clinical Medicine, UO Hematology, AOUP University of Pisa, Pisa, Italy
| | | | - Francesco Ghio
- Department of Experimental and Clinical Medicine, UO Hematology, AOUP University of Pisa, Pisa, Italy
| | - Enrico Orciuolo
- Department of Experimental and Clinical Medicine, UO Hematology, AOUP University of Pisa, Pisa, Italy
| | | | - Francesca Martini
- Department of Experimental and Clinical Medicine, UO Hematology, AOUP University of Pisa, Pisa, Italy
| | | | - Sara Galimberti
- Department of Experimental and Clinical Medicine, UO Hematology, AOUP University of Pisa, Pisa, Italy
| | - Mario Petrini
- Department of Experimental and Clinical Medicine, UO Hematology, AOUP University of Pisa, Pisa, Italy
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22
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van Oostrum I, Ouwens M, Remiro-Azócar A, Baio G, Postma MJ, Buskens E, Heeg B. Comparison of Parametric Survival Extrapolation Approaches Incorporating General Population Mortality for Adequate Health Technology Assessment of New Oncology Drugs. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2021; 24:1294-1301. [PMID: 34452709 DOI: 10.1016/j.jval.2021.03.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 12/31/2020] [Accepted: 03/01/2021] [Indexed: 06/13/2023]
Abstract
OBJECTIVES Survival extrapolation of trial outcomes is required for health economic evaluation. Generally, all-cause mortality (ACM) is modeled using standard parametric distributions, often without distinguishing disease-specific/excess mortality and general population background mortality (GPM). Recent National Institute for Health and Care Excellence guidance (Technical Support Document 21) recommends adding GPM hazards to disease-specific/excess mortality hazards in the log-likelihood function ("internal additive hazards"). This article compares alternative extrapolation approaches with and without GPM adjustment. METHODS Survival extrapolations using the internal additive hazards approach (1) are compared to no GPM adjustment (2), applying GPM hazards once ACM hazards drop below GPM hazards (3), adding GPM hazards to ACM hazards (4), and proportional hazards for ACM versus GPM hazards (5). The fit, face validity, mean predicted life-years, and corresponding uncertainty measures are assessed for the active versus control arms of immature and mature (30- and 75-month follow-up) multiple myeloma data and mature (64-month follow-up) breast cancer data. RESULTS The 5 approaches yielded considerably different outcomes. Incremental mean predicted life-years vary most in the immature multiple myeloma data set. The lognormal distribution (best statistical fit for approaches 1-4) produces survival increments of 3.5 (95% credible interval: 1.4-5.3), 8.5 (3.1-13.0), 3.5 (1.3-5.4), 2.9 (1.1-4.5), and 1.6 (0.4-2.8) years for approaches 1 to 5, respectively. Approach 1 had the highest face validity for all data sets. Uncertainty over parametric distributions was comparable for GPM-adjusted approaches 1, 3, and 4, and much larger for approach 2. CONCLUSION This study highlights the importance of GPM adjustment, and particularly of incorporating GPM hazards in the log-likelihood function of standard parametric distributions.
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Affiliation(s)
- Ilse van Oostrum
- Ingress Health, Rotterdam, The Netherlands; Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | | | | | - Gianluca Baio
- Department of Statistical Science, University College London, London, UK
| | - Maarten J Postma
- Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Economics, Econometrics & Finance, University of Groningen, Faculty of Economics & Business, Groningen, The Netherlands
| | - Erik Buskens
- Department of Economics, Econometrics & Finance, University of Groningen, Faculty of Economics & Business, Groningen, The Netherlands; Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Bart Heeg
- Ingress Health, Rotterdam, The Netherlands
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23
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Yoo KH, Yoon DH, Kang HJ, Lee WS, Kim K, Kim JS, Kim JA, Kim SH, Kwak JY, Kim YS, Min CK, Lee JJ, Yoon SS, Suh C, Baz R, Lee JH. Multicenter, phase II study of response-adapted lenalidomide-based therapy for transplant-ineligible patients with newly diagnosed multiple myeloma without high-risk features. Curr Probl Cancer 2021; 46:100788. [PMID: 34454742 DOI: 10.1016/j.currproblcancer.2021.100788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 07/04/2021] [Accepted: 07/27/2021] [Indexed: 11/26/2022]
Abstract
Lenalidomide and low-dose dexamethasone (Rd) are a standard treatment for older adults with multiple myeloma (MM). Lenalidomide monotherapy has rarely been evaluated for newly diagnosed transplant-ineligible MM patients. This multicenter phase II trial evaluated a response-adapted strategy for elderly patients with newly diagnosed MM without high-risk features. Patients were administered single-agent lenalidomide for the first 21 days of two 28-day cycles. Patients with progressive disease received Rd. The primary endpoint was progression-free survival using the uniform response assessment from the International Myeloma Working Group . Of the 34 enrolled patients, 28 were included in the efficacy analysis. The overall response rate (ORR, ≥ partial response [PR]) to single-agent lenalidomide or lenalidomide plus prednisone was 64.3%. Ten patients received Rd after disease progression, with an Rd ORR of 70%. The ORR of response-adapted lenalidomide-based therapy was 75%. After the median follow-up of 35.6 months, the median progression-free survival was 33.5 months (95% confidence interval [CI], 16.9-50.2), and the median overall survival was 51.8 months (95% CI, 22.0-81.6). The most common adverse event was neutropenia (46.7%), and 17 patients (56.7%) experienced infection including pneumonia. Response-adapted lenalidomide-based therapy was feasible in newly diagnosed, transplant-ineligible MM patients without high-risk features.
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Affiliation(s)
- Kwai Han Yoo
- Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Dok Hyun Yoon
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hye Jin Kang
- Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Won Sik Lee
- Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Kihyun Kim
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Seok Kim
- Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
| | - Jeong-A Kim
- St. Vincent Hospital College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Sung-Hyun Kim
- Dong-A Medical Center, Dong-A University College of Medicine, Busan, Korea
| | - Jae-Yong Kwak
- Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | | | - Chang-Ki Min
- Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Je-Jung Lee
- Chonnam University Hwasun Hospital, Hwasun, Korea
| | | | - Cheolwon Suh
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Rachid Baz
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Jae Hoon Lee
- Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea.
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24
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Sorrentino VG, Thota S, Gonzalez EA, Rameshwar P, Chang VT, Etchegaray JP. Hypomethylating Chemotherapeutic Agents as Therapy for Myelodysplastic Syndromes and Prevention of Acute Myeloid Leukemia. Pharmaceuticals (Basel) 2021; 14:641. [PMID: 34358067 PMCID: PMC8308509 DOI: 10.3390/ph14070641] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 12/11/2022] Open
Abstract
Myelodysplastic Syndromes (MDSs) affect the elderly and can progress to Acute Myeloid Leukemia (AML). Epigenetic alterations including DNA methylation and chromatin modification may contribute to the initiation and progression of these malignancies. DNA hypomethylating agents such as decitabine and azacitidine are used as therapeutic treatments and have shown to promote expression of genes involved in tumor suppression, apoptosis, and immune response. Another anti-cancer drug, the proteasome inhibitor bortezomib, is used as a chemotherapeutic treatment for multiple myeloma (MM). Phase III clinical trials of decitabine and azacitidine used alone and in combination with other chemotherapeutics demonstrated their capacity to treat hematological malignancies and prolong the survival of MDS and AML patients. Although phase III clinical trials examining bortezomib's role in MDS and AML patients are limited, its underlying mechanisms in MM highlight its potential as a chemotherapeutic for such malignancies. Further research is needed to better understand how the epigenetic mechanisms mediated by these chemotherapeutic agents and their targeted gene networks are associated with the development and progression of MDS into AML. This review discusses the mechanisms by which decitabine, azacitidine, and bortezomib alter epigenetic programs and their results from phase III clinical trials.
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Affiliation(s)
- Vincent G. Sorrentino
- Department of Biological Sciences, Rutgers University—Newark, Newark, NJ 07102, USA; (V.G.S.); (S.T.); (E.A.G.)
| | - Srijan Thota
- Department of Biological Sciences, Rutgers University—Newark, Newark, NJ 07102, USA; (V.G.S.); (S.T.); (E.A.G.)
| | - Edward A. Gonzalez
- Department of Biological Sciences, Rutgers University—Newark, Newark, NJ 07102, USA; (V.G.S.); (S.T.); (E.A.G.)
| | - Pranela Rameshwar
- Department of Medicine, Division of Hematology/Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA;
| | - Victor T. Chang
- Department of Medicine, Division of Hematology/Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA;
- Veteran Affairs New Jersey Health Care System, East Orange, NJ 07018, USA;
| | - Jean-Pierre Etchegaray
- Department of Biological Sciences, Rutgers University—Newark, Newark, NJ 07102, USA; (V.G.S.); (S.T.); (E.A.G.)
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25
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Schjesvold F, Oriol A. Current and Novel Alkylators in Multiple Myeloma. Cancers (Basel) 2021; 13:2465. [PMID: 34070213 PMCID: PMC8158783 DOI: 10.3390/cancers13102465] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/22/2021] [Accepted: 05/11/2021] [Indexed: 12/22/2022] Open
Abstract
A large number of novel treatments for myeloma have been developed and approved; however, alkylating drugs continue to be part of standard regimens. Additionally, novel alkylators are currently being developed. We performed a non-systematized literary search for relevant papers and communications at large conferences, as well as exploiting the authors' knowledge of the field, to review the history, current use and novel concepts around the traditional alkylators cyclophosphamide, bendamustine and melphalan and current data on the newly developed pro-drug melflufen. Even in the era of targeted treatment and personalized medicine, alkylating drugs continue to be part of the standard-of-care in myeloma, and new alkylators are coming to the market.
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Affiliation(s)
- Fredrik Schjesvold
- Oslo Myeloma Center, Oslo University Hospital, 0450 Oslo, Norway
- K.G. Jebsen Centre for B-Cell Malignancies, University of Oslo, 4950 Oslo, Norway
| | - Albert Oriol
- Institut Josep Carreras and Institut Català d’Oncologia, Hospital Germans Trias I Pujol, 08916 Badalona, Spain;
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26
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Noguchi Y, Iriyama N, Takahashi H, Uchino Y, Nakagawa M, Hamada T, Iizuka K, Koike T, Kurihara K, Endo T, Yoshida T, Miura K, Nakayama T, Hatta Y, Takei M. Maintenance Therapy With Bortezomib and Dexamethasone for Transplant-ineligible Patients With Multiple Myeloma. CANCER DIAGNOSIS & PROGNOSIS 2021; 1:35-42. [PMID: 35403126 PMCID: PMC8962762 DOI: 10.21873/cdp.10006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 04/13/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND/AIM Here, we investigated whether bortezomib as a maintenance therapy affected outcomes in transplant-ineligible patients with multiple myeloma (MM). PATIENTS AND METHODS Following induction therapy with bortezomib, maintenance therapy with bortezomib (1.3 mg/m 2 ) and dexamethasone (20 mg) was administered once or twice every 4 weeks until disease progression. The endpoints of this study were time to next treatment and overall survival. RESULTS Seventy-six newly diagnosed, transplant-ineligible patients were treated with a bortezomib-based regimen; 28 discontinued induction therapy, 27 did not receive maintenance therapy after induction therapy (the non-maintenance group), and 21 did (the maintenance group). In the three groups, the median times to the next required treatment were 3, 14, and 37 months, respectively. The 3-year overall survival rates were 55%, 69%, and 85%, respectively. There were no significant differences in patient characteristics between the non-maintenance and maintenance groups, except for poorer estimated glomerular filtration rates in the maintenance group. CONCLUSION Bortezomib maintenance therapy may be a useful option for transplant-ineligible patients with MM.
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Affiliation(s)
- Yurika Noguchi
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Noriyoshi Iriyama
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Hiromichi Takahashi
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
- Division of Laboratory Medicine, Department of Pathology and Microbiology,Nihon University School of Medicine, Tokyo, Japan
| | - Yoshihito Uchino
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Masaru Nakagawa
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Takashi Hamada
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Kazuhide Iizuka
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Takashi Koike
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Kazuya Kurihara
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Toshihide Endo
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Tsutomu Yoshida
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Katsuhiro Miura
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Tomohiro Nakayama
- Division of Laboratory Medicine, Department of Pathology and Microbiology,Nihon University School of Medicine, Tokyo, Japan
| | - Yoshihiro Hatta
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
| | - Masami Takei
- Division of Hematology and Rheumatology, Department of Medicine,Nihon University School of Medicine, Tokyo, Japan
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27
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Mina R, Bonello F, Petrucci MT, Liberati AM, Conticello C, Ballanti S, Musto P, Olivieri A, Benevolo G, Capra A, Gilestro M, Galieni P, Cavo M, Siniscalchi A, Palumbo A, Montefusco V, Gaidano G, Omedé P, Boccadoro M, Bringhen S. Carfilzomib, cyclophosphamide and dexamethasone for newly diagnosed, high-risk myeloma patients not eligible for transplant: a pooled analysis of two studies. Haematologica 2021; 106:1079-1085. [PMID: 32107329 PMCID: PMC8018137 DOI: 10.3324/haematol.2019.243428] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 02/19/2020] [Indexed: 12/11/2022] Open
Abstract
Despite remarkable advances in the treatment of multiple myeloma in the last decades, the prognosis of patients harboring high-risk cytogenetic abnormalities remains dismal as compared to that of standard-risk patients. Proteasome inhibitors demonstrated to partially ameliorate the prognosis of high-risk patients. We pooled together data from two phase I/II trials on transplant-ineligible patients with multiple myeloma receiving upfront carfilzomib cyclophosphamide and dexamethasone followed by carfilzomib maintenance. The aim of this analysis was to compare treatment outcomes in patients with standard- versus high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) analysis. High risk was defined by the presence of at least one chromosomal abnormality, including t(4;14), del17p and t(14;16). Overall, 94 patients were included in the analysis: 57 (61%) in the standard-risk and 37 (39%) in the high-risk group. Median follow-up was 38 months. In standard- vs. high-risk patients, we observed similar progression-free survival (3-year PFS: 52% vs. 43%, respectively; p=0.50), overall survival (3-year OS: 78% vs. 73%; p=0.38), and overall response rate (88% vs 95%; p=0.47), with no statistical differences between the two groups. No difference in terms of progression-free survival was observed between patients with or without del17p. Carfilzomib, used both as induction and maintenance agent for transplant-ineligible newly diagnosed multiple myeloma patients, mitigated the poor prognosis carried by high-risk cytogenetics and resulted into similar progression-free survival and overall survival, as compared to standard-risk patients. ClinicalTrials.gov IDs: NCT01857115 (IST-CAR-561) and NCT01346787 (IST-CAR-506).
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Affiliation(s)
- Roberto Mina
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero- Universitaria Citta della Salute e della Scienza di Torino, Torino
| | - Francesca Bonello
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero- Universitaria Citta della Salute e della Scienza di Torino, Torino
| | - Maria Teresa Petrucci
- Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome
| | - Anna Marina Liberati
- Universita degli Studi di Perugia, Struttura Complessa Universitaria Oncoematologia - Azienda Ospedaliera Santa Maria di Terni, Terni
| | | | - Stelvio Ballanti
- Reparto di Ematologia con TMO, Ospedale Santa Maria della Misericordia, Perugia
| | | | - Attilio Olivieri
- Clinica di Ematologia, Universita Politecnica delle Marche, Ancona
| | | | - Andrea Capra
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero- Universitaria Citta della Salute e della Scienza di Torino, Torino
| | - Milena Gilestro
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero- Universitaria Citta della Salute e della Scienza di Torino, Torino
| | - Piero Galieni
- Division of Hematology, Ospedale “C. e G. Mazzoni”, ASUR Marche-AV5, Ascoli Piceno
| | - Michele Cavo
- "Seragnoli" Institute of Hematology, Bologna University School of Medicine, Bologna
| | | | - Antonio Palumbo
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero- Universitaria Citta della Salute e della Scienza di Torino, Torino
| | | | - Gianluca Gaidano
- Division of Hematology, Department of Translational Medicine, Universita del Piemonte Orientale, Novara, Italy °PM is currently at the Department of Emergency and Organ Transplantation, "Aldo Moro" University School of Medicine, Unit of Hematology and Stem Cell Transplantation, AOU Consorziale Policlinico, Bari
| | - Paola Omedé
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero- Universitaria Citta della Salute e della Scienza di Torino, Torino
| | - Mario Boccadoro
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero- Universitaria Citta della Salute e della Scienza di Torino, Torino
| | - Sara Bringhen
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero- Universitaria Citta della Salute e della Scienza di Torino, Torino
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Sive J, Cuthill K, Hunter H, Kazmi M, Pratt G, Smith D. Guidelines on the diagnosis, investigation and initial treatment of myeloma: a British Society for Haematology/UK Myeloma Forum Guideline. Br J Haematol 2021; 193:245-268. [PMID: 33748957 DOI: 10.1111/bjh.17410] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 12/23/2020] [Indexed: 11/29/2022]
Affiliation(s)
- Jonathan Sive
- University College London Hospitals NHS Foundation Trust, London, UK
| | | | - Hannah Hunter
- University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Majid Kazmi
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Guy Pratt
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Dean Smith
- Nottingham University Hospitals NHS Trust, Nottingham, UK
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29
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Blommestein HM, Franken MG, van Beurden-Tan CHY, Blijlevens NMA, Huijgens PC, Sonneveld P, Uyl-de Groot CA, Zweegman S. Cost-effectiveness of Novel Treatment Sequences for Transplant-Ineligible Patients With Multiple Myeloma. JAMA Netw Open 2021; 4:e213497. [PMID: 33779744 PMCID: PMC8008287 DOI: 10.1001/jamanetworkopen.2021.3497] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
IMPORTANCE Although the number of treatments for elderly patients with non-transplant-eligible (NTE) multiple myeloma (MM) has increased substantially, evidence is lacking on the clinical effectiveness and cost-effectiveness of novel treatment sequences. OBJECTIVE To determine the optimal sequence of treatment for patients with NTE MM from the perspective of the patient, physician, and society. DESIGN, SETTING, AND PARTICIPANTS Using data from a Dutch observational registry, this economic evaluation combined evidence from network meta-analyses in a patient-level simulation model and modeled time-to-event and types of events from a hospital perspective with a lifetime horizon. Data analysis was performed from June 2019 to September 2020. INTERVENTIONS Thirty treatment sequences, including up to 3 lines of therapy, were compared with bortezomib-melphalan-prednisone (VMP)-lenalidomide-dexamethasone (LenDex)-pomalidomide-dexamethasone (PomDex). MAIN OUTCOMES AND MEASURES The primary outcomes of the model were overall survival (OS), quality-adjusted life-years (QALYs), costs, and cost-effectiveness. RESULTS Sequences starting with daratumumab-VMP (second line: carfilzomib-lenalidomide-dexamethasone or elotuzumab-lenalidomide-dexamethasone) or bortezomib-melphalan-prednisone-thalidomide-maintenance bortezomib-thalidomide (VMPT-VT) (second line: daratumumab-lenalidomide-dexamethasone) had the largest expected OS (7.5 years), which is 3.5 additional life-years compared with VMP-LenDex-PomDex. Total costs per patient for these sequences ranged between $786 024 and $1 085 794. The sequence VMPT-VT-carfilzomib-lenalidomide-dexamethasone-panobinostat-bortezomib-dexamethasone had the most favorable cost-effectiveness ratio ($98 585 per life-year gained and $132 707 per QALY gained vs VMP-LenDex-PomDex). CONCLUSIONS AND RELEVANCE These findings suggest that sequences including novel treatments were highly effective, but the cost-effectiveness ratios were above currently accepted willingness-to-pay thresholds. Treating MM with novel agents necessitates either a large increase in budget or a substantial reduction of drug costs by price negotiations, and these findings can support these reimbursement decisions and price negotiations.
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Affiliation(s)
- Hedwig M. Blommestein
- Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, the Netherlands
| | - Margreet G. Franken
- Institute of Medical Technology Assessment, Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, the Netherlands
| | | | | | - Peter C. Huijgens
- Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Pieter Sonneveld
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Carin A. Uyl-de Groot
- Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, the Netherlands
- Institute of Medical Technology Assessment, Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, the Netherlands
| | - Sonja Zweegman
- Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, the Netherlands
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Kaweme NM, Changwe GJ, Zhou F. Approaches and Challenges in the Management of Multiple Myeloma in the Very Old: Future Treatment Prospects. Front Med (Lausanne) 2021; 8:612696. [PMID: 33718400 PMCID: PMC7947319 DOI: 10.3389/fmed.2021.612696] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 02/03/2021] [Indexed: 12/14/2022] Open
Abstract
The increasing incidence of geriatric patients with multiple myeloma has elevated concerns in clinical practice. While the introduction of novel therapeutic agents has substantially improved outcomes in younger patients with myeloma, poorer outcomes remain in older patients. Managing older patients requires a multidisciplinary team approach to consider factors that may influence both treatment selection and outcomes. Aging is associated with remodeling of vital organs, physiological downregulations of basal metabolism, susceptibility to multiple comorbidities with ultimate frailty, thereby contributing to the underrepresentation and exclusion of very old patients from clinical trials. Therefore, timely confirmation of a precise diagnosis is crucial for prompt initiation of treatment if the desired outcome is to be achieved. Adequate and judicious assessment using comprehensive geriatric assessment tools minimizes toxicities and treatment discontinuation. Initiating treatment with combinational therapy requires knowledge of indications and anticipated outcomes, as well as individualized therapy with appropriate dose-adjustment. Individualized therapy based on good clinical acumen and best practices obverts unwanted polypharmacy, preventing iatrogenic harm. This review will therefore address the approaches and challenges faced in managing myeloma in geriatric patients aged 80 years and older, highlighting recommended therapeutic strategies and future prospective regimens.
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Affiliation(s)
| | | | - Fuling Zhou
- Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, China
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Franchi M, Vener C, Garau D, Kirchmayer U, Di Martino M, Romero M, De Carlo I, Scondotto S, Stival C, Della Porta MG, Passamonti F, Corrao G. Bortezomib-based therapy in non-transplant multiple myeloma patients: a retrospective cohort study from the FABIO project. Ther Adv Hematol 2021; 12:2040620721996488. [PMID: 33747423 PMCID: PMC7905486 DOI: 10.1177/2040620721996488] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 01/25/2021] [Indexed: 12/22/2022] Open
Abstract
Introduction: Randomized clinical trials showed that bortezomib, in addition to
conventional chemotherapy, improves survival and disease progression in
multiple myeloma (MM) patients not eligible for stem cell transplantation.
The aim of this retrospective population-based cohort study is the
evaluation of both clinical and economic profile of bortezomib-based
versus conventional chemotherapy in daily clinical
practice. Methods: Healthcare utilization databases of six Italian regions were used to identify
adult patients with non-transplant MM, who started a first-line therapy with
bortezomib-based or conventional chemotherapy. Patients were matched by
propensity score and were followed from treatment start until death, lost to
follow-up or study end-point. Overall survival (OS) and restricted mean
survival time (RMST) were estimated using the Kaplan–Meier method.
Association between first-line treatment and risk of death was estimated by
a conditional Cox proportional regression model. Average mean cumulative
costs were estimated and compared between groups. Results: In the period 2010–2016, 3509 non-transplant MM patients met the inclusion
criteria, of which 1157 treated with bortezomib-based therapy were matched
to 1826 treated with conventional chemotherapy. Median OS and RMST were 33.9
and 27.9 months, and 42.9 and 38.4 months, respectively, in the two
treatment arms. Overall, these values corresponded to a HR of death of 0.79
(95% CI 0.71–0.89) over a time horizon of 84 months. Average cumulative cost
were 83,839 € and 54,499 €, respectively, corresponding to an incremental
cost-effectiveness ratio of 54,333 € per year of life gained, a cost
coherent with the willingness-to-pay thresholds frequently adopted from
Western countries. Conclusions: These data suggested that, in a large cohort of non-transplant MM patients
treated outside the experimental setting, first-line treatment with
bortezomib-based therapy was associated with a favourable effectiveness and
cost-effectiveness profile.
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Affiliation(s)
- Matteo Franchi
- Laboratory of Healthcare Research & Pharmacoepidemiology, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Building U7, Via Bicocca degli Arcimboldi 8, Milan, 20126, Italy
| | - Claudia Vener
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | | | - Ursula Kirchmayer
- Department of Epidemiology ASL Roma 1, Lazio Regional Health Service, Rome, Lazio, Italy
| | - Mirko Di Martino
- Department of Epidemiology ASL Roma 1, Lazio Regional Health Service, Rome, Lazio, Italy
| | - Marilena Romero
- Department of Medical, Oral and Biotechnological Sciences - Section of Pharmacology and Toxicology, University of Chieti, Italy
| | - Ilenia De Carlo
- Regional Centre of Pharmacovigilance, Regional Health Authority, Marche Region, Ancona, Italy
| | - Salvatore Scondotto
- Department of Health Services and Epidemiological Observatory, Regional Health Authority, Palermo, Sicily Region, Palermo, Italy
| | - Chiara Stival
- National Centre for Healthcare Research and Pharmacoepidemiology, Milan, ItalyLaboratory of Healthcare Research & Pharmacoepidemiology, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Lombardia, Italy
| | - Matteo Giovanni Della Porta
- Humanitas Clinical and Research Hospital - IRCCS and Department of Biomedical Sciences, Humanitas University, Rozzano, Italy
| | - Francesco Passamonti
- Department of Medicine and Surgery, University of Insubria and ASST Sette Laghi, Ospedale di Circolo of Varese, Varese, Lombardia, Italy
| | - Giovanni Corrao
- National Centre for Healthcare Research and Pharmacoepidemiology, Milan, Italy
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Grant SJ, Mian HS, Giri S, Boutin M, Dottorini L, Neuendorff NR, Krok-Schoen JL, Nikita N, Rosko AE, Wildes TM, Zweegman S. Transplant-ineligible newly diagnosed multiple myeloma: Current and future approaches to clinical care: A Young International Society of Geriatric Oncology Review Paper. J Geriatr Oncol 2020; 12:499-507. [PMID: 33342724 DOI: 10.1016/j.jgo.2020.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 12/02/2020] [Accepted: 12/02/2020] [Indexed: 12/29/2022]
Abstract
Multiple myeloma is the second most common hematological malignancy in the USA and Europe. Despite improvements in the 5-year and overall survival rates over the past decade, older adults (aged ≥65 years) with multiple myeloma continue to experience disproportionately worse outcomes than their younger counterparts. These differences in outcomes arise from the increased prevalence of vulnerabilities such as medical comorbidities and frailty seen with advancing age that can influence treatment-delivery and tolerance and impact survival. In general, geriatric assessments can help identify those patients more likely to benefit from enhanced toxicity risk-prediction and aid treatment decision-making. Despite the observed benefits of geriatric assessments and other screening frailty tools, provider and systems-level barriers continue to influence the overall perception of the feasibility of geriatric assessments in clinical practice settings. Clinical trials are underway evaluating the efficacy and safety of various multiple myeloma therapies in less fit/frail older adults, with a minority examining fitness-based/risk-adapted approaches. Thus, significant gaps exist in knowing which myeloma therapies are most appropriate for older and more vulnerable adults with multiple myeloma. The purpose of this Review is to discuss how geriatric assessments can be used to guide the management of transplant-ineligible patients; and to highlight frontline therapies for standard-risk and high-risk cytogenetic abnormalities [i.e., t(4;14), t(14;16), and del(17p)] associated with multiple myeloma. We also discuss the current shortcomings of the existing clinical approaches to care and highlight ongoing clinical trials evaluating newer fitness-based approaches to managing transplant-ineligible patients.
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Affiliation(s)
- Shakira J Grant
- Division of Hematology-Oncology, University of Washington-Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
| | - Hira S Mian
- Department of Oncology, McMaster University, Ontario, Canada
| | - Smith Giri
- Division of Hematology-Oncology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Melina Boutin
- Department of Hemato-Oncology, Université of Sherbrooke, Québec, Canada
| | - Lorenzo Dottorini
- Oncology Unit, Medical Sciences Department, ASST Bergamo Est, Alzano Lombardo, Bergamo, Italy
| | - Nina R Neuendorff
- Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Jessica L Krok-Schoen
- School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Nikita Nikita
- Department of Medical Oncology, Sidney Kimmel Cancer Center at Jefferson, Sidney Kimmel Medical College, Philadelphia, PA, USA
| | - Ashley E Rosko
- Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA
| | - Tanya M Wildes
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
| | - Sonja Zweegman
- Department of Hematology, Amsterdam UMC, VU University Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
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Chitty DW, Hartley-Brown MA, Abate M, Thakur R, Wanchoo R, Jhaveri KD, Nair V. Kidney transplantation in patients with multiple myeloma: narrative analysis and review of the last 2 decades. Nephrol Dial Transplant 2020; 37:1616-1626. [PMID: 33295615 DOI: 10.1093/ndt/gfaa361] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Indexed: 12/17/2022] Open
Abstract
There have been significant advances in the treatment of multiple myeloma in the last 2 decades. Approximately 25% of patients with newly diagnosed myeloma have some degree of kidney impairment. During the course of illness, nearly 50% of myeloma patients will develop kidney disease. Moreover, approximately 10% of myeloma patients have advanced kidney disease requiring dialysis at presentation. Hemodialysis is associated with a significantly reduced overall survival. In the setting of prolonged long-term overall survival due to the use of newer immunotherapeutic agents in the treatment of myeloma, patients with myeloma and advanced kidney disease may benefit from more aggressive management with kidney transplantation. Unfortunately, most data regarding outcomes of kidney transplantation in patients with myeloma come from single center case series. With the advent of novel treatment choices, it remains unclear if outcomes of kidney transplant recipients with myeloma have improved in recent years. In this descriptive systematic review, we coalesced published patient data over the last 20 years to help inform clinicians and patients on expected hematologic and kidney transplant outcomes in this complex population. We further discuss the future of kidney transplantation in patients with paraproteinemia.
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Affiliation(s)
- David W Chitty
- Divisions of Hematology-Oncology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, New York, USA.,Northwell Health Cancer Institute, Hematology/Medical Oncology, New Hyde Park, New York, USA
| | - Monique A Hartley-Brown
- Divisions of Hematology-Oncology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, New York, USA.,Northwell Health Cancer Institute, Hematology/Medical Oncology, New Hyde Park, New York, USA
| | - Mersema Abate
- Kidney Diseases and Hypertension, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, New York, USA
| | - Richa Thakur
- Divisions of Hematology-Oncology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, New York, USA.,Northwell Health Cancer Institute, Hematology/Medical Oncology, New Hyde Park, New York, USA
| | - Rimda Wanchoo
- Kidney Diseases and Hypertension, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, New York, USA
| | - Kenar D Jhaveri
- Kidney Diseases and Hypertension, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, New York, USA
| | - Vinay Nair
- Kidney Diseases and Hypertension, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, New York, USA
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Tacchetti P, Pantani L, Patriarca F, Petrucci MT, Zamagni E, Dozza L, Galli M, Di Raimondo F, Crippa C, Boccadoro M, Barbato S, Tosi P, Narni F, Montefusco V, Testoni N, Spadano A, Terragna C, Pescosta N, Marzocchi G, Cellini C, Galieni P, Ronconi S, Gobbi M, Catalano L, Lazzaro A, De Sabbata G, Cangialosi C, Ciambelli F, Musto P, Elice F, Cavo M. Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study. LANCET HAEMATOLOGY 2020; 7:e861-e873. [PMID: 33242443 DOI: 10.1016/s2352-3026(20)30323-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 09/03/2020] [Accepted: 09/16/2020] [Indexed: 01/12/2023]
Abstract
BACKGROUND The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. METHODS In this randomised, open-label, phase 3 study, patients aged 18-65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1-2, 4-5, 8-9, and 11-12 in the VTD regimen, and 40 mg on days 1-4 and 9-12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. FINDINGS Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2-131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28-41) compared with 17% (13-23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50-0·77]; p<0·0001). 60% (95% CI 54-67) of patients in the VTD group were alive at 10 years versus 46% (40-54) of patients in the TD group (HR 0·68 [95% CI 0·51-0·90]; p=0·0068). VTD was an independent predictor of improved progression-free survival (HR 0·60 [95% CI 0·48-0·76]; p<0·0001) and overall survival (HR 0·68 [0·50-0·91]; p=0·010). The incidence of second primary malignancies per 100 person-years was 0·87 (95% CI 0·49-1·44) in the VTD group compared with 1·41 (0·88-2·13) in the TD group. INTERPRETATION Incorporation of VTD into double autologous HSCT resulted in clinically meaningful improvements in long-term progression-free survival and overall survival, confirming that a regimen including bortezomib and an immunomodulatory drug is the gold standard treatment for patients with newly diagnosed myeloma who are fit for high-dose chemotherapy. FUNDING Seràgnoli Institute of Haematology, University of Bologna, and BolognAIL.
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Affiliation(s)
- Paola Tacchetti
- Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy
| | - Lucia Pantani
- Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy
| | - Francesca Patriarca
- Clinical Hematology and Bone Marrow Transplant Centre, S Maria della Misericordia University Hospital, DAME, University of Udine, Udine, Italy
| | - Maria Teresa Petrucci
- Hematology Unit, and Department of Translational and Precision Medicine, Azienda Ospedaliera Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Elena Zamagni
- Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy
| | - Luca Dozza
- Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy
| | - Monica Galli
- Hematology and Bone Marrow Transplant Unit, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Francesco Di Raimondo
- Division of Hematology, Azienda Ospedaliero-Universitaria Policlinico, Department of Surgery and Medical Specialties, University of Catania, Catania, Italy
| | - Claudia Crippa
- Unità Operativa Complessa di Ematologia, Spedali Civili Brescia, Brescia, Italy
| | - Mario Boccadoro
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Cittàdella Salute e della Scienza, Turin, Italy
| | - Simona Barbato
- Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy
| | - Patrizia Tosi
- Unità Operativa, Ematologia, Ospedale Infermi di Rimini, Rimini, Italy
| | - Franco Narni
- Programma Trapianti Cellule Staminali Emopoietiche, Università di Modena e Reggio Emilia, Azienda Ospedaliero-Universitaria, Policlinico di Modena, Modena, Italy
| | - Vittorio Montefusco
- Department of Hematology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Nicoletta Testoni
- Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy
| | - Antonio Spadano
- Unità Operativa Complessa, Ematologia Clinica, Azienda Sanitaria Locale di Pescara, Pescara, Italy
| | - Carolina Terragna
- Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy
| | - Norbert Pescosta
- Reparto di Ematologia e Centro Trapianto Midollo Osseo, Ospedale Centrale, Bolzano, Italy
| | - Giulia Marzocchi
- Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy
| | - Claudia Cellini
- Unità Operativa Complessa Ematologia, Ospedale Santa Maria delle Croci, Ravenna, Italy
| | - Piero Galieni
- Unità Operativa Complessa Ematologia e Terapia cellulare, Ospedale Costanzo e Giacomo Mazzoni, Ascoli Piceno, Italy
| | - Sonia Ronconi
- IRCCS, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy
| | - Marco Gobbi
- Dipartimento di Medicina interna, Clinica Ematologica, Policlinico Ospedale San Martino, Genoa, Italy
| | - Lucio Catalano
- Unità Operativa Ematologia, Azienda Ospedaliero-Universitaria Federico II, Napoli, Italy
| | - Antonio Lazzaro
- Division of Hematology and Bone Marrow Transplant Center, Department of Oncology-Hematology, Guglielmo da Saliceto Hospital, Piacenza, Italy
| | - Giovanni De Sabbata
- Struttura Complessa Ematologia, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy
| | - Clotilde Cangialosi
- Divisione di Ematologia ad indirizzo oncologico con Trapianto, Azienda Ospedali Riuniti "Villa Sofia Cervello", Presidio Ospedaliero "V Cervello", Palermo, Italy
| | - Fabrizio Ciambelli
- Struttura Complessa di Ematologia, Azienda Socio Sanitaria Territoriale della Valle Olona, Busto Arsizio, Italy
| | - Pellegrino Musto
- "Aldo Moro" University School of Medicine, Unit of Hematology and Stem Cell Transplantation, AOUCPoliclinico, Bari, Italy; Unit of Hematology and Stem Cell Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy
| | - Francesca Elice
- Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy
| | - Michele Cavo
- Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy.
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Hanafi HHW, Husin A, Yaacob NM, Abdullah AD. Relapsed/Progressive Disease and Its Prognostic Factors among Multiple Myeloma Patients Receiving Novel Agent Treatment in North East Peninsular Malaysia: A Single Centre Experience. Malays J Med Sci 2020; 27:62-77. [PMID: 33154703 PMCID: PMC7605841 DOI: 10.21315/mjms2020.27.5.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 08/10/2020] [Indexed: 11/25/2022] Open
Abstract
Background Some multiple myeloma (MM) patients still relapse/progress despite novel agent therapy and relapse/progression in MM is therefore a vital area of ongoing research in the novel treatment era. This retrospective cohort study aimed to evaluate the time to relapse/progression (TTP) among MM patients who received novel agents and to determine the associated prognostic factors. Methods This study included 89 MM patients treated at Hospital Universiti Sains Malaysia. We analysed the TTP and the type of relapse/progression (biochemical versus clinical), and a Cox proportional hazard model was used to identify the significant prognostic factors. Results Sixty-four percent of patients had biochemical relapse/progression. The overall median TTP among MM patients who received the novel agent(s) was 29.33 months (95% CI: 21.36–37.29). The type of paraprotein at diagnosis (P = 0.026, P = 0.228), International Staging System (ISS) score (P = 0.036, P = 0.067) and autologous stem cell transplant (ASCT) (P = 0.002) were prognostic factors for relapse/progression by simple Cox regression, but ASCT was the only significant predictor detected by multiple Cox regression (P = 0.003). Conclusion Our study reflects the importance of paraprotein monitoring to detect early features of relapse/progression. ASCT is the most prognostic factor that may lengthen the TTP.
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Affiliation(s)
- Hany Haqimi Wan Hanafi
- Haematopoietic Stem Cell Transplant Unit, Hospital Universiti Sains Malaysia, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.,Department of Internal Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Azlan Husin
- Haematopoietic Stem Cell Transplant Unit, Hospital Universiti Sains Malaysia, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.,Department of Internal Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Najib Majdi Yaacob
- Unit of Biostatistics and Research Methodology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Abu Dzarr Abdullah
- Haematopoietic Stem Cell Transplant Unit, Hospital Universiti Sains Malaysia, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.,Department of Internal Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
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36
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Montefusco V, Mussetti A, Salas MQ, Martinelli G, Cerchione C. Old and new generation proteasome inhibitors in multiple myeloma. Panminerva Med 2020; 62:193-206. [PMID: 32957744 DOI: 10.23736/s0031-0808.20.04148-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Proteasome inhibitors (PIs) represent a recently developed drug class that inhibit the ubiquitin-proteasome system, thus interfering with the intracellular machinery who has the duty of misfolded proteins disposal. Myeloma plasma cells are structurally aimed at the production of large quantities of immunoglobulins. This explains their vulnerability to any perturbation of intracellular protein homeostasis. Bortezomib is the first-in-class PI and nowadays, in combination with other compounds, is the cornerstone of multiple myeloma (MM) treatment in several settings. Bortezomib has several attractive features for its inclusion in the induction phase of therapy: high efficacy, rapid cytoreduction, absence of nephrotoxicity, fast reduction of plasmacytomas, and fast pain control. However, the safety profile of bortezomib is characterized by a not negligible peripheral neuropathy. Newer PIs, such as carfilzomib and ixazomib, have been developed and each offers specific advantages. Carfilzomib is extremely efficient in proteasome inhibition. This results in high efficacy but suffers from a significant cardiotoxicity. Ixazomib is the first oral PI with a proteasome inhibition profile similar to bortezomib, with lower neurotoxicity. PIs mechanism of action is complementary with other drug classes, and this explains the synergism between PIs and other drugs, in particular steroids and immunomodulators. PIs are frequently used in doublets and triplets. Also, they can be associated with anti-CD38 monoclonal antibodies. This review summarizes the principal biological and clinical features of PIs in the MM treatment.
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Affiliation(s)
| | - Alberto Mussetti
- Department Clinical Hematology, Institut Català d'Oncologia-Hospitalet, Barcelona, Spain.,Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Maria Q Salas
- Department Clinical Hematology, Institut Català d'Oncologia-Hospitalet, Barcelona, Spain.,Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Giovanni Martinelli
- Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy
| | - Claudio Cerchione
- Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy
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Loke C, Mollee P, McPherson I, Walpole E, Yue M, Mutsando H, Wong P, Weston H, Tomlinson R, Hollingworth S. Bortezomib use and outcomes for the treatment of multiple myeloma. Intern Med J 2020; 50:1059-1066. [DOI: 10.1111/imj.14886] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 04/30/2020] [Accepted: 05/01/2020] [Indexed: 11/26/2022]
Affiliation(s)
- Crystal Loke
- School of Pharmacy The University of Queensland Brisbane Queensland Australia
| | - Peter Mollee
- Department of Cancer Services Princess Alexandra Hospital Brisbane Queensland Australia
| | - Ian McPherson
- Department of Cancer Services Princess Alexandra Hospital Brisbane Queensland Australia
| | - Euan Walpole
- Department of Cancer Services Princess Alexandra Hospital Brisbane Queensland Australia
| | - Mimi Yue
- Department of Cancer Services Princess Alexandra Hospital Brisbane Queensland Australia
| | - Howard Mutsando
- Toowoomba Hospital Darling Downs Hospital and Health Services Toowoomba Queensland Australia
| | - Phillip Wong
- Toowoomba Hospital Darling Downs Hospital and Health Services Toowoomba Queensland Australia
| | - Helen Weston
- Regional Cancer Care, Cancer Care Services Sunshine Coast University Hospital Sunshine Coast Queensland Australia
| | - Ross Tomlinson
- Regional Cancer Care, Cancer Care Services Sunshine Coast University Hospital Sunshine Coast Queensland Australia
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38
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Manda S, Yimer HA, Noga SJ, Girnius S, Yasenchak CA, Charu V, Lyons R, Aiello J, Bogard K, Ferrari RH, Cherepanov D, Demers B, Lu V, Whidden P, Kambhampati S, Birhiray RE, Jhangiani HS, Boccia R, Rifkin RM. Feasibility of Long-term Proteasome Inhibition in Multiple Myeloma by in-class Transition From Bortezomib to Ixazomib. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:e910-e925. [PMID: 32912820 PMCID: PMC7336931 DOI: 10.1016/j.clml.2020.06.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/17/2020] [Accepted: 06/30/2020] [Indexed: 10/26/2022]
Abstract
BACKGROUND The ongoing US MM-6 study is investigating in-class transition (iCT) from parenteral bortezomib-based induction to all-oral IRd (ixazomib-lenalidomide-dexamethasone) with the aim of increasing proteasome inhibitor (PI)-based treatment adherence and duration while maintaining patients' health-related quality of life (HRQoL) and improving outcomes. PATIENTS AND METHODS US community sites are enrolling non-transplant-eligible patients with newly diagnosed multiple myeloma (MM) with no evidence of progressive disease after 3 cycles of bortezomib-based therapy to receive IRd (up to 39 cycles or until progression or toxicity). The patients use mobile or wearable digital devices to collect actigraphy (activity and sleep) data and electronically complete HRQoL, treatment satisfaction and medication adherence questionnaires. The primary endpoint is progression-free survival. The key secondary endpoints include response rates and therapy duration. RESULTS At the data cutoff, 84 patients had been treated (median age 73 years; 44% aged ≥ 75 years; 49% men; 15% Black or African American; and 10% Hispanic or Latino). Of the 84 patients, 62% were continuing therapy. The mean duration of total PI therapy was 10.1 months and for the IRd regimen was 7.3 months. With an 8-month median follow-up, the 12-month progression-free survival rate was 86% (95% confidence interval, 73%-93%) from both the start of bortezomib-based treatment and the start of IRd. The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after iCT. The IRd safety profile was consistent with previous clinical trial data, and HRQoL and treatment satisfaction were maintained. CONCLUSION The patients included in the US MM-6 study are representative of the real-world US MM population. The use of iCT might permit prolonged PI-based therapy with promising efficacy, without impacting patients' HRQoL or treatment satisfaction.
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Affiliation(s)
- Sudhir Manda
- Arizona Oncology/US Oncology Research, Tucson, AZ
| | | | - Stephen J Noga
- Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | | | | | | | - Roger Lyons
- Texas Oncology/US Oncology Research, San Antonio, TX
| | | | - Kimberly Bogard
- Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Renda H Ferrari
- Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Dasha Cherepanov
- Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Brittany Demers
- Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Vickie Lu
- Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Presley Whidden
- Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | | | - Ruemu E Birhiray
- Hematology Oncology of Indiana/American Oncology Network, Indianapolis, IN
| | | | - Ralph Boccia
- Center for Cancer and Blood Disorders, Bethesda, MD
| | - Robert M Rifkin
- Rocky Mountain Cancer Centers/US Oncology Research, Denver, CO.
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Poh C, Keegan T, Rosenberg AS. Second primary malignancies in multiple myeloma: A review. Blood Rev 2020; 46:100757. [PMID: 32972803 DOI: 10.1016/j.blre.2020.100757] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 07/24/2020] [Accepted: 08/27/2020] [Indexed: 12/16/2022]
Abstract
As survival times of multiple myeloma (MM) patients continue to improve, second primary malignancies (SPM) have become an increasingly relevant long-term risk among MM survivors. Population studies since the 1950s have consistently observed an increased incidence of hematologic SPMs, specifically acute leukemia, among MM survivors. Prolonged treatment with alkylators, especially melphalan, was associated with an increased hematologic SPM risk; likewise, autologous stem cell transplantation appeared to minimally increase SPM risk. Immunomodulatory drugs, specifically lenalidomide, was associated with an increased SPM incidence, although most studies concluded that the benefits of therapy outweighed any risks of SPM. Newer anti-myeloma therapy such as proteasome inhibitors and monoclonal antibodies did not appear to increase SPM risk although robust long-term follow-up is lacking. This review discusses current understanding regarding SPMs among survivors of MM, how different host-, disease- and treatment-related factors contribute to SPM incidence and highlights emerging screening guidelines and prognosis for SPMs.
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Affiliation(s)
- Christina Poh
- University of California, Davis Comprehensive Cancer Center, Sacramento, CA, USA; University of Washington, Department of Medicine, Division of Medical Oncology, Seattle, WA, USA.
| | - Theresa Keegan
- University of California, Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Aaron Seth Rosenberg
- University of California, Davis Comprehensive Cancer Center, Sacramento, CA, USA
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Tundo GR, Sbardella D, Santoro AM, Coletta A, Oddone F, Grasso G, Milardi D, Lacal PM, Marini S, Purrello R, Graziani G, Coletta M. The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges. Pharmacol Ther 2020; 213:107579. [PMID: 32442437 PMCID: PMC7236745 DOI: 10.1016/j.pharmthera.2020.107579] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 05/05/2020] [Indexed: 01/10/2023]
Abstract
Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.
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Affiliation(s)
- G R Tundo
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
| | | | - A M Santoro
- CNR, Institute of Crystallography, Catania, Italy
| | - A Coletta
- Department of Chemistry, University of Aarhus, Aarhus, Denmark
| | - F Oddone
- IRCCS-Fondazione Bietti, Rome, Italy
| | - G Grasso
- Department of Chemical Sciences, University of Catania, Catania, Italy
| | - D Milardi
- CNR, Institute of Crystallography, Catania, Italy
| | - P M Lacal
- Laboratory of Molecular Oncology, IDI-IRCCS, Rome, Italy
| | - S Marini
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - R Purrello
- Department of Chemical Sciences, University of Catania, Catania, Italy
| | - G Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - M Coletta
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
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Zhang PF, Zhang MX, Wu QJ, Li Q. WITHDRAWN: Cost-effectiveness analysis of daratumumab plus bortezomib, melphalan and prednisone for newly diagnosed multiple myeloma ineligible for stem cell transplantation. Leuk Res 2020. [DOI: 10.1016/j.leukres.2020.106444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Fotiou D, Ntanasis-Stathopoulos I, Gavriatopoulou M, Dimopoulos MA. Multiple myeloma: Current and future management in the aging population. Maturitas 2020; 138:8-13. [DOI: 10.1016/j.maturitas.2020.04.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 04/20/2020] [Accepted: 04/24/2020] [Indexed: 12/11/2022]
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Zanwar S, Abeykoon JP, Kapoor P. Challenges and Strategies in the Management of Multiple Myeloma in the Elderly Population. Curr Hematol Malig Rep 2020; 14:70-82. [PMID: 30820879 DOI: 10.1007/s11899-019-00500-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE OF REVIEW Approximately one half of the patient-population in multiple myeloma (MM) is > 70 years at diagnosis. Despite notable strides in the management and improved survival, MM remains incurable, with an increasing proportion of elderly patients comprising the relapsed-refractory cohort. RECENT FINDINGS The arbitrary age cutoff at 65 years to define the elderly patient-population has evolved to a more nuanced categorization, incorporating a comprehensive assessment for determining frailty prior to commencing treatment. This step is critical in determining the therapy-intensity, including transplant-eligibility, to minimize toxicity. Dose-modifications are crucial, as the merits of continuous therapy are becoming evident in this patient-population. Bortezomib, lenalidomide, and dexamethasone (VRd) combination has emerged as standard of care for newly diagnosed MM. Fixed-duration Rd followed by reduced-dosed continuous R may be considered in select frail patients with standard-risk MM. Herein, we review the unique challenges encountered in elderly MM and discuss strategies for optimal management.
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Affiliation(s)
- Saurabh Zanwar
- Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | | | - Prashant Kapoor
- Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Usui Y, Ito H, Koyanagi Y, Shibata A, Matsuda T, Katanoda K, Maeda Y, Matsuo K. Changing trend in mortality rate of multiple myeloma after introduction of novel agents: A population-based study. Int J Cancer 2020; 147:3102-3109. [PMID: 32506433 DOI: 10.1002/ijc.33135] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/28/2020] [Indexed: 11/07/2022]
Abstract
Previously, the main treatment for multiple myeloma (MM) was cytotoxic chemotherapies, including autologous stem-cell transplantation (ASCT), but survival benefit in the elderly was limited. More recently, clinical trials and practical experience with novel agents with superior efficacy have shown improved survival, including in the elderly. However, this improvement cannot be simply interpreted as a decline in mortality rate that is an important public health measure of progress against cancer. Here, we assessed the trends in mortality rates of MM in parallel with incidence rates in Japan and the U.S. We used national mortality data and population-based cancer registry data in both countries from 1995 to 2015, during which 74 972 patients in Japan and 229 290 patients in the U.S. died of MM. Trends in mortality and incidence rates were characterized using joinpoint regression analysis. Despite upward trends in incidence, mortality rates showed a significant decrement after 2005 in Japan, with an annual percent change [APC (95% confidence interval)] of -2.5% (-2.9% to -2.1%), and after 2002 in the U.S., with an APC of -2.0% (-2.6% to -1.5%). In both countries, the change in mortality trend coincided with the introduction of the novel agents. Moreover, improvements in mortality were particularly large in patients aged 70 to 79 years, who cannot receive ASCT. Our results indicate that the benefits of novel agents for MM are appreciable at the population level and may encourage further development of novel agents for malignancies that can be widely applied to the patients.
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Affiliation(s)
- Yoshiaki Usui
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
- Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceuticals Sciences, Okayama, Japan
| | - Hidemi Ito
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
- Division of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuriko Koyanagi
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
| | - Akiko Shibata
- Center for Cancer Registries, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan
| | - Tomohiro Matsuda
- Center for Cancer Registries, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan
| | - Kota Katanoda
- Division of Cancer Statistics Integration, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan
| | - Yoshinobu Maeda
- Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceuticals Sciences, Okayama, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
- Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Schjesvold F. Evolution of diagnostic workup and treatment for multiple myeloma 2013-2019. Eur J Haematol 2020; 105:434-448. [PMID: 32557833 DOI: 10.1111/ejh.13464] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 06/01/2020] [Accepted: 06/03/2020] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To evaluate changes in diagnostic and therapeutic approach in multiple myeloma among Norwegian hematologists in the current decade. METHODS This nationwide study in Norway is based on results of surveys conducted among professionally active hematologists from 2013 to 2019. Every year, respondents participating in the survey suggested treatment regimens used in typical clinical situations in patients with multiple myeloma, as well as diagnostic routines. RESULTS The use of regimens containing alkylators and thalidomide was common at the beginning of the studied period. Later, lenalidomide became the most preferred treatment in most first-line patients. Bortezomib maintained a stable position in the treatment of myeloma in patients with renal insufficiency. The lenalidomide, bortezomib, and dexamethasone combination became the preferred frontline triplet for transplant-ineligible patients and induction therapy before transplant. Nowadays, the relapse after lenalidomide-based treatment is managed using both bortezomib-based therapies and combinations with the newest agents. Together with the therapeutic landscape, the use of diagnostic criteria and workup as well as supportive care changed in the period influenced by local and international guidelines and recommendations. CONCLUSION Norwegian hematologists gradually adopt new clinical concepts, guidelines, and recommendations in their practice.
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Affiliation(s)
- Fredrik Schjesvold
- Oslo Myeloma Center, Oslo University Hospital, Oslo, Norway.,KG Jebsen Center for B cell Malignancies, University of Oslo, Oslo, Norway
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Ishida T, Kimura H, Ozaki S, Kubo K, Sunami K, Takezako N, Fujita H, Hayashi T, Kiguchi T, Ohashi K, Yamamoto S, Takamatsu H, Kosugi H, Ohta K, Sakai R, Handa H, Kondo S, Abe Y, Omoto E, Mitani K, Morita S, Murakami H, Shimizu K. Continuous lenalidomide treatment after bortezomib-melphalan-prednisolone therapy for newly diagnosed multiple myeloma. Ann Hematol 2020; 99:1063-1072. [PMID: 32248251 DOI: 10.1007/s00277-020-03988-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 03/01/2020] [Indexed: 01/24/2023]
Abstract
These are the results of phase II study of bortezomib-melphalan-prednisolone (VMP) induction therapy followed by lenalidomide-dexamethasone (Rd) consolidation and lenalidomide maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rates (ORRs), and safety. Eighty-three eligible patients were enrolled between October 2012 and August 2014. The median PFS was 28.0 months (95% CI 19.6-36.7) and the median OS was 55.3 months (95% CI 51.6-NA). Among the patients who received lenalidomide maintenance therapy, median PFS was significantly improved in patients who had achieved a very good partial response (VGPR) or better (41.8 vs 20.7 months, p = 0.0070). As the best response, the rates of partial response or better were 85.5% comprising stringent complete response (sCR, 21.7%), complete response (CR, 10.8%), VGPR (18.1%), and partial response (PR, 34.9%). The most frequently observed grade 3 or higher adverse events during the VMP therapy were anemia (28.9%), neutropenia (15.6%), thrombocytopenia (6.0%), and peripheral neuropathy (2.4%). The most frequently observed grade 3 or higher adverse events during the Rd therapy were anemia (3.5%), neutropenia (1.8%), and skin rush (5.3%). The most frequently observed grade 3 or higher adverse events during lenalidomide maintenance therapy were anemia (7.4%) and neutropenia (24.1%). Thus, VMP induction therapy followed by Rd consolidation and lenalidomide maintenance is considered a well-tolerated and effective regimen in transplant-ineligible NDMM. This trial is registered with UMIN-CTR with the identification number UMIN000009042.
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Affiliation(s)
- Tadao Ishida
- Department of Hematology, Japanese Red Cross Medical Center, 4-1-22, Hiroo, Shibuya-ku, Tokyo, 150-8935, Japan. .,Sapporo Medical University, Sapporo, Japan.
| | - Hideo Kimura
- Kita-Fukushima Medical Center, Date, Japan, Fukushima, Japan
| | - Shuji Ozaki
- Tokushima Prefectural Central Hospital, Tokushima, Japan
| | - Koumei Kubo
- Aomori Prefectural Central Hospital, Aomori, Japan
| | - Kazutaka Sunami
- National Hospital Organization Okayama Medical Center, Okayama, Japan
| | | | | | - Toshiaki Hayashi
- Sapporo Medical University, Sapporo, Japan.,Teine Keijinkai Hospital, Sapporo, Japan
| | | | - Kazuteru Ohashi
- Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan
| | | | | | | | | | | | - Hiroshi Handa
- Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Seiji Kondo
- Saga-Ken Medical Center Koseikan, Saga, Japan
| | - Yu Abe
- Department of Hematology, Japanese Red Cross Medical Center, 4-1-22, Hiroo, Shibuya-ku, Tokyo, 150-8935, Japan
| | - Eijiro Omoto
- Yamagata Prefectural Central Hospital, Yamagata, Japan
| | - Kinuko Mitani
- Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirokazu Murakami
- Gunma University Graduate School of Health Sciences, Maebashi, Japan
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Oriol A. A critical evaluation of pembrolizumab in addition to lenalidomide and dexamethasone for the treatment of multiple myeloma. Expert Rev Hematol 2020; 13:435-445. [PMID: 32182438 DOI: 10.1080/17474086.2020.1744432] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Several modalities of immunotherapy have proved successful in multiple myeloma, including immunomodulatory agents, monoclonal antibodies directed to plasma cell surface antigens and chimeric antigen receptor T cells. The PD-1 pathway is implicated in the progression of multiple myeloma. Several properties of lenalidomide are potentially synergistic with PD-1/PD-L1 blockade.Areas covered: Preclinical data related to anti-PD-1/PD-L1 antibodies and the results of early clinical trials of pembrolizumab single-agent and in combination with lenalidomide and dexamethasone are discussed. Despite promising preliminary data, the pivotal phase III trial evaluating lenalidomide and dexamethasone in combination with pembrolizumab in patients with newly diagnosed multiple myeloma presented unexpected safety findings and was discontinued. Differences with previous results and the findings of other trials involving pomalidomide as an immunomodulatory agent or nivolumab as anti-PD-1 antibody are discussed.Expert opinion: Disappointing efficacy outcomes of the combination of checkpoint blockade antibodies and immunomodulating agents in multiple myeloma along with toxicity issues make the combination unattractive in comparison with available alternatives. It is essential to critically review preclinical and clinical datha to understand the pitfalls of lenalidomide with pembrolizumab and similar combinations in multiple myeloma to gain insight on the future role of anti-PD-1 agents in emerging therapeutic scenarios.
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Affiliation(s)
- Albert Oriol
- Josep Carreras Leukemia Research Institute, Hematology Service and Hemato-Oncology Clinical Trial Unit, Institut Català d'Oncologia, Barcelona, Spain
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48
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Ramasamy K, Dhanasiri S, Thom H, Buchanan V, Robinson S, D'Souza VK, Weisel K. Relative efficacy of treatment options in transplant-ineligible newly diagnosed multiple myeloma: results from a systematic literature review and network meta-analysis. Leuk Lymphoma 2020; 61:668-679. [PMID: 31709875 DOI: 10.1080/10428194.2019.1683736] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 10/07/2019] [Accepted: 10/13/2019] [Indexed: 01/30/2023]
Abstract
Established treatments for transplant-ineligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) include melphalan and prednisone (MP) combined with either bortezomib (VMP) or thalidomide (MPT), or lenalidomide plus low-dose dexamethasone (Rd). New treatments for TNE NDMM include Rd plus bortezomib (RVd) and daratumumab plus VMP (VMP + D), daratumumab plus lenalidomide and dexamethasone (D + Rd). Relative efficacy of these treatments was compared using a network meta-analysis. Eight trials identified by a systematic literature review were included in the primary analysis; hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were used. Rd was superior to other MP-based regimens for OS and PFS. There was strong evidence that, compared with Rd, both D + Rd and RVd improved PFS (HR 0.57; 95% credible interval (CrI) 0.43, 0.73 and HR 0.72; 95% CrI 0.56, 0.91, respectively). However, there was strong evidence only for RVd in respect to OS (HR 0.72; 95% CrI 0.52, 0.96).
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Affiliation(s)
- Karthik Ramasamy
- National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | | | - Howard Thom
- Bristol Medical School, University of Bristol, Bristol, UK
| | | | | | | | - Katja Weisel
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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49
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Hock BD, Mulholland KS, Ganly P, McKenzie JL, Pearson JF, MacPherson SA. Impact of increased access to novel agents on the survival of multiple myeloma patients treated at a single New Zealand centre. Intern Med J 2020; 49:598-606. [PMID: 30411451 DOI: 10.1111/imj.14155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 10/11/2018] [Accepted: 10/29/2018] [Indexed: 11/28/2022]
Abstract
BACKGROUND The impact of changes in novel agent (NA) usage on the survival of multiple myeloma (MM) patients in real-world hospital settings is unclear. In New Zealand (NZ) in 2011, frontline bortezomib became available and thalidomide availability was expanded. AIM This retrospective study analyses the impact these change had on the survival of MM patients treated at a NZ hospital. METHODS Clinical and overall survival (OS) data were collected on MM patients who were treated at Christchurch Hospital during 2000-2009 (pre-cohort, n = 337) and 2011-2017 (post-cohort, n = 343). Outcomes were compared using pre-cohort data truncated at 2011. RESULTS Patients in the post-cohort had significant increases (P < 0.001) in not only NA usage (85 vs 55%) and OS (median = 56 vs 44 months) but also the proportion (74 vs 49%) of young patients (age < 70) who received an autologous stem cell transplant (ASCT). Separate analysis of older patients demonstrated that those in the post-cohort had significantly longer OS (median OS 28 vs 17, P < 0.001) although 5-year relative survival remained less than 50%. Separate analysis of young patients demonstrated that those in the post-cohort had significantly increased initial OS with the survival curves converging at 5 years. Although ASCT-treated patients had similar OS in each cohort, their progression-free survival (PFS) was significantly increased in the post-cohort (median 40 vs 20 months, P < 0.0001). CONCLUSION In the setting of a NZ hospital the increased availability of NA was associated with a significant improvement in both the OS of older patients and the PFS of ASCT patients.
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Affiliation(s)
- Barry D Hock
- Haematology Research Group, Christchurch Hospital and Department of Pathology and Biomedical Science, Christchurch, New Zealand
| | | | - Peter Ganly
- Haematology Department, Christchurch Hospital, Christchurch, New Zealand
| | - Judith L McKenzie
- Haematology Research Group, Christchurch Hospital and Department of Pathology and Biomedical Science, Christchurch, New Zealand
| | - John F Pearson
- Biostatistics and Computational Biology Unit, Christchurch, New Zealand
| | - Sean A MacPherson
- Haematology Research Group, Christchurch Hospital and Department of Pathology and Biomedical Science, Christchurch, New Zealand.,Haematology Department, Christchurch Hospital, Christchurch, New Zealand
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50
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Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Krevvata M, Chen Y, Wang J, Kudva A, Ukropec J, Wroblewski S, Qi M, Kobos R, San-Miguel J. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet 2020; 395:132-141. [PMID: 31836199 DOI: 10.1016/s0140-6736(19)32956-3] [Citation(s) in RCA: 298] [Impact Index Per Article: 59.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/20/2019] [Accepted: 11/28/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. METHODS ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. FINDINGS 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4-43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46-0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2-82·0) in the D-VMP group and 67·9% (62·6-72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34-0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]). INTERPRETATION D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. FUNDING Janssen Research & Development.
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Affiliation(s)
- Maria-Victoria Mateos
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
| | - Michele Cavo
- Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy
| | - Joan Blade
- Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | | | - Kenshi Suzuki
- Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
| | | | - Stefan Knop
- Würzburg University Medical Center, Würzburg, Germany
| | - Chantal Doyen
- CHU UCL Namur, Université catholique de Louvain, Yvoir, Belgium
| | - Paulo Lucio
- Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Zsolt Nagy
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Ludek Pour
- University Hospital Brno, Brno, Czech Republic
| | - Mark Cook
- University Hospitals Birmingham NHS Trust, Birmingham, UK
| | - Sebastian Grosicki
- Department of Hematology and Cancer Prevention, Chorzów School of Public Health, Medical University of Silesia, Katowice, Poland
| | - Andre Crepaldi
- Clínica de tratamento e pesquisa em Hematologia e Oncologia, Cuiaba, Brazil
| | | | | | | | - Sung-Soo Yoon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | | | | | - Mamta Garg
- Department of Haematology, Leicester Royal Infirmary, Leicester, UK
| | | | - Ying Chen
- Janssen Research & Development, Raritan, NJ, USA
| | | | - Anupa Kudva
- Janssen Research & Development, Raritan, NJ, USA
| | - Jon Ukropec
- Janssen Global Medical Affairs, Horsham, PA, USA
| | | | - Ming Qi
- Janssen Research & Development, Spring House, PA, USA
| | - Rachel Kobos
- Janssen Research & Development, Raritan, NJ, USA
| | - Jesus San-Miguel
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IDISNA), Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Pamplona, Spain
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