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Rajkumar SV. Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol 2024; 99:1802-1824. [PMID: 38943315 PMCID: PMC11404783 DOI: 10.1002/ajh.27422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 06/11/2024] [Indexed: 07/01/2024]
Abstract
DISEASE OVERVIEW Multiple myeloma accounts for approximately 10% of hematologic malignancies. DIAGNOSIS The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L and urine monoclonal protein is ≥200 mg/24 h), or >1 focal lesion on magnetic resonance imaging. RISK STRATIFICATION The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma. RISK-ADAPTED INITIAL THERAPY In patients who are candidates for autologous stem cell transplantation, induction therapy consists of anti-CD38 monoclonal antibody plus bortezomib, lenalidomide, dexamethasone (VRd) followed by autologous stem cell transplantation (ASCT). Selected standard risk patients can delay transplant until first relapse. Frail patients who not candidates for transplant are treated with VRd for approximately 8-12 cycles followed by maintenance or alternatively with daratumumab, lenalidomide, dexamethasone (DRd) until progression. MAINTENANCE THERAPY Standard risk patients need lenalidomide maintenance, while bortezomib plus lenalidomide maintenance is needed for high-risk myeloma. MANAGEMENT OF RELAPSED DISEASE A triplet regimen is usually needed at relapse, with the choice of regimen varying with each successive relapse. Chimeric antigen receptor T (CAR-T) cell therapy and bispecific antibodies are additional options.
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Fonseca R, Rossi A, Medhekar R, Voelker J, Homan T, Wilcock J, Karakusevic A, Cochrane J, Bridge D, Perry R, Kaila S, Davies FE. Clinical consensus on treatments for transplant-ineligible newly diagnosed multiple myeloma: double-blinded Delphi panel. Future Oncol 2024; 20:1645-1656. [PMID: 38861282 PMCID: PMC11485956 DOI: 10.1080/14796694.2024.2342228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 04/09/2024] [Indexed: 06/12/2024] Open
Abstract
Aim: Obtain clinical consensus on factors impacting first-line prescribing for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM).Materials & methods: A double-blinded, modified Delphi panel was employed. USA-based hematologists/oncologists who treat TIE patients with NDMM were selected as expert panelists.Results: Consensus was reached that patient frailty, performance status, comorbidities, treatment efficacy, and adverse event profile affect first-line prescribing. All panelists agreed it is important to use the most efficacious treatment first; 88% of panelists considered daratumumab-containing regimens the most efficacious. Panelists agreed treatment should be continued until progression while benefits outweigh risk.Conclusion: Findings reinforce the importance of using the most efficacious regimen upfront for TIE NDMM, and nearly all panelists considered daratumumab-containing regimens the most efficacious treatment.
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Affiliation(s)
- Rafael Fonseca
- Division of Hematology and Medical Oncology, Mayo Clinic in Arizona, Phoenix, AZ, USA
| | - Adriana Rossi
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | | | | | | | | | | | | | | | - Faith E Davies
- Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
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Chen X, Shukla M, Saint Fleur-Lominy S. Disparity in hematological malignancies: From patients to health care professionals. Blood Rev 2024; 65:101169. [PMID: 38220565 DOI: 10.1016/j.blre.2024.101169] [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: 11/19/2023] [Revised: 01/03/2024] [Accepted: 01/04/2024] [Indexed: 01/16/2024]
Abstract
In the recent few decades, outcomes in patients diagnosed with hematological malignancies have been steadily improving. However, the improved prognosis does not distribute equally among patients from different backgrounds. Besides cancer biology, demographic and geographic disparities have been found to impact overall survival significantly. Specifically, patients from underrepresented minorities including Black and Hispanics, and those with uninsured status, having low socioeconomic status, or from rural areas have had worse outcomes historically, which is uniformly true across all major subtypes of hematological malignancies. Similar discrepancy is also seen in the health care professional field, where a gender gap and a disproportionally low representation of health care providers from underrepresented minorities have been long existing. Thus, a comprehensive strategy to mitigate disparity in the health care system is needed to achieve equity in health care.
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Affiliation(s)
- Xiaoyi Chen
- Department of Medicine, Division of Hematology and Medical Oncology, New York University, Grossman School of Medicine, NY, New York, USA.
| | - Mihir Shukla
- Department of Medicine, Division of Hematology and Medical Oncology, New York University, Grossman School of Medicine, NY, New York, USA.
| | - Shella Saint Fleur-Lominy
- Department of Medicine, Division of Hematology and Medical Oncology, New York University, Grossman School of Medicine, NY, New York, USA; Perlmutter Cancer Center, NYU Langone Health, NY, New York, USA.
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Bar N, Firestone RS, Usmani SZ. Aiming for the cure in myeloma: Putting our best foot forward. Blood Rev 2023; 62:101116. [PMID: 37596172 DOI: 10.1016/j.blre.2023.101116] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 08/20/2023]
Abstract
Frontline therapy for multiple myeloma (MM) is evolving to include novel combinations that can achieve unprecedented deep response rates. Several treatment strategies exist, varying in induction regimen composition, use of transplant and or consolidation and maintenance. In this sea of different treatment permutations, the overarching theme is the powerful prognostic factors of disease risk and achievement of minimal residual disease (MRD) negativity. MM has significant inter-patient variability that requires treatment to be individualized. Risk-adapted and response-adapted strategies which are increasingly being explored to define the extent and duration of therapy, and eventually aim for functional curability. In addition, with T-cell redirection therapies rapidly revolutionizing myeloma treatments, the current standard of care for myeloma will change. This review analyzes the current relevant literature in upfront therapy for fit myeloma patients and provides suggestions for treatment approach while novel clinical trials are maturing.
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Affiliation(s)
- Noffar Bar
- Section of Hematology, Department of Internal Medicine, Yale School of Medicine University, New Haven, CT, USA.
| | - Ross S Firestone
- Multiple Myeloma Service, Department of medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Saad Z Usmani
- Multiple Myeloma Service, Department of medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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5
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Rajkumar SV. Multiple myeloma: 2022 update on diagnosis, risk stratification, and management. Am J Hematol 2022; 97:1086-1107. [PMID: 35560063 PMCID: PMC9387011 DOI: 10.1002/ajh.26590] [Citation(s) in RCA: 407] [Impact Index Per Article: 135.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/05/2022] [Accepted: 05/06/2022] [Indexed: 12/22/2022]
Abstract
DISEASE OVERVIEW Multiple myeloma accounts for approximately 10% of hematologic malignancies. DIAGNOSIS The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥ 100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging. RISK STRATIFICATION The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. The presence of any two high risk factors is considered double-hit myeloma, and three or more high risk factors is triple-hit myeloma. RISK-ADAPTED INITIAL THERAPY In patients who are candidates for autologous stem cell transplantation, induction therapy consists of bortezomib, lenalidomide, dexamethasone (VRd) given for approximately 3-4 cycles followed by autologous stem cell transplantation (ASCT). In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard-risk patients can collect stem cells, get additional cycles of induction therapy, and delay transplant until first relapse. Patients who are not candidates for transplant are treated with VRd for approximately 8-12 cycles followed by maintenance or alternatively with daratumumab, lenalidomide, dexamethasone (DRd) until progression. MAINTENANCE THERAPY Standard-risk patients need lenalidomide maintenance, while bortezomib plus lenalidomide maintenance is needed for high-risk myeloma. MANAGEMENT OF RELAPSED DISEASE A triplet regimen is usually needed at relapse, with the choice of regimen varying with each successive relapse.
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6
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Requirements for operational cure in multiple myeloma. Blood 2021; 138:1406-1411. [PMID: 34324647 DOI: 10.1182/blood.2021012854] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/26/2021] [Indexed: 11/20/2022] Open
Abstract
Multiple myeloma is usually considered as an incurable disease. However, with the therapeutic improvement observed in the last few years, achievement of an "operational" cure is increasingly becoming a realistic goal. The advent of novel agents, with or without high-dose chemotherapy and autologous transplantation, uncovered a correlation between the depth of response to treatment and the outcome. Of note, minimal residual disease (MRD) negativity is increasingly shown to be associated with improved progression-free survival (PFS), and MRD status is becoming a well-established and strong prognostic factor. Here, we discuss the impact of MRD negativity on PFS and long-term disease control, as a surrogate for a potential cure in a significant proportion of patients. The MRD value and impact should be examined by focusing on different parameters: (i) sensitivity or lower limit of detection level (method used); (ii) timing of assessment and sustainability (iii) type and duration of treatment; (iv) initial prognostic factors (most importantly, cytogenetics) and (v) patient age. Currently, the highest probability of an operational cure is in younger patients receiving the most active drugs, in combination with autologous transplantation followed by maintenance therapy. Older patients are also likely to achieve operational cure, especially if they are treated upfront with an anti-CD38 antibody-based therapy, but also with novel immunotherapies in future protocols. The incorporation of MRD as a surrogate endpoint in clinical trials, would allow the shortening of these, leading to more personalised management, and achievement of long-term cure.
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Long-term outcomes after autologous stem cell transplantation for multiple myeloma. Blood Adv 2020; 4:422-431. [PMID: 31990333 DOI: 10.1182/bloodadvances.2019000524] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 11/01/2019] [Indexed: 01/07/2023] Open
Abstract
As multiple myeloma (MM) treatments evolve, frequent updates are required to monitor the long-term effect of changes in approach. Traditionally, MM is considered an incurable disease, with most patients eventually relapsing. However, improvements in treatments has raised the possibility that MM might be functionally curable. To examine improvements in long-term survival, we followed 4329 patients with newly diagnosed MM treated with autologous stem cell transplantation (ASCT) at the University of Arkansas for Medical Sciences from 1989 through 2018. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier analysis, Cox proportional hazards models, relative survival analysis, and cure modeling among different time periods, risk groups, and demographic traits. Steady improvements in OS were found, with patients treated in 2014 or later having superior OS (hazard ratio, 0.35; 95% confidence interval [CI], 0.27-0.45) and reduced excess risk for MM death (relative excess risk, 0.30; 95% CI, 0.22-0.41) compared with patients treated in 1997 or earlier. Patients treated during intervening time periods often had intermediate survival, but trends in OS, PFS, and landmarked analyses were inconsistent. Cure models support the potential for cure, ranging from 6.3% to 31.3%, depending on the year of treatment, with 10.0% to 18.6% of patients achieving their normal life expectancy across multiple periods. There was some evidence of reductions in early mortality within 3 years of diagnosis, longer complete response (CR) duration, and reductions in relapse after achieving CR. However, results differed depending on age, risk group, and cytogenetic characteristics.
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8
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Terpos E, Ntanasis-Stathopoulos I, Roussou M, Kanellias N, Fotiou D, Migkou M, Eleutherakis-Papaiakovou E, Gavriatopoulou M, Kastritis E, Dimopoulos MA. Long PFS of more than 7 years is achieved in 9% of myeloma patients in the era of conventional chemotherapy and of first-generation novel anti-myeloma agents: a single-center experience over 20-year period. Ann Hematol 2020; 99:1257-1264. [DOI: 10.1007/s00277-020-04060-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 04/27/2020] [Indexed: 12/01/2022]
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Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol 2020; 95:548-567. [PMID: 32212178 DOI: 10.1002/ajh.25791] [Citation(s) in RCA: 505] [Impact Index Per Article: 101.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 03/18/2020] [Indexed: 12/11/2022]
Abstract
DISEASE OVERVIEW Multiple myeloma accounts for approximately 10% of hematologic malignancies. DIAGNOSIS The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE) namely CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging (MRI). RISK STRATIFICATION The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma. RISK-ADAPTED INITIAL THERAPY In transplant eligible patients, induction therapy consists of bortezomib, lenalidomide, dexamethasone (VRd) given for approximately 3-4 cycles followed by autologous stem cell transplantation (ASCT). In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard risk patients can get additional cycles of induction, and delay transplant until first relapse. Patients not candidates for transplant are typically treated with VRd for approximately 8-12 cycles followed by lenalidomide; alternatively these patients can be treated with daratumumab, lenalidomide, dexamethasone (DRd). MAINTENANCE THERAPY After ASCT, standard risk patients need lenalidomide maintenance, while bortezomib-based maintenance is needed for patients with high-risk myeloma. MANAGEMENT OF REFRACTORY DISEASE Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse.
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Pacini S, Montali M, Mazziotta F, Schifone CP, Macchia L, Carnicelli V, Panvini FM, Barachini S, Notarfranchi L, Previti GB, Buda G, Petrini M. Mesangiogenic progenitor cells are forced toward the angiogenic fate, in multiple myeloma. Oncotarget 2019; 10:6781-6790. [PMID: 31827721 PMCID: PMC6887577 DOI: 10.18632/oncotarget.27285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 10/04/2019] [Indexed: 11/25/2022] Open
Abstract
Multiple myeloma (MM) progresses mainly in the bone marrow where the involvement of a specific microenvironment plays a critical role in maintaining plasma cell growth, spread, and survival. In active disease, the switch from a pre-vascular/non-active phase to a vascular phase is coupled with the impairment of bone turnover. Previously, we have isolated Mesangiogenic Progenitor Cells (MPCs), a bone marrow population that showed mesengenic and angiogenic potential, both in vitro and in vivo. MPC differentiation into musculoskeletal tissue and their ability of sprouting angiogenesis are mutually exclusive, suggesting a role in the imbalancing of the microenvironment in multiple myeloma. MPCs from 32 bone marrow samples of multiple myeloma and 23 non-hematological patients were compared in terms of frequency, phenotype, mesengenic/angiogenic potential, and gene expression profile. Defective osteogenesis was recorded for MM-derived MPCs that showed longer angiogenic sprouting distances respect to non-hematological MPCs, retaining this capability after mesengenic induction. This altered MPCs differentiation potential was not detected in asymptomatic myelomatous disease. These in vitro experiments are suggestive of a forced angiogenic fate in MPCs isolated from MM patients, which also showed increased sprouting activity. Taking together our results suggest a possible role of these cells in the “angiogenic switch” in the MM micro-environment.
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Affiliation(s)
- Simone Pacini
- Department of Clinical and Experimental Medicine, Hematology Division, University of Pisa, Pisa, Italy
| | - Marina Montali
- Department of Clinical and Experimental Medicine, Hematology Division, University of Pisa, Pisa, Italy
| | | | - Claudia P Schifone
- Department of Clinical and Experimental Medicine, Hematology Division, University of Pisa, Pisa, Italy
| | - Lucia Macchia
- Department of Laboratory Medicine, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Vittoria Carnicelli
- Department of Surgical, Medical, and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Francesca M Panvini
- Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Serena Barachini
- Department of Clinical and Experimental Medicine, Hematology Division, University of Pisa, Pisa, Italy
| | - Laura Notarfranchi
- Department of Medicine and Surgery, Hematology Division, University of Parma, Parma, Italy
| | | | - Gabriele Buda
- Department of Clinical and Experimental Medicine, Hematology Division, University of Pisa, Pisa, Italy
| | - Mario Petrini
- Department of Clinical and Experimental Medicine, Hematology Division, University of Pisa, Pisa, Italy
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11
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Multiple myeloma: 2018 update on diagnosis, risk‐stratification, and management. Am J Hematol 2018; 93:981-1114. [PMID: 30400719 PMCID: PMC6223128 DOI: 10.1002/ajh.25117] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 04/17/2018] [Indexed: 12/22/2022]
Abstract
Disease overview Multiple myeloma accounts for approximately 10% of hematologic malignancies. Diagnosis The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hyperc alcemia, r enal failure, a nemia, or lytic b one lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging. Risk stratification Patients with del(17p), t(14;16), and t(14;20) have high-risk multiple myeloma. Patients with t(4;14) translocation and gain(1q) have intermediate-risk. All others are considered standard-risk. Risk-adapted initial therapy Initial treatment consists of bortezomib, lenalidomide, dexamethasone (VRd). In high-risk patients, carfilzomib, lenalidomide, dexamethasone (KRd) is an alternative to VRd. In eligible patients, initial therapy is given for approximately 3–4 cycles followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT at first relapse. Patients not candidates for transplant are treated with VRd for approximately 8–12 cycles followed by lenalidomide or lenalidomide plus dexamethasone. Maintenance therapy After ASCT, lenalidomide maintenance is recommended for standard risk patients, while maintenance with a bortezomib-based regimen is needed for patients with intermediate or high-risk disease. Management of refractory disease Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse. Aggressive relapse with extramedullary plasmacytomas or plasma cell leukemia may require anthracycline containing combination chemotherapy regimens.
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Moon SH, Choi WH, Yoo IR, Lee SJ, Paeng JC, Jeong SY, Lee SW, Kim K, Choi JY. Prognostic Value of Baseline 18F-Fluorodeoxyglucose PET/CT in Patients with Multiple Myeloma: A Multicenter Cohort Study. Korean J Radiol 2018; 19:481-488. [PMID: 29713226 PMCID: PMC5904475 DOI: 10.3348/kjr.2018.19.3.481] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 10/18/2017] [Indexed: 01/09/2023] Open
Abstract
Objective We investigated the prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with multiple myeloma (MM). Materials and Methods Subjects were 76 patients with newly diagnosed myeloma and pretreatment with 18F-FDG PET/CT from four hospitals. The PET/CT features were evaluated and the clinical characteristics were reviewed. Prognostic factors related to poor progression-free survival (PFS) and overall survival (OS) were identified using a Cox proportional hazards regression model and a prediction scale was developed based on the identified factors. Results Multivariate analysis showed that the presence of 18F-FDG-avid focal bone lesions (≥ 3) was a significant and independent predictor of PFS (hazard ratio [HR] = 3.28, p = 0.007) and OS (HR = 11.78, p = 0.001). The presence of extramedullary disease on PET/CT scan was also a significant predictor of poor PFS (HR = 2.79, p = 0.006) and OS (HR = 3.89, p = 0.003). A prognostic scale was developed using these two predictors. An increase in score on the scale corresponded to a significantly increased risk of poor OS (p = 0.005). In addition, Kaplan-Meier analysis demonstrated that patient survival varied significantly according to the scale (p < 0.001 for OS and p = 0.001 for PFS). Conclusion 18F-FDG-avid focal lesions and the presence of extramedullary disease on PET/CT scan are significantly associated with poor OS in MM patients. The scale developed according to these predictors represents a potential prognostic tool for evaluation of patients with MM.
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Affiliation(s)
- Seung Hwan Moon
- Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Woo Hee Choi
- Department of Radiology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Korea
| | - Ie Ryung Yoo
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Soo Jin Lee
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jin Chul Paeng
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Shin Young Jeong
- Department of Nuclear Medicine, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu 41566, Korea
| | - Sang-Woo Lee
- Department of Nuclear Medicine, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu 41566, Korea
| | - Kihyun Kim
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Joon Young Choi
- Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
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Steinbach M, Richards T, Faiman B. Strategies for Selecting the Optimal Treatment in Newly Diagnosed Multiple Myeloma Patients. Semin Oncol Nurs 2017; 33:254-264. [PMID: 28683956 DOI: 10.1016/j.soncn.2017.05.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
OBJECTIVE To review the current evidence on strategies for selecting the optimal treatment for newly diagnosed patients with multiple myeloma (MM). DATA SOURCES Journal articles, research reports, state of the science papers, and clinical practice guidelines. CONCLUSION Despite the plethora of drugs to effectively treat MM, the optimal induction regimen for patients with newly diagnosed MM is unknown. Rapid control of the disease, appropriate treatment selection and effective supportive care strategies remain integral to prevention and management of the disease. Strategies for selecting the optimal treatment include considering inherent patient characteristics, frailty, and existing clinical practice guidelines. IMPLICATIONS FOR NURSING PRACTICE Nurses should provide patients with disease- and treatment-related education to enhance patient and caregiver understanding of the disease and treatment options, taking into consideration clinical data and overarching goals of treatment.
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Multiple myeloma patients in long-term complete response after autologous stem cell transplantation express a particular immune signature with potential prognostic implication. Bone Marrow Transplant 2017; 52:832-838. [PMID: 28368375 DOI: 10.1038/bmt.2017.29] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 01/10/2017] [Accepted: 01/20/2017] [Indexed: 01/20/2023]
Abstract
The proportion of multiple myeloma patients in long-term complete response (LTCR-MM) for more than 6 years after autologous stem cell transplantation (ASCT) is small. To evaluate whether this LTCR is associated with a particular immune signature, peripheral blood samples from 13 LTCR-MM after ASCT and healthy blood donors (HBD) were analysed. Subpopulations of T-cells (naïve, effector, central memory and regulatory), B-cells (naïve, marginal zone-like, class-switched memory, transitional and plasmablasts) and NK-cells expressing inhibitory and activating receptors were quantified by multiparametric flow cytometry (MFC). Heavy/light chains (HLC) were quantified by nephelometry. The percentage of CD4+ T-cells was lower in patients, whereas an increment in the percentage of CD4+ and CD8+ effector memory T-cells was associated with the LTCR. Regulatory T-cells and NK-cells were similar in both groups but a particular redistribution of inhibitory and activating receptors in NK-cells were found in patients. Regarding B-cells, an increase in naïve cells and a corresponding reduction in marginal zone-like and class-switched memory B-cells was observed. The HLC values were normal. Our results suggest that LTCR-MM patients express a particular immune signature, which probably reflects a 'high quality' immune reconstitution that could exert a competent anti-tumor immunological surveillance along with a recovery of the humoral immunity.
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Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 2016; 91:719-34. [PMID: 27291302 PMCID: PMC5291298 DOI: 10.1002/ajh.24402] [Citation(s) in RCA: 321] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 04/25/2016] [Indexed: 02/07/2023]
Abstract
Multiple myeloma accounts for approximately 10% of hematologic malignancies.The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging. Patients with del(17p), t(14;16), and t(14;20) have high-risk multiple myeloma. Patients with t(4;14) translocation and gain(1q) have intermediate-risk. All others are considered standard-risk. Initial treatment consists of bortezomib, lenalidomide, dexamethasone (VRD). In high-risk patients, carfilzomib, lenalidomide, dexamethasone (KRD) is an alternative to VRD. In eligible patients, initial therapy is given for approximately 3-4 months followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT at first relapse. Patients not candidates for transplant are treated with Rd until progression, or alternatively, a triplet regimen such as VRD for approximately 12-18 months. After ASCT, lenalidomide maintenance is considered for standard risk patients especially in those who are not in very good partial response or better, while maintenance with a bortezomib-based regimen is needed for patients with intermediate or high-risk disease. Patients with indolent relapse can be treated with 2-drug or 3-drug combinations. Patients with more aggressive relapse require a triplet regimen or a combination of multiple active agents. Am. J. Hematol. 91:720-734, 2016. © 2016 Wiley Periodicals, Inc.
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Zhang H, Lv J, Lv C, Zhang H. Presentation of multiple myeloma mimicking bone metastasis from colon adenocarcinoma: A case report and literature review. Mol Clin Oncol 2016; 4:31-34. [PMID: 26870352 PMCID: PMC4727162 DOI: 10.3892/mco.2015.650] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 09/10/2015] [Indexed: 12/22/2022] Open
Abstract
We herein present the case report of a 83-year-old female patient who had undergone right colon resection for adenocarcinoma 2 years earlier, and developed osteolytic lesions of the right femur 6 months ago. A roentgenogram of the right thigh, technetium-99m phosphate bone scintigraphy and combined 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography imaging were performed, and the results revealed multiple osteolytic lesions in the humerus bilaterally, the right scapula and the right femur. The lesions were suspected to be colon cancer metastases. To improve the quality of life of the patient, palliative surgery was performed. However, the intraoperative biopsy of the focal lesions and immunohistochemical evaluation revealed multiple myeloma (MM). Chemotherapy was administered 2 weeks after surgery and the patient recovered uneventfully. The manifestations of MM and bone metastases are occasionally similar. Although the coexistence of the two diseases is rare, both conditions should be considered in the differential diagnosis of osteolytic lesions.
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Affiliation(s)
- Haicheng Zhang
- Department of Surgery, Jinxiang People's Hospital, Jining, Shandong 272200, P.R. China
| | - Jurong Lv
- Department of Surgery, Jinxiang People's Hospital, Jining, Shandong 272200, P.R. China
| | - Chaoliang Lv
- Department of Spine Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Hongmei Zhang
- Department of Spine Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
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Katodritou E, Papadaki S, Konstantinidou P, Terpos E. Is it possible to cure myeloma without allogeneic transplantation? Transfus Apher Sci 2016; 54:63-70. [PMID: 26850930 DOI: 10.1016/j.transci.2016.01.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
During the last decades, a better understanding of the biology of multiple myeloma (MM) has led to the application of novel treatment strategies for MM patients. The new anti-myeloma regimens produce higher incidence of durable and of better quality responses and they improve overall survival, challenging the dogma of incurable disease, outside the context of allogeneic transplantation. This review presents all these strategies that aim to cure MM, including continuous treatment i.e. induction, consolidation and maintenance, treatment of asymptomatic MM and monitoring minimal residual disease using modern techniques, such as multi-parameter flow cytometry, molecular assays and advanced imaging.
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Affiliation(s)
- Eirini Katodritou
- Department of Hematology, Theagenion Cancer Hospital, Thessaloniki, Greece; Greek Myeloma Study Group, Athens, Greece
| | - Sofia Papadaki
- Department of Hematology, Theagenion Cancer Hospital, Thessaloniki, Greece
| | | | - Evangelos Terpos
- Greek Myeloma Study Group, Athens, Greece; Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
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Cartier S, Zhang B, Rosen VM, Zarotsky V, Bartlett JB, Mukhopadhyay P, Wagner S, Davis C. Relationship between Treatment Effects on Progression-Free Survival and Overall Survival in Multiple Myeloma: A Systematic Review and Meta-Analysis of Published Clinical Trial Data. Oncol Res Treat 2015; 38:88-94. [DOI: 10.1159/000375392] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 01/12/2015] [Indexed: 11/19/2022]
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Mikhael JR. A practical approach to relapsed multiple myeloma. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2014; 2014:262-267. [PMID: 25696865 DOI: 10.1182/asheducation-2014.1.262] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
There has been tremendous progress made in multiple myeloma in the last decade, resulting in improved overall survival for all patients, including those with high-risk disease and those ineligible for transplantation. However, despite the addition of several novel agents, unprecedented response rates, and our ability to achieve complete remission in the majority of patients, the disease remains incurable in nearly all and will require repeated therapies. With many options available to the clinician, there is no simple or ideal sequence of treatments that has been established, so the choice of relapsed therapy is based on a series of factors that include response and tolerability of prior therapies, risk status, available novel agents, aggressiveness of relapse, renal function, performance status, cost, etc. This chapter provides practical guidance in selecting relapsed therapies structured through a series of 5 questions that can inform the decision. Specific emphasis is placed on the 2 most recent novel agents, carfilzomib and pomalidomide, but agents in development are also included.
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Faiman B. Myeloma Genetics and Genomics: Practice Implications and Future Directions. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2014; 14:436-40. [DOI: 10.1016/j.clml.2014.07.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 07/08/2014] [Indexed: 02/02/2023]
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Identifying Professional Education Gaps and Barriers in Multiple Myeloma Patient Care: Findings of the Managing Myeloma Continuing Educational Initiative Advisory Committee. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2014; 14:356-69. [DOI: 10.1016/j.clml.2014.04.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Revised: 03/26/2014] [Accepted: 04/03/2014] [Indexed: 12/31/2022]
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Rajkumar SV. Multiple myeloma: 2014 Update on diagnosis, risk-stratification, and management. Am J Hematol 2014; 89:999-1009. [PMID: 25223428 DOI: 10.1002/ajh.23810] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 07/16/2014] [Indexed: 12/21/2022]
Abstract
DISEASE OVERVIEW Multiple myeloma accounts for approximately 10% of hematologic malignancies. DIAGNOSIS The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end-organ damage. If end-organ damage is not present, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma. RISK STRATIFICATION In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high-risk myeloma. Patients with t(4;14) translocation are considered intermediate-risk. All others are considered as standard-risk. Risk-adapted initial therapy: Standard-risk patients can be treated with lenalidomide plus low-dose dexamethasone (Rd), or a bortezomib-containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate-risk and high-risk patients require a bortezomib-based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients who are not candidates for transplant, initial therapy is given for approximately 12 to 18 months. Maintenance therapy: After initial therapy, lenalidomide maintenance is considered for standard risk patients who are not in very good partial response or better, while maintenance with a bortezomib-based regimen should be considered in patients with intermediate or high risk myeloma. Management of refractory disease: Patients with indolent relapse can be treated first with 2-drug or 3-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents.
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Abstract
"The daintiest last, to make the end most sweet," comes to us from Shakespeare’s Richard II, but in the most recent edition of Blood, the paper from Martinez-Lopez et al suggests that by using minimal residual disease (MRD) testing by sequencing, we may be nearing the "end most sweet" or, in 21st century vernacular, the cure of myeloma.
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Swetz KM, Burkle CM, Berge KH, Lanier WL. Ten common questions (and their answers) on medical futility. Mayo Clin Proc 2014; 89:943-59. [PMID: 24726213 DOI: 10.1016/j.mayocp.2014.02.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 02/07/2014] [Accepted: 02/12/2014] [Indexed: 12/25/2022]
Abstract
The term medical futility is frequently used when discussing complex clinical scenarios and throughout the medical, legal, and ethics literature. However, we propose that health care professionals and others often use this term inaccurately and imprecisely, without fully appreciating the powerful, often visceral, response that the term can evoke. This article introduces and answers 10 common questions regarding medical futility in an effort to define, clarify, and explore the implications of the term. We discuss multiple domains related to futility, including the biological, ethical, legal, societal, and financial considerations that have a bearing on definitions and actions. Finally, we encourage empathetic communication among clinicians, patients, and families and emphasize how dialogue that seeks an understanding of multiple points of view is critically important in preventing or attenuating conflict among the involved parties.
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Affiliation(s)
- Keith M Swetz
- Department of Medicine, Section of Palliative Medicine and Biomedical Ethics Program, Mayo Clinic, Rochester, MN.
| | | | - Keith H Berge
- Department of Anesthesiology, Mayo Clinic, Rochester, MN
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Ria R, Reale A, Vacca A. Novel agents and new therapeutic approaches for treatment of multiple myeloma. World J Methodol 2014; 4:73-90. [PMID: 25332907 PMCID: PMC4202483 DOI: 10.5662/wjm.v4.i2.73] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Revised: 01/28/2014] [Accepted: 04/17/2014] [Indexed: 02/06/2023] Open
Abstract
This review summarizes the therapeutic strategies and the drugs actually in development for the management of myeloma patients. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein (immunoglobulins, Bence Jones protein and free light chains). Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly, despite the introduction of several new therapeutic agents (bortezomib, lenalidomide and thalidomide) which have changed its natural history. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. Thus, the choice of the best treatment is a difficult issue. However, the introduction of new drugs has made it possible to achieve high response rates and good quality responses with long-term disease control. Interactions between tumor cells and their bone marrow microenvironment play a pivotal role in the development, maintenance, and progression of myeloma, inducing also drug resistance. These knowledges have improved treatment options, leading to the approval of new drugs which not only target the malignant cell itself, but also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control, but their use is still not approved outside of clinical trials.
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26
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Jurczyszyn A, Zebzda A, Czepiel J, Perucki W, Bazan-Socha S, Cibor D, Owczarek D, Majka M. Geldanamycin and Its Derivatives Inhibit the Growth of Myeloma Cells and Reduce the Expression of the MET Receptor. J Cancer 2014; 5:480-90. [PMID: 24959301 PMCID: PMC4066360 DOI: 10.7150/jca.8731] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 03/19/2014] [Indexed: 11/05/2022] Open
Abstract
Introduction. Geldanamycin (GA) is an ansamycin antibiotic that exhibits potent anti-neoplastic properties. The aim of this study was to assess the impact of GA and its derivatives on the growth and invasiveness of myeloma cell lines and CD138+ cells derived from the bone marrow of patients with multiple myeloma. Materials and methods. We evaluated cell proliferation, survival, apoptosis, cell cycle of myeloma cells, and the expression of cell surface proteins after incubation with geldanamycin or its derivatives. Results. GA and its analogs have an effect on myeloma cells by inhibiting their growth in a time and dose-dependent manner. Myeloma cell lines demonstrated decreased proliferation after incubation with 10 nM of GA or 100 nM GA analogs. The first significant effects of GA on U266 cells was observed after 24 hours. After 24 hours, U266 cells incubated with 100 nM GA were in both early and late stages of apoptosis; 17AEP and 17DMAG caused apoptosis of similar intensity to GA. It has been observed that GA and its derivatives cause caspase-3 activation. Analysis of the activity of AKT and MAP 42/44 kinases was performed by incubating U266 cells for 24 and 48 hours in100 nM of GA and its derivatives. After 24 hours incubation, no significant changes in protein expression were observed, while after 48 hours, the strongest changes were seen in AKT protein expression after incubation with GA and 17AEP-GA. In studies of the cell cycle, it was found that 100 nM 17AEP-GA and 17-DMAP-GA cause cell cycle abnormalities. We observed a nearly two-fold increase in U266 cells in the G1 phase and a simultaneous decrease in the percentage of cells in the G2/M phase, indicating that cells were halted in the G1 phase. In the case of the INA6 cells, proliferation was halted in both the G1 and G2/M phases. Conclusions. GA and the analogues that we tested can inhibit myeloma cell growth by induction of apoptosis and blockage of cell cycle progression, and have an effect on the down-regulation of the MET receptor. The GA derivatives tested, despite their modifications still retain strong anticancer properties. Specifically, two analogues of GA, 17AEP-GA and 17DMAG due to their properties can be more effective and safer chemotherapeutic agents than 17AAG, which is currently used and described in literature.
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Affiliation(s)
- Artur Jurczyszyn
- 1. Department of Hematology, Jagiellonian University Medical College, Krakow, Poland
| | - Anna Zebzda
- 2. Department of Transplantology, Jagiellonian University Medical College, Krakow, Poland
| | - Jacek Czepiel
- 3. Department of Gastroenterology, Hepatology and Infectious Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - William Perucki
- 4. Students' Scientific Society, Jagiellonian University Medical College, Krakow, Poland
| | - Stanisława Bazan-Socha
- 5. Second Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Dorota Cibor
- 3. Department of Gastroenterology, Hepatology and Infectious Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Danuta Owczarek
- 3. Department of Gastroenterology, Hepatology and Infectious Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Marcin Majka
- 2. Department of Transplantology, Jagiellonian University Medical College, Krakow, Poland
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Park S, Lee SJ, Chang WJ, Maeng CH, Hong JY, Choi MK, Kim YS, Jung CW, Jang JH, Kim SJ, Kim WS, Choi JY, Kim K. Positive correlation between baseline PET or PET/CT findings and clinical parameters in multiple myeloma patients. Acta Haematol 2013; 131:193-9. [PMID: 24296366 DOI: 10.1159/000354839] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 07/07/2013] [Indexed: 11/19/2022]
Abstract
Recently, positron emission tomography (PET) has been incorporated into a series of prospective studies as a predictor of outcomes in multiple myeloma (MM), and the number of (18)F-fluorodeoxuglucose (FDG)-avid focal lesions (FLs) and the intensity of tumor metabolism have been designated as important surrogate markers for predicting prognosis. Here, we compared initial clinical characteristics of MM patients with baseline PET parameters: the number of FLs and the maximum standardized uptake value (SUVmax). A total of 59 patients diagnosed with MM between August 2004 and February 2012 were reviewed. At diagnosis, 23 patients (40.0%) had ≤3 FLs, 11 patients (18.6%) 4-9 FLs, and 25 patients (42.4%) ≥10 FLs. The median SUVmax was 5.3 (range 0-24.3), and 40 patients (67.8%) showed a SUVmax >4. No clinical characteristics were significantly different between groups with a SUVmax ≤4 and a SUVmax >4. However, there were significant differences in several clinical indices between the FLs ≤3 and FLs >3 groups; elevated β2-microglobulin, elevated lactate dehydrogenase, anemia and more advanced disease by the Durie-Salmon stage corresponded to FLs >3 at baseline PET. Adverse baseline PET findings are positively correlated with prognostically relevant clinical parameters. Regarding PET parameters, FLs are more likely to be well correlated with disease aggressiveness and pathophysiology compared to SUVmax.
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Affiliation(s)
- Silvia Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Kapoor P, Kumar SK, Dispenzieri A, Lacy MQ, Buadi F, Dingli D, Russell SJ, Hayman SR, Witzig TE, Lust JA, Leung N, Lin Y, Zeldenrust SR, McCurdy A, Greipp PR, Kyle RA, Rajkumar SV, Gertz MA. Importance of achieving stringent complete response after autologous stem-cell transplantation in multiple myeloma. J Clin Oncol 2013; 31:4529-35. [PMID: 24248686 DOI: 10.1200/jco.2013.49.0086] [Citation(s) in RCA: 132] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE To study the impact of achieving stringent complete response (sCR), an increasingly attainable goal, after autologous stem-cell transplantation (ASCT) in patients with multiple myeloma (MM). PATIENTS AND METHODS Maximal response rates were determined in 445 consecutive patients who underwent ASCT within 12 months of diagnosis of MM. The patients achieving varying degrees of complete response (CR) are the focus of our study. RESULTS One hundred and nine patients (25%) achieved sCR after ASCT. The median overall survival (OS) rate from the time of transplantation for patients attaining sCR was not reached (NR), in contrast to those patients achieving conventional complete response (CR; n = 37; OS, 81 months) or near CR (nCR; n = 91; OS, 60 months; P < .001). Five-year OS rates were 80%, 53%, and 47% for sCR, CR, and nCR, respectively. The median time to progression (TTP) from ASCT of patients achieving sCR was significantly longer (50 months) than TTP of patients achieving CR or nCR (20 months and 19 months, respectively). On multivariable analysis, post-ASCT response of sCR was an independent prognostic factor for survival (hazard ratio, 0.44; 95% CI, 0.25 to 0.80; versus CR; P = .008), in addition to proliferation rate, pre-ASCT cytogenetics, and performance status. OS rates of patients attaining sCR continued to remain superior at 2-year landmark (median, NR v 70 months for conventional CR group; P = .007). CONCLUSION Improved long-term outcome is seen after ASCT with achievement of sCR when compared with lesser degrees of responses. Myeloma trials reporting the response rates should identify patients achieving sCR and CR separately, owing to markedly disparate outcomes of the two categories.
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The impact of upfront versus sequential use of bortezomib among patients with newly diagnosed multiple myeloma (MM): a joint analysis of the Singapore MM Study Group and the Korean MM Working Party for the Asian myeloma network. Leuk Res 2013; 37:1070-6. [PMID: 23816344 DOI: 10.1016/j.leukres.2013.06.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 05/29/2013] [Accepted: 06/05/2013] [Indexed: 11/22/2022]
Abstract
From the comprehensive MM registries of the Singapore (SG) and South Korea (SK) MM study groups, we study the survival data of 432 unselected and previously untreated MM patients diagnosed from 2006 to 2009. Although novel agents were introduced to both countries which have compatible healthcare standards at the same time, MM patients with high-risk features in SG could receive frontline bortezomib while bortezomib could only be approved for salvage setting in SK. After a median follow-up of 19 months, despite 26% of patients in SG versus none in SK having received frontline bortezomib, the overall bortezomib-exposure rate was higher in SK (60% versus 47%, p<0.001). Significantly more patients had no response to induction in SK. Although the median overall survival (OS) of patients in SG and SK was not significantly different (not reached versus 4.83 years respectively, p=0.2), corresponding 2-year OS for high-risk ISS patients treated in SG and SK was 81% and 67% respectively (p=0.01). On multivariate analysis stratified by country, the attainment of ≥ VGPR was the only significant prognostic factor in SG while the presence of high-risk ISS has significant early prognostic impact in SK. Frontline use of bortezomib compared to its sequential may avert early mortality especially among patients with high-risk MM.
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Srivastava G, Rana V, Lacy MQ, Buadi FK, Hayman SR, Dispenzieri A, Gertz MA, Dingli D, Zeldenrust S, Russell S, McCurdy A, Kapoor P, Kyle R, Rajkumar SV, Kumar S. Long-term outcome with lenalidomide and dexamethasone therapy for newly diagnosed multiple myeloma. Leukemia 2013; 27:2062-6. [PMID: 23648667 DOI: 10.1038/leu.2013.143] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 05/01/2013] [Indexed: 01/25/2023]
Abstract
The combination of lenalidomide and dexamethasone (Len-Dex) is a commonly used initial therapy for newly diagnosed multiple myeloma (MM). Although the initial response rates and toxicity are well known, long-term outcome is not well described. We studied 286 consecutive patients with newly diagnosed MM initially treated with Len-Dex. The median (range) age at diagnosis was 63 (28-92) years, 166 (58%) patients ≤ 65 years and 175 (61%) male. The median estimated duration on Len-Dex was 5.3 months with overall response (≥ partial response) of 72%, including 26% with very good partial response or better. The median overall survival (OS) from the diagnosis was not reached (NR) and the estimated 5-year survival was 71%. The median time to first disease progression, irrespective of transplant status, was 30.2 months. Overall, 143 (50%) patients underwent stem cell transplant. The median OS was NR for patients ≤ 70 years and 5.8 years for the older patients (P=0.01). The 5-year OS estimate for patients in International Staging System stage 1, 2 and 3 were 82, 65, and 44% respectively. There were 21 new second malignancies after MM diagnosis (6.6%). The median survival exceeding 7 years reflects the efficacy of novel agents. The risk of second malignancies doesn't appear to be excessive in this population.
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Affiliation(s)
- G Srivastava
- Division of Hematology and Blood and Marrow Transplant, Department of Medicine, Mayo Clinic, Rochester, MN, USA
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Félix J, Aragão F, Almeida JM, Calado FJ, Ferreira D, Parreira ABS, Rodrigues R, Rijo JFR. Time-dependent endpoints as predictors of overall survival in multiple myeloma. BMC Cancer 2013; 13:122. [PMID: 23497363 PMCID: PMC3607860 DOI: 10.1186/1471-2407-13-122] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 03/07/2013] [Indexed: 02/01/2023] Open
Abstract
Background Supporting health care sector decisions using time-dependent endpoints (TDEs) such as time to progression (TTP), progression-free survival (PFS), and event-free survival (EFS) remains controversial. This study estimated the quantitative relationship between median TDE and median overall survival (OS) in multiple myeloma (MM) patients. Methods Studies (excluding allogeneic transplantation) published from 1970 to 2011 were systematically searched (PubMed). The nonparametric Spearman’s rank correlation coefficient measured the association between median TDE and OS. The quantitative relationship between TDEs and OS was estimated with a two-step approach to a simultaneous Tobit model. Results We identified 153 studies: 230 treatment arms, 22,696 patients and mean study duration of 3.8 years. Mean of median TDEs was 22.5 months and median OS was 39.1 months. Correlation coefficients of median TTP, PFS, and EFS with median OS were 0.51 (P = 0.003), 0.75 (P < 0.0001), and 0.84 (P < 0.0001), respectively. We estimate a 2.5 month (95% confidence interval, 1.7–3.2) increase in median OS for each additional month reported for median TDEs. There was no evidence that this relationship differed by type of surrogate. Conclusion TDEs predict OS in MM patients; this relationship may be valuable in clinical trial design, drug comparisons, and economic evaluation.
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Affiliation(s)
- Jorge Félix
- Exigo Consultores, Av. Humberto Delgado 33, Alhos Vedros 2860-021, Portugal.
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Rajkumar SV. Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol 2013; 88:226-35. [PMID: 23440663 DOI: 10.1002/ajh.23390] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 01/08/2013] [Indexed: 12/22/2022]
Abstract
DISEASE OVERVIEW Multiple myeloma accounts for approximately 10% of hematologic malignancies. DIAGNOSIS The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end-organ damage. In addition, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma regardless of the presence or absence of end-organ damage. RISK STRATIFICATION In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high-risk myeloma. Patients with t(4;14) translocation are considered intermediate-risk. All others are considered as standard-risk. RISK-ADAPTED INITIAL THERAPY: Standard-risk patients can be treated with lenalidomide plus low-dose dexamethasone (Rd), or a bortezomib-containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate-risk and high-risk patients require a bortezomib-based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard-risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients are not candidates for transplant, initial therapy is given for approximately 12-18 months. MAINTENANCE THERAPY After initial therapy, lenalidomide maintenance is considered for standard-risk patients who are not in very good partial response or better, while maintenance with a bortezomib-based regimen should be considered in pateints with intermediate or high-risk myeloma. MANAGEMENT OF REFRACTORY DISEASE Patients with indolent relapse can be treated first with two-drug or three-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents.
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Affiliation(s)
- S. Vincent Rajkumar
- Division of Hematology; Mayo Clinic College of Medicine; Rochester; Minnesota
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Abstract
Multiple myeloma is a rare, largely incurable malignant disease of plasma cells. Patients usually present with hypercalcemia, renal insufficiency, anemia and/or lytic bony lesions along with a monoclonal protein in the serum and/or urine in addition to an increase in the number of clonal plasma cells in the bone marrow. Patients with myeloma live on an average for five to seven years, with their survival dependent on the presence or absence of different prognostic markers. Treatment of younger fit patients is with induction therapy consisting of steroids with one or more novel anti-myeloma agents followed by high dose melphalan and autologous stem cell transplantation, while older and less fit patients are treated with melphalan-based combination chemotherapy. Supportive care is of paramount importance and includes the use of bisphosphonates, prophylactic antibiotics, thrombosis prophylaxis and the use of hematopoietic growth factors along with the treatment of complications of disease and its therapy. As more progress is being made and deeper responses are being attained, the disease might turn into a potentially curable one in the near future.
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Affiliation(s)
- Khalil Al-Farsi
- Department of Hematology, Sultan Qaboos University Hospital PO Box 38, Al-Khodh, PC 320, Sultanate of Oman
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Palumbo A, Niesvizky R. Sustained disease control in transplant-ineligible patients: the role of continuous therapy. Leuk Res 2013. [PMID: 23176720 DOI: 10.1016/s0145-2126(12)70005-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Many patients with multiple myeloma (MM) are elderly (aged >65 years) or unfit, and therefore ineligible for stem-cell transplantation. The novel agents thalidomide, bortezomib, and lenalidomide have shown improved outcomes in these patients. This article discusses the role of continuous therapy in improving patient outcomes and how novel agents with better tolerability profiles could lead to a change in the treatment paradigm. According to the proposed concept, treatment of transplant-ineligible patients with MM should include achievement of high-quality responses with effective induction combination regimens, as well as maintenance of the response with long-term therapy for optimal sustained efficacy.
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Affiliation(s)
- Antonio Palumbo
- Myeloma Unit, Division of Hematology, University of Turin, Azienda Ospedaliero-Universitaria, San Giovanni Battista di Torino, Turin, Italy.
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Abstract
Abstract
The treatment of multiple myeloma is evolving rapidly. A plethora of doublet, triplet, and quadruplet combinations have been studied for the treatment of newly diagnosed myeloma. Although randomized trials have been conducted comparing older regimens such as melphalan-prednisone with newer regimens containing drugs such as thalidomide, lenalidomide, or bortezomib, there are few if any randomized trials that have compared modern combinations with each other. Even in the few trials that have done so, definitive overall survival or patient-reported quality-of-life differences have not been demonstrated. Therefore, there is marked heterogeneity in how newly diagnosed patients with myeloma are treated around the world. The choice of initial therapy is often dictated by availability of drugs, age and comorbidities of the patient, and assessment of prognosis and disease aggressiveness. This chapter reviews the current data on the most commonly used and tested doublet, triplet, and quadruplet combinations for the treatment of newly diagnosed myeloma and provides guidance on choosing the optimal initial treatment regimen.
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Bergantim R, Trigo F, Guimarães JE. Impact of tandem autologous stem cell transplantation and response to transplant in the outcome of multiple myeloma. Exp Hematol Oncol 2012; 1:35. [PMID: 23210890 PMCID: PMC3547750 DOI: 10.1186/2162-3619-1-35] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Accepted: 11/21/2012] [Indexed: 12/22/2022] Open
Abstract
Background Multiple Myeloma (MM) is the commonest indication for autologous stem cell transplantation (ASCT). Methods We retrospectively analysed data from 85 patients with MM submitted to ASCT in our centre from 2000 to 2010: 132 ASCT were realized, 80 of them as tandem. Results After induction, 17.6% were in complete remission (CR), 41.2% in very good partial remission (VGPR) and 41.2% in partial remission (PR). After transplant 44.7% were in CR, 15.3% in VGPR and 40% in PR. With 22 months (range – 3 to 117 months) of median follow-up, median overall survival (OS) was 43 months and progression-free survival (PFS) 22 months. At 5 years, OS was 45.3% (36.7-53.9%, 95%) and PFS 24.5% (18-31%, 95%). Patients with CR after ASCT had significantly longer PFS as compared to patients with PR (27 vs 7 months; p = 0.034) but not when compared to patients with VGPR (27 vs 19 months, p = 0.485). The tandem approach represented an advantage in OS and PFS when compared to only one ASCT (31 vs 19 months - p = 0.018, and 40 vs 31 - p = 0.04, respectively). Conclusions Our results highlight the impact of response to transplant in patients PFS and tandem modality showed to carry better PFS and OS then the single transplant.
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Affiliation(s)
- Rui Bergantim
- Service of Clinical Hematology, Hospital São João, Porto, Portugal.
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Naumann-Winter F, Greb A, Borchmann P, Bohlius J, Engert A, Schnell R. First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies. Cochrane Database Syst Rev 2012; 10:CD004626. [PMID: 23076906 PMCID: PMC11495656 DOI: 10.1002/14651858.cd004626.pub3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Several clinical studies have compared single with tandem (also called double) autologous stem cell transplantation (ASCT) as first-line treatment in patients with symptomatic multiple myeloma (MM), one of the leading indications for ASCT worldwide. OBJECTIVES The present Cochrane Review compares tandem autologous stem cell transplantation (TASCT) with single autologous stem cell transplantation (SASCT) as first-line treatment in patients with symptomatic MM with respect to overall survival (OS), event-free survival (EFS), quality of life (QoL) and treatment- or transplantation-related mortality. SEARCH METHODS We systematically identified controlled trials published between January 1995 and May 2011 in two bibliographic databases (MEDLINE and CENTRAL) and in clinical trial registries. SELECTION CRITERIA One researcher screened references for controlled trials to determine eligibility for the systematic review (SR) according to pre-specified inclusion and exclusion criteria, reflecting characteristics of disease and the interventions. We required a minimal set of details to be reported for observational studies for the studies to be included. DATA COLLECTION AND ANALYSIS We critically evaluated eligible trials with respect to quality of design and actual performance. One researcher extracted individual trial results, which were checked by another researcher. We recapitulated the results of the individual trials in a standardised way for the SR in order to allow a systematic assessment of potential sources of bias. MAIN RESULTS Overall, we identified 14 controlled studies. One registered randomised controlled trial (RCT) is still recruiting patients at the time of this review and no clinical results have been published. Two registered RCTs have remained unpublished despite their termination. Publications on one RCT had been retracted. We excluded five observational studies since neither patients nor treatment regimens were sufficiently characterised to allow an assessment of potential confounding by indication. We conducted a SR of study designs, definition of endpoints, treatment regimens and baseline characteristics of patients in the five included RCTs (two full-text publications, three conference presentations) enrolling1506 patients in total. Because we identified substantial clinical and methodological heterogeneity, we refrained from conducting a formal meta-analysis.While we included only previously untreated, symptomatic patients with MM the treatment regimens differed notably with respect to acute toxicity, between trials and also between study arms. Compared to state of the art treatment standards, the treatment regimens applied in all trials have to be considered as below standard from a contemporary perspective in at least one component.Three trials were likely to have the potential of being highly biased while two RCTs had a moderate potential for bias. The observed treatment effects in the set of included trials may have been influenced by a steep decrease in compliance with the second ASCT and the concomitant selection of patients. In addition, OS data were confounded by the treatment subsequent to first-line therapy.OS was statistically significantly improved in one trial only. While EFS was prolonged in four of the five trials, the median prolongation ranged between three to 12 months, with an uncertain direction of bias in the individual trials. QoL was not reported in any study. Results concerning treatment- or transplantation-related mortality could not be adequately assessed due to substantial differences in definitions between trials and low reporting quality. AUTHORS' CONCLUSIONS We did not consider any study to be sufficiently informative for contemporary treatment decisions concerning the question single versus tandem ASCT in view of inherent biases. In addition, none of the trials integrated the so-called "novel agents" which are now considered standard treatment for MM. To improve the quality of future studies, sample size calculations should consider the potentially steep decrease in compliance with the second ASCT. Reporting of results of treatment- or transplantation-related mortality should clearly specify the type and number of events (the numerator) in a well-defined population (the denominator).
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Curability of multiple myeloma. BONE MARROW RESEARCH 2012; 2012:916479. [PMID: 22675638 PMCID: PMC3366198 DOI: 10.1155/2012/916479] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2011] [Accepted: 02/23/2012] [Indexed: 11/18/2022]
Abstract
Among 792 patients with multiple myeloma treated from 1987 to 2010 and assessed after 18 months, there were 167 patients with complete remission. For those 60 patients treated between 1987–1998 and with long followup, the latest relapse occurred after 11.8 years, so that 13 patients have remained in sustained complete remission for longer than 12 years (range 12–22 years). These results suggest that 3% of all patients treated during that period may be cured of multiple myeloma. In addition to immunofixation, more sensitive techniques for the detection of residual disease should be applied more consistently in patients with apparent complete remission in order to identify those with potential cure.
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Bilotti E, Faiman BM, Richards TA, Tariman JD, Miceli TS, Rome SI. Survivorship care guidelines for patients living with multiple myeloma: consensus statements of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs 2012; 15 Suppl:5-8. [PMID: 21816706 DOI: 10.1188/11.s1.cjon.5-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Novel therapies approved over the past decade for the management of multiple myeloma have contributed to improved overall survival in patients with newly diagnosed and relapsed disease. Nurses play a key role in educating, advocating for, and supporting patients throughout the continuum of care. Identifying potential and actual comorbid conditions associated directly with multiple myeloma and its treatment is important, as is confirming those that are patient specific so that prompt intervention can take place; therefore, the International Myeloma Foundation Nurse Leadership Board identified the most significant needs of patients diagnosed with multiple myeloma as bone health, health maintenance, mobility and safety, sexual dysfunction, and renal health. The Nurse Leadership Board then developed a survivorship care plan to assist healthcare providers and patients with multiple myeloma, their partners, and their caregivers to identify these needs.
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Affiliation(s)
- Elizabeth Bilotti
- Multiple Myeloma Division of John Theurer Cancer Center, Hackensack University Medical Center, New Jersey, USA.
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Abstract
DISEASE OVERVIEW Multiple myeloma accounts for ∼10% of all hematologic malignancies. DIAGNOSIS The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of end-organ damage felt to be related to the underlying plasma-cell disorder. RISK STRATIFICATION Patients with 17p deletion, t(14;16), t(14;20), or high-risk gene expression profiling signature have high-risk myeloma. Patients with t(4;14) translocation, karyotypic deletion 13, or hypodiploidy are considered to have intermediate-risk disease. All others are considered to have standard-risk myeloma. RISK-ADAPTED THERAPY Standard-risk patients are treated with nonalkylator-based therapy such as lenalidomide plus low-dose dexamethasone (Rd) followed by autologous stem-cell transplantation (ASCT). An alternative strategy is to continue initial therapy after stem-cell collection, reserving ASCT for first relapse. Intermediate-risk and high-risk patients are treated with a bortezomib-based induction followed by ASCT and then bortezomib-based maintenance. Patients not eligible for ASCT can be treated with Rd for standard risk disease, or with a bortezomib-based regimen if intermediate-risk or high-risk features are present. To reduce toxicity, when using bortezomib, the once-weekly subcutaneous dose is preferred; similarly, when using dexamethasone, the low-dose approach (40 mg once a week) is preferred, unless there is a need for rapid disease control. MANAGEMENT OF REFRACTORY DISEASE Patients with indolent relapse can be treated first with two-drug or three-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. The most promising new agents in development are pomalidomide and carfilizomib.
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Yao H, Ashihara E, Strovel JW, Nakagawa Y, Kuroda J, Nagao R, Tanaka R, Yokota A, Takeuchi M, Hayashi Y, Shimazaki C, Taniwaki M, Strand K, Padia J, Hirai H, Kimura S, Maekawa T. AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model. Blood Cancer J 2011; 1:e43. [PMID: 22829079 PMCID: PMC3256754 DOI: 10.1038/bcj.2011.41] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2011] [Revised: 07/16/2011] [Accepted: 09/09/2011] [Indexed: 01/14/2023] Open
Abstract
Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.
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Kumar SK, Lacy MQ, Hayman SR, Stewart K, Buadi FK, Allred J, Laumann K, Greipp PR, Lust JA, Gertz MA, Zeldenrust SR, Bergsagel PL, Reeder CB, Witzig TE, Fonseca R, Russell SJ, Mikhael JR, Dingli D, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol 2011; 86:640-5. [PMID: 21630308 DOI: 10.1002/ajh.22053] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Accepted: 04/08/2011] [Indexed: 12/22/2022]
Abstract
The combination of lenalidomide and low-dose dexamethasone is an effective treatment for multiple myeloma (MM). Addition of alkylating agents to lenalidomide or thalidomide results in increased response rates and deeper responses. We designed this trial to study the combination of cyclophosphamide, lenalidomide, and dexamethasone (CRd) as initial therapy for MM. Fifty-three patients with previously untreated symptomatic MM was enrolled. Patients received 4-week treatment cycles consisting of lenalidomide (25 mg daily for 3 weeks), dexamethasone (40 mg weekly), and cyclophosphamide (300 mg/m(2) weekly for 3 weeks). A partial response or better was seen in 85% of patients including 47% with a very good partial response or better. The toxicities were manageable with over 80% of planned doses delivered; six patients went off study for toxicity. The median progression free survival (PFS) for the entire group was 28 months (95% CI: 22.7-32.6) and the overall survival (OS) at 2 years was 87% (95% CI: 78-96). Importantly, 14 patients with high-risk MM had similar PFS and OS as the standard-risk patients (n = 39). CRd is an effective and well-tolerated regimen for upfront therapy of MM with high response rates and excellent 2-year OS, and is suitable for long-term therapy.
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Affiliation(s)
- Shaji K Kumar
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
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Kvam AK, Fayers PM, Wisloff F. Responsiveness and minimal important score differences in quality-of-life questionnaires: a comparison of the EORTC QLQ-C30 cancer-specific questionnaire to the generic utility questionnaires EQ-5D and 15D in patients with multiple myeloma. Eur J Haematol 2011; 87:330-7. [PMID: 21668504 DOI: 10.1111/j.1600-0609.2011.01665.x] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVES The aims of this study were to (i) compare the responsiveness of the EORTC QLQ-C30 cancer-specific questionnaire and the generic questionnaires EQ-5D and 15D used for economic evaluation of healthcare interventions and (ii) determine the minimal important differences (MIDs) in these questionnaires. The MID is the smallest change in a quality-of-life score considered important to patients. METHODS Between 2006 and 2008, 239 patients with multiple myeloma completed the questionnaires at inclusion (T1) and after 3 months (T2). At T2, patients were asked whether they had noticed any change in their quality of life. Responsiveness and MIDs were determined by mean score changes (T2-T1) for patients who, in the interview, stated they had improved, deteriorated, or were unchanged. Responsiveness was also assessed using standardized response means. Wilcoxon tests for pair differences were used to evaluate the statistical significance of the changes. RESULTS Patients who improved had significantly (P < 0.01) higher scores at T2 in all three questionnaires. Patients who deteriorated reported lower scores at T2; however, for the 15D, the differences in score were not statistically significant. The MIDs for the QLQ-C30, EQ-5D, and 15D were 8, 0.08, and 0.03 in patients who improved and 12, 0.10 and 0.02 in patients who deteriorated, respectively. CONCLUSIONS All three questionnaires showed an acceptable responsiveness in patients who improved. However, the 15D did not respond optimally in patients who deteriorate and cannot be recommended for use in patients with myeloma.
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Affiliation(s)
- Ann Kristin Kvam
- Department of Haematology, Oslo University Hospital, Ullevaal Faculty of Medicine, University of Oslo, Oslo, Norway.
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Abstract
In this Perspective, we summarize some of the most contentious issues surrounding diagnosis and treatment of myeloma. We outline how a fundamental clash of philosophies, cure versus control, may be at the heart of many of the controversies. From the very definition of the disease to risk stratification to the validity of current clinical trial endpoints, we highlight the major areas of debate and provide alternative viewpoints that have implications for trial design and interpretation, as well as clinical practice.
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Abstract
The treatment of multiple myeloma has changed dramatically in the past decade. The increase in the number of active agents has generated numerous possible drug combinations that can be used in the first-line and relapsed settings. As a result, there is considerable confusion about the choice of regimens for initial therapy, role of transplantation in the era of new drugs, end points for therapy, and the role of maintenance therapy. A hotly debated area is whether treatment approaches should achieve cure or disease control, which impacts greatly on the treatment strategy employed. This article provides an update on the treatment of multiple myeloma, with a focus on recent advances, newly diagnosed disease, role of transplantation and maintenance therapy. A synthesized approach to the treatment of myeloma is presented, along with a discussion of key paradigms that need to be challenged.
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Affiliation(s)
- S Vincent Rajkumar
- Division of Hematology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
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Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement. Leukemia 2011; 25:749-60. [DOI: 10.1038/leu.2011.3] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Rajkumar SV. Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 2011; 86:57-65. [PMID: 21181954 DOI: 10.1002/ajh.21913] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
DISEASE OVERVIEW Multiple myeloma is malignant plasma-cell disorder that accounts for ∼10% of all hematologic malignancies. DIAGNOSIS The diagnosis requires (1) 10% or more clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma plus (2) evidence of end-organ damage felt to be related to the underlying plasma cell disorder. RISK STRATIFICATION Patients with 17p deletion, t(4;14), t(14;16), t(14;20), and karyotypic deletion 13 or hypodiploidy are considered to have high-risk myeloma. All others are considered to have standard-risk disease. RISK-ADAPTED THERAPY Standard-risk patients are treated with nonalkylator-based therapy such as lenalidomide plus low-dose dexamethasone (Rd) followed by autologous stem-cell transplantation (ASCT). If patients are tolerating the induction regimen treatment well, an alternative strategy is to continue initial therapy after stem-cell collection, reserving ASCT for first relapse. High-risk patients are treated with a bortezomib-based induction followed by ASCT and then bortezomib-based maintenance. Patients not eligible for ASCT can be treated with Rd for standard risk disease or a bortezomib-based regimen if high-risk features are present. To reduce toxicity, when using bortezomib, the once-weekly dose is preferred; similarly, when using dexamethasone, the low-dose approach (40 mg once a week) is preferred, unless there is a need for rapid disease control. MANAGEMENT OF REFRACTORY DISEASE Patients with indolent relapse can be treated first with lenalidomide, bortezomib, or alkylators plus low-dose corticosteroids. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. The most promising new agents in development are pomalidomide and carfilizomib.
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Affiliation(s)
- S Vincent Rajkumar
- Division of Hematology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
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