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International Journal of Medical... 2021Multiple myeloma (MM) is incurable in spite of recent treatment improvements, highlighting the development of new therapies. Chimeric antigen receptor (CAR) T-cell... (Meta-Analysis)
Meta-Analysis
Multiple myeloma (MM) is incurable in spite of recent treatment improvements, highlighting the development of new therapies. Chimeric antigen receptor (CAR) T-cell therapy has dramatically changed the therapeutic effectiveness in high-risk B-cell malignancies. For relapsed/refractory multiple myeloma (RRMM), preclinical evaluations of CAR-T therapy have shown promising efficacy, thus various active clinical trials are under way. Herein, we conducted this review to summarize efficacy and safety of CAR-T therapy and provide more evidence to guide clinical treatments. We systematically searched literature based on databases (PubMed, EMBASE, Cochrane Central Register of Controlled Trials), and conference abstracts reported from American Society of Hematology (ASH), European Hematology Association (EHA) and American Society of Clinical Oncology (ASCO), in addition to other sources (www.clinicaltrials.gov, article citations). Data assessed efficacy and safety of CAR-T therapy in patients with RRMM were extracted and evaluated, and then systematically analyzed by Comprehensive Meta-analysis 3.0 (CMA 3.0). A total of 23 studies including 350 participants from different countries, diagnosed as RRMM and treated with CAR-T therapy (containing 7 antigens targeted by CARs) were combined. In summary, we discovered the pooled overall response rate (77%), complete response rate (37%) and minimal residual disease (MRD) negativity rate within responders (78%). Furthermore, the pooled relapse rate of responders was 38% and median progression-free survival was 8 months. The pooled survival rate was 87% at last follow-up (median, 12 months). In addition, the pooled grade 3-4 rates of cytokine release syndrome (CRS) and neurologic toxicities (NT) were 14% and 13%, respectively. Our study suggests that CAR-T therapy has demonstrated efficacy and safety in RRMM patients. BCMA-targeted CAR-T and anti-BCMA contained regimen have shown better efficacy.
Topics: B-Cell Maturation Antigen; Clinical Trials as Topic; Drug Resistance, Neoplasm; Follow-Up Studies; Humans; Immunotherapy, Adoptive; Multiple Myeloma; Neoplasm Recurrence, Local; Progression-Free Survival; Receptors, Chimeric Antigen
PubMed: 33746596
DOI: 10.7150/ijms.46811 -
American Journal of Hematology Jun 2021Surrogate endpoints are being used more frequently in randomized controlled trials, even though they do not consistently corelate with patient outcomes. We systemically...
Surrogate endpoints are being used more frequently in randomized controlled trials, even though they do not consistently corelate with patient outcomes. We systemically evaluated the use of surrogate endpoints in multiple myeloma randomized controlled trials over the past 15 years. We searched three databases (Pubmed, Embase, Cochrane) for multiple myeloma randomized controlled trials from January 1, 2005 to December 30, 2019. The primary outcome of our study was the proportion of randomized controlled trials that used overall survival as their primary endpoint. Secondary outcomes included the use of surrogate endpoints, and trends over time, and whether they differed based on study sponsorship. We included 151 randomized controlled trials in our analysis. The primary endpoint was overall survival (OS) in 17 (11.3%) of studies, progression free survival (PFS) or event-defined endpoints in 91 studies (60.3%) and response-based endpoints in 44 studies (29.1%). Quality of life was a primary endpoint in only three studies (2%). The use of OS as a primary endpoint decreased from 28.5% of trials from 2005 to 2009 to 5.5% from 2015 to 2019. There has been a decrease in the clinically meaningful endpoint of OS over the past 15 years in multiple myeloma randomized controlled trials. Use of quality of life as a primary endpoint remains exceedingly low. It remains paramount to recognize that the use of surrogate endpoints is imperfect, and care based upon them requires constant physician and patient re-analysis.
Topics: Biomarkers; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Multicenter Studies as Topic; Multiple Myeloma; Neoplasm, Residual; Progression-Free Survival; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis; Time Factors
PubMed: 33735453
DOI: 10.1002/ajh.26166 -
Blood Cancer Journal Mar 2021Great progress in the treatment of patients with multiple myeloma (MM) has been made due to the development of novel drugs. Patients with relapsed/refractory MM (RRMM)... (Meta-Analysis)
Meta-Analysis
Great progress in the treatment of patients with multiple myeloma (MM) has been made due to the development of novel drugs. Patients with relapsed/refractory MM (RRMM) can be enrolled in early-phase clinical trials, but their performance across the last decade is unknown. We conducted a meta-analysis on the overall response rate (ORR) and toxicity. PubMed, Embase, and Cochrane Library were systematically searched for phase I and phase II trials investigating an experimental compound as a single agent or in combination with dexamethasone, published from January 1, 2010 to July 1, 2020. Eighty-eight articles were included, describing 61 phase I trials involving 1835 patients and 37 phase II trials involving 2644 patients. There was a high degree of heterogeneity. Using a random-effects model, the 95% CIs of the estimated ORR were 8-17% for phase I trials and 18-28% for phase II trials. There were significant subgroup differences in ORR between the years of publication in phase I trials and between drug classes in both phase I and phase II trials. The ORR in early-phase clinical trials in RRMM is substantial, especially in phase II trials, but due to high heterogeneity a general assessment of clinical benefit before participation is difficult to offer to patients.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Development; Humans; Multiple Myeloma; Treatment Outcome
PubMed: 33649328
DOI: 10.1038/s41408-021-00441-3 -
Blood Advances Feb 2021
Meta-Analysis
Topics: Cell- and Tissue-Based Therapy; Humans; Immunotherapy, Adoptive; Multiple Myeloma; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 33606005
DOI: 10.1182/bloodadvances.2020004017 -
Medicine Feb 2021Presently, whether interleukin-6 (IL-6) gene-174 G/C promoter polymorphism is correlated to the susceptibility of multiple myeloma (MM) remains controversial. For this... (Meta-Analysis)
Meta-Analysis
Interleukin-6 gene-174 G/C promoter polymorphism is not associated with multiple myeloma susceptibility: evidence from meta-analysis: A systematic review and meta-analysis.
PURPOSE
Presently, whether interleukin-6 (IL-6) gene-174 G/C promoter polymorphism is correlated to the susceptibility of multiple myeloma (MM) remains controversial. For this reason, the method of meta-analysis was applied to exploring the association between IL-6 gene-174 G/C promoter polymorphism and MM.
METHOD
Two independent researchers systematically searched PubMed, EMBASE, Google academic, Cochrane Library and Chinese literature databases to screen case-control studies on IL-6 gene-174 G/C promoter polymorphism and MM susceptibility. The retrieval period was limited from the formation of the database to January 2020, and data analysis was conducted by employing Stata 11.0 software.
RESULT
Seven articles were ultimately included in the present study, including 594 MM patients and 681 controls. Integration analysis exhibited that compared with GC or CC genotype, GG genotype did not increase MM susceptibility (OR = 0.95, 95% CI 0.75-1.22; OR = 0.79, 95% CI 0.52-1.19, respectively). Further, in comparison with CC genotype, GC genotype also presented no effect on increasing MM susceptibility (OR = 0.79, 95% CI 0.53-1.16), while compared with GC+CC genotype, GG genotype had no significant relationship with MM susceptibility (OR = 0.94, 95% CI 0.75-1.19). In subsequent analysis, an observation was made that allele G or C was not related to MM susceptibility (OR = 0.92, 95% CI 0.76-1.12). Funnel chart and Begg test did not reveal publication bias in the included articles.
CONCLUSION
The results of the present study advocate that there is no testimony to support the relationship between IL-6 gene-174 G/C promoter polymorphism and MM susceptibility.
Topics: Adult; Alleles; Case-Control Studies; China; Data Management; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-6; Multiple Myeloma; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 33578591
DOI: 10.1097/MD.0000000000024647 -
BMC Musculoskeletal Disorders Jan 2021Transthyretin and immunoglobulin light-chain amyloidoses cause amyloid deposition throughout various organ systems. Recent evidence suggests that soft tissue amyloid...
BACKGROUND
Transthyretin and immunoglobulin light-chain amyloidoses cause amyloid deposition throughout various organ systems. Recent evidence suggests that soft tissue amyloid deposits may lead to orthopedic conditions before cardiac manifestations occur. Pharmacologic treatments reduce further amyloid deposits in these patients. Thus, early diagnosis improves long term survival.
QUESTIONS/PURPOSES
The primary purpose of this systematic review was to characterize the association between amyloid deposition and musculoskeletal pathology in patients with common orthopedic conditions. A secondary purpose was to determine the relationship between amyloid positive biopsy in musculoskeletal tissue and the eventual diagnosis of systemic amyloidosis.
METHODS
We performed a systematic review using PRISMA guidelines. Inclusion criteria were level I-IV evidence articles that analyzed light-chain or transthyretin amyloid deposits in common orthopedic surgeries. Study methodological quality, risk of bias, and recommendation strength were assessed using MINORS, ROBINS-I, and SORT.
RESULTS
This systematic review included 24 studies for final analysis (3606 subjects). Amyloid deposition was reported in five musculoskeletal pathologies, including carpal tunnel syndrome (transverse carpal ligament and flexor tenosynovium), hip and knee osteoarthritis (synovium and articular cartilage), lumbar spinal stenosis (ligamentum flavum), and rotator cuff tears (tendon). A majority of studies reported a mean age greater than 70 for patients with TTR or AL positive amyloid.
CONCLUSIONS
This systematic review has shown the presence of amyloid deposition detected at the time of common orthopedic surgeries, especially in patients ≥70 years old. Subtyping of the amyloid has been shown to enable diagnosis of systemic light-chain or transthyretin amyloidosis prior to cardiac manifestations.
LEVEL OF EVIDENCE
Level IV.
Topics: Aged; Amyloid Neuropathies, Familial; Humans; Immunoglobulin Light-chain Amyloidosis; Orthopedic Procedures; Osteoarthritis, Hip; Osteoarthritis, Knee
PubMed: 33419417
DOI: 10.1186/s12891-020-03912-z -
Annals of Hematology Apr 2021Monoclonal gammopathy of undetermined significance (MGUS), precursor of multiple myeloma, is an asymptomatic plasma cell disorder that overproduces serum monoclonal...
Monoclonal gammopathy of undetermined significance (MGUS), precursor of multiple myeloma, is an asymptomatic plasma cell disorder that overproduces serum monoclonal protein. Older age, male sex, black race, and family history of MGUS increase the risk of MGUS, yet other risk factors are known. We systematically reviewed observational epidemiological studies that examined sociodemographic, clinical, and behavioral risk factors for the development of MGUS. The protocol for this study was registered on the PROSPERO registry for systematic reviews. We identified epidemiological studies from PubMed and Scopus. Articles were limited to those written in English and published before February 2019. Five case-control and three cohort studies were eligible for data extraction. Studies evaluating factors associated with MGUS risk are limited, with conflicting conclusions regarding risk associated with obesity. Despite the limited research, a significant elevated risk for being diagnosed with MGUS was associated with several specific prior infections, inflammatory disorders, and smoking. The sparse existing literature suggests an increased risk of MGUS associated with several risk factors related to immune function. Further research is needed to explore the potential mechanisms underlying the development of MGUS and to confirm risk factors, both modifiable and non-modifiable.
Topics: Age Factors; Aged; Antigens; Autoimmune Diseases; Case-Control Studies; Comorbidity; Diet; Europe; Female; Humans; Hypersensitivity; Infections; Inflammation; Male; Middle Aged; Monoclonal Gammopathy of Undetermined Significance; Obesity; Observational Studies as Topic; Risk Factors; Sex Factors; Smoking; Socioeconomic Factors; United States
PubMed: 33416902
DOI: 10.1007/s00277-021-04400-7 -
Annals of Hematology Feb 2021Autologous stem cell transplantation as a frontline treatment for patients with multiple myeloma (MM) requires an adequate peripheral blood stem cell (PBSC) collection... (Comparative Study)
Comparative Study Meta-Analysis
Comparison of the efficiency, safety, and survival outcomes in two stem cell mobilization regimens with cyclophosphamide plus G-CSF or G-CSF alone in multiple myeloma: a meta-analysis.
Autologous stem cell transplantation as a frontline treatment for patients with multiple myeloma (MM) requires an adequate peripheral blood stem cell (PBSC) collection before processing. Granulocyte-colony stimulating factor (G-CSF) with or without cyclophosphamide (CTX) is a common regimen for PBSC mobilization; their benefits and risks are controversial. To compare the efficiency, safety, and survival outcomes between the two regimens, we conducted a meta-analysis including 18 studies with 4 prospective and 14 retrospective studies; a total of 2770 patients with MM were analyzed. The CTX plus G-CSF regimen had higher yields of total CD34 cells (SMD = 0.39, 95% CI (0.30, 0.49)), and higher mobilization rates of the target ⩾ 2 × 10/kg (OR = 3.34, 95% CI (1.82, 6.11)) and 4 × 10/kg (OR = 2.16, 95% CI (1.69, 2.76)) cells. A favorable event-free survival (EFS) (HR = 0.73, 95% CI (0.58, 0.93), p = 0.01) and better 3-year EFS rate (OR = 1.65, 95% CI (1.1, 2.47), p = 0.02) were also reached in the patients with CTX plus G-CSF mobilization, although the risks of admission (OR = 26.49, 95% CI (7.31, 95.97)) and fever (OR = 13.66, 95% CI (6.21, 30.03)) during mobilization were increased, the treatment-related mortality was consistent (p = 0.26). The CTX plus G-CSF regimen was superior to the G-CSF-alone regimen for PBSC mobilization in patients with MM.
Topics: Autografts; Cyclophosphamide; Disease-Free Survival; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Multiple Myeloma; Safety; Survival Rate
PubMed: 33404694
DOI: 10.1007/s00277-020-04376-w -
Blood Advances Dec 2020The prognostic value of minimal residual disease (MRD) for progression-free survival (PFS) and overall survival (OS) was evaluated in a large cohort of patients with... (Meta-Analysis)
Meta-Analysis
The prognostic value of minimal residual disease (MRD) for progression-free survival (PFS) and overall survival (OS) was evaluated in a large cohort of patients with multiple myeloma (MM) using a systematic literature review and meta-analysis. Medline and EMBASE databases were searched for articles published up to 8 June 2019, with no date limit on the indexed database. Clinical end points stratified by MRD status (positive or negative) were extracted, including hazard ratios (HRs) on PFS and OS, P values, and confidence intervals (CIs). HRs were estimated based on reconstructed patient-level data from published Kaplan-Meier curves. Forty-four eligible studies with PFS data from 8098 patients, and 23 studies with OS data from 4297 patients were identified to assess the association between MRD status and survival outcomes. Compared with MRD positivity, achieving MRD negativity improved PFS (HR, 0.33; 95% CI, 0.29-0.37; P < .001) and OS (HR, 0.45; 95% CI, 0.39-0.51; P < .001). MRD negativity was associated with significantly improved survival outcomes regardless of disease setting (newly diagnosed or relapsed/refractory MM), MRD sensitivity thresholds, cytogenetic risk, method of MRD assessment, depth of clinical response at the time of MRD measurement, and MRD assessment premaintenance and 12 months after start of maintenance therapy. The strong prognostic value of MRD negativity and its association with favorable outcomes in various disease and treatment settings sets the stage to adopt MRD as a treatment end point, including development of therapeutic strategies. This large meta-analysis confirms the utility of MRD as a relevant surrogate for PFS and OS in MM.
Topics: Cytogenetics; Humans; Multiple Myeloma; Neoplasm, Residual; Prognosis; Treatment Outcome
PubMed: 33284948
DOI: 10.1182/bloodadvances.2020002827 -
European Review For Medical and... Nov 2020Hematologic cancer patients with Coronavirus Disease 2019 (COVID-19) tend to have a more serious disease course than observed in the general population. Herein, we...
OBJECTIVE
Hematologic cancer patients with Coronavirus Disease 2019 (COVID-19) tend to have a more serious disease course than observed in the general population. Herein, we comprehensively reviewed existing literature and analyzed clinical characteristics and mortality of patients with hematologic malignancies and COVID-19.
MATERIALS AND METHODS
Through searching PubMed until June 03, 2020, we identified 16 relevant case studies (33 cases) from a total of 45 studies that have reported on patients with COVID-19 and hematologic malignancies. We investigated the clinical and laboratory characteristics including type of hematologic malignancies, initial symptoms, laboratory findings, and clinical outcomes. Then, we compared those characteristics and outcomes of patients with hematologic malignancies and COVID-19 to the general population infected with COVID-19.
RESULTS
The median age was 66-year-old. Chronic lymphocytic leukemia was the most common type of hematologic malignancy (39.4%). Fever was the most common symptom (75.9%). Most patients had normal leukocyte counts (55.6%), lymphocytosis (45.4%), and normal platelet counts (68.8%). In comparison to patients with COVID-19 without underlying hematologic malignancies, dyspnea was more prevalent (45.0 vs. 24.9%, p=0.025). Leukocytosis (38.9 vs. 9.8%, p=0.001), lymphocytosis (45.4 vs. 8.2%, p=0.001), and thrombocytopenia (31.3 vs. 11.4%, p=0.036) were significantly more prevalent and lymphopenia (18.2 vs. 57.4%, p=0.012) less prevalent in patients with hematologic malignancies. There were no clinical and laboratory characteristics predicting mortality in patients with hematologic malignancies. Mortality was much higher in patients with hematologic malignancies compared to those without this condition (40.0 vs. 3.6%, p<0.001).
CONCLUSIONS
Co-occurrence of hematologic malignancies and COVID-19 is rare. However, due to the high mortality rate from COVID-19 in this vulnerable population, further investigation on tailored treatment and management is required.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; COVID-19; Child; Child, Preschool; Dyspnea; Female; Fever; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytosis; Lymphocytosis; Lymphoma, Non-Hodgkin; Lymphopenia; Male; Middle Aged; Multiple Myeloma; Thrombocytopenia; Young Adult
PubMed: 33275265
DOI: 10.26355/eurrev_202011_23852