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Critical Reviews in Oncology/hematology May 2018Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids.... (Review)
Review
Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (n = 5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ≥3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20-27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20-56 and 20-70 mg/m2 dose of CFZ vs standard 20-27 mg/m2 dose in NDMM and RRMM.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Humans; Lenalidomide; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Thalidomide; Treatment Outcome
PubMed: 29650268
DOI: 10.1016/j.critrevonc.2018.02.008 -
Clinical Therapeutics Mar 2018New therapies, including daratumumab plus lenalidomide plus dexamethasone (DRd) and daratumumab plus bortezomib plus dexamethasone (DVd), have recently been approved in... (Comparative Study)
Comparative Study Meta-Analysis
PURPOSE
New therapies, including daratumumab plus lenalidomide plus dexamethasone (DRd) and daratumumab plus bortezomib plus dexamethasone (DVd), have recently been approved in the United States for patients with multiple myeloma (MM) who have received at least 1 prior line of therapy. However, few treatments have been compared in head-to-head clinical trials to determine the most efficacious therapy. In an update of the POLLUX (Phase 3 Study Comparing DRd Versus Rd in Subjects with Relapsed or Refractory Multiple Myeloma [RRMM]) trial, median progression-free survival (PFS) for DRd was not reached; the hazard ratio compared with Rd was 0.41. In an update of the CASTOR (Phase 3 Study Comparing DVd Versus Vd in Subjects with RRMM) trial, median PFS for DVd was 16.7 months, compared with 7.1 months for Vd with a PFS hazard ratio of 0.31. A systematic literature review and network meta-analysis (NMA) was performed to estimate the relative efficacy of treatments for previously treated patients with MM.
METHODS
A systematic search of MEDLINE, EMBASE, BioSciences Information Service, and the Cochrane Library databases was conducted from initiation to September 2016. Abstracts published by international congresses (2014-2016) and bibliographies of pertinent systematic reviews and meta-analyses were also searched. Eligible studies consisted of randomized controlled trials (RCTs) or long-term follow-up studies with >1 treatment arm assessing the efficacy or safety of MM therapies. An NMA was conducted by using Bayesian fixed effect mixed-treatment comparisons. Outcomes considered were hazard ratios for PFS and odds ratios for overall response rate (ORR).
FINDINGS
In total, 108 articles reporting 27 RCTs were included in the NMA. Data formed 2 evidence networks: RCTs with DRd and RCTs with DVd. Primary analysis of PFS found that DRd and DVd had a higher probability of being the best treatments (probability, 0.997 and 0.999, respectively) and had the lowest risk of progression or death than other treatments approved by the US Food and Drug Administration for the treatment of MM. Results from sensitivity analyses using time to progression as a proxy for missing PFS data were consistent. DRd and DVd also showed improved ORR compared with other treatments. Subgroup analyses of PFS in patients treated with only 1 prior therapy were like the results of the primary analyses.
IMPLICATIONS
This NMA provides comparative efficacy for MM treatments not studied in head-to-head RCTs. The NMA suggests that, compared with other approved MM treatments in the United States, DRd and DVd have a higher probability of providing the longest PFS in patients who have received at least 1 prior therapy and in patients who have received only 1 prior therapy.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Bortezomib; Dexamethasone; Humans; Lenalidomide; Multiple Myeloma; Network Meta-Analysis; Randomized Controlled Trials as Topic
PubMed: 29500140
DOI: 10.1016/j.clinthera.2018.01.014 -
JAMA Oncology Mar 2018Cardiovascular adverse events (CVAE) with carfilzomib in patients with multiple myeloma can be potentially life-threatening and remain incompletely characterized. We... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Cardiovascular adverse events (CVAE) with carfilzomib in patients with multiple myeloma can be potentially life-threatening and remain incompletely characterized. We performed the first systematic review and meta-analysis of carfilzomib-associated CVAE.
OBJECTIVE
To determine the incidence of carfilzomib-associated CVAE and to compare the rates of carfilzomib CVAE among different doses and companion therapies.
DATA SOURCES
PubMed, EMBASE, Web of Science, and clinicaltrials.gov were queried for the keywords "carfilzomib," "Kyprolis," and "PX-171" through January 1, 2017.
STUDY SELECTION
Phase 1 to 3 prospective clinical trials of carfilzomib in patients with multiple myeloma with evaluable toxic effects data were eligible for meta-analysis.
DATA EXTRACTION AND SYNTHESIS
Data were independently extracted by 2 reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Pooled incidence rates and relative risks (for randomized trials) and 95% confidence intervals were calculated using a random effects model. Subgroup analyses were performed to assess study-level characteristics associated with CVAE.
MAIN OUTCOMES AND MEASURES
Cardiovascular adverse events were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grades 3 or higher AEs and study characteristics were recorded.
RESULTS
A total of 514 studies were assessed for eligibility. Of those, 24 studies were eligible, including a total of 2594 patients with multiple myeloma. All-grade and grades 3 and higher CVAE were seen in 617 (18.1%) and 274 (8.2%), respectively. Phase 2 or 3 studies and carfilzomib doses of 45 mg/m2 or higher were associated with high-grade CVAE. Median age older than 65 years, prior myeloma therapies, and concurrent myeloma therapies were not associated with CVAE. For the 3 randomized clinical trials, the summary relative risk of all-grade and grade 3 or higher CVAE for patients receiving carfilzomib compared with noncarfilzomib-receiving control patients were 1.8 and 2.2, respectively.
CONCLUSIONS AND RELEVANCE
Carfilzomib was associated with a significant incidence of CVAE, with higher rates seen with higher doses of carfilzomib. Phase 1 studies may be underdetecting CVAE. Future studies are needed to identify patients at high risk for CVAE, develop optimal monitoring strategies, and explore strategies to mitigate these risks.
Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Humans; Incidence; Middle Aged; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Randomized Controlled Trials as Topic
PubMed: 29285538
DOI: 10.1001/jamaoncol.2017.4519 -
The Cochrane Database of Systematic... Apr 2016Multiple myeloma is a malignancy of plasma cells accounting for approximately 1% of cancers and 12% of haematological malignancies. The first-in-class proteasome... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple myeloma is a malignancy of plasma cells accounting for approximately 1% of cancers and 12% of haematological malignancies. The first-in-class proteasome inhibitor, bortezomib, is commonly used to treat newly diagnosed as well as relapsed/refractory myeloma, either as single agent or combined with other therapies.
OBJECTIVES
We conducted a systematic review and meta-analysis to assess the effects of bortezomib on overall survival (OS), progression-free survival (PFS), response rate (RR), health-related quality of life (HRQoL), adverse events (AEs) and treatment-related death (TRD).
SEARCH METHODS
We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE (till 27 January 2016) as well as conference proceedings and clinical trial registries for randomised controlled trials (RCTs).
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared i) bortezomib versus no bortezomib with the same background therapy in each arm; ii) bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s) and iii) bortezomib dose comparisons and comparisons of different treatment administrations and schedules.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted outcomes data and assessed risk of bias. We extracted hazard ratios (HR) and their confidence intervals for OS and PFS and odds ratios (OR) for response rates, AEs and TRD. We contacted trial authors to provide summary statistics if missing. We estimated Logrank statistics which were not available. We extracted HRQoL data, where available.
MAIN RESULTS
We screened a total of 3667 records, identifying 16 relevant RCTs involving 5626 patients and included 12 trials in the meta-analyses. All trials were randomised and open-label studies. Two trials were published in abstract form and therefore we were unable to assess potential risk of bias in full.There is moderate-quality evidence that bortezomib prolongs OS (four studies, 1586 patients; Peto OR 0.77, 95% CI 0.65 to 0.92) and PFS (five studies, 1855 patients; Peto OR 0.65, 95% CI 0.57 to 0.74) from analysing trials of bortezomib versus no bortezomib with the same background therapy in each arm.There is high-quality evidence that bortezomib prolongs OS (five studies, 2532 patients; Peto OR 0.76, 95% CI 0.67 to 0.88) but low-quality evidence for PFS (four studies, 2489 patients; Peto OR 0.67, 95% CI 0.61 to 0.75) from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s).Four trials (N = 716) examined different doses, methods of administrations and treatment schedules and were reviewed qualitatively only.We identified four trials in the meta-analysis that measured time to progression (TTP) and were able to extract and analyse PFS data for three of the studies, while in the case of one study, we included TTP data as PFS data were not available. We therefore did not analyse TTP separately in this review.Patients treated with bortezomib have increased risk of thrombocytopenia, neutropenia, gastro-intestinal toxicities, peripheral neuropathy, infection and fatigue with the quality of evidence highly variable. There is high-quality evidence for increased risk of cardiac disorders from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or versus other agents. The risk of TRD in either comparison group analysed is uncertain due to the low quality of the evidence.Only four trials analysed HRQoL and the data could not be meta-analysed.Subgroup analyses by disease setting revealed improvements in all outcomes, whereas for therapy setting, an improved benefit for bortezomib was observed in all outcomes and subgroups except for OS following consolidation therapy.
AUTHORS' CONCLUSIONS
This meta-analysis found that myeloma patients receiving bortezomib benefited in terms of OS, PFS and response rate compared to those who did not receive bortezomib. This benefit was observed in trials of bortezomib versus no bortezomib with the same background therapy and in trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s). Further evaluation of newer proteasome inhibitors is required to ascertain whether these agents offer an improved risk-benefit profile, while more studies of HRQoL are also required.
Topics: Antineoplastic Agents; Bortezomib; Humans; Multiple Myeloma; Randomized Controlled Trials as Topic
PubMed: 27096326
DOI: 10.1002/14651858.CD010816.pub2 -
Journal of the National Cancer Institute Mar 2016Immunomodulatory drugs (IMiDs) and proteasome inhibitors have dramatically changed management of multiple myeloma (MM). While MM remains incurable, consolidation and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Immunomodulatory drugs (IMiDs) and proteasome inhibitors have dramatically changed management of multiple myeloma (MM). While MM remains incurable, consolidation and maintenance therapy aimed at improving duration of response can potentially improve survival outcomes. A majority of randomized controlled trials (RCTs) have demonstrated benefit of IMiD-based maintenance therapy in delaying disease progression; however, whether this therapy can lead to improved survival remains controversial.
METHODS
PubMed and abstract databases of major hematology and/or oncology meetings were searched for RCTs that studied maintenance therapy with IMiDs in MM. A meta-analysis was conducted to systematically evaluate the impact of IMiD-based maintenance therapy on survival outcomes and serious adverse events associated with the therapy. All statistical tests were two-sided.
RESULTS
Eighteen phase 3 RCTs enrolling 7730 patients were included. IMiD-based maintenance therapy statistically significantly prolonged progression-free survival (PFS; hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.57 to 0.67, P < .001) but failed to improve overall survival (OS; HR = 0.93, 95% CI = 0.85 to 1.01, P = .082). Stratified analyses demonstrated that both thalidomide and lenalidomide provided PFS but not OS benefit in transplantation as well as nontransplantation settings. IMiD-based maintenance therapy in MM led to a higher risk of grade 3-4 thromboembolism (risk ratio = 2.52, 95% CI = 1.41 to 4.52, P = .002). Thalidomide maintenance therapy increased the risk of peripheral neuropathy; lenalidomide maintenance therapy increased the risks of myelosuppression and second primary hematological malignancies.
CONCLUSIONS
Thalidomide- or lenalidomide-based maintenance therapy improves PFS but not OS in MM and increases risks of grade 3-4 adverse events, including thromboembolism, peripheral neuropathy, neutropenia, and infection.
Topics: Disease-Free Survival; Humans; Immunosuppressive Agents; Infections; Lenalidomide; Maintenance Chemotherapy; Multiple Myeloma; Neoplasms, Second Primary; Neutropenia; Peripheral Nervous System Diseases; Randomized Controlled Trials as Topic; Risk; Severity of Illness Index; Survival Analysis; Survival Rate; Thalidomide; Thromboembolism
PubMed: 26582244
DOI: 10.1093/jnci/djv342 -
Future Oncology (London, England) 2015Novel drugs such as immunomodulators and proteasome inhibitors have improved the survival of patients with multiple myeloma. Like all therapeutic agents, appropriate... (Review)
Review
Novel drugs such as immunomodulators and proteasome inhibitors have improved the survival of patients with multiple myeloma. Like all therapeutic agents, appropriate dosing based on metabolism and clearance is important to maintain efficacy while avoiding toxicity. Hepatic impairment (HI) in multiple myeloma patients is rare but well described either due to disease or therapy-related factors. However, limited data are available on the appropriate use and dosing of the novel agent therapeutics in myeloma patients with HI. Furthermore, data on HI secondary to the novel agent toxicity are also sparse. This systematic review highlights the evidence on the use of novel agents like thalidomide, lenalidomide, pomalidomide, bortezomib and carfilzomib in patients with HI as well as their associated hepatic toxicities.
Topics: Antineoplastic Agents; Humans; Immunologic Factors; Liver Diseases; Multiple Myeloma; Proteasome Inhibitors; Treatment Outcome
PubMed: 25675129
DOI: 10.2217/fon.14.270 -
Current Oncology (Toronto, Ont.) Aug 2014We conducted a systematic review to determine the appropriate use of bortezomib alone or in combination with other agents in patients with multiple myeloma (mm). We... (Review)
Review
We conducted a systematic review to determine the appropriate use of bortezomib alone or in combination with other agents in patients with multiple myeloma (mm). We searched medline, embase, the Cochrane Library, conference proceedings, and the reference lists of included studies. We analyzed randomized controlled trials and systematic reviews if they involved adult mm patients treated with bortezomib and if they reported on survival, disease control, response, quality of life, or adverse effects. Twenty-six unique studies met the inclusion criteria. For patients with previously untreated mm and for candidates for transplantation, we found a statistically significant benefit in time to progression [hazard ratio (hr): 0.48, p < 0.001; and hr: 0.63, p = 0.006, respectively] and a better response with a bortezomib than with a non-bortezomib regimen (p < 0.001). Progression-free survival was longer with bortezomib and thalidomide than with thalidomide alone (p = 0.01). In non-candidates for transplantation, a significant benefit in overall survival was observed with a bortezomib regimen (hr compared with a non-bortezomib regimen: 0.61; p = 0.008), and in transplantation candidates receiving bortezomib, the response rate was improved after induction (p = 0.004) and after a first transplant (p = 0.016). In relapsed or refractory mm, overall survival (p = 0.03), time to progression (hr: 1.82; p = 0.000004), and progression-free survival (hr: 1.69; p = 0.000026) were significantly improved with bortezomib and pegylated liposomal doxorubicin (compared with bortezomib alone), and bortezomib monotherapy was better than dexamethasone alone (hr: 0.77; p = 0.027). Bortezomib combined with thalidomide and dexamethasone was better than either bortezomib monotherapy or thalidomide with dexamethasone (p < 0.001). In previously untreated or in relapsed or refractory mm patients, bortezomib-based therapy has improved disease control and, in some patients, overall survival.
PubMed: 25089109
DOI: 10.3747/co.21.1798 -
Critical Care Medicine Oct 2009To review current knowledge about the impact of prolonged mechanical ventilation on diaphragmatic function and biology. (Review)
Review
OBJECTIVE
To review current knowledge about the impact of prolonged mechanical ventilation on diaphragmatic function and biology.
MEASUREMENTS
Systematic literature review.
CONCLUSIONS
Prolonged mechanical ventilation can promote diaphragmatic atrophy and contractile dysfunction. As few as 18 hrs of mechanical ventilation results in diaphragmatic atrophy in both laboratory animals and humans. Prolonged mechanical ventilation is also associated with diaphragmatic contractile dysfunction. Studies using animal models revealed that mechanical ventilation-induced diaphragmatic atrophy is due to increased diaphragmatic protein breakdown and decreased protein synthesis. Recent investigations have identified calpain, caspase-3, and the ubiquitin-proteasome system as key proteases that contribute to mechanical ventilation-induced diaphragmatic proteolysis. The scientific challenge for the future is to delineate the mechanical ventilation-induced signaling pathways that activate these proteases and depress protein synthesis in the diaphragm. Future investigations that define the signaling mechanisms responsible for mechanical ventilation-induced diaphragmatic weakness will provide the knowledge required for the development of new medicines that can maintain diaphragmatic mass and function during prolonged mechanical ventilation.
Topics: Animals; Antioxidants; Calpain; Caspase 3; Critical Illness; Diaphragm; Enzyme Inhibitors; Humans; Muscle Contraction; Muscular Atrophy; Proteasome Endopeptidase Complex; Respiration, Artificial; Risk Factors; Ubiquitin; Ventilator Weaning
PubMed: 20046120
DOI: 10.1097/CCM.0b013e3181b6e760