PURPOSE: Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016. RESULTS: A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION: BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.

• MeSH
• aplikace orální MeSH
• bortezomib aplikace a dávkování   škodlivé účinky   MeSH
• dexamethason aplikace a dávkování   škodlivé účinky   MeSH
• doba přežití bez progrese choroby MeSH
• lidé středního věku MeSH
• lidé MeSH
• melfalan aplikace a dávkování   škodlivé účinky   MeSH
• primární amyloidóza farmakoterapie   patologie   MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

The randomized phase 3 ENDEAVOR study (N=929) compared carfilzomib and dexamethasone (Kd) with bortezomib and dexamethasone (Vd) in relapsed multiple myeloma (RMM). We performed a subgroup analysis from ENDEAVOR in patients categorized by number of prior lines of therapy or by prior treatment. Median progression-free survival (PFS) for patients with one prior line was 22.2 months for Kd vs 10.1 months for Vd, and median PFS for patients with ⩾2 prior lines was 14.9 months for Kd vs 8.4 months for Vd. For patients with prior bortezomib exposure, the median PFS was 15.6 months for Kd vs 8.1 months for Vd, and for patients with prior lenalidomide exposure the median PFS was 12.9 months for Kd vs 7.3 months for Vd. Overall response rates (Kd vs Vd) were 81.9 vs 65.5% (one prior line), 72.0 vs 59.7% (⩾2 prior lines), 71.2 vs 60.3% (prior bortezomib) and 70.1 vs 59.3% (prior lenalidomide). The safety profile in the prior lines subgroups was qualitatively similar to that in the broader ENDEAVOR population. In RMM, outcomes are improved when receiving treatment with carfilzomib compared with bortezomib, regardless of the number of prior therapy lines or prior exposure to bortezomib or lenalidomide.

• MeSH
• bortezomib aplikace a dávkování   terapeutické užití   MeSH
• dexamethason aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom farmakoterapie   mortalita   MeSH
• oligopeptidy aplikace a dávkování   terapeutické užití   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• recidiva MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• záchranná terapie metody   mortalita   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m(2) on days 1 and 2 of cycle 1; 27 mg/m(2) thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.

• MeSH
• anemie chemicky indukované   MeSH
• cyklofosfamid aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• dospělí MeSH
• hormony kůry nadledvin aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mnohočetný myelom komplikace   farmakoterapie   mortalita   MeSH
• neutropenie chemicky indukované   MeSH
• oligopeptidy aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• recidiva MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• trombocytopenie chemicky indukované   MeSH
• záchranná terapie škodlivé účinky   metody   mortalita   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

A primary analysis of the ASPIRE study found that the addition of carfilzomib to lenalidomide and dexamethasone (carfilzomib group) significantly improved progression-free survival (PFS) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the carfilzomib group, 103/396 patients were ≥70 years old, and in the control group, 115/396 patients were ≥70 years old. Median PFS for patients <70 years old was 28·6 months for the carfilzomib group versus 17·6 months for the control group [hazard ratio (HR), 0·701]. Median PFS for patients ≥70 years old was 23·8 months for the carfilzomib group versus 16·0 months for the control group (HR, 0·753). For patients <70 years the overall response rate (ORR) was 86·0% (carfilzomib group) and 66·9% (control group); for patients ≥70 years old the ORR was 90·3% (carfilzomib group) and 66·1% (control group). Within the carfilzomib group, grade ≥3 cardiovascular adverse events occurred more frequently among patients ≥70 years old compared with patients <70 years old. Carfilzomib-lenalidomide-dexamethasone has a favourable benefit-risk profile for patients with RMM, including elderly patients ≥70 years old. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01080391.

• MeSH
• dexamethason aplikace a dávkování   MeSH
• dospělí MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom farmakoterapie   MeSH
• oligopeptidy aplikace a dávkování   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• recidiva MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• thalidomid aplikace a dávkování   analogy a deriváty   MeSH
• věkové faktory MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391.

• MeSH
• dexamethason aplikace a dávkování   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mladiství MeSH
• mnohočetný myelom farmakoterapie   mortalita   MeSH
• oligopeptidy aplikace a dávkování   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• protokoly antitumorózní kombinované chemoterapie aplikace a dávkování   MeSH
• recidiva MeSH
• rizikové faktory MeSH
• senioři MeSH
• thalidomid aplikace a dávkování   analogy a deriváty   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

DNA repair in blood cells was observed to be suboptimal in cancer patients at diagnosis, including colorectal cancer (CRC). To explore the causality of this phenomenon, we studied the dynamics of DNA repair from diagnosis to 1 yr follow-up, and with respect to CRC treatment. Systemic CRC therapy is targeted to DNA damage induction and DNA repair is thus of interest. CRC patients were blood-sampled three times in 6-mo intervals, starting at the diagnosis, and compared to healthy controls. DNA repair was characterized by mRNA levels of 40 repair genes, by capacity of nucleotide excision repair (NER), and by levels of DNA strand breaks (SBs). NER and base excision repair genes were significantly under-expressed (P < 0.016) in patients at diagnosis compared to controls, in accordance with reduced NER function (P = 0.008) and increased SBs (P = 0.015). Six months later, there was an increase of NER capacity, but not of gene expression levels, in treated patients only. A year from diagnosis, gene expression profiles and NER capacity were significantly modified in all patients and were no longer different from those measured in controls. All patients were free of relapse at the last sampling, so we were unable to clarify the impact of DNA repair parameters on treatment response. However, we identified a panel of blood DNA repair-related markers discerning acute stage of the disease from the remission period. In conclusion, our results support a model in which DNA repair is altered as a result of cancer.

• MeSH
• antitumorózní látky terapeutické užití   MeSH
• kolon účinky léků   metabolismus   MeSH
• kolorektální nádory krev   farmakoterapie   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• oprava DNA * účinky léků   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• rektum účinky léků   metabolismus   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• zlomy DNA účinky léků   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH