BACKGROUND: In the phase 3 ALCYONE study, the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) significantly improved outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma. Here, we present results from the final analysis of ALCYONE. METHODS: ALCYONE was an international, multicentre, randomised, open-label, active-controlled, phase 3 trial in adults aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or presence of substantial comorbidities, and had an Eastern Cooperative Oncology Group performance status of 0-2. Patients were enrolled between Feb 9, 2015, and July 14, 2016, and were randomly assigned (1:1) by randomly permuted blocks using an interactive web-based randomisation system to receive bortezomib, melphalan, and prednisone (VMP) alone or D-VMP, with randomisation stratified by International Staging System disease stage, geographical region, and age. Patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area, twice per week on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9), oral melphalan (9 mg/m2, once daily on days 1-4 of each cycle), and oral prednisone (60 mg/m2, once daily on days 1-4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab at a dose of 16 mg/kg once weekly during cycle 1, once every 3 weeks in cycles 2-9, and once every 4 weeks thereafter until disease progression, unacceptably toxicity, or the end of study. The primary endpoint, progression-free survival, has been previously reported. The ALCYONE study has completed; presented here are final analyses for selected secondary endpoints related to overall survival, depth of response, subsequent therapy, and safety. The intention-to-treat population was the primary analysis population (including for overall survival), defined as all patients who were randomly assigned to study treatment. The safety population, consisting of patients who received any dose of study treatment, was used in safety analyses. This trial is registered with ClinicalTrials.gov, NCT02195479. FINDINGS: In total, 706 patients were enrolled and randomly assigned to receive D-VMP (n=350) or VMP (n=356). Baseline characteristics were balanced between the two treatment groups; most participants were female (379 [54%] of 706 patients) and White (601 [85%] of 706 patients). At a median follow-up of 86·7 months (IQR 28·5-85·2), median overall survival was 83·0 months (95% CI 72·5-not estimable) with D-VMP versus 53·6 months (46·3-60·9) with VMP (hazard ratio [HR] 0·65 [95% CI 0·53-0·80]; p<0·0001). The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (140 [40%] of 346 patients in the D-VMP group vs 138 [39%] of 354 patients in the VMP group), thrombocytopenia (120 [35%] vs 134 [38%]), and anaemia (63 [18%] vs 70 [20%]). Serious treatment-related adverse events occurred in 74 (21%) of 346 patients in the D-VMP group and 56 (16%) of 354 patients in the VMP group. Deaths due to treatment-related adverse events occurred in five (1%) of 346 patients in the D-VMP group (pneumonia, acute myocardial infarction, neuroendocrine tumour, tumour lysis syndrome, and acute respiratory failure) and three (1%) of 354 patients in the VMP group (acute myeloid leukaemia, pulmonary embolism, and bacterial pneumonia). INTERPRETATION: With more than 7 years of follow-up, D-VMP continued to elicit clinical benefits in transplant-ineligible patients with newly diagnosed multiple myeloma, supporting the efficacy and safety of frontline daratumumab-based therapy in this patient population. FUNDING: Janssen Research & Development.

• MeSH
• bortezomib 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
• mnohočetný myelom * farmakoterapie   patologie   mortalita   MeSH
• monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• prednison aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• 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
• Názvy látek
• bortezomib MeSH
• daratumumab MeSH Prohlížeč
• melfalan MeSH
• monoklonální protilátky MeSH
• prednison MeSH

Parkinson's disease (PD) is one of the most common progressive neurodegenerative pathologies that leads to dopaminergic deficiency and motor manifestations. Alpha-synuclein aggregation is a characteristic hallmark of PD pathogenesis. These aggregates facilitate the formation of Lewy bodies and degeneration. The epidemiological evidence demonstrates a definitive association of diabetes with PD risk. Considering this, many antidiabetic agents such as GLP-1 agonists and DPP-4 inhibitors are being explored as alternative PD therapeutics. This study evaluated the neuroprotective effect of the DPP-4 inhibitor sitagliptin mediated by the PI3K/AKT and Nrf2 pathways in PD models. In silico studies were conducted to determine the binding affinity, stability, and ADMET properties of DPP-4 inhibitors with target proteins. Sitagliptin (15 mg/kg p.o.) was administered in rotenone (30 mg/kg p.o. for 28 days)-induced and MPTP/P (25 mg/kg i.p. MPTP and 100 mg/kg probenecid i.p. twice a week for 5 weeks)-induced PD mouse (C57/BL6) models. Neurobehavioral assessments were carried out throughout the study. Biochemical (GSH, MDA), molecular estimations (AKT, Nrf2, PI3K, GSK-3β, GLP1, CREB, BDNF, NF-κB, alpha-synuclein), histopathological studies, and immunohistochemistry were carried out at the end of the study. The in silico studies demonstrate better binding, stability, and ADMET profile of sitagliptin with both target proteins. Sitagliptin restored cognitive and motor deficits in both rotenone- and MPTP/P-induced mouse models. There was upregulation of PI3K, AKT, Nrf2, CREB, and BDNF levels and downregulation of GSK-3β, NF-κB, and alpha-synuclein levels in both models after treatment with sitagliptin. However, GLP1 levels were not significantly restored, indicating a GLP1-independent mechanism. It also restored histopathological alterations and TH+ neuronal loss induced by rotenone and MPTP/P. These findings demonstrate that sitagliptin exhibits neuroprotective action mediated by upregulation of the PI3K/AKT and Nrf2 pathways in rotenone and MPTP/P mouse models of PD.

• Klíčová slova
• DPP-4 inhibitors, Nrf2, PI3K/AKT, Parkinson’s disease, alpha-synuclein, sitagliptin,
• MeSH
• faktor 2 související s NF-E2 * metabolismus   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• inhibitory dipeptidylpeptidasy 4 * farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neuroprotektivní látky * farmakologie   MeSH
• parkinsonské poruchy * metabolismus   farmakoterapie   MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• rotenon MeSH
• signální transdukce účinky léků   MeSH
• sitagliptin fosfát * farmakologie   MeSH
• upregulace účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• faktor 2 související s NF-E2 * MeSH
• fosfatidylinositol-3-kinasy MeSH
• inhibitory dipeptidylpeptidasy 4 * MeSH
• neuroprotektivní látky * MeSH
• Nfe2l2 protein, mouse MeSH Prohlížeč
• protoonkogenní proteiny c-akt * MeSH
• rotenon MeSH
• sitagliptin fosfát * MeSH

Bioluminescence is the production of visible light by living organisms. It occurs through the oxidation of luciferin substrates catalysed by luciferase enzymes. Auxiliary proteins, such as fluorescent proteins and luciferin-binding proteins, can modify the light emitted wavelength or stabilize reactive luciferin molecules, respectively. Additionally, calcium ions are crucial for the luminescence across various species. Despite the large phylogenetic distribution of bioluminescent organisms, only a few systems have been comprehensively studied. Notably, cnidarian species of the Renilla genus utilize a coelenterazine-dependent luciferase, a calcium-dependent coelenterazine-binding protein and a green fluorescent protein. We investigated the bioluminescence of three sea pen species: Pennatula phosphorea, Anthoptilum murrayi and Funiculina quadrangularis (Pennatuloidea, Anthozoa). Their light-emission spectra reveal peaks at 510, 513 and 485 nm, respectively. A coelenterazine-based reaction was demonstrated in all three species. Using transcriptome analyses, we identified transcripts coding for luciferases, green fluorescent proteins and coelenterazine-binding proteins for P. phosphorea and A. murrayi. Immunodetection confirmed the expression of luciferase in P. phosphorea and F. quadrangularis. We also expressed recombinant luciferase of A. murrayi, confirming its activity. We highlighted the role of calcium ions in bioluminescence, possibly associated with the mechanism of substrate release at the level of coelenterazine-binding proteins. The study proposes a model for anthozoan bioluminescence, offering new avenues for future ecological and functional research on these luminous organisms.

• Klíčová slova
• Anthoptilidae, Funiculidae, Pennatulidae, bioluminescence, coelenterazine, luciferase, luciferin-binding protein, luminous system,
• MeSH
• fylogeneze MeSH
• imidazoly metabolismus   MeSH
• korálnatci * genetika   metabolismus   MeSH
• luciferasy metabolismus   genetika   MeSH
• luminescentní proteiny metabolismus   genetika   MeSH
• luminiscence MeSH
• luminiscenční měření metody   MeSH
• pyraziny metabolismus   MeSH
• stanovení celkové genové exprese * MeSH
• transkriptom * MeSH
• zelené fluorescenční proteiny metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• coelenterazine MeSH Prohlížeč
• imidazoly MeSH
• luciferasy MeSH
• luminescentní proteiny MeSH
• pyraziny MeSH
• zelené fluorescenční proteiny MeSH

Frontline daratumumab-based triplet and quadruplet standard-of-care regimens have demonstrated improved survival outcomes in newly diagnosed multiple myeloma (NDMM). For patients with transplant-ineligible NDMM, triplet therapy with either daratumumab plus lenalidomide and dexamethasone (D-Rd) or bortezomib, lenalidomide and dexamethasone (VRd) is the current standard of care. This phase 3 trial evaluated subcutaneous daratumumab plus VRd (D-VRd) in patients with transplant-ineligible NDMM or for whom transplant was not planned as the initial therapy (transplant deferred). Some 395 patients with transplant-ineligible or transplant-deferred NDMM were randomly assigned to eight cycles of D-VRd or VRd followed by D-Rd or Rd until progression. The primary endpoint was overall minimal residual disease (MRD)-negativity rate at 10-5 by next-generation sequencing. Major secondary endpoints included complete response (CR) or better (≥CR) rate, progression-free survival and sustained MRD-negativity rate at 10-5. At a median follow-up of 58.7 months, the MRD-negativity rate was 60.9% with D-VRd versus 39.4% with VRd (odds ratio, 2.37; 95% confidence interval (CI), 1.58-3.55; P < 0.0001). Rates of ≥CR (81.2% versus 61.6%; P < 0.0001) and sustained MRD negativity (≥12 months; 48.7% versus 26.3%; P < 0.0001) were significantly higher with D-VRd versus VRd. Risk of progression or death was 43% lower for D-VRd versus VRd (hazard ratio, 0.57; 95% CI, 0.41-0.79; P = 0.0005). Adverse events were consistent with the known safety profiles for daratumumab and VRd. Combining daratumumab with VRd produced deeper and more durable MRD responses versus VRd alone. The present study supports D-VRd quadruplet therapy as a new standard of care for transplant-ineligible or transplant-deferred NDMM. ClinicalTrials.gov registration: NCT03652064 .

• MeSH
• bortezomib * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• dexamethason * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• lenalidomid * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   diagnóza   mortalita   patologie   MeSH
• monoklonální protilátky * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• reziduální nádor MeSH
• senioři nad 80 let MeSH
• senioři 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
• Názvy látek
• bortezomib * MeSH
• daratumumab MeSH Prohlížeč
• dexamethason * MeSH
• lenalidomid * MeSH
• monoklonální protilátky * MeSH

BACKGROUND: Whether fixed-duration acalabrutinib-venetoclax (with or without obinutuzumab) would result in better progression-free survival than chemoimmunotherapy in patients with untreated chronic lymphocytic leukemia (CLL) is unknown. METHODS: In this phase 3, open-label trial, we included patients 18 years of age or older who had an Eastern Cooperative Oncology Group performance-status score of 0 to 2 (range, 0 to 5, with higher numbers indicating greater disability) and who did not have a 17p deletion or TP53 mutation. Patients were randomly assigned, in a 1:1:1 ratio, to receive acalabrutinib-venetoclax (acalabrutinib, cycles 1 to 14; venetoclax, cycles 3 to 14), acalabrutinib-venetoclax-obinutuzumab (as above, plus obinutuzumab, cycles 2 to 7), or chemoimmunotherapy with the investigator's choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab (cycles 1 to 6). The primary end point was progression-free survival (acalabrutinib-venetoclax vs. chemoimmunotherapy) in the intention-to-treat population, assessed by blinded independent central review. RESULTS: A total of 867 patients underwent randomization: 291 were assigned to receive acalabrutinib-venetoclax, 286 acalabrutinib-venetoclax-obinutuzumab, and 290 chemoimmunotherapy (of whom 143 received fludarabine-cyclophosphamide-rituximab and 147 bendamustine-rituximab). The median age of the patients was 61 years (range, 26 to 86), 64.5% were men, and 58.6% had unmutated IGHV. Estimated 36-month progression-free survival at a median follow-up of 40.8 months was 76.5% with acalabrutinib-venetoclax, 83.1% with acalabrutinib-venetoclax-obinutuzumab, and 66.5% with chemoimmunotherapy (hazard ratio for disease progression or death with acalabrutinib-venetoclax vs. chemoimmunotherapy, 0.65 [95% confidence interval {CI}, 0.49 to 0.87], P = 0.004; for the comparison of acalabrutinib-venetoclax-obinutuzumab with chemoimmunotherapy, P<0.001). Estimated 36-month overall survival was 94.1% with acalabrutinib-venetoclax, 87.7% with acalabrutinib-venetoclax-obinutuzumab, and 85.9% with chemoimmunotherapy. Neutropenia, the most common adverse event of clinical interest of grade 3 or higher, was reported in 32.3%, 46.1%, and 43.2% in the three groups, respectively; death from coronavirus disease 2019 was reported in 10, 25, and 21 patients in the three groups. CONCLUSIONS: Acalabrutinib-venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients with previously untreated CLL. (Funded by AstraZeneca; AMPLIFY ClinicalTrials.gov number, NCT03836261.).

• MeSH
• analýza podle původního léčebného záměru MeSH
• bendamustin hydrochlorid aplikace a dávkování   MeSH
• benzamidy * aplikace a dávkování   škodlivé účinky   MeSH
• bicyklické sloučeniny heterocyklické aplikace a dávkování   škodlivé účinky   MeSH
• chronická lymfatická leukemie * farmakoterapie   genetika   mortalita   MeSH
• cyklofosfamid aplikace a dávkování   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• protokoly protinádorové kombinované chemoterapie * aplikace a dávkování   škodlivé účinky   MeSH
• pyraziny * aplikace a dávkování   škodlivé účinky   MeSH
• rituximab aplikace a dávkování   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sulfonamidy * aplikace a dávkování   škodlivé účinky   MeSH
• vidarabin aplikace a dávkování   škodlivé účinky   analogy a deriváty   analogy a deriváty   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
• srovnávací studie MeSH
• Názvy látek
• acalabrutinib MeSH Prohlížeč
• bendamustin hydrochlorid MeSH
• benzamidy * MeSH
• bicyklické sloučeniny heterocyklické MeSH
• cyklofosfamid MeSH
• fludarabine MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• obinutuzumab MeSH Prohlížeč
• pyraziny * MeSH
• rituximab MeSH
• sulfonamidy * MeSH
• venetoclax MeSH Prohlížeč
• vidarabin MeSH

BACKGROUND: Bortezomib, lenalidomide, and dexamethasone (VRd) is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear. METHODS: In an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)-negative status in patients with a complete response. RESULTS: A total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P = 0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P = 0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups. CONCLUSIONS: Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. (Funded by Sanofi and a Cancer Center Support Grant; IMROZ ClinicalTrials.gov number, NCT03319667.).

• MeSH
• bortezomib * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• dexamethason * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• humanizované monoklonální protilátky terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• Kaplanův-Meierův odhad MeSH
• lenalidomid * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   mortalita   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• reziduální nádor MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• 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
• Názvy látek
• bortezomib * MeSH
• dexamethason * MeSH
• humanizované monoklonální protilátky MeSH
• isatuximab MeSH Prohlížeč
• lenalidomid * MeSH

WHAT IS THIS SUMMARY ABOUT?: This summary describes the first analysis of the PERSEUS study, which looked at adults with multiple myeloma that had never been treated before, also called newly diagnosed multiple myeloma. Multiple myeloma is a type of cancer in the blood, specifically in plasma cells within the soft, spongy tissue in the center of most bones, called the bone marrow. Researchers wanted to see if adding daratumumab (D) to a standard treatment of three other medicines called VRd, which stands for bortezomib (V), lenalidomide (R), and dexamethasone (d), could stop the multiple myeloma from getting worse and help participants live longer without multiple myeloma.Half of the participants were assigned to the treatment plan with daratumumab; they received D-VRd during initial treatment phases (induction and consolidation), followed by daratumumab as well as lenalidomide (D-R) in the maintenance phase. The other half of participants received treatment without daratumumab; they received VRd induction and consolidation followed by lenalidomide alone (R) maintenance. In addition, all participants were able to receive an autologous stem cell transplant, a procedure used to further help reduce multiple myeloma. WHAT WERE THE RESULTS?: At the time of this analysis of PERSEUS, about 4 years after participants started the study, participants who received D-VRd treatment followed by D-R maintenance had a better response to treatment (as measured by specific markers of multiple myeloma) and were more likely to be alive and free from their multiple myeloma getting worse in comparison to participants who received VRd followed by R maintenance. Side effects (unwanted or undesirable effects of treatment) in both treatment groups were in line with the known side effects of daratumumab and VRd. WHAT DO THE RESULTS MEAN?: The results of the PERSEUS study showed that including daratumumab in D-VRd induction/consolidation and D-R maintenance was better for treating multiple myeloma than the current standard VRd treatment followed by R maintenance alone in adults with a new diagnosis of multiple myeloma who were also able to receive an autologous stem cell transplant. Of importance, there were no unexpected side effects in either group.Clinical Trial Registration: NCT02874742 (GRIFFIN) (ClinicalTrials.gov).

• Klíčová slova
• VRd, blood, cancer, daratumumab, multiple myeloma, plain language summary,
• MeSH
• bortezomib * aplikace a dávkování   terapeutické užití   MeSH
• dexamethason * aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• klinické zkoušky, fáze II jako téma MeSH
• lenalidomid * aplikace a dávkování   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   diagnóza   MeSH
• monoklonální protilátky * aplikace a dávkování   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• randomizované kontrolované studie jako téma MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• informační letáky pro pacienty MeSH
• Názvy látek
• bortezomib * MeSH
• daratumumab MeSH Prohlížeč
• dexamethason * MeSH
• lenalidomid * MeSH
• monoklonální protilátky * MeSH

BACKGROUND: Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast cancer (TNBC). Preclinical data suggest that TNBC is dependent on proteasomes; however, clinical observations indicate that the efficacy of proteasome inhibitors in TNBC may be limited, suggesting the need for combination therapies. METHODS: We compared bortezomib and carfilzomib and their combinations with nelfinavir and lopinavir in TNBC cell lines and primary cells with regard to their cytotoxic activity, functional proteasome inhibition, and induction of the unfolded protein response (UPR). Furthermore, we evaluated the involvement of sXBP1, ABCB1, and ABCG2 in the cytotoxic activity of drug combinations. RESULTS: Carfilzomib, via proteasome β5 + β2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits β5 + β1 proteasome subunits. The cytotoxicity of carfilzomib was significantly potentiated by nelfinavir or lopinavir. Carfilzomib with lopinavir induced endoplasmic reticulum stress and pro-apoptotic UPR through the accumulation of excess proteasomal substrate protein in TNBC in vitro. Moreover, lopinavir increased the intracellular availability of carfilzomib by inhibiting carfilzomib export from cells that express high levels and activity of ABCB1, but not ABCG2. CONCLUSION: Proteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.

• MeSH
• ABC transportér z rodiny G, člen 2 * metabolismus   antagonisté a inhibitory   MeSH
• apoptóza účinky léků   MeSH
• bortezomib * farmakologie   MeSH
• inhibitory HIV-proteasy * farmakologie   MeSH
• inhibitory proteasomu farmakologie   MeSH
• lidé MeSH
• Lopinavir * farmakologie   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny antagonisté a inhibitory   metabolismus   MeSH
• nelfinavir * farmakologie   MeSH
• oligopeptidy * farmakologie   MeSH
• P-glykoproteiny metabolismus   MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   MeSH
• signální dráha UPR * účinky léků   MeSH
• stres endoplazmatického retikula účinky léků   MeSH
• synergismus léků * MeSH
• triple-negativní karcinom prsu * farmakoterapie   patologie   MeSH
• XBP1 metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 * MeSH
• ABCB1 protein, human MeSH Prohlížeč
• ABCG2 protein, human MeSH Prohlížeč
• bortezomib * MeSH
• carfilzomib MeSH Prohlížeč
• inhibitory HIV-proteasy * MeSH
• inhibitory proteasomu MeSH
• Lopinavir * MeSH
• nádorové proteiny MeSH
• nelfinavir * MeSH
• oligopeptidy * MeSH
• P-glykoproteiny MeSH
• XBP1 protein, human MeSH Prohlížeč
• XBP1 MeSH

BACKGROUND: Triplet or quadruplet therapies incorporating proteasome inhibitors, immunomodulators, and anti-CD38 antibodies have led to prolonged survival among patients with newly diagnosed multiple myeloma; however, most patients have a relapse. Frontline lenalidomide therapy has increased the number of patients with lenalidomide-refractory disease at the time of the first relapse. METHODS: In this phase 3, randomized, open-label trial, we evaluated belantamab mafodotin, pomalidomide, and dexamethasone (BPd), as compared with pomalidomide, bortezomib, and dexamethasone (PVd), in lenalidomide-exposed patients who had relapsed or refractory myeloma after at least one line of therapy. The primary end point was progression-free survival. Disease response and safety were also assessed. RESULTS: A total of 302 patients underwent randomization; 155 were assigned to the BPd group, and 147 to the PVd group. At a median follow-up of 21.8 months (range, <0.1 to 39.2), the 12-month estimated progression-free survival with BPd was 71% (95% confidence interval [CI], 63 to 78), as compared with 51% (95% CI, 42 to 60) with PVd (hazard ratio for disease progression or death, 0.52; 95% CI, 0.37 to 0.73; P<0.001). Data on overall survival were immature. The percentage of patients with a response to treatment (partial response or better) was 77% (95% CI, 70 to 84) in the BPd group and 72% (95% CI, 64 to 79) in the PVd group; 40% (95% CI, 32 to 48) and 16% (95% CI, 11 to 23), respectively, had a complete response or better. Grade 3 or higher adverse events occurred in 94% of the patients in the BPd group and 76% of those in the PVd group. Ocular events occurred in 89% of the patients who received BPd (grade 3 or 4 in 43%) and 30% of those who received PVd (grade 3 or 4 in 2%); ocular events in the BPd group were managed with belantamab mafodotin dose modification. Ocular events led to treatment discontinuation in 9% of the patients in the BPd group and in no patients in the PVd group. CONCLUSIONS: Among lenalidomide-exposed patients with relapsed or refractory myeloma, BPd conferred a significantly greater benefit than PVd with respect to progression-free survival, as well as deeper, more durable responses. Ocular events were common but were controllable by belantamab mafodotin dose modification. (Funded by GSK; DREAMM-8 ClinicalTrials.gov number, NCT04484623; EudraCT number, 2018-004354-21.).

• MeSH
• bortezomib aplikace a dávkování   škodlivé účinky   MeSH
• chemorezistence MeSH
• dexamethason * aplikace a dávkování   škodlivé účinky   MeSH
• doba přežití bez progrese choroby * MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   škodlivé účinky   MeSH
• Kaplanův-Meierův odhad MeSH
• lenalidomid aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru diagnóza   farmakoterapie   mortalita   MeSH
• mnohočetný myelom * diagnóza   farmakoterapie   mortalita   MeSH
• oční nemoci chemicky indukované   epidemiologie   MeSH
• progrese nemoci MeSH
• protokoly protinádorové kombinované chemoterapie * aplikace a dávkování   škodlivé účinky   MeSH
• recidiva MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• thalidomid * aplikace a dávkování   škodlivé účinky   analogy a deriváty   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
• srovnávací studie MeSH
• Názvy látek
• belantamab mafodotin MeSH Prohlížeč
• bortezomib MeSH
• dexamethason * MeSH
• humanizované monoklonální protilátky * MeSH
• lenalidomid MeSH
• pomalidomide MeSH Prohlížeč
• thalidomid * MeSH

BACKGROUND: Belantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies. METHODS: In this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status. RESULTS: In total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved. CONCLUSIONS: As compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.).

• MeSH
• bortezomib * aplikace a dávkování   škodlivé účinky   MeSH
• dexamethason * aplikace a dávkování   škodlivé účinky   MeSH
• doba přežití bez progrese choroby * MeSH
• dospělí MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   mortalita   MeSH
• monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• progrese nemoci MeSH
• protokoly protinádorové kombinované chemoterapie * aplikace a dávkování   škodlivé účinky   MeSH
• reziduální nádor MeSH
• senioři nad 80 let MeSH
• senioři 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
• srovnávací studie MeSH
• Názvy látek
• belantamab mafodotin MeSH Prohlížeč
• bortezomib * MeSH
• daratumumab MeSH Prohlížeč
• dexamethason * MeSH
• humanizované monoklonální protilátky MeSH
• monoklonální protilátky MeSH