14 research outputs found
THE ANALYSIS OF EPIGENOE OF MULTIPE MYELOMA REVEALS A HYPERMETHYLATION OF THE DNA IN SPECIFIC ENHANCER REGIONS OF B CELLS
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Phase II Clinical and Pharmacokinetic Study of Plitidepsin 3-Hour Infusion Every Two Weeks Alone or with Dexamethasone in Relapsed and Refractory Multiple Myeloma
Purpose: This trial evaluated the antitumor activity and safety of the marine-derived cyclodepsipeptide
plitidepsin in patients with relapsed/refractory multiple myeloma.
Experimental Design: This was a prospective, multicenter, open-label, single-arm, phase II trial with
plitidepsin at 5 mg/m2 as a 3-hour i.v. infusion every two weeks. The protocol was amended to allow
patients with suboptimal response to single-agent plitidepsin to add 20 mg/day on days 1 to 4 of oral
dexamethasone every two weeks.
Results: Fifty-one patients started treatment with plitidepsin and 47 were evaluable for efficacy. The
overall response rate (complete response plus partial response plus minimal response) was 13% with
plitidepsin alone and 22% in the cohort of patients with the addition of dexamethasone (n = 19, 18
evaluable). Both plitidepsin alone and with dexamethasone were feasible and well tolerated. Anemia
(29%) and thrombocytopenia (18%) were the most frequent grade 3/4 hematologic toxicities. Fatigue
(16%), muscular toxicity (6%), and transient alanine aminotransferase/aspartate aminotransferase
(27%) and creatine phosphokinase (23%) increases were the most relevant nonhematologic side effects.
A prolonged plasma half-life was observed in responding patients as compared with nonresponding patients
(P = 0.009).
Conclusions: Single-agent plitidepsin has limited but reproducible activity in relapsed/refractory multiple
myeloma patients. Activity observed after dexamethasone addition merits further study. Both regimens
were well tolerated in this heavily pretreated population
Phase II Clinical and Pharmacokinetic Study of Plitidepsin 3-Hour Infusion Every Two Weeks Alone or with Dexamethasone in Relapsed and Refractory Multiple Myeloma
Purpose: This trial evaluated the antitumor activity and safety of the marine-derived cyclodepsipeptide
plitidepsin in patients with relapsed/refractory multiple myeloma.
Experimental Design: This was a prospective, multicenter, open-label, single-arm, phase II trial with
plitidepsin at 5 mg/m2 as a 3-hour i.v. infusion every two weeks. The protocol was amended to allow
patients with suboptimal response to single-agent plitidepsin to add 20 mg/day on days 1 to 4 of oral
dexamethasone every two weeks.
Results: Fifty-one patients started treatment with plitidepsin and 47 were evaluable for efficacy. The
overall response rate (complete response plus partial response plus minimal response) was 13% with
plitidepsin alone and 22% in the cohort of patients with the addition of dexamethasone (n = 19, 18
evaluable). Both plitidepsin alone and with dexamethasone were feasible and well tolerated. Anemia
(29%) and thrombocytopenia (18%) were the most frequent grade 3/4 hematologic toxicities. Fatigue
(16%), muscular toxicity (6%), and transient alanine aminotransferase/aspartate aminotransferase
(27%) and creatine phosphokinase (23%) increases were the most relevant nonhematologic side effects.
A prolonged plasma half-life was observed in responding patients as compared with nonresponding patients
(P = 0.009).
Conclusions: Single-agent plitidepsin has limited but reproducible activity in relapsed/refractory multiple
myeloma patients. Activity observed after dexamethasone addition merits further study. Both regimens
were well tolerated in this heavily pretreated population
Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma
Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic
heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized.
In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated
that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in
part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the
NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast
differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and
clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin
(TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM.
Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell
phenotype
Mechanical ventilation in patients with cardiogenic pulmonary edema : a sub-analysis of the LUNG SAFE study
Patients with acute respiratory failure caused by cardiogenic pulmonary edema (CPE) may require mechanical ventilation that can cause further lung damage. Our aim was to determine the impact of ventilatory settings on CPE mortality. Patients from the LUNG SAFE cohort, a multicenter prospective cohort study of patients undergoing mechanical ventilation, were studied. Relationships between ventilatory parameters and outcomes (ICU discharge/hospital mortality) were assessed using latent mixture analysis and a marginal structural model. From 4499 patients, 391 meeting CPE criteria (median age 70 [interquartile range 59-78], 40% female) were included. ICU and hospital mortality were 34% and 40%, respectively. ICU survivors were younger (67 [57-77] vs 74 [64-80] years, p < 0.001) and had lower driving (12 [8-16] vs 15 [11-17] cmHO, p < 0.001), plateau (20 [15-23] vs 22 [19-26] cmHO, p < 0.001) and peak (21 [17-27] vs 26 [20-32] cmHO, p < 0.001) pressures. Latent mixture analysis of patients receiving invasive mechanical ventilation on ICU day 1 revealed a subgroup ventilated with high pressures with lower probability of being discharged alive from the ICU (hazard ratio [HR] 0.79 [95% confidence interval 0.60-1.05], p = 0.103) and increased hospital mortality (HR 1.65 [1.16-2.36], p = 0.005). In a marginal structural model, driving pressures in the first week (HR 1.12 [1.06-1.18], p < 0.001) and tidal volume after day 7 (HR 0.69 [0.52-0.93], p = 0.015) were related to survival. Higher airway pressures in invasively ventilated patients with CPE are related to mortality. These patients may be exposed to an increased risk of ventilator-induced lung injury. Trial registration Clinicaltrials.gov NCT02010073