Exposure-response analyses for selection/confirmation of optimal isatuximab dosing regimen in combination with pomalidomide/dexamethasone treatment in patients with multiple myeloma.

Isatuximab is an approved anti-CD38 monoclonal antibody with multiple antitumor modes of action. An exposure-response (E-R) analysis using data from patients with relapsed/refractory multiple myeloma (RRMM) enrolled in a phase Ib clinical study who received isatuximab at doses from 5 to 20 mg/kg weekly for 1 cycle (4 weeks) followed by every 2 weeks thereafter (qw/q2w) in combination with pomalidomide/dexamethasone (n = 44) was first used to determine the optimal dose/schedule for the phase III ICARIA-MM study. It was complemented by an E-R analysis from a second phase Ib study of patients who received isatuximab at doses from 3 to 10 mg/kg q2w or 10 or 20 mg/kg qw/q2w in combination with lenalidomide/dexamethasone (n = 52). Plasma trough concentration at week 4 (CT4W) was the best predictor for response, and the benefit of the initial 4-weekly administration was confirmed. Although the predicted overall response rate (ORR) was higher at 20 mg/kg vs. 10 mg/kg, the 95% confidence intervals were overlapping. Considering the high probability of success to reach the targeted ORR of greater than or equal to 60%, 10 mg/kg qw/q2w was selected. Results of the E-R analysis from the lenalidomide/dexamethasone study and published disease modeling using data from both phase Ib clinical studies reinforced 10 mg/kg qw/q2w as the optimal dose/schedule for the phase III ICARIA-MM study. E-R analysis showed that higher CT4W was associated with higher ORR. Developed models supported the phase III isatuximab dosing regimen selection/confirmation of 10 mg/kg qw/q2w for use in combination with pomalidomide/dexamethasone in patients with RRMM.

Dietary patterns, digestive symptoms, and health-related quality of life in women reporting minor digestive symptoms.

OBJECTIVE: Digestive symptoms are reported to result from a wide range of dietary components. Dietary pattern analysis is a useful method when considering the entire diet, rather than individual foods or nutrients, providing an opportunity to take interactions into account. The aim of the present study was to investigate, using a dietary pattern approach, the relationship between diet, digestive symptoms, and health-related quality of life (HRQoL) in women reporting minor digestive symptoms. METHODS: Analysis was performed on dietary and digestive symptoms data collected in France. Women (N = 308, ages 18-60 y) reporting a bowel movement frequency within the normal range (3-21 stools/wk) but with minor digestive symptoms in the previous month were studied. Dietary data was collected using three 24-h recalls. K-means was used to divide the dietary data into clusters. The frequency of digestive symptoms (abdominal discomfort or pain, bloating, flatulence, borborygmi) and bowel movements were evaluated over a 2-wk period. HRQoL was also assessed. RESULTS: Four dietary clusters were identified and characterized as unhealthy, balance, healthy, and convenience. No differences were found in the frequency of digestive symptoms according to dietary cluster, except for flatulence (P = 0.030), which was more prevalent in the unhealthy and convenience clusters. No significant differences were observed in HRQoL according to dietary clusters. CONCLUSIONS: Results from the present study demonstrated that even within a relatively homogeneous sample of French women, distinct dietary patterns can be identified but without significant differences in digestive symptoms (except for flatulence) or HRQoL.

Dietary patterns differently associate with inflammation and gut microbiota in overweight and obese subjects.

BACKGROUND: Associations between dietary patterns, metabolic and inflammatory markers and gut microbiota are yet to be elucidated. OBJECTIVES: We aimed to characterize dietary patterns in overweight and obese subjects and evaluate the different dietary patterns in relation to metabolic and inflammatory variables as well as gut microbiota. DESIGN: Dietary patterns, plasma and adipose tissue markers, and gut microbiota were evaluated in a group of 45 overweight and obese subjects (6 men and 39 women). A group of 14 lean subjects were also evaluated as a reference group. RESULTS: Three clusters of dietary patterns were identified in overweight/obese subjects. Cluster 1 had the least healthy eating behavior (highest consumption of potatoes, confectionary and sugary drinks, and the lowest consumption of fruits that was associated also with low consumption of yogurt, and water). This dietary pattern was associated with the highest LDL cholesterol, plasma soluble CD14 (p = 0.01) a marker of systemic inflammation but the lowest accumulation of CD163+ macrophages with anti-inflammatory profile in adipose tissue (p = 0.05). Cluster 3 had the healthiest eating behavior (lower consumption of confectionary and sugary drinks, and highest consumption of fruits but also yogurts and soups). Subjects in this Cluster had the lowest inflammatory markers (sCD14) and the highest anti-inflammatory adipose tissue CD163+ macrophages. Dietary intakes, insulin sensitivity and some inflammatory markers (plasma IL6) in Cluster 3 were close to those of lean subjects. Cluster 2 was in-between clusters 1 and 3 in terms of healthfulness. The 7 gut microbiota groups measured by qPCR were similar across the clusters. However, the healthiest dietary cluster had the highest microbial gene richness, as evaluated by quantitative metagenomics. CONCLUSION: A healthier dietary pattern was associated with lower inflammatory markers as well as greater gut microbiota richness in overweight and obese subjects. TRIAL REGISTRATION: ClinicalTrials.gov NCT01314690.