Exposure-Response-Based Multiattribute Clinical Utility Score Framework to Facilitate Optimal Dose Selection for Oncology Drugs.

Purpose: The advent of new therapeutic modalities highlighted deficiencies in the traditional maximum tolerated dose approach for oncology drug dose selection and prompted the Food and Drug Administration (FDA)'s initiative, which suggests that sponsors take a holistic approach, including efficacy, safety, and pharmacokinetic (PK) and pharmacodynamic data, in conjunction with integrated exposure-response (ER) analyses. However, this method comes with an inherent challenge of the collation of the multisource data. To address this issue, an ER-based clinical utility score (CUS) framework, combining benefit and risk into a single measurement, was developed.

Pharmacodynamic changes in tumor and immune cells drive iberdomide's clinical mechanisms of activity in relapsed and refractory multiple myeloma.

Iberdomide is a next-generation cereblon (CRBN)-modulating agent in the clinical development in multiple myeloma (MM). The analysis of biomarker samples from relapsed/refractory patients enrolled in CC-220-MM-001 (ClinicalTrials.gov: NCT02773030), a phase 1/2 study, shows that iberdomide treatment induces significant target substrate degradation in tumors, including in immunomodulatory agent (IMiD)-refractory patients or those with low CRBN levels.

Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma.

Background: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide.

Methods: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma.

Association Between Human Leukocyte Antigen Polymorphism and Human Papillomavirus Infection in Brazilian Women.

Background:: Human papillomavirus (HPV) infection is a necessary cause for cervical cancer, but the majority of genital HPV infections clear spontaneously. Human leukocyte antigen (HLA) polymorphism influences immune response and genetic susceptibility, and its association with cervical cancer was extensively investigated, but few reports focused on HPV infection.

Methods:: We performed molecular typing of , , and genes as well as of HPV in 1226 women enrolled in the Ludwig-McGill cohort study and investigated the influence on cumulative HPV positivity.

Model-based analysis for the population pharmacokinetics of iberdomide and its major active metabolite in healthy subjects and patients with relapsed and refractory multiple myeloma.

Aims: A parent-metabolite population pharmacokinetic (popPK) model of iberdomide and its pharmacologically active metabolite (M12) was developed and the influence of demographic and disease-related covariates on popPK parameters was assessed based on data from 3 clinical studies of iberdomide (dose range, 0.1-6 mg) in healthy subjects (n = 81) and patients with relapsed and refractory multiple myeloma (n 245).

Methods: Nonlinear mixed effects modelling was used to develop the popPK model based on data from 326 subjects across 3 clinical studies.