Bristol-Myers Squibb (Switzerland)

In the phase 2, double-blind, randomized controlled BEYOND trial (NCT03342404), luspatercept increased hemoglobin levels in patients with non-transfusion-dependent β-thalassemia (NTDT). This study assessed long-term effects of luspatercept on patient-reported outcomes (PROs), using data from BEYOND and patients who continued luspatercept treatment in the phase 3b long-term follow-up (LTFU) study (NCT04064060). In BEYOND, patients received luspatercept or placebo Q3W for ≥ 48 weeks. PRO instruments included NTDT-PRO (BEYOND only), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and 36-Item Short Form Survey (SF-36). Mixed-effects models with repeated measures estimated least squares mean changes from baseline in PROs. PROs were evaluable in 144 patients (luspatercept 95, placebo 49) from BEYOND and 58 (luspatercept) from LTFU. Luspatercept improved NTDT-PRO tiredness/weakness and shortness of breath domain, FACIT-F fatigue subscale, and SF-36 vitality scores versus placebo through double-blind treatment (generally maintained through week 96). In LTFU patients, significant, meaningful improvements from baseline in FACIT-F fatigue subscale and SF-36 vitality scores were observed within 12 weeks of treatment initiation and maintained for up to 5 years. Other FACIT-F and SF-36 domains improved or were maintained throughout LTFU. Luspatercept offers rapid and durable benefits by improving anemia-related symptoms and quality of life in patients with NTDT. Trial Registration: ClinicalTrials.gov Identifier: NCT03342404; NCT04064060.

Carla Marques e Noémia Jorge entrevistam Miguel Real

B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.

190 Background: Microsatellite stable colorectal cancer (MSS-CRC) in advanced-stage disease remains a major therapeutic challenge due to its molecular heterogeneity. While classification frameworks such as CMS (Consensus Molecular Subtypes) and IMF (Intrinsic CMS, MSI, Fibrosis) have improved understanding of localized CRC, they offer limited insight into the biology of metastatic tumors. To address this gap, we implemented a multi-omic study of a cohort of treatment-naïve MSS-CRC patients with synchronous liver metastases (CRLM) and a large MSS-CRC Real World Dataset (RWD). Methods: Paired primary CRC and CRLM specimens from 20 patient underwent comprehensive profiling, including Whole Exome, Transcriptome: bulk and single-nucleus RNA sequencing (snRNA-seq) analysis. The intrinsic CMS framework (iCMS) was applied to characterize tumor-intrinsic states across primary CRC and CRLM. iCMS scores were inferred using previously published templates. Key findings were validated in a real-world dataset (TEMPUS MSS-CRC) profiled using multi-omics approaches. Results: Analysis of 388,018 single nuclei revealed 6 epithelial clusters associated with specific iCMS subtypes, supported by concordant bulk RNA-seq calls. Subtype composition at snRNA-seq level revealed that approximately one-third of tumors exhibited a hybrid phenotype with admixture of iCMS2 and iCMS3 epithelial cells. Tumors that were iCMS-unclassified in bulkRNAseq consistently displayed hybrid composition in snRNA-seq. Similarity metrics (cosine distance) from bulk data correlated with admixture proportions in snRNAseq. Genomic analysis revealed mutations in APC and KRAS as the predominant genetic events in non-hybrid iCMS2 and iCMS3 tumors, aligned with their differential WNT and MAPK pathway activity, respectively. In contrast, iCMS-hybrid tumors were significantly enriched for clonal co-mutations in WNT and MAPK drivers, with overrepresentation of specific KRAS variants (G12D, G13D). These iCMS-hybrid tumors exhibited intermediate WNT-MAPK co-activation. In the metastatic setting, iCMS2 and iCMS3 tumors maintained their subtype identity, whereas iCMS-hybrid primary tumors showed a shift toward iCMS2 dominance in liver, suggesting that the liver microenvironment promotes expansion of the iCMS2 state. Conclusions: Our study identifies a novel iCMS-hybrid phenotype with transcriptomic plasticity and co-activation of WNT and MAPK pathways, offering refined molecular resolution and potential to guide precision therapy in advanced MSS-CRC.

Channel sounding is crucial for achieving Extremely High Throughput (EHT) and Ultra-high reliability (UHR) in next-generation Wi-Fi systems, i.e., Wi-Fi 7 and beyond. In Downlink Multi-User Multiple-Input Multiple-Output (DL MUMIMO) communications, data rate significantly deteriorates under time-varying channel with Doppler effect. Therefore, effective channel sounding mechanisms must balance the Channel State Information (CSI) overhead and CSI staleness, which is governed by the channel coherence time. Despite its critical importance, channel sounding optimization under time-varying channel conditions remains under-explored. This paper addresses this research gap by proposing a cross-layer optimization problem for the channel sounding period with the objective of maximizing data rate by considering the CSI overhead over the MAC layer and the channel capacity degradation over the PHY layer. This problem is then converted into an equivalent formulation leveraging the EHT sounding protocol, which can be solved efficiently using our proposed optimal search algorithm. Through simulations, we evaluate the baseline EHT sounding using outdated beamforming matrices and benchmark it against our proposed solution. The numerical results demonstrate that the channel sounding period optimization significantly reduces CSI overhead by up to 11% while boosting the average data rate by up to 8%.

This article presents the genesis of a magazine, Papeles de Son Armadans, one of the most important periodical publications of the second half of the 20th century. Its biography deserves to be recounted in order to understand the Spanish literary scene during the Franco dictatorship and the early years of democracy, reflected in the many authors and texts published in it. Its longevity, which reached twenty-three years, requires a panoramic and diachronic view, since each of the two hundred and seventy-six issues that comprise the collection tells, in turn, its own story. This is the story of one of the fundamental projects in the life of Camilo José Cela, whose work as a cultural manager was parallel to his literary creation.