Abstract Introduction: In RRMM, increasing rates of pt attrition and decreasing durability of responses with each line of therapy (LOT) necessitate early treatment (tx) with the most effective therapies. Immunotherapies that are widely accessible across different MM tx settings have the potential to change the trajectory of RRMM. Teclistamab (Tec), the first approved BCMA×CD3 bispecific antibody (BsAb) for heavily pretreated RRMM, provided deep, durable responses in MajesTEC-1, with improved efficacy and safety in earlier LOTs. Daratumumab (Dara), a standard-of-care (SoC) foundational CD38 targeted therapy with direct on-tumor activity, has been shown to deplete immunosuppressive T-cells and expand cytotoxic T-cells, creating an immune-permissive microenvironment for synergistic Tec-mediated killing of MM cells. MajesTEC-3 (NCT05083169) evaluates Tec-Dara vs SoC DPd/DVd in RRMM. We report initial results for this first phase 3 study of BsAb therapy in MM. Methods: Eligible pts had 1-3 prior LOTs including a PI and lenalidomide (Len; pts with 1 prior LOT must have been Len-refractory) with progressive disease (PD) on or after the last LOT. Pts with prior BCMA-directed therapy or refractory to anti-CD38 were excluded; prior anti-CD38 exposure was permitted. Pts were randomized 1:1 to Tec-Dara or DPd/DVd. The Tec-Dara group received 28-day cycles (C) of Tec (1.5 mg/kg QW in C1-2 [C1 preceded by the approved step-up dose schedule]; 3 mg/kg Q2W in C3-6; and 3 mg/kg Q4W in C7+) with Dara; steroids were not required after C1 Day 8. Tec and Dara dosing were aligned with the approved Dara schedule. DPd/DVd were administered per approved schedules. Progression-free survival (PFS) by IRC was the primary endpoint; secondary endpoints included complete response or better (≥CR), overall response, minimal residual disease (MRD) negativity (10–5; next-generation sequencing), overall survival (OS), time to worsening of symptoms (MySIm-Q), and safety. Results: 587 pts were randomized (Tec-Dara, n=291; DPd/DVd, n=296). Median (range) age was 64 (25-88) yrs, median number of prior LOTs was 2 (1-3). With 34.5-mo median follow-up, Tec-Dara significantly improved PFS vs DPd/DVd (HR, 0.17; 95% CI, 0.12-0.23; P<0.0001); mPFS was NR and 18.1 mo, and 36-mo PFS rate was 83.4% and 29.7%, respectively. PFS benefit was consistent across all prespecified and clinically relevant pt subgroups, including age ≥75 yrs, Len-refractory, high-risk cytogenetics, ≥60% bone marrow plasma cells, soft-tissue plasmacytomas, and anti-CD38 exposed. Significantly higher rates of ≥CR (81.8% vs 32.1%; OR, 9.56; 95% CI, 6.47-14.14), overall response (89.0% vs 75.3%; OR, 2.65; 95% CI, 1.68-4.18), and MRD-negativity (58.4% vs 17.1%; OR, 6.78; 95% CI, 4.53-10.15) were observed with Tec-Dara (P<0.0001). There were 45 deaths with Tec-Dara and 96 with DPd/DVd, primarily due to PD (4.6%; 20.3%). OS significantly favored Tec-Dara (HR, 0.46; 95% CI, 0.32-0.65; P<0.0001), including across all prespecified subgroups. The 36-mo OS rates were 83.3% and 65.0%, respectively and >90% of Tec-Dara pts alive at 6 mo were also alive at 30 mo. Median time to worsening of MM symptoms was NR with Tec-Dara vs 39.9 mo with DPd/DVd (HR, 0.50; 95% CI, 0.34-0.72; P=0.0002). At data cutoff, 49.4% of pts remained on study tx (Tec-Dara, 71.0%; DPd/DVd, 28.3%). Median tx duration was twice as long with Tec-Dara vs DPd/DVd (32.4 vs 16.1 mo). Frequency of grade 3/4 (Tec-Dara, 95.1%; DPd/DVd, 96.6%) and grade 5 (7.8%; 6.2%) treatment-emergent adverse events (TEAEs), were comparable (safety set: Tec-Dara, n=283; DPd/DVd, n=290). Serious TEAEs occurred in 70.7% Tec-Dara and 62.4% DPd/DVd pts; tx discontinuations due to TEAEs were low (4.6% vs 5.5%). Any grade infections occurred in 96.5% and 84.1% of Tec-Dara and DPd/DVd pts, respectively; grade 3/4 infections occurred in 54.1% and 43.4%. New onset grade ≥3 infections decreased over time, coinciding with transition to Q4W dosing and supported by antimicrobial and Ig prophylaxis guidance. CRS rate was 60.1% (grade 1/2: 44.2%/15.9%) and ICANS was 1.1% with Tec-Dara. Conclusion: We demonstrate the clinically remarkable and statistically significant PFS and OS benefits of Tec-Dara vs SoC triplets in RRMM, with 83.4% of Tec-Dara pts alive and progression-free at 3 yrs. Infections with Tec-Dara were well managed with established protocols. This highly effective, off-the-shelf, immunotherapy combination represents a new SoC for RRMM as early as first relapse.
Abstract Background and aims Excess dietary sodium intake is a major contributor to hypertension and vascular disease and has recently been implicated in cerebral small vessel disease and vascular cognitive impairment through mechanisms beyond blood pressure, including endothelial dysfunction and tau pathology. Despite clear recommendations, sodium consumption remains excessively high due to poor long-term adherence. Substitution of regular salt with plant-based alternatives derived from Salicornia, naturally lower in sodium and enriched in potassium, fiber, and polyphenols, may offer a feasible and sustainable strategy to improve cerebrovascular health and delay cognitive decline. Methods To determine whether reducing dietary sodium by substituting Salicornia-derived vegetable salt (50% less sodium) improves neurovascular function and cognitive outcomes. Secondary aims include identifying vascular and molecular biomarkers and estimating potential population-level effects. Results The project combines preclinical and clinical approaches. In spontaneously hypertensive rats, vegetable salt will be compared with regular salt, assessing cognition, vascular stiffness, neuroimaging, histopathology, and proteomic biomarkers. A prospective, randomized, open-label pilot trial in individuals ≥60 years with transient ischemic attack, small vessel cerebrovascular disease, or cognitive impairment will compare Salicornia salt versus conventional salt over six months. Outcomes include 24-hour urinary sodium, blood pressure, pulse wave velocity, and cognitive performance (MoCA). The project also includes discovery of proteomic biomarkers and population-level analyses using electronic health records to investigate hypertension, treatments, stroke, and cognitive outcomes. Conclusions Primary outcomes include cognitive performance and vascular aging markers. Secondary outcomes include blood pressure control, sodium reduction, molecular signatures, and sex-specific effects. Conflict of interest
Abstract H3K27-mutant diffuse midline gliomas include a rare group of primary spinal tumours which constitute <1% of all pediatric central nervous system tumors. There is a paucity of data on their clinical and radiological characteristics, genomic landscape, and their respective impact on patient outcomes. Here, we present an interim analysis of an international, multi-institutional retrospective cohort study including patients aged <18 years from the International DIPG/DMG Registry, SIOPE (European Society for Paediatric Oncology) and HIT-HGG groups, assessing overall survival (OS) at 12 months, between January 2012 and December 2023. 86/103 patients met study inclusion criteria (54 female (63%), 32 male (37%) with median age at presentation 8 years. The median symptom interval at presentation was 5.5 weeks. 90% of patients presented with back pain and ataxia, with bladder/bowel incontinence in 10%. Median OS was 12 months. Univariate analyses demonstrated no significant association between age (<10-years vs. >10-years), sex, tumor location (cervical vs. thoracolumbar), extent of resection (subtotal/gross-total, HR = 1.094/1.128, respectively), chemotherapy (HR = 1.14), radiotherapy (photon and proton, HR = 0.93), and targeted therapy (HR = 1.2) with overall survival. Neuroimaging characteristics in 32 patients such as spinal canal widening (91%), posterior vertebral scalloping (77%), minor oedema (50%), moderate enhancement (38%), intratumoral hemorrhage (12%), and necrosis (22%) were not associated with overall survival. Of 41 (48%) patients who underwent molecular profiling, 24/41 (59%) had co-occurring TP53 somatic variants (HR = 0.67) or MAPK pathway alterations (12; 29%). Germline NF1 mutation was identified in one patient. DNA methylation profiles of 24 patients (28%) demonstrated high confidence scores (>0.9) in 7 (29%) and MGMT promoter methylation in 9 (38%). Primary spinal DMG appear to share the same molecular profile and clinical outcome with its intracranial counterpart. Understanding clinical, radiological, and biological features of these rare tumors may help to identify early prognostic indicators and improve patient survival and quality of life.
Recent studies suggest that copy number variants (CNVs) may contribute to the missing heritability of complex diseases such as Alzheimer's disease (AD) and related dementias (ADRD). We performed a CNV analysis using genotyping data (Axiom 815 K Spanish biobank array) from the GR@ACE/DEGESCO dementia dataset (n = 20,067) of the Spanish population. Applying PennCNV and extensive quality control, 8275 controls and 7818 dementia cases were selected for gene-level case/control associations. We identified 43,833 CNVs with deletions (47%) and duplications (53%). No genome-wide significant associations were found, but nominal associations were observed in PKP3-SIGIRR and FBRSL1 loci. CNVs in 2970 genes were exclusive to dementia cases and enriched in vascular-related pathways. Notable findings included 14q11.2 duplication and VPS13B deletions in ADRD cases, the latter confirmed by optical genome mapping. Our findings suggest potential novel genes associated with ADRD in the Spanish population. However, the limited resolution of array-based technologies in detecting CNVs warrants further investigation.
Abstract Background and aims Dyslipidemia is a key modifiable vascular risk factor closely linked to recurrent cerebrovascular events and cognitive decline. Polyphenol-rich Salicornia extracts have demostrated vascular and metabolic benefits in experimental settings; however, their effects on lipid profiles in humans remain insufficiently explored. Methods We conducted a pooled analysis of randomized, double-blind, placebo-controlled clinical studies evaluating effects of a 1-g daily dose of a polyphenol-rich Salicornia extract in healthy volunteers and in patients with transient ischemic attack or lacunar stroke. Changes in lipid parameters, including total cholesterol, LDL and HDL cholesterol were analysed over follow-up and compared between Salicornia and placebo groups. Results The pooled analysis included 241 participants. Patients with dyslipidemia exhibited lower baseline levels of total cholesterol, HDL, and LDL. At 12 months, participants receiving Salicornia supplementation showed a greater reduction in total cholesterol compared with placebo (coefficient of variation: −9.76%, p=0.041), along with a parallel decrease in HDL levels (coefficient of variation: −4.2%, p=0.001). In the subgroup of patients on statin therapy, Salicornia was associated with a more pronounced reduction in total cholesterol; however, this difference didn't reach significance. Conclusions In this pooled analysis, polyphenol-rich Salicornia extract was associated with favourable modulation of lipid profiles, particularly total cholesterol. The modest magnitude of the observed effects, especially among patients receiving concomitant statin therapy, may partly reflect a ceiling effect due to optimized baseline lipid-lowering treatment. Overall, these findings support the potential role of Salicornia supplementation as an adjunctive strategy for vascular risk factor management after cerebrovascular events and warrant confirmation in larger trials. Conflict of interest All authors: nothing to disclose except Joan Montaner: co-founder and minority shareholder of the startup Marisma Biomed.
