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7516 Background: With the growing use of anti-CD38 therapies in early multiple myeloma (MM) management, there is a need for data in patients previously exposed to anti-CD38 therapy to guide decision making. In the Phase 3 IRAKLIA trial (NCT05405166), patients with relapsed/refractory MM (RRMM) received the anti-CD38 monoclonal antibody isatuximab (Isa) subcutaneously (SC) delivered via an innovative on-body injector (OBI) or intravenously (IV), with pomalidomide and dexamethasone (Pd). In this post hoc analysis, we examined outcomes in IRAKLIA patients with vs without prior anti-CD38 exposure. Methods: RRMM patients ≥18 years with ≥1 prior line of therapy including lenalidomide and a proteasome inhibitor were randomized to receive Isa SC (n=263) or IV (n=268) weekly in Cycle 1, then every 2 weeks, with Pd. Patients with prior anti-CD38 exposure <9 months (mos) before randomization or intolerance to anti-CD38 were excluded. Refractory patients were defined as those who failed to achieve minimal response on treatment or had progression within 60 days after last dose. Patients receiving Isa SC or IV were pooled. Results: Overall, 67 patients (12.6%) had prior anti-CD38 exposure with a median washout period of 20.2 mos, of which 26 (38.8%) were anti-CD38 refractory. Baseline characteristics were largely consistent between patients with or without prior anti-CD38 exposure; the median follow-up for the overall population was 12 mos. Patients with prior anti-CD38 exposure had an overall response rate (ORR) of 52.2%, 12-mo progression-free survival (PFS) rate of 40.6%, and median PFS of 8.5 mos. In patients without prior exposure, an ORR of 73.5%, 12-mo PFS of 68.8%, and non-estimable (NE) median PFS were reported. Anti-CD38 non-refractory vs refractory patients had an ORR of 48.8% vs 57.7%, 12-mo PFS of 38.9% vs 42.2%, and median PFS of 9.0 vs 7.5 mos. Patients with a longer washout period (>median of 20.2 mos) had an ORR of 63.6%, 12-mo PFS of 61.8% and NE median PFS, whereas patients whose prior anti-CD38 therapy ended more recently (≤median of 20.2 mos) had an ORR of 41.2%, 12-mo PFS of 19.2%, and median PFS of 6.7 mos. The safety profile of Isa + Pd was similar in patients with vs without prior anti-CD38 exposure. Conclusions: Isa + Pd demonstrated clinical benefit across anti-CD38–naïve, anti-CD38–exposed, and anti-CD38–refractory patients. A washout period >median of 20.2 mos resulted in outcomes comparable to those in anti-CD38–naïve patients, and outcomes were consistent between anti-CD38–exposed and anti-CD38–refractory patients after a >9-mo washout period. Efficacy of Isa + Pd in patients with prior anti-CD38 exposure from the IRAKLIA trial presents an opportunity to address an unmet need in a difficult-to-treat patient population. Clinical trial information: NCT05405166 .

7011 Background: Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) will relapse or have refractory disease following 1L treatment (Tx) with SOC chemoimmunotherapy regimens R-CHOP or Pola-RCHP. High risk (HR) populations include those with International Prognostic Index (IPI) score 3–5 and IPI 1–2 with either ≥1 lesion ≥7 cm or baseline LDH >1.3×ULN. GOLCA is a potential, first-in-class, oral CELMoD designed for the Tx of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA induces rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing and immunomodulatory activity. GOLCA 0.4 mg + R-CHOP has shown promising safety, a ≥90% minimal residual disease (MRD) negativity rate, and durable efficacy (24-mo PFS, 79%) in 1L a-BCL (Nowakowski et al, ASH 2025, 476) and is being evaluated in the Phase (Ph) 3 study GOLSEEK-1 (NCT06356129). We report initial Ph1b results with GOLCA + Pola-RCHP in 1L a-BCL. Methods: Pts aged ≥18 y with ECOG PS ≤2, IPI 0–5 (Part 2A) or 2–5 (Part 2B), and newly diagnosed a-BCL with measurable tumorous disease were included. Pts were treated with GOLCA + Pola-RCHP for six 21-day (D) cycles or until disease progression/unacceptable toxicity/study withdrawal. In dose escalation, GOLCA was dosed at 0.2 and 0.4 mg D1–7. In dose expansion, pts were randomized 1:1 to Pola-RCHP + GOLCA 0.2 or 0.4 mg. Primary endpoint: safety; efficacy was a secondary endpoint. Results: At data cutoff, 57 pts were treated with GOLCA + Pola-RCHP (0.2 mg, n=28; 0.4 mg, n=29). Median age was 63 y. Most pts had HR disease (86%) and DLBCL not otherwise specified histology (84%). For known cell of origin (COO), 47% were germinal center B cell (GCB) and 39% non-GCB by Hans algorithm. Forty-seven pts (83%) completed Tx and 52 (91%) entered the follow-up (f/u) period. Grade 3/4 Tx-emergent adverse events occurred in 95% of pts, most frequently neutropenia (86%; an on-target side effect of GOLCA) and anemia (39%). Median relative dose intensity for GOLCA and Pola-RCHP components was >95%. At 15.5 mo median f/u, end of Tx (EOT) complete metabolic response (CMR) rate was 69% at 0.2 mg, 82% at 0.4 mg, and similar across COO subtypes. EOT CMR was consistent in HR pts (65% at 0.2 mg, 83% at 0.4 mg). The 12-mo DOR and PFS rates were 92% and 88% at 0.2 mg, and 96% and 96% at 0.4 mg. In pts with both pre-Tx and EOT ctDNA analysis, 65% and 83% at 0.2 and 0.4 mg achieved MRD negativity (PhasED-Seq) at EOT. Conclusions: GOLCA + Pola-RCHP demonstrated a predictable and manageable safety profile, and addition of GOLCA did not compromise median dose intensity of Pola-RCHP. GOLCA 0.4 mg + Pola-RCHP resulted in a high rate of durable CMRs, high rate of MRD negativity, and a promising 12-mo PFS rate. These data continue to show that GOLCA + SOC regimens R-CHOP and Pola-RCHP has potential to improve outcomes in 1L HR a-BCL. Clinical trial information: NCT04884035 .

Abstract Introduction Transthoracic echocardiography (TTE) identifies a hypercontractile phenotype (HP) in chronic coronary syndromes (CCS), characterized by elevated resting left ventricular (LV) elastance (force = systolic blood pressure/end-systolic volume). To evaluate the prognostic significance and functional correlates of HP. Methods In a prospective multicentre study, 10 677 patients with CCS underwent resting TTE to assess LV ejection fraction (EF), stroke volume, and force by quantitative volumetric echocardiography. All patients were followed for the endpoint of all-cause mortality. In a subset of 5834 patients, stress echocardiography (exercise or dobutamine) was performed for LV contractile reserve and heart rate reserve. Results Patients were stratified into Force quintiles (Q1–Q5). Patients with hypercontractile phenotype exhibited lower stroke volume at rest (Q5 = 34.8 ± 12.3 vs Q1–Q4 = 57.4 ± 19.1 mL; P &lt; .01) and higher EF at rest (Q5 = 64.8 ± 6.9% vs Q1–Q4 = 58.1 ± 8.7%, P &lt; .01). During a median follow-up of 24 months (interquartile range = 12–40 months), 509 deaths occurred. The exposure-adjusted death rate was lowest in Q3 (3.53–4.51 mmHg/mL; 1.03 per 100 person/years) and higher in Q1 (≤2.62 mmHg/mL, 2.88), Q2 (2.63–3.52 mmHg/mL, 1.86), Q4 (4.52–6.11 mmHg/mL, 1.56), and Q5 (HP, &gt;6.11 mmHg/mL; 1.88; P &lt; .0001 vs Q1 and Q3). Multivariable analysis identified HP (Q5; HR 1.531 vs Q3, 95% CI 1.116–2.099; P = .006) and EF (HR 0.963, 95% CI 0.953–0.972; P &lt; .0001) as independent predictors of death. During exercise or dobutamine stress, HP showed reduced LV contractile reserve (ΔEF: Q5 = 4.3 ± 9.4% vs Q1–Q4 = 7.0 ± 9.3%; P &lt; .001) and blunted heart rate reserve (Q5 = 1.77 ± 0.33 vs Q1–Q4 = 1.85 ± 0.39; P &lt; .01). All patients with force-based LV contractile reserve &gt;4.1 (present in 185, 3.2% of the population) survived. Conclusion Patients with CCS with HP assessed by resting TTE demonstrate higher mortality and multilayered functional impairment, including reduced LV contractile and chronotropic reserves. Hypercontractile phenotype improved the prediction of mortality by EF. A ‘stronger’ heart is, in fact, functionally and prognostically weaker.

Purpose: To evaluate the impact of PSMA PET versus conventional imaging for staging, and the effect of dose escalation (DE) to metastatic lymph nodes in cN1 prostate cancer patients treated with EBRT and ADT. Methods: A retrospective multicenter analysis included 197 propensity score-matched patients (77 staged with PSMA PET, 120 with conventional imaging) treated with EBRT and ADT, with or without DE to lymph node metastases. Matching criteria were T stage, nodal involvement, imaging modality, Gleason score, and ADT duration. Primary endpoint was metastasis-free survival (MFS); secondary endpoints included overall survival (OS), locoregional control (LRC), and toxicity. Results: Median follow-up was 42 months (IQR: 25–59). Median EQD2 (alpha/beta=1.5) to elective nodes was 46 Gy, and to metastatic nodes, 66 Gy (PSMA PET) and 63 Gy (conventional imaging). The 3-year MFS was 80.5% (95% CI: 71.3–90.8%) for PSMA PET and 77.2% (95% CI: 69.5–85.8%) for conventional imaging; 5-year MFS was 59.3% versus 65.8% ( P =0.57). OS at 5 years was 82.2% (PSMA PET) and 77.4% (conventional imaging) ( P =0.72). On multivariable analysis, ISUP grade group 3–5 predicted earlier metastasis (HR: 4.03, 95% CI: 1.61–10.06; P =0.003); higher prostate dose (EQD2 ≥113 Gy) improved MFS (HR: 0.53, 95% CI: 0.30–0.95; P =0.033); long-term ADT (≥24 mo) improved OS (HR: 0.38, 95% CI: 0.19–0.78; P =0.009). No significant difference in toxicity was observed between groups. Conclusions: PSMA PET staging and nodal dose escalation >60 Gy were safe but did not improve MFS, OS, or LRC. ISUP grade group 3–5 and higher prostate dose significantly influenced outcomes.

Abstract Aims Mitral valve prolapse (MVP) is a common valvular disorder associated with ventricular arrhythmias (VAs) in a subgroup of patients, known as arrhythmic MVP (AMVP). Arrhythmic MVP patients with malignant VAs typically receive an implantable cardioverter-defibrillator (ICD) for secondary prevention. However, data regarding the incidence of appropriate ICD therapy and the type of arrhythmia recurrence in this population remain scarce. This study aimed to evaluate the incidence of appropriate ICD therapies and type of arrhythmia recurrence in AMVP patients with an ICD implanted for secondary prevention. Methods and results A systematic literature search was conducted in PubMed/MEDLINE and EMBASE databases until January 2025. Studies reporting the incidence of appropriate ICD therapy in AMVP patients were included. A total of 9 studies met the inclusion criteria, resulting in 166 AMVP patients with ICDs for secondary prevention. The mean age was 41.8 years, with 55.8% of patients being female. Over a weighted mean follow-up of 4.9 ± 3.1 years, 34.9% [95% confidence interval (CI): 28.1–42.5] of the patients experienced recurrence of VA. The pooled incidence of appropriate ICD therapies during follow-up was 8.1 per 100 person-years (95% CI: 5.6–10.5, I2: 11.7%). Regarding the type of arrhythmic recurrence, the majority of arrhythmias (53.8%, 95% CI: 44.3–63.0%) were in the form of ventricular fibrillation or polymorphic ventricular tachycardia (VT), while the remaining arrhythmias were reported as monomorphic VT. Among 67 ventricular arrhythmic episodes reported in 7 studies with available data, 65 required shock therapy, corresponding to a shock proportion of 97.0% (95% CI: 89.6–99.6%). Conclusion Arrhythmic MVP patients with ICDs for secondary prevention exhibit a high risk of recurrent arrhythmias, with recurrences in the form of polymorphic VA occurring in more than half of the cases. PROSPERO registration number: CRD42024588610

Sleep disturbances are common in multiple sclerosis (MS) and contribute to increased symptom burden. Behavioral sleep hygiene practices are potentially modifiable factors influencing sleep and related symptoms, yet their role in MS remains insufficiently explored. This cross-sectional study comprised 175 MS patients. Sleep hygiene was assessed using a behavioral checklist covering a regular sleep schedule, avoidance of daytime naps, limitation of evening caffeine intake, reduced evening screen exposure, and optimization of the sleep environment. The instruments included the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS), the Athens Insomnia Scale (AIS), the Epworth Sleepiness Scale (ESS), and the Hospital Anxiety and Depression Scale (HADS). Higher sleep hygiene adherence was associated with lower daytime sleepiness (ESS: r = −0.18, p = 0.020), anxiety (HADS-A: r = −0.16, p = 0.034), and depression (HADS-D: r = −0.15, p = 0.047). Patients with higher adherence (score ≥ 3) demonstrated significantly lower MFIS, AIS, ESS, and HADS-D scores compared with those with lower adherence (all p < 0.05). Multivariate regression showed that sleep hygiene adherence was independently associated with lower MFIS (β = −3.24, 95% CI: −6.06 to −0.41, p = 0.025), ESS (β = −0.85, 95% CI: −6.06 to −0.41, p = 0.016), HADS-A (β = −0.67, 95% CI: −1.23 to −0.11, p = 0.019), and HADS-D scores (β = −0.62, 95% CI: −1.17; −0.08, p = 0.026). Better adherence to sleep hygiene practices may be associated with a lower symptom burden in MS.

Abstract Background While immunologic aging impacts immune responses to vaccination, consistent biomarkers associated with aging of the immune system and suboptimal serologic response to influenza vaccination have not been well-studied. Identification of readily measurable biomarkers of immunosenescence may have predictive clinical utility and inform targeted influenza vaccination strategies and future research into aging of the immune system. Methods We quantified multiple serum/plasma and cell-based parameters related to immune aging (CMV serostatus, plasma cytokines/chemokines, TREC, TERT, NK cell functionality, and DNA methylation clock) at baseline in an adult (age range 18-85) cohort of 2019-2020 influenza vaccine recipients (n=337) and evaluated their associations with vaccine-induced HAI response to influenza A/H1N1, A/H3N2 and B/Victoria strains. Results CMV IgG titers were significantly positively correlated with vaccine-induced increases in HAI antibody titers to influenza A/H1N1 ( p= 0.02) and A/H3N2 ( p =0.014). CMV IgG titers ( p= 0.00096) and CMV seropositivity ( p= 0.003) were also associated with Day 28 HAI seropositivity against influenza A/H3N2 in subjects seronegative at baseline. Conversely, plasma MCP-1 levels were negatively associated with HAI responses to the A/H3N2 ( p= 0.04) strain. These findings were significant independent of age, sex or vaccine type received (high vs standard-dose seasonal influenza vaccine) Conclusions Our identification of significant relationships between easily quantifiable immune markers and HAI responses to influenza A vaccine strains across sex and age enhances our knowledge of specific links between immune aging and influenza vaccine-induced immunity. These markers could be leveraged for predicting response to influenza immunization.

PURPOSE BRCA carriers face high risks of developing both breast and ovarian/fallopian tube cancers (hereafter referred to as ovarian ). Among BRCA carriers with ovarian cancer, it is not clear whether the risk of breast cancer is sufficiently high that risk-reducing mastectomy should be offered. This study aimed to assess the risk of breast cancer BRCA carriers after a diagnosis of ovarian cancer. METHODS We included women with a pathogenic/likely pathogenic variant in BRCA1 or BRCA2 , a diagnosis of ovarian cancer, and no other cancer history and no risk-reducing bilateral mastectomy. Women were followed for incident breast cancer from the date of ovarian cancer diagnosis or the date of baseline questionnaire, whichever came last. The 5-, 10-, and 15-year cumulative risks of breast cancer were compared for women with ovarian cancer and an age-matched set of control women without ovarian cancer. RESULTS A total of 960 participants with ovarian cancer were identified (814 BRCA1 and 146 BRCA2 carriers). After a mean follow-up of 4.9 years, 41 women (4.3%) developed breast cancer, at a mean age at diagnosis of 57.5 years (range, 39-74). Actuarial cumulative breast cancer risks after ovarian cancer were 4.4%, 8.9%, and 11.5% at 5, 10, and 15 years, respectively. Only three breast cancer–related deaths occurred. Among 741 age-matched BRCA carriers without ovarian cancer, actuarial cumulative risks of breast cancer were 20.9%, 38.6%, and 47.2% at 5, 10, and 15 years, respectively. The hazard ratio for breast cancer, after an ovarian cancer diagnosis, compared with no ovarian cancer, was 0.18 ([95% CI, 0.12 to 0.27]; P < .0001). CONCLUSION After ovarian cancer, BRCA carriers have a relatively low risk of breast cancer. Risk-reducing mastectomy should not be recommended routinely, but might be considered for long-term survivors. Magnetic resonance imaging surveillance and/or mammography is a realistic alternative.

Obesity is increasingly prevalent among living kidney donor candidates, presenting complex clinical, ethical, and logistical challenges. Although obesity is linked to increased post-donation hypertension, diabetes, proteinuria, and chronic kidney disease, the overall absolute risks are modest and may differ depending on metabolic health and patterns of fat distribution. Current reliance on body mass index alone fails to capture the full spectrum of obesity-related risks, leading to inconsistent donor selection practices and potential inequities. This review examines the pathophysiological mechanisms of obesity-related kidney injury and available evidence on comorbidities and postdonation outcomes related to obesity. We discuss tools for better risk stratification, such as imaging-based adiposity assessment and personalized weight management strategies, and note that some risks may remain after weight loss. Barriers such as rigid body mass index cutoffs, limited access to treatment, and lack of long-term follow-up exacerbate disparities in access to donation. We argue for a shift toward individualized, risk-based evaluation supported by multidisciplinary care. We underscore the importance of donor counseling and advocate for a comprehensive, rather than paternalistic approach to living kidney donor selection. Advancing safe and equitable living donation in the context of rising obesity rates will necessitate revised guidelines, improved access to treatment, and an ongoing commitment to donor well-being.

Background Measles remains a public health threat in the United States with over 50,000 cases being reported from 1989 through 1991 with continued smaller outbreaks. Measles vaccine failure is in part to blame for these large-scale outbreaks. The human leukocyte antigen (HLA) genes are important determinants of immune response to measles virus and vaccine. To examine the influence that HLA polymorphisms may have on measles vaccine antibody response, we compared the distribution of HLA-DRB1 alleles between measles vaccine nonresponders and hyper-responders. Methods We determined the seroprevalence of measles antibody in 881 school children immunized with measles-mumps-rubella-II at age 15 months using a whole virus IgG EIA. We performed class II HLA-DR typing by PCR with sequence specific primers (PCR-SSP) on 81 nonresponders (IgG seronegative) and 65 hyper-responders (from the upper 10th percentile of IgG levels of all subjects). We then compared the distribution of alleles between nonresponders and hyper-responders. Results The distribution of HLA-DRB1 alleles among nonresponders compared to hyper-responders was significantly different ( p = 0.014). Nonresponders were significantly less likely to carry the HLA-DRB1*13 alleles than were hyper-responders (7.4% vs 16.2%; p = 0.02). Nonresponders also had an excess of HLA-DRB1*07 alleles (15.4% vs 6.2%; p = 0.015). Conclusions The absence of HLA-DRB1*13 alleles is associated with measles vaccine nonresponse. The absence of this allele has also been associated with susceptibility to other infectious diseases. The role of this gene in the immunogenetic response to infectious diseases requires further study.