Citations

Abstract Seizure forecasting has progressed from theoretical aspiration to a rapidly advancing research domain, yet clinical translation remains limited. Over the past decades, advances in algorithm development, chronic electroencephalography (EEG), wearable sensors, and the characterization of seizure cycles have demonstrated that seizure risk is not random but fluctuates according to identifiable biological rhythms and patient‐specific patterns. Forecasting algorithms have shown promising performance across diverse retrospective datasets, including intracranial EEG, subscalp recordings, wearable physiological signals, and even self‐reported diaries. However, the clinical value of forecasting is contentious. Prospective real‐world validation and regulatory approval of patient‐facing forecasting systems remain rare. This review incorporates perspectives presented at the 5th International Congress on Mobile Health and Digital Technology in Epilepsy (2025). We examine barriers impeding clinical translation and current attempts to address them. Crucially, forecasting performance cannot be evaluated in isolation from intended use. Applications range from low‐risk uses, like scheduling diagnostic monitoring or visualization of historical trends, to higher risk interventions, including medication titration and adaptive neuromodulation. Each application entails distinct performance thresholds, ethical considerations, and regulatory requirements. Translational challenges include reliable seizure annotation, nonstationarity dynamics of biological cycles, and practical constraints for real‐time deployment. Ethical concerns center on miscalibrated reliance on low‐risk states, potential anxiety associated with high‐risk advisories, and the heterogeneity of patient preferences and risk tolerance. Regulatory pathways are likely to depend on clearly defined use cases and clinically meaningful endpoints, which may extend beyond seizure counts to include quality of life, anxiety, locus of control, and other patient‐reported outcomes. Ultimately, translation will require rigorous prospective evaluation against transparent benchmarks, sustainable scientific–commercial partnerships, and integration of probabilistic risk information into clinical workflows. With careful implementation, seizure forecasting may evolve from proof‐of‐concept research into a clinically meaningful component of epilepsy management, and we remain cautiously optimistic.

Abstract The International League Against Epilepsy (ILAE) has updated the operational classification of epileptic seizures, building upon the framework established in 2017. This revision, informed by the implementation experience, involved a working group appointed by the ILAE Executive Committee. Comprising 37 members from all ILAE regions, the group utilized a modified Delphi process, requiring a consensus threshold of more than two thirds for any proposal. Following public comments, the Executive Committee appointed seven additional experts to the revision task force to address and incorporate the issues raised, as appropriate. The updated classification maintains four main seizure classes: Focal, Generalized, Unknown (whether focal or generalized), and Unclassified. Taxonomic rules distinguish classifiers, which are considered to reflect biological classes and directly impact clinical management, from descriptors, which indicate other important seizure characteristics. Focal seizures and those of unknown origin are further classified by the patient's state of consciousness (impaired or preserved) during the seizure, defined operationally through clinical assessment of awareness and responsiveness. If the state of consciousness is undetermined, the seizure is classified under the parent term, that is, the main seizure class (focal seizure or seizure of unknown origin). Generalized seizures are grouped into absence seizures, generalized tonic–clonic seizures, and other generalized seizures, now including recognition of negative myoclonus as a seizure type. Seizures are described in the basic version as with or without observable manifestations, whereas an expanded version utilizes the chronological sequence of seizure semiology. This updated classification comprises four main classes and 21 seizure types. Special emphasis was placed on ensuring translatability into languages beyond English. Its aim is to establish a common language for all health care professionals involved in epilepsy care, from resource‐limited areas to highly specialized centers, and to provide accessible terms for patients and caregivers.

Abstract Outcomes are poor in triple-class–exposed (TCE) relapsed and refractory multiple myeloma (R/RMM). In the phase 3 KarMMa-3 trial, patients with TCE R/RMM and 2 to 4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary end point; 13.3 vs 4.4 months; P < .0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median was 41.4 (95% CI, 30.9 to not reached [NR]) vs 37.9 (95% CI, 23.4 to NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI, 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE R/RMM. This trial was registered at www.ClinicalTrials.gov as #NCT03651128.

Introduction In the KarMMa-3 trial (NCT03651128), ide-cel, a BCMA-directed CAR T cell therapy (Tx), significantly improved median progression-free survival (13.3 vs 4.4 mo, HR 0.49, P < 0.001) and overall response rate (71% vs 42%, P < 0.001) vs std regimens in pts with RRMM who were TCE to immunomodulatory (IMiD ®) agents, proteasome inhibitors (PIs), and daratumumab (Rodríguez-Otero NEJM 2023). Early high-grade (gr) cytopenias and severe infections have been reported post-CAR T cell infusion (Logue Blood 2022, Thibaud Blood 2022), and persistent cytopenias and infections can pose clinical challenges in pt care. In this safety analysis of KarMMa-3, we report frequency, kinetics of occurrence, and management of cytopenias and infections post-Tx with ide-cel or std regimens. Methods This international, randomized, multicenter phase 3 trial enrolled pts with RRMM who received 2-4 prior Txs (an IMiD agent, a PI, and daratumumab) and were refractory to the last Tx. Pts were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd) selected by investigator based on prior anti-MM Tx. In the ide-cel arm, pts could have ≤ 1 cycle of optional bridging Tx (BTx) for disease control. Treated population (pop; ide-cel: pts who received leukapheresis [LA], BTx, lymphodepleting chemotherapy, or ide-cel; std regimens: pts who received any dose of study Tx) was used to assess adverse events (AEs), gr 3/4 AEs, and serious AEs. Safety pop (pts who received ide-cel or any dose of std regimens) was used to assess treatment-emergent AEs, AEs of special interest, investigator-identified neurotoxicity/cytokine release syndrome and others. In pts who had documented disease progression on std regimens and then underwent LA to receive ide-cel, only AEs before LA were included. In this analysis, incidence of cytopenias and infections at various time intervals and management, types of infections, and incidence of hypogammaglobulinemia (HGG) were assessed. Results At data cutoff (Oct 3, 2022), median follow-up was 24.1 (range 5.9−41.0) mo in the 386 randomized pts. In the treated pop, 248/249 (99.6%) vs 124/126 (98.4%) pts had any-gr AEs, 234 (94.0%) vs 96 (76.2%) had gr 3/4, and 36 (14.5%) vs 9 (7.1%) had gr 5 in ide-cel vs std regimens arms, respectively. Of the gr 5 AEs, 18/36 and 3/9 had verbatim terms consistent with progressive disease. In the safety pop, incidence of gr 3/4 cytopenias with ide-cel were higher early after infusion but generally resolved over time (196 [87.1%] pts at < 3 mo, 52 [24.1%] pts at 3−< 6 mo, 30 [14.7%] pts at ≥ 6 mo; Table 1) vs std regimens, which showed lower rate of resolution over time. More pts in the ide-cel (16 [7.1%]) vs std regimens arms (3 [2.4%]) had any-gr febrile neutropenia. Cytopenias were mainly managed using colony-stimulating factor in both arms (55.5% and 58.7%, respectively); RBC (48%) and platelet transfusions (32%) were more common in the ide-cel arm. Overall, incidence of gr 3/4 infections was high at < 3 mo and remained consistent over time in both arms (ide-cel: 17 [7.6%] pts at < 3 mo, 18 [8.3%] pts at 3−< 6 mo, 13 [6.4%] pts at ≥ 6 mo; Table 2). Any-gr bacterial infections were more common in the ide-cel vs std regimens arms with higher incidence at < 3 mo (10% vs 6%) but lowered at later timepoints. Incidence of gr ≥ 3 viral infections remained low and consistent with time; fungal infections were uncommon. Deaths due to infections occurred in 3 (1.3%) vs 1 (0.8%) pts at < 3 mo, 0 pts at 3−< 6 mo, and 7 (3.4%) vs 2 (2.6%) pts at ≥ 6 mo in the ide-cel vs std regimens arms, respectively. Indence of any-gr new HGG was higher in the ide-cel vs std regimens arms but decreased over time: 15 (6.7%) vs 2 (1.6%) pts at < 3 mo, 3 (1.4%) vs 1 (0.9%) at 3−< 6 mo, and 5 (2.5%) vs 0 at ≥ 6 mo, respectively; of these, 13 (5.8%) vs 1 (0.8%), 2 (0.9%) vs 1 (0.9%), and 5 (2.5%) vs 0 pts received IV immunoglobulin replacement Tx at the respective time intervals. Incidence rate (% per 100 pt-years, 95% CI) of second primary malignancies remained low and similar between arms (ide-cel, 4.0 [2.4−6.7]; std regimens, 4.4 [1.9−10.7]). Conclusion In KarMMa-3, most severe cytopenias associated with ide-cel occurred early, with a low incidence of prolonged cytopenias; all were largely manageable. Any-gr bacterial infections decreased over time while viral infections remained the same. No new safety concerns were identified for ide-cel; safety profile was consistent with previous reports. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Introduction: Patients with TCE RRMM have a high disease burden and often report worsening HRQoL with additional lines of therapy. The single-arm, phase 2 KarMMa study demonstrated that ide-cel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy, improved HRQoL from baseline in patients with TCE RRMM who had received ≥ 3 prior regimens (Delforge M, et al. Blood Adv 2022;6:1309-1318). Furthermore, in the phase 3 KarMMa-3 clinical trial (NCT03651128), ide-cel significantly improved progression-free survival and response compared with standard regimens in patients with TCE RRMM who had received 2-4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014). Here we assessed the comparative effects of ide-cel versus standard regimens on HRQoL in patients with TCE RRMM who had received 3-4 prior regimens including an immunomodulatory agent, a proteasome inhibitor, and daratumumab (an anti-CD38 monoclonal antibody) using data from the KarMMa-3 study. Methods: Patient-reported outcomes (PROs) were assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20), and EQ-5D-5L. The pre-specified primary domains of interest included EORTC QLQ-C30 global health status/QoL, physical functioning, cognitive functioning, fatigue, and pain; EORTC QLQ-MY20 disease symptoms and side effects of treatment; and the EQ-5D-5L visual analog scale (EQ-5D VAS). PROs were collected at screening (baseline), the day of ide-cel infusion (ide-cel) or first treatment dose (standard regimens), monthly from 2 to 28 months, and thereafter every 3 months. Comparisons were performed on least squares (LS) mean changes from baseline through 28 months between arms using constrained longitudinal data analysis (cLDA). Effect size was estimated by Hedges' g. The comparative effects of ide-cel versus standard regimens on time to confirmed improvement and time to confirmed deterioration (defined by prespecified change thresholds) were assessed via stratified Cox proportional hazards regression analyses. All P values are nominal and not adjusted for multiple testing. Statistical significance was set at P < 0.05. Results: Baseline characteristics were well balanced among the patients in the ide-cel arm (n = 167) and the standard regimen arm (n = 93), with a median age of 63 years and a median time of 4.7 years from RRMM diagnosis to study screening. Completion rates of HRQoL assessments were high over time for most visits (> 75%). At baseline, mean HRQoL domain scores were similar between arms. Overall LS mean changes from baseline to 28 months showed significant differences in favor of ide-cel versus standard regimens (nominal P < 0.05) for 11 domains (effect sizes of 0.26-0.82), and 7 (4 primary: global health status/QoL, cognitive functioning, pain, EQ-5D VAS; 3 secondary: dyspnea, insomnia, constipation) of them exceeded the prespecified MID thresholds (Table). Time to confirmed improvement was significantly shorter (nominal P < 0.05) in the ide-cel arm than in the standard regimen arm for 10 domains, including all primary domains except pain. Time to confirmed deterioration was longer in the ide-cel arm than the standard regimen arm for most domains, with significant differences in emotional functioning, cognitive functioning, and dyspnea (EORTC QLQ-C30). Finally, side effects of treatment favored the ide-cel versus standard regimen arm (EORTC QLQ-MY20) (Table). Conclusions: These patient-reported findings demonstrate that compared with standard regimens, treatment with ide-cel improved MM-relevant disease symptoms, functioning, and overall health status/HRQoL of patients with TCE RRMM in the KarMMa-3 trial. These data further substantiate the superior treatment outcomes of ide-cel over standard regimens in this patient population. Overall, treatment with ide-cel may help alleviate detriments to HRQoL in these patients with complex disease.

Background: An interim analysis (data cutoff date April 18, 2022) of the international, open-label, phase 3 KarMMa-3 trial (NCT03651128) showed the chimeric antigen receptor T cell therapy idecabtagene vicleucel (ide-cel) significantly improved progression-free survival and treatment response rates, as well as HRQoL, as compared with standard regimens, in patients with triple-class exposed (TCE) RRMM who had received 2-4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014; Delforge M, et al., HemaSphere, 2023;7(S3):P905). The aim of the present study was to analyze the effect of ide-cel versus standard regimens (daratumumab [DARA], pomalidomide, and dexamethasone [DEX]; DARA, bortezomib, and DEX; ixazomib, lenalidomide, and DEX; carfilzomib and DEX; or elotuzumab, pomalidomide, and DEX) on HRQoL in KarMMa-3 trial participants with an extended follow-up of patient-reported outcomes (PRO) data collection (data cutoff date April 28, 2023). Methods: In KarMMa-3, HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20), and EQ-5D-5L. HRQoL assessments were completed at screening (baseline); the day of ide-cel infusion or the first dose of standard treatment; and monthly from 2 to 28 months; and every 3 months thereafter. The prespecified primary outcomes of interest were EORTC QLQ-C30 global health status/QoL, physical functioning, cognitive functioning, fatigue, and pain; EORTC QLQ-MY20 disease symptoms and side effects of treatment; and the EQ-5D visual analog scale (EQ-VAS). Least squares (LS) mean changes from baseline through month 25 for ide-cel and standard regimens were compared by constrained longitudinal data analysis (cLDA). Effect sizes were estimated by Hedges' g. The effect of ide-cel versus standard regimens on time to confirmed improvement and deterioration in HRQoL (defined by prespecified change thresholds and sustained duration) were compared by stratified Cox proportional hazards regression. There was no adjustment for multiple testing, and all P values reported are nominal. Results: Overall, 254 patients were randomized to the ide-cel arm and 132 to the standard regimens arm. Baseline characteristics were well balanced across treatment arms; both arms had a median age of 63 years, a median of 3 prior anti-myeloma regimens, and median time from MM diagnosis to screening was 4 years. The baseline HRQoL scores were generally comparable between treatment arms. Overall LS mean changes from baseline to month 25 showed significant differences (nominal P value < 0.05) in favor of ide-cel for 18 out of 21 HRQoL domains, with effect sizes (Hedges' g) of 0.27 to 0.82 (Table). For 13 of these domains (including 6 primary domains of interest), the difference in overall LS mean change from baseline exceeded the prespecified minimum important difference (MID) threshold. Time to confirmed improvement was significantly shorter in the ide-cel arm than the standard regimens arm for 19 domains, including all primary domains of interest (Table). Time to confirmed deterioration showed trends of being longer in the ide-cel arm than the standard regimens arm for most domains and was significantly longer for emotional functioning, cognitive functioning, social functioning, dyspnea, and constipation as measured by the EORTC QLQ-C30. The time to confirmed deterioration in side effects of treatment (based on the EORTC QLQ-MY20) was significantly longer for patients in the ide-cel arm and time to confirmed improvement was significantly faster, as compared with the standard regimens arm (Table). Conclusions: In the KarMMa-3 trial, patients with TCE RRMM who had received 2-4 prior regimens, ide-cel significantly and meaningfully improved MM-relevant symptoms, functioning, and overall health status/HRQoL compared with standard regimens. Confirmed HRQoL improvements in the ide-cel arm occurred sooner than standard regimens. PRO improvements were sustained over more than 2 years, which is notable after a single infusion treatment with ide-cel. These patient-reported findings further support the benefit of ide-cel in this patient population.

Introduction A single ide-cel infusion showed significantly longer median progression-free survival (PFS) vs std regimens (13.3 vs 4.4 months [mo], HR 0.49, 95% CI 0.38-0.65, P < 0.001) with deep, durable responses in heavily pretreated TCE RRMM at an interim analysis (IA) of KarMMa-3 (NCT03651128); safety data were consistent with prior studies (Rodríguez-Otero et al. NEJM 2023). Ide-cel benefits were consistent across pts in high-risk subgroups and across 2-4 prior lines of therapy (Tx). Results of the preplanned final PFS analysis of KarMMa-3 with 12.3 mo additional follow-up are reported. Methods In the phase 3 KarMMa-3 trial, pts with RRMM who received 2-4 prior regimens, including an immunomodulatory agent, proteasome inhibitor, and daratumumab, and were refractory to last regimen were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd). In the ide-cel arm, pts could receive ≤ 1 cycle of optional bridging Tx for disease control. Pts in the std regimens arm could receive ide-cel after confirmed disease progression (PD). The primary endpoint was IRC-assessed PFS in the ITT population; final PFS was planned to be analyzed with ~289 events. Key secondary endpoints were IRC-assessed overall response rate (ORR) and overall survival (OS); other secondary endpoints included complete response rate (CRR), duration of response (DOR), minimal residual disease (MRD) status, time to next anti-myeloma Tx (TTNT; time from randomization to next anti-myeloma Tx [MTx]), event-free survival (EFS; time from randomization to first PD, next MTx or any-cause death, whichever is first), PFS2 (time from randomization to second objective PD or any-cause death, whichever is first), safety, and health-related quality of life (QOL). Results Of 386 randomized pts (ide-cel, n = 254; std regimens, n = 132), 225 received ide-cel and 126 received a std regimen. Baseline characteristics were generally balanced. Median follow-up from randomization to data cutoff (April 28, 2023) was 30.9 mo (range 12.7-47.8). Ide-cel significantly improved median PFS (95% CI) vs std regimens (13.8 [11.8-16.1] vs 4.4 [3.4-5.8] mo), representing a 51% reduced risk of PD or death (HR 0.49, 95% CI 0.38-0.63; Figure); 18 mo PFS rates were 41% vs 19%, respectively. Ide-cel significantly improved ORR vs std regimens (71% vs 42%) with deeper (CRR 44% vs 5%; ≥CR and MRD negative status [sensitivity level 10 -5], 22% vs 1%), more durable responses (median DOR 16.6 vs 9.7 mo; Table). PFS and ORR benefits of ide-cel vs std regimens were consistent with the IA. Interim OS will be included in the presentation. In pts who received ide-cel (n = 225) or a std regimen (n = 126), median PFS (95% CI) was 15.7 (12.5-18.9) vs 4.4 (3.4-5.8) mo, respectively. In the ITT population, median TTNT, EFS, and PFS2 were numerically longer with ide-cel vs std regimens. Median (range) TTNT was 20.9 (16.6-24.2) vs 7.0 (5.3-8.5) mo. Median (95% CI) EFS was 13.3 (11.3-15.7) vs 3.9 (3.0-5.3) mo. Median PFS2 (95% CI) was 23.5 (18.4-27.9) vs 16.7 (12.2-20.3) mo; ide-cel was next MTx in 70 (53%) pts in the std regimens arm. In the treated population, grade (gr) 3/4 infections occurred in 66/249 (27%) pts in the ide-cel arm vs 25/126 (20%) in the std regimens arm. In the ide-cel safety population, any gr cytokine release syndrome occurred in 197/225 (88%) pts, gr ≥ 3 in 11 (5%); median time to first onset was 1 d (1-14), median duration was 4 d (1-51). Any gr investigator-identified neurotoxicity occurred in 34/225 (15%) pts, gr ≥ 3 in 7 (3%); median time to onset was 3 d (range 1-317); median duration was 2.5 d (range 1-252). Ide-cel continued to demonstrate durable, clinically meaningful improvements in pt-reported outcomes, including symptoms, functioning, and QOL vs std regimens. Conclusions In this final PFS analysis of KarMMa-3, significantly longer PFS was maintained with ide-cel; PD or death risk reduced by 51%; responses were deeper and more durable vs std regimens. CRR with ide-cel increased since the IA, indicating a deepening response, but were unchanged with std regimens. A single ide-cel infusion vs continuous treatment with std regimens resulted in longer median TTNT and PFS2, indicating improved long-term disease control. The ide-cel safety profile was consistent with previous reports, with no parkinsonism or Guillain-Barré syndrome reported. These data continue to support use of ide-cel in pts with TCE RRMM. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

The primary mediator of transforming growth factor β (TGFβ) responses are the Smad proteins. Here, we identify sorting nexin 9 (SNX9) as being required for Smad3 (but not Smad2) nuclear translocation and cell stimulation. SNX9 principally interacts with phosphorylated (p) Smad3 and promotes more rapid nuclear delivery from that observed independent of ligand. Although SNX9 does not bind Imp7, Impb, Nup153 or Nup214, it mediates the association of pSmad3 with Imp8 and the nuclear membrane. This facilitates recruitment of pSmad3/SNX9 to the nuclear pore, heterodimerization of Imp8 with Impb, and nuclear translocation of pSmad3, but not SNX9. The demonstration that Smad3 is regulated in a distinct manner from Smad2 provides the opportunity to develop intervention strategies to enhance or dampen specific aspects of the cellular response to TGFβ. Support or Funding Information This work was supported by Public Health Service grants GM‐055816 and GM‐054200 from National Institutes of General Medical Sciences.