Abstract Background Watchful waiting is a common option for pts with asymptomatic FL/MZL. Anti-tumor immunization may delay or even avoid subsequent need for more toxic therapies. EO is designed from non-self-protein sequences derived from gut bacteria, including 4 HLA-A2 CD8 T cell epitopes (synthetic mimic peptides), exhibiting molecular mimicry with specific epitopes on B cell markers (CD20, CD22, CD37, BAFF-receptor). EO also contains a CD4 helper epitope UCP2. EO expands pre-existing memory CD8 T cells recognizing non-self-epitopes from gut bacteria that cross-react with B cell antigens on tumor cells. Methods Cohort 2 (C2; planned accrual 25 pts) of EONHL1-20/SIDNEY includes HLA-A2+ pts with previously untreated FL/MZL not in need of treatment. Pts receive EO (300μg/peptide) SC with adjuvant Montanide, q2 weeks (w) x 4, then q4w, for 12 total doses. For antigen-specific immune responses, peripheral blood mononuclear cells were assayed by flow cytometry using EO-mimic or B cell peptide specific tetramers without in vitro stimulation. IFN-γ ELISPOT was used to evaluate response to UCP2 and anti-CD3. Primary endpoint is objective response rate (ORR) per Lugano 2014. A pre-defined futility boundary was applied (ORR uninteresting=5%/promising=20%). Finding at least 3 of 25 pts with ORR would meet criteria to continue development (chance of 13% and 90% for true ORR of 5% and 20%, respectively). Results As of July 2025, 22 pts had started EO. Median age 59 years (range 32-86); 9 female; 19 ECOG 0/3 ECOG 1; 19 FL/3 extranodal MZL (ENMZL); 3 Ann Arbor stage I-II/8 stage III/11 stage IV; FLIPI low risk 8/intermediate 8/high 6; FLIPI-2 low risk 12/intermediate 7/high 3; 19 GELF neg/3 pos. At a median follow-up for progression of 9.4 months, 9 pts completed EO, 4 stopped for progressive disease (PD), 2 due to PI/pt decision; 7 ongoing. Median treatment duration 38 w (range 4-39). Among 19 evaluable pts, best Lugano response was 3 complete (CR) and 6 partial responses (PR) (ORR 47% [95% CI 24%–71%]; CR-rate 16% [3%-40%]), 6 stable disease (SD), and 4 PD. ORR by PET-CT was 29% (n=14) w6, 39% (n=18) w19, 46% (n=13) w42; corresponding CR rates were 0%, 11%, 15%. Median time to response 17.1 w (range 5.3-41.1). Currently there are only 2 confirmed PD events in pts with prior PR/CR. Among 8 pts with an initial indeterminate response per LyRIC 2016 followed by a confirmatory scan, 4 pts did not have confirmed PD; a possible atypical response pattern rate of 50% on EO (occurring 5.3-41.9 w after start of EO). In 16 immune response evaluable pts, 88% and 81% had expansion of CD8 T cells specific for EO mimic and B cell target peptides, respectively. Expanded specific CD8 T cells had a memory phenotype dominated by effector memory (TEM) and central memory cells. At w5, 7 clinical responders and 7 non-responders were evaluable; more responders had a positive immune response against EO mimic (Chi-square p=0.025) and B cell target (p=0.047) peptides. Max expansion (response sum for 4 EO mimic or 4 B cell target peptides at a single timepoint w3-w8) of specific CD8 T cells (% of all peripheral CD8 T cells) was higher for responders than non-responders both for EO mimic (Mann Whitney p=0.018) and B cell target (p=0.017) peptides. Pts (4) with an initial indeterminate response (LyRIC 2016) had a higher max expansion of B cell target peptide specific CD8 T cells vs 4 pts with a typical progression pattern (Mann Whitney p=0.018) and vs all other 12 pts evaluable for immune response (p=0.029). There was no difference in CD4 T cell response to UCP2 in responders vs non-responders (induction or max immunity w3-w8). Anti-CD3 expansion of T cells indicating T cell intrinsic activation potential did not correlate with clinical response (baseline or max). The most common EO-related adverse events (AEs) were Gr (Grade) 1 (10 pts) and Gr 2 (6 pts) local administration site reactions. Other related AEs in >1 pt were Gr 1 headache (3 pts) and Gr 1-2 fatigue (3 pts). Asthenia lasting 2 days was the only related Gr 3 AE. There were 4 unrelated Gr 3 AEs (gastroenteritis, GI-hemorrhage, inguinal hernia, and syncope). There were no Gr 4-5 AE. ConclusionsEO has a favorable safety profile and is preliminary associated with an ORR of 47%, exceeding the pre-specified boundary for promising activity. The speed and level of expansion of both EO mimic and B cell target peptide specific CD8 memory T cells are associated with objective response. Results will be updated.

Abstract Background: Mosunetuzumab is the first FDA- and EMA-approved CD20xCD3 T-cell engaging bispecific antibody for the treatment of R/R FL after ≥2 prior lines of therapy. In a pivotal Phase II study (NCT02500407), fixed-duration mosunetuzumab demonstrated high response rates, durable remissions, and a manageable safety profile in patients with R/R FL (Budde et al. Lancet Oncol 2022; Shadman et al. ASH 2024; Cheah et al. EHA 2025). We report updated efficacy and safety data for mosunetuzumab in patients with R/R FL after a median follow-up of 5 years. Methods: Eligible patients with R/R FL Grade 1–3a and ≥2 prior therapies received intravenous mosunetuzumab for a fixed duration with step-up dosing in Cycle (C)1. Hospitalization was not mandatory. Patients with a complete response (CR) by C8 completed therapy with no additional cycles; patients with partial response or stable disease post C8 could continue treatment for up to 9 additional cycles (a total of 17 cycles). Efficacy analyses by investigator assessment (Cheson et al. 2007 criteria) included CR rate, overall response rate (ORR), duration of response (DOR), duration of CR (DOCR), progression-free survival (PFS), overall survival (OS) and time to next treatment (TTNT). Safety and tolerability were assessed by describing the incidence and severity of adverse events (AEs). After the AE reporting period (90 days after the last dose or start of new anti-lymphoma treatment), mosunetuzumab-related serious AEs were to be reported. Results: Ninety patients with R/R FL were enrolled, of whom 52% had a history of disease progression within 24 months from the start of first-line therapy (POD24) and 53% were double refractory. Median age was 60 years (range: 29–90) and median prior lines of therapy was 3 (range: 2–10). As of May 1, 2025, median time on study was 60.2 months (range: 2–72). In the overall population (N=90), the ORR and CR rate were 78% and 60%, respectively; median DOR (n=70) was 46.4 months (95% confidence interval [CI]: 18.7–not estimable [NE]), and median DOCR (n=54) was not reached (95% CI: 44.1–NE). The 54-month DOR and DOCR rates were 46% (95% CI: 33.8–59.1) and 52% (95% CI: 36.2–67.9), respectively. Median PFS was 24.0 months (95% CI: 12.0–53.2) in all patients, and 61.0 months (95% CI: 47.6–NE) in patients who achieved CR. The 5-year PFS rates were 36% (95% CI: 25.3–47.7) and 57% (95% CI: 42.0–71.6) in all patients and patients with CR, respectively. Median OS was not reached (95% CI: NE), and the 5-year OS rate was 78% (95% CI: 69.6–87.4). Eighteen deaths were reported; 13 due to progressive disease, 1 each due to unexplained death, cardiac arrest and sepsis, and 2 with unknown cause. The median TTNT in all patients was 64.1 months (95% CI: 21.7–NE), and the 5-year TTNT rate was 51% (95% CI: 39.8–61.8). Five patients received mosunetuzumab retreatment of whom 3 achieved a subsequent CR. In the 47 patients with POD24, the ORR (81%) and CR rate (60%) were consistent with those observed in the overall population. Median DOCR was 50.1 months (95% CI: 18.7–NE), and the 54-month DOCR rate was 48% (95% CI: 24.9–71.5); median PFS was 21.7 months (95% CI: 11.6–61.0) and the 5-year PFS rate was 36.9% (95% CI: 20.7–53.1), with a small number of patients remaining at risk. No new AEs were reported since the 4-year follow-up. All patients had at least one AE; the most common AE was cytokine release syndrome (CRS; 44%). CRS events were mainly Grade 1/2 (Grade 1, n=23; Grade 2, n=15; Grade 3, n=1; Grade 4, n=1) and were all resolved. AEs leading to treatment discontinuation occurred in 4% of patients; no treatment-related Grade 5 AEs occurred. The recovery of B cells and immunoglobulin M (IgM) was observed in patients with a CR. Conclusions: This report represents the longest follow-up for a CD20xCD3 bispecific antibody in R/R FL. Fixed-duration mosunetuzumab treatment yields durable responses, and long-term survival continues to be observed in patients with heavily pre-treated R/R FL. The data highlight the durable long-term remissions achieved with mosunetuzumab in this setting. Updated data confirm that B-cell recovery is observed and sustained. In parallel, IgM levels recover with a similar time course. In both cases after 2 years a majority of patients have recovered to normal levels. The safety profile remained manageable, with no new toxicities reported.

INTRODUCTION Multiple myeloma (MM) is a genetically and clinically heterogeneous plasma cell malignancy that remains incurable despite advances in therapeutic strategies. While several transcriptomic classifiers have been proposed, the integration of transcriptional subtypes with genomic alterations and treatment response remains poorly understood. In the randomized phase 3 GEM2017FIT trial, patients received either induction with 18 cycles of VMP followed by Rd (control) or KRd ± Daratumumab (D-KRd/KRd). We performed integrative bulk multiomic analyses to investigate whether transcriptional profiling at diagnosis can stratify patients by outcome. METHODS Baseline bone marrow aspirates from 109 newly diagnosed MM patients were analyzed. DNA and RNA was co-isolated from isolated CD138+ plasma cells for bulk RNA sequencing and whole-exome sequencing (WES). Paired tumor-normal WES was performed in 54 cases. Non-negative matrix factorization (NMF) of transcriptomic data identified five discrete transcriptional subgroups (A–E). Groups were characterized by mutational profiles, structural variants (SVs), copy number alterations (CNAs), and pathway enrichment analyses. Clinical outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed with transcriptional groups and treatment regimens. RESULTS We analyzed 109 MM patients selected by their best achieved response during the treatment. 54 patients achieved complete response and negative MRD; 12 patients achieved complete response with positive MRD; 25 patients achieved partial response; and 18 patients were primary refractory. The five transcriptional subgroups identified (A–E) demonstrated distinct molecular characteristics suggesting that transcriptional stratification captures unique and clinically relevant biological dimensions. Each transcriptional group exhibited a distinct genomic and functional landscape. Groups A and C shared transcriptional hallmarks related to energy metabolism, including oxidative phosphorylation and mitochondrial activity. Group A was further characterized by hyperdiploidy and NOTCH1 mutations, whereas no defining genomic biomarker was identified for Group C. Notably, patients in these two groups demonstrated exceptional clinical outcomes regardless of treatment modality, with only one relapse observed among a combined total of 31 patients, suggesting the presence of a favorable intrinsic transcriptional program. Group E, defined by the presence of ANKRD26 and BRAF mutations, was enriched not only for energy-related metabolic pathways but also for protein biosynthesis and translational machinery. This group exhibited a differential response to treatment: patients receiving D-KRd achieved 100% PFS, while those treated with KRd alone showed no PFS benefit compared to control arm VMP-Rd after 56 months of follow-up, highlighting a strong predictive interaction between this transcriptional subtype and response to Daratumumab. In contrast, Groups B and D were enriched for oncogenic signaling and immune-related pathways, with BRAF and PRPF8 mutations characterizing Group B, and del(13q) and CREBBP mutations prominent in Group D. Importantly, patients within these groups achieved superior PFS and OS when treated with KRd without Daratumumab, indicating a differential benefit profile where the addition of anti-CD38 therapy may not confer further advantage. Collectively, these findings demonstrate that the transcriptional landscape of MM at diagnosis provides prognostic and predictive information beyond cytogenetics or mutational status alone. The transcriptional subtypes not only delineate distinct biological behaviors but also predict differential therapeutic responses, supporting their integration into treatment decision-making frameworks. CONCLUSIONS Transcriptomic profiling at diagnosis reveals distinct molecular subtypes of MM with differential genomic features, biological pathway activation, and treatment responses. These findings underscore the prognostic and predictive utility of transcriptional classification, advocate for the superiority of KRd-based regimens over VMP+Rd and highlight the selective benefit of Daratumumab in specific subtypes. Prospective integration of transcriptomic data may refine patient stratification and guide personalized therapy in MM. Ongoing analyses of APOBEC signatures and mutational signatures aim to elucidate the underlying drivers of therapy resistance and disease progression.

Abstract Introduction: There is no established standard of care for relapsed or refractory (R/R) marginal zone lymphoma (MZL). Zanubrutinib, a second generation covalent BTK inhibitor, was approved for R/R-MZL based on the results of the phase 2 MAGNOLIA trial, which included 68 patients (pts). We aimed to evaluate the characteristics and outcomes of 118 pts with R/R MZL treated with zanubrutinib in routine clinical practice across Spain. Methods: This retrospective study included adult pts with R/R MZL previously treated with at least one anti-CD20-based regimen and requiring further therapy. Pts received zanubrutinib at 39 Spanish centers (GELTAMO). All MZL subtypes were included: mucosa-associated lymphoid tissue (MALT), splenic (SMZL), and nodal (NMZL). Baseline characteristics, prior lines of treatment (LoT), response rates, survival, adverse events (AEs), and reasons for discontinuation were analyzed. Results: A total of 118 pts were analyzed. Median age at zanubrutinib initiation was 75 years (range, 36-96) and 56% were females. According to MZL type: 55.3% were SMZL, 18.9% MALT, 19.8% NMZL, and 6% no-classifiable. Median number of previous LoT was 2 (range 1-7): 59 pts 1L, 30 pts 2L and 29 pts ≥3L. Thirty pts were refractory to the prior therapy immediately preceding zanubrutinib and 59% (69/116) were POD24 (R/R within the 24 months after first line treatment initiation). Median time from diagnosis to zanubrutinib was 56.7 months (IQR 25.2-93). At zanubrutinib start, 84% had stage III/IV disease, 32% had B-symptoms, and 15% had ECOG ≥2. MYD88 L265P status was available in 35 pts; 7 cases (20%) mutated. Thirty-one pts (26.3%), including 8 with ≥1 MAGNOLIA exclusion criteria, would not have qualified for the trial. The most common reasons were thrombocytopenia <75 × 10⁹/L (n=8), neutropenia <1 × 10⁹/L (n=6), elevated bilirubin (n=6), poor performance status (n=4), creatinine clearance <30 mL/min (n = 4), AST/ALT >2.5× ULN (n = 3), prior treatment with BTKi (n = 2), and CNS involvement (n = 1). No pts had prior histological transformation. Comorbidities were frequent: 68% had ≥1 cardiovascular risk factor (hypertension 48%, diabetes 29%, cardiopathy 22%, including 10 with AF), and fifty-one pts (43%) presented with ≥2 comorbidities. Anticoagulant or antiplatelet therapy was used in 33 pts (28%), with 2 pts receiving both therapies. Zanubrutinib was started at standard dose in 111 patients (160 mg BID or 320 mg QD), and at reduced dose in 7 (80 mg BID or 240 mg QD). Overall response rate (ORR) was 76.0%, with complete response (CR) in 22.2%. Median duration of response was 6.8 months (IQR 4.5 -9.6), and median time to best response was 5.8 months (IQR 3.7-9.9). ORR/CR was not significantly affected by MZL subtype, stage, MYD88 status, POD24, MAGNOLIA eligibility, age, or refractoriness to immediately prior line. However, number of prior LoT did influence outcomes (ORR/CR: 84.7%/30.5% for 1 LoT, 73.5%/10% for 2 LoT, 55.6%/17.2% for >2 LoT; p<0.05). With a median follow-up of 14 months, one-year progression-free survival (PFS) was 79.4 (95% CI 72.1-87.6), median PFS not reached. One-year PFS was 77.8% (SMZL), 77% (MALT), 88.6% (NMZL), and 77.8% (unclassifiable)(p=0.475). At last follow-up, 86 pts (72.8%) remained on treatment. One-year OS was 86.8% (95% CI 80.5-93.5). Sixteen pts had died (8 from lymphoma). Response to zanubrutinib significantly impacted both PFS and OS (p<0.001), while number of prior LoT impacted PFS only (p<0.001). No significant differences in survival were seen by MZL subtype, POD24, or MAGNOLIA eligibility. Regarding toxicity, 49 AEs were reported in 40 pts (34.1%), of which 17 (34.6%) were grade ≥3. Most common AEs included bleeding (n=13), infections (n=10), cytopenias (n=8), and diarrhea (n=5). Bleeding was higher among those on anticoagulants (p=0.039). No cases of atrial fibrillation or grade 5 AEs occurred. Nine pts discontinued zanubrutinib due to toxicity (median time to discontinuation: 5.4 months (IQR 2.6-11.1)). MAGNOLIA ineligible pts had higher AE incidence (p=0.017) and discontinuation rates (p=0.009). Conclusions: This is the largest real-world series of zanubrutinib in R/R MZL to date. Zanubrutinib demonstrated favorable efficacy and safety across all MZL subtypes, independently of MAGNOLIA trial eligibility. Outcomes were significantly better in pts treated earlier in their disease course, supporting the use of zanubrutinib as a second-line option in R/R MZL. (*AMP & FMM contributed equally)

Introduction. The outcomes of older adults with classical Hodgkin Lymphoma (cHL) have improved in recent decades. However, despite having better treatment strategies and better supportive care, the prognosis remains poor for those aged ≥70 years. Frailty has been associated with poor outcomes and worse tolerance of treatments in older patients with hematological malignancies. Hence, there are recommendations to perform geriatric assessment (GA) and to integrate it into the treatment decision plan, but the implementation in clinical practice is still limited. Methods. We conducted a retrospective, multicenter study in the Spanish Lymphoma Registry (RELINF) of the Spanish Lymphoma Group (GELTAMO). Hereby, we enrolled in this study 673 patients with cHL aged 60 years or above from 46 Spanish centers. We analyzed the impact of comorbidities and frailty on their outcome. We collected baseline patient characteristics, including activities of daily living (ADL), instrumental activities of daily living (IADL), geriatric syndromes, and comorbidities scored with CIRS-G. Statistical analyses were done with R. Results. Median age at diagnosis was 72 years (range 60-93), 57.8% were male, 65.7% were diagnosed with advanced stage, and 43.9% with extranodal involvement. CIRS score was collected in 417 patients, with a median score of 4 (range 0-13). Activities of daily living (ADL) were collected in 569 patients, with 79 (13.9%) of them showing impairments. Instrumental activities of daily living (IADL) were collected in 532 patients, with impairments in 94 (17.7%) of them. Geriatric syndromes were detected in 84 patients (14.4%). In the univariate analyses, age >71 years (HR 1.08, 95%CI 1.06-1.10, p<0.001), previous history of cardiovascular disease (HR 1.79, 95%CI 1.35-2.39, p<0.001), extranodal involvement (HR 1.69, 95%CI 1.28-2.23, p<0.001), advanced stage (HR 4.99, 95%CI 2.18-11.4, p<0.001), ECOG >2 (HR 10.4, 95%CI 6.64-16.2, p<0.001), impairment in ADL (HR 3.78, 95%CI 2.66-5.36, p<0.001), and IADL (HR 3.75, 95%CI 2.65-5.30, p<0.001), presence of geriatric syndromes (HR 1.83, 95%CI 1.25-2.68, p=0.002), and cardiac (HR 1.85, 95%CI 1.28-22.65, p=0.001), and psychiatric (HR 1.80, 95%CI 1.21-2.67, p=0.004) comorbidities had a negative impact in the survival. In lab tests, only absolute lymphocyte counts (ALC), hemoglobin, albumin and ESR had impact in survival. With regard to treatments, no differences were seen among all therapies. Only palliative regimens showed shorter survival (HR 11.5, 95%CI 7.73-17.2, p<0.001). In the multivariate analysis, age, ECOG, anemia, geriatric syndromes and palliative therapy had an impact on OS. Conclusions. Functional reserve and resilience have an impact on the outcome of older patients with cHL. Frailty assessment through a GA should be incorporated in the evaluation of older patients with cHL to identify those patients at higher risk. Better and safer treatment strategies are needed to overcome the poorer prognosis of this group of patients.

Single-agent R is a common 1st-line therapy for patients (pts) with FL, especially those with low-tumor burden advanced stage disease or comorbidities. EO is a therapeutic vaccine generated from non-self-protein sequences from gut bacteria, including 4 HLA-A2 CD8 T cell epitopes that mimic B cell-specific markers: CD20, CD22, CD37 and BAFF-receptor. EO also contains a CD4 helper epitope UCP2. EO expands pre-existing memory CD8 T cells recognizing non-self-protein sequences from gut bacteria which can cross-react with B cell antigens on tumor cells. The aim adding EO to R is to safely increase the depth and duration of responses. Cohort 3 (C3) of trial EONHL1-20/SIDNEY includes pts with HLA-A2 and previously untreated low-tumor burden (GELF) FL grade 1-3A in need of treatment (per pt/treating physician). Pts receive EO (300μg/peptide) SC with adjuvant Montanide, q2 weeks (w) x 4, then q4w for a total of 12 doses, combined with R starting at w7 (375 mg/m2 IV q1w x4, then q8w x4). For immune responses blood mononuclear cells were assayed by flow cytometry and EO-mimic or B cell peptide specific tetramers without in vitro stimulation. The primary objective is to assess safety; secondary objectives include EO immunogenicity and preliminary efficacy. As of July 2025, the 6 planned pts had started EO. Median age was 66 years (range 46-73); 5 ECOG 0/1 ECOG 1; 1 Ann Arbor stage III/5 stage IV; FLIPI low risk 2/intermediate 2/high 2; FLIPI-2 low risk 2/intermediate 4. At median follow-up 10.6 months (mo) 4 pts completed and 2 are ongoing on EO. Median treatment duration was 43 w (range 2-43). Best response by Lugano in the 6 pts included 4 complete (CR) and 2 partial responses (PR). Median time to PR/CR was 17.1 w (range 6.0-18.0). Currently there is only 1 (not yet confirmed) progression at 20.5 mo. All 5 immune response evaluable pts had expansion of CD8 T cells specific for EO mimic and B cell target peptides during treatment; 4 of 5 had detectable expansions at w5 (1st testing time). Currently, the longest tested immune response is at w65 and positive for both EO mimic and B cell target peptides. Expanded specific CD8 T cells had a memory phenotype predominantly composed of effector memory (TEM) cells but also including central memory (TCM) and terminally differentiated effector memory CD8 T (TEMRA) cells. Across the 5 pts, the medians of max % (sum of specific CD8 T cells targeting either the 4 EO mimic peptides or the 4 B cell antigen epitopes at a specific timepoint) among all peripheral CD8 T cells were 0.71% (range 0.19-3.97) for EO mimic and 0.33% (0.20-1.30) for B cell target peptides. The most common EO-related adverse events (AEs) were local administration site reactions (erythema, pain, induration). These included Gr (Grade) 1 reactions in 3 pts, Gr 2 in 1 pt, and Gr 3 in 1 pt; latter being ulceration with EO-interruption at w10.1, and in context of a strong immune response against EO mimic [3.97% of all peripheral CD8 T cells at w5] and B cell target [1.30%] peptides, and CR from w16.7. Other EO related AEs were Gr 1 lymph node pain (1 pt), and related to both EO and R were Gr 2 urticaria (1 pt) and Gr 1 fatigue (1 pt). Only R related were Gr 2 infusion related reaction (3 pts), Gr 2 enterocolitis infection (1 pt), and in 1 pt each Gr 1 flushing, anemia, headache and diarrhea. There were no further Gr 3-4 AE and no death on treatment/follow-up. Complete B cell depletion was seen in 5 pts tested at w18 (R added w7); no recovery in the range of w30-65. Only 3 infections were reported, per above enterocolitis, and 2 cases of COVID-19 both resolved without sequalae. ConclusionsThe combination of EO with R has a predictable and manageable safety profile, with EO only adding local administration site reactions to the well-known R safety profile. In this feasibility cohort all evaluable pts developed a specific immune response against EO and B cell targets, and a Lugano objective response. The combination of EO and R is feasible and can be evaluated in further trials. Updated results will be presented at the meeting.

First-line treatment is curative in more than 80% of patients with Hodgkin lymphoma (HL). However, ~20% of cases relapse or progress due to the persistence of undetectable active tumor cells (known as minimal residual disease, MRD), and currently we cannot identify this subgroup of patients with enough precision and anticipation. Response assessment in HL is currently based on positron emission tomography (PET); however, sensitivity and, particularly the specificity of PET-based response assessments can be limited. Overall, there is a high unmet clinical need for better biological risk classification and novel response assessment in HL. Detecting circulating tumor DNA (ctDNA) is a tool that allows for diagnostic molecular profiling, response assessment and monitoring of minimal residual disease (MRD). - To analyze a series of patients with newly diagnosed HL using ctDNA to identify molecular markers of the tumor. - To evaluate MRD after two cycles of treatment using highly sensitive ctDNA techniques, to compare the results with those of PET/CT and to assess its prognostic impact on final response and survival. - Patients: HL diagnosed between 2017 and 2021 in Castile and León. - Samples: peripheral blood at baseline (n=74) and after two cycles of treatment (PET2) (n=45). - Methods: Circulating DNA (cDNA) was analyzed using a custom Next Generation Sequencing (NGS) capture panel including 46 genes related to HL. Unique molecule identifiers (UMIs) were employed to increase sensitivity and reducing sequencing artifacts. - PET/CT evaluation was performed by using the Deauville score. At diagnosis, adequate cDNA was obtained in 65/74 (88%) patients, and tumor-specific mutations were identified in 45/65 (69%) for MRD follow-up. After baseline and PET2 NGS studies, evaluable results were obtained in 42 patients. The median age was 35y (range 15-76), being 58% of them male and younger than 60y (80%). 35% of them were at early stage, with 16% stage III and 49% stage IV. The histological classification was Nodular lymphocyte predominant HL in 4.4%, Mixed Cellularity in 29%, Nodular Sclerosis in 55.6%, Lymphocyte-Rich HL in 6.6% and unclassifiable in 4.4%. ECOG was 2 or higher in 16% of cases and a bulky disease was annotated in 16% as well. B symptoms at diagnosis were seen in 56% of cases. First-line treatment was ABVD based therapy in all cases, with 13% experiencing some modifications based on the age and comorbidities. Only 4% were escalated to eBEACOPP after PET2(+) results. Thirteen patients (24%) received combined radiotherapy. Genotyping revealed somatic variants in the following genes: SOCS1 (58%), IGLL5 (40%), B2M (33%), GNA13 (31%), STAT6 (29%), ITPKB (28%) and TNFAIP3 (27%). At the time of PET2, we obtained an MRD(–) result by NGS in 34/42 patients (81%), while PET2 was negative (Deauville 1-3) in 26/42 (62%). Of the 42 patients with results from both techniques, 32 (76%) were concordant. Among the 10 discordant cases, one was MRD(+)/PET2(–) (relapsed at 72 months), and nine cases showed MRD(–)/PET2(+), of which 3 of them relapsed at 18, 20, and 46 months. Of the patients who had a positive PET2, only two were subsequently treated with intensified chemotherapy regimens (BEACOPP). Regarding progression-free survival (PFS), PET2(–) patients displayed significantly superior PFS than PET2(+) patients (92% vs. 50% at 3 years, p<0.05). Overall survival (OS) also showed this trend, although not reaching statistical significance (100% vs. 74% at 5 years, p=0.056). Furthermore, MRD(–) patients showed statistically significant differences compared to MRD(+) patients in both PFS (88% vs. 25% at 3 years, p<0.001) and OS (100% vs. 45% at 5 years, p<0.001). Combining PET2 and MRD strategies, 3 prognostic groups were identified with a 3-year PFS of 92% (–/–), 73% (+/–) and 17% (+/+) (p<0.001). CONCLUSION:Finally, we confirm that combining PET/CT & MRD assessment by cfDNA sequencing improves prognostic stratification of HL patients.

The rapid and accurate laboratory identification of targetable therapeutic genes, together with the implementation of measurable residual disease (MRD) based decision is essential for optimal clinical management in acute myeloid leukemia (AML). The PETHEMA (Programa Español de Tratamientos en Hematología) cooperative group comprises nine laboratories that perform centralized molecular studies by conventional PCR and Real-time quantitative PCR (RT-qPCR) for AML patients. With the aim to validate laboratories performances, we conducted three rounds of interlaboratory cross validation (ICV) for the quantification of CBFB::MYH11, RUNX1::RUNX1T1 and NPM1 and one round to determine the mutational status of NPM1, FLT3 (ITD and TKD2) IDH1 and IDH2. For RT-qPCR a total of 19 samples were tested and only 3 (15.8 %) failed to achieve 100 % concordance, corresponding to samples with low target gene mean ratios (ICV1-S4, ICV2-S1, ICV2-S6). For mutation detection in a total of 227 returned results, concordance rate ranged from 95 % to 100 %. FLT3-ITD and NPM1 mutation detection had 100 % concordant results. One false negative was reported for IDH2- R140 mutation and 4 false positives were detected: 2 FLT3-TKD2 and 2 IDH1-R132, likely reflecting differences in assay sensitivity. Overall, the results were highly satisfactory, particularly regarding MRD assessment, and highlighted key points for improvement, especially in baseline detection of FLT3-TKD2 and IDH1 mutations. This study represents the first collaborative initiative to evaluate performance of AML molecular targets within a laboratory network and underscores the importance of regular exercises to monitor performance, identify and resolve technical or interpretive discrepancies to ultimately ensure accurate clinical decision-making.

Diffuse Large B-Cell Lymphoma (DLBCL) is a heterogeneous disease characterized by a limited number of molecularly defined subtypes. Recently, genomic-based algorithms have been proposed for the classification of this disease. The whole exome sequencing was conducted on 108 diagnostic samples of diffuse large B-cell lymphoma (DLBCL). Somatic variants, predicted copy number alterations (CNAs), and available fusion data were utilized to classify the cases. Additionally, the enrichment of mutations in the TP53, MYC, and MAPK/ERK pathways was analyzed. Genetic subtypes were identified in approximately 55% of the cases. Cases with a specific genetic subtype exhibited a significantly higher Tumor Mutation Burden compared to molecularly unclassified cases (Mann-Whitney U test, p = 0.024). The prevalence of subtypes varied according to the cell of origin phenotypes. GC-B type DLBCL NOS were classified as EZB (5 cases, 16%), ST2 (5 cases, 16%), and BN2 (1 case, 3%). Four cases (13%) were genetically composite. Three cases of HGBCL/DLBCL double-hit (MYC & BCL2) were classified as EZB-MYC. Forty-three non-GC-B type DLBCL cases were classified as ST2 (5 cases, 11%), BN2 (6 cases, 14%), and MCD (3 cases, 7%). Nine cases were genetically composite (20%). MYC pathway mutations were enriched in cases with EZB and ST2 genetic features, while they were absent in the MCD subtype. TP53 mutations were identified in 11% of the cases. Plasmablastic lymphomas exhibit genetic diversity, with 27% of tumors classified as ST2. Recurrent somatic mutations indicate dysregulation of the JAK/STAT, MAPK/ERK, and tyrosine kinase signaling pathways.

Introduction: Current identification of high-risk Multiple Myeloma (HRMM) primarily relies on the Revised International Staging System (R-ISS and R2-ISS). However, cytogenetic abnormalities evaluated in these systems may no longer accurately capture prognosis in the era of novel and combination therapies and exclude key prognostic factors such as molecular alterations. Recently, the International Myeloma Society, along with the International Myeloma Working Group (IMS-IMWG) proposed a new Consensus Genomic Staging (CGS) system for MM. We aimed to validate the genomic alterations included in the CGS in a group of newly diagnosed MM. Methods: A total of 1,079 newly diagnosed MM patients were included from four clinical trials: elderly-fit, (n=460, 43%; NCT03742297), transplant-eligible (n=332, 31%; NCT01916252, NCT02406144), and unfit (n=287, 27%; NCT02575144) patients. Cytogenetic alterations were centrally assessed by FISH on sorted CD138+ plasma cells, and TP53 mutations were analyzed by next-generation sequencing (NGS). Modified genomic HRMM by CGS was defined as the presence of ≥1 of the following: del(17p) with >20% clonal fraction and/or TP53 mutation; an IgH translocation, including t(4;14), or t(14;16), along with 1q+ and/or del(1p32); or monoallelic del(1p32) plus 1q+. Traditional HRMM genomic alterations included del(17p), t(4;14), or t(14;16). Results: Median age at diagnosis was 73.8 years (IQR 71.1-77.4). The prevalence of high-risk CGS alterations was as follows: 6.7% for del(17p) with clonal fraction >20% (“high del(17p)”); 5.4% for monoallelic del(1p32) combined with 1q+ (“del1p+1q”); 5.2% for t(4;14) with either monoallelic del(1p32) or 1q+ (“t(4;14)+1p/q”); and 2.4% for t(14;16) with either monoallelic del(1p32) or 1q+ (“t(14;16)+1p/q”). TP53 mutations were identified in only 12 of 287 evaluated patients (4.2%). At a median follow-up of 51.1 months (IQR 35-65-1), the 3-year overall survival (OS) and progression-free survival (PFS) were 76% (95% CI 73-79%) and 67% (95% CI 64-70%), respectively. High del(17p) (p=0.008), del(1p)+1q (p=0.023), and t(4;14)+1p/q (p=0.012) were associated with shorter PFS in univariable models. Only t(4;14)+1p/q remained associated with higher hazard of death (p=0.001). Among 287 patients with available TP53 NGS data, a high-risk CGS genomic alteration was identified in 26% of the cases. Of these, 41% had previously been categorized as standard-risk by traditional criteria. Conversely, 7.1% of patients now classified as standard-risk were formerly considered high-risk. The 3-year OS was lower in the GCS high-risk compared to GCS standard-risk group (73% [95% CI 64-84] vs. 85% [95% CI 80-90], p=0.022). At 3-year PFS was also numerically lower in the GCS high-risk group (57% [95% CI 47-69] vs. 71% [95% CI 65-77], p=0.069). In multivariable models adjusting for clinical trial enrollment, CGS high-risk status remained independently associated with worse OS (HR 1.77 [95% CI 1.08-2.90], p=0.024) and PFS (HR 1.64 [95% CI 1.23-2.18], p=0.045). In contrast, 3-year OS and PFS were similar across the traditional high-risk and traditional standard-risk group (OS: 74% [95% CI 63-86] vs. 83% [95% CI 79-88], p=0.2; PFS: 62% [95% CI 50-76] vs. 69% [95% CI 63-75], p=0.3). Notably, among patients whose risk categorization changed between the CGS and traditional classification systems, the 3-year OS was 100% (95% CI, 100–100) for those reclassified as standard-risk (n = 15), and 85% (95% CI, 71-100%) for those reclassified as high-risk (n = 31). Conclusions: We validated the IMS-IMWG CGS system for HRMM in a large and diverse cohort of newly diagnosed individuals, including fit, unfit, and transplant-eligible MM patients. The CGS independently predicts clinical outcomes and effectively reclassifies a substantial proportion of patients previously misclassified by traditional criteria. These findings support incorporating NGS alongside FISH in the MM diagnostic workflow, and the clinical implementation of CGS to guide risk-adapted therapeutic strategies.

Introduction: Although TP53 gene alterations—such as 17p deletion and TP53 mutations—occur at relatively low frequency in multiple myeloma (MM), they remain among the most powerful adverse prognostic factors. However, the functional status of p53 may be disrupted through mechanisms beyond coding sequence abnormalities. To investigate this possibility, we expanded our analysis to include TP53 intronic variants, the expression of p53-regulated and p53-regulating genes, microRNAs involved in p53 signaling, and p53 protein isoforms, aiming to explore their potential association with disease outcome. Methods: We included bone marrow samples from 150 newly diagnosed MM patients enrolled in the GEM2012 clinical trial (NCT01916252). A DNA capture-based NGS panel was employed to sequence the entire TP53 gene. In parallel, a targeted RNA sequencing panel was used to assess the expression of 64 genes, including p53 targets and regulators. MicroRNA expression was quantified by RT-qPCR, while protein expression of p53 and its isoforms was analyzed using capillary nanoimmunoassay technology (EA Rojas, AJH 2022). The integrative analysis was conducted using all p53-related data from 92 patients, employing the Multi-Omics Factor Analysis (MOFA2) package in R. As input features, all variables analyzed at the four omic levels were included. Results: A total of 10 single nucleotide variants (SNVs) in the TP53 coding DNA sequence were identified in 11 patients with a negative impact on progression free survival (PFS) and overall survival (OS) (p ≤ 0.001), regardless of the VAF. The analysis of non-coding regions showed 3 SNVs in the 3´ UTR in 11 patients, and 53 SNVs within intronic regions in 91 patients. These intronic variants were grouped into six distinct clusters by Louvain method. The third group, which included SNVs in introns 1, 3, and 9, was associated with longer PFS (p = 0.023). Among the 7 miRNAs analyzed, the most expressed were the direct regulators of TP53, miR-125b, miR-25, and miR-30d. High levels of miR-25 and miR-125 were associated with lower levels of p53 protein (p = 0.023 and p = 0.017, respectively). Notably, high expression of miR-30d and miR-34 impacted positively on PFS (p < 0.05). RNA-seq of p53 targets and regulators showed 48 genes differentially expressed compared to normal plasma cells from healthy controls (26 underexpressed and 22 overexpressed genes): GADD45, SEMA3A, and CCND1 were overexpressed in MM patients, while KITLG, APAF1, and TP73 showed a marked underexpression. Interestingly, TP73 and CCND1 were the only genes significantly downregulated in patients harboring del(17p), whereas they were upregulated in those patients with t(11;14). Meanwhile, patients with TP53 mutations or TP53 double hit alterations had lower levels of TNFRSF10B when compared to the rest of patients without this condition (adj p < 0.05). High TNFRSF10B and CCND1 expression were associated with longer OS (p ≤ 0.01). The optimal MOFA2 model was established with 7 latent factors. Clustering based on the 7 latent factors was performed using the PAM algorithm resulting in 3 groups with distinct profiles in terms of PFS. Cluster 1 exhibited the poorest prognosis, whereas Cluster 3 showed the most favorable (p = 0.02). Further characterization of these groups revealed that Cluster 1 had a higher proportion of patients with plasmacytomas (31%) compared to Clusters 2 and 3 (7.5% and 19%, respectively; p = 0.049). In addition, Clusters 1 and 2 were enriched in 1q gain, observed in 72% and 60% of patients, respectively, in contrast to only 11.5% in Cluster 3 (p < 0.001). Conclusions:Patients with TP53 exonic variants exhibited worse outcomes.A group of TP53 intronic variants was associated with a favorable prognostic impact.High levels of miR-34a, which is a direct target of p53, and miR-30d were associated with longer PFS.Differential expression of p53 targets and regulators genes in MM highlights a distinct molecular profile linked to TP53 abnormalities, with high TNFRSF10B and CCND1 expression emerging as potential markers of improved OS.p53 functional status defined three distinct groups with clear differences in PFS. This work has been funded by ISCIII (PI23/00319) (co-financed by FEDER), Junta de Castilla y León (GRS 2331/A/21), AECC (PROYE20047GUTI) and International Myeloma Foundation (BDNovis Research Award).

Abstract Background: In a pivotal Phase II study (NCT02500407), subcutaneous (SC) mosunetuzumab (Mosun), a CD20xCD3 T-cell engaging bispecific antibody, achieved high response rates and durable remissions, and demonstrated pharmacokinetic non-inferiority to the intravenous (IV) formulation in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) after ≥2 prior lines of therapy, including those with high-risk features (Bartlett et al. ASH 2024; Hess et al. EHA 2025). We report updated efficacy and safety data from the pivotal Phase II study of Mosun SC in pts with R/R FL after three years of follow-up. Methods: Pts had R/R FL Grade (Gr) 1–3a and ≥2 prior therapies. Fixed-duration Mosun SC was administered (≤1mL volume) in 21-day cycles with step-up dosing in Cycle (C)1 (C1 Day [D]1, 5mg; C1D8, 45mg; C1D15, 45mg; C2D1 onwards, 45mg). Hospitalization was not mandatory. Pts with a complete response (CR) by C8 completed treatment without additional cycles; those with a partial response or stable disease could continue therapy for up to 17 cycles. Pts who achieved a CR with initial treatment and relapsed after the end of treatment were eligible for re-treatment. Responses were assessed per Cheson 2007 criteria. CR rate, overall response rate (ORR), duration of (complete) response (DO[C]R), progression-free survival (PFS) and overall survival (OS), and safety endpoints were investigator-assessed. Time to next treatment (TTNT) and response to re-treatment were exploratory endpoints. Results: Ninety-four pts were enrolled in this pivotal cohort; median age was 65 years (range: 35–84), 87% had Ann Arbor Stage III/IV disease, 66% were refractory to prior anti-CD20 therapy, 43% had progressed within 24 months from start of first-line treatment (POD24), 30% had elevated lactate dehydrogenase, and 23% had bulky disease (>7cm). As of May 1, 2025, median follow-up was 35.5 months (range: 1–48). The ORR and CR rate in the overall population were 74% and 63%, respectively. Median DOR and DOCR were 25.1 months (95% confidence interval [CI]: 21–39) and 33.6 months (95% CI: 22–not estimable [NE]), respectively. Median PFS was 18.5 months (95% CI: 11–28) and median OS was not reached (95% CI: NE); the estimated 30-month PFS and OS rates were 37% (95% CI: 27–48) and 83% (95% CI: 75–91), respectively. Median TTNT was 39.7 months (95% CI: 36–NE). In 59 pts with a CR, the 30-month PFS and OS rates were 56% (95% CI: 42–69) and 92% (95% CI: 85–100), respectively, and median PFS was 35.9 months (95% CI: 25–NE). Of 9 pts re-treated with Mosun, 7 (78%) responded, and 6 (67%) achieved a CR. At the clinical cut-off date, 4/7 re-treated pts with a response remained in remission. In pts with POD24, the ORR and CR rates were 70% and 58%, respectively. Median PFS was 15.7 months (95% CI: 6–NE) and the 30-month PFS rate was 41% (95% CI: 25–57). In pts with bulky disease, the ORR was 68% and CR rate was 55%. Median PFS was 28.3 months (95% CI: 6–NE) and the 30-month PFS rate was 42% (95% CI: 18–66), though few pts remained at risk. No new cytokine release syndrome (CRS) events or fatal, serious, or Gr ≥3 adverse events (AEs) were reported since the previous analysis. Injection site reactions remained the most common AE (69%). Fatal AEs occurred in 5 pts (COVID-19 pneumonia, n=2; COVID-19, n=1; hemophagocytic lymphohistiocytosis, n=1 [with active Epstein-Barr virus, cytomegalovirus, and lymphoma transformation]; general physical health deterioration, n=1). CRS events occurred in 30% of pts (Gr 3: n=2) and all resolved. Infections were reported in 55% of pts (Gr 1/2: 36%; Gr 3/4: 16%; Gr 5: 3%). Gr 3 febrile neutropenia was reported in 2 pts. No immune effector cell-associated neurotoxicity syndrome events were reported. The safety profile during re-treatment was consistent with initial therapy, with only 2 (10%) Gr 1 CRS events, 1 serious AE, and no fatal AEs. Conclusions: In this updated analysis, with a median follow-up of 35.5 months, fixed-duration Mosun SC continued to demonstrate durable responses, similar to those previously reported for Mosun IV in a comparable patient population. The safety profile was manageable with low rates of CRS and infections, consistent with previous analyses. Mosun SC has a favorable benefit-risk profile with the convenience of outpatient accessibility and short administration times.

Background: CD20/CD3 bispecific antibodies (BsAbs) have reshaped the treatment of relapsed/refractory large B-cell lymphoma (LBCL) and follicular lymphoma (FL). Their use in routine care brings new challenges, especially in managing T cell–mediated toxicities such as CRS and ICANS, underscoring the need for multidisciplinary strategies and real-world data to refine clinical pathways and resource use. Methods: We conducted a retrospective, multicenter study of consecutive adults with relapsed/refractory B-cell lymphoma treated with commercial CD20/CD3 BsAbs across the GELTAMO network. Since glofitamab (glofit) is not reimbursed in Spain, that group was included through an early access program, as was epcoritamab (epco) in FL. Patient data included baseline demographics, prior treatments, toxicity, clinical management approaches, hospital resource utilization, response rates per Lugano 2014 and survival outcomes. Results: Among 168 patients, 86 (51%) received epco, 59 (35%) mosunetuzumab (mosun), and 23 (14%) glofit. The median age was 64 years (range 36-86), and 59% were male. Regarding histology, 58% had LBCL —including 12% with high-grade B-cell lymphoma (HGBCL)— and 42% had FL. Overall, 38% of patients would not have met the general eligibility criteria commonly applied in clinical trials, primarily due to organ dysfunction or cytopenias. In the LBCL cohort, 64% of patients were primary refractory, 51% were refractory to last previous treatment, 33% had bulky disease, and 78% presented extranodal involvement. The median number of prior treatment lines was 3 (range 2–4), with 45% having received two lines and 55% three or more. Additionally, 54% had previously received CAR-T therapy, and 9% had undergone a hematopoietic stem cell transplant. In the FL cohort, the median number of prior lines was also 3 (range 2–5); 44% had received two lines and 56% more than two. Progression within 24 months of first-line therapy (POD24) occurred in 62% of patients. Prior bendamustine exposure was reported in 44%, including 16% who received it within 9 months before BsAb initiation. Twenty-nine percent of patients had undergone a prior transplant, and 10% had received CAR-T therapy. Patients with aggressive lymphomas predominantly received epco (75%) and glofit (25%), while FL-patients received mosun (80%) and epco (20%). Treatment was delivered in an inpatient setting in 86% of cases and, among the 14% without a planned admission, most (90%) received mosun. The median cumulative hospital stay during the entire Step-Up dosing schedule was 12 days (range 1–92). Focusing on toxicity, CRS was observed in 42% of patients (45% epco, 45% glofit, 48% mosun): Severe CRS (Grade ≥3) appeared in 2% (0% epco, 4% glofit, 1.8% mosun). Most (71%) CRS events occurred during cycle 1. Tocilizumab was administered in 31% and corticosteroids in 37%. The median duration of steroid use was 3 days (range 1–12). ICANS occurred in 4.3% of patients, predominantly grade 1 (98%), with only one case each of grade 2 and 3. Any grade cytopenias occurred in 40% (grade ³3 in 30%). Infections were reported in 27% (9.5% were grade ³3) predominantly respiratory (77%) and mainly during the first four cycles. , Among the 8% of patients requiring ICU admission, 9 cases were due to CRS (in 2, ICU stay was solely for treatment administration), 3 were related to severe infections, and 1 patient was admitted for complete AV block requiring pacemaker placement. There were 34 deaths, 24 (71%) related with lymphoma progression (7 FL, 17 LBCL). Non-relapse mortality was 5.9%, mainly due to infections (80%). Regarding efficacy, overall response rate (ORR) and complete response (CR) rates were 43% (23%) in LBCL and 75% (49%) in FL. In patients previously treated with CAR-T therapy, ORR(CR) was 44.6% (21.7%) in LBCL and 66.7% (50%) in FL. With a median follow-up of 8.8 months, median progression-free survival and overall survival were 4.0 months (95% CI: 2.8–9.0) and 11 months (95% CI: 6.8–NR) for LBCL, and 17 months (95% CI: 7.1–NR) and not reached for FL. Conclusions: In this large, real-world BsAb cohort, efficacy was lower than pivotal trials, likely reflecting the broader and frailer patient population treated in routine practice. Overall toxicity was comparable to trials, but hospitalization duration remained substantial, emphasizing the need for optimized outpatient management. Infections were frequent and contributed significantly to non-relapse mortality.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The primary analysis of the Ro-CHOP phase III randomized controlled trial (ClinicalTrials.gov identifier: NCT01796002 ) established that romidepsin (Ro) plus cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) did not yield an increased efficacy compared with CHOP alone as first-line treatment of peripheral T-cell lymphoma. We report the planned final analysis 5 years after the last patient enrolled. With a median follow-up of 6 years, median progression-free survival (PFS) was 12.0 months compared with 10.2 months (hazard ratio [HR], 0.79 [95% CI, 0.62 to 1.005]; P = .054), while median overall survival was 62.2 months (35.7-86.6 months) and 43.8 months (30.1-70.2 months; HR, 0.88 [95% CI, 0.68 to 1.14]; P = .324) in the Ro-CHOP and CHOP arms, respectively. In an exploratory analysis, the median PFS in the centrally reviewed follicular helper T-cell lymphoma subgroup was significantly longer in the Ro-CHOP arm (19.5 v 10.6 months, HR, 0.703 [95% CI, 0.502 to 0.985]; P = .039). Second-line treatments were given to 251 patients with a median PFS2 and OS2 after relapse or progression of 3.3 months and 11.5 months, respectively. Within the limits of highly heterogeneous second-line treatments, no specific regimen seemed to provide superior disease control. However, a potential benefit was observed with brentuximab vedotin in association with chemotherapy even after excluding anaplastic large-cell lymphoma subtype or after adjusting for histology and international prognostic index in a multivariate model (HR for PFS, 0.431 [95% CI, 0.238 to 0.779]; P = .005).

Nowadays, companies collect massive quantities of data to enhance their operations, often at the expense of sharing user sensible information. This data is widely used to train Deep Learning (DL) neural networks to model, classify, or recognize complex data. These activities enable companies to offer an array of services to users, such as precise advertising and optimal location services. This study explores potential solutions for preserving privacy while utilizing DL applications. To address the privacy issue, we develop a privacy-preserving framework specifically designed for fog computing environments. Unlike traditional cloud computing architectures, fog embedded architectures only share a small portion of user data with a nearby fog node, ensuring that the majority of sensitive data remains secure. Within these fog nodes, we incorporate two additional algorithms, namely Generalization and Threshold, to enhance the privacy-preserving capabilities of the framework. The first algorithm, Generalization, introduces a validation dataset within the fog nodes which not only increases the accuracy of the fog-embedded framework but also ensures that user data is preserved. The second algorithm, Threshold, is responsible for protecting user data samples and reducing the amount of information sent to the server. By combining these two algorithms, we are able to provide an additional layer of protection for user privacy while still maintaining the accuracy of the model. We conduct an evaluation to test its effectiveness using two separate datasets. In addition, we analyze them through a Feed Forward Neural Network (FFNN) and compare the results with a traditional centralized architecture to validate the effectiveness of the proposed framework. The results of our evaluation demonstrate that the proposed privacy-preserving framework, when combined with the Generalization and Threshold algorithms, can preserve up to 38.44% of user data. Additionally, we were able to extend the framework to multiple fog nodes without compromising the network's accuracy, as we only observed a 0.1% decrease in accuracy when using the proposed architecture. This study emphasizes the importance of preserving user information while using DL applications and provides a solution that trains the desired network without violating user privacy, hence preserving their anonymity. Overall, the study highlights the potential of Federated Deep Learning to improve the accuracy and privacy of DL applications in fog computing environments.

The widespread use of smart devices and the numerous security weaknesses of networks has dramatically increased the number of cyber-attacks in the internet of things (IoT). Detecting and classifying malicious traffic is key to ensure the security of those systems. This paper implements a distributed framework based on deep learning (DL) to prevent many different sources of vulnerability at once, all under the same protection system. Two different DL models are evaluated: feed forward neural network and long short-term memory. The models are evaluated with two different datasets (i.e.NSL-KDD and BoT-IoT) in terms of performance and identification of different kinds of attacks. The results demonstrate that the proposed distributed framework is effective in the detection of several types of cyber-attacks, achieving an accuracy up to 99.95% across the different setups.

S12patients with a resistant clone that did not respond or only very partly responded to treatment, > 50% of the malignant PCs were found in the BM post-treatment (5/12 patients, 42%); and patients with clonal selection, indicating that the significant clone has been replaced by a small or undetectable clone at baseline (4/12 patients, 33%).For these four patients identified with clonal selection, one was observed with branching evolution, and the other three were observed with differential evolution.Transcriptional differences among sensitive clones, resistant clones, and selective clones were detected based on a pairwise comparison of the gene expressions.A large number of differentially expressed genes with reported MM resistant-related functions were observed in the resistant clones, including previously reported 1q-related genes such as CKS1B, HNRNPU, and H3F3A; cell cycle-and cell proliferation-related genes such as TUBA1B, STMN1, and HMGB2.For selective clones, an evident activation of the NF-kB signaling pathway was observed.Conclusions: Together, our study confirms that clonal dynamics of the evolving PC clones may occur early after upfront therapy, and reveals that the acquisition of therapeutic resistant pathways is associated with early adaptation to treatment.

Abstract Multiple myeloma (MM) patients with t(11;14) present unique biological features and their prognosis is not well established. We report a retrospective study of 591 MM patients, 17.6% of whom had t(11;14). It was designed to determine the prognostic impact of this abnormality and the effect of novel agents on the response and outcomes. Three groups were established based on their cytogenetics: 1) t(11;14); 2) high-risk chromosomal abnormalities; and 3) standard risk (SR). After 80.1 months (1.2-273.8 months) of follow-up, no differences were observed in overall survival (OS) between the t(11;14) and SR groups (75.8 vs. 87.2 months; P = 0.438). However, in ISS-1 stage patients, MM t(11;14) individuals had shorter OS than those in the SR group (62.9 vs. 126.7 months; P = 0.004). Treatment of MM t(11;14) with novel agents did not improve their overall response rate (ORR) or complete response (CR) compared with those who received conventional therapy (ORR: 87.2% vs. 79.5%, P = 0.336; CR: 23.4% vs. 12.8%, P = 0.215). This effect translated into similar PFS (39.6 vs. 30.0 months; P = 0.450) and OS (107.6 vs. 75.7 months; P = 0.175). In summary, MM t(11;14) patients did not benefit from the introduction of novel agents as much as SR patients did, indicating that other therapies are needed if their outcome is to be improved.