Patients with newly diagnosed large B-cell lymphoma (LBCL) and International Prognostic Index (IPI) scores ≥3 have inferior outcomes with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We evaluated efficacy and safety of epcoritamab plus R-CHOP in newly diagnosed LBCL in Arm 1 of the phase 1b/2 EPCORE NHL-2 trial. Adults with CD20+ LBCL and IPI scores 3-5 received R-CHOP (6 cycles) plus epcoritamab for a total of 1 year of treatment. Primary endpoint was investigator-assessed overall response rate (ORR). Key secondary endpoints included complete response (CR) rate, duration of CR (DOCR), progression-free survival (PFS), overall survival (OS), minimal residual disease (MRD) negativity, and safety. Forty-seven patients were treated. Median age was 64 years, 89% had Ann Arbor stage IV, and 53% had bulky disease (≥7 cm). ORR was 98% (95% CI, 89-100) and CR rate 85% (95% CI, 72-94). At median follow-up of 44.2 months, median DOCR, PFS and OS were not reached (NR; 95% CI, NR-NR); estimated 2-year PFS and OS rates were 80% (95% CI, 65-89) and 87% (95% CI, 73-94), respectively. MRD-negativity was achieved in 100% of MRD-evaluable patients. Most common adverse events were neutropenia (74%), anemia (72%), and cytokine release syndrome (CRS; 60%). CRS events were predominantly grade 1-2; all resolved. Epcoritamab plus R-CHOP induced high response rates in patients with newly diagnosed LBCL and IPI scores 3-5. These promising findings support the ongoing phase 3 evaluation of this treatment regimen. This trial was registered at ClinicalTrials.gov (NCT04663347).

Bleximenib, a potent and selective menin inhibitor, in combination with intensive chemotherapy (IC) has previously exhibited an acceptable safety profile and efficacy in participants (pts) with newly diagnosed (ND) NPM1-mutated (NPM1m) or KMT2A-rearranged (KMT2Ar) acute myeloid leukemia (AML). We report updated safety and efficacy data (cut-off: July 2025) from this study.In the ALE1002 Phase 1b, multicenter, dose-finding study (NCT05453903), pts received a ‘7+3’ regimen of cytarabine 200 mg/m2/day and daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day in combination with bleximenib 30–100 mg twice daily (from Day 4 of induction, including during count recovery). Pts who achieved a complete remission (CR) received consolidation therapy with up to 4 cycles of intermediate-dose cytarabine plus bleximenib. Those not proceeding to allogeneic hematopoietic stem cell transplant could continue bleximenib for up to 12 months. The safety dataset included all pts who received bleximenib 30–100 mg, and the intention-to-treat (ITT) efficacy dataset included those who received bleximenib 100 mg. Investigators assessed response criteria according to European LeukemiaNet (ELN) recommendations.The safety analysis set included 44 pts with ND AML (median age, 57.0 years [range, 19–71]; 52.3% female; 56.8% NPM1m, 43.2% KMT2A; 15.9% FLT3 co-mutations; ELN risk classification: 44.2% favorable, 27.9% intermediate, 27.9% adverse). The median duration of follow-up was 6.3 months (range, 1.31–22.51). All pts had ≥1 treatment-emergent adverse event (TEAE, all grades), the most common being thrombocytopenia (35/44; 79.5%), neutropenia (32/44; 72.7%), diarrhea (31/44; 70.5%), nausea (30/44; 68.2%), anemia, and febrile neutropenia (both 28/44; 63.6%). Most cytopenia TEAEs were Grade 3/4, consistent with an IC backbone. The 30- and 60-day mortality was 0/44 (0%) and 1/44 (2.3%), respectively. No differentiation syndrome was observed. Three TEAEs of QT prolongation were reported, all of which were Grade 1/2 and resolved without bleximenib interruption. Of 24 pts (NPM1m, n=15; KMT2Ar, n=9) in the ITT efficacy dataset, overall response rate (≥partial response) was 95.8%, composite CR (CR + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery rate) was 87.5%, and CR/CRh was 75%. Responses were similar across mutational subtypes. Median (range) time to CR was 28 days (21–36), similar to the median time to first response. Median duration of response was not reached. Among 37 pts achieving composite CR the median (range) time from Day 1 of induction to platelet count recovery was 32.0 days (22.0–82.0), and the median time to neutrophil count recovery was 30.0 days (21.0–71.0).In ND NPM1m or KMT2Ar AML, the safety profile of bleximenib + ‘7+3’ was consistent with a ‘7+3’ IC backbone, which, combined with promising early efficacy data, supports the planned Phase 3 study.

Teclistamab is the first approved B-cell maturation antigen×CD3 bispecific antibody with weight-based dosing for triple-class-exposed relapsed/refractory multiple myeloma (RRMM). We evaluated the safety and efficacy of teclistamab combined with the anti-CD38 monoclonal antibody daratumumab in the phase 1b TRIMM-2 study. Eligible patients had RRMM (≥3 prior lines of therapy [LOT] or were double-refractory to a proteasome inhibitor and immunomodulatory drug); prior anti-CD38 exposure was permitted. Patients received subcutaneous daratumumab per approved schedule plus weight-based or fixed-dose subcutaneous teclistamab. The primary endpoint was safety; secondary endpoints included overall response rate (ORR) and duration of response (DOR). Progression-free survival (PFS) was an exploratory endpoint. Sixty-one patients received the weight-based recommended phase 2 doses (RP2D; teclistamab 1.5 mg/kg QW or 3.0 mg/kg Q2W); median number of prior LOTs was 5 (range, 1-14). Median follow-up was 12.0-months. The most common treatment-emergent adverse events (TEAEs) were infections, cytokine release syndrome, neutropenia, and anemia; grade 3/4 TEAEs occurred in 93.4% and 7 died from TEAEs. No dose-limiting toxicities occurred. ORR was 68.9% (complete response or better, 44.3%); median DOR was not reached. Median PFS was 26.3 months. A cohort exploring fixed-dose teclistamab (100-300 mg) ended prematurely after a safety signal for fatal infections was identified; out of an abundance of caution, all patients were switched to weight-based dosing. In conclusion, the fully immune-based combination of weight-based RP2D teclistamab plus daratumumab demonstrated deep and durable responses, with a well-characterized safety profile. Results highlight the importance of infection management, including early immunoglobulin replacement. Registered at ClinicalTrials.gov: NCT04108195.

Introduction: Talquetamab (Tal, anti-GPRC5D×CD3) and teclistamab (Tec, anti-BCMA×CD3) are the first bispecific antibodies (BsAbs) approved as monotherapies for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). In previous results from the phase 1b portion of RedirecTT-1 (NCT04586426, March 2024 data cut; median follow-up [mFU] 20.3 mo), Tal + Tec elicited deep, durable responses and demonstrated a safety profile generally consistent with each monotherapy across all dose levels (DLs), including at the recommended phase 2 regimen (RP2R) of Tal 0.8 mg/kg + Tec 3.0 mg/kg Q2W and in patients (pts) with true extramedullary disease (EMD). We report efficacy and ongoing safety from phase 1b of RedirecTT-1 at an extended mFU of 36.2 mo. Methods: Pts had TCE RRMM with measurable disease per IMWG criteria and were refractory, relapsed, or intolerant to the last line of therapy. True EMD was defined as ≥1 nonradiated soft tissue plasmacytoma noncontiguous with bone ≥2 cm in 1 dimension (with or without paramedullary plasmacytomas). Primary objectives were to evaluate safety and identify a RP2R. Investigator-assessed confirmed response per IMWG criteria was reported in all treated pts. EMD response was assessed by CT, PET-CT, or MRI whole-body scans. Results: As of July 2025, 94 pts received Tal + Tec (44 pts at the RP2R), with a mFU of 36.2 mo (34.1 mo at the RP2R). Baseline characteristics were as previously reported; 23 (45.1%) pts had high-risk cytogenetics. Dose-limiting toxicities occurred in 3 pts across non-RP2R DLs (all grade [gr] 3; oral herpes, oral candidiasis, increased alanine/aspartate aminotransferase) and in 1 pt at the RP2R (gr 4 thrombocytopenia). Most common adverse events (AEs) were CRS (80.9%; gr 3, 2.1%; no gr 4/5), neutropenia (74.5%; gr 3/4, 70.2%), taste changes (66.0%; all gr 1/2), and non-rash skin AEs (62.8%; gr 3, 2.1%). Infections occurred in 93.6% of pts (gr 3/4, 68.1% [54.5% at the RP2R]). The most common infection was COVID-19 (40.4%; gr 3/4, 17.0%); pts were screened for enrolment between 2020–2023, concurrent with the COVID-19 pandemic. Opportunistic infections occurred in 16 (17.0%) pts. Eighty-four (89.4%) pts had posttreatment hypogammaglobulinemia; 61 (64.9%) pts received ≥1 dose of IgG. ICANS occurred in 3.2% of pts (gr 3/4, 1.1%). Overall, 18 (19.4%) pts discontinued Tal + Tec due to AEs (6 [14.0%] at the RP2R), of which 9 were deemed drug-related by investigator (2 at the RP2R); 12 discontinuations were due to infections (5 at the RP2R). One pt discontinued Tal only. In total, 18 (19.1%) pts died due to AEs (6 [13.6%] at the RP2R), of which 9 (9.6%) were deemed drug-related by investigator (2 [4.5%] at the RP2R). At the RP2R, overall response rate (ORR) was 79.5%, with a ≥CR rate of 61.4%; ORR was 61.1% (≥CR, 44.4%) in pts with EMD and 92.3% (≥CR, 73.1%) in pts without EMD. Across all DLs, ORR was 77.7% (≥CR, 52.1%). Responses continued to be durable at the RP2R and across all DLs, including in pts with EMD, consistent with previous results. The median duration of response (DOR) was non-estimable (NE) at the RP2R (NE with and without EMD), as well as across all DLs, with 36-mo DOR rates of 71.1% at the RP2R (61.4% with EMD, 76.4% without EMD) and 58.5% across all DLs. Progression-free survival (PFS) and overall survival (OS) were promising at an extended mFU. Median PFS was NE at the RP2R (21.6 mo with EMD, NE without EMD) and 38.6 mo across all DLs, with 36-mo PFS rates of 57.9% at the RP2R (39.7% with EMD, 70.5% without EMD) and 52.6% across all DLs. Median OS was NE at the RP2R (NE with and without EMD), as well as across all DLs, with 36-mo OS rates of 73.9% at the RP2R (57.0% with EMD, 83.2% without EMD) and 65.8% across all DLs. Conclusions: At an extended mFU of ~3 yrs, Tal + Tec continued to have a safety profile that was generally consistent with each monotherapy, with no exacerbation of AEs with the combination. The infection profile supported prophylaxis and vigilant monitoring and management. Tal + Tec led to a high ORR and deep, durable responses in all pts, including at the RP2R and in pts with true EMD, contributing to durable PFS observed across all pts. DOR and prolonged survival in pts with and without EMD exceeded all therapies for pts with TCE RRMM. These data continue to highlight the clinical benefit of the novel combination of Tal + Tec in pts with TCE RRMM, validating the RP2R and the ongoing phase 2 analyses in pts with true EMD.

The treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains challenging, with inadequate responses to salvage chemoimmunotherapy limiting patients’ ability to receive potentially curative treatments like autologous stem cell transplantation (ASCT). Epcoritamab, a subcutaneous CD3×CD20 bispecific antibody, has demonstrated antitumor activity in R/R DLBCL as a monotherapy and in combination with chemotherapy. In Arm 4 of the EPCORE® NHL-2 phase 1b/2 trial (NCT04663347), transplant-eligible patients with CD20+ R/R DLBCL received epcoritamab plus rituximab, dexamethasone, cytarabine, oxaliplatin/carboplatin (R-DHAX/C). Patients could continue epcoritamab until ASCT or progression. Twenty-nine patients received epcoritamab plus R-DHAX/C; 72% had stage IV disease; 66% had primary refractory disease. As of January 15, 2025 (median follow-up 40.4 months), overall response rate (primary endpoint) was 79%, and complete response rate was 69%. Sixteen patients (55%) proceeded to ASCT and five remained on epcoritamab monotherapy. At 36 months, an estimated 70% of responses were ongoing, 59% of patients were progression-free, and 76% were alive. Common treatment-emergent adverse events (TEAE) were thrombocytopenia (90%), anemia (66%), and neutropenia (59%). Cytokine release syndrome occurred in 45% of patients; all were grade 1–2 and resolved after a median of 2 days. Immune effector cell-associated neurotoxicity syndrome occurred in one patient. No fatal TEAE or clinical tumor lysis syndrome were observed. Epcoritamab plus R-DHAX/C achieved deep, durable responses with manageable safety. Over half of patients proceeded to ASCT, a potentially curative treatment. These findings suggest the potential of epcoritamab combined with standard chemoimmunotherapy as an effective salvage treatment for patients with R/R DLBCL.

e19046 Background: While outcomes in pts with R/R FL have improved with current SOC treatments (Tx), there remains a need for safe, efficacious, and convenient Tx options. GOLCA is a potential, first-in-class, oral CELMoD designed for 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 + R was well tolerated and effective in heavily pretreated pts in the two-part Ph 1/2 study, CC-99282-NHL-001. Here, we provide longer f/u in pts with R/R FL from Part B of the study. Methods: Pts with R/R FL with ≥2 prior lines of Tx (≥1 if prior anti-CD20 Tx) received GOLCA orally, once daily at 0.2 mg (n=22) or 0.4 mg (n=38) ± R for up to 2 y or until progressive disease (PD)/unacceptable toxicity. Primary endpoints included safety and RP2D determination; secondary endpoints are preliminary efficacy and PK. Results: As of September 15, 2025, 60 pts were enrolled. In 0.2 and 0.4 mg groups, median prior Tx lines were 3 and 3, 32% and 32% had prior lenalidomide (LEN), 27% and 29% had prior T-cell–redirecting Tx (CAR T and/or bispecific antibody) and 32% and 32% were refractory to last regimen. Tx is ongoing in 6 (27%) and 17 (45%) pts at 0.2 and 0.4 mg, respectively; discontinuations (d/c) were mostly due to PD. Neutropenia, an on-target side effect of GOLCA, was the most common grade 3/4 Tx-emergent adverse event (TEAE) occurring in 59% and 68% of pts at 0.2 and 0.4 mg, followed by anemia (9% and 16%) and febrile neutropenia (9% and 8%). Median time to resolution of neutropenia was 8 days. Dose reductions occurred in 14% and 37% of pts at 0.2 and 0.4 mg, most commonly due to neutropenia (5% and 21%) and febrile neutropenia (5% and 5%). No d/c or deaths were from GOLCA-related TEAEs. Non-hematologic TEAEs were infrequent and mostly low grade. In efficacy-evaluable pts (GOLCA 0.2 and 0.4 mg + R, n=22 and n=36), median f/u was 14.03 months (mo), overall response rate (ORR) was 77% (complete response rate [CRR], 41%) at 0.2 mg, and 97% (CRR, 78%) at 0.4 mg. In the 0.4 mg group, responses were consistent in high-risk subsets including pts with prior LEN (ORR, 100%; CRR, 75%) and/or T-cell–redirecting Tx (ORR, 91%; CRR, 64%). GOLCA 0.4 mg + R demonstrated durable responses (median DOR, 9.17 mo; 91% of pts who achieved a CR remained in CR at cutoff). Conclusions: With longer f/u, GOLCA + R demonstrated promising efficacy with durable responses and no new safety signals. The 0.4 mg group had higher ORR and CRR than 0.2 mg, including in pts with prior LEN-based and/or T-cell–redirecting Tx, with a manageable safety profile at both doses. The results support the development of GOLCA + R as a fixed-duration, chemotherapy-free outpatient Tx in the Ph 3 GOLSEEK-4 study in 2L+ FL (NCT06911502). Clinical trial information: NCT03930953 .

Background:Activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) has worse outcomes than the germinal center B-cell (GCB) subtype, but underlying molecular mechanisms remain poorly understood. Methods:Transcriptomic analysis on 43 DLBCL samples (23 GCB and 20 ABC) was performed using NanoString PanCancer Immune Profiling Panel with 30 cell-of-origin genes. Tumor microenvironment characterization was performed using CIBERSORTx and gene set enrichment analysis (GSEA) deconvolution. Based on our previous findings of MAPK10 downregulation in ABC lymphomas, MAPK10 promoter methylation was studied via pyrosequencing. Prognostic biomarkers were identified using the Cox regression and least absolute shrinkage and selection operator (LASSO) regularization. Therapeutic candidates were identified through connectivity mapping. Results:ABC lymphomas showed distinct profiles with the overexpression of VTCN1, CDK4, and CXCR5 and the downregulation of MMP9 and MAPK10. GSEA revealed enrichment of inflammatory pathways with immunosuppressive signals in ABC cases. Confirming our prior observations, MAPK10 downregulation in ABC tumors was associated with promoter hypermethylation and inferior overall survival (p < 0.01). Immune deconvolution revealed greater microenvironmental diversity in ABC cases with significant eosinophil enrichment. High CD8+ T-cell abundance was associated with improved survival, particularly in ABC patients (p < 0.01). Multivariate analysis identified CCL18 as an independent adverse prognostic factor (HR: 1.87, 95% CI: 1.25-2.79, p < 0.01). Connectivity mapping identified proteasome inhibitors and CDK4/6 inhibitors as promising therapeutic candidates. Conclusions:We validated MAPK10 promoter hypermethylation and CCL18 overexpression as prognostic biomarkers in ABC DLBCL. These findings, derived from integrative transcriptomic and immunogenomic profiling, provide clinically relevant insights into disease biology and support biomarker-guided strategies for precision treatment in aggressive B-cell lymphomas.

Background:Healthcare is shifting from a disease-centered to patient-centered approach, and aspects of health such as quality of life (QoL) are becoming increasingly relevant. "E-Res Salud" for hematological malignancies is a value-based healthcare program aiming to improve patient experience and outcomes. The program collects e-PROMs via automatically deployed, validated questionnaires over a mobile application. Methods:A multicenter prospective observational cohort study including 243 patients with Hodgkin and non-Hodgkin lymphoma receiving outpatient intravenous immunochemotherapy at four teaching hospitals in Madrid, Spain, of whom 121 participated in the "E-Res Salud" program. Results:We found that adverse event reporting differs significantly between patients and healthcare professionals. Participants showed significantly lower rates of emergency department visits (37.2% vs. 56.6%; p < 0.01) and unplanned hospital admissions (21.5% vs. 32.8%; p < 0.05), as well as significantly higher rates of treatment completion and overall survival (88.4% vs. 79.5% after 18 months of follow-up; stratified hazard ratio, 2.30; 95% CI 1.25-4.22; p = 0.007). Conclusions:An e-PROMS program for patients with lymphoma is associated with lower use of healthcare and improved clinical outcomes. Patients and hematologists report adverse events differently, demonstrating the importance of patient-reported outcome measurement to improve symptom management in clinical practice. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

PURPOSE:Performance status (PS) assessment is used to determine clinical trial eligibility among patients with cancer, but may be inaccurately assessed by oncology clinicians. Wearable accelerometers may allow objective assessment of physical activity, a proxy for PS. In this analysis of two prospective studies, we derive and externally validate objective PS (OPS) by measuring the association between daily physical activity and overall survival among patients with metastatic cancer. MATERIALS AND METHODS:For the derivation cohort, we prospectively measured daily physical activity using a wearable accelerometer among patients with metastatic cancer during the screening period for a phase 1 clinical trial in Spain. We used univariable survival analysis, AUCs, and Youden's index to derive an OPS cutoff in mean daily distance walked. We used a multivariable Cox model to calculate the association between OPS and 180-day mortality. We subsequently externally validated OPS in a separate prospective trial of patients with metastatic lung and GI cancers receiving chemotherapy at a large academic health center in the United States. RESULTS:Full data were available for 123 patients (70 derivation; 53 validation). In the derivation cohort, we defined an OPS cutoff at 1,200 m walked per day. Poor OPS was associated with higher mortality than good OPS in the derivation (180-day mortality, 81.6% v 38.4%; adjusted hazard ratio [aHR], 6.82 [95% CI, 3.44 to 13.5]; P < .001) and external validation cohorts (180-day mortality, 36% v 8%; aHR, 7.07 [95% CI, 1.37 to 36.6]; P = .02). CONCLUSION:OPS is an independent, externally validated prognostic indicator and could serve as an objective surrogate for traditional methods of PS assessment in clinical trials and choice of therapy for patients with cancer.

BACKGROUND:Talquetamab (anti-G protein-coupled receptor family C group 5 member D) and teclistamab (anti-B-cell maturation antigen) are bispecific antibodies that activate T cells by targeting CD3 and that have been approved for the treatment of triple-class-exposed relapsed or refractory multiple myeloma. METHODS:We conducted a phase 1b-2 study of talquetamab plus teclistamab in patients with relapsed or refractory multiple myeloma. In phase 1, we investigated five dose levels in a dose-escalation study. Talquetamab at a dose of 0.8 mg per kilogram of body weight plus teclistamab at a dose of 3.0 mg per kilogram every other week was selected as the recommended phase 2 regimen. The primary objective was to evaluate adverse events and dose-limiting toxic effects. RESULTS:A total of 94 patients received treatment, with the recommended phase 2 regimen used in 44. The median follow-up was 20.3 months. Three patients had dose-limiting toxic effects (including grade 4 thrombocytopenia in 1 patient with the recommended phase 2 regimen). Across all dose levels, the most common adverse events were cytokine release syndrome, neutropenia, taste changes, and nonrash skin events. Grade 3 or 4 adverse events, most commonly hematologic events, occurred in 96% of the patients. Grade 3 or 4 infections occurred in 64% of the patients. With the recommended phase 2 regimen, a response occurred in 80% of the patients (including in 61% of those with extramedullary disease); across all dose levels, a response occurred in 78%. The likelihood of patients continuing in response at 18 months was 86% with the recommended phase 2 regimen (82% among those with extramedullary disease) and 77% across all dose levels. CONCLUSIONS:The incidence of grade 3 or 4 infections with talquetamab plus teclistamab was higher than has been observed with either therapy alone. A response was observed in a high percentage of patients across all dose levels, with durable responses with the recommended phase 2 regimen. (Funded by Janssen Research and Development; RedirecTT-1 ClinicalTrials.gov number, NCT04586426.).

Introduction While outcomes in patients with R/R FL have improved with T-cell–redirecting treatments (e.g. CAR T-cell therapy, bispecific antibodies), there remains an unmet need for safe, efficacious, and more convenient chemotherapy-free treatment options (Caridà et al, Eur J Haematol. 2025). GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin) and immunomodulatory activity. In the two-part, multicenter, first-in-human Phase 1/2 study (CC-99282-NHL-001; NCT03930953), GOLCA was well tolerated and effective in patients with R/R FL (Cordoba et al, ICML 2025, #441). Here, we provide longer follow-up in patients with R/R FL from Part B of the study. Methods Patients with R/R FL with ≥ 2 prior lines of therapy (≥ 1 in Part B if prior anti-CD20 therapy) were included in the study. Patients received GOLCA monotherapy orally, once daily at different dosing schedules in Part A. In Part B, GOLCA was dosed at 0.2 or 0.4 mg (14 days on/14 days off) ± R. Total GOLCA treatment duration was up to 2 years or until progressive disease (PD)/unacceptable toxicity. Primary objectives included safety and recommended Phase 2 dose determination. Results As of April 3, 2025, a total of 72 patients with R/R FL were enrolled: 12 in Part A (GOLCA monotherapy) and 60 in Part B Cohort D (22 received GOLCA 0.2 mg + R; 38 received GOLCA 0.4 mg + R). Patients were heavily pre-treated. Median number of prior treatments was 4.5 (range, 2–6) in Part A and 3 (range, 1–12) in Part B Cohort D. Approximately one-third of the treated patients were exposed to prior T-cell–redirecting therapy, approximately one-third had prior lenalidomide (len) exposure, and approximately one-third were refractory to the last regimen received. At the time of data cutoff, in Part A, 4 patients completed 2 years of GOLCA, remaining in remission at last follow-up; 8 discontinued due to PD. In Part B Cohort D, 41% of patients treated with 0.2 mg and 63% with 0.4 mg were ongoing. PD was the most common reason for discontinuation. In the safety evaluable population (n = 60; GOLCA 0.2 or 0.4 mg + R), neutropenia, an on-target side effect of GOLCA, was the most common grade 3/4 treatment-emergent adverse event (TEAE) and occurred in 65% of patients, followed by anemia (13%) and febrile neutropenia (8%). Serious AEs related to GOLCA occurred in 22% of patients, most commonly infections (17%) and febrile neutropenia (7%); pulmonary embolism occurred in 1 patient with 0.2 mg. The most common causes of GOLCA interruption in the overall safety population were infections (32%) and neutropenia (18%). Dose reductions were mostly due to neutropenia (10%) and febrile neutropenia (5%). No discontinuations or deaths occurred from GOLCA-related TEAEs. Non-hematologic TEAEs were infrequent and mostly low grade, with the most common being gastrointestinal disorders (7%). In the efficacy evaluable patients (n = 56; GOLCA 0.2 or 0.4 mg + R) at a median follow-up of 10.8 months, the overall response rate (ORR) was 89% (complete response rate [CRR], 61%). With 0.2 mg, ORR was 81% (CRR, 43%) and with 0.4 mg, ORR was 94% (CRR, 71%). In the 0.4-mg group, responses were consistent in high-risk subsets, including patients with prior len (ORR, 100%; CRR, 73%) and/or T-cell–redirecting therapy (ORR, 91%; CRR, 64%). With GOLCA 0.4 mg, 10 patients had response lasting > 12 months, including 5 with prior T-cell–redirecting therapy and 6 with prior len. Conclusions With additional follow-up, GOLCA + R continued to show promising efficacy with durable responses and no new safety signals. A higher ORR/CRR and similar tolerability were observed with GOLCA 0.4 mg + R vs GOLCA 0.2 mg + R, including in patients with prior len-based and/or T-cell–redirecting treatment. These data support continued development of GOLCA 0.4 mg + R as a fixed-duration, chemotherapy-free, outpatient option in the ongoing Phase 3 GOLSEEK-4 study in 2L+ FL (NCT06911502).

Patients (pts) with R/R DLBCL ineligible for chimeric antigen receptor T cell (CAR T) therapy or autologous stem cell transplant (ASCT) have limited treatment (tx) options and poor outcomes. In R/R DLBCL, standard salvage therapy with gemcitabine plus oxaliplatin (GemOx) yielded a complete response (CR) rate of 25%, overall response rate (ORR) of 41%, median progression-free survival (mPFS) of 3.6 mo, and median overall survival (mOS) of 12.9 mo (Abramson JS, et al. Lancet 2024;404:1940–1954). In the EPCORE® NHL-2 trial (NCT04663347), epcoritamab (epcor), a CD3×CD20 bispecific antibody, combined with GemOx led to high response rates in pts with R/R DLBCL ineligible for ASCT. Here, we report long-term durability data from this cohort after >2 y of follow-up. Methods : Pts with CD20+ R/R LBCL ineligible for ASCT due to advanced age, performance status, or lack of response to prior ASCT received subcutaneous epcor (step-up doses: 0.16 mg, 0.8 mg; 48 mg thereafter) QW in cycles (C) 1–3, Q2W in C4–9, and Q4W in ≥C10. GemOx (gemcitabine 1000 mg/m², oxaliplatin 100 mg/m²) was given Q2W for 4 C (8 total doses). The primary endpoint was ORR by Lugano criteria. Minimal residual disease (MRD) negativity was assessed as a secondary endpoint, using the exploratory AVENIO Oncology circulating tumor DNA (ctDNA) method (cutoff: <1 mutant molecule per mL). Data cutoff was April 9, 2025; efficacy assessments were per investigator. Results : In total, 103 pts were treated. Median age was 72 y (range, 20–87). The pt population was 76% White, 4% Black/African American, and 4% Asian; pts were enrolled across the United States (US; 27%), Europe (72%), and Australia (1%). Pts had a median of 2 prior lines of tx (pLOT; range, 1–6); 37% had 1 pLOT; 61% had Ann Arbor stage IV, 7/66 (11%) assessed pts had double-hit/triple-hit disease, 33% had bulky disease (≥7 cm), 52% had primary refractory disease, 70% were refractory to last therapy, 10% had prior ASCT, and 28% had prior CAR T therapy. ORR was 81%, and 60% of pts had a CR. After a median follow-up of 27.9 mo (range, 1.0+ to 47.9), epcor + GemOx led to mPFS of 16.3 mo (95% CI, 8.3–not reached [NR]), and mOS of 28.2 mo (95% CI, 11.7–NR). At 2 y, an estimated 48% of all pts were progression-free and 53% were alive. Responses were durable, with a median duration of response of 27.3 mo (95% CI, 11.7–NR), and a median duration of complete response (mDOCR) of 40.7 mo (95% CI, 40.7–NR). An estimated 67% of complete responders remained in CR at 2 y. Among pts with 1 pLOT, CR rate was 74% and mDOCR was NR. Pts with >1 pLOT (some received up to 6 pLOTs) experienced clinically meaningful responses (CR rate: 52%), with mDOCR of 40.7 mo (95% CI, 17.5–NR). When analyzed by region, outcomes were consistent in pts from the US and Europe. Overall MRD negativity by C7 day 1 (D1), was observed in 71% (44/62) of MRD-evaluable pts. Deep and sustained MRD negativity through C7D1 was observed across difficult-to-treat subgroups. At data cutoff, 24% (25/103) of pts remained on tx. There were 16 pts who discontinued tx while in CR for reasons other than progressive disease or death; 12 (75%) of these pts remained in CR (median time since end of tx, 8.8 mo [range, 0.5–26.8]) at data cutoff. Safety was consistent with previous reports (Brody JD, et al. Blood 2025;145:1621–1631). Incidence of serious infections was highest (23%) in the first 24 weeks of tx, as expected, given known toxicities of the individual components, then decreased and remained consistent over time. With 14.7 mo more follow-up since the last report, 4 additional pts had an infection, and 4 additional pts experienced grade 5 treatment-emergent adverse events (pancreatic adenocarcinoma, lung infection, subacute sclerosing panencephalitis, COVID-19). Epcor + GemOx demonstrated sustained remissions of >2 y, prolonged PFS and OS, and deep MRD negativity in challenging-to-treat 2L+ R/R DLBCL; these results are widely applicable to a diverse pt population across the US and Europe. With longer follow-up, the safety profile remained consistent with previous reports. These findings support the combinability of epcor with standard-of-care chemotherapy and offer an effective option for ASCT-ineligible pts, a population with otherwise limited tx choices.

BACKGROUND:Talquetamab is the first GPRC5D × CD3 bispecific antibody approved for relapsed or refractory multiple myeloma. In phase 1 of the MonumenTAL-1 study, initial results of subcutaneous talquetamab 0·4 mg/kg once a week and 0·8 mg/kg every 2 weeks showed preliminary clinical activity. We describe safety and activity results in patients treated with talquetamab, including patients who had received previous T-cell redirection therapy (TCR). This post-hoc analysis was done with more mature median follow-up to evaluate duration of response in patients treated with talquetamab 0·8 mg/kg every 2 weeks. METHODS:MonumenTAL-1 is a multicentre, open-label, phase 1-2 study of talquetamab, phase 1 of which has previously been published. The 0·4 mg/kg once a week and 0·8 mg/kg every 2 weeks recommended subcutaneous doses identified in phase 1 were evaluated in phase 2 in patients who were 18 years of age or older, had at least three previous lines of therapy, had an Eastern Cooperative Oncology Group performance status of 0 to 2, and were naive or exposed to previous TCR. The primary endpoint was overall response rate assessed by independent review committee in all patients who received at least one dose of talquetamab. Safety was assessed in all patients who received at least one dose of talquetamab. This study was registered with ClinicalTrials.gov, NCT03399799 (phase 1) and NCT04634552 (phase 2). FINDINGS:Between Jan 3, 2018, and Feb 20, 2023, 735 patients were screened across all phase 1-2 cohorts. Of these, 537 patients screened for inclusion were treated across phase 1 and 2 cohorts, of whom 198 (27%) patients were excluded from the study, most commonly due to not meeting eligibility criteria or not having measurable disease. As of Oct 11, 2023, 375 patients had received recommended talquetamab doses across three groups: 143 (0·4 mg/kg once a week group) and 154 (0·8 mg/kg every 2 weeks group) TCR-naive patients and 78 with previous TCR who received either recommended dose (previous TCR group). 217 (58%) of 375 patients were male and 158 (42%) were female. 325 (87%) of 375 patients were White and 32 (9%) patients were Black. Median follow-up was 25·6 months (IQR 8·5-25·9) in the 0·4 mg/kg once a week group, 19·4 months (9·2-20·7) in the 0·8 mg/kg every 2 weeks group, and 16·8 months (7·6-18·7) in the previous TCR group. Overall response rate was 74% (106 of 143 patients, 95% CI 66-81) in the 0·4 mg/kg once a week group, 69% (107 of 154 patients, 62-77) in the 0·8 mg/kg every 2 weeks group, and 67% (52 of 78 patients, 55-77) in the previous TCR group. Most common adverse events in the 0·4 mg/kg once a week, 0·8 mg/kg every 2 weeks, and previous TCR groups were cytokine release syndrome (113 [79%] of 143 patients, 115 [75%] of 154 patients, and 57 [73%] of 78 patients), taste changes (103 [72%], 110 [71%], and 59 [76%]), and infections (85 [59%], 105 [68%], and 59 [76%]). Most common grade 3-4 adverse events were neutropenia (44 [31%], 33 [21%], and 37 [47%]), anaemia (45 [31%], 40 [26%], and 21 [27%]), and lymphopenia (37 [26%], 40 [26%], and 13 [17%]). Fatal adverse events occurred in five patients in the 0·4 mg/kg once a week group, seven patients in the 0·8 mg/kg every 2 weeks group, and no patients in the previous TCR group; none were related to treatment. INTERPRETATION:Talquetamab continued to demonstrate high overall response rates in heavily pretreated patients with relapsed or refractory multiple myeloma with longer follow-up in this post-hoc analysis. Overall response rate was promising in patients with previous TCR, including therapies targeting BCMA. On-target, off-tumour adverse events were common but led to few treatment discontinuations. FUNDING:Janssen.

Introduction Approximately 40% of patients with DLBCL will experience relapse after initial treatment with standard-of-care chemo-immunotherapy. Effective treatment options are limited for patients who experience first-line treatment failure, particularly for those with R/R disease following CAR T-cell therapy or those not able to receive CAR T-cell therapy (Sehn et al, N Engl J Med. 2021). GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin) and immunomodulatory activity. In the two-part, multicenter, first-in-human Phase 1/2 study (CC-99282-NHL-001; NCT03930953), GOLCA was well tolerated and effective in patients with R/R DLBCL (Bachy et al, ICML 2025, #148). Here, we provide longer follow-up in patients with R/R DLBCL from Part B of the study. Methods Patients with R/R DLBCL and disease progression after ≥ 2 lines of therapy or transplant-ineligible patients after ≥ 1 line of therapy were included in the study. Patients received GOLCA monotherapy orally, once daily at different dosing schedules in Part A. In Part B, GOLCA was dosed at 0.2 or 0.4 mg (14 days on/14 days off) ± R. Total GOLCA treatment duration was up to 2 years or until progressive disease (PD)/unacceptable toxicity. Primary objectives included safety and recommended Phase 2 dose determination. Results As of April 3, 2025, a total of 77 patients with R/R DLBCL were enrolled in Part B Cohort C (GOLCA 0.2 mg + R, n = 39; GOLCA 0.4 mg + R, n = 38). Median age was 66 years (range, 20–86). Patients were heavily pre-treated; median number of prior treatments was 4 (range, 1–11), 55% of pts had prior CAR T-cell therapy, 38% had prior bispecific antibody treatment, and 44% were refractory to last treatment. Ten patients (13%) were ongoing, 4 completed 2 y of treatment, and 63 (82%) had discontinued treatment, mostly due to PD (n = 48 [62%]). The most common any-grade (G) treatment-emergent adverse events (AEs) in the 0.2- and 0.4-mg cohorts, respectively, were neutropenia (54% and 84%), an on-target side effect of GOLCA, and anemia (44% and 45%). G3/4 neutropenia was reported in 49% of patients with 0.2 mg and 79% with 0.4 mg, and febrile neutropenia (FN) in 5% and 16%, respectively. Granulocyte colony-stimulating factor was used in 81% and 88% of patients with neutropenia and 50% and 100% of patients with FN in the 0.2-mg and 0.4-mg cohorts. Dose interruptions (mainly due to infections/neutropenia) occurred in 49% and 53% of patients and discontinuations due to AEs occurred in 10% and 3% with 0.2 and 0.4 mg. One G5 pneumonia was considered related to study treatment (0.2 mg). The median follow-up was 11.8 months (range, 3.1–35.1) with 0.2 mg and 16.2 months (range, 3.8–31.4) with 0.4 mg. The overall response rate (ORR) in efficacy evaluable patients was 34% (complete response rate [CRR], 20%) with 0.2 mg (n = 35) and 58% with 0.4 mg (n = 36), including a CRR of 44% with this dose. In patients with prior T-cell–redirecting treatment, the ORR was 33% (CRR, 22%) with 0.2 mg (n = 18) and 56% (CRR, 38%) with 0.4 mg (n = 16). Seven of 35 (0.2 mg) and 14 of 36 (0.4 mg) patients experienced durable response > 12 months. The median time to response with both 0.2 and 0.4 mg was 1.8 months. In patients with durable responses (remained in response [CR or partial response] for more than two consecutive efficacy assessments) to GOLCA, circulating tumor DNA reduction from baseline continues to deepen over time. Response was similar across clones/tumor variants. Conclusions With additional follow-up, GOLCA + R continued to demonstrate a predictable and manageable safety profile, with no new safety signals observed at longer follow-up. Durable responses were shown in heavily pretreated patients with R/R DLBCL, including those with prior T-cell–redirecting therapy. GOLCA + R induced a decrease in circulating tumor DNA across tumor variants. These data support the ongoing development of GOLCA + R in patients with R/R non-Hodgkin lymphoma.