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Abstract Introduction Multiple myeloma (MM) is clinically heterogeneous, and therapeutic response is profoundly influenced by the complex cytokine milieu of the bone marrow microenvironment. Unlike most cancers, MM staging incorporates non–tumor-burden markers such as serum albumin, β₂-microglobulin, and LDH, which are prognostically useful but biologically nonspecific. Although individual cytokines (e.g., IL-6, IL-17, TGF-β) have been linked to disease activity, a comprehensive, systems-level assessment comparing an exhaustive list of cytokines, chemokines, and growth factors across large patient cohorts is lacking. Here, we present evidence for an actionable cytokine panel, using gene expression–derived cytokine bioactivity as a surrogate measure. Methods CD138 enriched bone marrow plasma cell RNA-seq, Seq-FISH, and clinical data were obtained from the MMRF CoMMpass study. Data were TMM-normalized, log₂(x + 1) transformed, and mean-centered. Bioactivity scores for 64 cytokines, chemokines, and growth factors were inferred using CytoSig (National Cancer Institute). CytoSig leverages transcriptomic data from over 20,000 samples treated with individual molecules to model gene expression changes of cytokine regulators, targets, and response elements to provide z-scores. Reverse validation of bioactivity between samples scoring top and bottom quartiles of each cytokine was done using pathway analysis via Gene Set Enrichemnent analysis platform that verifies bioactivity across 7561 well-studied gene sets.(MSigDB C2 2025). Cytokines with upregulation of associated pathways were considered for downstream analyses (Criteria: Normalized enrichment score > 1). Genes were ranked by sign(logFC) × –log₁₀(p), identifying 44 significantly enriched pathways. Univariate Cox regression identified prognostic cytokines. To account for variable correlation and improve prediction, Elastic Net Cox regression (α = 0.5) was used, combining LASSO (L1) and Ridge (L2) penalties. For biological validation, pathway analysis was done between samples with high vs low serum C-Reactive Protein(CRP). Survival kinetics and clinical characteristics were analyzed for the derived model. Results A total of 767 NDMM patients were included (median age 63 years, range 27–93); median overall survival (OS) was 44.4 months (IQR 70.9). Revised International Staging System (R2-ISS) distribution was: Stage I 14.7%, II 24.0%, III 34.7%, and IV 6.4%. Based on the International Myeloma Society–International Myeloma Working Group (IMS–IMWG) definition, 32.2% of patients were classified as high-risk. Supervised analysis identified 30 univariate prognostic cytokines. Elastic Net retained BMP-7, IGF-1, IL-3, NRG1, IL-17A, IL-2, IL-21, and TGF-A (positive coefficients), and IL-4, IL-18, BMP-4, palmitic acid, DHT, and BMP-2 (negative coefficients). In sensitivity analysis, after removing cytokines not passing GSEA validation, the cytokine score (CS) was established using BMP-7, IL-3, TGF-A, IL-17A, BMP-2, IL-18, BMP-4, and IL-4. High serum CRP–associated gene expression was linked to upregulation of IL-17 and BMP pathways and downregulation of IL-4 signaling. Patients with CS ≥ median had higher β2M (p < 0.001) and LDH (p = 0.005); creatinine (p = 0.07) and albumin (p = 0.6) were not significant. CS was higher in patients with del(17p), 1q21 gain, high-risk IGH, t(8;14), and del(1p), and lower in those with hyperdiploidy (all p < 0.01). CS achieved a C-index of 0.67. Median OS was 58.7 months in the high-CS group vs. 102.5 months in the low-CS group (p < 0.001). Adding continuous CS to a model with continuous β2M + continous albumin improved C-index from 0.65 to 0.72. ISS improved from 0.62 to 0.68; R2-ISS from 0.65 to 0.69. A multivariate model with β2M ≥ 5.5, del(1p) + 1q gain, t(4;14), deep del(1p), and del(17p) improved from 0.63 to 0.68 with CS. Discussion These findings require functional validation in patient samples through direct measurement of cytokine levels. BMP-7 remains understudied in MM. Elevated TGF-α, IL-3, and IL-17 promote angiogenesis, bone resorption, and immune dysfunction, while BMP-2 and BMP-4 act as tumor suppressors. IL-18 is being utilised to boost T-cell responses, and IL-4 is consistently reduced in MM. Conclusion This study provides evidence for a robust, clinically translatable cytokine, chemokine, and growth factor panel. IL-17, IL-4, and BMPs emerged as consistently regulated across all analyses. CS is associated with high-risk disease and inferior survival.

Abstract The CoMMpass study (NCT01454297) is a prospective, longitudinal observational trial involving 1,141 newly diagnosed, treatment-naïve multiple myeloma (NDMM) patients. Bone marrow aspirates from the study participants were collected, separated into CD138 negative and CD138 positive fractions for comprehensive molecular characterization of tumor (using bulk RNA sequencing and whole genome sequencing) and tumor immune microenvironment using 3' single-cell RNA sequencing (scRNA-seq). To support exploration of this rich multi-omic dataset, we developed CoMMpass Explorer (CE), an intuitive interactive platform that enables real-time analysis of clinical and genomic data from these study participants. CE provides four main views: Overall Summary for clinical feature distribution and Kaplan-Meier curves; Mutational Profile for visualizing and comparing somatic mutations; Tumor Profile for differential expression and gene set enrichment; and Immune Microenvironment for comparing cell type abundance and cell cycle dynamics between cohorts using scRNA-seq data. A central feature of CE is cohort building, where users can filter and stratify patients by clinical, genomic, and survival data elements to create custom cohorts for analysis. We validated CE by reproducing findings from two prior CoMMpass-based studies. In the first study by Simhal et al, we stratified patients using transcript-level expression by WEE1 into tertiles and confirmed that high WEE1 expression is associated with poorer progression-free survival across multiple genomic subgroups. In the second study by Manojlovic et al, we replicated mutation frequencies between African American and Caucasian patients by creating race-based cohorts. We further demonstrate CE's utility by identifying and comparing two NDMM cohorts of patients at baseline who have not received autologous stem cell transplant: cohort 1 includes patients that received up-front triplet therapy (N=342) and cohort 2 includes those who did not receive a triplet up-front (N=235). While survival differences between these two cohorts were not statistically significant (p>0.05), CE revealed elevated epithelial-mesenchymal transition (EMT) pathway activity in cohort 1. Immune profiling showed lower abundance of CD8+ T cells (p < 0.05) and NK cells (p = 0.01), but a higher abundance of B cells (p < 0.05) in cohort 1. Genomic data showed fewer EIF2AK3 mutations and higher transcript-level expression of EIF2AK3 in cohort 1. Notably, patients in cohort 1 with lower transcript-level expression of EIF2AK3 had better survival outcomescompared to patients in cohort 2. CE democratizes access to the CoMMpass multi-omic resource, allowing researchers to interrogate clinical and molecular heterogeneity with ease. By enabling hypothesis generation and replication of published results, CE serves as a valuable tool for identifying meaningful patterns in gene expression, mutation profiles, and immune contexture. It also highlights potential prognostic biomarkers, such as EIF2AK3 expression, that may inform treatment decisions in NDMM, especially in the context of triplet-based regimens.

Abstract Background: Haploidentical allogeneic stem cell transplantation (haplo-SCT) has been a transformative option for patients lacking matched donors. Post-transplant cyclophosphamide (PTCy) at 100 mg/kg total dose (50 mg/kg on Day +3 and +4) is a standard for graft-versus-host diseases (GvHD) prophylaxis. Efforts to decrease toxicity while maintaining efficacy have informed pursuits of dose de-escalation. However, data regarding the efficacy and safety of reduced-dose PTCy (<100 mg/kg) remain scattered and variably reported. Methods: We performed a systematic review registered on PROSPERO (CRD420250650291) and conducted per PRISMA guidelines. Six databases (Medline, Embase, Web of Science, Scopus, Cinahl, Cochrane) were searched initially up to May 2024. An updated search was conducted to include studies till June 2025. Eligible studies included prospective or retrospective cohorts or randomized trials evaluating low-dose PTCy in haplo-SCT recipients reporting on acute/chronic GvHD, overall survival (OS), relapse-free survival (RFS), immune reconstitution, or complications such as hemorrhagic cystitis or infections. Non-comparative studies, reviews, and abstracts were excluded. Data was extracted independently by two reviewers, and risk-of-bias (ROB) was assessed using ROBINS-I and Cochrane RoB-2 tools. Results: Thirty-three studies, including 31 observational studies and 2 randomized controlled trials (RCTs), encompassing over 2500 patients, met our eligibility criteria. Most studies originated from Asia, with smaller contributions from Europe, the United States, India and Latin America. Low-dose PTCy regimens ranged from 14.5 to 80 mg/kg, commonly administered as 50 mg/kg ×1 on day +3 or 40 mg/kg ×2 on days +3 and +4. Comparators included standard-dose PTCy (100 mg/kg), ATG-based prophylaxis, or other regimens. Median follow-up ranged from 4 months to over 5 years. Acute GvHD (grades II–IV) rates in low-dose PTCy arms ranged from 9% to 34%. Most observational data showed comparable or reduced incidence of aGvHD compared to controls. Chronic GvHD outcomes varied from 8-46% and showed no clear benefit of dose reduction in most studies.Two-year OS ranged widely from 47% to 100%, with some observational studies favoring low-dose PTCy but others showing no survival advantage. RFS was similarly variable. Hemorrhagic cystitis occurred in 3–33% of patients, with no clear dose-dependent pattern. Infections were inconsistently reported, but, when data were available, viral infections, including BK virus, CMV, and EBV reactivation, were common, with no consistent dose-dependent trend. Median time to immune reconstitution was slightly shorter in some cohorts, but clinical relevance remains uncertain. Two studies reported significantly reduced incidence of cardiac complications with lower PTCy exposure. One randomized controlled trial comparing 80 mg/kg PTCy + ATG with the Beijing Protocol reported significantly reduced aGvHD (11.5% vs. 39.3%, p=0.001) and better OS (75.4% vs. 54.1%, p = 0.021) and RFS ((72.7% vs. 55.0%, p = 0.044)) in the experimental arm. In contrast, the only other randomized study used ultra-low-dose PTCy (14.5 mg/kg ×2) vs. ATG and found no significant difference in acute GvHD (18.2% vs. 18.2%, p=0.996) or survival and was stopped early because of futility. Both RCTs showed comparable rates of cGvHD, toxicity, and immune reconstitution.Importantly, 87% of observational studies had a serious or critical ROB. Both RCTs had some concerns of bias due to inadequate allocation concealment and open-label design but were otherwise at low ROB. Conclusions: Low-dose PTCy for GvHD prophylaxis in haplo-SCT carries comparable or lower rates of acute GvHD, similar chronic GvHD incidence, and non-inferior survival outcomes in many studies. Marked heterogeneity in regimens, patient populations, high ROB, and selective reporting preclude definitive conclusions. Randomized trials must focus on identifying subgroups benefiting from de-escalated PTCy. Until then, low-dose PTCy remains a promising but investigational alternative in haploidentical transplantation.

Abstract Background: Mosunetuzumab (Mosun) is an off-the-shelf, CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate B cells, including those that cause malignant disease. Mosun is FDA- and EMA-approved for relapsed/refractory follicular lymphoma (FL) after ≥2 prior lines of therapy as a fixed-duration intravenous treatment, and can be given in an outpatient setting without mandatory hospitalization. Initial Phase I/II data with Mosun monotherapy have shown notable efficacy and manageable safety in patients with previously untreated diffuse large B-cell lymphoma (DLBCL; NCT03677154; Olszewski et al. ASH 2022). The Phase II MorningSun study is the first to assess the efficacy and safety of subcutaneous (SC) Mosun monotherapy in elderly/unfit patients with previously untreated DLBCL; we report an interim analysis for this study. Methods: MorningSun (NCT05207670) is an open-label, multicenter, Phase II, basket study evaluating the safety, efficacy, and pharmacokinetics of Mosun SC monotherapy in patients with B-cell non-Hodgkin lymphoma. In the DLBCL cohort, eligible patients aged ≥80 years or aged 65–79 and considered ineligible for chemoimmunotherapy (CIT) were enrolled, primarily in US community sites. Hospitalization was not mandatory. Step-up doses of Mosun SC were administered on Day (D) 1 (5mg), D8 (45mg) and D15 (45mg) of Cycle 1, followed by 45mg on D1 of 21-day cycles, for up to 17 cycles or until unacceptable toxicity. The primary endpoint in this cohort was progression-free survival (PFS) rate at 24 months after first study treatment. Secondary endpoints included objective response rate (ORR), complete response (CR) rate, time to response (TTR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), and safety. An exploratory circulating tumor DNA analysis was performed using an AOA-NHL assay. Results: Overall,49 patients were enrolled, the majority at community sites (community, n=34; academic, n=15). Thirty-six patients had DLBCL, 6 had high-grade [Gr] B-cell lymphoma, 2 had T-cell/histiocyte-rich large B-cell lymphoma, and 1 had Gr 3B FL (histology missing/other lymphoma, n=4). Median age was 82.5 years (range: 71–101); 63.3% and 20.4% of patients had an ECOG performance status of 1 and 2, respectively; 40.8% had Ann Arbor stage IV disease; 51.0% had extranodal involvement; 18.4% had bulky disease; and 53.1% had an IPI score of 3–5. At the clinical cut-off date of February 10, 2025, 23 (46.9%) patients had discontinued treatment, mainly due to progressive disease (n=12, 24.5%) or an adverse event (AE; n=5, 10.2%); the median duration of follow-up was 12.5 months (range: 1.4–30.8) and the median number of cycles received was 14 (range: 1–17). The PFS rate at 12 months was 68.8% (95% confidence interval [CI]: 52.1–80.6) and OS rate at 12 months was 77.2% (95% CI: 61.1–87.3). The ORR and CR rates were 73.5% and 59.2%, respectively. Median TTR was 2.7 (range: 2.5–6.1) months. DOR and DOCR rates at 12 months were 84.6% (95% CI: 66.8–93.3) and 95.0% (95% CI: 69.5–99.3), respectively. The most common AE (any grade) was injection site reaction (n=25, 51.0%), which was mostly Gr 1 (n=24, 49.0%). Gr 3/4 AEs occurred in 65.3% (n=32) of patients, most commonly infections (16.3% [n=8]) and decreased neutrophil count (10.2% [n=5]); serious AEs occurred in 42.9% (n=21) of patients. Four patients experienced Gr 5 AEs (congestive cardiac failure, volvulus, unexplained death and intracranial hemorrhage, n=1 each); none were related to Mosun per investigator assessment. Infections occurred in 46.9% (n=23) of patients (Gr 1/2, 30.6% [n=15]; Gr 3, 16.3% [n=8]); no Gr 4/5 infections were observed. No immune effector cell-associated neurotoxicity syndrome events occurred. Cytokine release syndrome was reported in 12.2% (n=6) of patients, with 10.2% (n=5) Gr 1 and 2.0% (n=1) Gr 2 events, all of which resolved. In evaluable patients with a CR (n=16), 68.8% (n=11) of patients were minimal residual disease negative (p-value cut-off 0.005).Conclusions: There remains an unmet need for effective chemotherapy-free options in previously untreated elderly and CIT-ineligible patients with DLBCL. Interim data from MorningSun demonstrate that fixed-duration Mosun SC monotherapy is active in these patients, with promising efficacy and a manageable safety profile, with predominantly mild-to-moderate AEs, allowing for outpatient administration in the community practice setting.

Abstract Background: Systemic mastocytosis (SM) comprises a spectrum of subtypes characterized by neoplastic mast cell (MC) infiltration of tissues and release of MC mediators. Non-advanced SM (NonAdvSM), including indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) subtypes, is the most prevalent form of SM. NonAdvSM can be associated with debilitating symptomology which can significantly impair quality of life. The gain-of-function somatic KIT c.2447 C>T (p.D816V) mutation is found in up to 95% of patients with SM. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. Results from Summit (NCT05186753) Part 1 informed the recommended phase 2 dose (100 mg QD bezuclastinib) for Part 2. We report topline results from the 24-week assessment of Summit Part 2. Methods: Summit is a multi-center, randomized, double-blind, placebo (PBO)-controlled Phase 2 trial of bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) medications. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), which is a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, and MS2D2 TSS, ≥30% TSS reduction. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or PBO + BSC. Results: As of May 22, 2025, 179 patients were enrolled in Part 2: 119 were randomized to receive bezuclastinib and 60 to placebo. Patients enrolled were representative of the NonAdvSM population with moderate to severe symptoms. Median age (range) was 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8); 82% of patients had ISM, 11% had BMM, and 7% had smoldering SSM. At baseline, median (range) KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. Bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints. At Week 24, bezuclastinib led to significantly greater symptom improvement vs placebo (LS mean [95% CI] MS2D2 TSS change: –24.3 [–27.6 to –21.1] vs –15.4 [–19.6 to –11.2]; placebo-adjusted difference: –8.9 points; P=0.0002). A ≥50% reduction in serum tryptase was achieved in 87.4% of bezuclastinib-treated patients vs 0% on placebo (P<0.0001). Significantly more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V VAF, serum tryptase, BM MCs (P<0.0001), MS2D2 TSS (P=0.01), and ≥30% reduction in MS2D2 TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (gr; 70% Gr 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring in greater frequency in the bezuclastinib arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased ALT/AST (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%). TEAEs (≥10%) that occurred more often in the placebo group were diarrhea (13% vs 18%), dizziness (10% vs 12%), fatigue (7% vs 12%), and arthralgia (6% vs 15%). ALT/AST elevations ≥Gr 3 were experienced by 5.9% of patients. The only hepatic adverse events (AEs) reported were transient lab abnormalities; none required hospitalization. Treatment-related AEs requiring dose reductions occurred in 11% of patients receiving bezuclastinib. All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significant improvements in symptom burden and biomarkers of disease vs placebo in patients with NonAdvSM. The treatment was generally well-tolerated and effective across a population that is representative of the real-world NonAdvSM population, including SSM. These results support the use of bezuclastinib to reduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact.

Abstract Background: Polycythemia vera (PV) is characterized by excessive erythrocytosis and elevated hematocrit (Hct), which is associated with increased risk of thrombotic events. Controlling Hct levels (<45%) is a key therapeutic goal to reduce thrombotic events. Sapablursen (ISIS 702843) is a liver-directed, ligand-conjugated antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6) to enhance hepcidin production thereby restricting iron availability and reduced erythrocytosis. We are reporting the topline results of the IMPRSSION study (NCT05143957), an ongoing global, open-label phase 2 trial evaluating the safety and efficacy of sapablursen for Hct control and reducing phlebotomy rate in patients with PV. Methods: Eligible patients met 2016 WHO diagnostic criteria for PV, were required to have >3 phlebotomies within six months prior to screening, including >1 phlebotomy in the last 12 weeks. There were no exclusions for HCT prior to randomization. Patients received monthly subcutaneous doses of sapablursen in Cohort A (high dose) or Cohort B (low dose), during a 37-week treatment period. The primary efficacy endpoint was the reduction in the frequency of phlebotomy during the last 20 weeks of the treatment period (Week 17-37) compared to baseline (defined as the mean weekly phlebotomy rate during the six months prior to screening through the first dose of sapablursen). Phlebotomy was performed when Hct levels were ≥45% or at the investigator's discretion, confirmation of Hct was not required for phlebotomy. Serial assessments of serum hepcidin, TSAT and ferritin were conducted. The 10-item Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) assessed the change in symptoms from baseline to Week 37. Results: Forty-nine (49) patients received at least one dose of sapablursen (full analysis set) in either Cohort A (n=32) or Cohort B (n=17). The median age was 61 years, 40 (82%) were male, and 29 (59%) classified as high risk. The primary endpoint was met at both dose levels. The weekly phlebotomy rate (mean±SD) decreased from baseline of 0.15±0.07 (~7.8/yr) to 0.05±0.09 (~2.6/yr) during the primary endpoint window (Week 17-37) in Cohort A (n=32, p<0.0001; 95%CI, -0.13, -0.07), and from 0.17±0.07 (~8.9/yr) to 0.07±0.07 (~3.6/yr) in Cohort B (n=17, p=0.0001; 95%CI, -0.14, -0.06). The mean MPN-SAF-TSS was reduced at Week 37 by 32% in Cohort A (change from baseline LSM -6.2, p=0.005) and 11% in Cohort B (change from baseline LSM -2.7, p=0.344). The proportion of patients with Hct control (<45%) without phlebotomy from week 17 to 37 in Cohort A and B was 53% (17/32) and 35% (6/17), respectively. Serum hepcidin was increased from baseline values of 0.25±0.6 to 5.05±4.7 nM at Week 13 in Cohort A (p<0.0001) and from 0.68±1.7 to 2.06±3.6 nM in Cohort B (p=0.0142). A sustained low TSAT was observed between Weeks 17-37 (6.0±2.1% and 5.5±2.0% in Cohort A and 8.9±5.0% and 7.0±3.4% in Cohort B). Serum ferritin increased over time from 18±22 ng/mL and 28±58 ng/mL at baseline in Cohort A and B, respectively, to 44±47 ng/mL and 41±85 ng/mL at Week 37, respectively. Sapablursen was generally safe and well-tolerated. The incidence of injection site reactions was 12.2% (6/49). Injection site reactions did not recur following multiple injections, were not progressive and resolved spontaneously. There was one death on study due to transformation to AML which was deemed as not related to the study drug. Conclusions: Treatment of PV patients with sapablursen increased serum hepcidin, controlled Hct, reduced phlebotomy need and improved quality of life in a dose-dependent manner. These findings highlight the potential of sapablursen as a therapeutic approach in PV and support further development.

Abstract Introduction: BTK inhibitors are effective treatments for CLL/SLL; however, treatment intolerance and resistance to BTK inhibitors are major clinical challenges for many patients. BGB-16673 is an orally available protein degrader that blocks BTK signaling by tagging BTK for degradation through the cell's proteasome pathway, leading to tumor regression. CaDAnCe-101 (BGB-16673-101; NCT05006716) is an ongoing open-label, phase 1/2 study evaluating BGB-16673 monotherapy in patients with B-cell malignancies. Here, updated phase 1 safety and efficacy data are reported for patients with relapsed/refractory (R/R) CLL/SLL. Methods: Eligible patients must have confirmed R/R CLL/SLL (≥2 prior therapies), an ECOG performance status of 0-2 (0-1 in the EU), and adequate organ function. In the US, EU, and Australia, patients must have previously received a covalent BTK inhibitor (cBTKi). Patients received BGB-16673 once daily orally. The primary phase 1 objectives were to assess safety/tolerability (NCI-CTCAE v5.0; iwCLL hematologic toxicity criteria) and to establish the maximum tolerated dose and recommended dose for expansion. A secondary objective was to assess overall response rate (ORR) per iwCLL 2018 criteria with partial response with lymphocytosis (PR-L) modification and per 2014 Lugano criteria for SLL, with the first response assessment after 12 weeks of treatment. Results: As of May 23, 2025, 67 patients with CLL/SLL were enrolled and treated (50 mg, n=1; 100 mg, n=22; 200 mg, n=17; 350 mg, n=15; 500 mg, n=12). Patients had a median age of 70 years (range, 47-91 years) and a median of 4 prior lines of therapy (range, 2-10), including cBTKis (n=63 [94.0%]), BCL2is (n=55 [82.1%]), and noncovalent BTK inhibitors (ncBTKis; n=14 [20.9%]). At study baseline, 65.7% (44/67) of patients had CLL/SLL with del(17p) and/or TP53 mutation, 77.6% (38/49) with unmutated IGHV, 38.1% (24/63) with BTK mutation, and 15.9% (10/63) with PLCG2 mutation. Median study follow-up was 18.0 months (range, 0.3-31.0 months); 39 patients (58.2%) remained on treatment at the data cutoff. Overall, 95.5% of patients had any-grade treatment-emergent adverse events (TEAEs); any-grade TEAEs in ≥25% of patients were fatigue (37.3%), contusion/bruising (31.3%), diarrhea (28.4%), and neutropenia (28.4%). Grade ≥3 TEAEs occurred in 62.7% of patients; grade ≥3 TEAEs in ≥5% of patients were neutropenia (23.9%), pneumonia (10.4%), and thrombocytopenia (6.0%). Eight patients (11.9%) had a TEAE leading to dose reduction. TEAEs led to treatment discontinuation in 12 patients (17.9%), three (4.5%) of whom had treatment-related TEAEs (subdural hemorrhage, maculopapular rash, and disseminated aspergillosis). Four patients (6.0%) had TEAEs that led to death (all due to infections, including 1 fungal infection); no deaths were deemed related to treatment. In 66 response-evaluable patients (1 patient on treatment did not reach the first assessment by the data cutoff), ORR (PR-L or better) was 86.4% (n=57), with a 4.5% (n=3) complete response (CR)/CR with incomplete marrow recovery rate. At 200 mg, ORR was 93.8% (15/16), including 1 CR. The median time to first response was 2.8 months (range, 2.0-19.4 months). Thirty-three patients (49.3%) remained on treatment for ≥12 months. Responses deepened over time: of 22 patients with initial PR-L, 15 transitioned to partial response (PR); of 16 patients with initial stable disease, 1 transitioned to PR-L and 10 to PR. Responses were seen in patients previously treated with a cBTKi (53/62 [85.5%]) or ncBTKi (10/14 [71.4%]), with double (cBTKi and BCL2i; 39/42 [92.9%]) and triple exposure (cBTKi, BCL2i, and ncBTKi; 9/12 [75.0%]), with (18/24 [75.0%]) and without (36/39 [92.3%]) BTK mutations, with del(17p) and/or TP53 mutation (35/43 [81.4%]), and with PLCG2 mutation (9/10 [90.0%]). The 12-month progression-free survival rate was 79.2%; 15 patients (22.4%) had progressive disease (2 associated with Richter transformation to diffuse large B-cell lymphoma), and 4 (6.0%) died. Further exploratory analyses will be presented at the meeting.Conclusions: Data from the ongoing CaDAnCe-101 study demonstrate that the novel BTK degrader BGB-16673 has a tolerable safety profile and shows robust and deepening responses in patients with heavily pretreated R/R CLL/SLL, including those with prior BTK inhibitor treatment and BTK mutations. The 200-mg dose of BGB-16673 is being evaluated in phase 2 and 3 studies in patients with R/R CLL/SLL.

Abstract Background: The International Prognostic Scoring System (IPSS; Cervantes et al. Blood 2009;113) and dynamic IPSS (DIPSS; Passamonti et al. Blood 2010;115:1703) were developed about 15 years ago, based on 5 clinical risk factors: age >65 years, hemoglobin <10 g/dl, white blood cell count (WBC) >25 x 109/L, peripheral blood (PB) blasts ³1%, and constitutional symptoms. DIPSS-independent genetic risk factors have since been incorporated into molecular risk models with higher predictive accuracy (Guglielmelli et al. JCO 2018;36:310; Tefferi et al JCO 2018;36:1769). Because of its accessibility, DIPSS is often preferred for use in patient selection for clinical trials. The objective of the current study was to revise DIPSS by incorporating new and refined clinical risk variables and excluding those that are subjective (e.g., symptoms) or could exaggerate the need for therapy for older adults (e.g., age). Methods: Diagnostic criteria were according to the International Consensus Classification (Arber et al. Blood 2022; 140:1200). Severity of anemia was adjudicated by the Revised International Working Group-European LeukemiaNet criteria (Blood 2024; 144:1813). Receiver operating characteristic curve analysis was utilized to determine the optimal cutoff points for age, WBC, PB blast percentage, absolute monocyte count (AMC), and platelet count. Data were collected retrospectively corresponding to the time of first referral, which, in the majority of cases, coincided within one year of initial diagnosis and before initiation of cytoreductive therapy. Survival analysis was censored for allogenic stem cell transplantation (ASCT). Time-specific AUC was computed at pre-defined landmark time points and used to compare model performance between DIPSS and the revised model (DIPSS-R). Results: The discovery cohort from the Mayo Clinic included 1,073 patients (median age 65 years; 61% males) and the validation cohort from Italy 635 patients (median age 63 years; 60% males). In the discovery cohort, median follow-up (% deaths, AML, ASCTs) was 45 months (49%, 10%, 17%) and in the validation cohort 60 months (42%, 11%, 5%). In univariate analysis, the following correlated with inferior survival, in both the discovery and validation cohorts, with significance confirmed by multivariable analysis (MVA) in the discovery cohort: severe anemia (transfusion-dependent or hemoglobin level <8 g/dL in women or <9 g/dL in men), moderate anemia (hemoglobin level 8 to <10 in women or 9 to <11 in men), marked leukocytosis (WBC ≥25 x 109/L), moderate leukocytosis (WBC 11 to <25 x 109/L), age >65 years, PB blast ≥2%, AMC ≥1 x 109/L, platelet count <150 x 109/L, constitutional symptoms, and male sex. After excluding age, sex, and constitutional symptoms, MVA-derived HRs (95% CI) were 3.5 (2.8-4.4) for severe anemia, 2.0 (1.5-2.5) moderate anemia, 2.4 (1.8-3.3) marked leukocytosis, 1.5 (1.2-1.9) moderate leukocytosis, 1.7 (1.4-2.1) PB blast ≥2%, 1.5 (1.2-2.0) AMC ≥1 x 109/L, and 1.5 (1.2-1.8) platelet count <150 x 109/L. An HR-weighted risk model was subsequently developed (Figure 1) and validated (Figure 2) using the discovery and validation cohorts, respectively: low risk (0 points; N=205; median survival 226 months), intermediate-1 risk (1 point; N=253; 131 months), intermediate-2 risk (2-3 points; N=457; 62 months), and high risk (4-7 points; N=153; 31 months); the corresponding median survival estimates in the validation cohort were “not reached”, 205 months, 96 months, and 44 months (inter-risk category p values <0.01 in all instances). Ten-year predictive accuracy was comparable between DIPSS-R (AUC 0.78) and DIPSS (AUC 0.78), despite the exclusion of age and constitutional symptoms, as risk variables, from the revised model. Furthermore, predictive performance was superior for DIPSS-R vs. DIPSS when analysis was stratified by age: >65 years (AUC 0.77 vs. 0.74) and ≤65 years (AUC 0.71 vs. 0.66). MVA that included high (ASXl1, SRSF2, U2AF1) and low (CALR type 1/like) risk mutations, karyotype, and DIPSS-R variables showed independent prognostic contribution from all except thrombocytopenia (p=0.2; Figure 3). Conclusion: DIPSS-R utilizes disease-related, as opposed to host-related, predictors of survival whose prognostic contribution was independent and complementary to genetic risk factors. The model preserves global applicability and allows for a more accurate assessment of disease severity for practice and research purposes.

Abstract Background Translocation of chromosomes 4 and 14 (t(4;14)) results in overexpression of MMSET and has been associated with poor clinical outcomes in patients (pts) with multiple myeloma (MM). KTX-1001 is a first-in-class, potent, and selective oral inhibitor of MMSET (also known as NSD2) developed as the first investigational therapy to directly target the high-risk t(4;14) translocation, a key molecular driver in MM. KTX-1001 binds to and inhibits the catalytic SET domain of MMSET, thereby suppressing the deposition of dimethylated histone H3 lysine 36 (H3K36me2), leading to downregulation of oncogenic histone modifications and epigenetic reprogramming of malignant plasma cells. Preclinically, KTX-1001 synergistically inhibited cell viability in MM cell lines when combined with a proteasome inhibitor (PI), immunomodulatory drug (IMiD), or cereblon E3 ligase modulator (CELMoD™). Preliminary findings were previously reported from the initial cohort of 18 pts enrolled in a first-in-human phase 1 trial evaluating KTX-1001 in relapsed/refractory multiple myeloma (RRMM; NCT05651932; Bories et al. Blood. 2024;144[Suppl 1]:3370). Here, we present updated results from this study. Methods RRMM pts who received ≥3 prior therapies, including PI, IMiD and anti-CD38 monoclonal antibody (anti-CD38 mAb), received oral KTX-1001 across 9 dose levels using a 3+3 dose-escalation design. Primary objective was to determine the recommended Phase 2 dose (RP2D) and the maximum tolerated dose (MTD). Secondary objectives included pharmacokinetics, pharmacodynamics (PD), and primary efficacy. The dose expansion phase has been initiated to evaluate KTX-1001 in combination with either carfilzomib or the investigational CELMoD™ mezigdomide in t(4;14) RRMM pts. Results As of 13 June 2025, 40 pts have been treated in the monotherapy dose-escalation phase. The maximum tolerated dose (MTD) was exceeded due to dose-limiting toxicities (DLTs) in 2 pts: two Grade (Gr) 4 thrombocytopenia and one Gr 3 epistaxis. Backfill at selected dose levels is ongoing to further characterize safety profile and refine dose optimization. The median time from initial MM diagnosis was 8 years (range:2-20) with a median of 6.5 prior lines of therapy (range: 3-25). This included stem cell transplant (70%), BCMA CAR-T (42.5%), and non-CAR-T BCMA targeted drugs such as antibody-drug conjugates and bispecific antibodies (57.5%). The median age was69 years (range:50-83); 21 were female and 19 were male. Extra-medullary disease was present in 13 (32.5%) pts. Nineteen (47.5%) pts had t(4;14) translocation, 5 (12.5%) had 1q21 gain and 4 (10%) had deletion 17p. A total of 16 (40%) pts have shown a treatment response according to IMWG criteria or have achieved stable disease: 1 VGPR (10+ months), 1 PR (4+ months), 2 MR (3+ and 12 months), 12 SD (2-20+ months). KTX-1001 has demonstrated a favorable tolerability profile. Grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 31 (77.5%) pts. The most frequent (≥20% pts) Gr 3/4 TEAEs were thrombocytopenia in 12 pts (30%; grade 4 in 8 [20%]), neutropenia in 12 pts (30%; febrile neutropenia in 2 [5%]), anemia in 10 (25%) pts. Gr 3 infections were observed in 5 (12.5%) pts and fatigue in 5 (10%) pts. The main reason for treatment discontinuation was progressive disease (57.5%), other pts discontinued due to physician decision (5%), consent withdrawal (5%), and one pt due to adverse event. Twelve (30%) pts remain on treatment. At Cycle 1 Day 15, drug exposure and steady-state concentrations of KTX-1001 increased with dose. A dose-dependent reduction in H3K36me2, the primary PD marker of KTX-1001 activity, was observed in peripheral blood at Cycle 2 Day 1 and beyond, which plateaued above dose-level 4. Paired bone marrow samples further confirmed on-target PD effects, with a marked reduction in H3K36me2 levels in MM cells at Cycle 2 Day 1 with observed anti-MM effect of reduced proliferation of MM cells with concomitant increased proliferation in immune cells in pts achieving clinical benefit. ConclusionsKTX-1001 is a novel agent showing tolerable safety profile in RRMM and demonstrating promising single agent activity in heavily pretreated, triple class refractory RRMM including those with high-risk features. KTX is currently evaluated in ongoing study in combination with carfilzomib and the investigational CELMoD™ mezigdomide in t(4;14) RRMM pts.

Abstract Background: Given a potential risk of extravasation with vesicants and irritants, central venous catheters (CVCs), such as port-a-cath or peripherally inserted central catheters (PICC), are commonly used for the administration of anthracycline-based chemotherapy. However, CVC placement can result in treatment delay, deep vein thrombosis (DVT), catheter malfunction, and added burdens (eg, financial, travel, etc), partly due to the need for regular flushing. Peripheral intravenous (PIV) access is often utilized in the academic setting with select frontline chemotherapy regimens. However, there is limited data reporting on the safety of PIV in this setting. This large, multicenter RWA evaluated the use and associated complications of PIV and CVC for administering CHOP- or ABVD-based chemotherapy in patients (pts) with lymphoma. Methods: We conducted a retrospective RWA across 8 U.S. centers among pts aged ≥18 years with non-Hodgkin lymphoma and Hodgkin lymphoma who were consecutively treated with ABVD or CHOP-based anthracycline chemotherapy via PIV or CVC access between 2010-2024. Choice of catheter placement was at the discretion of the pt's treating physician. Detailed baseline and safety data were collected. The primary outcome was extravasation; secondary outcomes included infiltration, DVT, cellulitis, erythema, and pain. Standard definitions of extravasation and other complications were used (Jackson-Rose J. CJON 2017). Rates of complications were compared via Fischer exact testing. Results: A total of 1,414 pts were included in the analysis: 790 in each arm (ie, PIV vs CVC). Of these, 624 were unique to each group, while 166 pts received chemotherapy via both modalities (PIV and CVC during the treatment course). Overall, 78.9% of pts completed all treatment as planned via PIV. Median age was 63 years (IQR 45–75) in the PIV group and 61 years (IQR 40–73) in the CVC group. Male sex comprised 57% vs 51%, ECOG 0–1 performance status was 83% vs 76%, and advanced-stage disease (stage III/IV) was present in 51% vs 62%, respectively. Lymphoma subtypes were comparable: DLBCL/high-grade/B-cell NOS (54.5% vs 56.1%), Hodgkin lymphoma (27.2% vs 27.5%), T-cell lymphoma (12.4% vs 6.6%), and indolent/mantle cell lymphoma (5.6% vs 6.7%). Among those receiving chemotherapy via CVC, 78.5% were treated through a port-a-cath and 21.5% via PICC. CHOP-based and ABVD-based regimens were administered to 68% and 32% of PIV pts, and 69.6% and 30.4% of CVC pts, respectively. A total of 4,084 (PIV) vs 3,859 (CVC) treatment cycles were delivered, corresponding to 4,347 (PIV) vs 4,884 (CVC) anthracycline infusion days. There was 1 documented case of extravasation in the CVC group and 2 suspected cases in the PIV group (p=0.9); for PIV, this translates to a per pt risk of 0.3% (or 0.05% of infusion days). The two PIV cases involved elderly women with DLBCL receiving CHOP. Both developed localized symptoms post-infusion and were treated conservatively (DMSO/warm compresses or dexrazoxane/ice), with full symptom resolution within 1 week and 1 day, respectively. No tissue or vascular injury occurred. Additionally, there were no significant differences between the PIV and CVC groups in the rates of induration/swelling (1.8% vs 2.0%, p=0.85), phlebitis/cellulitis (2.4% vs 2.4%, p=0.9), venous thromboembolism (VTE; 1.4% vs 2.0%, p=0.32), or erythema (3.8% vs 5.1%, p=0.27). Pain or tenderness at the infusion site (8.5% vs 2.9%, p=0.001) and infiltration (1.4 vs 0.13%, p=0.006) were more frequent in the PIV group. Chronic vascular complications related to prior VTE was slightly lower in the PIV group (0.13% vs 0.9%, p=0.06), but not significant. Additional details from a propensity score-matched analysis will be presented at the meeting. Conclusions: This is the largest known analysis to date evaluating the safety of PIV access for anthracycline-based chemotherapy in >1,500 lymphoma pts over a recent 15-year period, representing >9,000 total treatments with CHOP or ABVD. PIV access was found to be safe and associated with a low rate of serious complications. Moreover, extravasation was rare and there was not a significant difference observed between PIV and CVC use. While PIV use was associated with higher rates of local pain/tenderness and infiltration, the events were uncommon and self-limited. Despite the widespread default to CVC placement in many centers, these findings support the selective use of PIV in appropriate pts as elucidated here.