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GGGGCC (G 4 C 2 ) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxicity is thought to result from the accumulation of either repeat RNAs and/or dipeptide repeat proteins (DPRs) translated from repeat-containing transcripts through repeat-associated non-AUG (RAN) translation. To disentangle RNA from DPR toxicity, we mutated a CUG codon predominantly used to initiate DPR translation from all three reading frames. This mutation disrupted DPR synthesis while preserving the expression of repeat-containing RNAs. Despite the accumulation of RNA foci, behavioral deficits and pathological abnormalities, including p-TDP-43 inclusions, STING activation, motor neuron loss, neuroinflammation, and increased plasma neurofilament concentration, were alleviated in C9ORF72 mice. Base editing of the CUG codon also improved molecular phenotypes and survival in patient induced pluripotent stem cell–derived neurons, which highlights the potential of therapeutically targeting DPR production rather than repeat RNAs.

817 Background: Universal germline sequencing is increasingly utilized in practice, but existing evidence and guidelines are based on studies in predominantly white populations. This study aims to compare the prevalence of genetic alterations in white vs underrepresented minority (URM) populations and assess incremental findings discovered with universal testing beyond current guidelines. Methods: This prospective, multicenter study analyzed genetic alterations in white and URM cohorts with primary GI malignancies receiving care at Mayo Clinic cancer centers between April 2018 and April 2025. Patients underwent germline sequencing using a next-generation sequencing (NGS) platform targeting over 80 genes. We compared the distribution of results between white and URM populations. Concordance with NCCN testing guidelines and incremental findings were assessed. Results: A total of 1128 patients were studied, of which 758 were white and 370 were URM, (47.6% Hispanic, 22.7% Black, 13.8% Asian, 10.5% American Indian, 0.8% Pacific Islander, and 6.8% other). Pathogenic variants (PGV) were more common in the white population (16.1% vs 9.2% P < 0.001). Variants of uncertain significance (VUS) were more common in the URM population (53.2 vs 43.5%, P<0.001). A total of 156 patients were found to have a PGV. PGVs outside primary cancer genes were more common in white patients (57.4% vs. 32.4%; p=0.0241). Incremental findings from universal testing were higher in white patients (66.4% vs 35.3%; p=0.0011). Conclusions: This study reveals a significant difference in the prevalence of PGV and VUS between white and URM patients with primary GI malignancies. The higher rate of PGVs in white patients and VUS in URM patients highlights potential inequities in both detection and interpretation of genetic results. These findings emphasize the need for broader representation in genetic databases to ensure equitable access to precision oncology. Screening guidelines met by patients with PGV. White (N=122) URM (N=34) Total (N=156) p value Did they meet NCCN testing guidelines for their primary cancer? 0.0991 Yes 87 (71.3%) 29 (85.3%) 116 (74.4%) No 35 (28.7%) 5 (14.7%) 40 (25.6%) Was the PGV outside of the primary genes recommended for their primary cancer? 0.0241 Yes 70 (57.4%) 11 (32.4%) 81 (51.9%) No 47 (38.5%) 22 (64.7%) 69 (44.2%) Incremental Finding 0.0011 Yes 81 (66.4%) 12 (35.3%) 93 (59.6%) No 41 (33.6%) 22 (64.7%) 63 (40.4%)

Abstract Background Staphylococci are the most frequent microorganisms in periprosthetic joint infection (PJI) and treatment remains challenging. Phage is being considered as a potential treatment. Here, the in vitro activity of phages SaMD07FSphi1or SaNSI1469phi1, alone and in combination with vancomycin against staphylococcal biofilms was evaluated. Figure 1 In vitro activity of phage SaMD07FSphi1 against S. aureus and S. epidermidis biofilms Figure 2 In vitro activity of phage SaNSI1469phi1 against S. aureus and S. epidermidis biofilms Methods Biofilms were grown at 37°C on 4 cm stainless steel K-wires in tryptic soy broth (TSB) with 106 cfu/ml of S. epidermidis or S. aureus (8 PJI isolates with phage activity against planktonically-grown bacteria). After 24 h, 3 K-wires were quantitatively cultured to define pre-treatment bacterial loads, with the remaining assigned to one of four treatment groups: TSB, phage (4 x 106 plaque forming units/ml), vancomycin (16 µg/ml) or phage/vancomycin. K-wires were incubated for 6 or 24 h at 37°C, rinsed, sonicated, and quantitatively cultured. Testing was performed in triplicate and on 3 separate days and mean log10 cfu/K-wire reduction factors (LRFs) versus TSB calculated. Results Phage SaMD07FSphi1 (Figure 1) plus vancomycin showed LRFs of 2.8 (p, 0.0003) and 2.3 (p, 0.0177) log10 cfu/K-wire at 24 h for S. aureus IDRL-6121 and S. aureus IDRL-8454, respectively, whereas phage alone showed was 3.1 (p, 0.0003) and 3.0 (p, 0.0003), respectively. All treatments were ≤1.0 log10 cfu/K-wire 24 h LRFs for S. aureus IDRL-6175, S. epidermidis IDRL-5966 and S. epidermidis IDRL-6108.This phage plus vancomycin showed LRFs of 0.6 log10 cfu/K-wire at 6 h for S. epidermidis IDRL-5966 and S. aureus IDRL-6175, with bacterial regrowth at 24 h. Phage SaNSI1469phi1 (Figure 2) plus vancomycin showed 24 h LRFs of 2.0 (p, 0.02) and 3.2 (p, 0.003) log10 cfu/K-wire for S. epidermidis IDRL-6955 and S. aureus IDRL-7299, respectively, whereas phage alone was 0.2 (p, 0.17) and 0.5 (p, 0.03) log10 cfu/K-wire, respectively. All treatments showed ≤1.0 log10 cfu/K-wire 24-hour LRFs log10 cfu/K-wire for S. epidermidis IDRL-10273. This phage alone showed 6 h LRFs of 1.0 and 1.3 for S. epidermidis IDRL-6955 and S. aureus IDRL-7299, with bacterial regrowth at 24 h. Conclusion Phages SaMD07FSphi1 and SaNSI1469phi1 alone and with vancomycin showed activity against staphylococcal biofilms formed by 4 isolates. Increased activity was observed at 6 h in some cases, with bacterial regrowth at 24 h. Disclosures Robin Patel, MD, a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication, a patent on PET imaging of bacterial infection: a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication, a patent on PET imaging of bacterial infection|MicuRx Pharmaceuticals and bioMérieux: Grant/Research Support|PhAST, Day Zero Diagnostics, DEEPULL DIAGNOSTICS, S.L., Nostics, HealthTrackRx, bioMérieux and CARB-X: Advisor/Consultant|Up-to-Date and the Infectious Diseases Board Review Course: Honoraria

Abstract Introduction: Chimeric antigen receptor (CAR) T-cell therapies are an effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). Idecabtagene vicleucel (ide-cel) is a B-cell maturation antigen-targeted CAR T-cell therapy approved for patients with RRMM with ≥2 prior lines of therapy. Developing a better understanding of the relationship between patient age and CAR T-cell therapy outcomes may help guide treatment and clinical practice. This analysis of data from the KarMMa-3 trial (NCT03651128) describes efficacy and safety outcomes in older and younger patients who received either ide-cel or standard therapy regimens. Methods: KarMMa-3 is an open-label, phase 3 trial that includes adults with RRMM who have received 2-4 prior treatment regimens with disease refractory to the last therapy. Enrolled patients were randomized (2:1) to receive either a one-time infusion of ide-cel or 1 of 5 standard regimens. This subgroup analysis evaluated the efficacy and safety of ide-cel compared with standard regimens in KarMMa-3 patients by age group (≥70 vs &lt;70 yrs). Outcome measures assessed include overall response rate (ORR), progression-free survival (PFS), overall survival (OS), patient-reported quality of life (QoL), and incidence of selected adverse events. Results: A total of 386 patients were evaluated; 19.3% (49/254) of those receiving ide-cel and 20.5% (27/132) of those receiving standard regimens were aged ≥70 yrs. Compared with older patients, younger patients receiving ide-cel exhibited more high-risk baseline characteristics, including high-risk cytogenic abnormalities (44.4% vs 32.7%) and triple-class refractory disease (66.8% vs 55.1%). The median time to progression during the most recent prior anti-myeloma treatment was longer for patients aged ≥70 yrs who received ide-cel vs standard regimens (8.6 mo vs 6.7 mo) but was similar for patients aged &lt;70 yrs (6.5 mo vs 6.9 mo). ORR for patients aged &lt;70 yrs was 68.8% (95% CI: 62.4, 75.1) with ide-cel and 41.0% (95% CI: 31.5, 50.4) with standard regimens (P&lt;0.0001). Patients aged ≥70 yrs treated with ide-cel achieved an ORR of 81.6% (95% CI: 70.8, 92.5) vs 48.1% (95% CI: 29.3, 67.0) with standard regimens (P&lt;0.01). Median PFS for patients aged &lt;70 yrs was longer with ide-cel treatment vs standard regimens (12.5 mo [95% CI: 11.2, 15.4] vs 4.2 mo [95% CI: 3.5, 5.7]; P&lt;0.0001). Similar trends were seen in patients aged ≥70 yrs, where median PFS was 18.9 mo (95% CI: 12.1, 24.5) with ide-cel treatment and 5.7 mo (95% CI: 2.2, 12.2) with standard regimens (P&lt;0.01). Median OS was not reached in older patients in either treatment arm; in younger patients, median OS was 39.5 mo (95% CI: 27.8, NR) with ide-cel and 27.9 mo (95% CI: 20.6, NR) with standard regimens. Incidence of adverse events reported with ide-cel treatment was generally similar between age groups for cytokine release syndrome, neurotoxicity, and infections. Analyses of patient-reported QoL data and other relevant safety endpointsare ongoing and will be included in the presentation. Conclusions: In the KarMMa-3 trial, patients aged ≥70 years derived substantial benefit from ide-cel treatment, demonstrated by longer PFS and a notable ORR compared with standard regimens. While efficacy and safety outcomes of ide-cel treatment in older patients were consistent with younger patients, it is important to note that patients in the trial aged ≥70 yrs were more likely to have favorable baseline characteristics and less aggressive and heavily pretreated disease. This may reflect a selection bias towards enrolling older patients considered to be easier to treat. In contrast, real-world data from late-line settings suggest that older patients are undergoing treatment based on less restrictive selection criteria—eg, including those with higher-risk baseline features—reflecting a more representative and broader population. These observations reinforce the potential for durable benefit with a single ide-cel infusion in a real-world context without additional adverse safety signals, supporting its use across age groups.

Abstract Introduction: Patients (pts) with soft tissue plasmacytomas noncontiguous with bone (true extramedullary disease [EMD]) have poor outcomes with standard therapies shown by low overall response rates (ORRs), which are not durable. Talquetamab (Tal; anti-GPRC5D×CD3) and teclistamab (Tec; anti-BCMA×CD3) are first-in-class bispecific antibodies (BsAbs) approved as monotherapies for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). Primary analysis from the RedirecTT-1 (NCT04586426) dedicated phase 2 EMD cohort (March 2025 data cut; median follow-up [mFU] 12.6 mo) showed Tal + Tec elicited an ORR of 78.9% (assessed by independent review committee) and a 12-mo progression-free survival (PFS) of 61.0%. Here, we report updated efficacy, using investigator assessment, and safety results from the phase 2 RedirecTT-1 EMD cohort with Tal + Tec. Importantly, we report EMD location and a novel analysis of tumor burden as a prognostic indicator of ORR. Methods: Pts had TCE RRMM and true EMD defined as ≥1 nonradiated soft tissue plasmacytoma noncontiguous with bone ≥2 cm in 1 dimension (with or without paramedullary plasmacytomas). Nonsecretory/oligosecretory disease was permitted. Prior CAR-T and non-BCMA/-GPRC5D BsAb therapies were permitted. Pts received Tal 0.8 mg/kg + Tec 3.0 mg/kg Q2W, preceded by step-up doses, with a permitted switch to monthly dosing at investigator's discretion after cycle 6 or after cycle 4 with confirmed ≥VGPR. Response was assessed per IMWG; EMD response was assessed by PET-CT or MRI whole-body scans. Tumor burden was assessed by total EMD tumor volume. Results: As of July 2025, 90 pts received Tal + Tec, with a median follow-up of 16.3 mo (range 0.5–23.7). Baseline characteristics were as previously reported; 39% had nonsecretory/oligosecretory disease, 20% had prior anti-BCMA CAR-T therapy, and 9% had prior BsAb therapy (all anti-FcRH5). The median number of plasmacytomas was 2 (range 1–7); 17 (18.9%), 29 (32.2%), and 74 (82.2%) pts, respectively, had ≥1 nodal, organ, or soft tissue EMD, while 11 (12.2%) also had ≥1 additional paramedullary plasmacytoma. Of 268 EMDs across all pts, 95 (35.4%) were nodal EMD, 77 (28.7%) were organ EMD (most commonly liver), and 64 (23.9%) were soft tissue EMD; 32 (11.9%) were paramedullary. Baseline EMD tumor volume was &lt;25 cm2in 43 (47.8%) pts, 25–50 cm2 in 21 (23.3%) pts, and &gt;50 cm2 in 26 (28.9%) pts. Per investigator assessment, ORR (95% CI) was 77.8% (67.8–85.9); 50.0% had a ≥CR. Median duration of response (DOR) was not estimable (NE; 12-mo DOR rate, 60.1%), 12-mo PFS was 55.6%, and median overall survival (OS) was NE (12-mo OS rate 73.8%). ORR was 90.7% (77.9–97.4; ≥CR 60.5%) in pts with EMD tumor volume &lt;25 cm2, 66.7% (43.0–85.4; ≥CR 52.4%) for 25–50 cm2, and 65.4% (44.3–82.8; ≥CR 30.8%) for &gt;50 cm2. Common adverse events (AEs) included CRS (77.8%; no grade [gr] 3/4) and neutropenia (72.2%; gr 3/4 62.2%). Taste changes (78.9%), non-rash skin AEs (68.9%), and nail AEs (55.6%) were all gr 1/2, and rash AEs (30.0%) were mostly gr 1/2. ICANS occurred in 11 (12.2%) pts (gr 3, 1.1%; gr 4, 1.1%). Infections occurred in 72 (80.0%) pts (gr 3/4 40.0%), most commonly upper respiratory tract infection (26.7%; gr 3/4 5.6%); IVIG was highly recommended to prevent and manage hypogammaglobulinemia and infection. Ten (11.1%) pts discontinued Tal + Tec due to treatment-emergent AEs (4 pts due to infections and 6 due to gr 5 AEs). Two pts discontinued Tal only due to AEs. In total, 11 (12.2%) pts had gr 5 AEs (6 due to infections), 6 of which were deemed to be drug related by investigators. Data will be updated with an additional 4 mo of follow-up for the presentation. Conclusions: With longer follow-up in pts with TCE RRMM with true EMD regardless of baseline tumor characteristics, Tal + Tec efficacy exceeded all approved therapies, including T-cell redirecting and cellular therapies, noting limitations of cross-study comparisons. Lower total EMD tumor volume was associated with a higher ORR but low pt numbers in each group and lack of statistical testing limits robust interpretation. The safety profile of Tal + Tec was generally consistent with each monotherapy; AEs were not exacerbated with the combination. These data continue to highlight the clinical benefit of the novel combination of Tal + Tec in pts with true EMD, a population with high disease burden and significant unmet need.

Abstract Introduction: The introduction of the Bruton tyrosine kinase inhibitor acalabrutinib combined with bendamustine and rituximab (ABR) as first-line (1L) therapy for mantle cell lymphoma (MCL) in older patients (pts) is reshaping the approach to treatment sequencing in this disease. The primary analysis of the phase 3 ECHO trial (NCT02972840) with data cutoff Feb 15, 2024 (median time on study 44.9 mo) demonstrated improved progression-free survival (PFS) with ABR vs placebo plus BR (PBR; hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.57–0.94; P=0.0160) in pts ≥65 y with treatment-naive (TN) MCL. Here we present updated results after 50 mo of follow-up, including time to next treatment 2 (TTNT2; ie, initiation of third-line [3L] therapy). Methods: Pts aged ≥65 y with TN MCL and ECOG performance status ≤2 were randomly assigned 1:1 to receive ABR or PBR. Randomization was stratified according to geographic region and simplified MIPI score. BR was given for 6 cycles followed by rituximab maintenance for 2 y in pts achieving a partial or complete response (CR). Acalabrutinib (100 mg twice daily) or placebo was administered at study start until progressive disease (PD) or unacceptable toxicity. Crossover to acalabrutinib was permitted at PD. The primary endpoint was PFS per independent review committee. TTNT2, which was used as a surrogate for PFS2 (time from initial treatment to second disease progression), was defined as time from randomization to second subsequent (3L) antilymphoma therapy after discontinuation of randomized treatment or death. Results: In total, 299 pts were randomized to each arm; median age was 71 y. At data cutoff (February 15, 2025), median (range) time on study was 51.86 (0.03–93.04) mo and median (range) follow-up through reverse Kaplan-Meier method for PFS was 60.8 (0–88.5) mo. Median TTNT2 was not reached (NR) in the ABR arm and 73.8 mo in the PBR arm, establishing a 24% reduction in the risk of initiating 3L therapy or death with ABR vs PBR (stratified HR 0.76; 95% CI 0.59–0.98). In total, 33 (11.0%) and 100 (33.4%) pts received second-line [2L] treatment (median time to 2L therapy, 26.3 vs 19.6 mo) and 10 (3.3%) and 37 (12.4%) received 3L treatment in the ABR and PBR arms, respectively. When COVID-19 deaths were censored (in alignment with prespecified analyses from the primary study), the HR further improved (stratified HR 0.67; 95% CI 0.50–0.89; median TTNT2 NR in any arm). In total, 71.6% and 78.3% of pts discontinued acalabrutinib and placebo, respectively; the most common reasons (&gt;5%) for discontinuation were adverse events (AEs; 44.5%, ABR; 32.4%, PBR) and objective PD (12.7%, ABR; 30.8%, PBR). Median PFS was 72.5 and 47.8 mo in the ABR and PBR arms, respectively (stratified HR 0.68; 95% CI 0.53–0.87; P=0.002). In total, 108 (36.1%) and 116 (38.8%) pts in each arm died; median overall survival (OS) was NR in both arms (stratified HR 0.87; 95% CI 0.67–1.13), with a 36-mo OS rate of 73.8% with ABR vs 68.3% with PBR. With 1 additional year of follow-up since the primary analysis, rates of grade ≥3 AEs and serious AEs in the ABR arm were comparable to previously reported rates, indicating that prolonged acalabrutinib exposure does not appear to result in cumulative toxicities. Three new cases of grade 3/4 neutropenia were reported, with no marked changes in the rates of grade ≥3 or serious infections. The rate of grade ≥3 cardiac events remained consistent with the primary analysis. In the ABR arm, 1 new case of grade 3/4 atrial fibrillation and 1 new case of grade 3/4 hypertension were reported. Rates of thrombocytopenia, major hemorrhage, and ventricular tachyarrhythmia remain unchanged. Conclusion: In this updated analysis of the ECHO trial, despite crossover to acalabrutinib being permitted in the PBR arm, fewer pts in the ABR arm were in need of subsequent treatment (2L and 3L), with longer TTNT2 in the ABR arm. These results suggest that 1L treatment with ABR provides a 24% reduction in risk of initiating 3L therapies or death. Further follow-up has demonstrated that ABR offers improved efficacy (ie, PFS) vs PBR, with no long-term safety concerns with acalabrutinib maintenance. The updated safety findings further support the favorable benefit–risk profile of acalabrutinib in TN MCL. Altogether, these data support the potential of acalabrutinib in combination with BR as 1L treatment, rather than in later lines, to modify long-term treatment outcomes in pts with TN MCL.

Abstract Introduction: The CARTITUDE-4 study (NCT04181827), which enrolled patients with lenalidomide-refractory multiple myeloma (MM) after 1–3 prior lines of therapy (pLOT), demonstrated a significant benefit of ciltacabtagene autoleucel (cilta-cel) over established triplet regimens. However, the benefit of cilta-cel for patients with standard-risk cytogenetics remains less defined. Here, we report outcomes in patients with standard-risk cytogenetics from the intent-to-treat and as-treated populations in CARTITUDE-4. Methods: InCARTITUDE-4, patients randomized to the cilta-cel arm underwent apheresis and bridging treatment with either pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd), followed by lymphodepletion therapy with cyclophosphamide and fludarabine, and then a single cilta-cel infusion. Progression-free survival (PFS) was assessed using a validated computerized algorithm. The intent-to-treat population included 208 patients; 32 patients progressed or died on bridging therapy, resulting in an as-treated population of 176 patients. Patients with high-risk cytogenetics, defined as del(17p), t(14;16), t(4;14), gain/amp(1q) (n=105), or with unknown cytogenetics (n=12), were excluded from the as-treated analysis. The 12-month minimal residual disease (MRD)-negative complete response (CR) was defined per the International Myeloma Working Group criteria as the proportion of participants with CR or better prior to and at 12 months (±3 months), achieving MRD-negative status at 12 months (+3 months) after cilta-cel infusion, as determined by next-generation sequencing (10-5), prior to progressive disease or subsequent anti-myeloma therapy. For the as-treated population, PFS rates were measured from the time of cilta-cel infusion. Results: In CARTITUDE-4, in the intent-to-treat population, at a median follow-up of 33.6 months, patients with standard-risk cytogenetics had a 30-month PFS rate (95% CI) of 71.0% (58.8–80.2) in the cilta-cel arm (N=69) vs 43.2% (31.3–54.5) in the standard-of-care (SOC) arm (N=70). Patients with standard-risk cytogenetics in the as-treated population (n=59) had a 30-month PFS rate of 80.5% (95% CI, 67.2–88.8). In CARTITUDE-1 (NCT03548207), which evaluated cilta-cel in patients with heavily pretreated relapsed/refractory MM (RRMM; ≥3 pLOT), the 30-month PFS rate among patients with standard-risk cytogenetics (negative for del(17p), t(14;16), or t(4;14); n=68) was 59.9% (95% CI, 47.2–70.5). In the CARTITUDE-4 as-treated population with standard-risk cytogenetics, 8 PFS events occurred within 1 year and 4 PFS events beyond 1 year of cilta-cel infusion. Twenty-six patients achieved MRD-negative CR at 12 months after cilta-cel; 100.0% of these patients were progression free at 30 months. Fourteen patients were not evaluable for MRD due to: calibration failure (n=12), no sample availability for testing (n=1), or indeterminate results post baseline (n=1). Conclusions: The PFS rate at 2.5 years for patients with standard-risk RRMM was higher in CARTITUDE-4 compared with CARTITUDE-1, supporting the use of cilta-cel as early as second line in the treatment course. In CARTITUDE-4 (as-treated population), 80.0% of patients with standard-risk cytogenetics were progression free and off treatment at 2.5 years. In patients with standard-risk disease who achieved MRD-negative CR at 1 year, this rate increased to 100.0%. The low rate of progression events in cilta-cel-treated patients with standard-risk cytogenetics shows the profound benefit of a single cilta-cel infusion in this population.

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.

PURPOSE This analysis aimed to contextualize the symptoms of peripheral neuropathy (PN) experienced by patients with triple-class refractory (TCR) multiple myeloma (MM) treated with elranatamab in the MagnetisMM-3 clinical trial with those experienced by patients with TCR MM receiving a new line of physician's choice of therapy in the real-world MagnetisMM-14 study. METHODS MagnetisMM-3 included 123 patients and MagnetisMM-14 included 35 who had TCR MM and were enrolled under the same eligibility criteria. Patient-reported symptoms of PN were collected monthly using the Chemotherapy-Induced Peripheral Neuropathy-20 item (CIPN20) questionnaire and compared for clinically meaningful differences across sensory, motor, and autonomic domains. Higher scores indicated worse patient-reported PN symptoms. RESULTS Baseline demographics and clinical characteristics for patients in MagnetisMM-3 and MagnetisMM-14 were generally similar. Patients in MagnetisMM-3 had a median of five ( v four in MagnetisMM-14) prior lines of therapy. In MagnetisMM-14, common index therapies included elotuzumab + pomalidomide (23%), carfilzomib + pomalidomide (19%), or carfilzomib + cyclophosphamide (19%), all with corticosteroids. Mean scores for sensory (15.8 v 14.8) and motor (14.4 v 12.2) domains of the CIPN20 were similar between MagnetisMM-3 and MagnetisMM-14 at baseline. Mean scores for the autonomic domain were 14.0 versus 21.3 at baseline, respectively. No clinically meaningful differences for any domain were found between month 6 scores or changes in scores from baseline to month 6 between MagnetisMM-3 and MagnetisMM-14 populations. CONCLUSION These findings suggest that elranatamab treatment was not associated with a worsening of patient-reported PN symptoms across the sensory, motor, and autonomic domains of the CIPN20. Moreover, PN symptoms reported with elranatamab treatment were similar to those reported with other common therapies used in real-world clinical practice for the management of MM. MagnetisMM-3 ClinicalTrials.gov identifier: NCT04649359 .