Gatt, Moshe E.

7508 Background: Data on response to BCMA-targeted therapies among BCMA-exposed pts with RRMM are limited. Outcomes after sequential/subsequent anti-BCMA bispecific T-cell engagers (Bs-TCE) are vital to evaluate. Etentamig is a next-generation differentiated BCMA x CD3 Bs-TCE composed of a bivalent BCMA-binding domain with a high-avidity, low-affinity CD3-binding domain potentially reducing cytokine release syndrome (CRS), and a silenced Fc tail for extended half-life and convenient monthly (Q4W) dosing. Phase 1 results of etentamig in RRMM showed robust efficacy and potential best-in-class safety. Methods: Arm B of the open-label, Phase 1b MOVISO study (NCT05650632) evaluated etentamig in pts with RRMM with ≥2 prior lines of therapy (PLT), including triple-class and prior BCMA exposure (antibody-drug conjugate [ADC] >30 days or CAR-T >6 months [mo] after last exposure). Primary safety endpoints were CRS and immune effector cell-associated neurotoxicity syndrome (ICANS); efficacy endpoints included objective response rate (ORR; IMWG 2016), duration of response (DoR), and progression-free survival (PFS). Pts received etentamig (60 mg IV; no step-up dosing [SUD]) on Cycle 1 Day 1 and Q4W thereafter. Results: At cutoff (June 11, 2025), 41 prior BCMA-exposed pts (CAR-T, n=24; ADC, n=17) had been treated; 24 (57%) were male, 38 (93%) were White, median (mdn) (range) age was 68 (43–89) years, 37 (88%) had ECOG PS ≤1, and 34 (81%) were triple-class refractory. Mdn (range) PLT was 6 (3–15). For 21 (51%) pts, the last PLT was BCMA directed; 23 (56%) had previously responded to anti-BCMA therapy (17/24 [71%] for CAR-T and 6/17 [35%] for ADC). Mdn (range) time from last prior CAR-T or ADC to first dose of etentamig was 15 (1–30) and 4 (1–45) mo, respectively. Mdn (range) follow-up was 5.5 (0.2–17.1) mo. Despite no SUD, CRS and ICANS were reported in 24 (57%) and 3 (7%) pts, respectively; all G1/2 events, except 1 G3 ICANS. G3/4 neutropenia and infections were reported in 15 (36%) and 17 (41%) pts, respectively. Efficacy outcomes are detailed in the Table (NE, not estimable). For pts whose last PLT was BCMA directed, MRD negativity (clonoSEQ, 10 –5 ) was seen in 2/3 (67%) evaluable pts, along with robust peak activation and proliferation of CD8+ T cells. Conclusions: Pts treated with etentamig achieved durable responses; rates were higher in pts who received CAR-T as last line. No new safety signals were observed; only low-grade CRS was seen despite no SUD. Clinical trial information: NCT05650632 . All prior BCMA (N=41) Prior BCMA CAR-T (N=24) ORR, n/n (%) [95% CI] Overall 17/36 (47) [30–65] 11/22 (50) [28–72] BCMA-directed last PLT 11/19 (58) [34–80] 7/11 (64) [31–89] Mdn DoR, mo [95% CI], No. of pts Overall 13 [7–NE], N=17 13 [7–NE], N=11 BCMA-directed last PLT 13 [7–NE], N=11 13 [7–NE], N=7 Mdn PFS, mo [95% CI], No. of pts Overall 3.4 [3–11], N=41 8.3 [2–NE], N=24 BCMA-directed last PLT 9.4 [2–NE], N=21 9.4 [2–NE], N=12

PURPOSE Venetoclax, an oral BCL-2 inhibitor, has efficacy in t(11;14)-positive relapsed/refractory multiple myeloma (RRMM), which is enhanced by dexamethasone, which promotes BCL-2 dependency. METHODS The randomized, open-label, phase III CANOVA study (ClinicalTrials.gov identifier: NCT03539744 ) enrolled adults with t(11;14)-positive RRMM who had received ≥2 previous lines of therapy. Patients were randomly assigned (1:1) to venetoclax-dexamethasone or pomalidomide-dexamethasone until progression or intolerable toxicity. The primary end point was independent review committee assessed–progression-free survival (PFS) in the intention-to-treat population analyzed by stratified log-rank test (two-sided type I error rate, α = .05), with hazard ratio (HR) and 95% CI estimated by stratified Cox proportional hazard model. Secondary end points included response rates, overall survival (OS), minimal residual disease (MRD) negativity rate (<10 –5 ), and safety. RESULTS Overall, 263 patients were randomly assigned (venetoclax-dexamethasone, n = 133; pomalidomide-dexamethasone, n = 130). Median PFS was 9.9 months (95% CI, 6.9 to 12.6) with venetoclax-dexamethasone versus 5.8 months (95% CI, 3.8 to 9.2) with pomalidomide-dexamethasone (HR, 0.823 [95% CI, 0.596 to 1.136]; P = .24). Overall response and very good partial response or better rates were 62% and 39%, respectively, with venetoclax-dexamethasone versus 35% and 14% with pomalidomide-dexamethasone. MRD negativity rate was 8% with venetoclax-dexamethasone and 0% with pomalidomide-dexamethasone. Median OS was 32.4 months (95% CI, 26.4 to 40.7) with venetoclax-dexamethasone and 26.9 months (95% CI, 20.4 to 38.9) with pomalidomide-dexamethasone (HR, 0.856 [95% CI, 0.612 to 1.197]). Grade ≥3 treatment-emergent adverse event rates were 67% with venetoclax-dexamethasone versus 83% with pomalidomide-dexamethasone. There were 16 (12%) treatment-emergent deaths with venetoclax-dexamethasone versus 8 (6%) with pomalidomide-dexamethasone. CONCLUSION The primary end point of PFS was not met. PFS and OS were numerically longer with venetoclax-dexamethasone versus pomalidomide-dexamethasone in t(11;14)-positive RRMM. Consistent with previous studies, infections were associated with venetoclax-dexamethasone; no new safety signals were observed.

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 Systemic light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in vital organs, often resulting in irreversible organ damage. While plasma cell-directed therapies have improved clinical outcomes, the molecular mechanisms driving disease pathogenesis remain poorly understood. Our previous studies identified overactivation of the PI3K/AKT signaling pathway in AL amyloidosis (Zvida et al., Blood, 2024; Fishov et al., Cancer Med., 2023), a central regulator of cellular and lipid metabolism. Dysregulated lipid metabolism has been implicated in several hematologic malignancies, yet its role in AL amyloidosis remains largely unexplored. Objectives To characterize the lipidomic landscape in AL amyloidosis compared to multiple myeloma (MM) and healthy controls (HC) in the context of inflammatory signaling. The ultimate goal of this work is to uncover novel metabolic-immunologic targets for therapeutic intervention. Methods Lipidomic profiling was performed by liquid chromatography-mass spectrometry (LC-MS) on plasma samples from AL patients (n=30), MM (n=30), and HCs (n=15). Fatty acid synthase (FASN) expression was validated by qRT-PCR in CD138+ bone marrow (BM) samples. A lipogenesis index was calculated using the ratio of palmitoleic acid to linoleic acid as a surrogate marker of FASN activity. Additionally, RNA-seq was conducted on CD138⁺ BM cells from AL and HC samples (n=8). Cytokine profiling was performed on serum from AL, MM, and HC subjects (n=10 each). Functional assays and lipidomic analysis were conducted in ALMC1 cells using the FASN inhibitor TVB-2640 and the MEK inhibitor cobimetinib. Results Lipidomic analysis of pre-treatment plasma samples revealed a significant increase in the lipogenesis index in AL patients, indicating elevated FASN activity. This was consistent with increased FASN mRNA expression in bone marrow CD138⁺ cells, suggesting both transcriptional upregulation and enzymatic activation. In ALMC1 cells, dose- and time-dependent FASN inhibition with TVB-2640 (0-2 μM, 24-72h) significantly reduced cell viability (IC50=1.3 μM), suggesting that FASN activity supports AL plasma cell survival. In addition, AL patients demonstrated a significant decrease in polyunsaturated fatty acids (PUFAs) levels, including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and linoleic acid (LA), compared to MM and HC. As PUFAs are known suppressors of FASN expression and activity, their depletion may contribute to sustained FASN upregulation and a metabolic shift toward de novo lipogenesis. Pathway enrichment analysis of patient lipidomic data revealed significant enrichment of omega-3/6 fatty acid metabolism, ATP generation, and inflammation-related pathways. Notably, imbalances in omega-3 and omega-6 fatty acids ratio have been associated with heightened inflammatory responses. In parallel, RNA-seq analysis identified several upregulated pathways in AL amyloidosis patients compared to controls, including immune regulation, MAPK signaling, mitochondrial dysfunction, oxidative phosphorylation, and IL-13 signaling. Both IL-13 and MAPK are known to transcriptionally induce FASN and regulate immune responses, providing a possible mechanistic link between inflammation and lipid remodeling. Cytokine profiling revealed elevated levels of IL-1β, IL-13, IL-8, IFN-γ, MIP-1α (CCL3), G-CSF, MCP-1 (CCL2), and IP-10 (CXCL10) in AL serum samples, consistent with a systemic inflammatory phenotype. Pharmacologic inhibition of MAPK signaling (by cobimetinib) in ALMC1 cells led to restoration of PUFA levels and a concurrent reduction in cytokine secretion, suggesting that MAPK activity sustains both the inflammatory and lipogenic phenotype in AL. ConclusionsOur findings identify metabolic-inflammatory axis in AL amyloidosis, in which IL-13 and MAPK signaling may promote fatty acid reprogramming through FASN activation and PUFA suppression. This axis sustains a pro-inflammatory environment that may contribute to disease pathogenesis. Thus, FASN and MAPK may represent promising metabolic-immunologic targets for therapeutic intervention in AL amyloidosis.

Background: Systemic light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chain products in vital organs, leading to significant organ dysfunction. The molecular mechanisms underlying its pathogenesis remain incompletely elucidated. Identifying the molecular mechanisms and novel therapeutic targets is critical for improving treatment strategies and patient outcomes. Our previous research work identified that the PI3K/AKT signaling pathway is overexpressed in AL amyloidosis (Zvida et al., Blood, 2022, Fishov et al., Cancer Med., 2023). This pathway plays a critical role in regulating cellular metabolism. Specifically activated AKT can phosphorylate and regulate various target proteins involved in metabolic processes. One of the significant targets is fatty acid synthase (FASN), an enzyme responsible for the synthesis of fatty acids. AKT can enhance FASN expression and activity, thereby promoting lipid biosynthesis. Additionally, elevated FASN levels can drive inflammation through increased fatty acid synthesis, which activates inflammatory signaling pathways and enhances cytokine production (Acosta-Martinez et al.,IJMC, 2022). Elevated levels of FASN have been associated with hematological malignancies and cell survival (Vanauberg, et al., Oncogenesis, 2023). However, its role in AL amyloidosis is yet to be elucidated. Aim: To determine the role of FASN in the pathology and inflammatory response in AL amyloidosis, and to evaluate the potential of targeting FASN and the PI3K/AKT pathway for therapeutic intervention. Methods: We profiled FASN expression in CD138+ bone marrow (BM) samples from patients with AL amyloidosis (n=20), Multiple Myeloma (MM) (n=20), Monoclonal Gammopathy of Undetermined (MGUS) (n=8) and Healthy Controls (HC) (n=6), using qRT-PCR. To further explore the relationship between the PI3K/AKT pathway and FASN, we treated ALMC-1 cells with Capivasertib (an AKT inhibitor) and assessed FASN protein levels, cell proliferation by WST-1 assay, cell cycle distribution by flow cytometry, light chain secretion by ELISA, and expression of AKT and its downstream targets via western blot analysis. Furthermore, TVB-2640 (FASN inhibitor) was used to evaluate the cell response to FASN inhibition. Results: Our analysis revealed a significant upregulation of FASN in AL amyloidosis BM samples compared to MM, MGUS, and HCs. Capivasertib treatment resulted in a dose-dependent reduction in FASN protein levels. Additionally, Capivasertib treatment inhibited cell proliferation, induced G1 phase cell cycle arrest, reduced light chain secretion, and decreased AKT protein expression and its downstream targets p4EBP pS6 and pERK. Elevated levels of proinflammatory cytokines, including TNF and IP-10 (CXCL-10), were observed in AL amyloidosis serum samples, suggesting the involvement of immune mechanisms and the PI3K/AKT pathway, potentially induced by FASN. Finally, treatment with TVB-2640 reduced cell viability and decreased the protein expression of LIPIN-1, which is one of the key target genes regulated by FASN. Conclusions: Our findings highlight the significant upregulation of FASN in AL amyloidosis and its regulation by the PI3K/AKT pathway. The observed effects of Capivasertib on FASN expression and cell proliferation, along with the upregulation of inflammatory cytokines, underscore the potential for targeting the PI3K/AKT signaling pathway and FASN in developing more specific therapeutic strategies for AL amyloidosis.

Background: Proven salvage therapies for pts with triple-class refractory MM who progress on BCMA-targeted therapies are lacking.Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage. Cevostamab is a FcRH5xCD3 BsAb that facilitates T cell-mediated killing of MM cells. In an initial Phase I study (GO39775), cevostamab monotherapy was clinically active and had manageable toxicity in pts with heavily pretreated relapsed/refractory MM (Trudel et al. ASH 2021). In Cohort A1 of the subsequent Phase I/II CAMMA 2 study (CO43476; NCT05535244), cevostamab was highly active and had manageable safety at the 160mg target-dose (TD) level in pts with triple-class refractory MM who had received a prior BCMA-targeted antibody-drug conjugate (ADC; overall response rate [ORR]: 60%, 6/10 pts) or chimeric antigen receptor T-cell (CAR-T) therapy (ORR: 73%, 8/11 pts) but had not received a prior BCMA-targeted BsAb (Kumar et al. EHA 2024). We present initial results from Cohort A2, which enrolled pts with triple-class refractory MM who had received prior BCMA-targeted therapies, including ≥1 BCMA-targeted BsAb. An exploratory analysis of baseline patient and tumor-related factors is also presented. Methods: Cevostamab was initiated with step dosing (Cycle [C] 1 Day [D] 1: 0.3mg; C1D2, D3, or D4 depending on the emergence of cytokine release syndrome [CRS] after the initial administration: 3.3mg) and continued at the 160mg TD on C1D8 and on D1 of each subsequent 21-day cycle until disease progression (PD) or unacceptable toxicity. Cytokine, tumor antigen, T-cell function/activation, and inhibitory immune checkpoint expression were assessed in blood and tumor samples collected at baseline and during treatment. Results: As of February 23, 2024, 21 pts (median age: 64 years, range: 46-84) had been enrolled into Cohort A2. Seven pts (33%) had extramedullary disease and 5/12 pts (42%) with a conclusive assay result had high-risk cytogenetics (t(4;14), t(14;16), or del(17p)). All pts were heavily pretreated (median prior lines of therapy: 8, range: 5-14); 62% had received ≥2 prior BCMA-targeted therapies (median time since last: 122 days, range: 68-558) and 33% had received ≥2 prior BsAbs (median time since last: 139 days, range: 68-782). Most pts (86%) were refractory to their last line of therapy; 62% were penta-drug refractory. Median follow-up was 173 days (range: 20-360). Grade (Gr) 3-4 adverse events (AEs) occurred in 71% of pts (15/21). Gr 3-4 AEs in &gt;3 pts were neutropenia, anemia, thrombocytopenia (38% each), and infections (29%). CRS occurred in 76% of pts (16/21) and was mainly Gr 1 (43%) or Gr 2 (29%); 1 patient had Gr 3 CRS. One treatment-related Gr 5 (fatal) AE of pneumonia was reported in the context of PD. No treatment-related AEs leading to cevostamab discontinuation occurred. Objective responses (partial response [PR] or better) were observed in 2/21 pts (ORR: 10%). Both pts achieved a very good PR and had ongoing responses at cut-off. Stable disease was observed in 10 pts (48%). Pts in the prior BsAb group had received more prior lines of therapy than those in the prior ADC and CAR-T groups (median 8 vs 5 and 6, respectively) and more prior BCMA-targeted therapies (median 2 vs 1 and 1). The percentage of pts with low levels (&lt;4.5 ng/mL) of soluble BCMA in plasma was also higher in the prior BsAb group (47% vs 0% and 18%). At baseline, inhibitory immune checkpoint expression across T-cell subsets was more common in the prior BsAb group. Notably, the median frequency of PD1+CD8+Tnaive and TIGIT+CD8+Tnaive cells in blood was higher in the prior BsAb group (21% and 29%, respectively) than in the prior ADC (3% and 6%) and CAR-T groups (4% each). Peak median IL-6 and IFN-γ levels were delayed until the first TD in the prior BsAb group, suggesting a different pharmacodynamic profile. Conclusions: Cevostamab has manageable safety in pts with triple-class refractory MM who have received prior BCMA-targeted therapies, including ≥1 BCMA-targeted BsAb. Clinical responses were less frequent in the prior BsAb group than in the prior ADC and CAR-T groups, which could be explained by the higher number of prior lines of therapy and T-cell exhaustion due to multiple prior exposures to BsAbs. Notably, the high frequency of CD8+ T-cell subsets expressing inhibitory immune checkpoints in the prior BsAb group suggests a level of T-cell dysfunction that could prevent effective T-cell activation.

Introduction Patients (pts) with multiple myeloma (MM) eventually become refractory to current treatments. There is an unmet need for new therapies with durable efficacy, favorable safety, and simplified dosing schedules. ABBV-383 is a unique BCMA x CD3 bispecific antibody T-cell engager comprising bivalent high-avidity BCMA binding domains, a low-affinity CD3-binding domain designed to minimize cytokine release and the risk for cytokine release syndrome (CRS), and a silenced Fc tail for extended half-life enabling dosing convenience. In an ongoing first-in-human (FIH) study (NCT03933735) in heavily pretreated pts with relapsed or refractory (RR) MM, ABBV-383 monotherapy (60 mg Q4W) resulted in deep and durable responses. Introduction of a modified dexamethasone (Dex) premedication (premed) schedule in cycle (C) 1 lowered incidence and severity of CRS (43% overall; 5% grade ≥2) vs pts treated with low Dex (71% overall; 20% grade ≥2) (JCO 2024;42[suppl 16]:7531). We now report results of Arm A of the open-label, phase 1b study (NCT05650632) evaluating 1 step-up dose (SUD) of ABBV-383 as a strategy to mitigate the risk of severe CRS and further assess ABBV-383 activity in pts with RRMM. Methods This study is enrolling pts with RRMM, ECOG performance status ≤2, and documented evidence of progression during or after the last treatment. Pts must have received ≥3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Arm A consists of a dose-optimization (DO) and a dose-expansion (DE) part. During DO, pts received a single SUD of intravenous ABBV-383 (2/4 mg) on C1 day (D) 1, followed by the target dose of 60 mg on D4. In the DE, based on DO findings, pts received the recommended ABBV-383 SUD on C1D1, followed by 60 mg on D4. The modified premed schedule that lowered incidence and severity of CRS in the FIH study was also introduced prior to target dose on C1D4. After C1, pts received 60 mg ABBV-383 Q4W on D1 of each cycle for DO and DE until disease progression, withdrawal, or discontinuation. Primary endpoint was grade ≥2 CRS events during C1. Other endpoints included any grade CRS events, treatment-emergent adverse events (TEAEs), immune pharmacodynamics, and clinical activity. Results As of April 2024, 70 pts were enrolled in Arm A: 47 in DO (2 mg SUD, n=26; 4 mg SUD, n=21) and 23 in DE. Median age was 69 years (range: 40-84), 59% were male, and 76% were triple-class refractory. Median prior lines of therapy was 4 (range: 3-10). Median follow-up time (months [mo]) was 6.5, 7.5, and 2.8 for 2 mg DO, 4 mg DO, and DE, respectively. Any grade CRS was reported in 10 (39%) and 11 (52%) pts during DO at 2 and 4 mg SUD; CRS grade ≥2 occurred in 3 (12%) pts in the 2 mg SUD and in 6 (29%) pts in the 4 mg SUD, leading to selection of 2 mg SUD for DE. In the DE, 7 (30%) pts experienced CRS; 1 (4%) pt experienced grade 2 CRS, there were no grade ≥3 events, and only 2 (9%) pts received tocilizumab to treat CRS. Overall, median time to CRS onset and resolution was 14.7 and 9 hours, respectively; no pts had CRS after C1. Immune effector cell-associated neurotoxicity syndrome occurred in 7 (10%) pts (grade 1: 4%; grade 2: 6%; grade 3: 4%). Most common TEAEs were CRS (40%), neutropenia (37%), diarrhea (29%), anemia (24%), and fatigue (20%); most common grade 3/4 TEAEs were neutropenia (31%), anemia (19%), thrombocytopenia (13%), and leukopenia (11%). Grade 5 TEAEs occurred in 5 pts; 1 event was deemed possibly related to ABBV-383 (COVID-19 pneumonia). In the efficacy-evaluable population (n=68), the objective response rate was 62% (95% CI: 49.2, 73.3); 35 (52%) pts had a VGPR or better. Median time to response was 1.1 mo (range: 1-4) and median duration of follow-up was 5.8 mo (range: 1-12). Response rates are expected to improve with longer follow-up. Maximum reduction in peak levels of CRS-related cytokines, including IL-6, were observed in DE compared with DO and 60 mg Q4W without SUD (FIH study). Peak activation and proliferation of CD8 T cells was comparable with ABBV-383 in DO, DE, and 60 mg Q4W-treated pts. Conclusions Introduction of 1 SUD of 2 mg on D1 followed by full dose of 60 mg on D4 in C1 combined with modification to the Dex premed schedule reduced the incidence and severity of CRS in pts with RRMM, further optimizing the safety profile of ABBV-383. Preliminary efficacy data show early and high response rates, consistent with outcomes from other ABBV-383 studies.

7510 Background: The randomized Phase 3 CANOVA study’s (NCT03539744) primary analysis showed multiple numerically improved efficacy endpoints with VenDex v PomDex, but the primary endpoint of mPFS by IRC was not statistically significant. Here, we report correlative biomarker analyses from CANOVA. Methods: CANOVA is a randomized, global, open-label Phase 3 study of VenDex v PomDex in pts with t(11;14)+ RRMM and ≥2 prior lines of therapy (LOTs). The primary endpoint was mPFS by IRC. Key secondary endpoints included ORR, ≥VGPR, mOS, and MRD negativity (<10-5). In post hoc mPFS sensitivity analysis, disease progression, death, and start of next LOT were defined as events. BCL2 gene expression by RNAseq (3.7 log2 FPKM prespecified median cutoff for BCL2high v BCL2low) and chr1q abnormalities by whole-exome sequencing (normal, gain, or amp) were assessed centrally from pretreatment, CD138-enriched BM aspirates. Results: mPFS, post hoc mPFS, and mOS in the VenDex arm were similar by BCL2 status, with numerically higher ORR, ≥VGPR, and MRD negativity rates in the BCL2highsubgroup. In contrast, mPFS and mOS within the PomDex arm were numerically longer in the BCL2lowsubgroup, despite equal ORR in both subgroups (Table). Presence of 1q abnormalities was evenly distributed across BCL2high v BCL2low subgroups in the VenDex arm (51% v 45%) but not in the PomDex arm (59% v 31%). Normal 1q and gain(1q) subgroups had numerically improved mPFS, mOS, ORR, ≥VGPR, and MRD negativity with VenDex; pts with amp(1q) had poor outcomes regardless of treatment, albeit the sample size was small. Conclusions: Pts with BCL2high or gain(1q) had numerically improved clinical efficacy with VenDex v PomDex. Clinical benefit was consistent across BCL2 subgroups ( BCL2high or BCL2low) with VenDex but not PomDex. Pts with amp(1q) fared poorly irrespective of treatment arm. Clinical trial information: NCT03539744 . [Table: see text]