Talati, Chetasi

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

Abstract Background B-cell maturation antigen (BCMA)-targeting immunotherapies represent a promising class of treatment for the management of immunoglobulin light chain (AL) amyloidosis, a disease that is related to clonal plasma cells. Etentamig is a 2nd generation, off-the-shelf, fully human BMCA X CD3 bispecific antibody with bivalent BCMA domain and low CD3 affinity that targets both BCMA-expressing plasma cells and CD3-expressing T cells. Etentamig monotherapy is being studied in multiple myeloma (MM) in an ongoing phase 3 study (NCT06158841). Here, we report the first safety and efficacy results from M24-209, an open-label phase 1/2 study evaluating etentamig monotherapy in patients (pts) with relapsed/refractory (RR) AL amyloidosis from dose level 1 (DL1). Methods The phase 1 dose escalation (ESC) portion of the study (NCT06158854) with etentamig enrolled pts with RR AL amyloidosis with ≥1 prior lines of therapy (LOT), including a proteasome inhibitor and an anti-CD38 monoclonal antibody with no prior BCMA exposure. Eligible pts were required to have a difference in involved and uninvolved serum free light chain (dFLC) of ≥50 mg/L, and pts with Mayo Clinic 2004 cardiac risk stage IIIb with NT-proBNP ≥8500 pg/ml were excluded. Three dose groups were explored in dose ESC (etentamig dose levels [DL] 1, 2, and 3). In all cohorts, pts will receive up to 24 cycles of treatment and will be followed until disease progression. In dose ESC, the primary objectives are to determine safety/tolerability, pharmacokinetic/pharmacodynamic, and recommended phase 2 dose. The secondary objectives include evaluation of efficacy as measured by hematologic response and organ response. Responses are investigator assessed per consensus guidelines (Comenzo, et al. Leukemia. 2012. 26[11]:2317-25; Palladini G, et al. Amyloid. 2021 [Epub];28[1]:1-2). Results As of 17 July 2025, all DLs in dose ESC have been fully enrolled, and 12 pts have been treated with etentamig at DL1. Due to short follow-up, this initial report only includes data from DL1, with further follow-up data from ESC to be included at the time of presentation. Median duration of follow up in DL1 was 9.4 months (8.3–13.8) with 83% of pts continuing treatment. Median age for pts was 72 years (range, 56–85 years). Median number of prior LOT was 2 (range, 1–6), and median time from initial diagnosis was 3.6 years. Thirty-three percent have received a prior stem cell transplant and 50% previously received the regimen of daratumumab with cyclophosphamide, bortezomib, and dexamethasone in combination. Median dFLC at study baseline was 110. 5 mg/L (range, 56.6–617.5). At baseline, 83% of pts had cardiac involvement, 25% had renal involvement, and 8% had hepatic involvement. Eighty-three percent of pts had lambda AL amyloidosis. Treatment-emergent adverse events were reported in 100% (42% Grade ≥3) of pts at DL1. Cytokine release syndrome (CRS) occurred in 2 pts (17%, all Grade 1), with no instances of any grade immune effector cell-associated neurotoxicity syndrome (ICANS). CRS occurring after the first dose had median time to onset of 6.8 hours (range, 6.7–6.9). Grade ≥3 infections occurred in 1 pt (8%, all Grade 3). Grade ≥3 neutropenia also occurred in 1 pt (8%, all Grade 3), and no Grade ≥3 events of thrombocytopenia or anemia occurred. No Grade 5 events have occurred. Within the dose ESC DL1 cohort, the overall hematologic response rate was 100%, with all pts achieving ≥VGPR and 83% of pts achieving complete response (CR). The median time to CR was 0.9 months (0.3–9.3). The median duration of response has not yet been reached and 100% of pts remain in their best overall response by investigator assessment. To date, no pts have experienced hematologic progression on study. Cardiac response was observed in 30% of evaluable pts. Renal response was seen in 67% of evaluable pts. Conclusions In the DL1 cohort, etentamig showed a manageable safety profile in AL amyloidosis with low incidence and severity of CRS, no ICANS, and limited Grade ≥3 cytopenia events. Deep and rapid hematologic responses were observed with 100% ≥VGPR rate and 83% hematologic CR rate. Additional dose-level data will be presented at the time of the meeting. All pts remain in ongoing follow-up and evaluation, and the study will begin the dose expansion (EXP) portion after dose selection.

Abstract Background: Clonotypic peptide detection by mass spectrometry (MS) leverages monoclonal protein (M-protein) de novo sequencing and peptide quantification to enable ultra-sensitive blood-based monitoring of multiple myeloma (MM) patient M-protein kinetics. Etentamig is a 2nd generation BCMA x CD3 bispecific antibody that has shown promising efficacy and a favorable safety profile in heavily pre-treated patients with relapsed or refractory (RR) MM (Journal of Clinical Oncology, 43;16:suppl.7527). In the current study, we explored the depth and kinetics of MS M-protein response to etentamig monotherapy in serum samples from Phase 1 M22-466 (NCT03933735) study patients. The correlation between blood-based MS M-protein levels and bone marrow minimal residual disease (MRD) negativity as determined by next generation sequencing (NGS) was also evaluated. Method: Clonotypic peptide MS using M-Insight (Sebia/Corgenix) was performed on serum samples from a subset of MRD evaluable patients enrolled into the Phase 1 (NCT03933735) clinical trial of etentamig monotherapy in patients with RRMM. Bone marrow MRD negativity (<10-5 and 10-6) analysis was determined by NGS (clonoSEQ, Adaptive Biotechnologies). Patient pre-treatment (Cycle [C] 1 Day [D] 1) serum samples were digested with proteolytic enzymes to permit sequencing of the M-protein heavy and light chain. Clonotypic peptides specific to the patient's complementarity-determining regions were selected for quantification by MS. Clonotypic peptide quantification by MS was performed on available tracking peripheral blood samples at C2D1, C3D1, C4D1, and C5D1 time points post etentamig monotherapy treatment. Results: Twenty patients who were MRD evaluable and treated with 40 mg and 60 mg doses of etentamig with available serum samples collected from C1D1–C5D1 time points were selected for M-Insight evaluation. Of the 20 patients, 16 (80%) had at least one clonotypic peptide identified prior to etentamig treatment that was utilized for tracking at subsequent time points. Rapid decline in MS M-protein levels was observed in patients treated with etentamig, which strongly correlated with the patients' best International Myeloma Working Group (IMWG) response. At C3D1 post etentamig treatment, patients with complete response (CR)/stringent CR (n=9) demonstrated a significant decline from MS M-protein levels (median: 1.8±0.9 g/dL at C1D1 to 0.03±0.2 g/dL at C3D1) (P<0.001). All evaluable subjects (n=16) had detectable MS M-protein at all time points (n=80). The lowest detectable M-protein level observed in the current dataset was 44 mg/dL (lower limit of quantitation of assay: 10 mg/dL). Subsequent analysis of differences in kinetics between MRD-negative (<10-5) (n=8) and MRD-positive (n=8) patients revealed a deeper reduction in M-protein levels for MRD-negative patients (median 0.02±0.2 g/dL at C3D1 compared with 0.4±0.3 g/dL at C3D1 for MRD-positive patients). Among the 8 patients who achieved MRD negativity at 10-5 threshold, 5 patients also achieved <10-6 threshold, and serum MS M-protein levels remained detectable in these patients (0.07±0.2 g/dL). Conclusions: Using MS-based clonotypic peptide detection, rapid and deep decline in serum M-protein levels was observed in RRMM patients treated with etentamig. Strong concordance was observed between MS M-protein levels and IMWG response, including in patients achieving MRD-negative CR at <10-5 and 10-6thresholds. Non-invasive and ultra-sensitive M-protein detection is feasible in MM and may serve as a key biomarker for enhancing the detection of residual disease in the future.

Abstract Background Etentamig is a second-generation B-cell maturation antigen (BCMA) x CD3 bispecific antibody that has shown promising efficacy and a favorable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). Etentamig possesses a unique combination of 2 high-affinity BCMA binding domains, coupled to a low-affinity CD3 binding domain that have been shown to reduce the negative impact of soluble BCMA (sBCMA), decrease risk for cytokine release syndrome (CRS), and drive sustained T-cell activation with reduced immune exhaustion in preclinical models of MM (Blood 2023;142 [suppl 1]:4666). Here, we describe correlative biomarker analyses from Phase 1 (NCT03933735) and Phase 1b (NCT05650632) clinical trials of etentamig in RRMM designed to assess the impact of sBCMA on clinical response and pharmacodynamic changes in proinflammatory cytokines, and T-cell redistribution, activation, proliferation, and exhaustion. Methods Peripheral blood and serum samples from patients with RRMM enrolled in Phase 1 and Phase 1b open-label studies who received etentamig monotherapy were collected at baseline, on treatment, and at disease progression. The Phase 1b study consisted of dose-optimization (DO) and dose-expansion (DE) phases. During DO, patients received a single step-up dose (SUD) of intravenous etentamig (2 or 4 mg) on Cycle (C) 1 Day (D) 1, followed by the target dose of 60 mg on D4. In DE, based on DO findings, patients received the recommended etentamig SUD (2 mg) on C1D1, followed by 60 mg on D4 with modified dexamethasone predosing. Samples were analyzed by flow cytometry for immune cell populations, Luminex® for cytokines, and electrochemiluminescence for sBCMA. Peripheral blood mononuclear cells and bone marrow mononuclear cells (BMMC) at baseline and on-treatment were subjected to single-cell Cellular Indexing of Transcriptomes and Epitopes sequencing (scCITEseq) and single-cell T-cell receptors (scTCR) / B-cell receptors clonality analyses. Results While baseline serum sBCMA levels did not correlate with clinical response to etentamig at the selected dose level of 60 mg every 4 weeks (Q4W) with 2 mg SUD, a reduction in sBCMA levels over time was associated with best International Myeloma Working Group response. Etentamig treatment led to a rapid and transient increase of proinflammatory cytokines and promoted T-cell redistribution, activation, and proliferation. Maximum reduction in peak levels of CRS-related cytokines, including (interleukin [IL]-6, IL-8, IL-10, tumor necrosis factor–a), were observed in DE compared with DO and 60 mg Q4W without SUD. Peak induction levels of proinflammatory cytokines during C1 correlated with occurrence of CRS (≥Grade [G] 1) as well as clinical response across dose levels. A modified dexamethasone premedication schedule of 2 mg/60 mg Q4W cohort for C1 resulted in significantly reduced baseline levels of IL-6 and key macrophage-associated cytokine/chemokines (eg, monocyte chemoattractant protein-1 and macrophage inflammatory protein-3 beta). Incidence of CRS was lowest in the 2 mg/60 mg Q4W cohort (26% G1, 4% G2, 0% ≥G3). Higher T-cell to myeloma cell ratio in BMMCs at baseline correlated with better response to etentamig. scCITEseq and scTCR analysis revealed that at baseline, responders also had greater CD8+ T-cell cytotoxic activities, increased TCR clonality, and elevated inflammatory signatures in T-cells from both peripheral blood and bone marrow. Etentamig at a dosage of 60 mg Q4W resulted in significant clonal expansion of CD8+ effector T-cells and enhanced gene expression signatures related to activation and cytotoxicity in both CD8+ T effector and natural killer cells. Along treatment cycles, responders maintained their T-cell fitness, high clonality, and low T-cell exhaustion levels. Frequency of baseline CD4+ or CD8+ T-cell exhaustion (programmed cell death receptor 1+/ T cell immunoglobulin and mucin-domain containing-3 +) did not impact clinical response at optimal dose level of 2 mg/60 mg Q4W etentamig. Conclusions Responses to etentamig were independent of baseline sBCMA levels and resulted in rapid and transient proinflammatory cytokine production that promoted robust T-cell redistribution, activation, and proliferation indicating that the optimal dose of etentamig (2 mg/60 mg Q4W) maximizes its clinical potential as a convenient, safe, and effective therapy for MM.

7527 Background: Etentamig (etenta) is a differentiated BCMA x CD3 bispecific T-cell engager composed of high avidity bivalent BCMA-binding domains, low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS), and silenced Fc tail for extended half-life enabling convenient dosing. We present long term results from 2 ongoing Ph 1 studies evaluating efficacy and safety of etenta in patients (pts) with RRMM. Methods: Data were from a Ph 1 multicenter, open-label, dose escalation/expansion (NCT03933735) trial and Arm A of a Ph 1b, open label (NCT05650632) trial of etenta; both enrolled pts ≥18 years with RRMM, ≥3 prior lines of therapy (LoT), and triple-class exposed. Pts received 60 mg Q4W or 40 mg Q3W, both regimens with similar dose intensity, in the Ph 1 trial; pts from Arm A of the Ph 1b trial received a step-up dose (SUD) on day 1 and full dose of 60 mg Q4W on day 4. This pooled analysis assessed long-term efficacy, safety, and tolerability. Tumor response was assessed per IMWG 2016 criteria. Results: Of 146 pts with RRMM who received etenta, 87 (60%) were male, median age (range) was 68 (40–87) years, median prior LoT were 4 (3–23), and median duration of follow-up was 13 (1–48) months (mo). ORR was achieved in 96 (66%) pts and ≥VGPR in 79 (54%) pts. Response rates across subgroups are reported in the Table. Median duration of response was not reached (NR) (NR–NR) among responders; Kaplan-Meier (KM) estimate at 12 mo was 71% (58.5%–80.5%). Median PFS (mPFS) was NR (8.7–NR) mo; KM estimate at 12 mo was 55% (44.9%–63.1%). Any grade and G3/4 treatment emergent adverse events (TEAEs) occurred in 145 (99%) pts and 116 (79%) pts. Most common G3/4 TEAEs (≥15%) were neutropenia (38%), anemia (23%), lymphopenia (25%), and thrombocytopenia (16%). Infections G3/G4 were reported in 32 (22%) pts; most common infections G3/G4 (≥5%) were pneumonia (12%) and sepsis (5%). TEAEs leading to etenta discontinuation were reported in 13 (9%) pts. Deaths from TEAEs were reported in 13 (9%) pts; 10 were not attributed to etenta treatment. In Arm A of Ph 1 study where 60mg Q4W was administered with SUD and modified dex as premedication, CRS incidence was 30% (4% G2; No ≥G3 events) with median time to CRS onset of 22.3 (5.5–29.6) hours; and median time to CRS resolution of 20.7 (1.8–131.7) hours. Conclusions: Etenta with SUD demonstrated a low CRS incidence, durable response, and tolerability in pts with heavily pretreated RRMM. Efficacy across all subgroups was comparable and maintained, suggesting therapeutic benefits among a broad population and supporting further exploration in the ongoing Ph 3 Cervino study. Subgroup ORR, n (%) ≥VGPR, n (%) mPFS, months (range) Age ≥75years 26 (72) 23 (63.9) NR (7.5–NR) Race: Black 15 (63) 13 (54.2) 13.7 (5.0–NR) High cytogenetic risk 21 (55) 18 (47.4) 7.4 (2.8–NR) 3 prior LoT 29 (64.4) 23 (51.1) 13.5 (5.6–NR) ≥4 prior LoT 67 (67) 56 (56) NR (8.3–NR)

Introduction ABBV-383 is a differentiated BCMA x CD3 bispecific antibody (fully humanized IgG4) T-cell engager composed of a bivalent BCMA binding domain with high avidity, a low-affinity CD3-binding domain, and a present but silenced-Fc tail retaining the FcRn binding allowing for an extended half-life and thereby, enabling dosing convenience. ABBV-383 monotherapy has shown promising activity and improved CRS safety profile with modified dexamethasone (Dex) premedication in patients (pts) with RRMM (NCT03933735; Rodriguez et al., JCO 2024;42[suppl 16]:7531). Here, ER and CRS PK/PD analyses supporting the selection of optimal SUD for ABBV-383 are reported. Methods ER-efficacy (N=286) and -safety (N=290) analyses were conducted using logistic regression methodology (R version 4.3.2) combining data from escalation (0.025-120 mg Q3W) and expansion (20, 40, 60 mg Q3W and 60 mg Q4W) cohorts of phase 1 study NCT03933735 and Arm A of phase 1b study NCT05650632 evaluating step-up dose (2 or 4 mg on Day 1) with a full dose (60 mg on Day 4) in pts with RRMM. Pts received modified Dex with full dose in expansion cohorts of 60 mg Q4W and 2/60 mg Q4W. In all other cohorts with or without SUD, pts received low Dex. Based on prior knowledge (JCO 2024;42[suppl 16]:7541), the safety endpoints (CRS: any-grade and ≥ G2) were modeled with Cycle 1 total (unbound + bound to soluble BCMA) Cmax, while objective response rate (ORR) was modeled with free (unbound + partially bound to soluble BCMA) Cavg. CRS ER models included a priori selected Dex (low vs. modified) and SUD (yes vs. no) as predictors. Relevant pt-specific covariates were tested in all models. CRS PK/PD analyses included total PK, IL-6, and CRS data (N=199) from the first 3 cycles of the above phase 1/1b studies. A semi-mechanistic indirect response PK/IL-6 model was developed to correlate total PK and IL-6 (NONMEM 7.5). Maximal IL-6 concentrations were derived using post hoc estimates from the PK/IL-6 model and correlated with CRS events (logistic regression; R version 4.3.2). The models included effects of time-dependent Dex (low vs. modified) and SUD (yes vs. no). The overall modeling approach was assessed by comparing observed and predicted CRS rates. Simulations were conducted for various dosing regimens, including one or two SUD and Dex premedication scenarios to support the selection of the optimal SUD. Results Consistent with clinical observations (separate abstract submission), any-grade CRS model predicted probabilities suggested two key outcomes: 1) premedication with modified Dex improves the CRS safety profile compared to the low Dex (42% vs 69% for 60 mg Q4W); 2) modified Dex with SUD further improves the CRS safety profile of ABBV-383 compared to low Dex with SUD (29% vs 43% for 2/60 mg Q4W). Consistent with prior work, no ER relationship was observed for ≥ G2 CRS (p > 0.05). The ORR model resulted in a predicted probability of 68% ORR (closely matching with overall observed 64% ORR) with no impact of SUD and modified Dex. Only soluble BCMA was selected as a covariate in the ORR ER model. The final semi-mechanistic PK/IL-6 model well captured the observed IL-6 data, and the CRS rates (predicted by the logistic regression models) closely matched with the observed data. The CRS PK/PD analyses findings were consistent with the clinical observations and ER analyses key outcomes 1 and 2. The CRS PK/PD analyses predictions comparing the 1-SUD vs 2-SUD (untested) regimens with modified Dex suggested that 1) among the 2-SUD regimens with modified Dex, the 2/3/60 mg regimen would have the maximum reduction of 4% points in any-grade CRS compared to the 2/60 mg 1-SUD regimen, however, with substantial overlap of confidence intervals and with no decrease in ≥ G2 CRS (< 0.5% point); 2) 4 mg as an intermediate SUD in a 2-SUD regimen would lead to higher any-grade and ≥ G2 CRS rates (~9% and 3% points higher, respectively), compared to the 2/60 mg Q4W regimen. Conclusions ER and CRS PK/PD analyses suggested that modified Dex and SUD improve the CRS safety profile of ABBV-383 with no impact on efficacy (ORR) in pts with RRMM. The CRS PK/PD predictions indicated that implementation of 2-SUDs provide minimal additional or no improvement in CRS safety profile compared to 1-SUD. Overall, the 1-SUD dosing regimen of 2 mg with modified premedication prior to the full dose of 60 mg Q4W showed promising results and can be considered for future evaluation and studies.

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.

7541 Background: ABBV-383 is a fully human, B-cell maturation antigen (BCMA) × CD3 T-cell–engaging IgG4 bispecific with an effector-silenced Fc region, 2 high-affinity BCMA- and a low-affinity CD3-binding domains. ABBV-383 monotherapy has shown promising activity in patients (pts) with RRMM (Blood 2023;142[suppl 1]:3378). Here, exposure-response (ER) analyses of efficacy and safety endpoints supporting the optimal therapeutic ABBV-383 dose selection are reported in alignment with US FDA’s Project Optimus. Methods: Efficacy (n=218) and safety (n=220) data from the phase 1 study (NCT03933735) escalation cohorts of 0.025 - 120 mg Q3W and expansion cohorts of 20, 40, 60 mg Q3W and 60 mg Q4W including objective response rate (ORR), very good partial response or better (≥VGPR), stringent complete response (sCR)/CR, adverse events (≥G3 and serious), infections (≥G3, overall and serious), cytokine release syndrome (CRS; any-grade, G1, G2, and ≥G2) were modeled. Total(unbound + bound to soluble BCMA) and free (unbound + partially bound to soluble BCMA) Cycle 1 AUCinf, Cmax, and Ctrough and population pharmacokinetic model-derived up to the time of event Cavg and avgCtrough metrics were utilized in the ER analyses (logistic regression; R Version 4.2.2). Relevant pt-specific covariates were tested. Dexamethasone premedication (36 vs 10 mg) was included in CRS models. The ER relationships were utilized to predict the probabilities of efficacy and safety endpoints for relevant doses and thereby, support justification of the optimal therapeutic dose selection. Results: Based on overall assessment, ORR, ≥VGPR, sCR/CR and ≥G3 neutropenia strongly correlated with free Cavg; CRS endpoints (any-grade CRS and G1 only CRS) strongly correlated with Cycle 1 total Cmax (p <0.05). No other endpoints had ER relationships (p >0.05). Only MM type (IgG vs Others) was selected in ≥VGPR and sCR/CR models. ER relationships suggested high response rates of >63% ORR, >53% ≥VGPR, and ≥30% sCR/CR for 40, 60 mg Q3W and 60 mg Q4W. Predictions demonstrated that 20 mg Q3W (<39% ORR and ≥VGPR; <13% sCR/CR) and untested 40 mg Q4W (<60% ORR, <45% ≥VGPR and <23% sCR/CR) provide suboptimal efficacy. The 60 mg Q4W with 36 mg dexamethasone in Cycle1 (limited follow-up and data) was predicted to have ~30% sCR/CR and 31% ≥G3 neutropenia (≈ 40 mg Q3W) and substantially lower any-grade CRS events compared with 40 and 60 mg doses with 10 mg dexamethasone in Cycle 1. Conclusions: While ER analyses indicated promising efficacy and acceptable safety profiles for 40, 60 mg Q3W, and 60 mg Q4W, they support 60 mg Q4W as the optimal ABBV-383 therapeutic dose due to its predicted better therapeutic benefit/risk profile (high response rates, improved/equivalent ≥G3 neutropenia, and lower CRS events) and extended dosing interval. ABBV-383 at 60 mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM.

7532 Background: ABBV-383 is a BCMA x CD3 bispecific antibody with 2 high-affinity BCMA-binding domains and a low-affinity CD3 engaging arm that has been shown to decrease the negative impact of soluble BCMA (sBCMA) and drive sustained T-cell activation with reduced cytokine release in preclinical models of MM. Here, we describe correlative biomarker results of baseline and longitudinal sBCMA levels and immune profiles in the ongoing first-in-human trial that supports 60 mg Q4W as the optimal therapeutic dose of ABBV-383 monotherapy. Methods: Peripheral blood and serum samples from patients with RRMM enrolled in the phase 1 open-label, dose-expansion study (NCT03933735) who received ABBV-383 at 20, 40, or 60 mg Q3W or 60 mg Q4W were collected at baseline (post-dexamethasone, pre–ABBV-383), on treatment, and at disease progression. Samples were analyzed by flow cytometry for immune cell populations, Luminex for cytokines, and electrochemiluminescence ligand binding for sBCMA. Results: Median sBCMA levels at baseline were highly variable among patients, but did not associate with clinical response (≥ partial response [PR]) to ABBV-383 at the selected optimal dose level of 60 mg Q4W (<PR: 244.7 ng/mL; ≥PR: 52.2 ng/mL; P=0.13). Reduction in sBCMA levels over time associated with clinical response (Cmin at cycle 5: <PR, 244.7 ng/mL; ≥PR, 4.7 ng/mL; P=0.04). ABBV-383 treatment led to a rapid and transient increase of proinflammatory cytokines, including IL-6, IL-8, IL-10, TNF-α (Cmax within cycle 1: 29, 349.5, 1375, 456.5 pg/mL, respectively), and promoted T-cell redistribution (89% reduction of CD8+ T cells from periphery), activation (1.9-fold increase in CD69+CD8+ T cells), and proliferation (2-fold increase in Ki67+CD8+ T cells) within cycle 1 in 60-mg Q4W-treated patients. The frequency of baseline CD8+ T-cell exhaustion (PD-1/TIM3) did not impact clinical response at the optimal dose level of 60 mg Q4W ABBV-383 (<PR: 3.5%; ≥PR: 3.9%; P=0.9). Peak induction levels of proinflammatory cytokines during cycle 1 correlated with occurrence of cytokine release syndrome (≥G1) as well as clinical response across dose levels. Conclusions: High-avidity BCMA binding coupled to low-affinity T-cell engagement distinguishes the resulting mechanism of action for ABBV-383. Responses to 60 mg Q4W ABBV-383 were independent of baseline sBCMA levels and resulted in rapid and transient proinflammatory cytokine production that promoted robust T-cell redistribution, activation, and proliferation, indicating that the optimal dose of ABBV-383 maximizes its clinical potential as a convenient, safe, and effective therapy for MM. Clinical trial information: NCT03933735 .

7531 Background: MM eventually becomes refractory to current treatments, and new therapeutic options with convenient dosing and improved safety are needed to enhance patient (pt) adherence, access, and outcomes. ABBV-383 is a distinctive next-generation BCMA x CD3 bispecific antibody composed of 2 high-affinity BCMA-binding domains, a low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS) risk, and a silenced Fc tail for an extended half-life allowing convenient dosing. ABBV-383 monotherapy has shown promising activity in the ongoing first-in-human phase 1 trial in RRMM (Vij et al. Blood 2023;142[suppl 1]:3378). Here, safety and efficacy results are reported that support the RP2D of 60mg Q4W as the optimal therapeutic ABBV-383 monotherapy dose. Methods: This phase 1 open-label, dose-escalation/expansion trial (NCT03933735) enrolled pts with RRMM who received ≥3 prior lines of therapy with exposure to PI, IMiD, and anti-CD38 mAb. ABBV-383 regimens explored in the expansion phase included 60mg Q4W and 40 or 60mg Q3W. A modified dexamethasone premedication schedule and shortened CRS monitoring period were implemented in the 60mg Q4W cohort for cycle 1. IV ABBV-383 was administered as a flat dose with no step-up schedule. Treatment was continued until disease progression/unacceptable toxicity. Primary objectives were to assess safety, tolerability, PK, PD, and determine the RP2D. Efficacy evaluation was a secondary objective. TEAEs were assessed per CTCAE v5.0 and tumor response per IMWG 2016 criteria. Results: As of May 2023, 220 pts received ABBV-383 (median age: 68 yr [35–92]; median prior therapy lines: 5 [3‒23]). Median FU was 4.1 mo (0.8–5.2) at 60mg Q4W (n=21), 12.2 mo (1.3–34.4) at 40mg Q3W (n=55), and 24.2 mo (0.6–33.4) at 60mg Q3W (n=61). At 60mg Q4W, with the modified premedication regimen, CRS was reported in 43% of pts (38% G1, 5% G2), and ICANS in 5% of pts (G2). In Q3W cohorts, CRS was reported in 71% (40mg; 45% G1, 25% G2) and 70% (60mg; 51% G1, 18% G2, 2% G3) of pts. The incidence of G3/4 neutropenia, anemia, and thrombocytopenia was 14/24/10% at 60mg Q4W, 31/31/16% at 40mg Q3W, and 34/13/13% at 60mg Q3W. G3/4 infections occurred in 10/24/34% of pts at 60mg Q4W, 40mg and 60mg Q3W, respectively. ORR and ≥VGPR were 65/50% at 60mg Q4W, 64/53% at 40mg Q3W, and 60/52% at 60mg Q3W. Corresponding exposure-response (ER) analyses and correlative analyses further supported RP2D determination (separate abstract submissions). Conclusions: The optimal therapeutic dose of 60mg Q4W ABBV-383 monotherapy was selected on the basis of safety, efficacy, and ER analyses. The extended interval of Q4W, with a shortened CRS monitoring period in cycle 1 and no step-up dosing, will improve convenience and reduce the treatment burden for pts. ABBV-383 at 60mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM. Clinical trial information: NCT03933735 .