Korde, Neha

Abstract Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma. To comprehensively investigate somatic drivers in relation to inherited genetics in multiple myeloma, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing multiple myeloma between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiologic data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop multiple myeloma at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes. Significance: Multiple myeloma is reported to occur at higher rates in individuals who self-identify as non-Hispanic Black. In this large dataset, genomic drivers occur at the same rate among ancestry groups, except for APOBEC mutagenesis. With equivalent therapy, clinical outcomes did not differ for patients grouped by genetic ancestry similarity.

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.

Abstract Consumption of a Western diet and high body mass index (BMI) are risk factors for progression from premalignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (HFPBD; meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible and improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease progression trajectory improved (n = 2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma precursor state, in which a high-fiber diet (HFD) delayed disease progression through improved metabolism and microbiome composition, leading to increased short-chain fatty acid production that reinvigorated antitumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A HFD is a low-risk intervention that may delay progression to myeloma. Significance: A HFPBD in participants with precursor plasma cell disorders and an elevated BMI improved metabolic, microbiome, and immune biomarkers of disease. In a subset, it may delay progression to myeloma. In mouse models, a HFD delayed progression to myeloma independent of calorie restriction. See related commentary by Fairfield and Reagan, p. 623

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 Poor diet quality, elevated body mass index (BMI), insulin resistance, microbiome dysbiosis, inflammation as well as immune dysfunction have all been implicated in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to multiple myeloma (MM). Plant-based diets have been associated with reduced risk of MGUS and MM in epidemiological studies. Whether a dietary intervention can impact these modifiable risk factors and delay disease progression has not been investigated. Methods We conducted a pilot, single-arm trial providing controlled high fiber plant based dietary (HFPBD) intervention for 12 weeks and health coaching for 24 weeks in 20 patients with MGUS/SMM with BMI≥25 (NCT04920084). The primary endpoint was feasibility (adherence and BMI reduction). Secondary and exploratory endpoints included quality of life, metabolic markers (insulin, adiponectin, leptin, LDL cholesterol), microbiome (diversity and composition by 16S and shotgun sequencing) and immune profiling in peripheral blood (flow cytometry and Olink inflammation panel) and bone marrow (scRNAseq and ATACseq). We also conducted an in vivo study in transgenic Vk*MYC mice fed a high fiber or control diet at the phase of mouse(m)SMM. The mice were monitored for the progression to active mMM. Differences in microbiome and immune response profiles between high fiber- and control-treated mice were assessed via microbiome 16S sequencing and flow cytometry. Results The HFPBD intervention was safe, feasible, improved quality of life and addressed modifiable risk factors - metabolic profile (improved BMI, insulin resistance, adiponectin leptin ratio), microbiome profile (increased alpha-diversity and butyrate producers) and immune (decreased inflammation and increased anti-inflammatory classical monocyte) subsets. A reduction in long-term progression trajectory was observed in 2 patients. Consistently, the high fiber diet delayed progression from mSMM to mMM in Vk*MYC mice increasing median progression-free survival from 12 weeks in the control arm to 30 weeks in the high fiber diet intervention arm. Additionally, in the intervention arm 40% of mice did not progress to mMM during the study period whereas all mice in the control arm progressed. Both human and mouse data showed that HFPBD modulated gut microbiota composition favoring the expansion of butyrate-producing bacteria. Additionally, short-chain fatty acids were increased in the feces of mice fed a high fiber diet. Integrated analysis from human bone marrow and peripheral blood analysis indicated that the dietary intervention reduced inflammatory biomarkers and skewed the immune response towards T helper and CD14+ monocytes. Consistently, the bone marrow of Vk*MYC mice fed high fiber diet was more infiltrated by IFNg-producing T lymphocytes while displaying less exhausted T cells and immunosuppressive myeloid cells. Conclusion This is the first interventional clinical trial and in vivo study to show that a HFPBD intervention may delay progression from MGUS/SMM to MM. To our knowledge there has been no similar dietary interventional study in hematological cancers or solid tumors. Together our in vivo and clinical data support the beneficial anti-inflammatory role of a HFPBD providing a link between diet, microbiota, and immune modulation to delay disease progression in MGUS/SMM.

Introduction The pathogenic role of somatic non-coding (nc) single nucleotide variants (SNVs) is underexplored in multiple myeloma (MM) and additional characterization of these regions has the potential to provide significant new insights into disease progression. To investigate the role of ncSNVs and their relationship with MM pathogenesis, we have characterized a novel series of WGS from 294 cases of MGUS, SMM, and MM using computational tools optimized to identify functional driver SNVs in these regions. We hypothesize the ncSNVs that co-localize to sites of super-enhancers (SEs) active in plasma cells (PC) are sites of high functional impact SNVs and these mutations lead to the dysregulated expression of genes that should be silent at the terminally differentiated stage of PCs, providing a selective advantage that shapes the fitness of the MM genomic landscape. Methods We analyzed 294 high-coverage matched tumor/normal pairs (80x tumor and 40x normal) derived from 21 MGUS, 86 SMM, 167 NDMM and 40 RRMM. In addition to previously sequenced samples, newly sequenced patients were obtained from NYU Langone Health, Memorial Sloan Kettering Cancer Center, University of Alabama at Birmingham and University of Miami following IRB-approved informed consent. DNA was extracted from CD138+ purified bone marrow plasma cells using standard approaches. We used the MGP1000 (https://github.com/pblaney/mgp1000) to process sequencing data which employs a union-consensus mechanism for determining the final set of variants. We collected enhancer elements (E/SEs) active in GC B-cells, ABC-DLBCL and GBC-DLBCL (Bal, et al. Nature, 2022) and PC specific E/SEs (Loven, et al. Cell 2013). FunSeq2 was used to score ncSNVs. GRAM was used to predict how variants alter TF binding and gene expression in a subset of 6 cases with paired WGS in our series and will expand this analysis on a validation set of 263 NDMM and 93 RRMM cases from University-Hospital Heidelberg enrolled in the GMMG-HD6 clinical trial. Results We identified 1,952,232 high-quality SNVs with 18,199 (0.93%) accumulating in 280 focal sites we termed “mutationally enriched regions” or MERs. To discern SNVs in MERs with the highest potential for imparting a selective advantage, we clustered mutations based on the density of FunSeq2 impact scores which uses reference data contexts on sequence conservation, modification of transcription factor (TF) binding, and gene linkage to regulatory elements and network hubs from pan-cancer studies. We show that MERs are enriched for ncSNVs with high impact scores (mean=2.57) compared to random similarly-sized regions of the genome (Fisher's exact test P<9.7e-12, OR=10.10 [3.88-37.40]). The high impact ncSNVs (hi-ncSNVs) in MERs (n=220) account for 8.09% of all hi-ncSNVs and are present in 46.3% of cases (136/294) with some patients having up to 7. The proportion of cases carrying a MER hi-ncSNVs was similar across disease stages (MGUS=42.9%, SMM=46.5%, MM=40.7%, and RR=47.5%). Analysis of the VAF of MER hi-ncSNVs shows a minor shift towards more clonal versus subclonal mutations (53.6% vs 46.4% VAF>=0.25) suggesting some high impact mutations are acquired in the GC but additional hi-ncSNV are acquired later in PC development, providing evidence that hi-ncSNVs accumulate in MERs throughout disease progression. We mapped these hi-ncSNVs to associated genes then intersected the loci with E/SEs active in GCBs and PCs to determine their functional context. This approach identified 12 genes affected by hi-ncSNVs including the previously identified nc-drivers NEAT1, MIR142, ZCCHC7, and IGLL5 as well as the PC differentiation genes IRF8, BACH2, proliferation genes RHOH, SPRED2, known coding MM drivers CCND1, ZFP36L1, and chr1q genes BTG2 and CROCC. We predicted the effect of ncSNVs on expression through modulation of TF binding at this set of putative nc drivers in MM and identified a trend towards increase in expression of SPRED2, CCND1, NEAT1, and IGLL5 compared to non-mutated cases (P=0.089). We will present data on the validation of this set of genes on a larger set of data derived from the Heidelberg group. Conclusions We identified a set of 12 putative nc driver genes in MM that modify expression and have the potential to significantly alter the pathogenesis of MM by providing a selective survival advantage. We will present the impact of these by clinical stage and on outcome.

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.

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 .