Chung, Alfred

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)

Background: Despite recent major advances, multiple myeloma (MM) remains incurable using therapies that are currently available to patients. There are no available/approved targeted therapies for MM that allow for individualized therapeutic approaches to the disease. Fifteen to 20% of newly diagnosed MM patients have a translocation of chromosomes 4 and 14 [t(4;14)]. This translocation puts transcription of the gene encoding Multiple Myeloma SET domain-containing protein (MMSET or NSD2), a histone 3 lysine 36 methyltransferase, under the control of the IgH super enhancer. The super enhancer drives the overexpression of MMSET resulting in an abnormal histone code that promotes myelomagenesis. Presence of t(4;14) is associated with poor clinical prognosis (Caro Am Soc Clin Oncol Educ Book 2021). KTX-1001 is a first-in-class, selective and potent small molecule inhibitor of MMSET, and is the first investigational drug that targets the t(4;14) MM patient population. Methods: This Phase 1, first-in-human open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001 in relapsed/refractory MM (RRMM) and has two parts: dose escalation (Part A) and dose expansion (Part B). In Part B, only t(4;14)+ MM patients will be evaluated in single agent and combination expansion cohorts. Patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody are eligible for the dose escalation part. The primary objective of the study is to determine a recommended phase 2 dose (RP2D) and schedule of KTX-1001. Secondary and exploratory objectives include pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of KTX-1001, and assessment of preliminary efficacy. KTX-1001 is administered orally until disease progression, unacceptable toxicity, or patient withdrawal from the study. A Safety Review Committee (SRC) reviews all data prior to each dose escalation decision and on a regular basis. Results: As of June 14, 2024, 17 patients (pts) have been treated with KTX-1001 in Part A across 6 dose levels (SRC reviewed). Dose Level 7 has been reached with no dose limiting toxicities (DLTs). Ten of these patients are t(4;14) positive. Patients have received a median of 5 prior lines of therapy (range: 3-17), including 7 pts with prior BCMA CAR-T, 6 pts with prior BCMA bispecific and/or ADC, 5 pts with prior non-BCMA bispecific, and 12 pts with prior transplant. Patient demographics include a median age of 68 years (range: 50-83), 10 male/ 7 female, 13 white, 2 black or African American, 2 as other identified race, and 3 Hispanic or Latino pts. Six pts remain on treatment. KTX-1001 shows excellent tolerability to date, with treatment emergent AEs (TEAEs) (CTCAEv5.0) predominantly of grade 1 and 2 severity. Most frequently observed TEAEs suspected to be related to KTX-1001 include fatigue (35%), diarrhea (24%), and constipation (24%), for which no grade 3 or 4 events have been observed. Frequency and/or severity of TEAEs have not increased with escalating doses nor treatment duration, and no patients have discontinued due to an AE. Two heavily pre-treated patients [one known to be t(4;14)+] have demonstrated long-lasting stable disease and clinical benefit at 10 and 7 months respectively. Both patients have been intra-patient dose escalated. For PK and PD data collected to date, drug exposure and steady-state concentration of KTX-1001 (at C1D15, when steady state concentration has been reached) appear to be dose-proportional. PD data indicate a dose-dependent decrease in the H3K36me2 mark on treatment versus baseline across dose levels 1 through 6, suggesting that the RP2D may be reached by year end. Updated results will be presented at the congress. Conclusions: Dose escalation of KTX-1001 is ongoing with an excellent tolerability profile to date and demonstration of on-target pharmacodynamics that will inform the determination of the RP2D(s). These PD data support the targeted mechanism of action of KTX-1001 to selectively inhibit MMSET and break the t(4;14) histone code. Given KTX-1001's promising safety profile, single-agent and combination expansion cohorts with standard-of-care MM agents/classes will begin in 2025 to further optimize doses and provide proof of concept in Part B of the Phase 1 study.

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 .

Background ABBV-383 is an off-the-shelf, fully human B-cell maturation antigen (BMCA) X CD3 bispecific antibody with bivalent BCMA domain and low CD3 affinity that targets both BCMA-expressing multiple myeloma (MM) cells and CD3-expressing T cells. ABBV-383 has shown promising activity in an ongoing phase 1 study in patients (pts) with relapsed/refractory (RR) MM ( Voorhees et al. ASH 2022; Weisel et al. EHA 2023). Here, we report the safety and efficacy results from the ABBV-383 IV Q3W at 20 mg, 40 mg and 60 mg dose levels. Methods The phase 1 dose escalation (ESC) and expansion (EXP) study (NCT03933735) of ABBV-383 enrolled pts with RRMM with ≥3 prior lines of therapy (LOT), including a PI, IMiD, and an anti-CD38 mAb with no prior BCMA exposure. After exploring 14 dose levels in dose ESC, 3 dose levels were further explored in dose EXP including ABBV-383 Q3W IV 20 mg, 40 mg, and 60 mg, until disease progression/unacceptable toxicity. The primary objectives were to determine safety/tolerability, PK/PD, and RP2D. The secondary objective was to evaluate clinical activity. Responses were investigator assessed per IMWG 2016 criteria and adverse events (AEs) by CTCAE v5.0. Results As of 17May2023, 220 pts were treated with ABBV-383, 73 pts in the dose ESC and 147 in the dose EXP with 32 pts at 20 mg, 55 pts at 40 mg, and 61 pts at 60 mg Q3W. Median duration of follow up was 7.1 (0.8-36.9), 12.2 (1.3-34.4) and 24.2 (0.6-33.4) months (mo) in the 20 mg, 40 mg and 60 mg dose levels with 25%, 36% and 21% pts continuing treatment (tx), respectively. Median age for all pts was 68 yrs (range, 35-92 yrs), Median prior LOT was 5 (range, 3-23), and 80% were triple-class refractory. Baseline characteristics are summarized in Table 1 by dose level. Treatment-emergent (TE) AEs were reported in 97% (78% ≥G3) of pts at 20 mg, 100% (84% ≥G3) of pts at 40 mg, and 100% (82% ≥G3) of pts at 60 mg. CRS, the most common TEAE, occurred in 50% (34% G1/13% G2/3% G3) of pts at 20 mg, 71%(45% G1/25% G2/0% ≥G3) of pts at 40 mg, and 70%(51% G1/18% G2/2% G3) of pts at 60mg. At the 3 dose levels, CRS occurring after the first dose had median time to onset of 1 day (range, 1-2) and median duration was 2 days (range, 1-10). ICANS occurred in 3% (3% G1/0% ≥G2) of pts at 20 mg, 5% (2 % G1/4% G2/0% ≥G3) of pts at 40 mg, and 5% (3% G2/2% G3) of pts at 60 mg. No G4/5 CRS or ICANS occurred. Infections occurred in 56% (25% ≥G3) of pts at 20 mg, 71% (26% ≥G3) of pts at 40 mg, and 57% (34% ≥G3) of pts at 60 mg; most frequently (≥10%) reported were upper respiratory tract infections (15%, G3/4 1%), pneumonia (14%, G3/4 12%), urinary tract infections (12%, G3/4 3%), and COVID-19 (11%, G3/4 1%). At 20 mg, 40 mg, and 60 mg, the incidence of neutropenia was 41% (25% ≥G3), 42% (31% ≥G3), and 43% (34% ≥G3); anemia 50% (25% ≥G3), 55% (31% ≥G3), and 38% (13% ≥G3); thrombocytopenia 44% (28% ≥G3), 36% (16% ≥G3) and 26% (13% ≥G3), respectively. The tx discontinuation due to AEs was 6%, 11%, 10% in 20 mg, 40 mg and 60 mg, respectively, with no single PT reported in &gt;2 pts. Clinical responses are shown in Figure 1. The median time to ≥VGPR was 0.7mo (0.7-5.8) at 20 mg, 1.0mo (0.7-10.4) at 40 mg, and 1.4 mo (0.7-7.8) at 60 mg. The median DOR was 9.7 mo (3.5-not reached (NR)) at 20 mg, and NR at 40 mg and 60 mg. The Kaplan-Meier (KM) estimates for DOR at 12 mo was 42% at 20 mg, 70% at 40 mg, 66% at 60 mg. The mPFS was 3.8 mo (2.4-7.9) at 20mg, 13.7mo (5.0-NR) at 40 mg, and 11.2 mo (4.8-NR) at 60 mg. The KM estimates for PFS at 12 mo was 19% at 20 mg, 51% at 40 mg, 49% at 60 mg. The median OS was 21.6 mo (7.9-NR) at 20 mg, and NR at 40 mg and 60 mg. ABBV-383 at 20 mg, 40 mg, and 60 mg led to rapid and transient production of key proinflammatory cytokines (IL-6, IL8, IFN-γ, and TNF-α), and reduction of soluble BCMA levels over time that were associated with disease response. ABBV-383 also promoted T-cell activation and proliferation with upregulation of CD69 and KI67 markers on peripheral CD4 and CD8 T cells in evaluable pts. Conclusions ABBV-383 showed a manageable safety profile at dosages of 20 mg, 40 mg, and 60 mg IV Q3W, with low incidence of TEAEs leading to discontinuation. Also, extended Q3W dosing interval with no step-up dosing schedule of ABBV-383 may provide enhanced convenience. However, 20 mg yielded numerically lower responses when compared to 40 mg and 60 mg. At 40 mg and 60 mg, ABBV-383 monotherapy yielded deep and durable responses with mPFS of 13.7 mo and 11.2 mo, and 12-month DOR of 70% and 66% (mDOR NR in pts with ≥CR), respectively. These results in heavily pretreated RRMM pts support further clinical evaluation.

Background: Despite the development and approval of effective therapies for multiple myeloma (MM), MM remains an incurable disease. Moreover, patients with high-risk cytogenetics, like translocation t(4;14), continue to have a poor prognosis compared to standard-risk patients. No novel agents have been approved specifically for this population. There remains an unmet need for precision therapies for MM that can target specific drivers of high-risk MM like t(4;14). Multiple myeloma SET domain-containing protein (MMSET) overexpression observed in 100% of patients with t(4;14) acts through the MMSET-H3K36me2 axis, which promotes malignant transformation through regulation of multiple oncogenic programs. KTX-1001, a methyl transferase inhibitor, is a novel, first-in-class, potent, oral, small molecule that inhibits MMSET and the methylation of lysine K36. KTX-1001 had favorable drug-like properties, demonstrated in vivo activity, and was well tolerated in non-clinical studies. Based on these data, KTX-1001 is now being studied in a Phase 1 dose escalation and expansion study in relapsed and refractory multiple myeloma (RRMM). Study Design and Methods: This multi-country, Phase 1, open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001. The study will also examine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and pharmacodynamics (PD). Part A of this trial includes an accelerated titration, followed by 3+3 dose escalation with backfill of cohorts for dose optimization prior to moving to Part B, which is an expansion phase at the RP2D (please see Figure 1 for study design schematic). The expansion phase will only include patients with t(4;14). KTX-1001 will be administered orally daily and given until disease progression, unacceptable toxicity, or withdrawal from the study. Estimated enrollment for Parts A and B will be approximately 60 patients. The study will enroll patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody. Patients must have measurable disease, be ≥18 years of age, have an Eastern Cooperative Oncology Group score of ≤2, and adequate bone marrow, liver, and kidney function. Key exclusion criteria include history of or current plasma cell leukemia, active central nervous system (CNS) disease, or active unstable cardiovascular function. The primary endpoints of safety and tolerability include incidence of dose-limiting toxicity (DLTs), treatment-emergent adverse events (AEs), and treatment-related AEs. Secondary endpoints include plasma concentrations of KTX-1001 and efficacy outcomes such as objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarker and pharmacodynamic assessments will also be performed. The sample size was not determined by formal statistical methods but will be sufficient to provide preliminary information on safety, PK, PD, and efficacy. Statistical analyses will be primarily descriptive. Conclusion: This Phase 1 study will evaluate a potential treatment for RRMM utilizing KTX-1001, which is a novel, first-in-class, potent, oral small-molecule MMSET inhibitor. The study is open and actively enrolling patients at centers in the United States, Spain, France, and Canada.