Polepally, Akshanth R.

ABSTRACT Myelofibrosis is characterized by perturbation of the JAK/STAT pathway and upregulation of anti‐apoptotic factors leading to myeloproliferation, bone marrow fibrosis (BMF), extramedullary hematopoiesis, splenomegaly, and cytopenias. Navitoclax, a potent oral B‐cell lymphoma (BCL)‐X L /BCL‐2 inhibitor, promotes apoptosis of malignant myelofibrosis cells. Herein, we present results of Cohort 3 of the Phase 2 REFINE study (NCT03222609), which evaluated efficacy and safety of navitoclax plus ruxolitinib in JAKi‐naïve patients with myelofibrosis. JAKi‐naïve patients with primary or secondary myelofibrosis (≥ 18 years with splenomegaly, DIPSS intermediate‐2 and high‐risk myelofibrosis, and ECOG 0–2) and platelet count > 100 × 10 9 /L were enrolled and treated with navitoclax 100 mg once daily (QD) or 200 mg QD according to platelet count (≤ 150 × 10 9 /L or > 150 × 10 9 /L, respectively). Ruxolitinib was given twice daily (dose per label). Primary endpoint: spleen volume reduction of ≥ 35% (SVR 35 ) at week 24. Secondary endpoints: ≥ 50% reduction in total symptom score (TSS 50 ) at week 24, change in grade of BMF, anemia response, and safety. Thirty‐two patients received ≥ 1 dose of navitoclax plus ruxolitinib. Median (range) duration of follow‐up was 44 months (5–58). 63% (20/32) of patients achieved SVR 35 at week 24; median (range) time to first SVR 35 was 12 weeks (11─48). Of 24 evaluable patients, 21% achieved ≥ 50% reduction in driver gene variant allele frequency (VAF). Of 27 evaluable patients, 11 (41%) achieved TSS 50 at week 24; median (range) time to first TSS 50 of 3 weeks (0─16). BMF improved from baseline by ≥ 1 grade in 13/27 patients (48%) at any time on study. Anemia response rates were 38% (5/13) for transfusion‐independent and 100% (2/2) for transfusion‐dependent patients. No bleeding events or deaths were attributed to navitoclax. These findings suggest navitoclax plus ruxolitinib has a tolerable safety profile and provides clinically meaningful improvements for JAKi‐naïve patients with myelofibrosis. Trial Registration NCT03222609.

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.

Introduction ABBV-383 is a fully human, silenced Fc region IgG4 monoclonal, BCMA × CD3 T-cell-engaging bispecific antibody with 2 BCMA-binding domains and a low-affinity CD3-binding domain. ABBV-383 has shown promising activity following intravenous (IV) infusion every three weeks (Q3W) as monotherapy in patients (pts) with RRMM in an ongoing phase 1 study (D'Souza A, et al. J Clin Oncol. 2022 Nov 1;40(31):3576-3586; Voorhees et al. Blood 2022;140[suppl 1]:4401). Herein, preliminary pharmacokinetic (PK) and immunogenicity results from Q3W regimens of this study and impact of soluble BCMA (sBCMA) on ABBV-383 PK are reported. Methods In the phase 1 study (NCT03933735), adult pts with RRMM, who were previously exposed to ≥3 prior multiple myeloma agents including ≥1 proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody, received Q3W IV infusion at doses 0.025 - 120 mg in escalation (ESC) phase, and at 20 mg, 40 mg, and 60 mg in expansion (EXP) phase. Serial blood samples for PK characterization were collected in cycles 1, 3, and 6 along with sparse/periodic samples throughout the study. Blood samples were also collected throughout the study to detect anti-drug antibodies (ADAs) for immunogenicity characterization and to determine sBCMA concentrations. Appropriate validated assays were used to determine ‘total’ (unbound and bound to sBCMA) and ‘free’ (unbound and partially bound to sBCMA) ABBV-383 serum concentrations, to detect/determine ADAs/titers, and to determine total sBCMA concentrations. ‘Total’ and ‘free’ ABBV-383 serum concentrations from cycles 1, 3, and 6 were used to calculate individual PK parameters (peak concentration [C max], trough concentration [C trough], area under the concentration-time curve [AUC], terminal phase elimination half-life [t 1/2], clearance [CL], and steady state volume of distribution [V ss]) using non-compartmental analysis in Phoenix WinNonlin Version 8.2. Immunogenicity was summarized using ADA/titer data. Impact of baseline/pre-dose sBCMA concentrations on ‘total’ and ‘free’ ABBV-383 PK parameters from cycles 1, 3, and 6 was explored. Results ‘Total’ and ‘free’ ABBV-383 intensive PK data (cycles 1, 3, and 6) were available from 169 and 157 pts, respectively, representing Q3W regimens in ESC and EXP cohorts and ADA data were available from 186 evaluable subjects. Preliminary PK results suggest that ‘total’ and ‘free’ ABBV-383 exhibited approximately dose-proportional PK between 5.4-120 mg Q3W. Estimated t 1/2 for ‘total’ and ‘free’ ABBV-383 ranged between 11-12 days and 8-11 days, respectively, with steady state achieved by cycle 4 in Q3W EXP cohorts. Estimated CL and V ss were consistent with those of a typical IgG4 antibody in humans. Across EXP Q3W regimens, accumulation (cycle 3 vs. cycle 1) was 30%-60% in C max and 60%-177% in C trough for ‘free’ and ‘total’ ABBV-383. ABBV-383 exposures (AUC tau and C trough) of ‘total’ ABBV-383 were 28-74% higher than those representing ‘free’ ABBV-383 among the EXP Q3W regimens with no/minimal observed differences in C max (≤21%). Higher sBCMA levels prior to treatment appeared to reduce ‘free’ ABBV-383 PK exposures with pronounced reduction at lower doses (e.g., 20 mg) and in cycle 1, however the effect diminished in later cycles (cycles 3 and 5). Preliminary assessment of immunogenicity indicated an ADA incidence of 3.8% (7/186) with low titers ranging between 11.7 and 187 titer units and no impact on PK. Conclusions ABBV-383 exhibited a PK profile with relatively long half-life and low incidence of immunogenicity. Overall, sBCMA impacted (reduced) the ‘free’ ABBV-383 (pharmacologically active component) PK exposures only, with pronounced effect at lower doses and the effect is consistent with understanding of treatment dependent sBCMA dynamics over time. Determination of both ‘total’ and ‘free’ ABBV-383 serum concentrations allowed to demonstrate such underlying impact of sBCMA on PK.

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 >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.

PURPOSE ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735 ) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. METHODS Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. RESULTS As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. CONCLUSION ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

Abstract Background Prognosis is poor for patients (pts) with relapsed/refractory multiple myeloma (RRMM; median overall survival: <1 year), indicating a clear need to identify agents with novel mechanisms of action. B-cell maturation antigen (BCMA) has recently emerged as a novel treatment target for MM due to its highly selective expression in plasma cells. TNB-383B, a BCMA x CD3 T-cell engaging bispecific antibody, was designed to overcome the toxicity limitations of existing BCMA therapies and has demonstrated promising results in an ongoing first-in-human phase 1 study in pts with RRMM (Rodriguez C, et al. Blood 2020;136[suppl 1]:43-44). Herein, we report the updated efficacy and safety outcomes of this phase 1 study. Methods This multicenter, phase 1, open-label, dose-escalation/expansion study (NCT03933735) enrolled pts with RRMM (≥3 prior lines of therapy that included a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody), estimated glomerular filtration rate ≥30 mL/min as calculated by the Modification of Diet in Renal Disease formula, and ECOG performance status ≤2. Prior BCMA-targeted therapy is prohibited. Primary objectives include safety/tolerability, pharmacokinetics (PK), and determination of recommended phase 2 dose (RP2D); secondary objectives include assessment of clinical activity (per IMWG criteria 2016). TNB-383B is administered intravenously over 1-2 hours every 3 weeks (Q3W) with the first dose administered inpatient. The study uses a 3+3 design with backfilling for dose and permits intrapatient dose escalation to highest safe dose. Dose expansion was initiated on selection of RP2D. Pts are treated until progression, unacceptable toxicity, or other discontinuation criteria are met. The efficacy-evaluable population includes all pts who received at least 1 dose of TNB-383B and have at least 1 postdose assessment. The safety population includes all pts who received at least 1 dose of study drug; adverse events (AEs) are graded according to NCI CTCAE v5.0. Results As of 10 May 2021, 103 pts (dose escalation, n=73; dose expansion, n=30) have been treated with TNB-383B (0.025-120 mg). The RP2D of 60 mg Q3W was selected on the basis of tolerability, safety, PK, and clinical activity. Pt demographics and baseline characteristics are summarized in Table 1. Three dose-limiting toxicities were reported in dose escalation (platelet count decreased: grade [Gr] 4, 60 mg; cytokine release syndrome [CRS]: Gr 3, 90 mg and 120 mg); none were reported as serious. Treatment-related AEs (TRAEs) were reported in 79 (77%) pts, with Gr ≥3 and serious AEs occurring in 33 (32%) and 23 (22%) pts, respectively. The most common TRAEs (Table 2) include CRS (n=54, 52%), neutropenia (n=18, 17%), and fatigue (n=14, 14%). At the RP2D (n=39), the Gr ≥3 CRS rate was 3% (n=1). Onset of CRS typically occurred on the same or next day following the first dose and all pts recovered using tocilizumab or standard supportive care measures. Treatment-emergent AEs (TEAEs) of infusion-related reactions were reported in 8 (8%) pts and infections occurred in 29 (28%) pts; pneumonia (n=5, 5%) and upper respiratory tract infection (n=4, 4%) were the most common. Five deaths from TEAEs were reported; all were unrelated to study drug. Forty-two (40%) pts discontinued treatment due to disease progression. In the dose-escalation cohorts of ≥40 mg Q3W (n=24), the objective response rate (ORR) was 79% (19/24), with a very good partial response or better (≥VGPR) rate of 63% (15/24), and a complete response (CR) rate of 29% (7/24) at the data cutoff date; these pts have the longest follow-up (ie, mature data) with median time on study of 6.1 months (Figure 1). At doses ≥40 mg in the combined dose-escalation and -expansion cohorts (n=44), the observed ORR, ≥VGPR, and CR rates were 64% (28/44), 43% (19/44), and 16% (7/44), respectively; these pts have shorter follow-up (ie, immature data) with median time on study of 3.1 months. Twenty-nine (66%) of the 44 pts administered ≥40 mg were triple-class refractory and reported an ORR of 55% (16/29). Conclusions TNB-383B in pts with RRMM is well tolerated with an ORR of 79% observed at doses ≥40 mg in the dose-escalation cohorts. Despite having a shorter follow-up period, this trend was also observed at doses ≥40 mg in the combined dose-escalation/expansion cohorts (ORR: 64%). Enrollment into the dose-expansion arm is ongoing; updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Kumar: Novartis: Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. D'Souza: Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Janssen, Prothena: Consultancy. Shah: Oncopeptides: Consultancy; Nektar: Research Funding; Poseida: Research Funding; Janssen: Research Funding; Indapta Therapeutics: Consultancy; GSK: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; CSL Behring: Consultancy; Teneobio: Research Funding; Kite: Consultancy; Sutro Biopharma: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy; Precision Biosciences: Research Funding; Sanofi: Consultancy. Rodriguez: Takeda: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau. Voorhees: AbbVie Inc, Bristol-Myers Squibb Company; Consulting Agreement: GlaxoSmithKline, Novartis, Oncopeptides: Other: Advisory Committee; Bristol-Myers Squibb Company.: Other: Data Safety & Monitoring. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Buelow: Teneobio, Inc.: Current Employment, Current holder of stock options in a privately-held company. Freise: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Yue: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Pothacamury: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Polepally: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria.