Citations

Summary Chimeric antigen receptor T‐cell (CAR‐T) therapy and bispecific T‐cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR‐T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo‐HCT). Thirty‐three MM patients with prior allo‐HCT received CAR‐T ( n = 24) or BsAb ( n = 9) therapy. CAR‐T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR‐T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR‐T and 78% of BsAb recipients, while immune effector cell‐associated neurotoxicity syndrome (ICANS) was observed in three CAR‐T patients. Infections of grade ≥3 were reported in 50% of CAR‐T and 44% of BsAb recipients. No exacerbation of graft‐versus‐host disease occurred except in one BsAb recipient. CAR‐T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo‐HCT.

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.