Dose Escalation and Expansion of Abbv-383 in Combination with Anti-Cancer Regimens in Relapsed or Refractory Multiple Myeloma

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow. Despite the more recent use of emerging therapies, patients will ultimately relapse with drug-resistant disease. Expected overall survival in patients with triple refractory disease is between 6–13 months. B-cell maturation antigen (BCMA) is a highly expressed protein on the surface of MM cells. ABBV-383 is a fully human bispecific antibody that targets BCMA and CD3, resulting in T-cell activation and selective destruction of BCMA-positive MM cells. Preliminary results from a Phase 1 trial of ABBV-383 in patients with triple-class exposed relapsed/refractory MM (RRMM) are highly encouraging and have shown a well-tolerated safety profile and an overall response rate (ORR) of 68%. The progression-free survival (PFS) estimate at 12 months was 58% (95% CI 45–69) for doses ≥40 mg, and most recently, the median duration of response (DOR) estimate was reported as 77% (95% CI 55–89) at 12 months for patients receiving 60 mg of ABBV-383. The most common adverse event (AE) was cytokine release syndrome (CRS). CRS events were mostly single Grade 1/2 events with median onset on Day 1 (after first dose of ABBV-383) and lasting 2 days; no events were life-threatening or fatal. Neutropenia (37%) and anemia (29%) were the most common hematological AEs. Preclinical data suggest that combining anti-BCMA therapy with current standard-of-care MM regimens may enhance overall treatment potency, supporting the hypothesis that combining ABBV-383 with current anti-MM regimens may increase the efficacy of ABBV-383. Aims: This open-label, multi-center, Phase 1b, dose-escalation and expansion study (NCT05259839) will evaluate the safety profile, tolerability, preliminary efficacy, pharmacokinetics and recommend Phase 2 dose of ABBV-383 in combination with pomalidomide-dexamethasone (Pd), lenalidomide-dexamethasone (Rd), daratumumab-dexamethasone (Dd) or nirogacestat (Niro) in patients with RRMM. Methods: Enrollment began in November 2022. Adults with RRMM, documented progression after last treatment (based on IMWG criteria), and an ECOG score ≤2 are eligible for enrollment across 45 centers globally. Patients must be naïve to BCMA-directed therapy. Dose escalation of ABBV-383 follows BOIN design with three planned dose levels. Treatment is administered intravenously on Day 1 of each cycle. Dose-limiting toxicities (DLT) are defined per protocol and will be evaluated for dose escalation decisions in cycle 1. Patients will receive treatment until documented progression, or other discontinuation criteria are met. Cytokine release and immune effector cell-associated neurotoxicity syndromes will be graded according to ASTCT 2019 guidelines. Other AEs will be graded according to the NCI Common Terminology Criteria for AEs v5. After the last dose of treatment, each patient will have survival follow up every 12 weeks for up to 12 months. The primary endpoint is DLT of ABBV-383 when given in combination with anti-myeloma regimens (Pd, Rd, or Dd) or Niro in patients with RRMM. Safety and tolerability of ABBV-383 will be assessed by evaluating AEs, physical examinations, and changes in laboratory data and vital signs, as well as drug discontinuation or dosing modification due to AEs. Pharmacokinetics will be evaluated for each combination cohort and compared against the historical monotherapy data. Efficacy endpoints include ORR, PFS, DOR, time to progression and minimal residual disease negativity. Results:Summary/Conclusion: Keywords: Phase I, Multiple myeloma, Dose escalation