Surzetoclax (ABBV-453) in combination with daratumumab and dexamethasone in biomarker-selected patients with Relapsed/Refractory multiple myeloma: A Phase 1/2, multicenter, open-label platform study

Abstract Background and Significance: Multiple myeloma (MM) is a plasma cell malignancy with complex cytogenetic abnormalities that contribute to its clinical heterogeneity. Patients (pts) harboring the t(11;14) translocation represent a distinct MM subgroup and may have a clinical course that differs from pts who are t(11;14)-negative. Overexpression of the B-cell lymphoma (BCL)-2 protein, which helps MM cells evade apoptosis, is notable in t(11;14)-positive pts. Presence of the t(11;14) translocation, therefore, can be used to predict BCL2 dependency and vulnerability to BCL2 inhibitor (BCL2i) therapy. Emerging evidence suggests a synergistic effect if a BCL2i is combined with anti-CD38 monoclonal antibodies (such as daratumumab [Dara]), especially in pts with t(11;14)-positive status and/or BCL-2high expression. Venetoclax, a selective BCL2i, has shown efficacy in relapsed/refractory MM (RRMM) when combined with Dara plus dexamethasone (Dex). Surzetoclax (ABBV-453) is a next-generation oral BCL2i designed with macrocyclic elements to enhance its molecular and biological properties. Surzetoclax possesses sub-nM affinity for BCL2 and high selectivity over other family members, such as BCL-XL and MCL-1, which translates into potent cytotoxicity in human tumor cell lines dependent on BCL2 for survival. Using a master protocol platform design, surzetoclax is being studied in clinically diverse populations, in varying lines of therapy, and as monotherapy or in combination with various antimyeloma regimens (NCT06953960/2024-517140-65). Here we describe the methods of the surzetoclax plus Dara+Dex substudy in biomarker-selected pts with RRMM. Study Design and Methods: This study is part of a Phase 1/2 international, multicenter, open-label, platform trial assessing the safety, tolerability, preliminary anti-MM activity, and pharmacokinetic profile of surzetoclax in combination with other antimyeloma agents in pts with RRMM. The primary objective of this substudy is to determine the recommended Phase 2 dose of surzetoclax plus Dara+Dex in pts with RRMM. This substudy consists of dose escalation of surzetoclax with dosing adjustments guided by Bayesian Optimal Interval criteria, followed by dose expansion and selection. Eligible pts (≥18 years) with RRMM must have documented evidence of progression; centrally determined t(11:14) and/or BCL2high status; no prior BCL2i exposure; and no CAR-T or autologous/allogeneic stem cell transplant ≤12 weeks of treatment. Pts are ineligible if they are anti-CD38 intolerant, refractory within their last treatment regimen, or exposed to anti-CD38 therapy ≤6 months of study treatment initiation. In the dose-escalation cohorts, pts must be triple-class exposed (protease inhibitor [PI], immunomodulatory drugs [IMiD], anti-CD38) with 3–5 prior lines of therapy (PLoT) and no other appropriate treatment options available per investigator judgment. For dose-expansion cohorts, pts must be double class exposed (PI, IMiD) with 1–3 PLoT. During the dose-escalation phase, the optimal dose of surzetoclax will be explored to maximize therapeutic benefit and minimize treatment-related toxicity. Approximately 3–15 pts per cohort will be enrolled. During dose escalation, surzetoclax will be administered orally (PO) in combination with subcutaneous Dara and Dex PO. During the dose expansion and selection phase, 2 doses of surzetoclax plus Dara+Dex will be investigated in separate cohorts, with a comparator cohort of pomalidomide plus Dara+Dex. Pts will be randomized 1:1:1 with approximately 20 pts in each cohort. Safety assessments include adverse events (AEs), clinical laboratory parameters, vital signs, and physical examinations and will be evaluated during dose escalation and expansion/selection phases. Primary outcome measures include dose-limiting toxicities and number of participants with AEs. Secondary outcome measures include efficacy data (overall response rate, progression-free survival, duration of response, time to progression, time to next treatment, minimal residual disease negativity, and overall survival). This is the first study to evaluate surzetoclax, a next-generation BCL2i, in a combination regimen. The trial in progress reported herein reflects advances in novel therapies for RRMM, providing greater insight on surzetoclax and its potential to address key unmet needs for t(11;14)-positive and/or BCL2high pts with MM. Enrollment is ongoing at active sites in the United States, Australia, and Israel.