A Phase 1/2, Open-Label, Platform Study to Evaluate Safety and Efficacy of the BCL-2 Inhibitor ABBV-453 given as Monotherapy or in Combination with Antimyeloma Regimens in Subjects with Multiple Myeloma

The primary objective of this study is to characterize the safety and tolerability of ABBV-453 monotherapy and/or in combination with antimyeloma agents in participants with multiple myeloma. This evaluation is clinically relevant for determining the acceptable toxicity profile and dose-limiting characteristics of the BCL-2 inhibitor ABBV-453 when administered alone or in combination regimens, which is essential for establishing its therapeutic viability in the treatment of multiple myeloma.

The secondary objectives include:

• To evaluate the preliminary antimyeloma activity of ABBV-453 monotherapy and/or in combination with antimyeloma agents in participants with multiple myeloma.

• To characterize the pharmacokinetic profile of ABBV-453 when given alone and/or in combination with antimyeloma agents in participants with multiple myeloma.

This clinical trial enrolled a total of **43 participants** diagnosed with **multiple myeloma**. The study population included both **male and female** adults and elderly individuals. All participants had a documented diagnosis of multiple myeloma based on standard International Myeloma Working Group diagnostic criteria. Participants were required to have **measurable disease** as determined by central laboratory assessment, defined by specific thresholds of serum M-protein, urine M-protein, or serum free light chain levels with an abnormal ratio. A key inclusion criterion was that participants must be treatment-naïve to **B-cell lymphoma-2 inhibitors**. The trial did not include vulnerable populations. The sponsor did not provide information regarding specific lifestyle considerations such as diet, physical activity, or habits of the participants.

This is a Phase 1/2, open-label, platform study designed to evaluate the safety and efficacy of the BCL-2 inhibitor ABBV-453 (surzetoclax) administered as monotherapy or in combination with antimyeloma regimens in participants with multiple myeloma. The study employs a platform design that allows for evaluation of multiple treatment combinations within a single protocol framework. The trial is not low-intervention and is categorized as a Phase 1/2 clinical investigation.

The primary objective is to characterize the safety and tolerability of ABBV-453 monotherapy and/or in combination with antimyeloma agents in participants with multiple myeloma. The investigational medicinal product surzetoclax is administered as a film-coated tablet via the oral route. Combination regimens include daratumumab administered via subcutaneous injection, dexamethasone administered orally as tablets, and pomalidomide administered orally as hard capsules. All participants must be BCL-2 inhibitor treatment naïve.

Key inclusion criteria require participants to have documented diagnosis of multiple myeloma based on standard International Myeloma Working Group diagnostic criteria. All participants must have measurable disease per central laboratory with at least one of the following assessed within 28 days prior to enrollment: serum M-protein ≥ 0.5 g/dL (≥ 5 g/L); urine M-protein ≥ 200 mg/24 hours; or for participants without measurable serum and urine M-protein, serum free light chain ≥ 10 mg/dL (100 mg/L), provided the serum free light chain ratio is abnormal.

The primary endpoints include assessment of dose limiting toxicities of ABBV-453 and evaluation of safety and tolerability through monitoring of adverse events, serious adverse events, clinical laboratory parameters, vital sign measurements, and electrocardiogram results. Secondary endpoints comprise Overall Response Rate, Progression-Free Survival, Duration of Response, Time-to-Progression, Time to Next Treatment, rate and depth of minimal residual disease negativity determined centrally, overall survival, and pharmacokinetic parameters including maximum concentration, time to maximum concentration, half-life, and area under the curve.

The estimated recruitment start date is December 15, 2025, with the estimated end date of May 30, 2029, resulting in an overall trial duration of approximately 42 months. The expected length of participant involvement will vary depending on individual response to treatment and disease progression. Conditions that may lead to early termination from the study include occurrence of dose limiting toxicities, unacceptable adverse events, disease progression, participant withdrawal of consent, or investigator decision based on safety concerns or protocol violations.

The experimental medicinal product Surzetoclax (ABBV-453) is administered as a film-coated tablet formulation containing surzetoclax as the active substance. Surzetoclax is a BCL-2 inhibitor of chemical origin. The medicinal product is administered via the oral route. Surzetoclax may be administered as monotherapy or in combination with antimyeloma regimens in participants with multiple myeloma.

Daratumumab is utilized as a combination treatment agent in this study. It is formulated as a solution for injection of biological/biotechnological origin, with daratumumab serving as the active substance characterized as a protein. The medicinal product is administered via the subcutaneous route.

Dexamethasone is employed as an antimyeloma agent in combination regimens. It is provided in tablet form as a chemical substance. Dexamethasone is administered via the oral route.

Pomalidomide is utilized as an additional antimyeloma combination agent. The medicinal product is formulated as a hard capsule containing pomalidomide as a chemical active substance. Administration is performed via oral use.

The primary efficacy endpoints include Overall Response Rate, Progression-Free Survival, Duration of Response, Time-to-Progression, Time to Next Treatment, Rate and Depth of minimal residual disease negativity determined centrally, and Overall Survival. Overall Response Rate will be evaluated to determine the proportion of participants achieving a response to treatment. Progression-Free Survival will be assessed to measure the time from treatment initiation until disease progression or death. Duration of Response will be analyzed to determine the length of time that participants maintain their response to therapy. Time-to-Progression will be measured to assess the interval from treatment start to documented disease progression. The rate and depth of minimal residual disease negativity will be determined centrally to evaluate the extent of disease eradication. Overall Survival will be monitored to assess the time from treatment initiation until death from any cause.