Phase 3 Multicenter Randomized Open-Label Study of ABBV-383 Monotherapy Versus Standard Therapy in Relapsed/Refractory Multiple Myeloma Patients

The primary objective of this Phase 3, multicenter, randomized, open-label study is to evaluate the **efficacy**, safety, and tolerability of ABBV-383 administered as monotherapy in adult subjects with **Relapsed or Refractory Multiple Myeloma (RRMM)** who have received at least two prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb). This objective is clinically relevant as it aims to assess the potential of ABBV-383 to provide a new therapeutic option for patients with RRMM, a condition characterized by the recurrence or resistance to standard treatments, thereby addressing an unmet medical need in this patient population.

The clinical trial involves a total of **251 participants** diagnosed with **Relapsed or Refractory Multiple Myeloma (RRMM)**. The study population comprises adult individuals, both male and female, aged 18 years and older. Participants were selected based on their eligibility to receive the Investigator's choice of Standard Available Therapies (SAT) and must have received at least two prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb). The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating a relatively stable general health status. Participants are required to have measurable disease and meet specific laboratory parameters as outlined in the study protocol. Lifestyle considerations such as diet and physical activity are not specified, but participants must consent to a fresh pretreatment bone marrow tumor aspirate and biopsy or provide adequate archival bone marrow tumor tissue. The trial also permits subjects with known HIV, provided they have an undetectable viral load and can tolerate the study treatment. The selection process ensures a diverse and representative sample of the RRMM patient population, including vulnerable groups.

The clinical trial is designed to evaluate the efficacy, safety, and tolerability of **ABBV-383** as a monotherapy in adult subjects with relapsed or refractory multiple myeloma (RRMM) who have received at least two prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb). This is a Phase 3, multicenter, randomized, open-label study comparing **ABBV-383** with standard available therapies (SAT). The trial is expected to commence recruitment on July 22, 2024, and conclude by December 6, 2027.

Participants will be randomly assigned to receive either **ABBV-383** or one of the pre-specified SATs, based on the investigator's choice and local standard of care. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be adults aged 18 years or older, with a confirmed diagnosis of RRMM, and to have measurable disease as defined by specific laboratory parameters. Participants must also have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less.

The expected duration of participant involvement is up to 12 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoints of the trial are progression-free survival (PFS) and overall response rate (ORR), assessed according to the International Myeloma Working Group (IMWG) 2016 response criteria. Secondary endpoints include overall survival (OS), rate of very good partial response (VGPR) or better, and patient-reported outcomes (PROs) related to disease symptoms and quality of life.

The clinical trial involves the administration of several experimental and non-experimental medications to evaluate their efficacy, safety, and tolerability in subjects with relapsed or refractory multiple myeloma. The primary experimental medication is **ABBV-383**, a solution for infusion containing a human IgG4 monoclonal antibody against BCMA and CD3. This medication is administered intravenously, with a maximum treatment period of 12 months. The dosing schedule and specific dosage are determined by the study protocol, and participant compliance is monitored throughout the trial.

**Paracetamol** is used in two forms: as a tablet for oral use and as a solution for injection for intravenous use. Both forms are sourced locally by investigational sites. The maximum treatment period for paracetamol is 12 months, and it is categorized under anilides. The specific dosage and administration frequency are defined in the study protocol.

**Bortezomib** is provided as a powder for solution for injection, administered either intravenously or subcutaneously. It is classified as an antineoplastic agent and is sourced locally or provided by AbbVie. The treatment period is up to 12 months, with dosing details specified in the protocol.

**Diphenhydramine** is available as both a tablet for oral use and a solution for injection for intravenous use. It is categorized as an anti-histamine and is locally sourced. The treatment duration is 12 months, with administration details outlined in the study protocol.

**Elotuzumab** is administered as a powder for injection for intravenous use. It is an antineoplastic agent, sourced locally or provided by AbbVie, with a treatment period of up to 12 months. The dosing schedule is specified in the protocol.

**Pomalidomide** is provided as a hard capsule for oral use. It is of chemical origin and is sourced locally or provided by AbbVie. The treatment period is 12 months, with specific dosing and administration frequency detailed in the study protocol.

**Dexamethasone** is available as a tablet for oral use and as a solution for injection/infusion for intravenous use. It is classified under glucocorticoids and is sourced locally or provided by AbbVie. The treatment duration is 12 months, with dosing details specified in the protocol.

**Selinexor** is administered as a film-coated tablet for oral use. It is an antineoplastic agent, sourced locally or provided by AbbVie, with a treatment period of up to 12 months. The dosing schedule is outlined in the study protocol.

**Carfilzomib** is provided as a solution for infusion for intravenous use. It is an antineoplastic agent, sourced locally or provided by AbbVie, with a treatment period of 12 months. The specific dosage and administration frequency are defined in the study protocol.

The efficacy of the investigational product, ABBV-383, in the treatment of **Relapsed or Refractory Multiple Myeloma (RRMM)** will be assessed through a series of primary and secondary endpoints. The primary endpoints include Progression Free Survival (PFS) and Overall Response Rate (ORR), both evaluated according to the International Myeloma Working Group (IMWG) 2016 response criteria, as assessed by an Independent Review Committee (IRC). The ORR is defined as the sum of Partial Response (PR), Very Good Partial Response (VGPR), Complete Response (CR), and stringent Complete Response (sCR).

Secondary endpoints encompass a range of efficacy measures, including Overall Survival (OS), the rate of ≥VGPR and ≥CR, and the rate of Minimal Residual Disease (MRD) negativity with ≥CR, determined by Next-Generation Sequencing (NGS) using Adaptive Clonoseq at a 10^-5 threshold. Additional secondary endpoints include changes from baseline to 6 months in disease symptoms and physical functioning, as measured by the EORTC QLQ-MY20 and EORTC QLQ-C30, respectively. Time to response (TTR), Duration of Response (DoR), Time to Disease Progression (TTP), Time to Next Therapy (TTNT), Event-Free Survival (EFS), and Patient Reported Outcomes (PROs) are also evaluated. PROs will be assessed using various instruments, including PROMIS Fatigue SF 7a, PRO-CTCAE, and EQ-5D-5L, among others. The occurrence of skeletal-related events (SREs) will also be monitored, defined by events such as spinal cord compression, pathologic fracture, surgery to bone, or radiation to bone.