Evaluation of Safety, Tolerability, and Clinical Activity of Forimtamig-Based Combinations in Relapsed or Refractory Multiple Myeloma Patients

The primary objective of this study is to evaluate the **safety** and tolerability of forimtamig, administered either as a monotherapy or in combination, in participants with relapsed or refractory **multiple myeloma**. This is clinically relevant as it aims to determine the potential adverse effects and overall acceptability of forimtamig, which is crucial for ensuring patient safety and guiding future therapeutic use.

Secondary objectives include:

• To evaluate the preliminary anti-tumor activity of forimtamig, either alone or in combination, by assessing progression-free survival (PFS), duration of response (DoR) for participants achieving a partial response (PR) or better, time to first response, time to best response, and overall survival (OS).
• To characterize the pharmacokinetics (PK) of forimtamig when administered alone or in combination.
• To evaluate the immune response to forimtamig.

The clinical trial involves a total of **62 participants** diagnosed with **multiple myeloma (MM)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including a documented diagnosis of MM according to the International Myeloma Working Group (IMWG) diagnostic criteria and evidence of progressive disease. The trial includes individuals who have previously received therapy, including immunomodulatory drugs and proteasome inhibitors, and encompasses both anti-CD38 naïve and anti-CD38 exposed/refractory participants. The health status of participants is generally characterized by an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population also includes a vulnerable population, as indicated by the selection criteria. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as an open-label, randomized Phase Ib/II study to evaluate the **safety** and tolerability of **forimtamig**-based treatment combinations in participants with relapsed or refractory **multiple myeloma**. The trial aims to assess the preliminary anti-tumor activity of forimtamig, both as a monotherapy and in combination with other treatments, by measuring objective response rate (ORR), complete response (CR)/stringent complete response (sCR) rate, and the rate of very good partial response (VGPR) or better. The study is expected to conclude by June 2027, with recruitment having commenced in August 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a documented diagnosis of multiple myeloma, evidence of progressive disease, and prior treatment history. The trial will include multiple follow-up visits to monitor the incidence and severity of adverse events, as well as to evaluate the clinical efficacy of the treatment regimen. The end-of-study visit will finalize data collection and assess the overall outcomes of the trial.

The expected duration of participant involvement will vary depending on individual response to treatment and the occurrence of any adverse events. Conditions that may lead to early termination from the study include significant adverse reactions or disease progression that necessitates alternative therapeutic interventions. The primary endpoints of the trial include the incidence and severity of adverse events, as well as the ORR, CR/sCR rate, and VGPR rate. Secondary endpoints will assess progression-free survival, duration of response, time to first and best response, overall survival, and the presence of anti-drug antibodies.

The clinical trial involves the administration of several experimental and non-experimental treatments to evaluate their safety, tolerability, and clinical activity in participants with relapsed or refractory **multiple myeloma**. The experimental medication **Forimtamig** is administered in two forms: as a **solution for injection/infusion** and as a **concentrate for solution for injection**. The active substance, Forimtamig, is a protein-based compound. The administration route for the solution is via injection or infusion, and the dosing schedule is determined based on the study protocol. Participant compliance is monitored through regular assessments and documentation of administration.

**Actemra**, containing the active substance **Tocilizumab**, is provided as a **solution for infusion**. Tocilizumab is a protein-based compound, and the administration is conducted via infusion. The frequency and dosage are specified in the study protocol, and compliance is ensured through monitoring by the clinical trial team.

**Darzalex** 1800 mg, with the active substance **Daratumumab**, is administered as a **solution for injection**. Daratumumab is a protein-based compound, and the administration route is injection. The dosing schedule is outlined in the study protocol, and participant adherence is tracked through clinical assessments.

**Kyprolis** 30 mg, containing the active substance **Carfilzomib**, is provided as a **powder for solution for infusion**. Carfilzomib is a chemical compound, and the administration is performed via infusion. The dosage and frequency are determined by the study protocol, with compliance monitored by the clinical team.

**Diphenhydramine**, a first-generation antihistamine, is administered in **tablet** form. The active substance is a chemical compound, and the administration route is oral. The dosage and frequency are specified in the study protocol, and participant compliance is monitored through regular follow-ups.

**Dexamethasone**, a corticosteroid, is provided as an **oral solution**. The active substance is a chemical compound, and the administration route is oral. The dosing schedule is outlined in the study protocol, and adherence is tracked through clinical assessments.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)**, the rate of **Complete Response (CR)/Stringent Complete Response (sCR)**, and the rate of **Very Good Partial Response (VGPR) or better**. These endpoints will provide a measure of the preliminary anti-tumor activity of **forimtamig** when administered alone or in combination with other treatments in participants with relapsed or refractory multiple myeloma.

Secondary endpoints will further evaluate efficacy by measuring **Progression-Free Survival (PFS)**, **Duration of Response (DoR)** for participants achieving a partial response or better, **Time to First Response**, **Time to Best Response**, and **Overall Survival (OS)**. Additionally, the study will assess the serum concentrations and pharmacokinetic (PK) parameters of forimtamig, as well as the presence of anti-drug antibodies (ADAs) during the study.