Optec: A Phase 2 Study to Evaluate Outpatient Administration of Teclistamab, a BCMA-Targeting Bispecific Antibody, in Patients with Multiple Myeloma

Abstract

Background: Teclistamab is the only approved BCMA×CD3 bispecific antibody with a personalized, weight-based dosing schedule for the treatment of triple-class exposed relapsed/refractory multiple myeloma (RRMM). It is FDA approved for patients (pts) of therapy (LOTs), including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. In the pivotal MajesTEC-1 study (Moreau et al NEJM 2022), teclistamab showed deep and durable responses and a manageable safety profile in heavily pretreated pts with RRMM who had limited treatment options. The incidence of all grade cytokine release syndrome (CRS) during the first 2 cycles was 70%. Most pts experienced CRS following step-up doses 1 (42%) or 2 (35%), or the initial treatment dose (24%); 33% of pts experienced recurrent CRS. Most CRS events were grade 1/2 and fully resolved without discontinuation or dose reduction of teclistamab. One (0.6%) case of grade 3 CRS occurred in a pt who pneumonia but resolved in 2 days. No grade 4 or 5 CRS occurred. Tocilizumab is a monoclonal antibody targeting the interleukin-6 receptor (IL-6R) which is used to manage CRS resulting from T-cell redirection therapy. Preclinical data indicate that inhibition of IL-6 signaling prior to teclistamab administration can prevent CRS development without impacting anti-tumor activity (Li et al Ann. Oncol. 2019). In MajesTEC-1, pts who received a single IV dose of tocilizumab before the first teclistamab step-up dose (n=23) showed a reduction in the incidence of all grades of CRS, compared with the overall study population (26% vs 72%). Currently, there are no data on the safety of administering the step-up doses of teclistamab in the outpatient (OP) setting, but OP step-up dosing may make teclistamab more accessible. Therefore, we seek to investigate whether the use of prophylactic tocilizumab can reduce the incidence and severity of CRS associated with teclistamab and allow safe OP administration of the step-up dosing. Methods: This single-arm, non-randomized, multicenter, prospective study (NCT05972135) will evaluate CRS incidence and severity after prophylactic tocilizumab in pts treated with teclistamab in the OP setting. A target of 50 participants will be enrolled with an initial PK/PD safety cohort (n=10). Objectives through end of study include recurrent CRS, grade ≥3 and any grade infections, neurotoxicity including ICANS, neutropenia, febrile neutropenia, and efficacy. Eligible pts are ≥18 years with a documented diagnosis of RRMM who have previously received ≥4 LOTs. Pts with rapidly progressing disease, central nervous system involvement, active infection, or contraindication to tocilizumab will be excluded from the trial. Prior to the treatment phase, pts will participate in a 28-day screening phase to determine study eligibility. During the treatment phase, a single dose of tocilizumab will be administered at 8 mg/kg IV, 2 to 4 hours prior to step-up dose 1 of teclistamab (Cycle 1 Day 1) in an outpatient setting (Figure 1). Teclistamab will then be administered at step-up doses of 0.06 mg/kg subcutaneously (SC) (Cycle 1 Day 1) and 0.3 mg/kg SC (Cycle 1 Days 3-5), followed by 1.5 mg/kg SC (Cycle 1 Day 8), with weekly administration for twelve 28-day cycles or until disease progression or unacceptable toxicity. Teclistamab may be reduced to 1.5 mg/kg SC every two weeks for participants who achieve partial response or better after 6 months of therapy. Safety evaluations will include physical examination, vital sign measurements, neurological examination, assessment of ECOG performance status, and clinical safety laboratory assessments. IVIG is recommended in pts with serum IgG <4 g/L. Follow-up of participants during the study will include monitoring for all adverse events, disease progression, and survival until end of study. By studying the feasibility and safety of administering the step-up dosing schedule in an outpatient setting, teclistamab may become more accessible to pts with RRMM and limited treatment options.