Paper Details

ABSTRACT

Introduction: The cell-surface receptor B-cell maturation antigen (BCMA) is highly expressed on malignant plasma cells, and multiple approved agents against BCMA have demonstrated robust efficacy in relapsed or refractory multiple myeloma (RRMM), with improvements in efficacy when used in earlier lines of therapy (LoT). Nevertheless, an unmet need remains for innovative treatment that combines robust efficacy and favorable safety in patients with RRMM. Etentamig is being developed as a next-generation differentiated BCMA x CD3 bispecific T-cell engager (TCE), optimized for convenient monthly (Q4W) dosing from the start, and composed of a bivalent BCMA-binding domain with high avidity and a low-affinity CD3-binding domain, potentially reducing cytokine release syndrome (CRS) and infection rates. The combination of an immunomodulatory drug with BCMA-directed immunotherapies, including TCEs, such as etentamig, is biologically and clinically relevant. Preclinical data support combining etentamig with pomalidomide, enhancing T-cell and natural-killer cell function, increasing T helper 1 cytokines such as interleukin-2 and interferon-γ, and improving immune synapse formation, thereby strengthening antitumor immunity. In the Kilimanjaro study (NCT05259839), etentamig was assessed in combination with standard-of-care therapies including pomalidomide plus dexamethasone, demonstrating robust efficacy with an 82% overall response rate and a 56% complete response (CR) or better rate after median follow up of 23 months, in heavily pre-treated patients (median 4 prior LoT) with more than half of these being pomalidomide refractory. Consistent with prior favorable monotherapy safety data, the overall CRS rate was low (~20%) with only Grade 1/2 events after introduction of 1 step-up dose (SUD) in Arm E. Additionally, the dose optimization, including delayed pomalidomide start in Cycle 2 in Arm E, demonstrated a reduction in infection rates.

Aim: Here, we describe the trial in progress of etentamig in combination with pomalidomide versus standard available therapies (SATs) in patients with RRMM who received 1–3 prior LoT.

Methods: This is a global (NCT07728188), phase 3, multicenter, randomized, open-label study enrolling adult patients with RRMM who received 1–3 prior LoT, including lenalidomide; patients exposed to only 1 LoT must be lenalidomide-refractory. Patients must not be previously exposed to etentamig and pomalidomide; patients with prior BCMA exposure (antibody-drug conjugate or chimeric antigen receptor T-cell therapy only) and anti-CD38–directed treatment are allowed. The study will include a safety lead-in of ~20 patients to confirm the safety, tolerability, and pharmacokinetics of etentamig in combination with pomalidomide, and support the decision to advance the randomized portion. Following review of the safety lead-in data with a minimum follow-up for 2 treatment cycles for each patient enrolled, the randomized study will proceed if stopping rule thresholds are not met. Patients will be randomized 1:1 to receive etentamig plus pomalidomide (Arm 1) or investigator’s choice of 1 of the following SATs (Arm 2): daratumumab, pomalidomide, and dexamethasone (DPd); daratumumab, carfilzomib, and dexamethasone (DKd); or teclistamab monotherapy. Etentamig will be administered as monotherapy with 1 SUD in Cycle 1 and may be managed in an outpatient setting per institutional guidelines. Combination of Q4W subcutaneous etentamig with pomalidomide 4 mg (given per label) begins in Cycle 2 and will continue for up to 36 cycles or until disease progression or other criteria for discontinuation, whichever occurs first. SATs will be administered according to approved label. For the randomized portion, the dual primary endpoint includes ≥CR and progression-free survival, both as defined by International Myeloma Working Group 2016 response criteria per independent review committee. Key secondary endpoints include negative measurable residual disease (10⁻⁵ assessed by next-generation sequencing) with ≥CR rate at 12 months and overall survival.