Etentamig plus pomalidomide-dexamethasone combination therapy in relapsed or refractory multiple myeloma: A phase 1b dose-escalation and safety expansion study Free

Introduction: Etentamig is a differentiated, 2^nd generation, B-cell maturation antigen (BCMA) x CD3 bispecific T-cell engager composed of a high avidity bivalent BCMA-binding domain, a low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS), and a silenced Fc tail for extended half-life, enabling convenient dosing (every 4 weeks [Q4W]). Long-term results from 2 ongoing Phase 1 studies evaluating efficacy and safety of etentamig in heavily pretreated patients (pts) with relapsed/refractory multiple myeloma (RRMM) demonstrate low incidence of CRS, durable response, and tolerability (NCT03933735/NCT05650632; Baljevic et al., 2025; DOI:10.1200/JCO.2025.43.16 suppl.7527). Preclinical data support combination with anti-myeloma regimens, including immunomodulatory (IMiD) agents to enhance etentamig activity. The current study evaluates the hypothesis that combining etentamig with pomalidomide plus dexamethasone (POM+DEX) is tolerable and results in enhanced anti-tumor activity in pts with RRMM.

Methods: TheKilimanjaro study (NCT05259839) isa multi-arm open-label, multi-center, Phase 1b, dose-escalation and -expansion study conducted in 7 countries. Key inclusion criteria included: adults (≥18 years) with an Eastern Cooperative Oncology Group performance status ≤2 and disease progression during or after the last treatment. Arm A evaluated etentamig in combination with POM+DEX in pts after ≥3 prior lines of therapy (LoT), including the IMiD lenalidomide, a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody (mAB). Pts received 20 mg or 40 mg etentamig Q4W without step-up in combination with 4 mg POM (given per label) and weekly 40 mg DEX. Responses were investigator assessed per International Myeloma Working Group 2016 criteria.

Results: As of April 11, 2025, 85 pts were enrolled and treated across the 20 mg and 40 mg etentamig doses in combination with POM+DEX. Median age (range) was 69 (33–88) years and 46 (54%) pts were male. Of pts, 73 (86%) were White, 7 (8%) were Asian, and 5 (6%) were Black/African American. International Staging System at study entry was I, II, or III in 26 (31%), 31 (37%), and 26 (31%) pts, respectively. Pts had received a median (range) of 4 (2–10) prior LoT, and 62 (73%) were triple-class refractory to an IMiD, a PI, and an anti-CD38 mAB. Forty-nine (58%) were exposed to POM in prior treatments with approximately half POM-refractory (42/85, 49%). At the data cutoff date, 50 (59%) pts remained on therapy.

Most common Grade 3/4 hematologic adverse events (AEs) were neutropenia (78%), anemia (28%), and thrombocytopenia (22%). CRS occurred in 31 (37%) pts after receiving etentamig target dose, with CRS events either Grade 1 (25%) or Grade 2 (12%) and no Grade ≥3 events. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 6 (7%) pts total; most ICANS events were Grade 1/2, except for 1 pt who experienced a Grade 3 event. Grade 3/4 infections were observed in 49% of pts, with the most common being pneumonia (17%). Two deaths were reported as possibly related to study treatment by investigator (influenza and worsening renal failure, both n=1). Majority of patients remain on study treatment; the most common reason for treatment discontinuation was disease progression (27%) followed by AE (11%).

At the time of data cutoff, 82 pts were evaluable for disease assessment with a median (range) follow-up of 18 (1–29) months. The aggregate overall response rate (ORR) and ≥very good partial response (VGPR) rate (95% CI) for the evaluable population was 81% (70%–88%) and 72% (61%–81%), respectively. Median progression-free survival (PFS) and duration of response (DoR) were not reached at time of analysis; 12-month estimates for PFS and DoR were 69.6% and 82.7%, respectively.

Conclusions: Preliminary data are promising and suggest etentamig in combination with POM+DEX is tolerable with robust efficacy (ORR and ≥VGPR: 81% and 72%, respectively) in pts with ≥3 prior LoT (median LoT = 4). In this heavily pretreated population, median PFS was not reached with a median follow up of 18 months, suggesting prolonged disease control with etentamig in combination with POM+DEX. Overall, these data support further exploration of the regimen in a randomized Phase 3 study.