The Kilimanjaro Phase 1b study evaluated etentamig, a second-generation BCMA×CD3 bispecific T-cell engager with bivalent BCMA binding and low-affinity CD3 binding enabling quarterly dosing, combined with pomalidomide-dexamethasone in relapsed/refractory multiple myeloma. Eighty-five heavily pretreated patients (median 4 prior lines, 73% triple-class refractory, 49% pomalidomide-refractory) received etentamig 20-40 mg every 4 weeks without step-up dosing. Results showed 81% overall response rate and 72% very good partial response or better among 82 evaluable patients at median 18 months follow-up. Median progression-free survival and duration of response were not reached, with 12-month estimates of 69.6% and 82.7% respectively. Safety profile showed CRS in 37% (all Grade 1-2), ICANS in 7%, Grade 3/4 neutropenia (78%), anemia (28%), and thrombocytopenia (22%). Most patients (59%) remained on therapy, supporting Phase 3 advancement.

Key Points:

• Impressive Response Rates: Overall response rate of 81% (95% CI: 70-88%) and very good partial response or better rate of 72% (61-81%) in heavily pretreated population with median 4 prior lines and 73% triple-class refractory
• Durable Disease Control: Median progression-free survival and duration of response not reached at median 18 months follow-up; 12-month PFS estimate of 69.6% and 12-month duration of response estimate of 82.7%
• Activity in Pomalidomide-Exposed Population: 58% of patients had prior pomalidomide exposure with approximately half (49% overall, 42/85 patients) pomalidomide-refractory, yet robust responses observed, demonstrating synergistic benefit of combination over pomalidomide monotherapy
• Favorable CRS Profile: Cytokine release syndrome occurred in 37% after target dose with only Grade 1 (25%) or Grade 2 (12%) events; no Grade 3 or higher CRS observed, validating differentiated design with low-affinity CD3 binding
• Minimal ICANS: Immune effector cell-associated neurotoxicity syndrome reported in only 7% of patients total, predominantly Grade 1-2 with single Grade 3 event and no Grade 4-5 events
• Manageable Hematologic Toxicity: Grade 3/4 hematologic adverse events included neutropenia (78%), anemia (28%), and thrombocytopenia (22%); Grade 3/4 infections in 49% with pneumonia most common (17%)
  High Treatment Retention: 59% of patients remained on therapy at data cutoff; primary discontinuation reasons were disease progression (27%) and adverse events (11%), with only 2 treatment-related deaths (influenza and worsening renal failure, each n=1)
• Convenient Quarterly Dosing: Etentamig administered every 4 weeks without step-up dosing requirement at either 20 mg or 40 mg doses, enabled by silenced Fc tail design providing extended half-life
• Heavily Pretreated Population: Median age 69 years (range 33-88), median 4 prior lines (range 2-10), 73% triple-class refractory to immunomodulatory drug, proteasome inhibitor, and anti-CD38 monoclonal antibody
• International Multi-Center Study: Enrolled and treated across 7 countries with diverse patient population including 86% White, 8% Asian, and 6% Black/African American patients

Conclusion:
The Kilimanjaro Phase 1b study establishes etentamig-pomalidomide-dexamethasone as highly promising for heavily pretreated relapsed/refractory myeloma, achieving 81% overall response rate and 72% very good partial response or better with median PFS not reached at 18 months despite 73% triple-class refractoriness and 49% pomalidomide-refractory status. The differentiated safety profile—37% CRS (all Grade 1-2), 7% ICANS, no step-up dosing required—combined with convenient quarterly administration and robust activity in pomalidomide-refractory patients demonstrates clear synergy between T-cell engagement and immunomodulation. With 59% remaining on therapy and disease control rivaling CAR-T outcomes without manufacturing complexity, these results strongly support Phase 3 advancement to establish this combination's role in the treatment landscape.

Authors:
Peter Voorhees, Anita D'Souza, Hang Quach, Sabine Gaerditz, Estrella Carrillo-Cruz, Michał Mielnik, Tomasz Wrobel, Matthew Pianko, Dickran Kazandjian, M Hasib Sidiqi, Valerio De Stefano, Cesar Rodriguez Valdes, Shonali Midha, Ariel Grajales-Cruz, Hideki Goto, Satoshi Ito, Claudio Cerchione, Ziyi Jin, Shane Lee, Akshanth Polepally, Sneha Rathi, Ross La Motte-Mohs, Kristin D'Amico, Thomas Doerr, Chetasi Talati, Leanne Lash Fleming, Linda Ho, Katja Weisel, Marek Hus, and Joaquin Martinez-Lopez.

Presented at ASH 2025 (Abstract #247)