Background: T-cell engager (TCE) therapies (talquetamab [anti-GPRC5D] and elranatamab [anti-BCMA]) demonstrate proven efficacy in heavily pretreated relapsed/refractory MM (RRMM), but resistance to TCE monotherapy can develop, leading to disease progression. Several trials have evaluated anti-BCMA (D'Souza et. al., 2024) and anti-GPRC5D (Matous et. al., 2023) combinations with pomalidomide (pom). Newer immunomodulatory agents such as iberdomide have been shown to induce phenotypic shifting of the bone marrow tumor microenvironment toward effector T and NK cells (Van Oeklen et al., 2024), providing therapeutic rationale for adding these agents to TCEs, particularly when progression is attributed to T-cell exhaustion. We report our single-center experience using TCE-pom salvage therapy in heavily pretreated RRMM, particularly those with disease progression on TCE monotherapy.

Methods: We performed a single-center retrospective review of all patients treated with talquetamab (Talq) or elranatamab (Elra) with pom at Hackensack University Medical Center between January 2024-July 2025 on an IRB-approved protocol. Patient data included demographics, disease characteristics, prior therapies, and current treatment regimens. All patients received TCEs via step-up dosing schedule administered inpatient, then transitioned to outpatient therapy. Pom was added following step-up completion during cycle 1 or with cycle 2 if there was no response to TCE monotherapy or to deepen the response. International Myeloma Working Group (IMWG) criteria were used to determine response depth and progression. Survival analysis was performed with the Kaplan-Meier method. CTCAE criteria were used to evaluate toxicity.

Results: As of July 31, 2025, we identified 16 patients treated with TCE-pom combination [9 Talq, 7 Elra]. Median follow-up was 5.5 months(mos). Median age was 70.1 years; 11/16 patients (68.7%) had high-risk cytogenetics [17p(-), t(4;14), t(14;16), 1q+]; patients received a median of 6 prior lines of therapy; 12/16 patients had prior CAR-T (anti-BCMA). All patients were previously pom-refractory with other combinations. Two patients were refractory to anti-BCMA CAR-T. Median PFS with CAR-T was 8.5 mos. 9/16 patients (56.2%) experienced grade 1 CRS; no ICANS was observed during TCE step-up dosing. Median time to pom addition was 1.1 months. Median time-to-response following pom addition was 1 month. Pom dose adjustment was required in 10/16 patients (62.5%), mostly due to neutropenia; median pom dose was 3mg. Grade ≥III neutropenia occurred in 62.5% patients after pom addition. Among Talq patients, 77.8% (7/9) reported skin toxicities (any grade) and 66.7% (6/9) reported dysgeusia (any grade). No Elra patients reported dysgeusia; only one reported skin changes. 8/16 patients (50%) had no response to TCE monotherapy. For TCE monotherapy-refractory patients, ORR following pom addition was 87.5% (7/8 patients). ORR for the entire cohort was 93.7%. 10/16 patients (62.5%) achieved ≥VGPR. At median follow-up of 5.5 mos, all except one patient remained progression-free.

Conclusion: TCE-pom combination treatment in heavily pretreated RRMM patients, including those with prior CAR-T and pom exposure, demonstrated efficacy consistent with prior studies. ORR was 93.7% with 87.5% salvage rate among TCE monotherapy-refractory patients. Safety profile showed predominantly grade 1 CRS without ICANS. This supports TCE-pom combinations as effective salvage therapy for heavily pretreated RRMM patients, particularly those refractory to TCE monotherapy. This study provides conceptual proof of the ability of pom to rescue T-cells from exhaustion by inducing an effector T cell phenotype that can overcome resistance to TCE monotherapy.

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2025
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