Background: Teclistamab (Tec) is a BCMA-directed T-cell engaging bispecific antibody for relapsed/refractory multiple myeloma (RRMM). Approved dosing is 1.5 mg/kg every 1-2 weeks indefinitely until disease progression (PD). In the phase 1/2 MajesTEC-1 study, 59.4% of patients (pts) achieved very good partial response (VGPR) or better; median response duration in ≥VGPR pts was 25.6 months (m). Given the deep, rapid responses achieved with Tec, limited-duration therapy may yield outcomes that are similar to continuous therapy while reducing long-term toxicities and costs and improving convenience and quality-of-life. We therefore initiated a prospective trial of monitored Tec discontinuation in pts with deep response.

Study Design and Methods: This is a multisite, single-arm, non-inferiority study (NCT05932680) in which pts with ≥VGPR after 6-9m of Tec at dose intensity ≥3 mg/kg/month discontinue Tec with plan to resume upon PD or early MM growth (increase in involved free light chain >20 mg/L with ratio >5 or “relapse from complete response” (CR) per IMWG criteria). To ease enrollment barriers, bone marrow biopsy (BMB) and research blood collection are optional, so not all pts are assessable for CR and correlative analyses. Primary endpoint is freedom from Tec failure (PD despite early Tec re-initiation, failure to re-respond to Tec after PD, or death due to Tec or MM complications) at 6m post-enrollment; in pts who fail to respond to Tec re-treatment, failure is defined as time of initial PD. We hypothesize that 6m failure-free probability (FFP) will be non-inferior to historical control of 79% derived from MajesTEC-1. Target enrollment is 64 evaluable pts. Here, we present descriptive interim outcomes without formal testing of the non-inferiority hypothesis due to ongoing enrollment.

Results: As of 7/15/2025, 43 pts (median age 73 yrs (range 43-92); 21 male; 25 White, 14 Black, 4 Hispanic) enrolled. 18/43 (42%) had ≥1 and 7/43 (16%) ≥2 high risk cytogenetic abnormalities (defined as del17p, t(14;16), t(4;14), 1q gain/amp). Median prior lines of therapy was 4 (range 2-13) with 95% triple-class and 44% penta-drug refractory. 10/43 (23%) had ≥1 prior BCMA-directed therapies (BCMA-DT) (4 bela-maf, 2 cilta-cel, 6 ide-cel). Median time from diagnosis to Tec initiation was 7.1 years (range 1-14.8). Median time from first full Tec dose to enrollment was 7.3m (range 5.7-9.5). Response to Tec at enrollment was VGPR in 72% (71% of which met serum/urine criteria for CR) and ≥CR in 28%. Median potential follow-up by reverse K-M is 10.6m (95% CI 7.2-15.6). 6 pts have met failure criteria (1 died due to PD before resuming Tec, 5 failed to respond to Tec re-treatment after PD). 4 additional pts have resumed Tec for PD and are pending response assessment; these 4 pts are counted as failures in this interim analysis. Estimated FFP at 6m post-enrollment is 77% (95% CI 64-92) and at 12m is 73% (95% CI 60-90). Similar outcomes were observed in pts with prior BCMA-DT (6m FFP 88%, 12m 70%) and <CR by serum/urine criteria (6m FFP 69%, 12m 69%).

Among 5 pts who resumed Tec and failed to respond, 4 had BMB at PD with BCMA immunohistochemistry: 1 had no detectable MM, 1 with PD at 14.6m post-enrollment had 5% plasma cells (PCs) that were BCMA+, and 2 with PD at 5.0m and 5.9m post-enrollment had 30% and 80% PCs that were BCMA-neg by IHC. BCMA gene sequencing on CD138-selected cells from the BMB with 30% BCMA-neg MM showed loss of the entire BCMA coding region and two BCMA splice-site mutations, indicating selection for multiple BCMA-neg clones. 3/3 pts with PD who received talquetamab (Tal) as next therapy responded (2 VGPR, 1 CR). Among all pts with evaluable samples, plasma soluble BCMA (sBCMA) gradually rose through 6m post-enrollment but remained at low end of normal range (median 2.3 ng/mL, IQR 1.6-3.7, at 6m) including in 4 samples collected at PD.

Conclusions: In this preliminary analysis, discontinuation of Tec after 6-9m yields outcomes comparable to historical expectations with continuous therapy with estimated median FFS of 73% at 12m post-discontinuation in a cohort with 23% prior BCMA-DT. Early instances of PD (<6m after Tec discontinuation) that were evaluable exhibited BCMA loss and were thus unlikely due to Tec discontinuation. Response to Tal immediately after failing Tec re-treatment and low sBCMA at PD further suggest resistance due to BCMA loss/mutation as an important mechanism of PD even months after Tec discontinuation.

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2025
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