Sequential Targeting in Multiple Myeloma: Talquetamab, a GPRC5D bispecific antibody, as a Bridge to BCMA CAR-T cell therapy

Abstract

Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), two BCMA-directed chimeric antigen receptor T cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma (RRMM); however, the 6-8 weeks manufacturing time risks disease progression or death in up to 10% of patients, highlighting the need for effective bridging strategies. Talquetamab, a GPRC5D-targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 US, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n=98 cilta-cel, n=21 ide-cel). Reasons for not proceeding (n=15) included progression (n=7), manufacturing failure (n=6), or patient decision (n=2). Median age was 65 years; patients had received a median 5 prior lines of therapy. High-risk cytogenetics and extramedullary disease were present in 44% and 41% respectively. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days (82% at 0.8 mg/kg biweekly). Toxicity was manageable: no grade ≥3 CRS, 2% grade 3 ICANS and grade 1-2 Talq unique toxicities (70% oral, 38% skin, 17% nail; 60% resolved). Talquetamab achieved 71% response rate. Post CAR-T 88% responded (54% complete response), with low-grade toxicities (2 grade≥3 CRS, 1 grade 3 ICANS and 5% grade≥3 infections). Two cases of facial palsy and one AML occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe enabling the majority of difficult to treat patients to successfully proceed to BCMA CAR-T therapy.