Sequential targeting in multiple myeloma: talquetamab, a GPRC5D bispecific antibody, as a bridge to BCMA CAR-T therapy
Binod Dhakal, Othman Salim Akhtar, David Fandrei, Alexandria Jensen, Rahul Banerjee, Darren Pan, Shambavi Richard, Reed Friend, Matthew J. Rees, Patrick Costello, Mariola Alejandra Vazquez Martinez, Oren Pasvolsky, Charlotte B Wagner, James A. Davis, Omar Castañeda Puglianini, Ran Reshef, Aimaz Afrough, Danai Dima, Manisha Bhutani, Omar Nadeem, Ricardo Parrondo, Ciara L. Freeman, Lekha Mikkilineni, Shahzad Raza, Larry D. Anderson, Prashant Kapoor, Hitomi Hosoya, Saurabh Chhabra, Ariel Grajales‐Cruz, Mahmoud Gaballa, Shonali Midha, Melissa Alsina, Douglas W. Sborov, Krina K. Patel, Yi Lin, Christopher J. Ferreri, Nico Gagelmann, Anupama Kumar, Doris K. Hansen, Andrew J. Cowan, Luciano J. Costa, Maximilian Merz, Surbhi Sidana
Abstract
ABSTRACT: Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), 2 B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma; however, the 6 to 8 weeks manufacturing time risks disease progression or death in up to 10% of patients. Talquetamab, a G-protein-coupled receptor, family C, group 5, member D (GPRC5D)-targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 United States, 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 and had median 5 prior lines of therapy. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days. Toxicity was manageable: no grade ≥3 cytokine release syndrome (CRS), 2% grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) and grade 1 to 2 talquetamab unique toxicities (70% oral, 38% skin, and 17% nail; 60% resolved). Talquetamab achieved 71% response rate. After 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 1 acute myeloid leukemia 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.