Sequential Targeting in Multiple Myeloma: Talquetamab, a GPRC5D bispecific antibody, as a Bridge to BCMA CAR-T cell therapy
Binod Dhakal, Othman Salim Akhtar, David Fandrei, Alexandria Jensen, Rahul Banerjee, Darren Pan, Shambavi Richard, Reed Friend, Matthew James Rees, Patrick Costello, Mariola Alejandra Vazquez Martinez, Oren Pasvolsky, Charlotte B. Wagner, James A Davis, Omar A. Castaneda Puglianini, Ran Reshef, Aimaz Afrough, Danai Dima, Manisha Bhutani, Omar Nadeem, Ricardo D Parrondo, Ciara L Freeman, Lekha Mikkilineni, Shahzad Raza, Larry D. Anderson, Prashant Kapoor, Hitomi Hosoya, Saurabh Chhabra, Ariel Grajales-Cruz, Mahmoud R. Gaballa, Shonali Midha, Melissa Alsina, Douglas W Sborov, Krina K. Patel, Yi Lin, Christopher J Ferreri, Nico Gagelmann, Anupama Deepa Kumar, Doris K Hansen, Andrew J Cowan, Luciano J. Costa, Maximilian Merz, Surbhi SidanaCiltacabtagene 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.