Talquetamab (tal) + daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Updated TRIMM-2 results.
Authors: Dholaria Bhagirathbhai R. , Weisel Katja , Mateos Maria-Victoria , Goldschmidt Hartmut , Martin Thomas G. , Morillo Daniel , Reece Donna Ellen , Rodríguez-Otero Paula , Bhutani Manisha , D'Souza Anita , Oriol Albert , Rosiñol Laura , Bahlis Nizar J. , Bakshi Kalpana , Kang Lijuan , Vandenberk Lien , Smit Marie-Anne Damiette , Wäsch Ralph , van de Donk Niels W.C.J. , Chari Ajai 
Published: June 2023

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Background: Tal is a T-cell redirecting bispecific antibody (BsAb) targeting G protein–coupled receptor family C group 5 member D. Dara is an anti-CD38 mAb with direct on-tumor and immunomodulatory actions. Combining immunomodulatory effects of tal + dara may lead to synergistic efficacy. Initial TRIMM-2 (NCT04108195) results showed that SC tal RP2Ds, 0.4 mg/kg QW or 0.8 mg/kg Q2W, + SC dara had promising efficacy and increased CD38+/CD8+ T cells and proinflammatory cytokines. We report updated results with additional pts and longer follow-up. Methods: Pts had MM, ≥3 prior lines of therapy (LOT; including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and IMiD, and had not received anti-CD38 therapy in ≤90 d. Pts received tal RP2Ds with step-up dosing + dara 1800 mg per approved schedule. AEs were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Responses were assessed per IMWG criteria. Results: As of Dec 12, 2022 (N = 65), median follow-up was 11.5 mo (range 1.0–27.3). Median age was 63 y (range 37–81); 18% of pts had high-risk cytogenetics; 25% had extramedullary plasmacytomas. Median prior LOT was 5 (range 2–16): 63% penta-drug exposed; 58% triple-class refractory. Prior treatments included anti-CD38 (88% [77% refractory]), anti-BCMA (54% [38%]), BsAb (25% [25%]), and anti-BCMA CAR-T (17% [2%]) therapy. All pts had ≥1 AE (grade [Gr] 3/4 78%), most commonly CRS (78%; all Gr 1/2), dysgeusia (75%), dry mouth (55%), anemia (52%), fatigue (45%), and skin exfoliation (45%). CRS had a median time to onset of 1 d after the most recent dose with median duration of 2 d. 63% of pts had infections (Gr 3/4 22%; Gr 5 3% [n = 2 pneumonia, possibly related to tal + dara]). 38% of pts had neutropenia (Gr 3/4 26%). 85% had postbaseline IgG < 500 mg/dL; of these, 32% received IVIg. ICANS occurred in 3 pts (5%; all Gr 1/2 and resolved in 1–2 d). ORR was 78% (66% ≥VGPR; 45% ≥CR) across RP2Ds (100% in anti-CD38 naïve pts), and responses deepened over time. In pts exposed/refractory to prior therapy, ORRs were 75%/76% for anti-CD38, 74%/64% for anti-BCMA, and 75%/75% for BsAb. Median time to first response was 1 mo (range 0.9–8.3); at 12 mo, 86% of responders (89% of pts with ≥CR) still had responses. At data cutoff, 84% of responders remain on therapy (83%/82% anti-CD38 exposed/refractory). mPFS was 19.4 mo; 12-mo PFS and OS rates were 76% and 93%, respectively. Conclusions: Steroid-sparing tal + dara showed deep and durable responses with promising mPFS in heavily pretreated pts with RRMM, including pts refractory to anti-CD38/BCMA and T-cell redirecting therapy, suggesting combined immunomodulatory actions can yield robust responses in pts with refractory disease. The safety profile was clinically manageable; no new signals were identified with longer follow-up.