Background: Talquetamab (tal) is the first bispecific antibody targeting the novel antigen, GPRC5D, approved in the US and EU for the treatment of patients (pts) with relapsed/refractory multiple myeloma (RRMM). Approval was based on data from the MonumenTAL-1 study demonstrating high overall response rates (ORRs) at the 0.4 mg/kg weekly (QW) and 0.8 mg/kg every other week (Q2W) recommended phase 2 doses (RP2Ds) of tal in pts with RRMM. Based on a 29 Jan 2024 data cut-off, ORRs were 74.1% and 69.5% in pts receiving the tal QW and Q2W schedules, respectively. Pts from Japan were not included in the initial MonumenTAL-1 study results. We report the primary analysis of the efficacy and safety of tal from the phase 2 Japan cohort in the MonumenTAL-1 study.

Methods: MonumenTAL-1 (NCT03399799/NCT04634552) is a first-in-human, phase 1/2, open-label, multicenter study of tal monotherapy in pts with RRMM. Phase 1 identified the 2 RP2Ds, 0.4 mg/kg QW and 0.8 mg/kg Q2W, which were further assessed in phase 2. The Japan cohort was enrolled in phase 2 (5 Jul 2022-5 Dec 2023), with pts receiving the tal 0.4 mg/kg QW schedule. Eligible pts had received ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 monoclonal antibody, and had not been exposed to T-cell redirection therapies. The primary endpoint of phase 2 was ORR. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by ASTCT criteria; all other adverse events (AEs) were graded by CTCAE v4.03. Response was assessed by independent review committee per International Myeloma Working Group criteria.

Results: As of 6 May 2024, with a median follow-up of 9.2 months (mo) in all pts and 9.5 mo in responders, 36 Japanese pts received tal 0.4 mg/kg QW. Median age was 70.5 years, and 55.6% of pts were male. Median prior LOT was 3.5 (range, 3-13). Twenty-five (69.4%) pts were triple-class refractory and 8 (22.2%) were penta-refractory. Four (11.1%) pts had International Staging System stage III disease, 2 (5.6%) had extramedullary disease, and 13 (of 33, 39.4%) had high-risk cytogenetics. Efficacy of tal in the Japan cohort was generally consistent with the global MonumenTAL-1 cohort. ORR was 77.8%, and 72.2% and 47.2% of pts had very good partial response or better (≥VGPR) and complete response or better (≥CR), respectively. Median time to first response was 1.2 mo, and median time to best response was 3.5 mo. The 6- and 9-mo duration of response (DOR) rates were both 88.4%. The 6- and 9-mo progression-free survival rates were 81.8% and 77.0%, respectively. The 6- and 9-mo overall survival (OS) rates were 91.5% and 84.1%, respectively. The safety profile in the Japan cohort was consistent with the global MonumenTAL-1 cohort. All pts reported ≥1 AE. Hematologic AEs were the most common grade (gr) 3/4 AEs (most commonly lymphopenia [44.4%]). CRS was the most common nonhematologic AE (75.0%). CRS events were all gr 1 (58.3%) or gr 2 (16.7%) and generally occurred during step-up and cycle 1 day 1 doses; no pts discontinued treatment due to CRS. Median time to onset and median duration of CRS were each 2 days. No pts reported an ICANS event; the only neurotoxicity event was a gr 1 headache. Infections occurred in 52.8% of pts, most commonly pneumonia (11.1%). Gr 3/4 infections occurred in 5 (13.9%; pneumonia [2], otitis media [1], sepsis [1], and staphylococcal sepsis [1]) pts; 1 gr 3/4 pneumonia resulted in death. On-target, off-tumor AEs (GPRC5D-associated AEs) included taste (eg, dysgeusia), non-rash skin, rash, and nail AEs, and occurred in 80.6%, 66.7%, 36.1%, and 61.1% of pts, respectively; these events were mainly gr 1/2, and none resulted in discontinuation. One pt skipped doses of tal but no pts delayed or reduced doses of tal due to dysgeusia. Weight loss was reported in 22.2% of pts (gr 3, 8.3%). AEs led to treatment discontinuation in 1 pt (staphylococcal sepsis) and death in 3 pts (respiratory failure, interstitial lung disease, and pneumonia); the pneumonia death was considered related to tal by the investigator.

Conclusions: Tal showed high rates of response (ORR, 77.8%) that were deep (≥VGPR, 72.2%; ≥CR, 47.2%) and durable (9-mo DOR, 88.4%), with promising initial OS (9-mo OS, 84.1%) and a manageable safety profile in heavily pretreated Japanese pts with RRMM. These data are consistent with the global MonumenTAL-1 population, supporting use of tal in a diverse group of pts.

Disclosures

Ito:Sanofi, Pfizer, Janssen, Chugai, BMS: Honoraria, Research Funding; Abbvie, GSK, Kissei: Research Funding; Takeda: Honoraria. Kuroda:Janssen Pharmaceutical, Takeda Pharmaceuticals, Bristol Myers Squibb, Sanofi, SymBio Pharmaceuticals, ONO PHARMACEUTICAL, AstraZeneca, ASAHI KASEI PHARMA, Amgen: Research Funding, Speakers Bureau. Sunami:Sanofi, Pfizer, Ono Pharmaceutical, Novartis, Mitsubishi Tanabe, Kyowa-Kirin, Incyte, GSK, Chugai, BMS, BeiGene, Abbvie: Research Funding; Janssen: Honoraria, Research Funding. Imada:(Honoraria) Janssen Pharmaceutical K.K.、Towa Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Alexion Pharmaceuticals, Inc., AbbVie GK., Astellas Pharma Inc., Amgen K.K., AstraZeneca K.K., DAIICHI SANKYO Co., Ltd.: Honoraria, Other: (Honoraria) Genmab K.K., Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., Ono Pharmaceutical Co. Ltd., Otuka Pharmaceutical Co. Ltd. and Pfizer Japan Inc., Patents & Royalties: (Honoraria) Gilead Sciences K.K., PharmaEssentia Japan KK, Kyowa Kirin Co., Ltd., Novartis Pharma K.K., Sanofi K.K., Asahi Kasei Pharma, Nippon Kayaku Co.,Ltd., Nippon Shinyaku Co., Ltd., Eisai Co., Ltd... Tamura:Bristol Meyers Squib: Speakers Bureau; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria. Takamoto:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company. Yamazaki:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company. Fujikawa:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company. Pei:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company. Masterson:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company. Campagna:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company. Lau:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company.

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2024
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