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8036 Background: Tal is a first-in-class BsAb targeting the novel antigen G protein–coupled receptor family C group 5 member D. In MonumenTAL-1 (NCT03399799/NCT04634552), tal showed promising efficacy and clinically manageable safety in patients (pts) with RRMM. We report pivotal phase 2 results in pts with and without prior T-cell redirection therapy. Methods: Eligible pts were intolerant to or progressed on established therapies (phase 1) or had ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 antibody (phase 2). Pts received RP2Ds of SC tal 0.4 mg/kg QW or 0.8 mg/kg Q2W with step-up doses. CRS and ICANS were graded by ASTCT criteria; all other AEs were graded by CTCAE v4.03. Response was assessed by IMWG criteria. Data cut-off was Sep 12, 2022 for efficacy and Oct 19, 2022 for safety. Data will be updated for the meeting. Results: From the pivotal cohorts, 288 pts received tal 0.4 mg/kg QW (n = 143) or 0.8 mg/kg Q2W (n = 145), and 51 pts with prior T-cell redirection therapy received either dose. In the QW, Q2W, and prior T-cell redirection cohorts, respectively, median prior LOT was 5–6; 74%, 69%, and 84% were triple-class refractory and 29%, 23%, and 41% were penta-drug refractory; 15%, 11%, and 12% received prior belantamab. In the prior T-cell redirection cohort, 71% received CAR-T therapy, 35% received a BsAb, and 6% received both. In the pivotal cohorts, ORR was 74% (QW, 14.9 mo median follow-up [mF/U]) and 73% (Q2W, 8.6 mo mF/U), with very good partial response or better (≥VGPR) in 59% (QW) and 57% (Q2W). ORR was consistent across subgroups, including baseline ISS stage III disease, cytogenetic risk, number of prior LOT, and belantamab exposure. In pts with baseline plasmacytomas, ORR was 49% in both pivotal cohorts. In the prior T-cell redirection cohort, ORR was 63% (53% ≥VGPR) at 11.8 mo mF/U. Median PFS was 7.5, 11.9 (61% censored), and 5.1 mo in the QW, Q2W, and prior T-cell redirection cohorts, respectively. Common AEs included CRS (79%, 75%, 77%), skin-related AEs (56%, 71%, 69%), nail-related AEs (54%, 53%, 61%), and dysgeusia (50%, 48%, 61%); most were grade 1/2 and clinically manageable. ICANS occurred in 11%, 11%, and 3% of pts. Infections occurred in 58%, 65%, and 71% (grade 3/4: 22%, 16%, 26%) of pts, with low rates of opportunistic infections. AEs resulted in dose reductions in 15%, 8%, and 10% of pts and discontinuation in 5%, 8%, and 6%. There were no tal-related deaths. Responders to tal had higher T cell counts and lower frequencies of exhausted T cells and CD38+ Tregs vs non-responders. Conclusions: Pivotal phase 2 tal data showed > 70% ORR in heavily pretreated pts with RRMM. High response rates were also seen in pts with prior T-cell redirection therapy. The safety profile was clinically manageable with low rates of high-grade infections and tal discontinuations. Clinical trial information: NCT03399799 , NCT04634552 .

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8015 Background: G protein-coupled receptor family C group 5 member D (GPRC5D), which has limited expression in normal human tissue but is highly expressed on malignant plasma cells, is a promising target for multiple myeloma (MM) immunotherapy. Talquetamab (JNJ-64407564) is a first-in-class, bispecific IgG4 antibody that binds to both GPRC5D and CD3 receptors, mediating T-cell–activated lysis of GPRC5D+ MM cells. Here we report updated results with additional patients (pts) and longer follow-up from MonumenTAL-1, a phase 1 trial of talquetamab in RRMM (NCT03399799). Methods: Eligible pts had RRMM or were intolerant to standard therapies; prior B-cell maturation antigen-directed therapies were permitted. The primary objectives were to identify the recommended phase 2 doses (RP2Ds) (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Collective safety, efficacy, PK, and PD data supported 2 RP2Ds for talquetamab: 405 μg/kg SC QW (n = 30) and 800 μg/kg SC Q2W (n = 44). Step-up dosing was used to mitigate against severe cytokine release syndrome (CRS); required premedications were limited to step-up doses and the first full dose of talquetamab. Adverse events (AEs) were graded by CTCAE v4.03 with CRS events graded per Lee et al 2014 criteria. Investigators assessed responses per International Myeloma Working Group criteria. Results: As of Jan 17, 2022, pts in the 405 μg/kg/800 μg/kg groups, respectively, received a median of 6 /5 prior lines of therapy, 100%/98% were triple-class (TC) exposed, 77%/75% were TC refractory. Median follow-up (range) was 11.7 (1.0–21.2)/4.2 (0.7–13.7) months. Most AEs were grade 1 or 2. The most common AEs were cytopenias and CRS. Cytopenias (including neutropenia [67%/36%; grade 3/4: 53%/23%]) were reversible, mostly confined to step-up and cycle 1–2 doses, and generally resolved within 1 week. Infections occurred in 47%/34% (grade 3/4: 7%/9%) of pts. CRS (77%/80%; grade 3: 3%/0%) mostly occurred during step-up dosing. Skin-related and nail disorder AEs occurred in 83%/75% of pts (most commonly skin exfoliation: 37%/39% [all grade 1 and 2]). Dysgeusia (63%/57%) was generally mild and managed with dose adjustments. The overall response rates in response-evaluable pts were 70% (21/30 pts)/64% (28/44 pts); very good partial response or better rate: 57%/52%; median time to first confirmed response (range): 0.9 (0.2–3.8)/1.2 (0.3–6.8) months. Median duration of response will be reported. No pts died due to drug-related AEs. The PK and PD profiles of both RP2Ds appear comparable. Conclusions: These data show that both RP2Ds of talquetamab have comparable safety, efficacy, and pharmacokinetic profiles and confirm talquetamab as a novel, first-in-class therapy with highly promising efficacy in a heavily pretreated RRMM pt population. Clinical trial information: NCT03399799.