Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Phase 1/2 Results from MonumenTAL-1

Introduction: G protein-coupled receptor family C group 5 member D (GPRC5D) has limited expression in normal human tissue but is highly expressed on malignant plasma cells, making it a promising immunotherapy target for patients (pts) with multiple myeloma (MM). Talquetamab is a first-in-class, off-the-shelf, T-cell redirecting bispecific antibody targeting both GPRC5D and CD3 receptors. MonumenTAL-1 is a phase 1/2 trial (NCT03399799/NCT04634552) of talquetamab in pts with RRMM. In phase 1 of MonumenTAL-1, collective safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) data supported selection of 2 recommended phase 2 doses (RP2Ds) for talquetamab: 0.405 mg/kg subcutaneous (SC) weekly (QW) and 0.8 mg/kg SC every other week (Q2W). Here, we report results for pts treated at these RP2Ds in phase 1 and 2 of MonumenTAL-1.

Methods: Eligible pts in phase 1 had measurable MM and had progressed on or were intolerant to standard therapies. Pts in phase 2 had received ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 monoclonal antibody (ie, triple-class exposed). In phase 1, 0.405 mg/kg SC QW was a putative RP2D; this was modified to 0.4 mg/kg SC QW in phase 2 for convenience. Phase 1 and 2 data were combined for analysis. Step-up dosing was used to mitigate risk of severe cytokine release syndrome (CRS). Primary endpoint of phase 2 was overall response rate (ORR) per IMWG criteria based on independent committee review. Key secondary endpoints were duration of response (DOR), rate of very good partial response or better (≥VGPR), rate of complete response or better (≥CR), time to response, progression-free survival (PFS), and incidence of AEs. AEs were graded by CTCAE v4.03; CRS events were graded per ASTCT criteria. PD parameters were measured at baseline and through day 1 of cycle 2.

Results: As of May 16, 2022, 288 pts with no prior exposure to T-cell redirecting therapies had received talquetamab at the RP2Ds in phase 1 or 2. In 143 pts treated at 0.4 mg/kg QW (median time since diagnosis: 6.7 years), median age was 67 years (range 46-86), pts received a median of 5 prior LOT (range 2-13), 31.1% had high-risk cytogenetics, 23% had extramedullary disease, 19.6% had ISS stage 3 disease, 100%/74% were triple-class exposed/refractory, and 73%/29% were penta-drug exposed/refractory; median follow-up was 11.0 months (range 0.5+-26.1). Baseline characteristics were similar among 145 pts who received 0.8 mg/kg Q2W (median follow-up: 5.1 months [range 0.2+-17.9]).

In 143 pts treated at 0.4 mg/kg QW, ORR was 73% (≥VGPR: 58%; ≥CR: 29%). Responses were durable and deepened over time (Figure). Median time to response was 1.2 months (range 0.2-5.0). Median time to CR was 2.1 months (range 1.1-12.4). Median DOR was 9.3 months (95% CI, 6.6-20.2; range 1-23+). Median PFS was 7.5 months (95% CI, 5.7-9.2 [38% censored]). ORRs in pts who were triple-class refractory (72% [76/106]) and penta-drug refractory (71% [30/42]) were comparable to the overall population. Efficacy at 0.8 mg/kg Q2W will be presented at the meeting.

The most common AEs at 0.4 mg/kg QW/0.8 mg/kg Q2W were CRS (79%/72%; grade 3: 2%/1%; grade 4: 0%/0%), dysgeusia (48%/46%; grade 3/4: not applicable [NA]), and anemia (45%/39%; grade 3: 31%/25%; grade 4: 0%/0%]); skin-related AEs occurred in 56%/68% (grade 3: 0%/1%; grade 4: NA) and nail disorders in 52%/43% (grade 3: 0%/0%; grade 4: NA) of patients. Cytopenias, including neutropenia in 34%/28% (grade 3: 20%/17%; grade 4: 10%/6%) and thrombocytopenia in 27%/27% (grade 3: 10%/8%; grade 4: 10%/8%), were generally limited to the first few cycles. At 0.4 mg/kg QW/0.8 mg/kg Q2W, infections occurred in 57%/50% of pts (grade ≥3: 19%/13%); 4.9%/6.2% discontinued, 8.4%/13.8% had dose delays, and 14.7%/6.2% had dose reductions due to AEs. There were 2 deaths due to COVID-19 (1 patient at each RP2D).

Talquetamab exposure was comparable at the two RP2Ds. No clinically significant effect of anti-talquetamab antibodies on PK, efficacy, or AEs was observed.

PD changes were comparable at both RP2Ds and consistent with talquetamab activity, including T-cell activation, redistribution, and induction of cytokines.

Conclusions: Talquetamab demonstrated robust efficacy and manageable safety in pts with heavily pretreated RRMM. Additional phase 1 studies (NCT04586426; NCT04108195; NCT05050097) are evaluating talquetamab in combination with other agents in pts with RRMM.

Schinke:Janssen: Honoraria. Minnema:Bristol Myers Squibb: Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medscape: Speakers Bureau. Berdeja:Legend Biotech: Consultancy; Zentalis: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Acetylon: Research Funding; SecuraBio: Consultancy; EMD Sorono: Research Funding; Novartis: Research Funding; Poseida: Research Funding; Teva: Research Funding; Lilly: Research Funding; 2Seventy bio: Research Funding; Karyopharm: Research Funding; Incyte: Research Funding; C4 Therapeutics: Research Funding; Ichnos Sciences: Research Funding; GlaxoSmithKline: Research Funding; Celularity: Research Funding; Fate Therapeutics: Research Funding; CARsgen: Research Funding; Amgen: Research Funding; Takeda: Consultancy, Research Funding; Kite Pharma: Consultancy; Cartesian Therapeutics: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Oriol:Sanofi: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Janssen: Consultancy; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Van De Donk:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero:Janssen, BMS, Sanofi, Pfizer, GSK.: Consultancy; BMS-Celgene: Speakers Bureau; Amgen: Speakers Bureau; Amgen, Sanofi, GSK, Janssen, BMS-Celgene, Regeneron: Speakers Bureau; GSK: Consultancy, Speakers Bureau; Pfizer: Consultancy; Regeneron Pharmaceuticals, Inc.: Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; BMS: Consultancy; Janssen: Consultancy, Speakers Bureau; Hematology Clínica Universidad de Navarra: Current Employment. Mateos:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees. Costa:Genentech: Research Funding; AbbVie: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Caers:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Consultancy, Research Funding. Rasche:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Krishnan:Sutro SAB: Speakers Bureau; Takeda, GSK, BMS: Speakers Bureau; Janssen: Research Funding; BMS: Current equity holder in publicly-traded company; BMS, Janssen, Adaptive, GSK, AbbVie, Regeneron, Sanofi, AstraZeneca: Consultancy; Artiva: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding; Regeneron: Consultancy; Adaptive: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Sutro: Consultancy; Bristol Myers Squibb: Consultancy, Other: Stock Ownership (not including stocks owned in a managed portfolio), Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Ma:Janssen: Current Employment. Qin:Janssen: Current Employment. Gries:Janssen Pharmaceutical: Current Employment, Current holder of stock options in a privately-held company. Campagna:Janssen: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Masterson:Janssen R&D, LLC: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Hilder:Janssen: Current Employment. Tolbert:Janssen Pharmaceuticals: Current Employment. Renaud:Janssen: Current Employment. Goldberg:Janssen: Current Employment, Current equity holder in private company. Heuck:Janssen R&D: Current Employment, Current equity holder in publicly-traded company. San-Miguel:Abbvie, Amgen, BMS, Celgene, GSK, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Takeda, Regeneron, Roche, Sanofi, and SecuraBio: Consultancy, Other: Advisory Board. Moreau:AbbVie, Janssen, Celgene, Amgen, and Sanofi: Honoraria.

at the time of abstract submission, talquetamab is being investigated for the treatment of multiple myeloma but is not yet not approved