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157 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-1Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Bispecific Monoclonal Antibodies in Myeloma
Hematology Disease Topics & Pathways:
Biological therapies, Research, Clinical Research, Plasma Cell Disorders, Diseases, Therapies, Lymphoid Malignancies
Saturday, December 10, 2022: 12:00 PM

Ajai Chari1*, Cyrille Touzeau2*, Carolina Schinke3, Monique C. Minnema, MD, PhD4, Jesus Berdeja, MD5, Albert Oriol6*, Niels WCJ Van De Donk, MD7, Paula Rodriguez Otero8*, Elham Askari9*, Maria-Victoria Mateos, MD10, Luciano J. Megala Costa, MD, PhD11, Jo Caers, PhD12, Leo Rasche, MD13*, Amrita Y. Krishnan, MD, FACP14, Deeksha Vishwamitra15*, Xuewen Ma15*, Xiang Qin15*, Katharine S. Gries, PhD, PharmD16*, Michela Campagna17*, Tara Masterson15*, Brandi Hilder15*, Jaszianne Tolbert15, Thomas Renaud18*, Jenna D. Goldberg18*, Christoph Heuck15*, Jesús San-Miguel, MD, PhD19 and Philippe Moreau, MD20*

1Mount Sinai School of Medicine, New York, NY
2Centre Hospitalier Universitaire de Nantes, Nantes, France
3Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR
4University Medical Center Utrecht, Utrecht, Netherlands
5Sarah Cannon Research Institute, Nashville, TN
6Hospital Germans Trias I Pujol, Barcelona, Spain
7Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
8University of Navarra, Pamplona, Spain
9Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
10University Hospital of Salamanca/IBSAL/CIC, Salamanca, Spain
11University of Alabama at Birmingham, Birmingham, AL
12University of Liege, Liege, Belgium
13University Hospital of Würzburg, Würzburg, Germany
14City of Hope Comprehensive Cancer Center, Duarte, CA
15Janssen Research & Development, Spring House, PA
16Janssen Global Services, Raritan, NJ
17Janssen-Cilag, Madrid, Spain
18Janssen Research & Development, Raritan, NJ
19Universidad de Navarra, Pamplona, Spain
20University Hospital Hôtel-Dieu, Nantes, France

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.

Disclosures: 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: Consultancy, Speakers Bureau; Hematology Clínica Universidad de Navarra: Current Employment; Pfizer: Consultancy; GSK: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; BMS-Celgene: Speakers Bureau; BMS: Consultancy; Regeneron Pharmaceuticals, Inc.: Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Amgen, Sanofi, GSK, Janssen, BMS-Celgene, Regeneron: Speakers Bureau; Janssen, BMS, Sanofi, Pfizer, GSK.: Consultancy. 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. Megala Costa: Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Research Funding; Genentech: 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: Takeda: Speakers Bureau; Amgen: Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Other: Stock Ownership (not including stocks owned in a managed portfolio), Speakers Bureau; Sutro: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Adaptive: Consultancy; Regeneron: Consultancy; Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy; Artiva: Consultancy; BMS, Janssen, Adaptive, GSK, AbbVie, Regeneron, Sanofi, AstraZeneca: Consultancy; BMS: Current equity holder in publicly-traded company; Janssen: Research Funding; Takeda, GSK, BMS: Speakers Bureau; Sutro SAB: 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, Amgen, Celgene, Janssen, Oncopeptides, Sanofi: Honoraria.

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

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