Cilta-Cel Efficacy and Safety in Patients with Progressive Multiple Myeloma after Exposure to Non-Cellular Anti-BCMA Immunotherapy

Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating cilta-cel, an anti-BCMA CAR-T therapy, in several multiple myeloma (MM) patient (pt) populations. Objective(s): To report updated results with longer follow-up on cohort C pts with previous exposure to a non-cellular anti- BCMA immunotherapy. Method(s): Cohort C pts had progressive MM after treatment (tx) with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non-cellular BCMA-targeting agent. A single cilta-cel infusion (target dose 0.75x106 CAR+ viable T cells/kg) was administered 5-7 days post lymphodepletion. Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Secondary endpoints included overall response rate (ORR), duration of response (DOR), and adverse events (AEs). Result(s): As of June 1, 2022, 20 pts (13 ADC exposed;7 BsAb exposed) were treated with cilta-cel;4 pts did not receive cilta-cel due to either low cellular yield (n=2, 1 in each group) or death due to progressive disease (PD) prior to dosing (n=2, 1 in each group) and 6 pts received anti-BCMA tx as their last line of therapy (n=4 ADC, n=2 BsAb). During prior anti-BCMA tx, best responses included VGPR (ADC: 2 pts;BsAb: 1 pt), sCR (ADC: 1 pt), and CR (BsAb: 1 pt);the rest had best response of stable disease or PD (1 pt not evaluable). Baseline characteristics are presented in Figure 1A. Median time from last anti- BCMA agent to cilta-cel infusion was 195 d;median administered dose of cilta-cel was 0.65x106 CAR+ viable T cells/kg. At a median follow-up of 18.0 mo, 7/10 evaluable pts (70%) were MRD negative at 10-5 (ADC: 5/7 [71.4%], BsAb: 2/3 [66.7%]). ORR: full cohort, 60%;ADC, 61.5%;BsAb, 57.1% (Figure 1B). Median DOR: full cohort, 12.8 mo;ADC, 12.8 mo;BsAb, 8.2 mo. Median PFS: full cohort, 9.1 mo;ADC, 9.5 mo;BsAb, 5.3 mo. Cilta-cel responders had a shorter median duration of last anti- BCMA agent exposure (29.5 d) compared with non-responders (63.5 d). Responders also had a longer median time from last anti-BCMA tx exposure to apheresis (161.0 d) than non-responders (56.5 d). Most common AEs were hematologic. CRS: n=12 (60%;all Gr1/2), median time to onset 7.5 d, median duration 6.0 d. ICANS: n=4 (20%, 2 Gr3/4), median time to onset 9.0 d, median duration 7.0 d. No patient had movement or neurocognitive tx emergent AE/parkinsonism. There were 12 deaths (PD: 8;COVID-19 pneumonia: 2 [not tx related];subarachnoid hemorrhage: 1 [not tx related];C. difficile colitis: 1 [tx related]). (Figure Presented)(Figure Presented)Conclusions: Pts with heavily pretreated MM and previous exposure to a non-cellular anti-BCMA therapy had favorable responses to cilta-cel. However, depth and DOR appear lower than that seen in anti-BCMA-naive pts treated with cilta-cel (at 27.7 mo, median DOR was not reached in heavily pre-treated but anti-BCMA naive CARTITUDE-1 pts). These data may inform tx plans, including sequencing and washout period between BCMA-targeting agentsCopyright © 2023 American Society for Transplantation and Cellular Therapy

TALQUETAMAB, A G PROTEIN-COUPLED RECEPTOR FAMILY C GROUP 5 MEMBER D X CD3 BISPECIFIC ANTIBODY, IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): UPDATED PHASE 1 RESULTS FROM MONUMENTAL-1

G protein-coupled receptor family C group 5 member D (GPRC5D) has limited expression in healthy human tissue but is highly expressed in malignant plasma cells, making it a promising target for immunotherapy approaches for MM. Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to both GPRC5D and CD3 receptors to redirect T cells to kill MM cells. Updated and new results of talquetamab at the recommended phase 2 doses (RP2Ds) are reported (NCT03399799). Eligible patients had RRMM or were intolerant to standard therapies. Patients who were previously treated with B-cell maturation antigen (BCMA)-directed therapies were eligible. This analysis focuses on patients who received talquetamab subcutaneously (SC;range: 5.0-800 μg/kg) weekly (QW) or biweekly (Q2W) with step-up dosing. The primary objectives were to identify the RP2D (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Adverse events (AEs) were graded by CTCAE v4.03;cytokine release syndrome (CRS) was graded per Lee et al 2014 criteria. Responses were investigator-assessed per IMWG criteria. As of July 19, 2021, 95 patients had received SC talquetamab. The original RP2D was 405 μg/kg SC talquetamab QW with step-up doses, and a second RP2D of 800 μg/kg SC talquetamab Q2W with step-up doses was also identified. 30 patients received 405 μg/kg QW (median 61.5 years [range 46-80];63% male;100% triple-class exposed;80% penta-drug exposed;77% triple-class refractory, 20% penta-drug refractory;30% prior BCMA-directed therapy;median follow-up [mF/U]: 7.5 mo [range 0.9-15.2]). 23 patients received 800 μg/kg Q2W (median 60.0 years [range 47-84];48% male;96% triple-class exposed;70% penta-drug exposed;65% triple-class refractory, 22% penta-drug refractory;17% prior BCMA-directed therapy;mF/U: 3.7 mo [range 0.0-12.0]). No treatment discontinuations due to AEs were reported at either RP2Ds. Most common AEs at the 405 μg/kg QW were CRS (73%;1 grade 3 CRS), neutropenia (67%;grade 3/4: 60%), and dysgeusia (60%;grade 2: 29%). Skin-related AEs occurred in 77% of patients and were all grade 1/2 (nail disorders: 30%). Infections occurred in 37% of patients (1 grade 3 COVID-19 pneumonia). Most common AEs at 800 μg/kg Q2W were CRS (78%;all grade 1/2), dry mouth (44%;all grade 1/2), and neutropenia (44%;grade 3/4: 35%). Skin-related AEs occurred in 65% of patients with grade 3 events in 13% (nail disorders: 17%). Infections occurred in 13% of patients (1 grade 3 pneumococcal sepsis). In 30 response-evaluable patients treated at 405 μg/kg QW, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR]: 57%). In 17 response-evaluable patients treated at 800 μg/ kg Q2W, the ORR was 71% (≥VGPR: 53%). Responses were durable and deepened over time with both RP2Ds (Figure). Median duration of response (DOR) was not reached at either RP2D;6-month DOR rate was 67% (95% CI: 41-84) at 405 μg/kg QW. Serum trough levels of talquetamab were comparable at both RP2Ds. Pharmacodynamic data at both RP2Ds showed peripheral T cell activation and induction of cytokines. SC talquetamab is well tolerated and highly effective at both RP2Ds. Preliminary data suggest that less frequent, higher doses of SC talquetamab do not negatively impact the safety profile. Further evaluation of talquetamab as monotherapy (phase 2;NCT04634552) and in combination with other therapies in patients with RRMM is underway. (Figure Presented) .

Updated Phase 1 Results from MonumenTAL-1: First-in-Human Study of Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

Introduction: Despite recent advances in treatment, patients with multiple myeloma (MM) continue to relapse. G protein-coupled receptor family C group 5 member D (GPRC5D) is a promising target for immunotherapy in patients with MM due to its high expression in malignant plasma cells and limited expression in normal human tissue;unlike other antigens targeted by MM therapies, there is no indication that GPRC5D sheds into the periphery. Talquetamab (JNJ-64407564) is a first-in-class bispecific IgG4 antibody that redirects T cells to kill MM cells by binding to both GPRC5D and CD3 receptors. Here we report updated and new results of talquetamab at the recommended phase 2 doses (RP2Ds) from a phase 1 trial in relapsed/refractory MM (RRMM;NCT03399799). Methods: Eligible patients with MM had relapsed or refractory disease or were intolerant to standard therapies;patients previously treated with B-cell maturation antigen (BCMA)-directed therapies were eligible. This analysis focuses on patients who received talquetamab subcutaneously (SC;range 5.0-800 µg/kg) weekly or biweekly. Step-up dosing was used as a patient management strategy to minimize the severity of cytokine release syndrome (CRS). The primary objectives were to identify the RP2D (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Adverse events (AEs) were graded by CTCAE v4.03 with CRS events graded per Lee et al 2014 criteria. Responses were investigator-assessed per International Myeloma Working Group criteria. Results: As of July 19, 2021, 95 patients have received SC talquetamab. The RP2D was originally identified as a weekly SC dose of 405 µg/kg talquetamab with step-up doses. However, alternative dosing schedules that require less frequent administration continue to be investigated. A biweekly RP2D was also identified as an SC dose of 800 µg/kg talquetamab with step-up doses. 30 patients received the 405 µg/kg weekly dosing schedule (median age: 61.5 years [range 46-80];63% male;100% triple-class exposed;80% penta-drug exposed;77% triple-class refractory, 20% penta-drug refractory;30% prior BCMA-directed therapy;median follow-up: 7.5 mo [range 0.9-15.2]). 23 patients received the 800 µg/kg biweekly dosing schedule (median age: 60.0 years [range 47-84];48% male;96% triple-class exposed;70% penta-drug exposed;65% triple-class refractory, 22% penta-drug refractory;17% prior BCMA-directed therapy;median follow-up 3.7 mo [range 0.0-12.0]). There were no treatment discontinuations due to AEs at either of the RP2Ds. The most common AEs at the 405 µg/kg weekly dose were CRS (73%;1 patient had grade 3 CRS), neutropenia (67%;grade 3/4: 60%), and dysgeusia (60%;grade 2: 29%);skin-related AEs occurred in 77% (all grade 1/2;nail disorders: 30%) of patients, and infections occurred in 37% of patients (1 patient had grade 3 COVID-19 pneumonia). The most common AEs at the 800 µg/kg biweekly dose were CRS (78%;all grade 1/2), dry mouth (44%;all grade 1/2), and neutropenia (44%;grade 3/4: 35%);skin-related AEs occurred in 65% of patients (grade 3: 13%;nail disorders: 17%) and infections occurred in 13% of patients (1 patient had grade 3 pneumococcal sepsis). In 30 response-evaluable patients treated with the 405 µg/kg weekly dose, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR] rate: 57%). In 17 response-evaluable patients treated with the 800 µg/kg biweekly dose, the ORR was 71% (≥VGPR rate: 53%). Responses were durable and deepened over time in both cohorts (Figure). Median duration of response (DOR) was not reached at either RP2D;the 6-month DOR rate for patients who received the 405 µg/kg weekly dose was 67% [95% CI: 41-84]. Serum trough levels of talquetamab were comparable at both RP2Ds. Consistent with the mechanism of action for talquetamab, pharmacodynamic data from cohorts treated at both dose levels showed peripheral T-cell activation and induction of cytokines. Conclusions: These findings indicate that SC talquetamab is well tolerated and highly effective at both RP2Ds. Preliminary data from the 800 µg/kg biweekly cohorts indicate that less frequent, higher doses of SC talquetamab do not have a negative impact on the previously described safety profile. Further investigation of talquetamab as monotherapy (phase 2;NCT04634552) and in combination with other therapies in patients with RRMM is underway. [Formula presented] Disclosures: Krishnan: MAGENTA: Consultancy;BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau;JANSSEN: Consultancy, Research Funding;City of Hope Cancer Center: Current Employment;REGENERON: Consultancy;SANOFI: Consultancy;GSK: Consultancy;Amgen: Speakers Bureau. Minnema: Celgene: Other: Travel expenses;Alnylam: Consultancy;Cilag: Consultancy;BMS: Consultancy;Janssen: Consultancy;Kite/Gilead: Consultancy. Berdeja: Lilly, Novartis: Research Funding;Abbvie, Acetylon, Amgen: Research Funding;Celularity, CRISPR Therapeutics: Research Funding;EMD Sorono, Genentech: Research Funding;Poseida, Sanofi, Teva: Research Funding;Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy;GSK, Ichnos Sciences, Incyte: Research Funding. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. van de Donk: Roche: Consultancy;Takeda: Consultancy;Cellectis: Research Funding;Amgen: Consultancy, Research Funding;Janssen: Consultancy, Research Funding;BMS/Celgene: Consultancy, Honoraria;Novartis /bayer/servier: Consultancy. Rodriguez-Otero: Clínica Universidad de Navarra: Current Employment;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer: Consultancy;Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria;Regeneron: Honoraria. Askari: Janssen: Research Funding. Mateos: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;Sea-Gen: 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;Regeneron: 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;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Honoraria;Bluebird bio: Honoraria;AbbVie: Honoraria;GSK: Honoraria;Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Costa: BMS: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau;Karyopharm: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Sanofi: Consultancy, Honoraria, Speakers Burea . Verona: Janssen: Current Employment. Ma: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Girgis: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Yang: Janssen: Current Employment. Hilder: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Russell: Janssen: Ended employment in the past 24 months. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Chari: Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees;Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding;Millenium/Takeda: Consultancy, Research Funding;Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Research Funding;Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Pharmacyclics: Research Funding;Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Research Funding;Genentech: Consultancy, Membership on an entity's Board of Directors or advisorycommittees;Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

P-137: ITHACA, a randomized multicenter phase 3 study of Isatuximab in combination with Lenalidomide and Dexamethasone in high-risk smoldering Multiple Myeloma: safety run-in preliminary results

Background: High-risk smoldering multiple myeloma (HR-SMM) is associated with a greater risk of progression to symptomatic disease, suggesting the need for early, efficacious therapeutic interventions to improve outcomes. The ongoing, randomized Phase 3 ITHACA study (NCT04270409) is evaluating efficacy and safety of the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with lenalidomide (R) and dexamethasone (d) (Isa-Rd) vs Rd in patients (pts) with HR-SMM. We report here preliminary results from the safety run-in part of this trial. Methods: The primary objective was to confirm the recommended dose of Isa in combination with Rd. Pts were eligible if diagnosed with SMM within 5 years and HR-SMM defined by the Mayo ‘20-2-20’ and/or updated PETHEMA model criteria. Minimal residual disease and imaging by MRI and low-dose whole-body CT/PET-CT will be assessed at fixed time points. Results: As of April 12, 2021, 23 pts (median age, 63 [28–85] years;median time from initial diagnosis, 1.14 [0.1–5.2] years) had received Isa 10 mg/kg once weekly then biweekly (QW-Q2W) in combination with Rd. The median number of cycles was 7 (range, 4–10) and median duration of treatment exposure was 29.7 (range, 16.0–38.0) weeks. Two pts met the Mayo clinical model criteria, 13 pts the PETHEMA model criteria, and 8 pts both models’ criteria for HR-SMM. No pt presented with focal lesions at baseline. Seven (30.4%) pts developed 8 grade ≥3 non-hematologic treatment-emergent adverse events (TEAEs): COVID-19 pneumonia, insomnia (2 each), papular rash, muscle spasm, retinal detachment and hyperglycemia (1 each);no pt experienced a grade 5 TEAE and no pt discontinued treatment due to a TEAE. Serious TEAEs were COVID-19 pneumonia (n=2, grade ≥3) and pneumonia, musculoskeletal chest pain and pyrexia (n=1 each, grade <3). The most common, mostly grade 1–2 TEAEs were insomnia (39%) and constipation, headache, and peripheral edema (22% each). Infusion reactions were reported in 2 pts (8.7%) (grade 2, infusion day 1/cycle 1). By laboratory results, no grade 3–4 anemia or thrombocytopenia was observed;grade 3 neutropenia was reported in 5 pts (21.7%), with no grade 4. Isa exposure and CD38 receptor occupancy were in accordance with other MM studies, reaching target saturation in bone marrow plasma cells. The overall response rate was 86.9%;21.7%, 17.4%, and 4.3% of pts have so far achieved very good partial response (VGPR), complete response (CR) and stringent CR (sCR), respectively. Conclusions: Addition of Isa 10 mg/kg QW-Q2W to Rd was associated with a favorable safety profile in pts with HR-SMM, which compares well with Rd literature data in the same patient population. Isa-Rd has shown encouraging preliminary efficacy (21.7% sCR/CR and 43.4% ≥VGPR rates) in pts with HR-SMM. These results confirm the recommended dose of Isa for the randomized part of the Phase 3 ITHACA study, which will further evaluate efficacy and safety of Isa-Rd in HR-SMM. Funding: Sanofi.