Introduction Triple-class-exposed pts with MM typically have a short duration of response (DOR) to subsequent therapies. ALNUC, a 2+1 BCMA x CD3 TCE with bivalent binding to BCMA, has demonstrated clinical activity in pts with RRMM treated with ≥ 3 prior lines of therapy (LOT) in an open-label phase 1 study (NCT03486067) when administered intravenously (Costa LJ et al. Blood. 2019;134[Suppl 1]:143). However, IV ALNUC was associated with a high rate of cytokine release syndrome (CRS; any grade, 89%; grade ≥ 3, 5%). Based on preclinical data suggesting subcutaneous (SC) administration may improve tolerability, we evaluated the safety and efficacy of SC ALNUC. Here, we present long-term follow-up data for IV ALNUC and preliminary data for SC ALNUC in pts with RRMM treated in the phase 1 study.

Methods Pts with MM who had received ≥ 3 prior LOT, including an immunomodulatory drug (IMiD®), a proteasome inhibitor, and an anti-CD38 therapy, were eligible. IV ALNUC was administered as previously reported at target doses of 0.15-10 mg, with both fixed and step-up dosing. SC ALNUC was given on day 1 (D1), 4, 8, 15, and 22 of cycle 1 (C1), QW in C2-3, Q2W in C4-6, and Q4W in C7 and beyond (28-d cycles). Pts received 2 step-up doses (3 mg on C1D1 and 6 mg on C1D4) and a ≥ 10 mg target dose on C1D8 and thereafter. Target doses tested in SC dose escalation were 10, 15, 30, and 60 mg, with 10 and 30 mg evaluated in dose expansion. Primary objectives included assessments of ALNUC safety and tolerability. Minimal residual disease (MRD) was assessed from bone marrow aspirate by Next Generation Flow using the EuroFlow panel.

Results At data cutoff on May 31, 2022, 70 pts have received IV ALNUC, 39% (27/70) achieved an objective response, and median progression-free survival was 13.3 wks (95% CI, 8.1-23.9). Median DOR in pts achieving a response with IV ALNUC was 146.1 wks (95% CI, 40.6-not reached).

Forty-seven pts were treated with SC ALNUC in dose escalation (10 mg: n = 6; 15 mg: n = 4; 30 mg: n = 6; 60 mg: n = 3) and dose expansion (10 mg: n = 19; 30 mg: n = 9). Median age was 63 yrs; 55% were female. Pts received a median of 4 prior regimens; 98% had myeloma refractory to the last LOT, 96%/62% had triple-class exposed/refractory myeloma, and 60%/21% had penta-drug exposed/refractory myeloma. At the May 31, 2022 data cutoff, median duration of follow-up was 2.6 mo (range, 0-11.4), and 68% (n = 32) of pts were continuing SC ALNUC treatment.

Any-grade/grade 3-4 treatment-emergent adverse events occurred in 89%/62% of treated pts; the most common were CRS (53%/0%), neutropenia (34%/30%), and anemia (34%/17%). All CRS events were limited to grade 1 (21 pts; 45%) or grade 2 (4 pts; 9%); 20 pts received ≥ 1 concomitant medication for CRS, including tocilizumab (n = 12) and/or corticosteroids (n = 8). Median time to CRS onset was 3 d (range, 1-20); median duration was 2 d (range, 1-11). In 16 pts with grade 3-4 neutropenia, median time to resolution (grade ≤ 2) was 6 d (range, 1-36). There was one grade 1 immune effector cell-associated neurotoxicity event. No pts discontinued treatment due to adverse events; no treatment-related deaths occurred.

Preliminary population pharmacokinetic analysis estimated SC ALNUC bioavailability of ~70%; 30 mg SC achieved similar concentrations observed with 10 mg IV Cmax by end of C1; baseline body weight was not a significant covariate of exposure. Hallmark pharmacodynamic effects of TCEs were observed with SC and IV ALNUC (peripheral blood immune cell redistribution, transient cytokine release, and induction of T-cell factors associated with antitumor activity).

Among 41 efficacy-evaluable (EE) pts treated with SC ALNUC (received ≥ 1 dose and had ≥ 1 post-baseline disease assessment), ORR was 51% (21/41 pts) across all dosing regimens and 77% (10/13 pts) in pts receiving target doses ≥ 30 mg (Figure). Among the 21 pts who achieved a response, 14 pts had evaluable MRD samples, and all (100%) were MRD negative (10-5 sensitivity) at C2D1 or C4D1. Median time to response was 4.3 wks (range, 4.1-17.4), and all 21 responses (100%) were ongoing.

Conclusions IV administration of ALNUC was associated with durable responses in heavily pretreated pts with RRMM. SC administration widened the therapeutic index with an improved safety profile compared with IV; CRS was limited to grade 1-2 events. SC ALNUC exhibited promising dose-dependent antitumor activity with a high proportion of MRD responses. Enrollment in the phase 1 study is ongoing and updated data will be presented.

Figure 1
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Wong:Patient Discovery: Research Funding; Catalent Biologics: Consultancy; Dren Bioscience: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; GSK: Research Funding; Fortis: Research Funding; Caelum: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding. Paris:Takeda: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hofmeister:Sanofi: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees. Hansson:Takeda: Consultancy; Janssen: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy; AstraZeneca: Consultancy; Celgene: Speakers Bureau. Santoro:Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Speakers Bureau; Eli-Lilly: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Abb-vie: Speakers Bureau; Roche: Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Consultancy; Incyte: Consultancy. Mateos:GSK: 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; Bristol Myers Squibb/Celgene: Honoraria, 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodríguez-Otero:Oncopeptides: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Regeneron: Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Encinas:Pfizer: Honoraria; Sanofi: Honoraria, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria. Yee:Sanofi: Consultancy; Takeda: Consultancy; Regeneron: Consultancy; Oncopeptides: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. Oriol:GlaxoSmithKline: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Janssen: Consultancy; Bristol Myers Squibb/Celgene: Consultancy, Speakers Bureau. Cerchione:Jazz Pharmaceutical: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Servier: Honoraria, Speakers Bureau; Sierra Oncology: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Menarini-Stemline: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Glycomimetics: Consultancy; Takeda: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. de la Rubia:Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Ablynx/Sanofi: Honoraria; GSK: Honoraria. Bermúdez:Pfizer: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Neovii: Consultancy, Speakers Bureau; Trecondi: Consultancy, Speakers Bureau; MSD: Consultancy. Boss:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Gaudy:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Li:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hsu:Bristol Myers Squibb: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Godwin:Pfizer: Research Funding; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Burgess:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. San-Miguel:Abbvie, Amgen, BMS, Celgene, GSK, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Takeda, Regeneron, Roche, Sanofi, and SecuraBio: Consultancy, Other: Advisory Board. Costa:AbbVie: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genentech: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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