Results: Of 73 pts treated with SC ALNUC in dose escalation (target dose: 10 mg, n = 6; 15 mg, n = 4; 30 mg, n = 6; 60 mg, n = 7) and dose expansion (target dose: 10 mg, n = 19; 30 mg, n = 21; 60 mg, n = 10), median age was 64 y; 58% were male. Pts had median of 4 prior regimens (range, 3–14); 96% were refractory to last LOT, 100%/78% had triple-class/penta-drug exposed MM, and 63%/19% had triple-class/penta-drug refractory MM. Median follow-up was 7.4 mo (range, 0.5–19.9).

All-grade/grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 99%/81% of pts; most common were CRS (56%/0%), neutropenia (55%/45%), anemia (47%/27%), and thrombocytopenia (37%/16%). All-grade/grade ≥ 3 infections occurred in 62%/16% of pts; infections occurring in ≥ 10% of pts were COVID-19 (23%/3%) and upper respiratory tract infections (12%/0%). Infections of special interest included grade 2 cytomegalovirus reactivation in 1 pt (1.3%); there were no grade ≥ 3 infections of special interest. Median time to CRS was 3 d (range, 1–20), with a median duration of 2 d (range, 1–11). CRS was most common after the first step-up dose (40% of pts). Of 887 doses administered at the fourth dose and beyond, the frequency of CRS per dose was < 1%. Two pts had grade 1 neurotoxicity suspected related to SC ALNUC; no grade ≥ 2 neurotoxicity was observed. One pt discontinued treatment due to a TEAE (grade 3 metastatic colon cancer not suspected related to treatment); 1 treatment-related death (cerebral hemorrhage) occurred at the 60-mg target dose.

Overall response rate (ORR) was 54% (39 of 72 efficacy-evaluable pts treated with SC ALNUC) across all doses, with responses deepening over time (Figure). ORR was 63% (27/43) at target doses ≥ 30 mg and 69% (18/26) at the 30-mg target dose. Median time to response was 1.2 mo (range, 0.9–4.0) and 77% (30/39) of responses were ongoing at data cutoff. Among efficacy-evaluable pts, median PFS was 10.1 mo (95% CI, 2.8–16.6) across all dose levels. For the 30‑mg target dose, at a median follow up of 9.3 mo, median PFS was not reached (95% CI, 4.7–NA) with a 12-mo PFS of 53% (95% CI, 30–71). Among the 39 pts who achieved a response, 28/28 pts (100%) with evaluable minimal residual disease (MRD) samples were MRD-negative (10−5 sensitivity by flow cytometry) at C2D1, C4D1, C6D1, or C8D1; of the 18 pts who achieved a response at the 30-mg target dose, 14/14 pts (100%) with available MRD data were MRD-negative.

Preliminary population pharmacokinetic analysis estimated ~60% SC ALNUC bioavailability with a 14-d half-life. Observed trough concentrations at the 30-mg target dose exceeded levels predicted for efficacy by C2D1. Hallmark pharmacodynamic effects of TCEs were observed.

Conclusions: SC ALNUC continued to demonstrate a safety profile consistent with the drug class and a low rate of severe infections. Across doses, responses were durable and deepened over time, with a high proportion of responders achieving MRD negativity. High antitumor activity was observed at target doses ≥ 30 mg and specifically at the 30-mg target dose. Enrollment in the phase 1 study is ongoing.

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.

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.

• The overall response rate (ORR) in all patients was 43.3% with a stringent complete response/complete response (sCR/CR) of 16.7%
• The likelihood of response was dose-dependent. ORR by CC-93269 dose:
  • Dose ≤ 3mg (n= 7): 0%
  • Dose 3 to 6 mg or fixed-dose 6 mg (n= 14): 7%
  • Dose 6 to 10 mg or fixed-dose 10 mg (n= 9): 88.9%
• Among the nine patients treated with 10 mg of CC-93269, the ORR was 88.9% with a sCR/CR of 44.4%
• The median time to response was 4.1 weeks (range; 4–13.1)
• Among 13 responding patients, 11 responses are ongoing
• Measurable residual disease (MRD) negativity was achieved by 12 of the 13 responding patients