Results: As of June 2, 2023, 40 pts; median age 66 years (range: 44-76) were enrolled; 38 received CART-ddBCMA (32, DL1; 6, DL2) & 38 were evaluable for initial safety & clinical response. Two pts who were not dosed had cell product manufactured but were not eligible for cell infusion due to medical complications. Pts had a median of 4 (range: 3-16) prior lines of therapy. All infused pts (100%) were triple-refractory, & 26 (68%) were penta-refractory; 34 pts (89%) were refractory to last-line of treatment; 9 pts (24%) had high tumor burden with ≥60% bone marrow plasma cells; 13 (34%) pts had extramedullary disease; & 11 (29%) pts had high-risk cytogenetics (Del 17p, t(14;16), t(4;14)) at baseline. Median follow-up after CART-ddBCMA infusion was 22 months (range: 9-40 months). CAR+ cells comprised a median 70% (range: 48-87%) of total CD3+ T cells; median vector copy number was 2.2 copies/cell (range: 1.1-3.5); median cell viability was 98% (range: 90-100%), & median cell manufacturing yield was 1174 ×106 CAR+ cells (range: 470-1626 ×106). CART-ddBCMA product characteristics were consistent with the specifications in all the lots, & there were no manufacturing failures. CRS occurred in 36/38 (95%) pts but only 1 pt in DL2 had grade (Gr) 3 CRS & all other cases were Gr≤2. ICANS occurred in 7 pts (5, Gr≤2; 2, Gr3), with 1 Gr3 case in each DL. All cases of CRS & ICANS resolved without further sequalae with management. No cases of off-tumor cell mediated toxicity, delayed neurotoxicity events (i.e., occurring after day 28), or Parkinsonian-like symptoms were observed. All 38 evaluable pts demonstrated investigator-assessed clinical response per 2016 IMWG criteria (ORR, 100%) with 22 sCR, 7 CR (≥CR rate, 76%), 6 VGPR (≥VGPR rate, 92%), & 3 PR. Responses deepened over time & conversion to CR/sCR was observed with longer follow-up (as late as month 12). Of those evaluable for MRD testing to date (n=29), 25 (86%) were MRD-neg at 10-5. Median duration of response, PFS, & OS were not reached at the time of data-cut because 25 of 38 evaluable pts (66%) had ongoing response. The Kaplan-Meier estimated PFS rates for 6, 12 & 18 months were 92%, 74%, & 67% respectively. Durable responses were also observed in patients with high-risk features (EMD, BMPC ≥ 60%, or B2M ≥ 5.5 at baseline) & high-risk cytogenetics. PFS rates at 6-, 12-, & 18-months are shown in Table 1. Based on the results from the study, a dose of 115 ± 10 ×106 cells, consistent with DL1, was recommended for the phase 2 study.

Conclusions: Adverse events with CART-ddBCMA, including CRS & ICANS, were manageable & no off-tumor tissue-targeted toxicity, delayed neurotoxicity, or Parkinsonian-like events were observed in the entire cohort at the time of data-cut. Ongoing efficacy results are encouraging, with 100% ORR, including 35 (92%) response of VGPR or better & 29 (76%) with CR/sCR. More importantly, clinical responses were durable with an overall estimated 18-mo PFS rate of 67% with comparable clinical responses seen in ‘high-risk’ patients known to have poor prognosis. Updated data with additional follow-up based on later data-cut will be presented.

At the last data-cut performed on May 3, 2022, 37 patients (pts, median age 66 (range: 44-76)) were enrolled, 33 received CART-ddBCMA and 31 were evaluable for initial safety and clinical response. Median follow-up after CART-ddBCMA infusion was 12.1 months. 27 subjects received DL1 (6 in dose escalation and 21 in dose expansion, 25 evaluable) and 6 received DL2 (all evaluable). CAR+ cells comprised median 72% (48-87%) of total CD3+ T cells; median VCN was 2.2 copies/cell (1.1-3.5); median cell viability was 99% (91-100%), and median cell manufacturing yield was 1159 million cells (470-1626).

Subjects had a median of 5 (3-16) prior lines of therapy. Twenty-four pts (77%) were "triple-refractory," and 21 (68%) were "penta-refractory"; 12 pts (39%) had high tumor burden with ≥ 50% bone marrow plasma cells; and 12 (39%) pts (50%) had extramedullary disease at baseline. CRS was seen in 28/31 (90%) pts but only 1 subject (in DL2) had grade (G) 3 CRS and all other cases were G≤2. ICANS was seen in 7 subjects (5, G≤2; 2, G3), with 1 G3 case in each DL. All cases resolved without sequalae with standard management. No cases of off-tumor cell mediated toxicity, no delayed neurotoxicity events (i.e., occurring after day 28), and no Parkinsonian-like symptoms.

All 31 evaluable subjects demonstrated clinical response per IMWG criteria (ORR, 100%) with 22 sCR/CR (≥CR rate, 71%), 7 VGPR (≥VGPR rate, 94%), and 2 PR. Responses deepened over time and conversion to CR/sCR was observed with longer follow-up (as late as month 12). Of those evaluable for MRD testing to date (n=22), 19 (86%) were MRD-neg at 10-5 or lower.

Median duration of response, PFS & OS were not evaluable at the time of data-cut because 22 of 31 evaluable subjects (71%) had ongoing response. In the patients with ≥12 months follow-up (n=16), which included 8 (50%) patients with EMD, ORR was 100%, ≥CR rate was 81% (13/16) and ≥VGPR rate was 88% (14/16). CART-ddBCMA product characteristics were consistent with the specifications in all the lots and there were no manufacturing failures.

Evaluable for efficacy and safety analysis were 31 patients, based on follow-up of at least one month, following treatment. These evaluable patients comprised the dose escalation cohorts for the first dose level (100 million CAR+ T cells, n=6), the second dose level (300 million CAR+T cells, n=6), and a dose expansion cohort at the recommended Phase 2 dose (RP2D) of 100 million CAR+T cells (n=19). All patients enrolled in the study have poor prognostic factors with 21 of 31 (68%) patients penta-refractory, 12 of 31 (39%) extramedullary disease (EMD), and all 31 patients having had at least three prior treatments.

The interim CART-ddBCMA clinical results (May 3, 2022 cutoff date) demonstrate deep and durable responses in patients with poor prognostic factors.

• Of the 31 evaluable patients with median follow-up of 12.1 months
  • 100% overall response rate (ORR) achieved in all patients per International Myeloma Working Group criteria
  • 22 of 31 (71%) evaluable patients achieved complete response (CR) or a stringent complete response (sCR)
  • 29 of 31 (94%) patients achieved > very good partial response (VGPR)
  • 2 of 31 (6%) patients achieved a partial response (PR)
  • 12 of 31 (39%) with extramedullary disease
• 13 of 16 patients (81%) dosed more than 12 months ago reached CR/sCR; 8 (50%) with EMD; 9 (56%) remain in ongoing response with a median follow up of 17.7 months
• Conversions to sCR have occurred as early as 1 month and also at ≥12 months
• CART-ddBCMA dosed at RP2D (100 million CAR+T cells) continues to be well-tolerated
  • Toxicities including CRS and ICANS have been manageable, and all resolved with standard management at both dose levels
  • No cases of delayed neurotoxicity events or parkinsonian symptoms
  • No cases of grade 3 (or greater) CRS and only one case (4%) of grade 3 ICANS event with no additional cases from previously reported.

As previously announced, as of the April 14, 2021 data cutoff:

• 12 of 12 patients achieved responses per IMWG criteria (median follow-up of 197 days; (Min – Max) 29-449 days)
  • 5 patients achieved stringent complete responses (sCR)
  • 1 patient achieved a complete response (CR)
  • 3 patients achieved very good partial responses (VGPR)
  • 3 patients achieved partial responses (PR)
• One patient achieved VGPR despite prior progression on BCMA-targeted therapy
• Responses in 11 patients are ongoing, with evidence that responses deepen over time

All patients enrolled in the study have poor prognostic factors with 10 of 12 patients penta-refractory and all 12 patients having had at least three prior treatments.