Results: As of July 18, 2023, based on ongoing clinical database, 39 subjects had received weekly IV infusions of ISB 1342 in 8 dose-escalation groups from 0.2/0.3 mg/kg to 4.0/16.0 mg/kg as priming/treatment dose; and 7 additional subjects had received weekly SC injections at 2.0/8.0 mg/kg. Two different formulations have been tested in SC group. Median number of cycles administered was 2. The majority were male (57%) and white (74%); 13% were Black or African American. The median age was 69 years (range, 54-76) and the median time since diagnosis was 6.6 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-12). Twenty-one (67%) subjects were considered to be triple-class refractory and 18 (48%) penta-drug refractory.

Forty-one (89%) subjects experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (37%), cytokine release syndrome (CRS, 34%, all grade 1or 2), anemia (24%), neutropenia (24%), and thrombocytopenia (17%). Five subjects in SC group (71% of SC) had injection site reaction, all grade 1 or 2. Grade 3 or higher TRAEs occurring in more than 5% of subjects were infusion related reaction (no grade 4), anemia (no grade 4), neutropenia, leukopenia. No Grade 5 TRAE was observed.

After QW IV infusion, ISB 1342 serum concentration peaked at the end of infusion and then showed bi-exponential decline. ISB 1342 serum exposures increased in a dose linear fashion across the tested IV infusion dose range. The limited PK data after SC injection suggest slow presentation of ISB 1342 into the systemic circulation leading to lower Cmax and delayed Tmax relative to IV. Transient increases in serum cytokines were observed within 24 hours after ISB 1342 dosing, including IFNg, TNFa, IL-2, IL-6 and IL-10. Transient increases in T-cell activation were observed by flow cytometry at 24-48 hours after ISB 1342 dosing at 1.0 / 4.0 μg/kg and above, based on increased expression of CD69 on peripheral blood CD4+ and CD8+ T-cell populations (Figure 1). Comparison of the available data from subjects treated at 2 / 8 μg/kg (Cohort 109) indicated reduced T-cell activation following SC compared to IV administration of ISB 1342. The efficacy signals observed in Cohorts 108 and 109 are consistent with the estimates of the lower boundary of the predicted efficacious dose range using a quantitative systems pharmacology (QSP) model based on preclinical data. Updated clinical data, including response rates and safety data, will be present at the meeting.

Conclusions: Treatment with ISB 1342 was well tolerated at higher dose levels evaluated. Observed CRS events were moderate. No increased risk of infection has been observed . Updated safety, efficacy, biomarker and PK data will be presented.

As of July 7, 2022, 24 patients had received a once weekly, IV infusion of ISB 1342 in 6 dose-escalation groups from 0.2/0.3 mg/kg dose level to 1.0 / 4.0 mg/kg dose level. The majority were males (63%) and white (67%); 21% were black or African American. The median age was 67 years (range, 54-76) and the median disease duration since onset was 6.7 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-10); 8 (33%) patients had received prior B cell maturation antigen (BCMA)-targeted therapy including bi-specifics, antibody drug conjugates (ADCs) and/or cell therapies. Twenty-one (88%) patients were considered to be triple-refractory and 18 (75%) were considered to be penta-refractory. Twenty-two (92%) patients experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (42%), anemia (21%), cytokine release syndrome (CRS, 17%), thrombocytopenia (17%), and diarrhoea (13%). Nine (38%) patients had grade 3 or higher TRAEs with only infusion related reactions occurring in more than 5% of patients (17%, all grade 3 events). No grade 5 TRAE was observed. One dose limiting toxicity (DLT), a Grade 3 delirium was observed in a 73-year-old patient treated at 0.3/0.55 dose level after the third dose of ISB 1342, and who also presented with Grade 4 pneumonia; three additional patients were enrolled at that dose level, no other DLT was observed, and dose escalation continued. The median duration of treatment was 2 months (range, 1-5). The ISB 1342 serum concentration-time profiles showed Cmax near the end of infusion, followed by a biphasic decline. The serum exposures showed a dose-dependent increase following both Q2W and Q1W regimens. With the Q1W regimen, the serum Ctrough was higher than that with the Q2W regimen at similar dose levels. Transient increases in serum cytokine levels were observed within 24 hours following ISB 1342 administration, including IFNg, TNFa, IL-2, IL-6 and IL-10.