ISB 2001 Shows Favorable Safety Profile and Antitumor Activity in R/R Multiple Myeloma

Treatment with the investigational BCMA/CD38/CD3–directed trispecific antibody ISB 2001 was associated with a manageable safety profile and robust activity in patients with relapsed/refractory multiple myeloma, according to findings from the dose-escalation portion of the phase 1b TRIgnite-1 study (NCT05862012), which were presented at the 22nd Annual International Myeloma Society Meeting and Exposition.1

At a median follow-up of 6.3 months (range, 1-16), among patients from the dose-escalation portion with at least 1 month of follow-up (n = 35), ISB 2001 was associated with manageable hematologic toxicities that enabled continuation of the drug. Any-grade and grade 3 or higher hematologic treatment-emergent adverse effects (TEAEs) occurred in 69% and 60% of patients, respectively. These included neutropenia (any-grade, 51%; grade ≥ 3, 43%), thrombocytopenia (49%; 23%), anemia (20%; 14%), and lymphopenia (11%; 9%). Any-grade and grade 3 or higher hematologic treatment-related TEAEs occurred in 57% and 49% of patients, respectively. These included neutropenia (any-grade, 34%; grade ≥ 3, 29%), thrombocytopenia (37%; 14%), anemia (6%; 6%), and lymphopenia (11%; 9%).

Nonhematologic AEs seen in the study were also deemed manageable. Any-grade and grade 3 or higher nonhematologic TEAEs occurred in 100% and 57% of patients, respectively. The most common any-grade nonhematologic TEAEs were infections (74%), cytokine release syndrome (CRS; 69%), injection site reaction (54%), nausea (31%), back pain (23%), headache (20%), increased alanine aminotransferase (ALT) levels (17%), increased aspartate aminotransferase (AST) levels (17%), diarrhea (17%), and fatigue (17%). The most common grade 3 or higher nonhematologic TEAEs were infections (29%), increased AST levels (6%), and diarrhea (6%).

“Deep and durable responses were [also] seen at dose level 3 and [above],” lead study author Hang Quach, MD, FRACP, FRCPA, MBBS, reported in a presentation of the data.

Quach is a professor of hematology at the University of Melbourne and the departmental head of Clinical Haematology and Clinical Haematology Research at St Vincent’s Hospital Melbourne in Australia.

What Is the Mechanism of Action of ISB 2001?

ISB 2001 employs enhanced avidity-based binding to myeloma cells with both BCMA and CD38 Fab domains. The binding affinity of the agent and distal positioning of the CD38 binders in relation to the CD3 binders induces potent tumor cell killing and minimizes the incidence of CD38-related off-tumor AEs.

What Was the Design of the TRIgnite-1 Study?

TRIgnite-1 enrolled patients with relapsed/refractory multiple myeloma who had progressed on at least 3 prior lines of therapy, including an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory drug.1,2 Patients were permitted to have received prior CAR T-cell therapy and/or bispecific antibodies.

In the dose-escalation portion, patients received weekly subcutaneous doses of ISB 2001 across 9 dose levels ranging from 5 µg/kg to 2700 µg/kg. Dosing was preceded by 2 step-up doses on days 1 and 4.

The primary end points were safety and tolerability, as well as the identification of the maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary end points included pharmacokinetics (PK), immunogenicity, and clinical activity by International Myeloma Working Group criteria.

What Were the Baseline Characteristics of Patients in the TRIgnite-1 Study?

Patients had a median age of 65 years (range, 47-82).1 In total, 34% of patients had extramedullary disease (EMD) at screening, 40% of patients had high-risk cytogenetics, and the median number of prior lines of therapy was 6 (range, 3-11). All patients were triple-class exposed, and 49% of patients were triple-class refractory. In total, 71% and 14% of patients were penta-drug exposed and penta-drug refractory, respectively. A total of 46% of patients had received prior BCMA-targeted therapies, and 43% of patients had received prior T-cell–directed therapies.

What Else Should Be Known About the Safety Profile of ISB 2001 in TRIgnite-1?

Any-grade and grade 3 or higher nonhematologic treatment-related TEAEs occurred in 91% and 20% of patients, respectively. The most common any-grade nonhematologic treatment-related TEAEs were infections (34%), CRS (69%), injection site reaction (54%), nausea (11%), back pain (3%), headache (11%), increased ALT levels (14%), increased AST levels (14%), and fatigue (11%). The most common grade 3 or higher nonhematologic TEAEs were infections (11%), and increased AST levels (3%).

No dose-limiting toxicities (DLTs) were reported across the full dose-escalation cohort. Notably, the CRS events were all grade 1 (57%) or grade 2 (11%) and often occurred after the first step-up dose only (50%). The median time to CRS was 2 days (range, 1-118), and the median duration of CRS was 2 days (range, 1-8). In total, 13 patients received tocilizumab for grade 2 (n = 4) and grade 1 (n = 9) CRS. No prophylactic tocilizumab was used.

One patient had grade 1 immune effector cell–associated neurotoxicity syndrome; no other drug-related neurologic AEs were observed. One patient had grade 5 cardiac arrest that was unrelated to study treatment; this patient had a significant cardiovascular medical history. Additionally, 1 patient discontinued treatment because of grade 2 bronchitis and sinusitis.

What Was the Efficacy of ISB 2001 in TRIgnite-1?

Among patients treated at dose levels 1 to 9, the overall response rate (ORR) was 74%, including stringent complete response (sCR), CR, very good partial response (VGPR), and PR rates of 17%, 11%, 32%, and 14%, respectively. The median duration of response (DOR) was not reached (NR; 95% CI, 7 months-NR), and the estimated 6-month DOR rate was 90% (95% CI, NR-NR).

Among patients treated at dose levels 3 to 9 (n = 33), the ORR was 79%, including sCR, CR, VGPR, and PR rates of 18%, 12%, 34%, and 15%, respectively.

The first objective response was observed at the 50-µg/kg dose level (dose level 3); this patient achieved an sCR and was minimal residual disease (MRD) negative at 10–5 sensitivity. Among responders, the median time to first response was 35 days (range, 29-205). Of the 10 patients who achieved a CR or better, 8 were evaluable for MRD. Of those patients, 75% were MRD negative at 10–5 sensitivity.

ISB 2001 elicited high response rates across difficult-to-treat subgroups (Figure). Among patients with no prior exposure to CAR T-cell therapy or bispecific antibodies (n = 19), the ORR was 84%, with sCRs in 21%, CRs in 11%, VGPRs in 41%, and PRs in 11% of patients. In patients who had progressed on prior CAR T-cell therapy or bispecific antibodies (n = 14), the ORR was 71%, including sCRs in 14%, CRs in 14%, VGPRs in 22%, and PRs in 21% of patients. For patients who had previously progressed on a BCMA-targeted therapy (n = 15), the ORR was 73%, with sCRs in 7%, CRs in 20%, VGPRs in 27%, and PRs in 20% of patients.

Among those refractory to their last line of therapy (n = 24), the ORR was 75%, with sCRs and CRs each observed in 13% of patients, VGPRs in 32%, and PRs in 17%. Patients refractory to CD38-directed treatments (n = 25) demonstrated an ORR of 72%, including sCRs and CRs each in 12% of patients, VGPRs in 32%, and PRs in 16%. In patients for whom 0 to 6 months had passed since their last CD38-directed therapy (n = 12), the ORR was 83%, with sCRs in 25%, CRs in 8%, VGPRs in 33%, and PRs in 17% of patients.

Among those with EMD at baseline (n = 11), the ORR was 82%, including sCR and CR each in 18% of patients, VGPR in 37%, and PR in 9%. Finally, patients with high-risk cytogenetics (n = 9) achieved an ORR of 78%, with sCRs and CRs each in 11% of patients, VGPRs in 56%, and no PRs observed.

“There was robust activity across key subgroups, including quadruple-exposed patients and patients with prior CAR T-cell [therapy] and T-cell engagers,” Quach concluded.

Of note, a PK analysis showed dose-proportional PKs with ISB 2001, which had a median half-life of 17 days; these data suggest the need for less-frequent dosing of the agent.

Part 2 of the study, which comprises the dose-expansion and -optimization portions, is ongoing to establish the RP2D and the best dosing schedule of ISB 2001 for future development.

Disclosures: Quach reported consulting/advisory roles/honoraria with BMS, Johnson & Johnson, GSK, AbbVie, Regeneron, and Pfizer; as well as research funding from GSK, BMS, AbbVie, Antengene, and Karyopharm.

Reference

1. Quach H, Augustson B, Levitz D, et al. TRIgnite-1 study: phase 1, first-in-human study of ISB 2001: a BCMAxCD38xCD3-targeting tri-specific antibody for patients with relapsed/refractory multiple myeloma (RRMM)—dose escalation (DE) results. Clin Lymphoma Myeloma Leuk. 2025;25(2):S23-S24. doi:10.1016/S2152-2650(25)03439-1
2. Study of ISB 2001 in relapsed/refractory multiple myeloma (TRIgnite-1).Clinicaltrials.gov. Updated September 11, 2025. Accessed September 17, 2025. https://clinicaltrials.gov/study/NCT05862012