ISB 2001 Yields Durable Responses, Manageable Safety in R/R Multiple Myeloma

Treatment with ISB 2001 led to an overall response rate of 74% across dose levels 1 to 9 in patients with relapsed/refractory multiple myeloma.

Results from the dose-escalation part of the phase 1b TRIgnite-1 study (NCT05862012) shared at the 22nd Annual International Myeloma Society Meeting and Exposition showed that ISB 2001, an investigational BCMA/CD38/CD3–directed trispecific antibody, was efficacious and had an acceptable safety profile in the treatment of patients with relapsed/refractory multiple myeloma.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 (f69%), 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, including:

1. Patients with no prior CAR T-cell therapy or bispecific antibodies (n = 19): ORR, 84% (sCR, 21%; CR, 11%; VGPR, 41%; PR, 11%)
2. Patients who had progressed on prior CAR T-cell therapy or bispecific antibodies (n = 14): ORR, 71% (sCR, 14%; CR, 14%; VGPR, 22%; PR, 21%)
3. Patients who had progressed on prior BCMA-targeted therapies (n = 15): ORR, 73% (sCR, 7%; CR, 20%; VGPR, 27%; PR, 20%)
4. Patients who were refractory to their last line of therapy (n = 24): ORR, 75% (sCR, 13%; CR, 13%; VGPR, 32%; PR, 17%)
5. Patients who were refractory to CD38-directed treatments (n = 25): ORR, 72% (sCR, 12%; CR, 12%; VGPR, 32%; PR, 16%)
6. Patients for whom 0 to 6 months had passed since their last CD38-directed treatment (n = 12): ORR, 83% (sCR, 25%; CR, 8%; VGPR, 33%; PR, 17%)
7. Patients with EMD at baseline (n = 11): ORR, 82% (sCR, 18%; CR, 18%; VGPR, 37%; PR, 9%)
8. Patients with high-risk cytogenetics (n = 9): ORR, 78% (sCR, 11%; CR, 11%; VGPR, 56%; PR, 0%)

“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. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-35.
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