Myeloma Novel Drug Targets and agents
Hang Quach, MBBS(Hons) FRACP FRCPA MD (she/her/hers)
Director of Haematology
St Vincent’s Hospital Melbourne, University of Melbourne, VIC, Australia
Melbourne, Victoria, Australia
MM remains an incurable disease and resistance mechanisms are emerging. ISB 2001, a first-in-class trispecific T cell engager, redirects cytotoxic T cells to BCMA and/or CD38-expressing myeloma cells. By simultaneously targeting two TAA, ISB 2001 enhances avidity binding to tumor cells in vitro, hence potency, while the distal positioning of the CD38 vs CD3 binders minimizes CD38-related off-tumor adverse events.
Methods: We report data from the DE portion of a Phase 1 study of ISB 2001, assessing safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) in RRMM patients (pts) exposed to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 therapies and refractory or intolerant to established therapies. Prior BCMA-targeted and/or T-cell directed therapies were allowed. ISB 2001 was administered weekly subcutaneously (SC), with double step-up doses on Days 1 and 4. DE utilized an accelerated titration design (initial 3 cohorts with single-patient dosing) followed by a standard 3+3 design. Adverse events (AEs) were graded by CTCAE v5.0; CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Overall response rate (ORR) was assessed by IMWG criteria.
Results:
As of May 08, 2025, 35 heavily pretreated pts received ISB 2001 across 9 dose levels (5–2700 μg/kg) with a median follow-up of 6.3 months (range: 1–16). Median age was 65 years; 66% male, 77% white with a median of 6 prior lines of therapy (range: 3-11). All pts were triple-exposed, 25/35 (71%) penta-exposed, including 5/25 (20%) penta-refractory, and 25/35 (71%) CD38-refractory. Sixteen (46%) and 15 (43%) pts received prior BCMA and T cell redirected (bispecifics and/or CART) therapies, respectively. Ten (40%) pts had a high cytogenetic risk and 12 (34%) had EMD at study entry. No DLT was observed. Overall, 100% of pts reported ≥1 AE regardless of causality, most commonly CRS (any grade [G]: 69%, G1: 54%, G2: 14%), infections (any G: 74%, G3/4: 29%) and
neutropenia (any G: 51%, G3/4: 43%). One patient (3%) reported a single G1 event of ICANS. One pt died due to unrelated AE.
ORR was 74% across all 9 doses. Among the 33 patients treated at active doses (≥50 µg/kg), ORR was 79%, ≥CR: 30%, ≥VGPR: 64%, MRD negativity rate: 75%. Most patients (81%) remain in response (median Duration of Response not reached). Median time to response was 35 days. ISB 2001 showed near dose-proportional PK, an estimated half-life of 17 days enabling monthly dosing, and consistent T-cell activation, supporting its mechanism of action.
Conclusions:
ISB 2001 was well tolerated with manageable adverse events and demonstrated robust anti-myeloma activity in heavily pretreated RRMM pts (NCT05862012). Expansion Cohorts to further optimize dose and treatment schedules following FDA Project Optimus are open to accrual.