Novel Trispecific Antibody May Offer “Renewed Hope” in R/R Multiple Myeloma

Hang Quach, MBBS, MD, FRACP, FRCPA

St Vincent’s Hospital Melbourne

The investigational trispecific antibody ISB 2001 produced “remarkable” outcomes among patients with relapsed/refractory multiple myeloma, according to Hang Quach, MBBS, MD, FRACP, FRCPA.

Quach, a professor of hematology at the University of Melbourne and head of the Department of Clinical Hematology and Clinical Hematology Research at St Vincent’s Hospital Melbourne in Australia, spoke with CancerNetwork® about updated efficacy and safety findings from the phase TRIgnite-1 study (NCT05862012) evaluating ISB 2001 among patients with relapsed/refractory multiple myeloma who progressed on at least 3 prior lines of treatment. She presented these findings at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Based on encouraging data, Quach highlighted robust responses across difficult-to-treat multiple myeloma subgroups, which included those with progression on CAR T-cell therapy or anti-BCMA therapy. Additionally, a favorable safety profile indicated low incidence of severe hematologic toxicity and infection. Looking ahead, Quach stated that moving ISB 2001 to earlier lines of therapy or combining the agent with other modalities may further improve outcomes.

“Part 1 of the TRIgnite-1 study demonstrated that ISB 2001 has quite an impressive efficacy and tolerability profile in [patients with] heavy pretreated, difficult-to-treat multiple myeloma,” Quach said. “For these patients [with] quite limited treatment options, this therapy can change the landscape of treatment for these patients and offer renewed hope.”

CancerNetwork: What was the background for this research?

Quach: At this ASCO meeting, I’ve been privileged to be able to present an update of the TRIgnite-1 study. The TRIgnite-1 study is a phase 1 first-in-human study looking at ISB 2001 in patients with relapsed/refractory multiple myeloma. ISB 2001 is a trispecific T-cell engager that targets both CD38 and BCMA on multiple myeloma cells and engages CD3 on T cells. What’s unique about this molecule is that the dual high-affinity binding to the tumor cells enhances T-cell–mediated cytotoxicity even at low antigen expression levels. In addition, the low-affinity binding to CD3 limits off-tumor toxicity as well as minimizes T cell exhaustion.

The data update at ASCO here pertains to 35 patients who were enrolled in the dose-escalation phase—part 1—of the TRIgnite-1 study exploring 9 dose levels of up to 2700 µg/kg of ISB 2001. Now, this [was] a group of heavily pretreated patients with a median of 6 prior lines of therapy. All were triple-class exposed. Around half of patients were triple-class refractory, and over 70% of patients were penta-drug exposed. In addition, 46% of patients...had [received] prior BCMA-targeted therapies.

Based on its trispecific antibody design, what improvements might ISB 2001 offer compared with other standards of care in relapsed/refractory multiple myeloma such as bispecific antibodies?

What makes ISB 2001 unique and distinctly different from other traditional bispecific antibodies is, firstly, the dual and high-affinity binding to CD38 and BCMA. This dual high-affinity binding allows for T-cell–mediated cytotoxicity even upon downregulation of BCMA or CD38, which is quite a common resistance mechanism that we see with other BCMA-targeted agents.

Secondly, the weak binding to CD3, or the low-affinity binding to CD3, allows for less off-tumor T-cell–mediated toxicity. In addition, it also reduces the risk of T-cell absorption that we may see with resistance. One more unique aspect is the fact that the CD38-binding epitope of ISB 2001 is distinct from that of a daratumumab [Darzalex] or isatuximab-irfc [Sarclisa], and this is the reason why we see people progressing on anti-CD38 monoclonal antibodies within 6 months still respond just as well, if not a bit better, than what we see with the overall patient population. Their overall response rates were in the order of higher than 80%. That’s quite remarkable, and it does pave the way for synergism if ISB 2001 is combined with anti-CD38 monoclonal antibodies.

What did data show about the efficacy of ISB 2001 in this population?

In terms of efficacy, we saw a response rate of 74% in all patients, and a CR or better [occurred in] 28%. But if we look at the subgroup of patients who [received] the therapeutic dose, that is dose level 3 to dose level 9, we saw a response rate of 79% with CRs or better in 30%. Importantly, these responses were quite durable, and some patients continued to respond beyond 12 months at the time of data cut off. This was after a median follow-up of about 6 months.The 6-month duration of response rate was 90%. This is especially remarkable considering how refractory this patient population was.

What was equally encouraging was the fact that we saw a robust response, even in difficult-to-treat subgroups of patients, including patients who’ve had prior CAR T cells or T-cell engagers, prior BCMA-targeted therapies, and [those] who were refractory to anti-CD38 monoclonal antibodies. In this subgroup of patients, we saw a response rate in the order of 71% to 73%, indicating that ISB 2001 may perhaps be able to overcome resistance to these agents.

What were the safety findings from this trial?

In terms of the tolerability profile, we saw quite a favorable safety profile. The rate of severe hematologic toxicity and infection was low. The rate of grade 3 or 4 [treatment-related] neutropenia, anemia, and thrombocytopenia [were] in the order of 29%, 6%, and 14%, respectively.The rate of grade 3 or 4 infection, both related and not related to treatment, was around 29%. Now, as expected, the level of cytokine release syndrome [CRS] was around 69%; that’s as expected for most T-cell engagers. Importantly, the majority were low grade [or] grade 1 and mostly confined to the first step-up dose.

Now, this is a promising safety profile, particularly because the patient population was quite heavily pretreated and some of these patients had quite marked tumor burden at the outset.

What are the next steps for researching ISB 2001 in multiple myeloma?

The immediate next step for the TRIgnite-1 study is to focus on the part 2 expansion focusing on dose and schedule optimization. This is important given the fact that the half-life of ISB 2001 is now deemed to be around 17 days. This supports a less frequent dosing regimen. If we can go towards a less frequent dosing schedule, that will be particularly beneficial for our patients in terms of convenience, tolerability, and perhaps decreasing an already low rate of adverse [effects] that we see in the immediate future. What I’d like to see is that this molecule would be prioritized for patients who have exhausted all prior therapies, particularly the so-called quad-exposed group of patients who’ve exhausted prior immunomodulatory drugs, proteasome inhibitors, CD38 monoclonal antibodies, and BCMA-targeted therapies. This is where the need is most urgent.

In the future, I see significant potential with respect to an even better outcome with this drug if we could move the drug to earlier lines of treatment where the immune system is more robust, perhaps even frontline treatment, to allow for an even better response. In addition, because of the favorable safety profile that we see, there is room to combine ISB 2001 with other therapeutic agents for synergism. For example, immunomodulatory drugs or even anti-CD38 monoclonal antibodies, particularly because the CD38-binding epitope of ISB 2001 is different to that of daratumumab. By combining the 2 [agents], we may be able to engage both the innate and the adaptive immune system for synergism, for even better anti-myeloma activity.

Reference

Lichtman E, Khot A, Augustson B, et al. Phase 1, first-in-human study of ISB 2001: a BCMAxCD38xCD3-targeting trispecific antibody for patients with relapsed/refractory multiple myeloma (RRMM)—dose escalation (DE) results. J Clin Oncol. 2025;43(suppl 16):7514. doi:10.1200/JCO.2025.43.16_suppl.7514