And How New Trispecific Antibodies May Transform Multiple Myeloma Treatment

We are back from an exciting ASH 2025 conference where we presented on our unique precision trial matching software. But when not presenting and talking to our foundation partners, we were attending the many sessions on stunning advances in cancer treatment now showing up in trials.

One of the most exciting innovations was trispecific antibodies for multiple myeloma treatment. Before we get to those trials, let’s discuss a bit more about how T cells work and how these drugs make them even more effective against cancer.

T cells are one of the body’s most powerful natural defenses against cancer. Their job is simple to describe but incredibly complex to execute: they patrol the body, identify dangerous cells, and eliminate them with precision.

But in cancers like multiple myeloma, malignant plasma cells learn to hide. They suppress the immune system, alter their surface markers, and exhaust the very T cells meant to destroy them. That’s why modern immunotherapy focuses not just on attacking cancer, but on re-energizing the immune system itself.

Among the most exciting innovations emerging from the recent ASH 2025 meeting that we just attended are trispecific antibodies — engineered molecules designed to bring T cells back into the fight with unprecedented accuracy and power.

How T Cells Recognize and Kill Cancer Cells

To understand why trispecific antibodies matter, it helps to understand how a T cell decides when to attack.

1. Recognition

T cells recognize signals on other cells using the T-cell receptor (TCR).
When the right signal appears — usually a fragment of a virus or tumor protein — the T cell becomes activated.

2. Activation

Once activated, a T cell:

• Releases cytotoxic granules (perforin and granzymes)

• Recruits other immune cells

• Begins rapid clonal expansion

But in cancers like myeloma, tumor cells can:

• Downregulate the markers T cells look for

• Create a suppressive microenvironment

• Overstimulate T cells into burnout (called T-cell exhaustion)

This is where T-cell redirecting antibodies — such as bispecifics and now trispecifics — have changed the landscape.

How Trispecific Antibodies Help T Cells Kill Better

A trispecific antibody binds three targets at once:

• BCMA (on myeloma cells)

• GPRC5D (on myeloma cells)

• CD3 (on T cells)

The two tumor-binding arms tightly latch onto myeloma cells, while the CD3 arm gently engages T cells to activate them only in the presence of tumor. This lowers toxicity, preserves T-cell fitness, and improves the quality of the “immune synapse” between T cell and cancer cell.

The result is:

• More precise killing

• Less exhaustion

• Lower chance of resistance through antigen loss

• Potential for deeper and longer-lasting responses

These therapies are early but represent some of the most exciting immunotherapy engineering in myeloma today.

Three Recruiting Trispecific Trials to Watch

Below are three currently-recruiting trials that showcase different design philosophies in trispecific T-cell engagers.
Each includes the NCT number so clinicians or patients can look it up easily.

🔹 1. JNJ-79635322 (BCMA × GPRC5D × CD3)

(https://app.cancerbot.org/t/NCT05652335)

What makes it unique:

This is one of the most advanced trispecific antibodies targeting both BCMA and GPRC5D simultaneously, the two dominant antigens in myeloma. Dual antigen anchoring is designed to:

• Enhance T-cell activation only when tightly bound to myeloma cells

• Reduce antigen escape

• Improve depth of response

It represents the “flagship” approach to trispecific design.

🔹 2. IBI3003 (BCMA × GPRC5D × CD3)

(https://app.cancerbot.org/t/nct060832)

What makes it unique:

IBI3003 is notable for its optimized CD3 affinity, engineered to reduce cytokine release while preserving strong tumor killing.
It also aims for:

• Better T-cell persistence

• Lower toxicity profile

• Strong engagement even in low-BCMA-expression disease

The construct reflects next-generation tuning of trispecific pharmacology.

🔹 3. SIM0500 (BCMA × GPRC5D × CD3)

(https://app.cancerbot.org/t/NCT06375044)

What makes it unique:

SIM0500 is designed for ultra-high avidity binding — its BCMA and GPRC5D arms are optimized to form a highly stable three-point tumor lock.
This stability may:

• Reduce “false activation” of T cells

• Enable efficient killing of heterogeneous myeloma clones

• Improve responses in heavily pretreated disease

It is one of the newest trispecifics to enter global clinical testing.

Why CancerBot Is Tracking These Trials Closely

Trispecifics represent a major shift in T-cell–redirecting therapy.
They combine:

• Multi-antigen tumor targeting

• Controlled T-cell activation

• Engineering approaches inspired by next-gen CAR-T platforms

If they continue to show deep and durable responses — especially in patients who relapsed after BCMA or GPRC5D agents — they may become part of the future standard of care.

CancerBot monitors emerging trial modalities like trispecifics, dual-target CAR-T, GPRC5D therapies, and CELMoDs so we can provide precise, real-time matching between patients and the most promising new options.