ASH Annual Meeting 2025 Day 3: Novel Antibody Therapies for High-Risk and Relapsed/Refractory Disease

For the last day of ASH, we’re taking a final look at some of the most exciting findings shared during Sunday’s sessions as well as late-breaking abstracts from this morning that highlight where myeloma research is headed next. Whether by investigating new regimens with already-approved treatments, or by developing unique, novel immunotherapies, the studies featured in our post today offer encouraging options for patients who need effective therapy options after relapsing.  

Read the MMRF’s key takeaways below, and catch up on day one and day two.

For a deeper dive into the most important findings from ASH, join us for our Conference Highlights Webinar on December 17. Register here.

Combining the BCMA-targeting bispecific antibody Tecvayli (teclistimab) with Darzalex (daratumumab) leads to lasting responses for relapsed/refractory patients

In a phase 3 study, more than 500 patients who had relapsed after 1-3 prior therapies were given either one of these treatments:  

• Tecvayli and Darzalex (TD) 
• Darzalex, Pomalidomide, dexamethasone (DPd) or Darzalex, Velcade, and dexamethasone (DVd)  

Patients taking the TD combination had a significant improvement in surviving without their disease progressing, compared to those who had either triplet therapy (83% vs. 29%). Disease did not progress in the TD group of patients for up to 3 years.  

Side effects were mostly comparable between groups, with infections slightly occurring more in patients who were taking TD. Patients taking TD also experienced cytokine release syndrome that was mild mainly treatable. 

Taken together, results from this late breaking abstract demonstrate that the combination of Tecvayli and Dazalex has the potential to be a new standard of care for patients who relapse early, especially on immunodmodulatory drugs like Revlimid or proteasome inhibitors like Velcade or Kyprolis.

New targets for bispecific and trispecific antibodies offer a path forward for relapsed/refractory patients with limited treatment options

Cevostamab: We heard new data on the bispecific antibody cevostamab as a treatment for relapsed/refractory myeloma, including patients with high-risk disease features and patients who have already received multiple other lines of therapies. Cevostamab targets a protein on myeloma cells called FCHR5—a different protein than the BCMA target used in Tecvayli, Lynozyfic,® and Elrexfio or the GPRC5D target used in Talvey (talquetamab). Therefore, it may help patients whose disease is resistant to those treatments. It is also given as an injection, rather than by IV, which provides greater convenience.

• In a phase 1b clinical trial, 58 RRMM patients, all of whom had previously received a median of five prior treatments, including other bispecific antibody therapies, were treated with cevostamab. Thirty-one percent had a very good partial response or better, and 20 percent achieved a complete response or better.
• An ongoing phase 1/2 trial is testing cevostamab in 27 patients with relapsed or refractory multiple myeloma who recently received CAR T-cell therapy. Most of the patients had high-risk features, such as certain genetic changes or cancer outside the bone marrow. Eighty-one percent had had a complete response, 95 percent of whom had no detectable cancer cells (MRD-negative). A year later, 93 percent were still cancer-free.
• Side efforts reported in both trials were mild to moderate.

IBI3003: IBI3003 is a new trispecific antibody that targets BCMA, GPRC5D, and CD3—combining the activity of two bispecifics in one drug. In a Phase 1 study of 28 patients who had received at least two prior treatments, all patients given the highest doses responded, including those with high-risk disease and those previously treated with BCMA or GPRC5D therapies like Tecvayli or Talvey. The most common side effects were fever and flu-like symptoms, and serious side effects were uncommon.

In patients who have exhausted treatment options targeting BCMA or GPRC5D with currently approved bispecifics or CAR T-cell therapy, these studies show that targeting other molecules on myeloma cells can offer therapeutic benefit. 

Bispecific antibody combination show promises for relapsed/refractory patients with high-risk disease

High-risk multiple myeloma is a more aggressive form of the disease, often characterized by certain genetic changes, high levels of specific blood markers, or myeloma growing outside the bone marrow (extramedullary disease or EMD). These features can make the cancer harder to treat and more likely to return sooner, so patients may need stronger or more tailored treatment approaches. A combination of two bispecific antibodies — Talvey and Tecvayli — is showing particular promise for these patients. 

Here’s a recap of the data:

• Across Phase 1B and Phase 2 studies in heavily pretreated relapsed/refractory multiple myeloma (including patients with EMD and other high-risk features), treatment with Talvey® and Tecvayli® produced overall response rates of ~75–90%, with ~50–60% achieving complete responses, with higher responses seen in patients with lower disease burden. 
• For patients in both trials, expected side effects of Talvey and Tecvayli (CRS, low white blood cell counts, taste changes, skin changes, and infections) were common but generally manageable. However, it is important to note that in the first study, about 68 percent had serious infections, with many patients needing an infusion of donated antibodies (IVIG) to help strengthen the immune system. And, in the second, about 40 percent of patients had serious and life-threatening infections, and 6.7 percent died from these infections.

Despite these safety risks, this combination remains one of the most effective treatments reported for patients with this aggressive form of myeloma who otherwise have limited treatment options. It’s important to review the potential benefits and risks with your care team when considering this approach.

What’s Down the Road: In-vivo CAR T-Cell Therapy 

Finally, in today’s late-breaking session, a phase 1 study explored the possibility of in-vivo CAR T therapy in a small group of 3 patients. Unlike traditional CAR T-cell treatment, which involves the removal of T-cells from patients and genetically reprogramming them in a lab, in-vivo CAR T can be accomplished inside the body, without the need for these steps or even bridging therapy. Simply put, a special infusion is given to patients that lets their own immune system generate CAR T-cells against BCMA.  

In the study, patients experienced low-grade cytokine release syndrome which was treatable. Within one month, each of them so far has no detectable disease in the bone marrow.  

While this study is early and involves only a small number of patients, it highlights the transformative potential of in-vivo CAR T therapy to simplify and broaden access to this powerful treatment approach. Notably, within the MMRF’s Myeloma Investment Fund portfolio, we have two in-vivo CAR T programs in development, an exciting step because eliminating the need for complex cell collection and manufacturing could make CAR T therapy more accessible to a much wider patient population. 

That wraps up our coverage from ASH 2025. Be sure to stay connected with the MMRF for updates as these findings continue to move from clinical trials toward everyday care.