ASH 2023: How Do We Apply T-Cell Redirection for Myeloma? Part 1: Bispecific Antibody Therapies

I was fortunate to virtually attend an ASH 2023 session “How Do We Apply T-Cell Redirection Therapy for Myeloma? CAR-T Cells and Bispecific Antibodies”.

Because of the amazing but plentiful information shared in this session, we will be breaking out the information into three different articles. 

Part one (this article) will focus on bispecific antibody therapy. 

It is incredibly encouraging to see the vast amount of research being done. I’ll be sharing some of the questions being studied and the emerging answers that will enhance the efficacy, safety, sequencing, and access to these remarkable immunotherapies. 

Below is a link to a HealthTree University video that teaches about immunotherapy antibodies if you want to review or learn more before you read on: Immunotherapy Antibody Education 

Dr. Nizar Bahlis of the University of Calgary chaired the session and began by examining bispecific antibodies - their design, structure, biology of resistance, and some of the emerging clinical applications of this research.

Are All Bispecific Antibodies the Same?

Bispecific antibodies are not all the same. They have different designs and structures, such as their geometry, size, and flexibility. 

The therapies in this class of drugs that are currently approved and being studied also vary in their myeloma antigen binding targets, B Cell Maturation Antigen (BCMA), GPRC5D, and FcRH5, to mention the most common. 

The strength of a connection between a bispecific antibody and its targets on the myeloma cells is crucial. 

These antibodies need to have a good match with the myeloma antigen and the CD3 on T cells. This match, also known as affinity, affects how well the antibody works and the likelihood of side effects like Cytokine Release Syndrome (CRS).

Imagine the bispecific antibody as a key trying to fit into two different locks: one on the myeloma cells and another on the T cells. 

If the key fits too tightly with a part called BCMA on the myeloma cells, it may get distracted by a soluble form of BCMA in the blood. This distraction weakens the antibody's ability to attack the myeloma cells effectively.

On the other hand, if the key fits too tightly with CD3 on T cells, it may end up binding with T cells elsewhere in the body, away from the myeloma cells. This misplacement can reduce the effectiveness of the antibody in reaching and destroying the myeloma cells. 

Finding the right balance in how the antibody connects with its targets is crucial for a successful treatment.

This knowledge combined with an understanding of mechanisms of resistance can be used to direct treatments. 

What Causes Resistance to Bispecific Antibodies? What Percentage of Myeloma Patients Are Resistant? 

About 30% of myeloma patients experience primary resistance after receiving a bispecific antibody in their initial treatment. This might look like a patient responding initially but quickly progressing. 

Some identified reasons for this resistance that Dr. Bahlis shared include: 

• High disease burden, Bone Marrow Plasma Cells ^≥50%
• International Staging System (ISS) Stage 3 
  • With GPRC5D-targeted bispecific antibody therapy, this was less of an influence
• Extramedullary (EM) disease
• Soluble BCMA (sBCMA) 
  • A Janssen multivariate regression analysis presented at this ASH meeting showed that individuals who did not respond well to the bispecific antibody treatment had high levels of both sBCMA and PD1.
  • PD1 is a protein related to the immune system, and it's considered a checkpoint inhibitor. Checkpoint inhibitors can sometimes hinder the immune system's response to cancer cells.
• Pre-existing T-cell exhaustion
  •  Can decrease response rate and progression-free survival in myeloma patients who respond to the initial treatment
  • Using single-cell sequencing to identify the types of T-cells within the immune system of responding and non-responding myeloma patients is leading to the development of predictive biomarkers determining whether or not the bispecific antibody therapy will be successful in said patient. 
• Interesting to note, high-risk cytogenetics did not seem to be an indicator of initial treatment resistance to bispecific antibody therapy 

Dr. Bahlis also addressed questions regarding the sequencing of bispecific antibodies. Please see common questions and answers below. 

Can you give another bispecific antibody therapy treatment directly after a patient has progressed on a bispecific antibody therapy? 

Data is pretty clear that after progression, you should not put the patient back on the same bispecific therapy that they just progressed on. 

Research is still coming on whether or not a bispecific antibody therapy with the same target would be an efficient next treatment option (i.e. giving elranatamab after teclistimab), as it can occasionally work but would not be the most optimal treatment. 

Most research indicates that if you can give another bispecific antibody with a different target (i.e. talquetamab or cevostamab- when approved- after teclistimab), that’s the most ideal choice regarding most likely efficacy. 

Can you give a CAR-T after a bispecific antibody therapy progression? 

There are issues that arise after patients receive CAR-T therapy after a bispecific antibody therapy, especially if they share the same target. T-cell exhaustion can affect the patient’s response and immune system, and the risk of serious infections should be considered. 

Can you give a bispecific antibody therapy after CAR T treatment? 

This seems to be the ideal choice amongst myeloma researchers investigating this field, especially if the CAR-T product and bispecific antibody therapy share different targets. This is currently providing the best overall response rates and durations of response.

Stay tuned for parts two and three of this session in future articles on our HealthTree News Website. 

ASH 2023 Resources

Would you like to watch ASH 2023 myeloma research interviews from the investigators themselves? Click "ASH 2023" here: HealthTree University Conference Coverage

To read other ASH 2023 articles, click here: HealthTree 2023 ASH Articles