Using Different Targets to Destroy Multiple Myeloma

This video discusses bispecific antibodies targeting antigens on myeloma cells and their potential in myeloma treatment.

• Bispecific antibodies can attach to myeloma cells and activate immune cells to destroy them.
• The BCMA antigen is commonly targeted by bispecific antibodies, such as teclistamab.
• New antigens like GPRC5D and FCRH5 have been discovered on myeloma cells, expanding treatment options.
• Diversifying targets helps combat myeloma's resistance to drugs and improves treatment outcomes.
• Bispecific antibodies targeting GPRC5D and FcRH5) show promise in treating myeloma.
• Expanding treatment options benefits patients, but each drug has its own risks and side effects.
• Infections may be reduced with GPRC5D and FcRH5 therapies, but they can have other side effects like taste changes and skin issues.
• Ongoing research aims to discover more myeloma targets and develop bispecific antibodies with broader capabilities, including engaging different immune cells like NK cells.

In earlier videos in this series, we described the concept of immunotherapy and how bispecific antibodies work. Like monoclonal antibodies, bispecific antibodies are able to attach to a myeloma cell by something on its surface, an antigen. But they're different in that they have a second arm that can engage a local immune cell to activate it, to destroy the myeloma cell. In this video, I will describe the antigens, or targets, on the surface of the myeloma cells and how bispecifics are being developed to attach to multiple targets on the myeloma cell.

The first two CAR, or chimeric antigen receptor T-cell therapies approved employ T-cells that target the BCMA antigen on the myeloma cell. BCMA stands for B-cell maturation antigen. It is expressed on nearly all myeloma cells and is very important for the growth and development of B-cells. Teclistamab, the first approved bispecific antibody, is also designed to attach to BCMA on the myeloma cell. It also attaches to the CD3 antigen on the surface of the local T-cell. By doing so, it can engage that T-cell to initiate the destruction of the myeloma cell.

As we learn more about the biology of myeloma, we have discovered different targets on the myeloma cells that could be used to diversify the way we use bispecific antibodies to target myeloma. The two most recently added antigens on the myeloma surface are GPRC5D, or G protein-coupled receptor family C, group 5, member D; and FcRH5, or FC receptor homolog 5. These antigens are both heavily expressed on myeloma cells, which means they can serve as a handle or a target for myeloma drugs. Thankfully, they are not expressed on many other tissues, which reduces the risk of complications if those cells are affected by the bispecific antibody.

Why is it so important that we discover new targets and develop drugs to attack those targets? First of all, we always want to develop new ways to attack myeloma. Unfortunately, we've not cured myeloma, so it is always our desire to expand the ways we can treat this disease. Furthermore, myeloma cells are smart and become resistant to the drugs we use, especially when a targeted therapy is used. We have seen this before with the CD38 antigen. One of the ways the disease progresses is by becoming resistant to anti-CD38 drugs. Similarly, patients treated with BCMA therapies can become resistant to them. We are still exploring the optimal sequencing of BCMA-directed therapies.

Practically, studies are showing that although it is feasible to go from one BCMA treatment to another, it may not always be ideal to target them sequentially. So now, newer bispecific antibodies, such as talquetamab, which targets GPRC5D, and cevostamab, which targets FcRH5, have been developed. Many others are also on the way. Early work with these drugs shows that, much like teclistamab, they can be effective in achieving response rates of over 60% in heavily-pretreated patients.

What does this mean for patients? Well, this step is a very positive move forward in the fight against myeloma, for many reasons. It provides more options for patients, and, as we noted, in a disease that we cannot yet cure, more options are critical. It also allows us to sequence therapies with different targets and potentially even improve outcomes for patients. It's also important to note, however, that every drug comes with risks and potential side effects. We are still learning a lot about targeting GPRC5D and FcRH5. In general, on the positive side, it appears that the risk of infection may be reduced with these treatments. Infections are a particular concern when using BCMA-driven bispecific antibodies. By contrast, however, newer side effects are also being seen with these targets. For example, GPRC5D therapies may cause changes in taste, as well as negative effects on skin, hair and nails.

In conclusion, many bispecific antibodies are being developed, not only targeting BCMA, but at least two other novel targets, GPRC5D and FcRH5. These advancements are excellent for the field of myeloma, as they will inevitably increase options for patients and allow for more time in remission. Looking ahead, we are seeking to discover even more targets. We're developing bispecific antibodies that may adhere to more than one target on the myeloma cell. In addition, newer agents are being built to not only engage T-cells, but other immune cells, such as NK, or natural killer cells. These are very exciting times for myeloma research and treatment.