Using Different Targets to Destroy Multiple Myeloma

Speaker 1: 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'll describe the antigens or targets on the  surface of the myeloma cells and how bispecifics ar

e 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've 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 five, member D. And FcRH5, or FC receptor  homolog fiv

e. These antigens are both heavily expressed on myeloma cells, which means they can  serve as a handle or a target from myeloma drugs. Thankfully, they're not expressed on many other  tissues, which reduces the risk of complications if those cells are affected by the bispecific  antibody. Well, 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 s

tudies are showing 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. Well, 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 F

cRH5. In general, on the positive side, it appears that  the risk of infection may be reduced with these treatments. Infections are 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 oth

er 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 exc

iting times for  myeloma research and treatment.