Myeloma Treatment with Bispecific Antibody Targets

In the “Myeloma Made Simple” series, we have discussed the importance of immunotherapy – where we employ a patient’s own immune system to fight their myeloma. One of the newest ways to do this is with bispecific antibodies. These are off-the-shelf drugs that bring together the myeloma cell and a local immune cell. They do so by their “bi,” or twofold nature, to bind to an antigen on the surface of the myeloma cell and to an immune cell at the same time. As they do this, they activate the immune cell (usually a T cell) to destroy the myeloma cell. 

In this video, I will explore the differences between the many bispecific antibodies (or, bispecifics) that are based on the antigen, or target, on the surface of the myeloma cell. This is an important concept. It allows the bispecific to target different antigens on the surface of the myeloma cell and expands our ability to treat patients with myeloma. The three targets I will discuss are BCMA (B Cell Maturation Antigen), GPRC5D, (G protein-coupled receptor family C, group 5, member D) and FcRH5, (Fc Receptor Homolog 5). 

While all bispecific antibodies share common features and side effects, they differ significantly based on the antigen that they target on the myeloma cell. 

BCMA, the most prevalent antigen on myeloma cells, is an ideal target due to its heavy expression, or presence. The goal is to target myeloma cells without affecting healthy cells.  

BCMA plays a crucial role in cell survival, making it a valuable target for cell destruction. Furthermore, BCMA’s versatility in immunotherapy extends beyond bispecific antibodies to include antibody-drug conjugates and CAR T-cell therapy. 

The first two FDA-approved bispecific antibodies for myeloma are teclistamab (also known as Tecvayli™), and elranatamab (Elrexfio™). They are both approved for patients who have had at least 4 lines of prior therapy, including a proteasome inhibitor, an immunomodulatory agent, and a monoclonal antibody.  

Both agents demonstrated impressive activity in heavily treated myeloma patients with response rates in the range of 60-70%.  

As described in the video “Bispecific Antibodies Made Simple,” these drugs can cause CRS (Cytokine Release Syndrome) and ICANS (Immune Effector Cell Associated Neurotoxicity Syndrome). 

That’s why these drugs must be administered at an approved location, and patients must be closely monitored for potential side effects. Long-term side effects include infections. Therefore, patients may require close monitoring of blood counts, immunoglobulin levels, and potential IVIG (intravenous immunoglobulin). 

The second antigen that can be targeted on a myeloma cell by a bispecific antibody is GPRC5D. This is also heavily expressed on myeloma cells, but we also see it on skin, nails, hair, and in the taste buds.  

One bispecific antibody is approved that targets GPRC5D, and it is teclistamab (Talvey™). It is approved for patients who have had at least 4 lines of prior therapy, including a proteasome inhibitor, an immunomodulatory agent, and monoclonal antibody. It is administered much like the BCMA-targeting bispecifics, but it may be given less frequently. It demonstrated a response rate of over 70% in patients with heavily treated disease.  

Unique side effects associated with the GPRC5D target include a reduction in taste (dysgeusia), loss of nails, thinning of the hair, and peeling of the skin. We are still working toward finding ways to reduce the severity of these side effects. Often, it does require dose adjustment. Yet, talquetamab may have a slightly lower risk of infections than BCMA-directed bispecific antibodies.  

The third target on the myeloma cell is FcRH5. This is also strongly expressed on myeloma cells and is an attractive means for bispecific antibodies to latch onto myeloma cells. Currently, no bispecific antibodies that target FcRH5 are approved, but these drugs are in development, including cevostamab. 

The future of bispecific antibodies is bright with several being developed to target myeloma. Interestingly, some are even being developed to engage immune cells other than T cells, such as Natural Killer (NK cells). 

In summary, the class of bispecific antibodies has become a critical part of therapy in myeloma. We now have at least three antigens or targets on the myeloma cell that these agents can use to engage T cells to treat myeloma. We also anticipate with time that these agents will be able to be used even earlier in the disease course. Clinical trials are even using these agents as frontline therapy.