Considerations for Multiple Myeloma Immune Therapy

This week's "Ask Dr. Durie" comes from a patient who is confused about what are called targets for immune therapy. And so, this is a very reasonable question. When we talk about immune therapy, we say that it's targeting this or that on the surface of the myeloma. And these are things that we call targets or receptors.   

And so, a receptor on the surface of the myeloma is an antigen, and the antigens that are attractive are ones where if you attack that antigen with an antibody, this triggers the destruction of the myeloma. And so, this is a very attractive target. And so, it's been discovered that there are several antigens on the surface of the myeloma where one can take advantage of this such that antibody treatment will lead to the destruction of the myeloma. 

 And so, thus far, there are two types of receptors that occur frequently, which is obviously important on the surface of the myeloma and which, when attacked, will lead to the destruction of the myeloma. And so these two receptors are BCMA, B-cell maturation antigen, and GPRC5D, which is a more complex antigen on the surface of the myeloma. 

And so, those are the basis for different treatments. For example, the commonest bispecific antibody that attacks BCMA is Teclistamab, which was recently approved by the FDA, and the bispecific antibody, which attacks the GPRC5D is Talquetamab, another very important antibody. And so, at the ASH meeting two years ago in 2022, a combination of those were attacking, both of those in a protocol called TT1 was particularly effective in wiping out myeloma cells even in patients with relapsed strong extramedullary disease—patients with disease, outside of the bone marrow. 

And so, paying attention to both those types of receptors is very, very important related to the ability to have a really deep response with the therapy. But for the patient, one of the main things to be aware of is the difference in the side effects with these treatments, treatments directed against the BCMA on the surface of the myeloma—those therapies tend to produce an increased risk of infection because there is a reduction in the normal B cells and the normal B cells in the bone marrow and elsewhere. These are what are called off-target effects. And there are also side effects against nerve tissue and can cause what we call neuropathy side effects. 

Conversely, with the GPRC5D the off-target effects are on skin and nails and also an effect on the taste buds. And so, there are peculiar side effects that occur with the treatment Talquetamab. And so, when we're looking at these targets, it's important to know that right now we are focused on two, but there will be more that emerge and are useful over time. 

And for the patient, the main thing will be to be alert to the side effects and to be alert that the side effects tend to be cumulative over time. And so, what we're very alert to is that we have to pay attention to the length of the treatment. Right now we have rather long durations of treatment out to two years. 

For example, with Teclistamab as a common protocol. And so, we need to be alert that maybe shorter treatment protocols would be helpful and also to pay attention to when does the best response occur and if treatment is stopped sooner, maybe the risk of side effects will be reduced. And for example, the side effects with Talquetamab affecting the skin and the nail and the taste buds, these could be reversible and go away. 

And so the BOTTOM LINE is that it is important to pay attention to these targets, both in terms of how well does the treatment work alone or maybe as a combo and what would be the side effects, which is very much related to the length of the treatment, which we know needs to be looked at closely as we move forward.