COMy 2026 | Insights into the disease biology & role of T-cell redirecting therapies in EMD

So, extramedullary disease has always been known as being a high-risk factor for patients with multiple myeloma. And we have two types of extramedullary disease, but here I’m specifically talking about soft tissue extramedullary disease. So this is not the same as periosteous extramedullary disease, where the soft tissue grows outside of the bone and is contiguous to the bone. We’re talking about discrete soft tissue plasmacytomas away from bone. And studies clearly show that these patients have a lower progression-free and overall survival. We’re learning more about the biology of this, and particularly with the spatial heterogeneity of what happens within the actual plasmacytoma. And what we see is interesting because what we see at relapse is very different from diagnosis. So in diagnosis, there is less of a crowded space within the plasmacytoma. And in relapse, however, it becomes very packed full of other microenvironmental cells. So this biology makes the relapsed plasmacytomas much more difficult to treat, and they are what we now call cold sites, because when we’re trying to give treatments, it’s very difficult for these treatments to actually penetrate within the plasmacytoma and lead to the death of those plasma cells. With the T-cell redirection, we’re seeing much stronger response rates and more durable responses compared to conventional treatments. However, those patients continue to do worse compared to patients who don’t have extramedullary disease. And if you think about it, what’s going on in terms of the biology is that the T-cell has to form an immune synapse to be able to kill the plasma cell. And because of the complexity of the microenvironment and other cells that are in place, it is very difficult for that T cell to form that immune synapse. So, we need to think about other ways of trying to improve T cell redirection to get better outcomes for extramedullary disease. The best data is by combining two different bispecific antibodies together. And it may be that the inflammatory response associated with this can convert that cold space into a warmer space for the T cells to migrate into and kill the cells. And then the other piece, which is of interest, is radiotherapy, because that can be highly effective for patients with extramedullary disease but also leads to an abscopal effect which essentially leads to reactivation of the T cells across the body, and we see interestingly improved responses with bispecific antibodies with radiotherapy.

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