ASH 2025 | Sequencing bispecific antibodies and CAR-T in multiple myeloma

We are in an interesting situation with multiple immunotherapies becoming available in myeloma. The golden question that we’re trying to elucidate is how best to sequence them. What we do know is that T-cells are very important as part of an immunotherapeutic process, but they’re not the only issue – one of the other major issues is about antigen loss or indeed mutation. And what we find with bispecific antibodies is that the major driver of resistance is actually mutations of the binding site as opposed to T-cell dysfunction. What we find with CAR T-cells is that at relapse, there is normally good T-cell function available, mainly because the relapse can often happen a few years after the time of the CAR T-cell delivery. The bottom line is that what we do see is that you can salvage patients who’ve had prior CAR T-cell therapy with a bispecific antibody or a trispecific antibody, but what we are trying to recommend is an antigen switch, if possible. We are fortunate because we have a number of different drugs available now with different targets. So, for example, if you were to give a patient a BCMA CAR T-cell, you could potentially salvage them with a GPRC5D-targeted bispecific antibody at relapse. The problem happens if you do it the other way around, because giving a bispecific antibody will lead to mutation forming in the binding site, but also does cause a degree of T-cell loss of fitness. So the problem is that harvesting a patient’s T-cells post a bispecific antibody can be problematic and indeed can impair the fitness of your CAR-T population and the ability to manufacture an adequate population. So in those situations, we always recommend giving the CAR T-cell first because you can salvage them with a bispecific afterwards as opposed to the other way around.

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