COMy 2023 | Determining the optimal sequencing of bispecifics and CAR-T cells in patients with myeloma
Salomon Manier, MD, Lille University Hospital, Lille, France, offers insight into the sequencing of bispecific antibody (BsAb) and CAR-T cell therapies in patients with multiple myeloma. Dr Manier notes mechanisms of resistance to these agents, including loss of target antigen and T-cell exhaustion. Dr Manier further explains that continuous administration of BsAbs has been shown to induce T-cell exhaustion, and that this is a crucial factor to consider in sequencing. To conclude, Dr Manier provides an overview of clinical evidence from the MajesTEC-1 trial (NCT03145181), evaluating teclistamab, and the MonumenTAL-1 trial (NCT03399799), evaluating talquetamab, which demonstrate that sequencing CAR-T cells before bispecifics appears to be more effective, although further research is required. This interview took place at the 9th World Congress on Controversies in Multiple Myeloma (COMy) 2023, held in Paris, France.
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Transcript (edited for clarity)
So we had a session on these new generation immunotherapies, CAR-T cells and bispecific antibodies, and we discussed the optimal sequence. Well, we probably don’t know which one is the optimal sequence, but we have interesting data to discuss this sequence of immunotherapy. The first thing is that it’s becoming more and more important in clinical practice because we now have access to different immunotherapies with approval or early access program in different CAR-T cells and bispecific antibodies and different targets as well...
So we had a session on these new generation immunotherapies, CAR-T cells and bispecific antibodies, and we discussed the optimal sequence. Well, we probably don’t know which one is the optimal sequence, but we have interesting data to discuss this sequence of immunotherapy. The first thing is that it’s becoming more and more important in clinical practice because we now have access to different immunotherapies with approval or early access program in different CAR-T cells and bispecific antibodies and different targets as well. So the first thing we discuss is the mechanism of efficacy and resistance of those agents with the loss of antigen. First, we know that it’s not very frequent with BCMA, but there are some reports of biallelic loss of BCMA. With GPRC5D, we have some information on the CAR-T cells targeting GPRC5D and in these clinical trials, just a few patients, but they observed two thirds of the patients who lost the expression of GPRC5D after exposure to the CAR-T cell and at relapse. So it means that probably there is more loss of GPRC5D than we see loss of BCMA. Second point is the T-cell exhaustion. Of course the T-cell fitness matters for those immunotherapies. We know basically that the higher proportion of memory phenotype T-cells and the lower proportion of exhausted T-cells is a favorable situation for both CAR-T cells and bispecific antibodies. Some data that we start to have is perhaps the continuous administration of bispecific antibodies can induce some exhaustion of the T-cells. So this is important when we consider sequencing those immunotherapies. And then now we have some clinical evidence. So basically, to summarize the clinical evidence we have from MajesTEC-1 with teclistamab, from MonumenTAL-1 with talquetamab, is that bispecific antibodies after CAR-T cells for example, or ADCs works well. In the talquetamab MonumenTAL-1 clinical trial, they had some patients coming off bispecific antibody receiving talquetamab and it seems that the efficacy is lower. So perhaps sequencing of bispecific after bispecific will need some washout time for example. And at the opposite the sequencing of CAR-T cells after ADC or bispecific antibody, here it seems that it does affect the efficacy a little bit more. So today what we understand of the sequencing of those immunotherapies is that probably giving CAR-T cells first will be a better option and then going to bispecific antibodies. Of course there are a lot of questions and it’s only a small amount of data that we have, so we need to study this more. But the washout time will be something probably important and I think the message is that we need to develop tools, simple tools to assess the T-cell function in clinical practice easily that will drive actually the decision of this sequencing of immunotherapies.
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