EMN 2021 | Novel immunotherapies for myeloma treatment
Hermann Einsele, MD, FRCP, University of Würzburg, Würzburg, Germany, discusses the use of novel immunotherapies for the treatment of multiple myeloma. Prof. Einsele highlights data from the Phase Ib trial (NCT03836053) of AMG 420, which demonstrated promising efficacy results, and gives a broad overview of other bispecific T-cell engagers (BiTEs) which are being developed for the treatment of multiple myeloma. Prof. Einsele also discusses biallelic BCMA-loss for patients receiving BCMA-targeted BiTEs, and talks about the importance of developing BiTEs with alternate targets, such as GPRC5D and FcRH5. Finally, Prof. Einsele discusses the use of chimeric antigen receptor (CAR) T-cells for the treatment of multiple myeloma. This interview took place during the 2021 European Myeloma Network (EMN) congress.
Transcript (edited for clarity)
Like in other hematological malignancies, immunotherapy, especially immune cell therapy, is also increasingly evaluated in patients with multiple myeloma. On the one hand we have the bispecific antibodies, so based on small constructs that are binding to T-cells we have a CD3 molecule and binding to the myeloma cell, by either targeting BCMA, CD19, FcRH5, or GPRC5D or CD38. So, there are quite a few targets that can be addressed with these bispecific antibodies, and they form a kind of immunological synapse, so activated T-cells that are directed against virus infected cells, for example, that are highly activated, can be redirected and can be forced to kill myeloma cells...
Like in other hematological malignancies, immunotherapy, especially immune cell therapy, is also increasingly evaluated in patients with multiple myeloma. On the one hand we have the bispecific antibodies, so based on small constructs that are binding to T-cells we have a CD3 molecule and binding to the myeloma cell, by either targeting BCMA, CD19, FcRH5, or GPRC5D or CD38. So, there are quite a few targets that can be addressed with these bispecific antibodies, and they form a kind of immunological synapse, so activated T-cells that are directed against virus infected cells, for example, that are highly activated, can be redirected and can be forced to kill myeloma cells.
And this has been very effective in patients with multiple myeloma. And the first trial that was performed with these bispecific antibodies was in patients with at least two prior lines of therapy, the AMG 420 trial, in which for the first time, it could be shown that patients with heavily pretreated myeloma show beautiful responses to these B-cell, to these bispecific antibodies, or like we also call them, T-cell engaging antibodies. And we had overall response rate of 70% and 50% complete remissions in MRD negativity, even in patients with very advanced multiple myeloma and the maximum tolerated dose.
The next step was to really develop these bispecific antibodies, which in the AMG 420 study had to be applied as a continuous infusion with all the issues of portal infection, central venous infection, and this overstimulation of T-cells. And therefore, the new formats allowed weekly or bi-weekly or even administration, every three weeks. So, it’s a very new strategy, which is much more patient friendly when compared to these continuous infusions.
And we have several of these bispecific antibodies targeting BCMA. So, one is AMG 701, the other is teclistamab, and we have also from Regeneron and other companies, other BCMA-directed – from Pfizer, we have other antibodies that are targeting BCMA and CD3 – and all of them look very promising, very low toxicity, very low cytokine release syndrome, low grade three or higher neurotoxicity. So, easily to administer. And in lymphoma, for example, it was shown that, for example, a CD3, CD20 bispecific can even be given to patients beyond age 80, beyond age 90. So, it’s really well tolerated. And I think it will be a treatment that will be available not only for patients that are transplant eligible, but also for the non-transplant eligible patients with multiple myeloma.
What we have learned, and I think we were the first ones that described the case like this, but also Nikhil Munshi and also the group from [inaudible] have recorded on this is that there are patients that have a complete BCMA loss, which is due to biallelic deletion of the gene segment that is coding for BCMA. And this can happen in patients receiving BCMA-directed CAR T-cells, as well as BCMA-directed bispecific antibodies. And therefore, we need additional targets. And for bispecific antibodies, we have them, and GPRC5D or FcRH5 are good targets, and there are already bispecific antibodies targeting these antigens on the myeloma cells and CD3 on the T-cell in the clinic.
So, things are really moving extremely well. The same issue are CAR T-cells, and on here they are even more effective and maybe, but also a slightly more toxic. I think if we aim for cure then probably the CAR T-cells will be the better option. But, probably, they will be restricted to patients with, that are transplant eligible. And thus, not as widely applicable as bispecific antibodies. And I think in the future, we’ll see a race between CAR T-cells and bispecific antibodies, and we’ll all watch this race. To continue. Thanks so much.
Read more...
