VJVirtual | Homozygous BCMA deletion in response to ide-cel in myeloma patient

Hello. My name is Leo Rasche from the University Hospital of Würzburg, And I would like to give you a short preview on our latest paper on homozygous BCMA gene deletion in response to anti-BCMA CAR T-cells in a patient with multiple myeloma. So this is the topic, we are interested in the selective pressure of anti-BCMA immunotherapies on the clonal architecture in multiple myeloma, and we want to learn about the mechanisms of the myeloma cells surviving this type of treatment, and finally leading to relapse. And this is a patient from our institute who had terrible myeloma disease. He was heavily pretreated. He presented with extramedullary disease, a biallelic TP53 lesion, high M protein levels, and high bone marrow infiltration prior to CAR T-cell therapies. We included this patient on the KarMMa trial evaluating ide-cel CAR T-cell treatment in relapsed refractory multiple myeloma. And after infusion, this patient shows a nice response, and the extra medullary disease disappeared, and M protein levels went down, and at the bone marrow, minimal residual disease was not detectable.

So after three months of treatment or follow-up, we did whole body MRI again, which was picking up a single small lymph node, suggesting early yet localized relapse, whereas the M protein levels went further down. At five months of follow-up, this patient experienced terrible disease relapse with extramedullary disease all over the place, including lymph nodes, the spleen, and the liver, high M protein levels, and an almost obliterative bone marrow infiltration. And this figure here gives you a first impression what was going on in this patient. So the red line indicates the M protein levels, which went down after ide-cel treatment and then remained down, but then increased at the time of relapse. The gray line indicates the numbers of CAR T-cells, which increased rapidly in the first days after infusion and then persisted quite nicely, including the time of relapse. And most importantly in this case, the blue line indicates soluble BCMA levels, which were high at inclusion and then went down after ide-cel treatment and remained below limit of detection, including the time of relapse, suggesting a BCMA loss in this patient.

And we did single-cell RNA-Seq, and at baseline we found a stable and consistent expression of BCMA which was not detectable at relapse, highlighting a BCMA loss. And we were able to confirm these RNA results on protein levels with immunohistochemistry, again showing a strong and clear BCMA expression prior to CAR T-cells and a complete BCMA loss at the time of relapse. We did whole genome sequencing of myeloma cells collected at relapse and we found numerous chromosomal aberrations, translocations, amplifications, and quite a lot of small deletions, including this biallelic TP53 event at chromosome 17, but also and most importantly deletion at 16p, the locus where BCMA is encoded. And we looked closer to this region and we identified a homozygous BCMA deletion.

So CAR T-cell therapy in this patient selected for a clone with homozygous BCMA gene deletion leading to irreversible BCMA loss on protein level. So in summary, we identified a tumor intrinsic escape mechanism to anti-BCMA CAR T-cell therapy and, saying that, I would like to mention that there are two other groups who presented very similar results at last year ASH, one from Canada by Nizar Bahlis and Paola Neri, and one from Boston, the group of Nikhil Munshi, who also reported on biallelic BCMA events underlying relapse from CAR T-cell therapy. And with this, I would like to thank all my co-authors who contributed to this paper. And if you are interested in the study, please check out our paper published in Nature Medicine.