Single- and double-hit events in genes encoding immune targets before and after T cell–engaging antibody therapy in MM

Author:

Truger Marietta S.1,Duell Johannes2,Zhou Xiang2,Heimeshoff Larissa2,Ruckdeschel Anna2,John Mara3,Riedel Angela3,Hüper Sebastian3,Peter Jessica2,Walter Wencke1ORCID,Haertle Larissa2ORCID,Meggendorfer Manja1,Topp Max S.2,Rosenwald Andreas4,Da Via Matteo Claudio56,Bolli Niccolo56,Weinhold Niels7,Einsele Hermann2,Haferlach Claudia1,Kortüm K. Martin2ORCID,Rasche Leo23ORCID

Affiliation:

1. MLL Munich Leukemia Laboratory, Munich, Germany;

2. Department of Internal Medicine 2, and

3. Mildred Scheel Early Career Center, University Hospital of Würzburg, Würzburg, Germany;

4. Institute of Pathology, University of Würzburg, Würzburg, Germany;

5. Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy;

6. Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; and

7. Medizinische Klinik 5, University Hospital of Heidelberg, Heidelberg, Germany

Abstract

Abstract T cell–engaging immunotherapies exert unprecedented single-agent activity in multiple myeloma (MM), thereby putting a yet unexplored selective pressure on the clonal architecture. In this study, we report on homozygous BCMA (TNFRSF17) gene deletion after BCMA-targeting T cell–redirecting bispecific antibody therapy in a heavily pretreated MM patient. Loss of BCMA protein expression persisted over subsequent relapses, with no response to treatment with anti-BCMA antibody drug conjugate. In light of the multiple alternative targets that are emerging in addition to BCMA, we extended our analyses to delineate a more complete picture of genetic alterations that may have an impact on immunotherapy targets in MM. We performed whole-genome sequencing and RNA sequencing in 100 MM patients (50 were newly diagnosed; 50 were relapsed/refractory) and identified a significant proportion of patients with aberrations in genes encoding immunotherapy targets; GPRC5D ranked first with 15% heterozygous deletions, followed by CD38 (10%), SDC1 (5%), and TNFRSF17 (4%). Notably, these heterozygous deletions did not lower the expression levels of respective genes, but they may represent a first hit that drives the acquisition of homozygous deletions and subsequent antigen-loss relapse upon targeted immunotherapy. In summary, we show preexisting vulnerability in genes encoding immunotargets before and homozygous deletions after T cell–engaging immunotherapy.

Publisher

American Society of Hematology

Subject

Hematology

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