Genomic and immune determinants of resistance to anti-CD38 monoclonal antibody-based therapy in relapsed refractory multiple myeloma.

Bachisio Ziccheddu; Claudia Giannotta; Mattia D’Agostino; Giuseppe Bertuglia; Elona Saraci; Stefania Oliva; Elisa Genuardi; Marios Papadimitriou; Benjamin T. Diamond; Paolo Corradini; David Glen Coffey; Ola Landgren; Niccolò Bolli; Benedetto Bruno; Mario Boccadoro; Massimo Massaia; Francesco Maura; Alessandra Larocca

doi:10.1101/2023.12.04.23299287

Genetic & Genomic MedicinemedRxivDec 4, 2023

Preprint

Genomic and immune determinants of resistance to anti-CD38 monoclonal antibody-based therapy in relapsed refractory multiple myeloma.

Bachisio Ziccheddu iD, Claudia Giannotta iD, Mattia D’Agostino iD, Giuseppe Bertuglia iD, Elona Saraci iD, Stefania Oliva iD, Elisa Genuardi iD, Marios Papadimitriou iD, Benjamin T. Diamond iD, Paolo Corradini iD, David Glen Coffey iD, Ola Landgren iD, Niccolò Bolli iD, Benedetto Bruno iD, Mario Boccadoro iD, Massimo Massaia iD, Francesco Maura iD, Alessandra Larocca iD

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Abstract

Anti-CD38 antibody therapies have transformed multiple myeloma (MM) treatment. However, a large fraction of patients inevitably relapses. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676). Whole genome sequencing (WGS) before and after treatment pinpointed genomic drivers associated with early progression, including RPL5 loss and APOBEC mutagenesis. Flow cytometry on 202 blood samples, collected every three months until progression for 31 patients, revealed distinct immune changes significantly impacting clinical outcomes. Progressing patients exhibited significant depletion of CD38+ NK cells, persistence of T cell exhaustion, and reduced depletion of T-reg cells over time. These findings underscore the influence of immune composition and daratumumab-induced immune changes in promoting MM resistance. Integrating genomics and flow cytometry unveiled associations between adverse genomic features and immune patterns. Overall, this study sheds light on the intricate interplay between genomic complexity and the immune microenvironment driving resistance to Dara-Rd.