Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma
Abstract
Abstract Monoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). Although they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor-cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, we analyzed whole-genome and whole-exome sequencing data from patients 701 newly diagnosed MM, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse after anti-CD38 antibodies. We report a loss of CD38 in 10 of 50 patients (20%) after CD38 therapy, 3 of whom exhibited a loss of both copies. Two of these cases showed convergent evolution in which distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that 2 variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies daratumumab and isatuximab. However, a third mutation, R140G, conferred selective resistance to daratumumab, while retaining sensitivity to isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies after disease progression and these data suggest that next-generation sequencing may play a role in subsequent treatment selection for a subset of patients.
Article Details
Authors (29)
Benjamin Diamond
University of Miami
Linda Baughn
2Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States
Mansour Poorebrahim
1University of Calgary, Arnie Charbonneau Cancer Institute, Calgary, Canada
Alexandra M. Poos
4Heidelberg Myeloma Center, Department of Internal Medicine V, Medical Faculty, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
Holly Lee
University of Calgary
Marcella Kaddoura
1Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL
J. Erin Wiedmeier-Nutor
2Department of Medicine, Mayo Clinic, Phoenix, AZ
Michael Durante
1Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL
Gregory Otteson
1Mayo Clinic, Division of Hematopathology, Rochester, United States
Dragan Jevremovic
1Mayo Clinic, Rochester, United States
Hongwei Tang
Stefan Fröhling
Marc A. Baertsch
4Heidelberg Myeloma Center, Department of Internal Medicine V, Medical Faculty, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
Marios Papadimitriou
1Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, United States
Bachisio Ziccheddu
Memorial Sloan Kettering Cancer Center, United States
Tomas Jelinek
Department of Hemato-oncology, University Hospital Ostrava, Ostrava, Czech Republic
Cendrine Lemoine
12Department of eBiology, Large Molecule Research, Sanofi R&D, Vitry-sur-Seine, France
Alexey Rak
13Department of Bio Structure and Biophysics, Integrated Drug Discovery, Sanofi R&D, Vitry-sur-Seine, France
Damian J. Green
Ola Landgren
Paola Neri
1University of Calgary
Leif Bergsagel
Esteban Braggio
2Department of Medicine, Mayo Clinic, Phoenix, AZ
Shaji Kumar
Marc S. Raab
Rafael Fonseca
IDOMED Vista Carioca, RIO DE JANEIRO, Brazil
Nizar Bahlis
2Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada
Niels Weinhold
Francesco Maura
Memorial Sloan Kettering Cancer Center, New York