Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma

Mehmet Kemal Samur (), Mariateresa Fulciniti, Anil Aktas Samur, Abdul Hamid Bazarbachi, Yu-Tzu Tai, Rao Prabhala, Alejandro Alonso, Adam S. Sperling, Timothy Campbell, Fabio Petrocca, Kristen Hege, Shari Kaiser, Hervé Avet Loiseau, Kenneth C. Anderson and Nikhil C. Munshi ()
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Mehmet Kemal Samur: Dana Farber Cancer Institute
Mariateresa Fulciniti: Dana Farber Cancer Institute, Harvard Medical School
Anil Aktas Samur: Dana Farber Cancer Institute
Abdul Hamid Bazarbachi: Dana Farber Cancer Institute, Harvard Medical School
Yu-Tzu Tai: Dana Farber Cancer Institute, Harvard Medical School
Rao Prabhala: Dana Farber Cancer Institute, Harvard Medical School
Alejandro Alonso: Dana Farber Cancer Institute, Harvard Medical School
Adam S. Sperling: Dana Farber Cancer Institute, Harvard Medical School
Timothy Campbell: Bristol-Myers Squibb
Fabio Petrocca: Bluebird Bio
Kristen Hege: Bristol-Myers Squibb
Shari Kaiser: Bristol-Myers Squibb
Hervé Avet Loiseau: University Cancer Center of Toulouse Institut National de la Santé
Kenneth C. Anderson: Dana Farber Cancer Institute, Harvard Medical School
Nikhil C. Munshi: Dana Farber Cancer Institute, Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-7

Abstract: Abstract BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.

Date: 2021
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DOI: 10.1038/s41467-021-21177-5

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