Genomic mechanisms of resistance to venetoclax in multiple myeloma with t(11;14)( <i>CCND1</i> ; <i>IGH</i> )
Abstract
Abstract Multiple myeloma (MM) with t(11;14)(CCND1;IGH) remains the only subset sensitive to the BCL2 inhibitor venetoclax. However, not all patients with t(11;14)(CCND1;IGH) respond to treatment, and some progress early after initial response. To investigate this, we examined 44 whole-genome and whole-exome sequencing data samples from 34 patients with t(11;14) MM treated with venetoclax. The presence of mutations in the RAS pathway was strongly associated with shortened progression-free survival (PFS) and was validated in an independent cohort of 21 patients with MM. The presence of 1q gain was also associated with shorter PFS in patients without RAS mutations. In 10 patients with paired prevenetoclax and postvenetoclax treatment samples, postvenetoclax progression was recurrently driven by the selection of genomic events in the BCL2/MCL1 and RAS pathways and of high-risk features (eg, loss of TP53 and CDKN2C). Overall, our study shows that comprehensive genomic profiling can identify most mechanisms underlying resistance to BCL2 inhibition in t(11;14)(CCND1;IGH) MM.
Article Details
Authors (28)
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
Vikas A. Gupta
3Department of Hematology and Medical Oncology, Emory University, Atlanta, GA
Tomas Jelinek
Department of Hemato-oncology, University Hospital Ostrava, Ostrava, Czech Republic
Bachisio Ziccheddu
Memorial Sloan Kettering Cancer Center, United States
Suganti Shivaram
6Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Hongwei Tang
Rebecca W. Owens
3Department of Hematology and Medical Oncology, Emory University, Atlanta, GA
Tereza Sevcikova
4Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Rodrigo Fonseca
2Department of Medicine, Mayo Clinic, Phoenix, AZ
Michael Durante
1Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL
Benjamin Diamond
University of Miami
Logan Zhao
2Department of Medicine, Mayo Clinic, Phoenix, AZ
Yuan X. Zhu
2Department of Medicine, Mayo Clinic, Phoenix, AZ
Chang-Xin Shi
2Department of Medicine, Mayo Clinic, Phoenix, AZ
Shannon M. Matulis
3Department of Hematology and Medical Oncology, Emory University, Atlanta, GA
Constantine S. Mitsiades
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Ola Landgren
Saad Usmani
8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Roman Hajek
Marta Chesi
P. Leif Bergsagel
Mayo Clinic Arizona, Scottsdale
Esteban Braggio
2Department of Medicine, Mayo Clinic, Phoenix, AZ
Lawrence H. Boise
3Department of Hematology and Medical Oncology, Emory University, Atlanta, GA
Rafael Fonseca
IDOMED Vista Carioca, RIO DE JANEIRO, Brazil
Shaji Kumar
Francesco Maura
Memorial Sloan Kettering Cancer Center, New York
Linda B. Baughn
6Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN