Genomic mechanisms of resistance to venetoclax in multiple myeloma with t(11;14)(CCND1;IGH)
Multiple myeloma (MM) with t(11;14)(CCND1;IGH) remains the only subset sensitive to the BCL2 inhibitor venetoclax. Not all t(11;14)(CCND1;IGH) patients respond to treatment and some progress early after initial response. To investigate this, we interrogated 44 whole genome and exome sequencing data 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 MM patients. Presence of 1q gain was also associated with shorter PFS in patients without RAS mutations. In 10 patients with paired, pre- and post-venetoclax treatment samples, post-venetoclax progression was recurrently driven by the selection of genomic events in BCL2/MCL1 and RAS pathways and of high-risk features (e.g., 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.
Authors
- Benjamin T. Diamond (ORCID: https://orcid.org/0000-0002-8638-9365)
- Saad Z. Usmani (ORCID: https://orcid.org/0000-0002-5484-8731)
- Lawrence Boise (ORCID: https://orcid.org/0000-0001-9436-8815)
- C. Mitsiades
- Hongwei Tang (ORCID: https://orcid.org/0000-0002-2053-788X)
- M. Chesi
- Linda Banovic Baughn (ORCID: https://orcid.org/0000-0001-5229-4897)
- Vikas A. Gupta (ORCID: https://orcid.org/0000-0002-8980-2338)
- R. Fonseca
- Bachisio Ziccheddu (ORCID: https://orcid.org/0000-0002-2746-0053)
- R Hajek
- Ševčíková Tereza
- Marcella Kaddoura (ORCID: https://orcid.org/0000-0002-4529-7405)
- Shannon M. Matulis (ORCID: https://orcid.org/0009-0009-4223-2006)
- Michael Durante (ORCID: https://orcid.org/0000-0003-3137-6847)
- Ola Landgren (ORCID: https://orcid.org/0000-0001-6485-4839)
- Francesco Maura (ORCID: https://orcid.org/0000-0001-6233-4864)
- Shaleen Kumar
- Tomas Jelinek
- Braggio Esteban
- P. Leif Bergsagel
- Chang-Xin Shi
- Suganti Shivaram
- Logan Zhao
- Julia Erin Wiedmeier-Nutor
- Rebecca W Owens
- Yuan Xiao Zhu
Institutions
- Mayo Clinic (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Miami (US)
- Emory University (US)
- University Hospital Ostrava (CZ)
- Dana-Farber Cancer Institute (US)
- Mayo Clinic in Arizona (US)
- Mayo Clinic Hospital (US)
- Sylvester Comprehensive Cancer Center (US)
Publication Details
- Journal
- Blood
- Published
- 2026-01-02
- DOI
- https://doi.org/10.1182/blood.2025029996
- Primary Topic
- Multiple Myeloma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00