Journal: Blood
This study evaluated why only some patients with t(11;14)(CCND1;IGH) multiple myeloma benefit durably from venetoclax.
Key points:
- Population and methods:
- • 44 whole-genome/whole-exome–sequenced samples from 34 patients with t(11;14) myeloma treated with venetoclax.
- • Findings were validated in an independent cohort of 21 additional venetoclax-treated patients.
- • Ten patients had paired samples before venetoclax and at progression.
- Baseline predictors of inferior outcome on venetoclax:
- • Mutations in the RAS pathway (e.g., KRAS/NRAS and related signaling alterations) were strongly associated with shorter progression-free survival.
- • This association with poor PFS was confirmed in the independent validation cohort.
- • Among patients without RAS-pathway mutations, gain of 1q was also linked to shorter PFS, indicating it is an additional adverse genomic feature in this setting.
- Mechanisms of acquired resistance (paired pre/post samples):
- • At progression on venetoclax, clonal selection frequently involved:
- • Genomic events affecting the BCL2/MCL1 axis (shifting dependency away from BCL2).
- • Additional RAS pathway alterations.
- • Emergence or enrichment of high-risk lesions such as TP53 loss and CDKN2C loss.
- Clinical implication:
- • In t(11;14) myeloma, venetoclax sensitivity is modulated by co-occurring genomic events.
- • Comprehensive genomic profiling (RAS-pathway status, 1q gain, TP53/CDKN2C and BCL2/MCL1 alterations) can identify patients at higher risk for primary resistance or early progression on venetoclax and clarify mechanisms of acquired resistance.