Genomic Landscape of t(11;14) in Multiple Myeloma

Background Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by multistep genetic alterations, including translocations, copy number aberrations (CNA), and mutations. Translocations involving the immunoglobulin heavy chain (IGH) locus contribute to plasma cell immortalization and consequent commitment to the MM disease pathway, however other genetic events largely underlie the complex genomic landscape of MM with molecular and clinical heterogeneity. The t(11;14) translocation is the most common IGH translocation in MM and has been identified as a predictive biomarker of response to venetoclax in relapsed/refractory MM. The objective of this study was to confirm that t(11;14) is stable across the course of disease and across lines of therapy, and to assess the unique genomic landscape of t(11;14) MM.

Methods This was a retrospective, single-center, non-interventional study. To confirm t(11;14) stability, longitudinal assessment of 272 patients for t(11;14) status by plasma cell-enriched FISH using the Vysis IGH/CCND1 XT DF FISH probe was performed on bone marrow aspirates (BMAs) collected at diagnosis and relapse. To assess the genomic landscape, 139 patient BMAs were collected from an approved biobank with informed consent and were analyzed by a targeted NGS panel. NGS was performed as described in Bolli et al. (Bolli et al. 2016) using an Agilent capture panel for sequencing on the Illumina NextSeq platform. Raw sequencing data was processed by an in-house bioinformatics pipeline to detect mutations, copy number aberrations and structural variants (SVs). Protein coding mutations with variant allele frequency >10% and minimum sequencing depth >=20X were selected. CNAs were defined as log ratio above 0.3 (copy number gain) or below -0.4 (copy number loss). SVs with 5 or more supporting reads were examined to detect translocations within the IGH locus.

Results Among the 272 patients assessed by longitudinal t(11;14) FISH, 118 were t(11;14)+ and 154 were t(11;14)-. All t(11;14)+ patients remained positive from their initial assessment to first and subsequent longitudinal assessments (Figure 1). The t(11;14) FISH fusion (F) patterns were also consistent across longitudinal assessments with 90% of patients possessing and maintaining either a 1F (18%), 2F (69%), or ≥3F (3%) translocation pattern. No t(11;14)- patients acquired the translocation at relapse. Among the 139 samples analyzed for t(11;14), 130 samples had results from both FISH and NGS with a 100% concordance rate; 66 were t(11;14)+ and 64 were t(11;14)-. The mutational landscape in highly recurrent genes was heterogeneous (Figure 2). MAPK pathway mutations were the most common (47/130 pts, 36.2%), with recurrent mutations in BRAF gene more prevalent in t(11;14)- vs t(11;14)+ pts (18.8% vs 6.1%, p<0.05). Conversely, mutations in DIS3 gene were more common in t(11;14)+ vs t(11;14)- pts (21.2% vs 4.7%, p<0.05). DIS3 and BRAF mutations have been associated with poor prognosis in MM. High CNAs are associated with increased genomic instability, resistance to therapy, and decreased survival in MM. Increased CNAs were observed in t(11;14)- vs t(11;14)+ MM (p<0.001).

Conclusion This study confirms in a large, longitudinal cohort of patients with MM that t(11;14) is stable from diagnosis to relapse. These analyses also begin to delineate the differentiated genetic architecture of t(11;14) MM, including fewer CNAs associated with increased genomic stability, but increased rates of DIS3 mutations that confer poor prognosis in MM.

Ross:AbbVie: Current Employment, Current equity holder in publicly-traded company. Avet-Loiseau:AbbVie: Research Funding. Li:Abbvie: Current Employment, Current equity holder in publicly-traded company. Thiebaut-Millot:AbbVie: Current Employment, Current equity holder in publicly-traded company. Hader:AbbVie: Current Employment, Current equity holder in publicly-traded company.

Venetoclax is a BCL-2 inhibitor that is FDA approved for multiple indications. Venetoclax is not currently approved for the treatment of multiple myeloma.