Utilizing Genomics to Identify Novel Immunotherapeutic Targets in Multiple Myeloma High-Risk Subgroups

Abstract Immunotherapy is now standard of care for multiple myeloma, where the most common targets are B cell maturation antigen, CD38, and G protein-coupled receptor class C group 5 member D but strategies to identify additional targets are needed. We have utilized two large datasets of genomic data and integrated them with existing databases to identify expressed cell surface targets in myeloma patients. Importantly, we also identify targets specific to genomic defined subgroups of patients including primary translocations and high-risk subgroups. Examples of subgroup targets include ROBO3 in t(4;14), CD109 in t(14;16), CD20 in t(11;14), GPRC5D in 1q+, and ADAM28 in biallelic TP53 samples. Expression was validated by flow cytometry and CRISPR-Cas9 knock out models. Sub-clonal differences in expression were noted, as was alternative splicing of existing immunotherapy targets such as FCRL5. These results highlight the use of genomic stratification to identify novel therapeutic targets. Competing Interest Statement V.S.C., H.H., F.Z. and M.N. declare financial competing interest and are employed by and hold stock in Genentech Inc. All other authors declare no financial or non-financial competing interests. Footnotes Conflict of Interest Statement: V.S.C., H.H., F.Z. and M.N. declare financial competing interest and are employed by and hold stock in Genentech Inc. All other authors declare no financial or non-financial competing interests.