Professor Indiana University Indianapolis, Indiana, United States
Introduction: Immunotherapies have shown promise in treating MM, although this has been limited to relapsed and refractory MM. However, their application is limited by short remission, potential toxicity, and genomic heterogeneity. Here, we used genomic subgroups and high-risk markers to identify additional potential therapeutic targets with low predicted toxicity and high specificity to MM and genomic subgroups.
Methods: RNA-seq data from 754 newly diagnosed MM (NDMM) and 98 relapsed and refractory MM (RRMM) samples with genomic annotation from the CoMMpass study were utilized. 32 NDMM and 43 RRMM in-house samples were used as validation. Genes with high surface potential were prioritized by annotations from 5 databases and annotation from the Human Protein Atlas was used to evaluate off-target toxicity. Candidates were further filtered to have high surface potential (>3 databases), low toxicity (normalized TPM>50 in < 3 non-immune organs) and high expression (median expression Log2(TPM+1)>3). Candidates were identified at both the population and cytogenetic subgroup levels.
Results: We identified 847 genes with high cell surface potential, of which 599 had low predicted off-target toxicity. 48 genes with high expression were identified as candidates in both the NDMM and RRMM population, all of which were validated with consistently high expression in the validation set. They included established targets such as SLAMF7/CD319, TNFRSF17/BCMA, GPRC5D, CD38, and FCRL5/FcRH5 as well as novel targets such as EVI2B, CD53, CD79A, CD79B, and CD48. High expression of CD53 and CD48 was also associated with poor progression-free survival with quartile analysis (p=0.03, p=0.01, logrank test). By splitting the population into cytogenetic subgroups 25 more candidates were identified, including significantly upregulated ROBO3 in t(4;14), SPN in t(14;16),t(14;20) and t(4;14) and MS4A1/CD20 in t(11;14) and t(14;16). SPN expression was significantly associated with overall survival in the three subgroups (p=0.0005, logrank test). 11 unique candidates were identified for other high-risk subgroups including 1q amp, biallelic TP53, and t(MYC). Some candidates were also associated with high-risk subgroups such as GPRC5D, IL6R and SPN which showed significantly elevated expression with increasing copies of 1q (p < 0.001, p< 0.001, p< 0.04, respectively). Using the DepMap database, IL6R was essential in the 1q-gained cell-line OCI-MY7 indicating that immune escape from this target may be difficult in some patients.
Conclusions: Our studies demonstrated the existence of novel increased expression of genes encoding surface proteins in NDMM patient samples that maintained their expression levels or increased when being exposed to existing standard of care in MM. In some instances, these genes associate with existing cytogenetic subgroups and may serve as novel proteins that can be further targeted by immune-related therapies.
