Abstract

Background: Multiple myeloma (MM) remains an incurable malignancy, but new treatment modalities can achieve durable remissions in most cases. Remission is generally regarded as a window of opportunity for active immunotherapy, aimed at eradicating residual disease. For immunotherapy, and vaccination in particular, the expression of cancer testis antigens (CTAs) in MM has emerged as a key target that is essentially tumor-specific. These CTAs are expressed at disease presentation, many confirmed also at the protein level. However, the question has remained whether treatment might critically alter the expression profile of CTAs. To address this, we have examined the expression levels of a large panel of known CTAs using gene expression profiles (GEPs) from patient cohorts in clinical trials at defined stages: at disease presentation in HOVON-65 and post-treatment in the APEX, SUMMIT and CREST trials.

Methods and results: The APEX, SUMMIT and CREST trials have been described by Mulligan et al. (

Blood
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109
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3177
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2007
) and data consist of GEPs obtained from 264 patients with relapse following prior therapies (median number of therapies, 3; min-max, 1–14). In the HOVON-65 study, GEPs of 204 previously untreated myeloma cases were obtained. For comparison of both studies, original raw data files (CEL-files) were obtained and analyzed using Partek software. After normalization and merging, the expression of 62 CTA genes and gene clusters was evaluated. 63 probe sets were used, of which 51 correspond to 50 unique genes and 12 correspond to clusters of cancer antigen genes. Normalized expression levels for 24/62 genes/gene clusters were well above cut-off, and for remainder (38/62) were generally low with medians below 30. High median expression values, in the top 10% of CTA expression values, were found for SSX2, MAGE-A3 and MAGE-C1. Genes in the bottom 10% include MAGE-B1 and SPACA3. Notably, of 62, the fold change in expression level before and after treatment was at most 1.5 in any of the genes studied, indicating that the expression of the majority of CTAs is unchanged by treatment. For 8 genes/gene clusters, significantly decreased expression was found in relapsed cases compared to untreated MM, including GAGE3 and a gene cluster containing the GAGE1 gene.

Conclusion: These clinical trial data indicate that targeting CTAs with immunotherapy during first remission or after relapse of MM remains a viable option.

Disclosures: Mulligan:Millenium Pharmaceuticals: Employment. Bryant:Millenium Pharmaceuticals: Employment.

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