Among patients with multiple myeloma (MM), intron retention-induced neoantigen (IR-neoAg) load may predict prognosis, according to research published in Oncogene.

While therapeutic advances, including the discovery of immune checkpoint inhibitors, over the last several decades have improved overall survival (OS) rates among patients with MM, relapse is frequently observed. This has necessitated both finding markers associated with responses to checkpoint inhibitors, and discovering combination therapies that may improve response likelihood.

Neoantigens, which are also known as tumor-specific antigenic peptides, have shown promise as signals of an anti-tumor immune response. However, despite contrasting findings with solid tumors, research in MM has suggested that mutation-derived neoantigen load predicts a poor prognosis.

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Other research suggests, however, that IR-neoAg levels may predict an immune response in MM. For this study, researchers evaluated RNA data obtained from the MM Research Foundation to determine any link between IR-neoAg levels, IR events, and clinical outcomes.

Overall, analysis suggested that high IR-neoAg load predicted poor OS regardless of whether the disease was newly diagnosed or relapsed. Among newly diagnosed patients, those with an IR-neoAg load exceeding the median had inferior OS (P =.027), as did patients at first relapse (P =.002). Patients with samples at relapse with lower IR-neoAg loads also had improved 2-year OS rates (85% vs 57% among patients with higher IR-neoAg loads).

The researchers also noted that high IR-neoAg loads positively correlated with T cell coinhibitory molecule expression and interferon signaling. MM cells with high IR levels, furthermore, had lower major histocompatibility complex-II protein levels—and that spliceosome inhibition in these cells increased major histocompatibility complex-I protein levels.

“In conclusion, while neoantigen load has been associated with favorable survival in many solid cancers, our study strongly suggests that IR-neoAg load may serve as a clinically relevant risk factor that negatively impacts myeloma patient survival,” the authors wrote.


Dong C, Cesarano A, Bombaci G, et al. Intron retention-induced neoantigen load correlates with unfavorable prognosis in multiple myeloma. Oncogene. Published online September 9, 2021. doi:10.1038/s41388-021-02005-y