High somatic mutation and neoantigen burden are correlated with decreased progression-free survival in multiple myeloma

A Miller,A K Stewart,D Auclair,E Braggio,L Cattaneo,S J Russell,Y Asmann,S Lonial,J Keats

doi:10.1038/bcj.2017.94

Abstract

Tumor-specific mutations can result in immunogenic neoantigens, both of which have been correlated with responsiveness to immune checkpoint inhibitors in highly mutagenic cancers. However, early results of single-agent checkpoint inhibitors in multiple myeloma (MM) have been underwhelming. Therefore, we sought to understand the relationship between mutation and neoantigen landscape of MM patients and responsiveness to therapies. Somatic mutation burden, neoantigen load, and response to therapy were determined using interim data from the MMRF CoMMpass study (NCT01454297) on 664 MM patients. In this population, the mean somatic and missense mutation loads were 405.84(s=608.55) and 63.90(s=95.88) mutations per patient, respectively. There was a positive linear relationship between mutation and neoantigen burdens (R2=0.862). The average predicted neoantigen load was 23.52(s=52.14) neoantigens with an average of 9.40(s=26.97) expressed neoantigens. Survival analysis revealed significantly shorter progression-free survival (PFS) in patients with greater than average somatic missense mutation load (N=163, 0.493 vs 0.726 2-year PFS, P=0.0023) and predicted expressed neoantigen load (N=214, 0.555 vs 0.729 2-year PFS, P=0.0028). This pattern is maintained when stratified by disease stage and cytogenetic abnormalities. Therefore, high mutation and neoantigen load are clinically relevant risk factors that negatively impact survival of MM patients under current standards of care.

Highlights

Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow, for which recent therapeutic advances have extended overall survival (OS), but most patients relapse.[1,2] There is, variability in response between patients and survival is known to vary with prognostic factors, including disease stage at diagnosis and cytogenetic abnormalities.[3]
Mutation and Neoantigen Load load were found to correlate with significantly decreased progression-free survival (PFS) time The interim data from the MMRF CoMMpass study (NCT 01454297)
After induction therapy, indicating the need for better treatment were used to assess mutation burden and predicted neoantigen options for this subset of patients. This provides the basis for load in a subset of 664 MM patients representative of the accrued optimizing personalized treatment approaches for MM patients CoMMpass population in terms of age, sex, race, international based on mutation and neoantigen load

Summary

Introduction

Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow, for which recent therapeutic advances have extended overall survival (OS), but most patients relapse.[1,2] There is, variability in response between patients and survival is known to vary with prognostic factors, including disease stage at diagnosis and cytogenetic abnormalities.[3]. One novel class of agents currently explored in clinical trials for MM is immunotherapeutic checkpoint inhibitors. Single-agent checkpoint inhibitors can reverse tumor-induced downregulation of T-cell function by blocking the engagement of checkpoint receptors like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed-death-1(PD-1) on the surface of T-cells with their cognate ligands expressed on tumor cells.[4,5,6] This allows activation of the cytotoxic T-cell via engagement of the T-cell receptor (TCR) with antigenic peptides presented in the class I major histocompatibility complex (MHC) on tumor cells

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