The Dynamics of Nucleotide Variants in the Progression from Low–Intermediate Myeloma Precursor Conditions to Multiple Myeloma: Studying Serial Samples with a Targeted Sequencing Approach

SIMPLE SUMMARY: Multiple myeloma (MM), characterized by the expansion of plasma cells in the bone marrow, is the second most common hematological malignancy. This incurable cancer is consistently preceded by non-malignant asymptomatic precursor conditions known as monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). These pre-stages are relatively frequent, but only a select percentage of them will progress to MM. However, it is still not possible to individually predict when and which patients will develop MM. Therefore, this study aimed to investigate the mutational profile in the progression in serial bone marrow samples with a custom targeted sequencing panel, designed to detect variants in myeloma-related genes. Remarkably, almost all variants identified in the MM samples were also already present in the pre-stages, sometimes even many years before the progression. These results provide new important insights into the molecular mechanisms of the precursor conditions and progression to MM. ABSTRACT: Multiple myeloma (MM), or Kahler’s disease, is an incurable plasma cell (PC) cancer in the bone marrow (BM). This malignancy is preceded by one or more asymptomatic precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). The molecular mechanisms and exact cause of this progression are still not completely understood. In this study, the mutational profile underlying the progression from low–intermediate risk myeloma precursor conditions to MM was studied in serial BM smears. A custom capture-based sequencing platform was developed, including 81 myeloma-related genes. The clonal evolution of single nucleotide variants and short insertions and deletions was studied in serial BM smears from 21 progressed precursor patients with a median time of progression of six years. From the 21 patients, four patients had no variation in one of the 81 studied genes. Interestingly, in 16 of the 17 other patients, at least one variant present in MM was also detected in its precursor BM, even years before progression. Here, the variants were present in the pre-stage at a median of 62 months before progression to MM. Studying these paired BM samples contributes to the knowledge of the evolutionary genetic landscape and provides additional insight into the mutational behavior of mutant clones over time throughout progression.