Plasma cell myeloma is a hematopoietic neoplasm with morphologic and genetic heterogeneity. Genetics have been shown to play an important role in risk stratification of plasma cell myeloma however the correlation between genetic aberrations and morphologic features is not well studied. In performing a systematic study of 266 multiple myeloma bone marrow biopsies from 329 patients, we initially investigated the association between bone marrow morphology, conventional cytogenetics, gene expression profiling and gene mutations. It is the first known study demonstrating the correlation between high tumor burden, diffuse sheet growth pattern, immature cell morphology, high mitotic index, and increased reticulin fibrosis with high risk disease determined by MyPRS gene expression profiles. Furthermore, the MyPRS risk stratification showed significant correlation of high risk cases with chromosomal alterations and specific gene mutations. In this more recent analysis, we demonstrate that poor prognostic histomorphologic features, genetic aberrations including high risk score of MyPRS and TP53 alterations do in fact have a negative effect on patient survival.