A Journey Through Myeloma Evolution: From the Normal Plasma Cell to Disease Complexity

Abstract

The knowledge of cancer origin and the subsequent tracking of disease evolution represent unmet needs that will soon be within clinical reach. This will provide the opportunity to improve patient's stratification and to personalize treatments based on cancer biology along its life history. In this review, we focus on the molecular pathogenesis of multiple myeloma (MM), a hematologic malignancy with a well-known multi-stage disease course, where such approach can sooner translate into a clinical benefit. We describe novel insights into modes and timing of disease initiation. We dissect the biology of the preclinical and pre-malignant phases, elucidating how knowledge of the genomics of the disease and the composition of the microenvironment allow stratification of patients based on risk of disease progression. Then, we explore cell-intrinsic and cell-extrinsic drivers of MM evolution to symptomatic disease. Finally, we discuss how this may relate to the development of refractory disease after treatment. By integrating an evolutionary view of myeloma biology with the recent acquisitions on its clonal heterogeneity, we envision a way to drive the clinical management of the disease based on its detailed biological features more than surrogates of disease burden.

Figure 1

Initiation of monoclonal gammopathies. Timeline of monoclonal gammopathies development. After the antigen encounter a pre-malignant clone starts to grow within the bone marrow. Germline predisposition (red), continuous antigen exposure, aberrant mutational processes or exogenous mutants (green) promote the clone expansion until it could be detected by serum protein electrophoresis due to the abnormal production of the monoclonal protein. Based on the mechanism of transformation, the monoclonal gammopathy may become evident (on average) at different ages in the life of the patient.

Figure 2

Progression of monoclonal gammopathies. After the onset of a monoclonal gammopathy, the disease proceeds to symptomatic Multiple Myeloma in two possible ways. 1) a MGUS-like pattern (purple), which may remain stable for life or result in the long-term expansion of an indolent disease until the acquisition of a malignant phenotype (red) and the subsequent evolution to MM. 2) an MM-like pattern, characterized by the presence of malignant features already at the onset of the disease (red), which make the clone more aggressive and able to evolve more rapidly.

Figure 3

Progression to high-risk myeloma. At diagnosis, MM is composed of a heterogeneous mixture of subclones. High risk features (black) may be absent or poorly represented and most cells would carry standard risk features (green). In high-risk groups, most cells at diagnosis would carry high-risk features. After treatment the disease burden shrinks, but residual cells are likely enriched in high-risk features and possibly pre-existing cells carrying mutations conferring chemo-resistance (red). At relapse, these two features are enriched explaining the lower response rates to subsequent treatments and often lack of response to re-treatment with first line drugs.

Figure 4

Patterns of clonal evolution from Diagnosis to disease relapse. Treatments that are applied after the symptomatic Multiple Myeloma diagnosis will impose a selective pressure supporting the emergence of peculiar resistant clones. (A) the founding clone (grey) and a minor subclone (blue) both respond to treatment, but both reemerge in different proportions at relapse. (B) At diagnosis, as in A a founding clone (gray) and a minor subclone (blue) constitute the disease burden. At relapse, the minor subclone takes over and from it a second subclone (red) emerges in a linear fashion. (C) Two subclones (yellow and blue) are present at diagnosis but are impacted differentially by treatment. At the time of relapse the yellow subclone becomes predominant owing to supposed intrinsic chemoresistance. (D) the founding clone (grey) and a minor subclone (blue) both respond to treatment, but at relapse a second subclone branches out from the founding clone and contributes to relapse. (E-F) Two examples of branching clonal evolution: a minor subclone (blue) is eradicated by treatment and disappears at time of relapse. In E, at relapse, a new subclone emerges (yellow) from the founding clone and, in a linear fashion, a second emerges from the latter (red); in F, the yellow subclone is already present at diagnosis, reemerges after treatment, again giving rise to a second subclone (red). The fishplots are just examples, and have been generated by the “Fishplot” R package (https://github.com/chrisamiller/fishplot).