Clonal Evolution of Multiple Myeloma-Clinical and Diagnostic Implications

Abstract

Plasma cell dyscrasias are a heterogeneous group of diseases characterized by the expansion of bone marrow plasma cells. Malignant transformation of plasma cells depends on the continuity of events resulting in a sequence of well-defined disease stages, from monoclonal gammopathy of undetermined significance (MGUS) through smoldering myeloma (SMM) to symptomatic multiple myeloma (MM). Evolution of a pre-malignant cell into a malignant cell, as well as further tumor progression, dissemination, and relapse, require development of multiple driver lesions conferring selective advantage of the dominant clone and allowing subsequent evolution under selective pressure of microenvironment and treatment. This process of natural selection facilitates tumor plasticity leading to the formation of genetically complex and heterogenous tumors that are notoriously difficult to treat. Better understanding of the mechanisms underlying tumor evolution in MM and identification of lesions driving the evolution from the premalignant clone is therefore a key to development of effective treatment and long-term disease control. Here, we review recent advances in clonal evolution patterns and genomic landscape dynamics of MM, focusing on their clinical implications.

Keywords: clonal evolution; genetic heterogeneity; multiple myeloma; tumor heterogeneity.

Figure 1

Evolution of plasma cell dyscrasias. Both primary and secondary genetic events are required for malignant transformation of a post-GC B cell to MM. New genetic events accumulate in malignant plasmocytes over time affecting the fitness of subclones and leading to further expansion of some and to the extinction of others. Progression from MGUS/SMM to MM is driven by subclonal competition (and likely by its cooperation) and by simultaneous changes in the tumor microenvironment. (1) Branching clonal evolution—the dominant evolutionary pattern in the progression of SMM to MM, with some subclones disappearing (pink, light blue) and others appearing (red, purple, brown) over time; (2) static clonal progression—evolutionary pattern in the progression of SMM to MM, in which the tumor’s subclonal architecture does not change significantly over time. Abbreviations: GC, germinal center; IgH, immunoglobulin heavy chain; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; SMM, smoldering multiple myeloma; PCL, plasma cell leukemia. The figure was prepared using images provided by Servier Medical Art (https://smart.servier.com accessed on 23 August 2021).

Figure 2

Main models of clonal evolution in multiple myeloma. Each color represents a single subclone. Progeny subclones arising during evolution are marked with arrows.

Figure 3

Clonal evolution of multiple myeloma during therapy. Each color represents a single subclone. (A) Treatment-resistant subclones evolve at the MRD stage, being the source for overt disease relapse; (B) Selection of preexisting subclones and formation of new subclones (marked with stars) during antimyeloma therapy. (C) Change in the subclonal architecture of multiple myeloma during therapy with the selection of some subclones (green, light blue, yellow, purple, lavender) and the disappearance of others (pink, dark blue). Abbreviations: MRD, measurable residual disease; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed/refractory multiple myeloma. The figure was prepared using images provided by Servier Medical Art (https://smart.servier.com accessed on 23 August 2021).