Evolutionary biology of high-risk multiple myeloma

Abstract

The outcomes for the majority of patients with myeloma have improved over recent decades, driven by treatment advances. However, there is a subset of patients considered to have high-risk disease who have not benefited. Understanding how high-risk disease evolves from more therapeutically tractable stages is crucial if we are to improve outcomes. This can be accomplished by identifying the genetic mechanisms and mutations driving the transition of a normal plasma cell to one with the features of the following disease stages: monoclonal gammopathy of undetermined significance, smouldering myeloma, myeloma and plasma cell leukaemia. Although myeloma initiating events are clonal, subsequent driver lesions often occur in a subclone of cells, facilitating progression by Darwinian selection processes. Understanding the co-evolution of the clones within their microenvironment will be crucial for therapeutically manipulating the process. The end stage of progression is the generation of a state associated with treatment resistance, increased proliferation, evasion of apoptosis and an ability to grow independently of the bone marrow microenvironment. In this Review, we discuss these end-stage high-risk disease states and how new information is improving our understanding of their evolutionary trajectories, how they may be diagnosed and the biological behaviour that must be addressed if they are to be treated effectively.

Somatic Genomic Mosaicism in Multiple Myeloma

“…Equally important, since different subpopulations can be molecularly profiled, especially after becoming dominant clones, a huge number of molecular mechanisms can be characterized. Data from recent studies illustrate diverse genetic variations in MM disease evolution Keats et al, 2012;Bolli et al, 2014Bolli et al, , 2018Pawlyn and Morgan, 2017;Aktas Samur et al, 2019;Maura et al, 2019). A better way to understand MM is to study the evolutionary mechanism of cancer (Ye et al, 2009), rather than continue identifying individual molecular mechanisms: when there are so many, the clinical prediction of any single mechanism is low due to highly dynamic evolutionary processes.…”

Bone Marrow Micro‐Environment in Normal and Deranged Hematopoiesis: Opportunities for Regenerative Medicine and Therapies

“…This formative stage may represent a window of opportunity to pursue aggressive preventative strategies to minimize the risk of transformation and help bolster innate mechanisms of abnormal clone clearance. Likewise, monoclonal gammopathy of undetermined significance (MGUS) denotes a benign accumulation of clonal plasma cells and a precursor state to MM, with a risk of transformation of about 1% annually . Genome sequencing has demonstrated that nearly all the genetic alterations found in MM can also be found in MGUS, and small studies looking at serial samples before and after conversion have revealed a limited number of new mutations .…”

“…Likewise, monoclonal gammopathy of undetermined significance (MGUS) denotes a benign accumulation of clonal plasma cells and a precursor state to MM, with a risk of transformation of about 1% annually. [132] Genome sequencing has demonstrated that nearly all the genetic alterations found in MM can also be found in MGUS, and small studies looking at serial samples before and after conversion have revealed a limited number of new mutations. [133] Extrinsic factors from the micro-environment are therefore proposed to constrain the development of clinical malignancy and early evidence suggests a potential immunemediated process.…”

Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial

“…The aetiology and progression of multiple myeloma are driven by the accumulation of acquired genetic events that affect clonal competition within the bone marrow microenvironment. 1,2 Tumour cell diversity increases as genetic lesions accumulate, and the disease progresses from monoclonal gammopathy of undetermined signif icance to myeloma, leading to substantial subclonal heterogeneity at the time of diagnosis. Applying induction treatment designed to eliminate susceptible clones might provide selective pressure for the expansion of resistant clones, resulting in early or late relapse.…”