Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma

Abstract

Multiple Myeloma (MM) is a haematological malignancy characterised by the clonal expansion of plasma cells (PCs) within the bone marrow. Despite advances in therapy, MM remains a largely incurable disease with a median survival of 6 years. In almost all cases, the development of MM is preceded by the benign PC condition Monoclonal Gammopathy of Undetermined Significance (MGUS). Recent studies show that the transformation of MGUS to MM is associated with complex genetic changes. Understanding how these changes contribute to evolution will present targets for clinical intervention. We discuss three models of MM evolution; the linear, the expansionist and the intraclonal heterogeneity models. Of particular interest is the intraclonal heterogeneity model. Here, distinct populations of MM PCs carry differing combinations of genetic mutations. Acquisition of additional mutations can contribute to subclonal lineages where "driver" mutations may influence selective pressure and dominance, and "passenger" mutations are neutral in their effects. Furthermore, studies show that clinical intervention introduces additional selective pressure on tumour cells and can influence subclone survival, leading to therapy resistance. This review discusses how Next Generation Sequencing approaches are revealing critical insights into the genetics of MM development, disease progression and treatment. MM disease progression will illuminate possible mechanisms underlying the tumour.

Subclonal evolution in disease progression from MGUS/SMM to multiple myeloma is characterised by clonal stability

“…Recent studies show that MM patients display complex mutational landscapes involving intraclonal genetic heterogeneity at the bulk tumour level, where mutations are acquired in a non-linear branching pattern [12–17]. Intraclonal heterogeneity has been observed at all stages of MM, suggesting that disease progression may be mediated through inter-subclone competition and outgrowth of the fittest of these subclones.…”

HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

“…2). In a small proportion of MGUS patients (1% per year), intrinsic genetic changes, coupled with extrinsic factors, lead to the proliferation of the multiple myeloma PCs and their dissemination to sites throughout the skeleton (3). Ultimately, multiple myeloma PC proliferation and dissemination results in hypercalcemia, renal insufficiency, anemia, and osteolytic bone disease, features characteristic of progressive disease (4).…”

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“…Log white blood cell (WBC) at diagnosis X 8 Fractures at diagnosis 0 none, 1 present X 9 Log %BM at diagnosis (log % plasma cells in bone marrow) X 10 % Lymphocytes in peripheral blood at diagnosis X 11 % Myeloid cells in peripheral blood at diagnosis X 12 Proteinuria at diagnosis X 13 Bence Jone protein in urine at diagnosis 1 present, 2 none X 14 Total serum protein at diagnosis X 15 Serum globin (gm%) at diagnosis X 16 Serum calcium (mgm%) at diagnosis…”

“…The abnormal plasma cells produce abnormal antibodies that cause kidney problems and overly thick blood [9][10][11]. The initially identified causes of MMC are obesity, radiation exposure, family history, and certain chemicals [12][13][14][15]. Generally, no specific risk factors or causes have been identified for patients diagnosed with MMC.…”