Clonal heterogeneity and clonal evolution have emerged as critical concepts in the field of oncology over the
past four decades, largely thanks to the implementation of novel technologies such as comparative genomic hybridization,
whole genome/exome sequencing and epigenetic analysis. Along with the identification of cancer stem cells in the majority
of neoplasia, the recognition of intertumor and intratumor variability has provided a novel perspective to understand
the mechanisms behind tumor evolution and its implication in terms of treatment failure and cancer relapse or recurrence.
First hypothesized over two decades ago, clonal heterogeneity and clonal evolution have been confirmed in multiple myeloma
(MM), an incurable cancer of plasma cells, almost universally preceded by a pre-malignant conditioned named
monoclonal gammopathy of undetermined significance (MGUS). The genetic events and molecular mechanisms underlying
such evolution have been difficult to dissect. Moreover, while a role for the bone marrow microenvironment in supporting
MM cell survival, proliferation and drug-resistance has been well established, whether it is directly involved in
driving evolution from MGUS to MM is at present unclear. We present in this review a historical excursus on the concepts
of clonal heterogeneity and clonal evolution in MM with a special emphasis on their role in the progression from
MGUS to MM; the contribution of the microenvironment; and the clinical implications in terms of resistance to treatment
and disease relapse/recurrence.