BackgroundAsymptomatic multiple myeloma (AMM) evolves from monoclonal gammopathy of unknown significance (MGUS) and progresses to symptomatic myeloma characterized by end organ damage. Here, three main questions are addressed: i) Which factors determine evolution and progression of asymptomatic myeloma, and what is their molecular background? ii) Is progression driven by ongoing molecular (clonal) evolution? iii) When to call a plasma cell malignant ? Methods CD138-purified plasma-cell samples of 2369 consecutive patients with MGUS (n=304), asymptomatic (n=432) and symptomatic myeloma (n=1633) were subjected to interphase fluorescence in situ hybridization (n=31898 measurements), and of these n=951 (n=62 MGUS, n=259 AMM, and n=630 symptomatic myeloma) likewise to gene expression profiling (GEP). Sixty-five patients were followed longitudinally. Serum/urine samples (n=8398) allowed modelling plasma cell doubling time in AMM and MGUS (n=322, and n=196, respectively).ResultsAccumulation rate, tumor mass, and molecular characteristics determine progression to symptomatic myeloma. Progression-associated chromosomal aberrations are multiplicatively associated with myeloma cell doubling time, explaining their increasing frequency from MGUS to asymptomatic- to symptomatic myeloma. Their number, rather than single aberrations, determines progression. The developed GEP-based HDAMM-score predicts progression of AMM-, symptomatic and MGUS-patients, as scores for symptomatic patients predict AMM-progression. The bulk of altered gene expression is already present in MGUS-patients with minor subsequent differences to AMM and symptomatic myeloma. Longitudinal patient samples rarely (9%) show de-novo-appearance of progression-associated aberrations. In evolution and progression of AMM, doubling times (18.0/5.1 years) and number of doublings (0.62/0.92) are incompatible with common de novo appearance of progression-driving aberrations.ConclusionsEvolution and progression of AMM can be explained by accumulation rate, tumor mass and molecular characteristics without necessity of de novo appearance of genetic alterations. Plasma cells at MGUS-stage should be considered malignant and the letters US be dropped from MGUS .
