Two major genetic categories of multiple myeloma (MM) exist. Hyperdiploid MM (48 to 74 chromosomes, median 53 chromosomes) is associated with trisomies especially of chromosomes 3, 7, 9, 11, 15, and 19, whereas the nonhyperdiploid (< 48="" chromosomes="" or="" more="" than="" 74="" chromosomes)="" mm="" is="" associated="" with="" primary="" translocations="" such="" as="" t(11;14),="" t(4;14),="" and="" t(14;16).="" whether="" this="" dichotomy="" exists="" in="" monoclonal="" gammopathy="" of="" undetermined="" significance="" (mgus)="" is="" uncertain="" due="" to="" limitations="" of="" current="" methods="" in="" the="" study="" of="" ploidy.="" this="" is="" especially="" true="" in="" mgus="" where="" the="" number="" of="" clonal="" plasma="" cells="" is="" small.="" in="" this="" study,="" we="" derived="" a="" fluorescent="" in="" situ="" hybridization="" (fish)-based="" trisomy="" index="" from="" pooled="" cytogenetic="" data="" (karyotype="" analysis)="" from="" 2="" large="" cohorts="" of="" patients="" with="" mm="" with="" abnormal="" karyotype,="" and="" then="" validated="" it="" in="" 2="" independent="" cohorts="" of="" patients="" who="" had="" known="" ploidy="" status="" either="" by="" karyotyping="" or="" dna="" content="" measurement="" using="" flow="" cytometry.="" using="" the="" criteria="" of="" 2="" or="" more="" trisomies="" from="" a="" 3-chromosome="" combination,="" hyperdiploid="" myeloma="" can="" be="" detected="" with="" high="" specificity.="" applying="" this="" index="" on="" 28="" patients="" with="" smoldering="" multiple="" myeloma="" (smm)="" or="" mgus="" (11="" smm,="" 17="" mgus)="" who="" had="" normal="" karyotype,="" 11="" cases="" of="" hyperdiploid="" smm/mgus="" were="" detected.="" this="" percentage="" (40%)="" is="" remarkably="" similar="" to="" the="" percentage="" of="" hyperdiploid="" mm="" reported="" in="" the="" literature,="" suggesting="" that="" hyperdiploid="" mm="" may="" originate="" early="" during="" disease="" evolution.="" (blood.="" 2005;106:="">