Type 2-diabetes (T2D) is thought to be a relevant risk factor for multiple myeloma (MM), but the relationship between both traits is still not well understood. Thus, we decided to conduct a population-based case-control study in a population of 1420 MM patients (705 women and 715 men) and 1858 controls (916 women and 942 men) to evaluate whether 58 genome-wide association studies (GWAS)-identified common variants for T2D influence the risk of developing MM. Logistic regression analyses showed that carriers of the KCNQ1rs2237892T allele or CDKN2A-2Brs2383208G/G, IGF-1rs35767T/T and MADDrs7944584T/T genotypes had an increased risk of MM (OR=1.32, 95%CI 1.01-1.71, P=0.039; OR=1.86, 95%CI 1.12-3.11, P=0.016; OR=2.13, 95%CI 1.35-3.37, P=0.001 and OR=1.33, 95%CI 1.06-1.67, P=0.014, respectively) whereas those carrying the KCNJ11rs5215C, KCNJ11rs5219T and THADArs7578597C alleles or the FTOrs8050136A/A and LTArs1041981C/C genotypes showed a decreased risk for the disease (OR=0.85, 95%CI 0.73-0.99, P=0.38; OR=0.84, 95%CI 0.72-0.99, P=0.034; OR=0.81, 95%CI 0.68-0.98, P=0.032; OR=0.78, 95%CI 0.64-0.95, P=0.013; and OR=0.76, 95%CI 0.58-0.99, P=0.042, respectively). The associations of these T2D-related variants with an increased or decreased risk of MM were due to non-diabetogenic alleles, which suggests a non-diabetogenic mechanism underlying the effect of these variants to determine the risk of the disease. A gender-stratified analysis also revealed a significant gender effect modification for ADAM30rs2641348, and NOTCH2rs10923931 SNPs (Pinteraction=0.001 and 0.0004 and Phet=0.19 and 0.60, respectively), which also underlies the importance of considering gender as a factor modifying the risk for MM. Men harbouring the ADAM30rs2641348C and NOTCH2rs10923931T alleles had a decreased risk of MM (OR=0.71, 95%CI 0.54-0.94, P=0.015 and OR=0.66, 95%CI 0.50-0.86, P=0.0019) whereas an opposite but not significant effect was observed in women. Finally, SNP-SNP interaction analysis revealed overall significant two- and three-locus interaction models to increase the risk of MM (FAM148Brs11071657-KCNJ11rs5219, and SLC30A8rs13266634-KCNJ11rs5219-FTOrs8050136; P=0.01 and 0.001, respectively) whereas a significant four-locus model was also found to increase the risk of MM in men (FADS1rs174550-TSPAN8rs7961581-PROX1rs340874-KCNJ11rs5219, P=0.001). Although further studies in independent populations are warranted to replicate these findings, these results suggest that TD2-related variants may influence the risk of developing MM, likely through non-diabetogenic mechanisms.Abstract 2044. Table 1Demographical characteristics of IMMEnSE cases and controls.CASESCONTROLSRegion*GenderM/F (Total)Mean Age(± STD)GenderM/F (Total)Mean Age(± STD)Control typeItaly117/107 (224)62.60±9.90127/105 (232)58.75±10.92General populationPoland173/198 (371)62.35±10.39124/226 (350)50.68±19.43Blood donorsSpain139/133 (272)63.06±11.04218/192 (410)63.12±11.94Hospitalized subjectsFrance42/33 (75)55.80±9.0495/89 (184)44.07±15.22Blood donorsPortugal32/35 (67)65.79±11.1652/42 (94)60.88±07.88Blood donorsHungary49/87 (136)65.83±11.1950/51 (101)73.18±10.10Hospitalized subjectsDenmark163/112 (275)55.20±07.32276/211 (487)43.26±11.84General populationTotal715/705 (1420)61.06±10.57942/916 (1858)53.56±16.45Table 2Selected type-2 diabetes-related polymorphismsGene namedbSNP rs#Gene namedbSNP rs#ADAM30rs2641348JAZF1rs864745ADAMTS9rs4607103KCNJ11rs5215ADCY5rs11708067rs5219ADRA2Ars10885122KCNQ1rs2237897ARAPI, CENTD2rs1552224rs2074196BCL11Ars10490072rs2237892CDC123rs12779790rs2237895CDKAL1rs7754840KCNQ1OT1rs231362CDKN2A-2Brs564398LTArs1041981rs10811661MADDrs7944584rs2383208MCR4rs12970134COL5A1rs4240702MTNR1Brs1387153CRY2rs11605924NOTCH2rs10923931DCDrs1153188PKN2rs6698181EXT2rs1113132PPARGrs1801282FADS1rs174550PRC1rs8042680FAM148Brs11071657PROX1rs340874FLJ39370rs17044137RBMS1rs7593730FTOrs8050136SLC2A2rs11920090G6PC2rs560887SLC30A8rs13266634GCKrs1799884TCF2rs7501939GCKRrs1260326TCF7L2rs7903146HHEXrs1111875TCF7L2rs12255372HMGA2rs1531343THADArs7578597HNF1A, TCF1rs7957197TP53INP1rs896854IGF1rs35767TSPAN8rs7961581IGF2BP2rs4402960VEGFArs9472138IL13rs20541WFS1rs734312IRS1rs2943641rs10010131 DisclosuresNo relevant conflicts of interest to declare.