Insulin-like growth factor (IGF)-1, insulin, and interleukin (IL)-6 are dysregulated in multiple myeloma pathogenesis and may also contribute to multiple myeloma etiology. To examine their etiologic role we prospectively analyzed concentrations of serologic markers in 493 multiple myeloma cases and 978 controls from eight cohorts in the Multiple Myeloma Cohort Consortium. We computed odds ratios (OR) and 95% confidence intervals (CI) for multiple myeloma per one-standard deviation (SD) increase in biomarker concentration using conditional logistic regression. We examined heterogeneity by time since blood collection (≤3, 4 to ≤6, and >6 years) in stratified models. Fasting IGF binding protein (IGFBP)-1 concentration was associated with multiple myeloma risk within three years (OR, 95% CI per 1-SD increase: 2.3, 1.4-3.8, p=0.001) and soluble IL-6 receptor (sIL6R) level was associated within six years after blood draw (OR(≤3years), 95% CI: 1.4, 1.1-1.9, p = 0.01; OR(4-≤6years), 95% CI: 1.4, 1.1-1.7, p=0.002). No biomarker was associated with longer-term multiple myeloma risk (i.e., >6 years). Interactions with time were statistically significant (IGFBP-1, p-heterogeneity=0.0016; sIL6R, p-heterogeneity=0.016). The time-restricted associations likely reflect the bioactivity of tumor and microenvironment cells in transformation from monoclonal gammopathy of undetermined significance or smoldering multiple myeloma to clinically manifest multiple myeloma.