Early CRAB-like Biomarker Signatures Reveal a Preclinical Susceptibility Continuum for Multiple Myeloma

Multiple myeloma (MM) evolves over decades, yet robust tools for identifying individuals at risk long before clinical onset remain limited. Using data from 378,930 UK Biobank participants, we systematically characterized the longitudinal dynamics and predictive value of routinely measured "CRAB-like" biomarkers, including hematologic indices, protein metabolism markers, renal function, and serum calcium. Across multivariable models, biomarkers reflecting anemia and protein imbalance (including hemoglobin, red blood cell indices, total protein, albumin, and the albumin/globulin ratio) showed strong and consistent associations with future MM, independent of demographic, lifestyle, clinical, and genetic risk factors. These markers displayed pronounced non-linear dose-response relationships and contributed substantially to 5- and 10-year MM risk discrimination, with the C-index improving from 0.66 to 0.76. Longitudinal analyses revealed progressive shifts in red cell morphology and protein metabolism profiles up to a decade before diagnosis, supporting the existence of a preclinical susceptibility continuum detectable in the general population. Our findings suggest that subtle yet quantifiable deviations in common laboratory tests reflect early microenvironmental changes that precede malignant plasma cell expansion, offering opportunities for risk stratification and targeted surveillance.