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Background: The recently released Myeloma Response Assessment and Diagnosis System (MY-RADS) for multiple myeloma (MM) evaluation by whole-body MRI (WB-MRI) describes the total burden score. However, assessment is confounded by red bone marrow hyperplasia in anemia. Objective: To assess utility of the MY-RADS total burden score, ADC, and fat fraction (FF) from WB-MRI in predicting early treatment response in patients with newly diagnosed MM and to compare these measures' utility between patients with and without anemia. Methods: This retrospective study included 56 patients (mean age 57.4±9.6 years; 40 men, 16 women) with newly diagnosed MM who underwent baseline WB-MRI including DWI and mDixon sequences. Two radiologists recorded total burden score using MY-RADS and measured ADC and FF of diffuse and focal disease sites. Mean values across sites were derived. Interobserver agreement was evaluated; readers' mean assessments were used for further analyses. Presence of deep response after four cycles of induction chemotherapy was recorded. Patients were classified as anemic if having hemoglobin less than 100 g/L. Utility of WB-MRI parameters in predicting deep response was assessed. Results: A total of 24/56 patients showed deep response; a total of 25/56 patients had anemia. Interobserver agreement, expressed using intraclass correlation coefficients, ranged from 0.95 to 0.99. Among patients without anemia, those with deep response compared with those without deep response exhibited lower total burden score (9.0 vs 18.0), lower ADC (0.79x10-3mm2/s vs 1.08x10-3mm2/s), and higher FF (0.21 vs 0.10) (all p 0.16 for FF) achieved sensitivity of 93.8%, specificity of 93.3%, and accuracy of 93.5% for predicting deep response. In patients with anemia, none of the three parameters were significantly different between those with and without deep response (all p>.05), and the combination of parameters achieved sensitivity of 56.3%, specificity of 100.0%, and accuracy of 72.0%. Conclusion: Low total burden score, low ADC, and high FF from WB-MRI may predict deep response in MM, though only among those patients without anemia. Clinical Impact: WB-MRI findings may help guide determination of prognosis and initial treatment selection in MM.