Identifying MRI-based radiomics features capable to assess response to systemic treatment in multiple myeloma (MM) patients. Retrospective analysis of whole-body MR-image data in 67 consecutive stage III MM patients (40 men; mean age, 60.4 years). Bone marrow involvement was evaluated using a standardized MR-imaging protocol consisting of T1w-, short-tau inversion recovery- (STIR-) and diffusion-weighted-imaging (DWI) sequences. Ninety-two radiomics features were evaluated, both in focally and diffusely involved bone marrow. Volumes of interest (VOI) were used. Response to treatment was classified according to International Myeloma Working Group (IMWG) criteria in complete response (CR), very-good and/or partial response (VGPR + PR), and non-response (stable disease (SD) and progressive disease (PD)). According to the IMWG-criteria, response categories were CR ( = 35), VGPR + PR ( = 19), and non-responders ( = 13). On apparent diffusion coefficient (ADC)-maps, gray-level small size matrix small area emphasis (Gray Level Size Zone (GLSZM) small area emphasis (SAE)) significantly correlated with CR ( < 0.001), whereas GLSZM non-uniformity normalized (NUN) significantly ( < 0.008) with VGPR/PR in focal medullary lesions (FL), whereas in diffuse involvement, 1st order root mean squared significantly ( < 0.001) correlated with CR, whereas for VGPR/PR Log (gray-level run-length matrix (GLRLM) Short Run High Gray Level Emphasis) proved significant ( < 0.003). On T1w, GLRLM NUN significantly ( < 0.002) correlated with CR in FL, whereas gray-level co-occurrence matric (GLCM) informational measure of correlation (Imc1) significantly ( < 0.04) correlated with VGPR/PR. For diffuse myeloma involvement, neighboring gray-tone difference matrix (NGTDM) contrast and 1st order skewness were significantly associated with CR and VGPR/PR ( < 0.001 for both). On STIR-images, CR correlated with gray-level co-occurrence matrix (GLCM) Informational Measure of Correlation (IMC) 1 ( < 0.001) in FL and 1st order mean absolute deviation in diffusely involved bone marrow ( < 0.001). VGPR/PR correlated at best in FL with GSZLM size zone NUN ( < 0.019) and in all other involved medullary areas with GLSZM large area low gray level emphasis ( < 0.001). GLSZM large area low gray level emphasis also significantly correlated with the degree of bone marrow infiltration assessed histologically ( = 0.006). GLCM IMC 1 proved significant throughout T1w/STIR sequences, whereas GLSZM NUN in STIR and ADC. MRI-based texture features proved significant to assess clinical and hematological response (CR, VPGR, and PR) in multiple myeloma patients undergoing systemic treatment.