Simple Summary: While MRI is primarily used for vitality analysis in multiple myeloma, the detection of osteolytic manifestations in the mineralized bone is performed on CT scans. For this study based on a homogenous sample of 20 patients with newly diagnosed multiple myeloma, we hypothesized that sequential CT studies can be used to validate remineralization quantitatively and qualitatively as a measure of treatment response. After six cycles of standardized induction therapy with the anti-SLAMF7 antibody elotuzumab in combination with carfilzomib, lenalidomide, and dexamethasone (E-KRd), we were able to record a substantial lesion size decrease associated with the formation of trabecular sclerosis in the majority of responding manifestations. Multiple myeloma (MM) frequently induces persisting osteolytic manifestations despite hematologic treatment response. This study aimed to establish a biometrically valid study endpoint for bone remineralization through quantitative and qualitative analyses in sequential CT scans. Twenty patients (seven women, 58 ± 8 years) with newly diagnosed MM received standardized induction therapy comprising the anti-SLAMF7 antibody elotuzumab, carfilzomib, lenalidomide, and dexamethasone (E-KRd). All patients underwent whole-body low-dose CT scans before and after six cycles of E-KRd. Two radiologists independently recorded osteolytic lesion sizes, as well as the presence of cortical destruction, pathologic fractures, rim and trabecular sclerosis. Bland–Altman analyses and Krippendorff's α were employed to assess inter-reader reliability, which was high for lesion size measurement (standard error 1.2 mm) and all qualitative criteria assessed (α ≥ 0.74). After six cycles of E-KRd induction, osteolytic lesion size decreased by 22% (p < 0.001). While lesion size response did not correlate with the initial lesion size at baseline imaging (Pearson's r = 0.144), logistic regression analysis revealed that the majority of responding osteolyses exhibited trabecular sclerosis (p < 0.001). The sum of osteolytic lesion sizes on sequential CT scans defines a reliable study endpoint to characterize bone remineralization. Patient level response is strongly associated with the presence of trabecular sclerosis. [ABSTRACT FROM AUTHOR]