Validation of novel low-dose CT methods for quantifying bone marrow in the appendicular skeleton of patients with multiple myeloma: initial results from the [18F]FDG PET/CT sub-study of the Phase 3 GMMG-HD7 Trial

Journal article, 2025

Purpose: The clinical significance of medullary abnormalities in the appendicular skeleton detected by computed tomography (CT) in patients with multiple myeloma (MM) remains incompletely elucidated. This study aims to validate novel low-dose CT-based methods for quantifying myeloma bone marrow (BM) volume in the appendicular skeleton of MM patients undergoing [¹⁸F]FDG PET/CT. Materials and methods: Seventy-two newly diagnosed, transplantation eligible MM patients enrolled in the randomised phase 3 GMMG-HD7 trial underwent whole-body [¹⁸F]FDG PET/CT prior to treatment and after induction therapy with either isatuximab plus lenalidomide, bortezomib, and dexamethasone or lenalidomide, bortezomib, and dexamethasone alone. Two CT-based methods using the Medical Imaging Toolkit (MITK 2.4.0.0, Heidelberg, Germany) were used to quantify BM infiltration in the appendicular skeleton: (1) Manual approach, based on calculation of the highest mean CT value (CTv) within bony canals. (2) Semi-automated approach, based on summation of CT values across the appendicular skeleton to compute cumulative CT values (cCTv). PET/CT data were analyzed visually and via standardized uptake value (SUV) metrics, applying the Italian Myeloma criteria for PET Use (IMPeTUs). Additionally, an AI-based method was used to automatically derive whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG) from PET scans. Post-induction, all patients were evaluated for minimal residual disease (MRD) using BM multiparametric flow cytometry. Correlation analyses were performed between imaging data and clinical, histopathological, and cytogenetic parameters, as well as treatment response. Statistical significance was defined as p < 0.05. Results: At baseline, the median CTv (manual) was 26.1 Hounsfield units (HU) and the median cCTv (semi-automated) was 5.5 HU. Both CT-based methods showed weak but significant correlations with disease burden indicators: CTv correlated with BM plasma cell infiltration (r = 0.29; p = 0.02) and β2-microglobulin levels (r = 0.28; p = 0.02), while cCTv correlated with BM plasma cell infiltration (r = 0.25; p = 0.04). Appendicular CT values further demonstrated significant associations with PET-derived parameters. Notably, SUVmax values from the BM of long bones were strongly correlated with both CTv (r = 0.61; p < 0.001) and moderately with cCTv (r = 0.45; p < 0.001). Patients classified as having increased [¹⁸F]FDG uptake in the BM (Deauville Score ≥ 4), according to the IMPeTUs criteria, exhibited significantly higher CTv and cCTv values compared to those with Deauville Score <4 (p = 0.002 for both). AI-based analysis of PET data revealed additional weak-to-moderate significant associations, with MTV correlating with CTv (r = 0.32; p = 0.008) and cCTv (r = 0.45; p < 0.001), and TLG showing correlations with CTv (r = 0.36; p = 0.002) and cCTv (r = 0.46; p < 0.001). Following induction therapy, CT values decreased significantly from baseline (median CTv = -13.8 HU, median cCTv = 5.2 HU; p < 0.001 for both), and CTv significantly correlated with SUVmax values from the BM of long bones (r = 0.59; p < 0.001). In parallel, the incidence of follow-up pathological PET/CT scans, SUV values, Deauville Scores, and AI-derived MTV and TLG values showed a significant reduction after therapy (all p < 0.001). No significant differences in CTv, cCTv, or PET-derived metrics were observed between MRD-positive and MRD-negative patients. Conclusions: Novel CT-based quantification approaches for assessing BM involvement in the appendicular skeleton correlate with key clinical and PET parameters in MM. As low-dose, standardized techniques, they show promise for inclusion in MM imaging protocols, potentially enhancing assessment of disease extent and treatment response.