Abstract
Multiple myeloma (MM) is a clonal plasma cell disorder originating in bone marrow. Whole body low-dose multidetector CT (MDCT) can depict bone marrow infiltration by myeloma cells in the adipose-rich fatty marrow of the appendicular skeleton. We previously reported that CT values (also known as Hounsfield Units (HU) scale) of bone marrow infiltrations in humeri and femora reflected disease stages in plasma cell dyscrasia and higher CT values predicted inferior prognosis (Nishida et al. Blood Cancer J 2015). However, automated and objective volume measurement of bone marrow infiltration has not been established, and its clinical relevance is not yet understood. To solve this problem, we developed a novel automated CT post-processing software tool (MABLE software) and evaluated the total sum of CT values (cumulative CT values, cCTv), representing mass of bone marrow infiltration by combining volume of myeloma infiltration and voxel-based CT values. cCTv was calculated for 91 patients with newly diagnosed symptomatic MM and 27 patients with smoldering MM (SMM) and 9 patients with monoclonal gammopathy of unknown significance (MGUS). Mean cCTv, expressed as log10 scale, was higher in patients with symptomatic MM than those with SMM or MGUS (mean ± SEM: 3.541 ± 0.06 vs 2.337 ± 0.1 and 3.541 ± 0.06 vs 2.582 ± 0.18, P < 0.0001 by one-way ANOVA). Among symptomatic MM patients, mean cCTv was highest in patients with revised international staging system (R-ISS) III (mean ± SEM: 3.96 ± 0.11, 3.49 ± 0.07, and 3.15 ± 0.14 in patients with R-ISS stage III, R-ISS stage II and R-ISS stage I, respectively; P < 0.0001 by one-way ANOVA). Age, serum albumin and serum or urine M-protein levels were independent predictors for cCTv by linear regression analysis. Mixed graphical model analysis revealed direct relationships between cCTv and age or R-ISS, indicating that cCTv was influenced by age and aggressive disease. Median follow-up duration of symptomatic MM patients was 30.2 months and 26 patients died during the observation period. Tree-structured survival analysis identified a group of patients with cCTv greater than or equal to 4.4 as the first split point, and another group with age above or equal to 84 years old as the second split point (Figure a, the entire cohort was defined as group 1; patients with cCTv ≥ 4.4 were defined as group 3 and patients ≥ 84 years old were defined as group 5). The patients in group 3 had shorter overall survival than those in group 4 (cCTv < 4.4 or younger than 84 years old (median survival, 8.6 months vs not reached, Hazard ratio: 0.129, P= 5.6 x 10-6, Figure b). Multivariate Cox analysis revealed that cCTv greater than or equal to 4.4 was an independent prognostic factor for overall survival (Hazard ratio: 6.09, P < 0.001). Anti-myeloma therapy reduced cCTv after treatment in 32 patients who received MDCT assessment as disease monitoring. Among patients who achieved complete response (CR), those achieved immunophenotypic CR had significantly greater difference of cCTv between before and after treatment than those achieved stringent CR or CR (mean difference ± SEM, 4.158 ± 0.107 vs 3.079 ± 0.263, P < 0.0001), raising the possibility that cCTv reduction predicts deeper response. Collectively, measuring cCTv identified a group of patients with very poor outcome irrespective of age or other clinical variables.
Mizobe: Canon Inc.: Employment. Yamamichi: Canon Inc.: Employment.
