Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data

Abstract

Multiple myeloma causes major morbidity resulting from osteolytic lesions that can be detected by metastatic bone surveys. Magnetic resonance imaging and positron emission tomography can detect bone marrow focal lesions long before development of osteolytic lesions. Using data from patients enrolled in Total Therapy 3 for newly diagnosed myeloma (n=303), we analyzed associations of these imaging techniques with baseline standard laboratory variables assessed before initiating treatment. Of 270 patients with complete imaging data, 245 also had gene expression profiling data. Osteolytic lesions detected on metastatic bone surveys correlated with focal lesions detected by magnetic resonance imaging and positron emission tomography, although, in two-way comparisons, focal lesion counts based on both magnetic resonance imaging and positron emission tomography tended to be greater than those based on metastatic bone survey. Higher numbers of focal lesions detected by magnetic resonance imaging and positron emission tomography were positively linked to high serum concentrations of C-reactive protein, gene-expression-profiling-defined high risk, and the proliferation molecular subgroup. Positron emission tomography focal lesion maximum standardized unit values were significantly correlated with gene-expression-profiling-defined high risk and higher numbers of focal lesions detected by positron emission tomography. Interestingly, four genes associated with high-risk disease (related to cell cycle and metabolism) were linked to counts of focal lesions detected by magnetic resonance imaging and positron emission tomography. Collectively, our results demonstrate significant associations of all three imaging techniques with tumor burden and, especially, disease aggressiveness captured by gene-expression-profiling-risk designation. (Clinicaltrials.gov identifier: NCT00081939).

Figure 1.

Comparisons of number of focal lesions (MRI-FLs and PET-FLs) and osteolytic lesions (MBS-OLs). For each patient, we calculated the difference in the total number of FLs and OLs detected with each method. The distributions of the differences for each pairwise comparison are presented as box-and-whisker plots in the figures below. The lower and upper edges of the box correspond to the first and third quartiles, respectively. The thicker bars in the middle represent the median, with the whiskers extending to the minimum and maximum values. P values from the Wilcoxon signed-rank test are given for each comparison. (A) Among all 270 patients with complete imaging information, no difference was noted between FLs detected by MRI and FLs detected by PET (middle box-whisker), whereas both MRI (left) and PET (right) detected more FLs than the number of OLs observed on MBS. (B) When limited to the 126 patients with at least one MBS-OL, MRI-FL was higher than MBS-OL (left) while no differences were noted between MRI-FL and PET-FL (middle) and between PET-FL and MBS-OL (right). (C) When restricted to the 188 subjects with at least one MRI-FL, data consistent with that noted in Figure 1A were observed. (D) This also applied to the 176 individuals with at least 1 PET-FL.

Figure 2.

Log odds ratios measuring the association of baseline prognostic factors with imaging parameters at baseline. DHIM comparisons were limited to the subset of participants with no detected MRI-FLs (n=82 for standard laboratory and imaging variables and n=74 for GEP variables). (A) MBS and MRI. Left: both MBS-OL cut-off points were correlated with both cut-off points for MRI-FL and PET-FL. Among GEP variables, high risk (70-gene model), PR subtype, and CI, all reflecting disease aggressiveness, were significantly linked to more than 2 MBS-OLs. DelTP53 was neutral relative to MBS-OLs. Among standard laboratory prognostic variables, high serum levels of β2M (>5.5 mg/L) were associated with more than 2 MBS-OLs. Middle: for both MRI-FL cut-off points, there were strong positive correlations with MBS-OLs and PET-FLs, but not with PET FL-SUV, EMD, or SUVdiff. Among GEP features, PI and CI positively correlated with MRI-FL >7. Among GEP-defined molecular subgroups, the PR subgroup positively correlated with MRI-FLs. Both MRI-FL cut-off points correlated with high-risk scores from the 70-gene model, but only the higher cut-off point (>7) was linked to high-risk scores from the 80-gene model. Among standard laboratory prognostic variables, CRP had significant positive correlations to MRI-FL >7. Right: for the subset with no MRI-FL, DHIM was associated with increased LDH and β2M. The comparison of GEP-80 risk groups was not possible because of the small number of GEP-80 high-risk subjects. Some parameters could not be estimated due to small sample sizes or association by definition (for example, MRI-FL >7 vs. MRI-FL >0). (B) PET. Left: PET-based FL number was examined for correlations with other imaging parameters, standard laboratory prognostic variables, and GEP variables. At both cut-off points (>0 and >3), PET-FLs had highly significant positive correlations with MBS-OLs and MRI-FLs. GEP-derived variables that were significantly positively associated with PET-FL included high-risk myeloma defined by the 70-gene model as well as PI and CI. Among GEP-defined molecular subgroups, the PR subgroup showed positive correlation and the LB subgroup negative correlation to PET-FLs. Among standard laboratory prognostic variables, elevated CRP and LDH were seen more often with more PET-FLs. Middle: PET FL-SUV was highly associated with more than 3 PET-FLs, high-risk disease (70-gene model), and SUVdiff. Right: PET-EMD was linked to high β2M. Comparison of the CD-1 sub-group versus all other GEP subgroups was not possible because of the small number of CD-1 subjects.