Correlation among DCE‐MRI measurements of bone marrow angiogenesis, microvessel density, and extramedullary disease in patients with multiple myeloma

We investigated correlations among angiogenesis parameters of the lumbar vertebrae measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), microvessel density (MVD) in bone marrow (BM), and extramedullary disease (EMD) in patients with multiple myeloma (MM). Forty-nine MM patients were enrolled. Two semiquantitative parameters, Peak and Slope, were obtained from the DCE-MRI signal-intensity curve; three more quantitative parameters, Amp, Kep, and Kel, were generated from bicompartmental modeling. Apart from Kep, all parameters were found to correlate positively with MVD (r range, 0.323– 0.594; all P < 0.03). Multivariate analysis indicated that the only factors significantly associated with MVD were Amp and plasma cell percentage in BM. Comparing angiogenesis parameters for patients with EMD at the time of DCE-MRI versus those who did not showed a high Amp ( 0.08) as the only significant factor associated with EMD (odds 6.33; P 5 0.045). During follow-up (median, 76 months), 4 more patients developed EMD. Accumulative incidence for developing EMD over time was significantly higher for patients with high Amp than those with low Amp (P 5 0.0254). In conclusion, Amp correlated strongly with MVD in BM and also EMD in patients with MM. Amp measurement might be helpful for identifying MM patients at risk for EMD. Multiple myeloma (MM) is a malignant plasma cell proliferation typically found in bone marrow (BM) [1]. Although MM cells (MCs) depend on the BM microenvironment to provide the signals essential for their growth and survival [2], in a fraction of patients MCs acquire the ability to proliferate in sites outside the BM. Such occurrences appear as extramedullary disease (EMD), indicating that MCs have become independent of the BM microenvironment [1]. The exact mechanism underlying the development of EMD in MM patients is not clear. One hypothesis suggests an alteration in the interaction between MCs and the BM microenvironment [2,3]. Within the BM microenvironment, angiogenesis might play a major role in not only promoting the growth and survival of MCs but also the disease progression itself [2–4]. The interaction between MCs and BM endothelial cells upregulates a number of angiogenic cytokines, such as vascular endothelial growth factor or matrix metalloproteinases. Such cytokines further stimulate BM angiogenesis and myeloma progression [5,6], as well as possible extramedullary dissemination [4]. To date, dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) is one of the most widely used noninvasive methods of measuring the perfusion and permeability of a biological tissue in the body, such as vertebral BM [7]. In MM patients, the angiogenesis parameters generated from DCE-MRI of vertebral BM reportedly correlate strongly with histological grade of infiltration, osteolytic bone involvement, microvessel density (MVD), and serum markers of disease activity [8,9]. However, prior to our study no data were available on the correlation between degree of BM angiogenesis and the development of EMD in MM patients. We thus examined the correlation between angiogenesis parameters generated from DCEMRI of vertebral bodies, together with MVD in BM (obtained from the posterior iliac crest), with the manifestation of EMD in patients with MM. Between September 2004 and April 2006, a total of 49 patients with MM were enrolled. Of this group, 27 (55%) patients had newly diagnosed MM (NDMM), 6 patients (12%) were in a post-treatment plateau (PTRP), and 16 (33%) had progressive disease (PD). This study was approved by our institutional ethics committee, and written informed consent was obtained from all patients in accordance with the Declaration of Helsinki (ClinicalTrials.gov Identifier: NCT00166855). The salient clinical characteristics of the 49 patients at enrollment are listed in Table I. Notably, 19 of the 49 patients (39%) had EMD at the time of their DCE-MRI, among whom 7 patients (37%) had more than one manifestation of EMD. BM samples were obtained from the posterior iliac crest in all 49 patients at approximately the same time as DCE-MRI was performed (median 2 days; range, -3 to 7 days). The mean MVD [vessels/4003 high-power field (HPF)] was 16.7 (range 1.5–40.2), with significant differences being found for patients in different subgroups (P 5 0.006). Patients with NDMM had a mean MVD of 20.3 (95% confidence interval [CI: 15.3–25.2]), patients in the PTRP group had a mean MVD of 3.2 (95% CI: 1.4–5.0), and patients with PD had a mean MVD of 15.7 (95% CI: 9.9–21.5). The time-signal intensity (SI) curve shown in DCE-MRI correlated strongly with tissue MVD, where a high peak and steep slope were associated with high MVD (Fig. 1A,B). By contrast, a lower peak and gentler slope were associated with lower MVD (Fig. 1C,D). Moderate correlations were found between MVD and the two semiquantitative parameters Peak and Slope (r 5 0.540 and 0.502, respectively; both P < 0.001). Amp and Kel, but not Kep, were also moderately correlated with MVD (r 5 0.594 and 0.323, respectively; P < 0.001 and P 5 0.024, respectively). Other salient characteristics significantly correlated with MVD were beta2-microglobulin (r 5 0.305; P 5 0.035), C-reactive protein (r 5 0.348; P 5 0.018), and percentage of MCs in BM (r 5 0.637; P < 0.001). Further multiple linear regression analysis showed that only Amp (r5 45.7; 95% CI: 13.0–78.3; P5 0.007) and percentage of MCs in BM (r5 0.18; 95% CI: 0.06–0.29; P 5 0.003) were independently correlated with MVD. Table II shows the results of our comparison of salient features and angiogenesis parameters between patients with and without EMD at the time of their DCE-MRI. When compared with patients without EMD, patients with EMD displayed significantly greater infiltration of MCs in BM and higher levels of the angiogenesis parameter Amp. Further multivariate analysis using a multiple logistic regression model showed that Amp was the only significant factor associated with EMD (OR 6.33; P 5 0.045). The median follow-up period was 76