Angiogenesis and multiple myeloma: is there a role for angiogenic biomarkers in the context of autologous stem cell transplant?

Tumor growth requires the development of an adequate blood supply via a process known as angiogenesis [1]. The recognition of the importance of angiogenesis to tumor biology has led to the development of novel therapeutics designed to target steps leading to new blood vessel growth. Indeed, several anti-angiogenic agents have been approved for use in the treatment of solid tumors. These include but are not limited to bevacizumab for metastatic colon carcinoma [2], glioblastoma multiforme [3,4], and non-small cell lung carcinoma [5]; sorafenib for renal cell carcinoma [6] and hepatocellular carcinoma [7]; and sunitinib for renal cell carcinoma [8] and gastrointestinal stromal tumor (GIST) [9]. Furthermore, cells and signaling proteins involved in vascularization have been studied as potential prognostic as well as predictive biomarkers for patients treated with angiogenesis inhibitors. These include the assessment of microvessel density (MVD), the measurement of angiogenic cytokines, radiographic correlates, and the enumeration of circulating angiogenic cell populations [10–13]. However, to date, no predictive angiogenic biomarker has yet emerged to guide clinical strategies for the treatment of solid tumors.

While cancer-related angiogenesis research has predominantly focused on solid tumors, a growing body of literature has identified potential roles for vessel development in hematologic malignancies. Indeed, previous reports have assessed MVD as a prognostic factor in multiple myeloma [14–16]. Moreover, newer myeloma therapies such as thalidomide and lenalidomide have been noted to have anti-angiogenic activity [17]. Therefore, there is great interest in studying the role of angiogenesis in multiple myeloma to define therapeutic targets as well as prognostic and predictive biomarkers.

In this issue of Leukemia and Lymphoma, Sucak et al. [18] report on their study of the prognostic value of bone marrow MVD and the measurement of angiogenic cytokines in patients with multiple myeloma undergoing autologous stem cell transplant. The authors collected serum and bone marrow samples in 29 patients who underwent autologous stem cell transplant (ASCT). Samples were collected at diagnosis, prior to ASCT, and at 3 and 6 months post-transplant. Bone marrow samples were assessed for MVD and bone marrow plasma cell (BMPC) number, while serum samples were assayed for interleukin-6 (IL-6), C-reactive protein (CRP), β2-microglobulin, IL-1β, fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) levels. Bone marrow MVD and BPMCs decreased from diagnosis through to the 6-month post-transplant time-point. Serum FGF and IL-1β decreased from diagnosis through to the 3-month post-transplant time-point. However, despite these changes, the levels of angiogenic cytokines and MVD did not show correlations with overall survival or progression-free survival. The authors therefore concluded that these assays provided neither prognostic value nor predictive value regarding outcome after ASCT. However, they did note that some previous studies have shown associations of bone marrow MVD with prognosis, and that these differences between trials may be related to small study sample size or methodological issues.

Since ASCT protocols utilize high-dose cytotoxic chemotherapy rather than anti-angiogenic agents, it is perhaps not surprising that vascular measurements did not predict outcome. However, because correlative studies were performed during the induction phase of therapy as well, the authors were able to assess the utility of biomarker analysis in the context of standard-dose therapies. While the authors noted that the significance of MVD reduction was more pronounced in VAD (vincristine, doxorubicin, and dexamethasone) responders compared to non-responders, measurement of MVD was not predictive of induction outcome. However, it is important to note that assay samples were collected at baseline and prior to transplant, not after VAD induction therapy specifically. Indeed, VAD non-responders received additional induction therapy with thalidomide and dexamethasone prior to undergoing ASCT. Since VAD non-responders received additional therapy with potential anti-angiogenic activity prior to biomarker assessment, directly comparing these groups was difficult. Given the larger MVD reduction in VAD responders observed even after thalidomide exposure, it would have been interesting to compare angiogenic biomarker levels between responders and non-responders after VAD alone.

While bone marrow MVD and angiogenic cytokines did not provide prognostic or predictive information, data illustrated in Figure 2 of the manuscript do show an impressive decrease in MVD from diagnosis till 6 months post-ASCT. It is difficult to determine whether these anti-angiogenic effects from therapy preceded response, or whether vascular density decreased secondary to direct plasma cell killing. The former hypothesis would support efforts to develop anti-angiogenic therapies for multiple myeloma, while the latter hypothesis would support the concept that direct tumor cell killing can have profound effects on vascular cells. Such observations nonetheless support efforts to better define interactions between myeloma cells and their microenvironment.

Do the results of the current study clearly rule out the clinical utility of measuring angiogenic biomarkers in patients with multiple myeloma undergoing ASCT? While the current study was small and its results conflicted with some previous trials, the data presented suggest that it is currently unlikely that this set of angiogenic assays will successfully be translated into clinical use for this particular group of patients. Instead, further biomarker research could be applied to the study of anti-angiogenic therapies in maintaining response after ASCT. Nonetheless, as noted above, the potential differences observed between VAD responders and non-responders, as well as changes in MVD over time, are intriguing. These data suggest that angiogenic biomarker development in multiple myeloma should be focused on patients receiving non-transplant regimens, particularly those undergoing treatment plans utilizing drugs with known anti-angiogenic activity.

Potential conflict of interest: A disclosure form provided by the author is available with the full text of this article at www.informahealthcare.com/lal.