Trial Information

Evaluation of VEGF Expression With 89Zr-bevacizumab PET Scan in Patients With Relapsing Multiple Myeloma; a Feasibility Study

Multiple Myeloma (MM) is a clonal B cell disorder characterised by a monoclonal plasma cell
population in bone marrow, with bone pain, anaemia, hypercalcaemia, and kidney dysfunction
as clinically presenting symptoms. Osseous involvement is one of the most predominant
features of patients with MM; 90% of the patients develop lytic bone lesions. Lytic bone
lesions are the result of increased bone resorption and reduced bone formation. The regular
method to detect bone lesions is skeletal survey. This technique can only detect lesions
that have lost 30% or more of the trabecular bone. Another weakness is the fact that lesions
persist after treatment with chemotherapy or radiotherapy and no clear distinction can be
made whether vital tumour cells persist in these lesions. New bone lesions are a sign of
disease progression. Furthermore they give clinical signs as bone pain and in the worse case
scenario pathological fractures. Alternative scanning methods have been developed to
visualize the malignant plasma for example by making use of enhanced metabolic activity of
the plasma cells defined by the uptake of 18F-fluorodeoxyglucose -Positron Emission
tomography (FDG-PET. The use of FDG-PET in newly diagnosed MM patients is well studied.

The increased FDG-uptake by the tumour is related to a high metabolic activity. This might
be a consequence of tumour hypoxia causing new vessel formation. There seems to be a
relationship between MM and angiogenesis, the formation of new blood vessels from exciting
blood vessels. There is an increased microvessel density (MVD) of the affected bone marrow
in patients with active MM. Vascular endothelial growth factor (VEGF) is an important
mediator of angiogenesis. MM cell lines were found to express VEGF mRNA and secrete the
protein in the extracellular environment thereby stimulating angiogenesis.

Inhibition of the process of angiogenesis is used in the treatment of MM, for instance by
means of thalidomide and lenalidomide. Blocking VEGF itself can be obtained by means of
bevacizumab, a recombinant, humanised monoclonal antibody that binds to all isoforms of
human VEGF with high affinity. Treatment with bevacizumab is well established in solid
tumours, like colon cancers and renal cell carcinomas and is currently tested in acute
myeloid leukaemia and MM.

VEGF imaging with radiolabeled bevacizumab has been developed. Bevacizumab binds VEGF and
can be labeled with the PET isotope Zirconium-89 (89Zr) while preserving VEGF binding
properties. In a human ovarian tumor xenograft, PET imaging 24 hours after injection of
89Zr-bevacizumab showed high uptake in well perfused organs and in the tumor.

The high VEGF production by myeloma cells makes VEGF a very interesting target for tumor
visualization. 89Zr-bevacizumab PET imaging could be more sensitive for myeloma lesions.

So, in conclusion, VEGF is expressed by MM plasma cells, thereby providing a rationale that
the assessment of VEGF-levels in the micro-environment of MM tumors could potentially be
used as a diagnostic tool to see if there is disease activity. Especially in the relapsed
setting this is of invaluable importance, since conventional skeletal survey has limitations
in this setting. Furthermore, 89Zr-bevacizumab PET imaging could provide information about
treatment options and treatment response.