89Zr-bevacizumab PET Scan in Patients With Relapsing Multiple Myeloma
89Zr-bevacizumab PET Scan in Patients With Relapsing Multiple Myeloma
The purpose of this study is to see whether 89Zr-bevacizumab PET scanning is feasible in
 relapsing multiple myeloma patients.
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.
Inclusion Criteria:

 Patients with relapsing multiple myeloma according to international defined guidelines:

 Relapse after having achieved complete remission:

 1. Reappearance of paraprotein

 2. More than 5% plasma cells in bone marrow.

 3. New lytic lesions or progression of old lesions.

 4. New hypercalcaeamia.

 Relapse after having achieved partial remission

 1. Increases of paraprotein with more than 25%

 2. Increase of urine paraprotein with more than 25%

 3. Increase of plasma cells in bone marrow with 10%

 4. New lytic lesions or progression of old lesions

 5. New hypercalcaemia -

 Exclusion Criteria:

 Radiotherapy in the last 3 months.

 -  Ineligible to lay supine during the PET scan.

 -  Age ≤18 years.

 -  Pregnancy.

 -  Claustrophobia

 -  Severe kidney dysfunction; serum-creatinine ≥250 µM