Evaluation of bone marrow hypoxia with 18F-FAZA PET in patients with relapsing multiple myeloma; a pilot study

1. Multiple myeloma and imaging techniques
Multiple Myeloma (MM) is clonal B cell disorder characterised by a monoclonal
plasma cell population in bone marrow, with bone pain, anemia, hypercalcaemia,
and kidney dysfunction as clinically presenting symptoms. In the majority of
the patients the disorder is disseminated through the bone marrow compartment.
The abnormalities of the skeleton can be identified by X-ray examination and
demonstrates frequently the characteristics osteolytic defects. Following
treatment with chemotherapy or radiotherapy the osteolytic defects persist and
no clear distinction can be made whether vital tumour cells persist in these
lesions. Also in relapsing disease the X-ray examination has a limited value
unless progressive defects are observed. Therefore alternative scanning methods
have been developed to visualize the emergence of new malignant plasma cells
that make use of tracers that identify tumour-specific receptors of identify
enhanced metabolic activity of the malignant plasma cells. Recently it was
shown that FDG-PET can demonstrate more abnormal lesions in relapsing MM than
whole body X-ray.

2. Tumour hypoxia
However the cause of the increased FDG-uptake is unclear. It might be related
to inappropriate tumour out-growth or as a consequence of tumour hypoxia due to
inappropriate blood supply. Alternatively the glycolytic pathway might be
installed due to malignant transformation. Recently we showed that the
transcription factor STAT5 up regulates hypoxia inducing factor (HIF)-2 and as
consequence an upregulation of genes involved in glucose up-take. Based on
these findings it is unclear so far whether the enhanced metabolic activity
defined by FDG-PET is related to hypoxia. There is evidence that HIF1α and
HIF2α can be upregulated in plasma cells and thereby triggering the VEGF
pathway. Other hypoxia related proteins like glucose transporter (GLUT)-1 and
-3 can be co-expressed with HIF1α.

3. 18F-FAZA scanning
Recently new scanning methods have been developed for demonstrating in vivo
tumour hypoxia. The developed PET tracer hypoxia, 1-α-D:
-(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole (18F-FAZA), has been
shown to accumulate in experimental models of tumour hypoxia. In a study
performed by Postema et al in 50 patients with different types of malignancy it
was shown that the used in vivo scanning method is feasible and save in
patients for showing in vivo hypoxia in a variety of tumour categories.

This pilot study will evaluate whether tumour hypoxia can be demonstrated in
the bone marrow compartment of relapsing MM patients by using the tracer
18F-FAZA. The results will be compared with the results of the FDG-PET scan.
In addition in vitro staining of bone marrow material will be performed to
demonstrate whether hypoxia related proteins are upregulated by plasma cells or
surrounding cells including HIF 1α , HIF2α , GLUT-1 and -3 and VEGF.

This is a pilot-study, thus no formal group size calculation can be given. For
the purpose of this study, 10 patients will be included. It is expected that
this number will cover the variability of 18F-FAZA uptake of MM patients.
Currently, the total number of patients fulfilling the eligibility criteria of
this study is 20-30 on a yearly basis.

Burden or risk:
- Hematoma at the intraveneus injection site.
- Radiation dose of 5.6 mSv.

Benefit:
more information about the skeletal lesions of the patient.