Imaging Studies and the Development of Multiple Myeloma

Background:

- Multiple myeloma (MM) is a plasma cell neoplasm with a median survival of 3-4 years.

- Monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM)
are premalignant plasma cell proliferative disorders characterized by elevated
monoclonal protein and bone marrow plasma cells. MGUS affects 3.2% of Caucasians over
the age of 50 and has a 1% annual risk of progression to MM. Approximately 3,000 cases
of SMM are diagnosed annually with a 10% annual risk of progression to MM.

- Currently, it is not possible to predict which patients will progress to MM, and the
biological changes occurring in those precursor states remain poorly understood.

- Angiogenesis is a hallmark of multiple myeloma and its precursor disease.

Angiogenesis has been measured using microvessel density. In a prior study, we have
demonstrated increased microvessel density using CD34 immunohistochemistry in patients with
multiple myeloma, compared to SMM or MGUS, suggesting that there is increased vascular
density as the disease progresses. A correlation between MM disease stage and prognosis has
been reported for several serum angiogenic factors and myeloma cells and bone marrow
endothelial cells have been shown to secrete and respond to angiogenic modulators.

- Dynamic contrast-enhanced (DCE)-MRI is a noninvasive way to evaluate angiogenesis. In a
prior NIH study, we have demonstrated that the kep (a measure of contrast influx in
vessels in the bone marrow microenvironment) to be gradually higher in MM> SMM> MGUS,
however it was limited to imaging a single field of view (i.e. the lumbar spine). This
is also highly correlated with microvessel density.

- Fluciclatide is a small cyclic peptide containing the RGD tri-peptide, which
preferentially binds with high affinity to Alpha(v)Beta(3) integrins, which are
up-regulated in angiogenesis.

- Alpha(v)Beta(3) integrins are also expressed on certain types of tumor cells and on
activiated osteoclasts.

- (18)Fluciclatide (previously known (18)F-AH111585) is a new radiopharmaceutical
developed for PET imaging, which targets Alpha(v)Beta(3) receptors.

- Novel imaging modalities using tracers specific for angiogenesis, using
(18)F-Fluciclatide whole-body PET/CT imaging may improve our ability to predict
patients who are at high risk of progression.

Objectives:

- The primary objective of the study is to explore the distribution of (18)F-Fluciclatide
PET/CT in bone marrow microenvironment in patients with multiple myeloma and its
precursor disease.

- The secondary objectives are to preliminarily evaluate the distribution of
(18)Fluciclatide PET/CT with respect to DCE-MRI and bone marrow vascularity determined
by immunohistochemistry (CD34) on the bone marrow biopsy specimen.

- To preliminarily evaluate the distribution of (18)F-Fluciclatide PET/CT with respect to
established clinical markers of progression from MGUS/SMM to MM, including serum
M-protein, percentage of plasma cells in the bone marrow, serum free light-chain
abnormalities and immunoparesis, and ratio of normal/abnormal plasma cells in the bone
marrow by flow cytometry.

Eligibility:

- A confirmed diagnosis of MGUS, SMM or MM (based on IMWG diagnostic criteria)

- Age greater than or equal to 18 years

- ECOG performance status in the range of 0-2

Design:

- This is a cross-sectional pilot study of patients with MGUS, SMM or MM.

- Subjects with frank multiple myeloma will be enrolled first. If the (18)F-Fluciclatide
PET/CT is negative in the first 5 subjects, the study will be aborted and we will not
proceed with MGUS or SMM patients. However if the 18F-Fluciclatide PET/CT is positive
in MM patients, then we will proceed with MGUS and SMM patients.

- Subsequently (18)F-Fluciclatide PET/CT and DCE-MRI imaging will be done in all the
patients. When feasible, an optional non-contrast wholebody MR may also be performed.

- 10 MM, 10 SMM and 10 MGUS patients will be enrolled on this protocol.

- Patients may donate cellular products or tissues as appropriate for research purposes.

- INCLUSION CRITERIA:

- Diagnosis of MGUS, SMM and MM will be made in accordance with the clinical diagnostic
criteria set forth by the International Myeloma Working Group. The diagnosis will be
confirmed by the following diagnostic tests:

- serum/urine protein electrophoresis

- serum/urine immunofixation,

- light-chain assays,

- a skeletal survey, or

- immunohistochemistry analyses of the bone marrow biopsy, or

- a combination of these at the NIH

Note: Written results from institutions outside of NIH for the above tests will be
accepted if available.

- Age greater than or equal to 18 years.

- ECOG performance status of 0-2.

- The patient must be competent to sign an informed consent form.

- Platelet count = or > 100,000. Subjects must weight < 320lbs

- Creatinine < 2.5 times ULN or eGFR> 30 ml/min/1.73m(2)

EXCLUSION CRITERIA:

- A medical history of other malignancy (apart from basal cell carcinoma of the skin or
in situ cervical carcinoma; also, for MM patients this does not include MM) except if
the patient has been free of symptoms and without active therapy during at least the
previous 3 years.

- Patients with documented metastatic lesions from another type of malignancy will be
excluded.

- Female subject is pregnant or breast-feeding.

- The subject has known allergy to gadolinium

- The subject has contraindications to MRI

- Subjects must weigh < 136 kg (weight limit for scanner table).

- Subjects cannot have pacemakers, cerebral aneurysm clips, shrapnel injury, or
other implanted electronic devices or metal not compatible with MRI.