Effects of bortezomib on bone turnover during treatment of relapsed multiple myeloma: a pilot study of quantitative in-vivo monitoring.

The persistence of suppressed bone formation in multiple myeloma patients even
after a good response to therapy is of concern in view of the morbidity of the
persisting risk of skeletal events. The availability of an agent that restores
bone formation at pathological sites would be a major innovation in MM therapy,
even in a palliative setting. The proteasome inhibitor bortezomib (Velcade®)
has a positive effect on bone formation reflected by biochemical markers in
serum and by an increase in activated osteoblasts in bone marrow biopsies.
Still, it remains to be demonstrated that bortezomib (Velcade®) actually leads
to an on-site restoration of bone formation at pathological sites, eventually
resulting in a decline in skeletal related events.
This study aims at visualizing the process of disease activity and bone
formation at pathological sites in correlation with in vitro markers of bone
turnover. The only known method to measure bone turnover is invasive:by bone
biopsies. Fluoride-PET scan can quantitatively measure bone turnover, at the
site of the osteolytic lesion and is non-invasive and thus could be used more
easily and frequently in patients. The pilot study is for validating the
accurateness of this quantitative in-vivo on-site imaging technique. The main
hypothesis is that treatment with bortezomib (Velcade®) results in normalized
or enhanced bone formation especially in areas of osteolysis. The second goal
of the study is to determine whether restoration of bone turnover is coupled to
the response of anti-myeloma therapy.

1. The accurateness of the imaging techniques will be evaluated for
quantitatively measuring in-vivo and on-site bone turnover in this specific
category of patients, i.e. patients with myeloma bone disease.
Bone turnover will be measured using
* in vivo imaging techniques to actually monitor on-site effects in terms of
bone remodelling and disease activity.
* in vivo determination of bone osteoblast number and bone mineral apposition
rate (MAR).
* in vitro markers reflecting osteoclast activity, bone degradation, osteoblast
activity and bone formation.
2. To determine if bortezomib restores bone remodelling in MM patients with
active bone disease at pathological sites.
Bone turn over will be measured using
* in vivo imaging techniques to actually monitor on-site effects in terms of
bone remodelling and disease activity,
* in vitro markers reflecting osteoclast activity, bone degradation, osteoblast
activity and bone formation.
3. To determine if bortezomib-induced changes in bone-remodeling are related to
anti-MM activity, or are exerted independently of disease response

The design of the study is a prospective non-randomised single center cohort
study of patients with relapsed myeloma referred for treatment with bortezomib.
Patients are required to have at least one osteolytic lesion. Bone turnover and
disease activity will be assessed after inclusion and after completion or
discontinuation of treatment.
The number of patients to be included must be large enough to demonstrate proof
of principle. Depending on the treatment status of patients before inclusion,
an expected (partial response or better) response rate of 30-50% after
completion of 8 cycles of bortezomib is to be expected. Bone turnover will be
measured both in responding and non-responding myeloma. In order to have at
least 10 patients in both of these groups, the aim is to include 25 consecutive
patients.
After inclusion of the first five patients completing at least 4 cycles of
bortezomib, an interim analysis of the imaging techniques will be performed. If
satisfactory discrimination of changes in bone turnover can be visualized in
these five patients (see paragraph 17.1), the study will be continued.

see point E