Effect of Low Dose Bortezomib on Bone Formation in Smoldering Myeloma Patients

Smoldering multiple myeloma (SMM) is usually followed expectantly without therapy. The
overall risk of progression to active multiple myeloma has been estimated up to 20% in the
first year from diagnosis (Kyle et al, 2007). An angiogenic switch has been postulated as a
pivotal event in the progression from MGUS to smoldering myeloma. Two trials for advanced
and refractory MM patients tested this hypothesis using Thalidomide as antiangiogenic agent
in association with biphosphonates showing and effect on disease progression (Barlogie et
al, 2008).

The ubiquitin-proteasome pathway, which has been shown to be an essential cellular
degradative system in myeloma cells, also regulates bone formation though effects on
osteoblast differentiation (Pennisi et al., 2008).

Retrospective analysis of ALP variation in 2 large Bortezomib trials in the refractory
setting confirmed the finding. In the SUMMIT trial (Zangari, et al., 2005), 77 patients were
evaluated. The media increment ALP in levels of responding patients (patients with >50%
decrease in paraprotein) upon completion of 3 cycles of therapy was statistically higher of
those individuals with less than partial response (week 8, P=0.0015; responder range, 62-837
mL/L). In the APEX trial (Zangari et al. 2005), 422 patients were analyzed; 217 patients
were randomized to bortezomib, 205 to dexamethasone. Within the bortezomib arm, the
increment in serum ALP levels in responder patients (>CR) was statistically higher at week 3
(P=0.014), week 6 (P=0.002; responder rage, 31-272 mL/L) and week 9 (P=0.036). Comparing
only responders patients in both arms of the study, we observed a significantly higher
median ALP increase in the bortezomib compared to the dexamethasone arm (P<0.01; responder
ran, 31-272 mL/L) (Zangari et al., 2007). A 25% increase in ALP (N=105) at week 6 was also
the strongest indicator associated with quality of response (P<0.0001) and also with the
time to progression (206 vs. 169 days) relative to patients with less than a 25% increase in
ALP (N=228; P=0.01) (Zangari et al., 2007). We will now test the bone anabolic effect of
bortezomib in a cohort of smoldering multiple myeloma patients.

Study rationale and selection of drug doses VELCADE has been shown to produce an anabolic
bone effect (increase bone ALP and osteocalcin) in relapsed/refractory patients. This study
will examine the bone anabolic effect in patients with smoldering myeloma who, with a median
age of 67 years, have frequent evidence of osteopenia not associated with lytic bone
disease. Risk of disease progression is estimated at 10% per year in this patient
population. The primary aim of this trial is to determine the effect of a short course (i.e.
9 cycles) of low-dose Bortezomib on bone remodeling and on disease progression. The dose of
bortezomib used in this trial of 0.7 mg/m2 is the lowest dose which has shown efficacy in
the 3 largest monotherapy trials with bortezomib. Seventeen percent of patients in the APEX
9% of patients in CREST and 24% in SUMMIT trials were treated with 0.7 mg/m2 dosages.
Bortezomib will be given on days 1, 8, 15, 22 over 42 days to reduce the incidence of
possible drug related side effects.

Inclusion Criteria:

- Patients with diagnosis of smoldering multiple myeloma

- Male or Female patients aged ≥ 18 years old

- Ability to provide written informed consent (obtained prior to participation in the
study and any related procedures being performed) with the understanding that consent
may be withdrawn by the subject at any time without prejudice to future medical care.

- Female subject is either post-menopausal or surgically sterilized or willing to use
an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study

- Male subject agrees to use an acceptable method for contraception for the duration of
the study.

- Serum M protein ≥3 g/dL and/or

- Bone marrow plasma cells ≥10%

- Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions

- ANC ≥ 1.5 x 109 /L

- Hemoglobin ≥ 10g/dl

- Platelets ≥ 100 x 109 /L

- AST and ALT ≤2.5 x ULN

- Serum bilirubin ≤2.0 x ULN

Exclusion Criteria:

- Platelet count of <100 109/L within 14 days before enrollment.

- Absolute neutrophil count of <1.0 109/L within 14 days before enrollment.

- Creatinine clearance of <30 mL/minute within 14 days before enrollment.

- Patient has Grade 2 peripheral neuropathy within 14 days before enrollment.

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled
angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
of acute ischemia or active conduction system abnormalities. Prior to study entry,
any ECG abnormality at Screening has to be documented by the investigator as not
medically relevant.

- Patient has hypersensitivity to bortezomib, boron or mannitol.

- Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum human chorionic gonadotropin (hCG)
pregnancy test result obtained during screening. Pregnancy testing is not required
for post-menopausal or surgically sterilized women.

- Patient has received other investigational drugs with 14 days before enrollment

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

- Patients currently taking bisphosphonates