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

OBJECTIVES Primary: To evaluate the bone anabolic effect of bortezomib in patients with smoldering myeloma. Secondary: To evaluate the effect of bortezomib on the natural history of smoldering myeloma.

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.

Bortezomib will be administered as a 3-5 second bolus IV injection at the dose of 0.7 mg/m2 on days 1, 8, 15, and 22 of each 42 day cycle. Patients will undergo nine 42-day cycles. At the end of this (day 378), patients will be assessed for bone remodeling changes. Evaluation for toxicities will be evaluated at the beginning of each cycle.

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