Effect of Low Dose Bortezomib on Bone Formation in Smoldering Myeloma Patients
|ClinicalTrials.gov Identifier: NCT00983346|
Recruitment Status : Terminated (Lab Staff that was required left the institution, therefore accrual closed prematurely)
First Posted : September 24, 2009
Results First Posted : November 30, 2015
Last Update Posted : July 11, 2016
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Cancer Myeloma Multiple Myeloma||Drug: Bortezomib||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||17 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Effect of Low Dose Bortezomib on Bone Formation in Smoldering Myeloma Patients|
|Study Start Date :||October 2009|
|Actual Primary Completion Date :||September 2014|
|Actual Study Completion Date :||September 2014|
Experimental: All patients
All participants enrolled.
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.
Other Name: Velcade
- Bone Anabolic Effect of Bortezomib in Patients With Smoldering Myeloma. [ Time Frame: Baseline and 6 weeks ]The primary endpoint is the change in bone Alkaline Phosphatase at baseline and 6 weeks.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00983346
|United States, Utah|
|Huntsman Cancer Institute|
|Salt Lake City, Utah, United States, 84112|
|Principal Investigator:||Maurizio Zangari, MD||University of Utah|