Clinical trial NCT01062230
Conditions: Multiple Myeloma
Keywords: Cancer Hematologic malignancy
Sponsor: University of Arkansas
Start date: 2010-01-01; Completion date: 2013-08-01
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary aim of this trial is to determine the effect of a short course (i.e., 3 cycles) of low-dose Bortezomib (Velcade) 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. 17% of patients in the APEX, 9% 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.

OBJECTIVES:

Primary Objective

The primary objective of this study is to:

* To evaluate the effect of Velcade at 0.7 mg/m2 dose on inducing osteoblast activation as measured by ALP and other bone markers in patients with relapsed/refractory myeloma.

Secondary Objectives

The secondary objectives of this study are to:

* To evaluate the association between osteoblastic activation and myeloma response to Velcade.
* To identify predictive factors for Velcade-associated osteoblastic activation.

Detailed description:
Multiple myeloma (MM) accounts for approximately 1% of all malignancies and 10% of hematological tumors, representing the second most frequently occurring hematological malignancy in the United States. At any one time, 50,000 people suffer from MM, and approximately 15,000 are diagnosed each year. The median age is approximately 65 years, although occasionally MM occurs in the second decade of life. Myeloma is a disease of neoplastic plasma cells that synthesize abnormal amounts of immunoglobulin or immunoglobulin fragments. Myeloma is the only hematological malignancy associated with bone disease. Myeloma is a B-cell neoplasia characterized by clonal expansion of plasma cells in the bone marrow. It is the most malignant stage of plasma cell dyscrasias, which also include the precursor stages of MGUS and indolent or smoldering myeloma. Myeloma is frequently associated with lytic bone disease that is responsible for the most debilitating manifestations of the disease, including bone pain and fractures.

Bone disease in myeloma results from the activation of osteoclast and suppression of osteoblast activity in the myelomatous bone marrow. Change in bone turnover rates, expressed as increased osteoblastic and osteoclastic activity, precede the progression pf MGUS or smoldering myeloma to overt myeloma by as long as three years.

Treatment with bisphosphonates reduces bone resorption and also to some degree, bone formation, and over the long-term moderately increases bone density. Other approved antiresorptive therapies have been shown to reduce the risk of fracture in osteoporotic women, but none have been shown to restore normal bone mass or strength. As a result, treatments that directly stimulate bone formation may overcome these limitations, increase bone mass, and improve the quality of life of myeloma patients. Bone disease is responsible for the most severe complications associated with multiple myeloma. As treatment and survival of myeloma patients improve, new therapies to improve complications are important and vitally needed VELCADE™ (bortezomib) for Injection is a small molecule proteasome inhibitor developed by Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies. VELCADE is currently approved by the United States Food and Drug Administration (US FDA) and it is registered in Europe for the treatment of multiple myeloma patients who have received at least one prior therapy.

The clinical response to bortezomib observed in a 63-year-old woman with multiple myeloma and the parallel increase in alkaline phosphatase (ALP) has led us and other groups to evaluate the correlation between bone anabolism and myeloma response to bortezomib. After similar elevations were noted in patients responding to bortezomib, thalidomide, dexamethasone combination, ALP levels were analysed in two large bortezomib trials (Roodman, 2008). Giuliani and coworkers (2007) found that bortezomib significantly increased the activity of the critical osteoblast transcription factor, RUNX2, in human osteoblast precursors and stimulated bone nodule formation in vitro. Importantly, they found a significant increase in the number of osteoblasts per mm2 of bone tissue and the number of RUNX2 positive osteoblastic cells in marrow biopsies from myeloma patients that responded to bortezomib. Again, the effect on osteoblasts was only seen in patients whose myeloma responded to bortezomib, making it difficult to distinguish if the increase in osteoblast activity was due to the anti-myeloma effects of bortezomib or direct effects on osteoblasts or both. Terpos and colleagues (2006) have reported that bortezomib also decreased DKK1 and RANKL concentrations and normalized bone remodeling indices in the serum of patients with relapsed myeloma. However, the majority of patients that showed an increase in bone formation markers also showed an antitumor response to bortezomib, making it unclear if the stimulatory effects on bone formation were secondary to the effects of bortezomib on myeloma or due to direct effects on osteoblast differentiation After similar elevations were noted in patients responding to bortezomib, thalidomide, dexamethasone combination, ALP levels were analysed in two large bortezomib trials.

We first completed a retrospective analysis of large Phase 3 trials comparing ALP levels in responders (≥PR) vs nonresponders (≤PR) patients.

Data obtained from the APEX Crest and Summit protocols, have shown that a total of 85 myeloma patients were treated with bortezomib at the dose of 0.7 mg/m2 for different reasons with significant antimyeloma efficacy for multiple cycles. This dose (0.7 mg/m2) will be used in this trial to test if the antimyeloma activity of bortezomib is still associated to bone anabolic effect. Data for the APEX, summit, and CREST trials is on file at Millennium Pharmaceuticals.

Given that this study is a continuation of a previous protocol (UARK 2004-22) when at the dose of 1.3 and 1.0 mg/m2 an antimyeloma effect and associated bone formation were observed. This trial will test the effect of 0.7 mg/m2 (which has been shown to be effective on antimyeloma treatment) on bone formation to determine the minimal dose associated to bone effect.

Arms: arm 1: All participants enrolled.
Interventions: intervention 1: Bortezomib (Velcade)
Intervention descriptions: intervention 1: Bortezomib will be administered as a 3-5 second bolus IV injection at the dose of 0.7 mg/m2 on days 1, 4, 8, and 11 q. 21 days times three cycles.

Patients will undergo three 21-day cycles.

Protocol documents: