Bortezomib (Velcade) in Patients With Untreated Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
Bortezomib (Velcade) has just recently been approved by the FDA for the treatment of multiple myeloma in patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. This study will determine if Velcade is effective in treating patients with multiple myeloma that have had no prior treatment for the disease. We will also use whole-genome scanning to identify drug response biomarkers in bone marrow samples as well as nerve fiber studies to compare nerves prior to the use of Velcade and after treatment with Velcade.

Detailed Description
-----------------
Primary Objective • To evaluate the objective response rate (CR + PR) to bortezomib alone in patients with newly diagnosed multiple myeloma. Secondary Objectives To evaluate the tolerability and toxicity. To evaluate time to progression. To assess the frequency and severity of peripheral neuropathy. To evaluate the impact of early intervention with dose modification and explore symptomatic treatment of peripheral neuropathy. Exploratory Objectives • To perform pharmacogenomic analysis of molecular markers associated with response or non-response. Statistical Design A one stage design is used to evaluate ORR. With 60 evaluable participants, if at least 27 objective responses are observed then bortezomib will be considered promising. The probability of concluding the treatment promising is >0.95 with a true ORR of 55% and <0.07 with a true ORR of 35%.

Official Title
-----------------
Phase II Trial of Velcade (Bortezomib) in Patients With Previously Untreated Multiple Myeloma

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: bortezomib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of multiple myeloma based upon standard criteria Measurable disease, defined as a monoclonal immunoglobulin spike on serum electrophoresis of > 1 g/dl and/or urine monoclonal immunoglobulin spike of > 200mg/24 hours. Karnofsky performance status of > 60 Hemoglobin > 8.0 g/dL AST (SGOT) < 3 x ULN ALT < 3 x ULN Total bilirubin < 2 x ULN Is infertile or is practicing an adequate form of contraception 18 years of age or older Exclusion Criteria: Prior treatment with systemic chemotherapy Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes Plasma cell leukemia Calculated or measured creatinine clearance < 30 mL/minute within 14 days of enrollment Grade 2 or greater peripheral neuropathy Hypersensitivity to bortezomib, boron or mannitol Severe hypercalcemia HIV positive Known active hepatitis B or C New York Hospital Association Class III or IV heart failure Second malignancy requiring concurrent treatment Other serious medical or psychiatric illness Pregnant women Dialysis dependent patients

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: bortezomib<br>Participants received intravenous bortezomib on a 3-week dosing cycle: 1.3 mg/m2 on days 1, 4, 8 and 11 followed by 10 day rest period for up to 8 cycles or for 2 cycles beyond complete response. Participants with progressive disease or unacceptable toxicity discontinued treatment. | Drug: bortezomib<br> <br> * Other names: Velcade;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) Rate | Objective response was defined as complete response (CR) or partial response (PR) according to European Group for Blood and Marrow Transplantation criteria (Blade J et al Br J Haematol 1998). CR required all of the following: Negative immunofixation on the serum and urine at two consecutive times for minimum 6 weeks; Disappearance of soft tissue plasmacytomas for at least 6 weeks; <5% plasma cells in bone marrow on 2 determinations for a minimum of 6 weeks; No increase in the size or number of lytic bone lesions. PR required all the following: ≥50% reduction in the level of the serum monoclonal protein on 2 determinations for minimum 6 weeks; If present, reduction in 24-hour urinary light chain excretion either by ≥90% or to <200 mg on 2 determinations for minimum 6 weeks; ≥50% reduction size of soft tissue plasmacytomas for minimum 6 weeks; No increase in the number or size of lytic bone lesions. Development of a compression fracture does not exclude response in either category. | Response was assessed every two cycles on treatment. Treatment duration in months was a median (range) of 5.1 (0.8-6.1). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Very Good Partial Response (VGPR) Rate | Very good partial response or better was defined per International Uniform Response criteria (Durie B, Harousseau JL, Miquel JS, et al Leukemia 2006). See CR requirements in primary outcome measure plus if serum and urine M protein were unmeasurable then immunoglobulin free light chain (FLC) must be in a normal ratio of 0.26-1.65 at two consecutive times. VGPR required the following: Serum and urine M-component detectable by immunofixation but not on electrophoresis; >=90% reduction in serum M-component plus urine M-component <100 mg per 24 hours (by SPEP and UPEP); if the serum and urine M protein were unmeasurable then a >90% decrease in the difference between involved and uninvolved FLC levels. | Response was assessed every two cycles on treatment. Treatment duration in months was a median (range) of 5.1 (0.8-6.1). | 
| Time to Progression (TTP) | TTP based on the Kaplan-Meier method is defined as the time from start of treatment to documentation of disease progression (PD). Participants without evidence of PD were censored at the latest date of last disease assessment or date of initiation of non-protocol therapy. PD was established based European Group for Blood and Marrow Transplantation criteria (Blade J et al Br J Haematol 1998). PD required 1 or more of the following: >25% increase in serum monoclonal protein with absolute minimum of 0.5 g/dL (confirmed on repeat investigation); >25% increase in 24-hour urinary light chain excretion with minimum absolute increase of 200 mg/24 hrs (confirmed on repeat investigation); >25% increase in bone marrow plasma cells with minimum absolute increase of 10%; Definite increase in size of existing or new soft tissue plasmacytomas and/or lytic lesions; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL not attributable to other cause). | Disease was assessed every two cycles on treatment and every 6 weeks in long-term follow-up. Median follow-up was 29 months. | 
| Progression-Free Survival (PFS) | PFS based on the Kaplan-Meier method is defined as the time from study entry to the earliest documentation of disease progression (PD) or death. Participants alive without evidence of PD were censored at the earliest date of last disease assessment or date of initiation of non-protocol therapy. PD was established based European Group for Blood and Marrow Transplantation criteria (Blade J et al Br J Haematol 1998). PD required 1 or more of the following: >25% increase in serum monoclonal protein with absolute minimum of 0.5 g/dL (confirmed on repeat investigation); >25% increase in 24-hour urinary light chain excretion with minimum absolute increase of 200 mg/24 hrs (confirmed on repeat investigation); >25% increase in bone marrow plasma cells with minimum absolute increase of 10%; Definite increase in size of existing soft tissue plasmacytomas and/or lytic lesions or new; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL not attributable to other cause). | Disease was assessed every two cycles on treatment and every 6 weeks in long-term follow-up. Median follow-up was 29 months as of the data analysis. | 
| Number of Participants With Treatment-Emergent Sensory Neuropathy | Number of participants experiencing any grade treatment-emergent sensory neuropathy events based on CTCAEv3 as reported on case report forms. | Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Treatment duration in months was a median (range) of 5.1 (0.8-6.1). | 
| Number of Participants With Treatment-Emergent Neuropathic Pain | Number of participants experiencing any grade treatment-emergent neuropathic pain events based on CTCAEv3 as reported on case report forms. | Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Treatment duration in months was a median (range) of 5.1 (0.8-6.1). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
multiple myeloma, Velcade, bortezomib