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Melphalan+Bortezomib as a Conditioning Regimen for Autologous and Allogeneic Stem Cell Transplants in Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT00948922
Recruitment Status : Active, not recruiting
First Posted : July 29, 2009
Results First Posted : October 12, 2018
Last Update Posted : October 12, 2018
Sponsor:
Collaborator:
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Multiple Myeloma
Interventions Drug: Bortezomib
Drug: Melphalan
Procedure: Autologous Stem Cell Transplant
Drug: Fludarabine
Procedure: Allogeneic Stem Cell Transplant
Enrollment 124
Recruitment Details Participants were enrolled at Moffitt Cancer Center August 2009 through April 2015.
Pre-assignment Details  
Arm/Group Title A: Allogeneic Stem Cell Transplant B: Autologous Stem Cell Transplant BE: Group B Expansion
Hide Arm/Group Description

Allogeneic Stem Cell Transplant: Fludarabine+Melphalan+Bortezomib followed by Allogeneic Rescue.

Bortezomib: AUTOLOGOUS ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows Melphalan infusion). ALLOGENEIC ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows fludarabine and melphalan infusion).

Melphalan: AUTOLOGOUS ARM: Day -4 and Day -3 Melphalan 100 mg/m^2/day IV over 30 minutes. ALLOGENEIC ARM: Day -4, Day -3 Melphalan 70 mg/m^2/day IV over 30 minutes.

Fludarabine: Days -6,-5,-4,-3 Fludarabine 30 mg/m^2/day IV

Allogeneic Stem Cell Transplant: Allogeneic Peripheral Blood Stem Cell Rescue. Day 0 Infusion of allogeneic peripheral blood stem cells. For the allogeneic matched-related donors peripheral blood stem cells will be harvested with granulocyte colony-stimulating factor (GCSF) mobilization and infused fresh to recipients. Allogeneic donor stem cells may be cryopreserved if they cannot be infused

Autologous Stem Cell Transplant: Melphalan+Bortezomib followed by Autologous Rescue.

Bortezomib: AUTOLOGOUS ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows Melphalan infusion). ALLOGENEIC ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows fludarabine and melphalan infusion).

Melphalan: AUTOLOGOUS ARM: Day -4 and Day -3 Melphalan 100 mg/m^2/day IV over 30 minutes. ALLOGENEIC ARM: Day -4, Day -3 Melphalan 70 mg/m^2/day IV over 30 minutes.

Autologous Stem Cell Transplant: Autologous Stem Cell Transplant: Autologous Peripheral Blood Stem Cell Rescue. Stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) at a dose of 10 μg/kg/day as per institutional standards. CD34+ peripheral blood stem cells will be collected following the administration of G-CSF as per institutional standards. Day 0 Infusion of autologous stem cells.

Group B Expansion on Bortezomib Maintenance: Autologous Only.

Bortezomib: AUTOLOGOUS ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows Melphalan infusion). ALLOGENEIC ARM: Day -3 bortezomib (1.3 mg/m^2) as an intravenous push over 3 to 5 seconds (follows fludarabine and melphalan infusion).

Melphalan: AUTOLOGOUS ARM: Day -4 and Day -3 Melphalan 100 mg/m^2/day IV over 30 minutes. ALLOGENEIC ARM: Day -4, Day -3 Melphalan 70 mg/m^2/day IV over 30 minutes.

Autologous Stem Cell Transplant: Autologous Stem Cell Transplant: Autologous Peripheral Blood Stem Cell Rescue. Stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) at a dose of 10 μg/kg/day as per institutional standards. CD34+ peripheral blood stem cells will be collected following the administration of G-CSF as per institutional standards. Day 0 Infusion of autologous stem cells.

Period Title: Overall Study
Started 34 51 39
Completed 26 39 35
Not Completed 8 12 4
Reason Not Completed
Did not start study treatment             2             5             0
Withdrawal by Subject             0             0             2
Adverse Event             0             0             2
Death             3             0             0
Disease progression             0             1             0
Insurance issues             1             0             0
Transplant eligibility issues             2             3             0
Not evaluable at time of analysis             0             3             0
Arm/Group Title A: Allogeneic Stem Cell Transplant B: Autologous Stem Cell Transplant BE: Group B Expansion Total
Hide Arm/Group Description Allogeneic Stem Cell Transplant: Fludarabine+Melphalan+Bortezomib followed by Allogeneic Rescue. Autologous Stem Cell Transplant: Melphalan+Bortezomib followed by Autologous Rescue. Group B Expansion on Bortezomib Maintenance: Autologous Only. Total of all reporting groups
Overall Number of Baseline Participants 34 51 39 124
Hide Baseline Analysis Population Description
Baseline: All participants enrolled on study. Adverse Events: All participants who received study treatment. Outcome Measures: All participants evaluable at time of analysis.
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 34 participants 51 participants 39 participants 124 participants
53.5
(32 to 76)
62
(31 to 79)
62
(39 to 78)
60
(31 to 79)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants 51 participants 39 participants 124 participants
Female
23
  67.6%
20
  39.2%
19
  48.7%
62
  50.0%
Male
11
  32.4%
31
  60.8%
20
  51.3%
62
  50.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants 51 participants 39 participants 124 participants
Hispanic or Latino
2
   5.9%
8
  15.7%
9
  23.1%
19
  15.3%
Not Hispanic or Latino
32
  94.1%
43
  84.3%
29
  74.4%
104
  83.9%
Unknown or Not Reported
0
   0.0%
0
   0.0%
1
   2.6%
1
   0.8%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants 51 participants 39 participants 124 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
1
   2.6%
1
   0.8%
Asian
1
   2.9%
1
   2.0%
0
   0.0%
2
   1.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   2.9%
7
  13.7%
3
   7.7%
11
   8.9%
White
32
  94.1%
38
  74.5%
32
  82.1%
102
  82.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
5
   9.8%
3
   7.7%
8
   6.5%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 34 participants 51 participants 39 participants 124 participants
34 51 39 124
1.Primary Outcome
Title Progression Free Survival (PFS)
Hide Description PFS: Number of participants, per treatment arm with progression free survival at time of analysis. Survival time will be measured from the date of transplant to the date of progression, death or the last follow-up, whichever comes first. Progressive Disease (PD): Increase of ≥ 25% from lowest response value in any one or more of the following: Serum M-component and/or; Urine M-component and/or; Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL; Bone marrow plasma cell percentage; absolute percentage ≥ 10%; Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia that can be attributed solely to the plasma cell proliferative disorder.
Time Frame End of 2 year, post transplant follow-up
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants evaluable at time of analysis
Arm/Group Title A: Allogeneic Stem Cell Transplant B: Autologous Stem Cell Transplant BE: Group B Expansion
Hide Arm/Group Description:
Allogeneic Stem Cell Transplant: Fludarabine+Melphalan+Bortezomib followed by Allogeneic Rescue.
Autologous Stem Cell Transplant: Melphalan+Bortezomib followed by Autologous Rescue.
Group B Expansion on Bortezomib Maintenance: Autologous Only.
Overall Number of Participants Analyzed 26 39 35
Measure Type: Count of Participants
Unit of Measure: Participants
17
  65.4%
25
  64.1%
19
  54.3%
2.Secondary Outcome
Title Overall Survival (OS) Rate
Hide Description Overall survival in participants with multiple myeloma treated with Bortezomib (Velcade®) containing conditioning regimen and autologous as well as allogeneic transplantation.
Time Frame End of 2 year, post transplant follow-up
Outcome Measure Data Not Reported
3.Secondary Outcome
Title Molecular Complete Response (CR) Rates in Patients With Multiple Myeloma
Hide Description Complete Response according to International Myeloma Working Group uniform response criteria. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow.
Time Frame End of 2 year, post transplant follow-up
Outcome Measure Data Not Reported
4.Other Pre-specified Outcome
Title Incidence of Acute or Chronic Graft-versus-host Disease (GVHD) Following Transplant
Hide Description Number of participants with Acute or Chronic GVHD following transplant, per study treatment arm.
Time Frame End of 2 year, post transplant follow-up
Outcome Measure Data Not Reported
Time Frame 7 years, 8 months
Adverse Event Reporting Description All Serious Adverse Events are reported, regardless of causality. For this study that includes patients undergoing hematopoietic cell transplantation (HCT), review and consideration was given for reporting of Other Adverse Events that are designated in the protocol as commonly observed after HCT. Patients are monitored for Serious Adverse Events and Other Adverse events beginning at on treatment date. Patients who did not receive treatment: not included in at risk numbers.
 
Arm/Group Title A: Allogeneic Stem Cell Transplant B: Autologous Stem Cell Transplant BE: Group B Expansion
Hide Arm/Group Description Allogeneic Stem Cell Transplant: Fludarabine+Melphalan+Bortezomib followed by Allogeneic Rescue. Autologous Stem Cell Transplant: Melphalan+Bortezomib followed by Autologous Rescue. Group B Expansion on Bortezomib Maintenance: Autologous Only.
All-Cause Mortality
A: Allogeneic Stem Cell Transplant B: Autologous Stem Cell Transplant BE: Group B Expansion
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/32 (9.38%)      0/42 (0.00%)      0/39 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
A: Allogeneic Stem Cell Transplant B: Autologous Stem Cell Transplant BE: Group B Expansion
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   13/32 (40.63%)      18/42 (42.86%)      10/39 (25.64%)    
Blood and lymphatic system disorders       
Blood/Bone Marrow - Other * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Haptoglobin * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Hemolysis * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Neutrophil count decreased * 1  0/32 (0.00%)  0 0/42 (0.00%)  0 2/39 (5.13%)  2
Cardiac disorders       
Supraventricular and nodal arrhythmia - Atrial fibrillation * 1  0/32 (0.00%)  0 3/42 (7.14%)  3 0/39 (0.00%)  0
Cardiac General - Other * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Cardiopulmonary arrest, cause unknown (non-fatal) * 1  0/32 (0.00%)  0 0/42 (0.00%)  0 1/39 (2.56%)  1
Hypotension * 1  1/32 (3.13%)  1 1/42 (2.38%)  1 0/39 (0.00%)  0
Gastrointestinal disorders       
Dehydration * 1  0/32 (0.00%)  0 0/42 (0.00%)  0 1/39 (2.56%)  1
Diarrhea * 1  0/32 (0.00%)  0 0/42 (0.00%)  0 1/39 (2.56%)  1
Dysphagia * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Esophagitis * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Gastrointestinal - Other * 1  1/32 (3.13%)  1 1/42 (2.38%)  1 0/39 (0.00%)  0
Mucositis/stomatitis * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Nausea * 1  1/32 (3.13%)  1 2/42 (4.76%)  2 2/39 (5.13%)  2
Typhlitis * 1  0/32 (0.00%)  0 0/42 (0.00%)  0 1/39 (2.56%)  1
Vomiting * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 1/39 (2.56%)  2
General disorders       
Fatigue * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Fever (in the absence of neutropenia) * 1  3/32 (9.38%)  3 0/42 (0.00%)  0 0/39 (0.00%)  0
Death not associated with CTCAE term * 1  3/32 (9.38%)  3 0/42 (0.00%)  0 0/39 (0.00%)  0
Immune system disorders       
Allergic reaction * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Infections and infestations       
Colitis, infectious * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 1/39 (2.56%)  1
Febrile neutropenia * 1  1/32 (3.13%)  1 1/42 (2.38%)  1 0/39 (0.00%)  0
Infection with normal ANC or Grade 1 or 2 neutrophils - Brain * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Infection with normal ANC or Grade 1 or 2 neutrophils - Lung * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Infection with normal ANC or Grade 1 or 2 neutrophils - Paranasal * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Infection with normal ANC or Grade 1 or 2 neutrophils - Salivary gland * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Infection with normal ANC or Grade 1 or 2 neutrophils - Skin * 1  0/32 (0.00%)  0 0/42 (0.00%)  0 1/39 (2.56%)  1
Infection with unknown ANC - Appendix * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Infection with unknown ANC - Gallbladder * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Infection with unknown ANC - Salivary gland * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Infection with unknown ANC - Skin * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Opportunistic infection associated with >= Grade 2 Lymphopenia * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Metabolism and nutrition disorders       
ALT, SGPT - Increase * 1  1/32 (3.13%)  1 1/42 (2.38%)  1 0/39 (0.00%)  0
AST, SGOT - Increase * 1  1/32 (3.13%)  1 1/42 (2.38%)  1 0/39 (0.00%)  0
Alkaline phosphatase * 1  1/32 (3.13%)  1 1/42 (2.38%)  1 0/39 (0.00%)  0
Calcium, serum-high (hypercalcemia) * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Hemorrhage/Bleeding - Other, knee effusion * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Arthritis (non-septic) * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Pain - Back * 1  1/32 (3.13%)  1 1/42 (2.38%)  1 0/39 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Secondary malignancy - possibly related to cancer treatment * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Nervous system disorders       
Ataxia * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Dizziness * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Encephalopathy * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Extrapyramidal/involuntary movement/restlessness * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Psychiatric disorders       
Mental status * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Renal and urinary disorders       
Renal failure * 1  2/32 (6.25%)  2 1/42 (2.38%)  1 2/39 (5.13%)  2
Renal/Genitourinary - Other, Renal insufficiency * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Renal/Genitourinary - Other, Hematuria * 1  0/32 (0.00%)  0 0/42 (0.00%)  0 1/39 (2.56%)  1
Respiratory, thoracic and mediastinal disorders       
Bronchospasm, wheezing * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Dyspnea * 1  2/32 (6.25%)  2 1/42 (2.38%)  1 0/39 (0.00%)  0
Edema, larynx * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
Hypoxia * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Pulmonary/Upper Respiratory - Other, Pneumonia * 1  1/32 (3.13%)  2 0/42 (0.00%)  0 0/39 (0.00%)  0
Pulmonary/Upper Respiratory - Other, Pulmonary edema * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
Pulmonary/Upper Respiratory - Other, Acute respiratory failure * 1  0/32 (0.00%)  0 0/42 (0.00%)  0 1/39 (2.56%)  1
Vascular disorders       
Thrombosis/embolism (vascular access-related) * 1  1/32 (3.13%)  1 1/42 (2.38%)  1 0/39 (0.00%)  0
Thrombosis/thrombus/embolism * 1  1/32 (3.13%)  1 0/42 (0.00%)  0 0/39 (0.00%)  0
1
Term from vocabulary, CTCAE (3.0)
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
A: Allogeneic Stem Cell Transplant B: Autologous Stem Cell Transplant BE: Group B Expansion
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/32 (0.00%)      1/42 (2.38%)      0/39 (0.00%)    
Blood and lymphatic system disorders       
Lymphopenia * 1  0/32 (0.00%)  0 1/42 (2.38%)  1 0/39 (0.00%)  0
1
Term from vocabulary, CTCAE (3.0)
*
Indicates events were collected by non-systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Dr. Melissa Alsina
Organization: H. Lee Moffitt Cancer Center and Research Institute
Phone: 813-745-7202
Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT00948922     History of Changes
Other Study ID Numbers: MCC-15697
XO5271 ( Other Grant/Funding Number: Millennium )
First Submitted: July 28, 2009
First Posted: July 29, 2009
Results First Submitted: August 7, 2018
Results First Posted: October 12, 2018
Last Update Posted: October 12, 2018