Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Transplant
Brief summary
The hypothesis for this study is that the regimen consisting of fludarabine, melphalan and bortezomib improves the progression free survival and the response rate compared to historical controls of fludarabine and melphalan alone.
Detailed description
Multiple myeloma is the second most prevalent blood cancer (10%) after non-hodgkin's lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset. The historical control 2-year progression-free survival (PFS) is assumed to be 35%. The proposed therapy of fludarabine, melphalan and bortezomib is expected to improve the PFS by 20%.
Interventions
DRUGFludarabine monophosphate, melphalan, Bortezomib
* Fludarabine will be administered at a dose of 30/mg/m2 IV daily for 4 days starting on transplant day -5. * Melphalan will be administered at a dose of 140 mg/m2 on transplant day-2 * Bortezomib will be administered by rapid IV push at a dose of 1.6mg/m2 on days-4 and -1. The bortezomib should be given at least 20 hours after the melphalan.
Sponsors
Hackensack Meridian Health
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 69 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of multiple myeloma * Have a suitable related or unrelated donor * Age ≥18 but \<70 yrs * KPS of ≥70% * Recovery from complications of previous therapies
Exclusion criteria
* Diagnosis other than multiple myeloma * Chemotherapy or radiotherapy within 21 days of initiating treatment in this study * Prior dose-intense therapy requiring HSC support within 56 days of initiating treatment in this study * Uncontrolled bacterial, viral, fungal or parasitic infections * Uncontrolled CNS metastases * Known amyloid deposition in heart * Organ dysfunction * LVEF \<40% or cardiac failure not responsive to therapy * FVC, FEV1, or DLCO \<50% of predicted and/or receiving supplementary continuous oxygen * Evidence of hepatic synthetic dysfunction, or total bilirubin \>2x or AST \>3x ULN * Measured creatinine clearance \<20 ml/min * Sensory peripheral neuropathy grade 4 within 14 days of enrollment * Karnofsky score \<70% unless a result of bone disease directly caused by myeloma * Life expectancy limited by another co-morbid illness * 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 * Female subject is pregnant or breast-feeding (women) or unwilling to use acceptable birth control methods (men or women) for twelve months after treatment. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. * Documented hypersensitivity to fludarabine or melphalan or to bortezomib, boron or mannitol or any components of the formulation * Patients unable or unwilling to provide consent * Patient has a sustained platelet count of \<30 x 10 9/L within 14 days before enrollment * Patient has a sustained absolute neutrophil count of \<1.0 x10 9/L 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 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 received other investigational drugs with 14 days before enrollment * Serious medical or psychiatric illness likely to interfere with participation in this clinical study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Subjects will be followed for progression-free survival for at least 36 months | The main primary endpoint of this study is two-year progression free survival. Patients are considered a failure with respect to PFS if they die or experience disease progression or relapse. The time to this event is the time from transplantation to relapse/progression, initiation of non-protocol anti-myeloma therapy, or death from any cause. Subjects alive without confirmed disease progression will be censored at the time of last disease evaluation. Deaths without progression are treated as failures no matter when they occur. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 3 years | Overall survival (OS): Defined as time from the first dose of administration to death from any cause |
| Overall Response Rate | Up to 3 years | Overall response rate: Defined as the composite endpoint of response to treatment which includes Complete Response (CR), Partial Response (PR), stable disease (SD) as defined in International Response Criteria. International Myeloma Working Group Response Criteria for Multiple Myeloma: CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow PR: \> 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by \>90% or to \< 200 mg/24 h SD: Not meeting criteria for CR, VGPR, PR, or progressive disease |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fludarabine, Melphalan, Bortezomib Fludarabine monophosphate, melphalan, Bortezomib: •Fludarabine will be administered at a dose of 30/mg/m2 IV daily for 4 days starting on transplant day -5.
* Melphalan will be administered at a dose of 140 mg/m2 on transplant day-2
* Bortezomib will be administered by rapid IV push at a dose of 1.6mg/m2 on days-4 and -1. The bortezomib should be given at least 20 hours after the melphalan. | 54 |
| Total | 54 |
Baseline characteristics
| Characteristic | Fludarabine, Melphalan, Bortezomib |
|---|---|
| Age, Continuous | 56 years |
| Region of Enrollment United States | 54 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 27 / 54 |
| other Total, other adverse events | 0 / 54 |
| serious Total, serious adverse events | 29 / 54 |
Outcome results
Primary
Progression Free Survival
The main primary endpoint of this study is two-year progression free survival. Patients are considered a failure with respect to PFS if they die or experience disease progression or relapse. The time to this event is the time from transplantation to relapse/progression, initiation of non-protocol anti-myeloma therapy, or death from any cause. Subjects alive without confirmed disease progression will be censored at the time of last disease evaluation. Deaths without progression are treated as failures no matter when they occur.
Time frame: Subjects will be followed for progression-free survival for at least 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine, Melphalan, Bortezomib | Progression Free Survival | 16.7 Months |
Secondary
Overall Response Rate
Overall response rate: Defined as the composite endpoint of response to treatment which includes Complete Response (CR), Partial Response (PR), stable disease (SD) as defined in International Response Criteria. International Myeloma Working Group Response Criteria for Multiple Myeloma: CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow PR: \> 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by \>90% or to \< 200 mg/24 h SD: Not meeting criteria for CR, VGPR, PR, or progressive disease
Time frame: Up to 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fludarabine, Melphalan, Bortezomib | Overall Response Rate | 45 Participants |
Secondary
Overall Survival (OS)
Overall survival (OS): Defined as time from the first dose of administration to death from any cause
Time frame: Up to 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine, Melphalan, Bortezomib | Overall Survival (OS) | 42 percentage |