Refractory Multiple Myeloma, Stage III Multiple Myeloma, Stage II Multiple Myeloma, Stage I Multiple Myeloma
Conditions
Brief summary
This pilot phase II trial studies how well giving high dose busulfan together with bortezomib works in treating patients with high risk multiple myeloma undergoing stem cell transplant. Drugs used in chemotherapy, such as busulfan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cells growth. Giving busulfan together with bortezomib before a stem cell transplant may kill more cancer cells
Detailed description
PRIMARY OBJECTIVES: I. To determine time to engraftment absolute neutrophil count (\> 0.5 x 10\^9/L for 3 consecutive days), and platelet (\> 20X 109\^/L for 3 consecutive days). 2\. Incidence and severity of acute graft-versus-host disease (GVHD) using fludarabine (fludarabine phosphate) / busulfan / bortezomib preparative regimen and triple immune suppression with tacrolimus, sirolimus and Thymoglobulin (anti-thymocyte globulin). 3\. To determine the safety related to this combination in the first six months post transplant, specifically, treatment related mortality and grade III and IV non hematologic toxicities, based on Common Terminology Criteria for Adverse Events (CTCAE) version 4 (v4). SECONDARY OBJECTIVES: I. Incidence of myeloma progression in this high risk group of patients. II. Incidence of transplant related mortality and morbidity. III. Incidence of thrombotic thrombocytopenic purpura (TTP) and sinusoidal obstructive syndrome (SOS). IV. Incidence and severity of chronic GVHD. V. Incidence of opportunistic infections including cytomegalovirus (CMV), herpes simplex virus (HSV), and Epstein-Barr virus (EBV) reactivation. I. Overall and progression free survival (PFS) at Day 100, 6 months, 1 & 2 years post transplant. VII. To determine recovery of T-cell, B cell, and natural killer (NK) cell phenotypes post transplant. OUTLINE: CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -7 to -3, busulfan IV on days -6 to -3, and bortezomib IV on day -2. GVHD PROPHYLAXIS: Patients receive anti-thymocyte globulin IV on days -3 to -1, sirolimus orally (PO) on day -3, and tacrolimus IV on day -3. Patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) on day 0. After completion of study treatment, patients are followed up for up to 2 years.
Interventions
OTHERpharmacological study
Correlative studies
DRUGtacrolimus
Given IV
DRUGsirolimus
Given PO
BIOLOGICALanti-thymocyte globulin
Given IV
DRUGfludarabine phosphate
Given IV
DRUGbusulfan
Given IV
DRUGbortezomib
Given IV
PROCEDUREallogeneic hematopoietic stem cell transplantation
Undergo allogeneic HSCT
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Barbara Ann Karmanos Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Ability to provide informed consent * Karnofsky Performance Status (KPS) \>= 70 * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 * Availability of a suitable allogeneic hematopoietic stem cell donor; minimum of human leukocyte antigen (HLA) 7/8 matched related or unrelated donor * High risk multiple myeloma with poor prognostic features based on having one or more of the following criteria: * Progressive disease after autologous transplant. No less than 3 months post auto transplant * Progressive or stable disease after induction chemotherapy using the most potent myeloma agents Lenalidomide and/or Bortezomib * Patients with high risk cytogenetic abnormalities documented on conventional cytogenetics or fluorescence in situ hybridization (FISH) (hypodiploidy, t(4:14), t(14:16) chromosome translocation, p53 and or complex cytogenetics) additionally, chromosome 13 deletion by standard cytogenetics * Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test for women, as well as implementation of birth control for men and women
Exclusion criteria
* Patients with prior allogeneic transplant, or more than one prior autologous transplant for any medical reason * Prior treatment with busulfan or gemtuzumab (Mylotarg ®) for any reason * Patient with history of allergy to boron, mannitol, or bortezomib * Creatinine clearance (CrCl) =\< 50 ml/min * Ejection Fraction \< 50% * Diffusion capacity of carbon monoxide (DLCO) \< 50% predicted * Forced expiratory volume in 1 second (FEV1) \< 50% predicted * Forced vital capacity (FVC) \< 50% predicted * Patients with uncontrolled arrhythmia or uncontrolled heart disease at the screening time; patients with coronary heart disease (recent myocardial infarctions, angina, cardiac stent, or bypass surgery in the last 6 months) need to be cleared with a stress echo or nuclear myocardial perfusion stress test, and cardiology consult; all other cardiac history will be at the discretion of the principal investigator * Liver enzymes \> 3 times upper limit normal * Bilirubin \> 2 mg/dl (except Gilbert's disease) * International normalized ratio (INR) \> 2 * Any previous history of liver failure, hepatitis, or cirrhosis * Systemic Amyloidosis Known history of hepatitis B, C, human immunodeficiency virus (HIV) or any current uncontrolled infection * Grade \> I neuropathy * Women who are pregnant or lactating * Current or history of alcohol or drug abuse * Use of other investigational agents within 30 days of enrollment to this study * Any patient with ascites * Any patient on home oxygen * Any clinical findings on history or physical exam which would in the opinion of the treating physician or principal investigator preclude the patient from participating in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and Severity of Acute GVHD Using Fludarabine Phosphate / Busulfan / Bortezomib Preparative Regimen and Triple Immune Suppression With Tacrolimus, Sirolimus and Anti-thymocyte Globulin | First 6 months post-transplant | Graded using the Glucksberg scale. Proportions and confidence intervals will be estimated. Estimated using binary proportion estimates as well as competing risk method. |
| Time to Platelet Absolute Neutrophil Recovery (Engraftment) | First 6 months post-transplant | Estimated using Kaplan-Meier method. |
| Treatment Related Mortality Defined as Death in Continuous or Complete Remission | From the date of transplant to the date of death, assessed up to 6 months post transplant | Based on National Cancer Institute (NCI) CTCAE version 4. |
| Grade III and IV Non Hematologic Toxicities | First 6 months post transplant | Based on NCI CTCAE version 4. |
Secondary
| Measure | Time frame |
|---|---|
| Incidence and Severity of Chronic GVHD | Up to 2 years post transplant |
| Incidence of Opportunistic Infections Including CMV, HSV, and EBV Reactivation | Weekly to day 100 |
| Incidence of Myeloma Progression | Time to the first observation of disease progression/relapse post transplant, assessed up to 2 years post transplant |
| Progression Free Survival | From the day of transplant to progression, death, or last contact, assessed up to 2 years |
| Recovery of T-cell, B Cell and NK Cell Phenotypes | Days 30, 60, 90, and at 6 months after transplant |
| Overall Survival | Up to 2 years post transplant |
| Incidence of Transplant Related Mortality and Morbidity | Up to 2 years post transplant |
| Incidence of TTP | Up to 2 years post transplant |
| Incidence of SOS | Up to 2 years post transplant |
Countries
United States
Participant flow
Recruitment details
Cancer center clinic.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Chemotherapy, Enzyme Inhibitor) CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -7 to -3, busulfan IV on days -6 to -3, and bortezomib IV on day -2.
GVHD PROPHYLAXIS: Patients receive thymoglobulin IV on days -3 to -1, sirolimus PO on day -3, and tacrolimus IV on day -3. Patients undergo allogeneic HSCT on day 0.
anti-thymocyte globulin : Given IV
pharmacological study : Correlative studies
fludarabine phosphate : Given IV
busulfan : Given IV
bortezomib : Given IV
allogeneic hematopoietic stem cell transplantation : Undergo allogeneic HSCT
tacrolimus : Given IV
laboratory biomarker analysis : Correlative studies
sirolimus : Given PO | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Treatment (Chemotherapy, Enzyme Inhibitor) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 46 years STANDARD_DEVIATION 0 |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 1 |
| serious Total, serious adverse events | 1 / 1 |
Outcome results
Primary
Grade III and IV Non Hematologic Toxicities
Based on NCI CTCAE version 4.
Time frame: First 6 months post transplant
Primary
Incidence and Severity of Acute GVHD Using Fludarabine Phosphate / Busulfan / Bortezomib Preparative Regimen and Triple Immune Suppression With Tacrolimus, Sirolimus and Anti-thymocyte Globulin
Graded using the Glucksberg scale. Proportions and confidence intervals will be estimated. Estimated using binary proportion estimates as well as competing risk method.
Time frame: First 6 months post-transplant
Population: Data was not collected, because funding was unavailable to continue study.
Primary
Time to Platelet Absolute Neutrophil Recovery (Engraftment)
Estimated using Kaplan-Meier method.
Time frame: First 6 months post-transplant
Primary
Treatment Related Mortality Defined as Death in Continuous or Complete Remission
Based on National Cancer Institute (NCI) CTCAE version 4.
Time frame: From the date of transplant to the date of death, assessed up to 6 months post transplant
Secondary
Incidence and Severity of Chronic GVHD
Time frame: Up to 2 years post transplant
Secondary
Incidence of Myeloma Progression
Time frame: Time to the first observation of disease progression/relapse post transplant, assessed up to 2 years post transplant
Secondary
Incidence of Opportunistic Infections Including CMV, HSV, and EBV Reactivation
Time frame: Weekly to day 100
Secondary
Incidence of SOS
Time frame: Up to 2 years post transplant
Secondary
Incidence of Transplant Related Mortality and Morbidity
Time frame: Up to 2 years post transplant
Secondary
Incidence of TTP
Time frame: Up to 2 years post transplant
Secondary
Overall Survival
Time frame: Up to 2 years post transplant
Secondary
Progression Free Survival
Time frame: From the day of transplant to progression, death, or last contact, assessed up to 2 years
Secondary
Recovery of T-cell, B Cell and NK Cell Phenotypes
Time frame: Days 30, 60, 90, and at 6 months after transplant