High Dose Busulfan and Bortezomib in Treating Patients With High Risk Multiple Myeloma Undergoing Stem Cell Transplant

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Pilot Study Using High Dose Busulfan and Bortezomib as Part of Allogeneic Transplant Conditioning Regimen for High Risk Multiple Myeloma Patients.

Conditions
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Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

Intervention / Treatment
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* Other: pharmacological study
* Drug: tacrolimus
* Drug: sirolimus
* Biological: anti-thymocyte globulin
* Drug: fludarabine phosphate
* Drug: busulfan
* Drug: bortezomib
* Procedure: allogeneic hematopoietic stem cell transplantation
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, enzyme inhibitor)<br>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. | Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Drug: tacrolimus<br>* Given IV<br>* Other names: Prograf;Drug: sirolimus<br>* Given PO<br>* Other names: SLM;Biological: anti-thymocyte globulin<br>* Given IV<br>* Other names: Thymoglobulin;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Drug: busulfan<br>* Given IV<br>* Other names: Myeloleukon;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Procedure: allogeneic hematopoietic stem cell transplantation<br>* Undergo allogeneic HSCT<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | First 6 months post-transplant | 
| Time to Platelet Absolute Neutrophil Recovery (Engraftment) | Estimated using Kaplan-Meier method. | First 6 months post-transplant | 
| Treatment Related Mortality Defined as Death in Continuous or Complete Remission | Based on National Cancer Institute (NCI) CTCAE version 4. | From the date of transplant to the date of death, assessed up to 6 months post transplant | 
| Grade III and IV Non Hematologic Toxicities | Based on NCI CTCAE version 4. | First 6 months post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Myeloma Progression |  | Time to the first observation of disease progression/relapse post transplant, assessed 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 | 
| 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 | 
| Overall Survival |  | 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 |