Help guide our efforts to modernize
Send us your comments by March 14, 2020. Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01534143
Recruitment Status : Terminated (Data was not collected, because funding was unavailable to continue study.)
First Posted : February 16, 2012
Results First Posted : December 16, 2013
Last Update Posted : April 5, 2017
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Zaid Al-Kadhimi, Barbara Ann Karmanos Cancer Institute

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

Condition or disease Intervention/treatment Phase
Refractory Multiple Myeloma Stage I Multiple Myeloma Stage II Multiple Myeloma Stage III Multiple Myeloma 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 Phase 2

Detailed Description:


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).


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.


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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study Using High Dose Busulfan and Bortezomib as Part of Allogeneic Transplant Conditioning Regimen for High Risk Multiple Myeloma Patients.
Study Start Date : February 2012
Actual Primary Completion Date : May 2013
Actual Study Completion Date : May 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: 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.

Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Drug: tacrolimus
Given IV
Other Names:
  • FK 506
  • Prograf

Drug: sirolimus
Given PO
Other Names:
  • AY 22989
  • Rapamune
  • rapamycin
  • SLM

Biological: anti-thymocyte globulin
Given IV
Other Names:
  • ATG
  • lymphocyte immune globulin
  • Thymoglobulin

Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara

Drug: busulfan
Given IV
Other Names:
  • BSF
  • BU
  • Misulfan
  • Mitosan
  • Myeloleukon

Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341

Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic HSCT

Other: laboratory biomarker analysis
Correlative studies

Primary Outcome Measures :
  1. Incidence and Severity of Acute GVHD Using Fludarabine Phosphate / Busulfan / Bortezomib Preparative Regimen and Triple Immune Suppression With Tacrolimus, Sirolimus and Anti-thymocyte Globulin [ Time Frame: 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.

  2. Time to Platelet Absolute Neutrophil Recovery (Engraftment) [ Time Frame: First 6 months post-transplant ]
    Estimated using Kaplan-Meier method.

  3. Treatment Related Mortality Defined as Death in Continuous or Complete Remission [ Time Frame: 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.

  4. Grade III and IV Non Hematologic Toxicities [ Time Frame: First 6 months post transplant ]
    Based on NCI CTCAE version 4.

Secondary Outcome Measures :
  1. Incidence of Myeloma Progression [ Time Frame: Time to the first observation of disease progression/relapse post transplant, assessed up to 2 years post transplant ]
  2. Incidence of Transplant Related Mortality and Morbidity [ Time Frame: Up to 2 years post transplant ]
  3. Incidence of TTP [ Time Frame: Up to 2 years post transplant ]
  4. Incidence of SOS [ Time Frame: Up to 2 years post transplant ]
  5. Incidence and Severity of Chronic GVHD [ Time Frame: Up to 2 years post transplant ]
  6. Incidence of Opportunistic Infections Including CMV, HSV, and EBV Reactivation [ Time Frame: Weekly to day 100 ]
  7. Overall Survival [ Time Frame: Up to 2 years post transplant ]
  8. Progression Free Survival [ Time Frame: From the day of transplant to progression, death, or last contact, assessed up to 2 years ]
  9. Recovery of T-cell, B Cell and NK Cell Phenotypes [ Time Frame: Days 30, 60, 90, and at 6 months after transplant ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01534143

Layout table for location information
United States, Michigan
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
Sponsors and Collaborators
Barbara Ann Karmanos Cancer Institute
National Cancer Institute (NCI)
Layout table for investigator information
Principal Investigator: Zaid Al-Kadhimi Barbara Ann Karmanos Cancer Institute

Layout table for additonal information
Responsible Party: Zaid Al-Kadhimi, Principal Investigator, Barbara Ann Karmanos Cancer Institute Identifier: NCT01534143    
Other Study ID Numbers: 2011-151
NCI-2012-00120 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: February 16, 2012    Key Record Dates
Results First Posted: December 16, 2013
Last Update Posted: April 5, 2017
Last Verified: March 2017
Additional relevant MeSH terms:
Layout table for MeSH terms
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Fludarabine phosphate
Antilymphocyte Serum
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents