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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.

Phase 2
18 Years
70 Years
Open (Enrolling)
Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

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Trial Information

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


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

VII. To determine recovery of T-cell, B cell, and natural killer (NK) cell phenotypes post


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.

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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Incidence and severity of acute GVHD using fludarabine phosphate / busulfan / bortezomib preparative regimen and triple immune suppression with tacrolimus, sirolimus and anti-thymocyte globulin

Outcome Description:

Graded using the Glucksberg scale. Proportions and confidence intervals will be estimated. Estimated using binary proportion estimates as well as competing risk method.

Outcome Time Frame:

First 6 months post-transplant

Safety Issue:


Principal Investigator

Zaid Al-Kadhimi

Investigator Role:

Principal Investigator

Investigator Affiliation:

Barbara Ann Karmanos Cancer Institute


United States: Federal Government

Study ID:




Start Date:

February 2012

Completion Date:

Related Keywords:

  • Refractory Multiple Myeloma
  • Stage I Multiple Myeloma
  • Stage II Multiple Myeloma
  • Stage III Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



Barbara Ann Karmanos Cancer Institute Detroit, Michigan  48201