Bortezomib Before Donor Stem Cell Transplant in Treating Patients With Multiple Myeloma
Bortezomib Before Donor Stem Cell Transplant in Treating Patients With Multiple Myeloma
Rationale: Giving bortezomib and low doses of chemotherapy and total-body irradiation before
 a donor stem cell transplant or peripheral blood stem cell transplant helps stop the growth
 of cancer cells. It also stops the patient's immune system from rejecting the donor's stem
 cells. The donated stem cells may replace the patient's immune cells and help destroy any
 remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a
 donor can also make an immune response against the body's normal cells. Giving sirolimus and
 tacrolimus before and after transplant may stop this from happening.

 Purpose: This phase I/II trial is studying the side effects and best dose of bortezomib
 before donor stem cell transplant in treating patients with multiple myeloma.
Objectives:

 I. To determine the maximum tolerated dose (MTD) of bortezomib when used in a novel
 conditioning regimen for patients undergoing allogeneic stem cell transplantation for
 multiple myeloma.

 II. To evaluate the tolerability and feasibility of this novel conditioning regimen and GVHD
 prophylaxis strategy incorporating several anti-myeloma agents, including bortezomib, in
 patients undergoing allogeneic stem cell transplantation for multiple myeloma.

 III. To obtain an initial assessment of the efficacy of this novel conditioning regimen.

 Outline: This is a phase I dose-escalation study of bortezomib followed by a phase II study.

 Reduced-Intensity Conditioning: Patients receive bortezomib IV and then undergo fractionated
 total-body irradiation on days -5 and -2. Patients receive thymoglobulin IV over 6 hours on
 days -5 to -2 and melphalan IV over 30 minutes on days -4 to -3.

 Allogenic Stem Cell Transplantation: Patients undergo bone marrow or peripheral blood stem
 cell transplant on day 0.

 Graft versus Host Disease Prophylaxis: Beginning on day -3, patients receive oral sirolimus
 and taper beginning on day 61. Beginning on day -2, patients receive oral or IV tacrolimus
 and taper beginning on day 101. After completion of the study treatment, patients are
 followed every 3 months.
Inclusion Criteria:

 -  ECOG performance status (PS) 0, 1, or 2

 -  Diagnosis of symptomatic multiple myeloma

 -  High risk myeloma as defined by progressive disease =< 12 months after high dose
 chemotherapy and autologous HSC transplant or presences of poor prognostic features
 such as deletion of chromosome 13 or hypodiploidy by standard cytogenetics, or t(4;
 14) by fluorescence in situ hybridization (FISH), or t(14;16) by FISH, or 17p- by
 FISH, or plasma cell labeling index >= 3%

 -  Availability of a HLA fully-matched or 1 mismatch related donor by low-resolution HLA
 typing for the loci A, B, C, DRB1 and DQB1 or HLA fully-matched unrelated donor by
 high-resolution typing for loci A, B, C and DRB1 and at least low-resolution for loci
 DQB1

 -  Recovery from toxicity of previous chemotherapy (excludes grade 1 neurotoxicity and
 hematological toxicity)

 -  Physically and psychologically capable of undergoing bone marrow or PBSC transplant

 -  Voluntary written informed consent before performance of any study-related procedure
 not part of normal medical care, with the understanding that consent may be withdrawn
 by the subject at any time without prejudice to future medical care

 -  Female subject is either post-menopausal or surgically sterilized or willing to use an
 acceptable method of birth control for the during of the study

 -  Male subject agrees to use an acceptable method for contraception for the duration of
 the study

 Exclusion Criteria:

 -  Myocardial infarction within 6 months prior to enrollment or has New York Heart
 Association (NYHA) Class III or IV hear failure, uncontrolled angina, severe
 uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
 ischemia or active conduction system abnormalities

 -  NOTE: Prior to study entry, and ECG abnormality at screening has to be documented by
 the investigator as not medically relevant

 -  Significant cardiac dysfunction defined as left ventricle ejection fraction < 40% or
 presence of symptomatic coronary artery disease

 -  Significant pulmonary disease defined as FEV < 50% or CLCO < 50% of the predicted
 values

 -  Pre existing peripheral neuropathy grade > 1

 -  Significant renal dysfunction defined as estimated creatinine clearance < 50 ml/min

 -  Significant liver dysfunction defined as total bilirubin >= 2 x upper limit of normal
 (ULN) or AST, ALT >= 3 x ULN

 -  Seroreactive for HIV, HTLV I or II, HBV, HCV

 -  Presence of uncontrolled bacterial, viral, or fungal infection

 -  Known allergy to any of the component of the investigational treatment regimen or
 required ancillary treatments

 -  Considered unable to tolerate the included doses of total body irradiation due to
 previous treatment with radiation

 -  Female subject is pregnant or breast-feeding

 -  Other active concurrent malignancy

 -  Prior allogeneic bone marrow/peripheral blood stem cell transplant

 -  Received other investigational drugs =< 14 days prior to enrollment