Melphalan+Bortezomib as a Conditioning Regimen for Autologous and Allogeneic Stem Cell Transplants in Multiple Myeloma

Phase 2

Completed

Conditions: Multiple Myeloma

Interventions: Drug: Bortezomib
Drug: Melphalan
Procedure: Autologous Stem Cell Transplant
Drug: Fludarabine
Procedure: Allogeneic Stem Cell Transplant

Registration Number: NCT00948922

Lead Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Brief Summary: The purpose of this study is to evaluate the effectiveness of Bortezomib when added to standard chemotherapy medicine(s) for treatment of Multiple Myeloma.

Detailed Description: The primary objectives of this study are:

* To determine the 2 year-progression free survival in multiple myeloma with an allogeneic transplant using a conditioning regimen of melphalan + fludarabine + Bortezomib in patients \< 60 years of age and available HLA-matched donor and compare it with the 2 year-progression-free-survival after an autologous stem cell transplant with melphalan+Bortezomib conditioning in patients \< 60 years.

* To determine the 2 year-progression free survival in multiple myeloma with an autologous stem cell transplant using a conditioning regimen of melphalan + Bortezomib. for patients \> 60 years of age and patients \< 60 years of age who decline allogeneic stem cell transplant.

The secondary objectives of this study are:

* To determine the overall survival in multiple myeloma with autologous or allogeneic stem cell transplants using the above conditioning regimens

* To determine the response rates in multiple myeloma using the above regimens.

* To determine minimal residual disease status using allele specific oligonucleotides (ASO-PCR) by PCR and flow-cytometry for multiple myeloma cells.

* To correlate minimal residual disease status with 2 year progression free survival and overall survival.

* To determine the incidence of acute and chronic graft-versus-host disease (GVHD) in multiple myeloma with allogeneic stem cell transplant using the above conditioning regimen.

* To examine quality of life in patients treated with allogeneic and autologous stem cell transplants using the above conditioning regimen.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 124

Inclusion Criteria

Multiple Myeloma Criteria(International Uniform Response Criteria for Multiple Myeloma)

Patients with responsive disease after any line of induction therapy
A complete response
A very good partial response
A partial response
Patients greater than or equal to 18 years of age are eligible. There is upper age limit of 60 years for allogeneic transplants.
Patients must have a histologically confirmed diagnosis.
All patients should have a life expectancy of at least 12 weeks.
Patients must have undergone a complete psychosocial evaluation and have been considered capable of compliance.
Meet the following criteria for allogeneic hematopoietic cell transplant:
Must have an identified donor match defined as: HLA-A, HLA-B, HLA- C, DRB1 8/8 allele matched sibling, family member, or unrelated donor. [7/8 would go on separate mismatched trials] and be < 60 years of age.
Calculated hematopoietic cell transplantation-specific comorbidity index (HCT-CI) <3

Exclusion Criteria

Patients who do not achieve at least a partial response (PR) by the criteria mentioned above with induction therapy.
Patient has a platelet count of <30 x 10^9/L within 14 days before enrollment.
Patient has >/= Grade 2 peripheral neuropathy within 30 days before enrollment.
Patient has an absolute neutrophil count of <1.0 x 10^9/L within 30 days before enrollment.
Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant in order for the subject to be considered eligible. Left ventricular ejection fraction (LVEF) by multiple gated acquisition (MUGA) scan < 40%.
Patient has hypersensitivity to bortezomib, boron or mannitol.
Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
Patient has received other investigational drugs with 30 days before enrollment
Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
Patients with a diffusing capacity of lung for carbon monoxide (DLCO) less than 50% (adjusted) of normal or with symptomatic obstructive or restrictive lung disease are ineligible.
Patients with a total bilirubin greater than 2.0 mg/dL excluding Gilbert's syndrome and serum glutamate oxaloacetate transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) greater than two and a half times normal (unless due to primary malignancy), or a history of severe hepatic dysfunction are ineligible.
Calculated creatinine clearance </= 30 ml/min within 30 days before enrollment
Patients with active infections are ineligible.
Patients who are HIV positive are ineligible.
Patients with active leptomeningeal involvement are ineligible. Patients with a history of previous cerebrospinal fluid (CSF) tumor involvement without symptoms or signs are eligible provided the CSF is now free of disease on lumbar puncture, and MRI of the brain shows no tumor involvement. Patients with severe symptomatic central nervous system (CNS) disease of any etiology are ineligible.
Patients with uncontrolled insulin-dependent diabetes mellitus defined as a random glucose level of > 400 in the 30 days prior to initiation of study therapy; or uncompensated major thyroid or adrenal dysfunction are ineligible.
Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of >/= 2(Karnofsky < 50%) are ineligible.
Patients with an ECOG performance status of 2 to 3(Karnofsky 30-50%), secondary to bone pain, may be enrolled.
Patients with an ECOG performance status of 2 to 3(Karnofsky 30-50%), secondary to a potentially reversible disease-related problem, may be enrolled.
Patients with any previous malignancy other than non-melanoma skin cancer are ineligible, unless the patient is without evidence of disease >/= 5 years after the treatment for the cancer was completed.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BE: Group B Expansion	Autologous Stem Cell Transplant	Group B Expansion on Bortezomib Maintenance: Autologous Only.
A: Allogeneic Stem Cell Transplant	Allogeneic Stem Cell Transplant	Allogeneic Stem Cell Transplant: Fludarabine+Melphalan+Bortezomib followed by Allogeneic Rescue.
B: Autologous Stem Cell Transplant	Autologous Stem Cell Transplant	Autologous Stem Cell Transplant: Melphalan+Bortezomib followed by Autologous Rescue.
A: Allogeneic Stem Cell Transplant	Melphalan	Allogeneic Stem Cell Transplant: Fludarabine+Melphalan+Bortezomib followed by Allogeneic Rescue.
A: Allogeneic Stem Cell Transplant	Bortezomib	Allogeneic Stem Cell Transplant: Fludarabine+Melphalan+Bortezomib followed by Allogeneic Rescue.
A: Allogeneic Stem Cell Transplant	Fludarabine	Allogeneic Stem Cell Transplant: Fludarabine+Melphalan+Bortezomib followed by Allogeneic Rescue.
BE: Group B Expansion	Bortezomib	Group B Expansion on Bortezomib Maintenance: Autologous Only.
B: Autologous Stem Cell Transplant	Melphalan	Autologous Stem Cell Transplant: Melphalan+Bortezomib followed by Autologous Rescue.
B: Autologous Stem Cell Transplant	Bortezomib	Autologous Stem Cell Transplant: Melphalan+Bortezomib followed by Autologous Rescue.
BE: Group B Expansion	Melphalan	Group B Expansion on Bortezomib Maintenance: Autologous Only.

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	End of 2 year, post transplant follow-up	PFS: Number of participants, per treatment arm with progression free survival at time of analysis. Survival time will be measured from the date of transplant to the date of progression, death or the last follow-up, whichever comes first. Progressive Disease (PD): Increase of ≥ 25% from lowest response value in any one or more of the following: Serum M-component and/or; Urine M-component and/or; Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be \> 10 mg/dL; Bone marrow plasma cell percentage; absolute percentage ≥ 10%; Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia that can be attributed solely to the plasma cell proliferative disorder.

Secondary Outcome Measures

Name	Time	Method
Molecular Complete Response (CR) Rates in Patients With Multiple Myeloma	End of 2 year, post transplant follow-up	Complete Response according to International Myeloma Working Group uniform response criteria. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow.
Overall Survival (OS) Rate	End of 2 year, post transplant follow-up	Overall survival in participants with multiple myeloma treated with Bortezomib (Velcade®) containing conditioning regimen and autologous as well as allogeneic transplantation.