Autologous Stem Cell Transplant Followed by Donor Stem Cell Transplant and Bortezomib in Treating Patients With Newly Diagnosed High-Risk, Relapsed, or Refractory Multiple Myeloma - Full Text View

Sponsors and Collaborators:	Fred Hutchinson Cancer Research Center National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00793572

Purpose

RATIONALE: Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Giving more chemotherapy together with total-body irradiation before a donor stem cell transplant helps stop the growth of any cancer cells that remain. It also stops the patient's immune system from rejecting the donor's stem cells. Undergoing an autologous stem cell transplant followed by a donor stem cell transplant and bortezomib may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects of two different ways of giving an autologous stem cell transplant followed by a donor stem cell transplant and bortezomib and to see how well they work in treating patients with newly diagnosed high-risk, relapsed, or refractory multiple myeloma.

Condition	Intervention	Phase
Graft Versus Host Disease Multiple Myeloma and Plasma Cell Neoplasm	Drug: bortezomib Drug: cyclosporine Drug: fludarabine phosphate Drug: melphalan Drug: mycophenolate mofetil Procedure: autologous hematopoietic stem cell transplantation Procedure: flow cytometry Procedure: fluorescence in situ hybridization Procedure: laboratory biomarker analysis Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation Procedure: polymerase chain reaction Procedure: total-body irradiation	Phase I Phase II

Genetics Home Reference related topics: aceruloplasminemia hemophilia

MedlinePlus related topics: Cancer Multiple Myeloma

Drug Information available for: Melphalan Fludarabine Fludarabine monophosphate Cyclosporin Cyclosporine Mycophenolate Mofetil Mycophenolate mofetil hydrochloride Bortezomib Melphalan hydrochloride Sarcolysin

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Open Label
Official Title:	Tandem Autologous HCT / Nonmyeloablative Allogeneic HCT From HLA-Matched Related and Unrelated Donors Followed by Bortezomib Maintenance Therapy for Patients With High-Risk Multiple Myeloma

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Progression-free survival at 2 years after the autologous HSCT (≤ 50% in historic controls) [ Designated as safety issue: No ]

Secondary Outcome Measures:

Overall survival at 2 years after the autologous HSCT [ Designated as safety issue: No ]
Non-relapse mortality at 200 days and 1 year after allogeneic non-myeloablative HSCT [ Designated as safety issue: No ]
Incidence of grades II-IV acute graft-vs-host disease (GVHD) and chronic extensive GVHD [ Designated as safety issue: No ]
Safety of bortezomib maintenance therapy after HSCT [ Designated as safety issue: Yes ]

Estimated Enrollment:	40
Study Start Date:	October 2008
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

Determine the progression-free survival of patients with newly diagnosed, high-risk, relapsed or refractory multiple myeloma 2 years after autologous hematopoietic stem cell transplantation (HSCT).
Improve progression-free survival and overall survival of patients with newly diagnosed high-risk, relapsed or refractory multiple myeloma after autologous HSCT followed by non-myeloablative allogeneic HSCT and bortezomib as maintenance therapy.

Secondary

Determine the overall survival of these patients 2 years after autologous HSCT.
Determine the incidence of non-relapse mortality at 200 days and 1 year after allogeneic non-myeloablative HSCT.
Determine the incidence of grade II-IV acute graft-vs-host disease (GVHD) and chronic extensive GVHD.
To determine the efficacy and safety of bortezomib as maintenance therapy after autologous HSCT and allogeneic non-myeloablative HSCT in these patients.

OUTLINE: This is a multicenter study.

Peripheral blood stem cell (PBSC) mobilization: Patients undergo PBSC mobilization and collection using the preferred regimens at the participating institution.
Conditioning chemotherapy and autologous hematopoietic stem cell transplantation (HSCT): Patients receive high-dose melphalan IV on day -2 followed by an autologous HSCT on day 0.
Non-myeloablative allogeneic HSCT: Beginning 40-120 days after autologous HSCT, patients receive 1 of the following regimens:
- HLA-identical related donor: Patients receive oral cyclosporine twice daily starting on days -3 to 56, and taper until day 180. Patients then undergo total-body irradiation (TBI) and non-myeloablative allogeneic HSCT on day 0. Four to six hours after completion of allogeneic HSCT, patients receive oral mycophenolate mofetil (MMF) twice daily on days 0-27.
- HLA-unrelated donor: Patients receive fludarabine phosphate IV on days -4 to -2. Patients also receive oral cyclosporine twice daily starting on days -3 to 100, and taper until day 180. Patients then undergo TBI and non-myeloablative allogeneic HSCT on day 0. Four to six hours after completion of allogeneic HSCT, patients receive oral MMF 2 times daily on days 0-27 and then 3 times daily on days 27-40 with taper of MMF on days 40-96.
Maintenance therapy: Beginning 60-120 days after allogeneic HSCT, patients receive bortezomib IV every 14 days for 9 months in the absence of disease progression or unacceptable toxicity.

Blood and bone marrow samples are collected at baseline and periodically during study for cytogenetics (PCR analysis), flow cytometry, and FISH studies.

After completion of study therapy, patients are followed every 3 months for 1 year and then annually for up to 5 years.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Meets Salmon/Durie criteria for initial diagnosis of multiple myeloma (MM)
- Newly diagnosed disease
- Relapsed or refractory disease
- High-risk disease
Must meet ≥ 1 of the following criteria A-I (A-G at time of diagnosis or pre-autograft):
- A: Any abnormal karyotype by metaphase analysis except for isolated t(11,14) and constitutional cytogenetic abnormality
- B: FISH translocation 4;14
- C: FISH translocation 14;16
- D: FISH deletion 17p
- E: β2-microglobulin > 5.5 mg/mL
- F: Cytogenetic hypodiploidy
- G: Plasmablastic morphology (≥ 2%)
- H: Recurrent or non-responsive (< partial response) MM after ≥ 2 different lines of conventional chemotherapy
- I: Progressive MM after a prior autograft (provided stored autologous CD34 cells are available)
Must have received induction therapy (e.g., vincristine, doxorubicin hydrochloride, and prednisone or thalidomide/dexamethasone) for ≥ 4 courses
- No conventional induction therapy
- May have failed prior autografts or ≥ 2 lines of prior chemotherapy
Available donor meeting any of the following criteria:
- HLA genotypically identical sibling or phenotypically matched relative
- HLA phenotypically matched unrelated donor
  - Matched for serologically recognized HLA-A and B and C antigens, and ≥ 5/6 HLA-A and B and C alleles
  - Matched for HLA-DRB1 and DQB1 at the allele level (defined by high-resolution typing)
- Not an identical twin
- Positive anti-donor cytotoxic mismatch

PATIENT CHARACTERISTICS:

Karnofsky performance status 70-100%
No life expectancy severely limited by disease other than malignancy
No HIV positivity
Not pregnant or nursing
Fertile patients must use effective contraception during and for 12 months after completion of study treatment
No active non-hematological malignancies (except nonmelanoma skin cancer) or patients with no evidence of disease who have > 20% chance of having disease recurrence within 5 years
No fungal infection and radiological progression after receipt of amphotericin B or active triazole for > 1 month
None of the following organ dysfunctions:
- Symptomatic coronary artery disease or ejection fraction < 40% (for patient with a history of anthracyclines or history of cardiac disease) or other cardiac failure requiring therapy
- DLCO < 50% and/or FEV_1 < 50% and/or receiving supplementary continuous oxygen
- Liver abnormalities including any of the following:
  - Fulminant liver failure
  - Cirrhosis of the liver with evidence of portal hypertension
  - Alcoholic hepatitis
  - Esophageal varices
  - History of bleeding esophageal varices
  - Hepatic encephalopathy
  - Uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time
  - Ascites related to portal hypertension
  - Bacterial or fungal liver abscess
  - Biliary obstruction
  - Chronic viral hepatitis with total serum bilirubin > 3 mg/dL
  - Symptomatic biliary disease
No poorly controlled hypertension and on multiple antihypertensives

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
At lease 30 days since high-dose cyclophosphamide
No other concurrent investigational agent
Concurrent palliative radiotherapy may be allowed

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00793572

Locations

United States, Washington
Fred Hutchinson Cancer Research Center	Recruiting
Seattle, Washington, United States, 98109-1024
Contact: Marco B. Mielcarek, MD 206-667-2827

Sponsors and Collaborators

Fred Hutchinson Cancer Research Center

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Marco B. Mielcarek, MD

Fred Hutchinson Cancer Research Center

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Responsible Party:	Fred Hutchinson Cancer Research Center ( Marco B. Mielcarek )
Study ID Numbers:	CDR0000619339, FHCRC-2070.00, IR-6772, MILLENNIUM-217915
Study First Received:	November 18, 2008
Last Updated:	December 9, 2008
ClinicalTrials.gov Identifier:	NCT00793572
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

graft versus host disease
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
refractory multiple myeloma

Study placed in the following topic categories:

Melphalan
Cyclosporine
Blood Protein Disorders
Graft versus host disease
Clotrimazole
Miconazole
Paraproteinemias
Hemostatic Disorders
Cyclosporins
Hemorrhagic Disorders
Multiple myeloma
Mycophenolate mofetil
Immunoproliferative Disorders

Hematologic Diseases
Blood Coagulation Disorders
Bortezomib
Vascular Diseases
Tioconazole
Fludarabine monophosphate
Multiple Myeloma
Homologous wasting disease
Graft vs Host Disease
Fludarabine
Lymphoproliferative Disorders
Neoplasms, Plasma Cell

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Antimetabolites, Antineoplastic
Neoplasms by Histologic Type
Immune System Diseases
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Enzyme Inhibitors

Immunosuppressive Agents
Pharmacologic Actions
Protease Inhibitors
Neoplasms
Antifungal Agents
Therapeutic Uses
Cardiovascular Diseases
Antirheumatic Agents
Dermatologic Agents

ClinicalTrials.gov processed this record on January 15, 2009