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

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ClinicalTrials.gov Identifier: NCT00793572
Recruitment Status : Completed
First Posted : November 19, 2008
Results First Posted : May 18, 2017
Last Update Posted : January 22, 2020
Sponsor:
Collaborators:
Millennium Pharmaceuticals, Inc.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Marco Mielcarek, Fred Hutchinson Cancer Research Center

Brief Summary:
This phase II trial studies the side-effects and anti-cancer effects of giving an autologous or syngeneic stem cell transplant followed by an allogeneic donor stem cell transplant and bortezomib. Patients treated on this trial have newly diagnosed high-risk, relapsed, or refractory multiple myeloma (MM). Giving chemotherapy before an autologous stem cell transplant slows or stops the growth of cancer cells by preventing them from dividing or killing them. Stem cells that were harvested earlier from the patient's blood and frozen are then returned to the patient to replace the blood-forming cells that were destroyed by chemotherapy. Giving chemotherapy and total-body irradiation before an allogeneic donor stem cell transplant also prevents the patient's immune system from rejecting the donor's stem cells. Undergoing an autologous or syngeneic stem cell transplantation followed by an allogeneic donor stem cell transplant and bortezomib may be overall more effective in killing cancer cells.

Condition or disease Intervention/treatment Phase
Refractory Plasma Cell Myeloma Procedure: Autologous Hematopoietic Stem Cell Transplantation Drug: Bortezomib Drug: Cyclosporine Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Drug: Melphalan Drug: Mycophenolate Mofetil Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation Procedure: Peripheral Blood Stem Cell Transplantation Procedure: Syngeneic Bone Marrow Transplantation Radiation: Total-Body Irradiation Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Progression-free survival (PFS) at 2 years after the autograft (=< 50% in historic controls).

SECONDARY OBJECTIVES:

I. Overall survival (OS) at 2 years after the autograft.

II. Non-relapse mortality (NRM) at 200 days and 1 year after allograft.

III. Incidence of grades II-IV acute graft-versus-host-disease (GVHD) and chronic extensive GVHD.

IV. Safety of bortezomib maintenance therapy after stem cell transplantation.

OUTLINE:

PERIPHERAL BLOOD STEM CELL (PBSC) MOBILIZATION: Patients undergo PBSC mobilization and collection using the preferred regimens at the participating institution.

CONDITIONING CHEMOTHERAPY AND AUTOLOGOUS OR SYNGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT): Patients receive high-dose melphalan intravenously (IV) on day -2 followed by an autologous or syngeneic HSCT on day 0.

NON-MYELOABLATIVE ALLOGENEIC HSCT: Beginning 40-180 days after autologous HSCT, patients receive 1 of the following regimens:

  1. HLA-IDENTICAL RELATED DONOR: Patients receive cyclosporine IV or orally (PO) twice daily (BID) 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 mycophenolate mofetil (MMF) PO BID on days 0-27.
  2. HLA-UNRELATED DONOR: Patients receive fludarabine phosphate IV on days -4 to -2. Patients also receive cyclosporine IV or PO BID 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 MMF PO thrice daily (TID) on days 0-27 and then BID on days 27-40 with taper of MMF on days 40-96.

MAINTENANCE THERAPY: Beginning 60-120 days after allogeneic HSCT, patients receive bortezomib subcutaneously (SC) on days 1 and 4 of 14-day cycles for 9 months or for up to 18 cycles in the absence of disease progression or unacceptable toxicity.

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 2008
Actual Primary Completion Date : October 2016
Actual Study Completion Date : October 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma
Drug Information available for: Bortezomib

Arm Intervention/treatment
Experimental: Tandem Auto-/Nonmyeloablative Allo-HCT and Maintenance Therapy
See Detailed Description
Procedure: Autologous Hematopoietic Stem Cell Transplantation
Undergo transplantation
Other Name: Autologous Stem Cell Transplantation

Drug: Bortezomib
Given SC
Other Names:
  • [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
  • LDP 341
  • MLN341
  • PS-341
  • PS341
  • Velcade

Drug: Cyclosporine
Given IV
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Neoral
  • OL 27-400
  • Sandimmun
  • Sandimmune
  • SangCya

Drug: Cyclosporine
Given PO
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Neoral
  • OL 27-400
  • Sandimmun
  • Sandimmune
  • SangCya

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • Oforta
  • SH T 586

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Melphalan
Given IV
Other Names:
  • Alanine Nitrogen Mustard
  • CB-3025
  • L-PAM
  • L-Phenylalanine Mustard
  • L-Sarcolysin
  • L-Sarcolysin Phenylalanine mustard
  • L-Sarcolysine
  • Melphalanum
  • Phenylalanine Mustard
  • Phenylalanine Nitrogen Mustard
  • Sarcoclorin
  • Sarkolysin
  • WR-19813

Drug: Mycophenolate Mofetil
Given PO
Other Names:
  • Cellcept
  • MMF

Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo transplantation
Other Names:
  • Non-myeloablative allogeneic transplant
  • Nonmyeloablative Stem Cell Transplantation
  • NST

Procedure: Peripheral Blood Stem Cell Transplantation
Undergo transplantation
Other Names:
  • PBPC transplantation
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplantation

Procedure: Syngeneic Bone Marrow Transplantation
Undergo transplantation

Radiation: Total-Body Irradiation
Undergo radiotherapy
Other Names:
  • TOTAL BODY IRRADIATION
  • Whole-Body Irradiation




Primary Outcome Measures :
  1. Number of Patients Surviving Progression-free [ Time Frame: At 2 years after the autograft ]

    Number of subjects surviving without progressive disease post-transplant.

    Progressive disease criteria:

    1. Greater than 25% increase in serum (absolute increase must be ≥0.5 g/dL) or urine (absolute increase must be ≥200 mg/24h) M proteins compared to best response status after autologous transplant.
    2. Appearance of new lytic bone lesions or plasmacytomas.


Secondary Outcome Measures :
  1. Number of Patients With Grade II-IV Acute GVHD [ Time Frame: 100 days post allo transplant ]

    Number of patients who developed acute GVHD post allogeneic transplant.

    aGVHD Stages

    Skin:

    1. - a maculopapular eruption involving < 25% BSA
    2. - a maculopapular eruption involving 25 - 50% BSA
    3. - generalized erythroderma
    4. - generalized erythroderma w/ bullous formation and often w/ desquamation

    Liver:

    1. - bilirubin 2.0 - 3.0 mg/100 mL
    2. - bilirubin 3 - 5.9 mg/100 mL
    3. - bilirubin 6 - 14.9 mg/100 mL
    4. - bilirubin > 15 mg/100 mL

    Gut:

    Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall.

    aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death


  2. Number of Patients With Chronic GVHD [ Time Frame: 1 year post allo ]
    Number of subjects with classic chronic or chronic extensive GVHD post allogeneic transplant.

  3. Number of Patients With Toxicities Related to Bortezomib Maintenance Therapy [ Time Frame: Up to 100 days after the autograft or allograft ]
    Number of subjects with toxicities related to bortezomib maintenance therapy post-transplant.

  4. Number of Patients With Non-relapse Mortality [ Time Frame: 200 and 365 days after allo ]
    Number of subjects with non-relapse mortalities post allogeneic transplant.

  5. Number of Patients Surviving Overall [ Time Frame: At 2 years after the autograft ]
    Number of subjects surviving two years post autologous 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.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Newly diagnosed patients must have received induction therapy (e.g., vincristine, doxorubicin, dexamethasone [VAD], thalidomide/dexamethasone) for a minimum of 4 cycles
  • Must have the capacity to give informed consent
  • Must have an human leukocyte antigen (HLA) genotypically identical sibling or a phenotypically matched relative or, at a minimum, a high likelihood of identifying an HLA-matched unrelated donor; the determination of availability of a suitable unrelated donor may be based on a World-Book search
  • In addition, patients must meet at least one of the 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) Fluorescence in situ hybridization (FISH) translocation 4;14
    • C) FISH translocation 14;16
    • D) FISH deletion 17p
    • E) Beta2-microglobulin > 5.5 mg/L
    • F) Cytogenetic hypodiploidy
    • G) Plasmablastic morphology (>= 2%)
  • DONOR: HLA genotypically identical sibling or phenotypically matched relative OR
  • DONOR: HLA phenotypically matched unrelated donor (according to Standard Practice HLA matching criteria, Grade #2.1)

    • Matched HLA-A, B, C, DRB1, and DQB1 alleles by high resolution typing.
    • Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing

Exclusion Criteria:

  • Recurrent or non-responsive (less than partial response [PR]) MM after at least two different lines of conventional chemotherapy
  • Progressive MM after a previous autograft
  • Life expectancy severely limited by disease other than malignancy
  • Seropositive for the human immunodeficiency virus (HIV)
  • Females who are pregnant or breastfeeding
  • Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
  • Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • Patients with fungal infection and radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
  • Patients with the following organ dysfunction:

    • Symptomatic coronary artery disease or ejection fraction < 40% or other cardiac failure requiring therapy; myocardial infarction within 6 months prior to enrollment or has New York Heart 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
    • Ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease
    • Diffusing lung capacity for carbon monoxide (DLCO) < 50%, forced expiratory volume in 1 second (FEV) < 50% and/or receiving supplementary continuous oxygen; the Fred Hutchinson Cancer Research Center (FHCRC) principle investigator (PI) of the study must approve of enrollment of all patients with pulmonary nodules
    • Liver function abnormalities: Patient with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; the patient will be excluded if he/she is found to have fulminant liver failure; cirrhosis of the liver with evidence of portal hypertension; alcoholic hepatitis; esophageal varices; a 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; and symptomatic biliary disease;
    • Karnofsky score < 70% for adult patients
  • Patient with poorly controlled hypertension and on multiple antihypertensives
  • Patients with current >= grade 2 peripheral neuropathy
  • Patient has an active bacterial or fungal infection unresponsive to medical therapy
  • DONOR: Identical twin
  • DONOR: Donors unwilling to donate PBSC
  • DONOR: Pregnancy
  • DONOR: Infection with HIV
  • DONOR: Inability to achieve adequate venous access
  • DONOR: Known allergy to G-CSF
  • DONOR: Current serious systemic illness
  • DONOR: Failure to meet FHCRC criteria for stem cell donation
  • DONOR: Age < 12 years
  • DONOR: A positive anti-donor cytotoxic crossmatch
  • DONOR: Patient and donor pairs must not be homozygous at mismatched allele

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 ClinicalTrials.gov identifier (NCT number): NCT00793572


Locations
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United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Millennium Pharmaceuticals, Inc.
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Marco Mielcarek Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Marco Mielcarek, Principal Investigator, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00793572    
Other Study ID Numbers: 2070.00
NCI-2009-01473 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MPI X05251
2070.00 ( Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
First Posted: November 19, 2008    Key Record Dates
Results First Posted: May 18, 2017
Last Update Posted: January 22, 2020
Last Verified: January 2020
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Cyclosporine
Mycophenolic Acid
Fludarabine
Bortezomib
Melphalan
Fludarabine phosphate
Mechlorethamine
Nitrogen Mustard Compounds
Cyclosporins
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents