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Reduced-Intensity Conditioning Followed By Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Multiple Myeloma

Primary Purpose

Refractory Multiple Myeloma

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
fludarabine phosphate
melphalan
total-body irradiation
mycophenolate mofetil
cyclosporine
nonmyeloablative allogeneic hematopoietic stem cell transplantation
peripheral blood stem cell transplantation
laboratory biomarker analysis
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Refractory Multiple Myeloma

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Meet Salmon and Durie criteria for initial diagnosis of MM; transplant will be offered to patients with previously treated MM who meet one of the following criteria: Patient received at least one prior autologous or syngeneic hematopoietic SCT (HSCT) and now has progressive disease (PD) (greater than 25% increase in serum or urine paraprotein levels compared to best response status after autograft or appearance of new lytic bone lesions or plasmocytomas) Patient is not able to collect autologous PBSC due to poor marrow reserve (insufficient HSC-mobilization: < 2.5 x 10^6 cluster of differentiation [CD]34+ cells/kg); or contraindications to undergoing HSC-mobilization; patient now has PD and has received at least 4 cycles of standard chemotherapy (e.g. vincristine sulfate, doxorubicin hydrochloride, and dexamethasone [VAD]) in the past Patients must have the capacity to give informed consent DONOR: Human leukocyte antigen (HLA) genotypically identical sibling or phenotypically matched relative DONOR: HLA phenotypically matched unrelated donor (according to Standard Practice HLA matching criteria) Matched for serologically recognized HLA-A or B or C antigens and at least five of six HLA-A or B or C alleles Matched for HLA DRB1 and DQB1 alleles (defined by high-resolution typing) at the allele level DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis for PBSC collection DONOR: Donor must have adequate veins for leukapheresis or agree to placement of a temporary central venous catheter Exclusion Criteria: Karnofsky score < 60% Left ventricular ejection fraction < 40% or symptomatic heart failure; ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are 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, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL,or symptomatic biliary disease Diffusion capacity of carbon monoxide (DLCO) < 50% (corrected) or receiving continuous supplemental oxygen Creatinine clearance < 40 mL/min Patients with poorly controlled hypertension Seropositive for the human immunodeficiency virus (HIV) Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence Pregnancy or breastfeeding Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment Not fully recovered from previous high-dose therapy: Persistent mucositis and gastrointestinal symptoms requiring hyperalimentation and/or intravenous hydration On steroids for autologous/syngeneic GVHD On IV antibiotics for documented infections Cytomegalovirus (CMV)-antigenemia positive On ganciclovir or foscarnet for previous CMV reactivation/infection; off of this therapy for less than two weeks despite documented CMV-antigenemia- negativity (identification [ID] should be consulted if there is persistent CMV antigenemia post autograft) Ongoing radiotherapy Patients who meet any of these criteria may be discussed with the principal investigator for recommendations as to the timing of the allograft Patients with active bacterial or fungal infections 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 Fred Hutchinson Cancer Research Center (FHCRC) criteria for stem cell donation DONOR: Age < 12 years DONOR: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion

Sites / Locations

  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  • University of Torino

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Related Donor

Unrelated Donor

Arm Description

PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors).

PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors).

Outcomes

Primary Outcome Measures

PFS
PFS will be calculated for all patients from the date of transplant until the time of progression, relapse, death, or the date the patient was last known to be in remission. Progressive disease is defined as greater than 25% increase in serum or urine M proteins compared to best response status after autologous transplant and/or appearance of new lytic bone lesions or plasmocytomas.
Non-relapse Mortality
Early NRM will be monitored in a sequential fashion.
Incidence of Acute GVHD (Grades III-IV)
Number of patients with Grade III-IV acute GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion.
Incidence of Chronic (Extensive) GVHD
Number of subjects with chronic extensive GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion.

Secondary Outcome Measures

OS
Number of subjects surviving. OS will be estimated by the method of Kaplan and Meier. Confidence intervals will be estimated.
Engraftment
Number of subjects who engrafted post-transplant. Engraftment will be monitored in a sequential fashion.
Relapse Rate
Number of subjects who relapsed after achieving CR post-transplant. Relapse rate will be summarized using cumulative incidence estimates.
Response Rate
Number of subjects who achieved CR post-transplant. Response rate will be summarized using cumulative incidence estimates.

Full Information

First Posted
February 5, 2003
Last Updated
September 14, 2017
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00054353
Brief Title
Reduced-Intensity Conditioning Followed By Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Multiple Myeloma
Official Title
Reduced-Intensity Allogeneic HSC Transplantation From HLA-Matched Related and Unrelated Donors for Patients With Multiple Myeloma - A Multi-Center Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2017
Overall Recruitment Status
Completed
Study Start Date
October 2002 (undefined)
Primary Completion Date
October 2009 (Actual)
Study Completion Date
October 14, 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I/II trial studies the side effects of giving reduced-intensity conditioning followed by donor peripheral blood stem cell transplant (PBSCT) and how well it works in treating patients with multiple myeloma (MM). Giving low doses of chemotherapy, such as fludarabine phosphate and melphalan, and total-body irradiation (TBI) before a donor PBSCT helps stop the growth of cancer cells. It may also stop 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 mycophenolate mofetil and cyclosporine after transplant may stop this from happening.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the efficacy of this approach by determining the 1-year progression-free survival (PFS) and overall survival (OS). II. To evaluate day 100 non-relapse mortality. III. To determine the incidences of grades II-IV acute graft-versus-host disease (GVHD) and chronic extensive GVHD. OUTLINE: PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or thrice daily (TID) on days 0-40 with taper to day 96 (unrelated donors). After completion of study treatment, patients are followed up at 3, 6, 12, 18, and 24 months, and then annually thereafter for 5 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Refractory Multiple Myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Related Donor
Arm Type
Experimental
Arm Description
PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors).
Arm Title
Unrelated Donor
Arm Type
Experimental
Arm Description
PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors).
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
melphalan
Other Intervention Name(s)
Alkeran, CB-3025, L-PAM, L-phenylalanine mustard, L-Sarcolysin
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
total-body irradiation
Other Intervention Name(s)
TBI
Intervention Description
Undergo TBI
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Other Intervention Name(s)
Cellcept, MMF
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
cyclosporine
Other Intervention Name(s)
ciclosporin, cyclosporin, cyclosporin A, CYSP, Sandimmune
Intervention Description
Given PO
Intervention Type
Procedure
Intervention Name(s)
nonmyeloablative allogeneic hematopoietic stem cell transplantation
Intervention Description
Undergo reduced-intensity allogeneic PBSCT
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Other Intervention Name(s)
PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell
Intervention Description
Undergo reduced-intensity allogeneic PBSCT
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
PFS
Description
PFS will be calculated for all patients from the date of transplant until the time of progression, relapse, death, or the date the patient was last known to be in remission. Progressive disease is defined as greater than 25% increase in serum or urine M proteins compared to best response status after autologous transplant and/or appearance of new lytic bone lesions or plasmocytomas.
Time Frame
At 1 year post-transplant
Title
Non-relapse Mortality
Description
Early NRM will be monitored in a sequential fashion.
Time Frame
At day 100
Title
Incidence of Acute GVHD (Grades III-IV)
Description
Number of patients with Grade III-IV acute GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion.
Time Frame
Up to 5 years
Title
Incidence of Chronic (Extensive) GVHD
Description
Number of subjects with chronic extensive GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion.
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
OS
Description
Number of subjects surviving. OS will be estimated by the method of Kaplan and Meier. Confidence intervals will be estimated.
Time Frame
At 6 months and then every year thereafter, up to 5 years
Title
Engraftment
Description
Number of subjects who engrafted post-transplant. Engraftment will be monitored in a sequential fashion.
Time Frame
Up to 5 years
Title
Relapse Rate
Description
Number of subjects who relapsed after achieving CR post-transplant. Relapse rate will be summarized using cumulative incidence estimates.
Time Frame
Up to 5 years
Title
Response Rate
Description
Number of subjects who achieved CR post-transplant. Response rate will be summarized using cumulative incidence estimates.
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Meet Salmon and Durie criteria for initial diagnosis of MM; transplant will be offered to patients with previously treated MM who meet one of the following criteria: Patient received at least one prior autologous or syngeneic hematopoietic SCT (HSCT) and now has progressive disease (PD) (greater than 25% increase in serum or urine paraprotein levels compared to best response status after autograft or appearance of new lytic bone lesions or plasmocytomas) Patient is not able to collect autologous PBSC due to poor marrow reserve (insufficient HSC-mobilization: < 2.5 x 10^6 cluster of differentiation [CD]34+ cells/kg); or contraindications to undergoing HSC-mobilization; patient now has PD and has received at least 4 cycles of standard chemotherapy (e.g. vincristine sulfate, doxorubicin hydrochloride, and dexamethasone [VAD]) in the past Patients must have the capacity to give informed consent DONOR: Human leukocyte antigen (HLA) genotypically identical sibling or phenotypically matched relative DONOR: HLA phenotypically matched unrelated donor (according to Standard Practice HLA matching criteria) Matched for serologically recognized HLA-A or B or C antigens and at least five of six HLA-A or B or C alleles Matched for HLA DRB1 and DQB1 alleles (defined by high-resolution typing) at the allele level DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis for PBSC collection DONOR: Donor must have adequate veins for leukapheresis or agree to placement of a temporary central venous catheter Exclusion Criteria: Karnofsky score < 60% Left ventricular ejection fraction < 40% or symptomatic heart failure; ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are 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, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL,or symptomatic biliary disease Diffusion capacity of carbon monoxide (DLCO) < 50% (corrected) or receiving continuous supplemental oxygen Creatinine clearance < 40 mL/min Patients with poorly controlled hypertension Seropositive for the human immunodeficiency virus (HIV) Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence Pregnancy or breastfeeding Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment Not fully recovered from previous high-dose therapy: Persistent mucositis and gastrointestinal symptoms requiring hyperalimentation and/or intravenous hydration On steroids for autologous/syngeneic GVHD On IV antibiotics for documented infections Cytomegalovirus (CMV)-antigenemia positive On ganciclovir or foscarnet for previous CMV reactivation/infection; off of this therapy for less than two weeks despite documented CMV-antigenemia- negativity (identification [ID] should be consulted if there is persistent CMV antigenemia post autograft) Ongoing radiotherapy Patients who meet any of these criteria may be discussed with the principal investigator for recommendations as to the timing of the allograft Patients with active bacterial or fungal infections 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 Fred Hutchinson Cancer Research Center (FHCRC) criteria for stem cell donation DONOR: Age < 12 years DONOR: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marco Mielcarek
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
University of Torino
City
Torino
ZIP/Postal Code
10126
Country
Italy

12. IPD Sharing Statement

Learn more about this trial

Reduced-Intensity Conditioning Followed By Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Multiple Myeloma

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