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

Reduced-Intensity Allogeneic HSC Transplantation From HLA-Matched Related and Unrelated Donors for Patients With Multiple Myeloma - A Multi-Center Trial

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.

Study Overview

• Status: Completed
• Conditions: Refractory Multiple Myeloma
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: fludarabine phosphate; Drug: melphalan; Radiation: total-body irradiation; Drug: mycophenolate mofetil; Drug: cyclosporine; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Torino, Italy, 10126
    • University of Torino
• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Related Donor; 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).	Other: laboratory biomarker analysis; Correlative studies; Drug: fludarabine phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; Drug: melphalan; Given IV; Other Names: Alkeran; CB-3025; L-PAM; L-phenylalanine mustard; L-Sarcolysin; Radiation: total-body irradiation; Undergo TBI; Other Names: TBI; Drug: mycophenolate mofetil; Given PO; Other Names: Cellcept; MMF; Drug: cyclosporine; Given PO; Other Names: ciclosporin; cyclosporin; cyclosporin A; CYSP; Sandimmune; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Undergo reduced-intensity allogeneic PBSCT; Procedure: peripheral blood stem cell transplantation; Undergo reduced-intensity allogeneic PBSCT; Other Names: PBPC transplantation; PBSC transplantation; peripheral blood progenitor cell transplantation; transplantation, peripheral blood stem cell
EXPERIMENTAL: Unrelated Donor; 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).	Other: laboratory biomarker analysis; Correlative studies; Drug: fludarabine phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; Drug: melphalan; Given IV; Other Names: Alkeran; CB-3025; L-PAM; L-phenylalanine mustard; L-Sarcolysin; Radiation: total-body irradiation; Undergo TBI; Other Names: TBI; Drug: mycophenolate mofetil; Given PO; Other Names: Cellcept; MMF; Drug: cyclosporine; Given PO; Other Names: ciclosporin; cyclosporin; cyclosporin A; CYSP; Sandimmune; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Undergo reduced-intensity allogeneic PBSCT; Procedure: peripheral blood stem cell transplantation; Undergo reduced-intensity allogeneic PBSCT; Other Names: PBPC transplantation; PBSC transplantation; peripheral blood progenitor cell transplantation; transplantation, peripheral blood stem cell

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	At 1 year post-transplant
Non-relapse Mortality	Early NRM will be monitored in a sequential fashion.	At day 100
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.	Up to 5 years
Incidence of Chronic (Extensive) GVHD	Number of subjects with chronic extensive GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS	Number of subjects surviving. OS will be estimated by the method of Kaplan and Meier. Confidence intervals will be estimated.	At 6 months and then every year thereafter, up to 5 years
Engraftment	Number of subjects who engrafted post-transplant. Engraftment will be monitored in a sequential fashion.	Up to 5 years
Relapse Rate	Number of subjects who relapsed after achieving CR post-transplant. Relapse rate will be summarized using cumulative incidence estimates.	Up to 5 years
Response Rate	Number of subjects who achieved CR post-transplant. Response rate will be summarized using cumulative incidence estimates.	Up to 5 years

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: October 1, 2002
• Primary Completion (ACTUAL): October 1, 2009
• Study Completion (ACTUAL): October 14, 2012

Study Registration Dates

• First Submitted: February 5, 2003
• First Submitted That Met QC Criteria: February 5, 2003
• First Posted (ESTIMATE): February 6, 2003

Study Record Updates

• Last Update Posted (ACTUAL): October 16, 2017
• Last Update Submitted That Met QC Criteria: September 14, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Melphalan; Fludarabine; Fludarabine phosphate; Mycophenolic Acid; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 1743.00 (OTHER: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2011-00386 (REGISTRY: CTRP (Clinical Trial Reporting Program))