Non-myeloablative Allogeneic Transplantation for the Treatment of Multiple Myeloma

Mixed chimerism transplantation is an approach to allogeneic transplants that attempts to decrease regimen-related toxicity by using non-myeloablative preparatory regimens; establish mixed chimerism using low dose total body irradiation along with immunosuppression using cyclosporine and mycophenolate mofetil; suppress graft-vs-host and host-vs-graft reactions to allow a mixed chimeric state to be established, encourage tolerance and prevent graft-vs-host disease (GvHD) during the mixed chimerism period and use donor lymphocyte infusions to convert the patient to a full chimera while developing a graft-vs-tumor effect.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma; Blood Cancer
• Intervention / Treatment: Procedure: Autologous hematopoietic cell transplant (Auto-HCT); Procedure: Allogeneic hematopoietic cell transplant (Allo-HCT); Drug: Cyclophosphamide; Drug: Filgrastim; Drug: Melphalan; Radiation: Total body irradiation (TBI); Procedure: Cyclosporine (CSP); Drug: Mycophenolate Mofetil (MMF)

Detailed Description

Participants are mobilized with cyclophosphamide 4 g/m2 and filgrastim 10 µg/kg/day for peripheral blood progenitor cell (PBPC) collection by apheresis. Transplant conditioning is high-dose melphalan 200 mg/m2, followed by PBPC infusion as melphalan rescue [ie, autologous hematopoietic cells transplant (auto-HCT)]. Post-infusion support includes filgrastim 5 µg/kg/day, starting 6 days following melphalan. Participants with stable or responsive disease at 4 weeks eligible to continue on to the planned allogenic HCT (allo-HCT). For allo-HCT, a sibling donor that is fully matched for human leukocyte antigen (HLA-matched) is identified. Participants receive a single dose of total body irradiation (TBI) 200 centigray (cGy) as well as immunosuppression with cyclosporine (CSP) 6.25 mg/kg and mycophenolate mofetil (MMF) 15 mg/kg. The HLA-matched donor begins filgrastim injections 16 µg/kg/day on day -4 continuing to Day 0, with apheresis collections on Day -1 and Day 0, to a target of > 5 x 10e6 CD34 cells/kg. Allo-HCT is infused to participant on Day 0, with premedication hydrocortisone 100 mg IV and diphenhydramine 50 mg IV. CSP will be tapered beginning Day 56 with a goal of discontinuing CSP on Day 180, adjusted as needed.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

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

PATIENT INCLUSION CRITERIA

• Multiple myeloma, early Stage II-III or relapsed / progression after initial treatment of Stage I disease
• Patient has HLA-identical sibling donor
• Age ≤ 70 years
• No prior therapy which would preclude the use of low-dose total body irradiation
• Pathology review and diagnosis confirmation by Stanford University Medical Center
• Karnofsky performance status (KPS) > 70%
• DLCO ≥ 60% predicted
• ALT and AST < 2 x upper limit of normal (ULN)
• Total bilirubin < 2 mg/dL
• Serum creatinine < 2.0, or 24-hour creatinine clearance ≥ 60 mL/min
• HIV-negative
• Signed informed consent document

PATIENT EXCLUSION CRITERIA

• Smoldering multiple myeloma; monoclonal gammopathy of unknown significance; or primary amyloidosis
• Severe psychological or medical illness
• Prior allogeneic hematopoietic cell transplantation
• Pregnant or lactating

ALLOGENEIC DONOR INCLUSION CRITERIA

• Age ≥ 17
• HIV-seronegative
• Signed informed consent document

ALLOGENEIC DONOR EXCLUSION CRITERIA

• Serious medical or psychological illness
• Pregnant or lactating
• Prior malignancies within the last 5 years, except for non-melanoma skin cancers

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Auto- then Allo-HCT; Auto-HCT mobilization is cyclophosphamide 4 g/m2 + filgrastim 10 µg/kg/day for peripheral blood progenitor cell (PBPC) collection by apheresis. Transplant conditioning is high-dose melphalan 200 mg/m2, followed by PBPC infusion as melphalan rescue [ie, autologous hematopoietic cells transplant (Auto-HCT)]. Post-infusion support is filgrastim 5 µg/kg/day, starting 6 days after melphalan. Stable/responsive disease at 4 weeks continues to allogenic HCT (Allo-HCT) from sibling donor fully-matched for human leukocyte antigen (HLA). Allo-HCT conditioning is total body irradiation (TBI) 200 centigray (cGy) + cyclosporine (CSP) 6.25 mg/kg + mycophenolate mofetil (MMF) 15 mg/kg. Donor mobilization is filgrastim 16 µg/kg/day on day -4 to Day 0; apheresis collections on Day -1 & Day 0, to a target of > 5 x 10e6 CD34 cells/kg. Allo-HCT is infused to participant on Day 0, with premedication hydrocortisone 100 mg IV & diphenhydramine 50 mg IV. CSP tapering on Day 56 to Day 180, adjusted as needed.

Procedure: Autologous hematopoietic cell transplant (Auto-HCT); The target cell dose is 2.6 x 10e6 CD34+ cells/kg; Procedure: Allogeneic hematopoietic cell transplant (Allo-HCT); The target cell dose is 5 x 10e6 CD34 cells/kg; Drug: Cyclophosphamide; Cyclophosphamide administered intravenously (IV) at 4 mg /m² mobilize peripheral blood progenitor cells (PBPC) for autologous re-infusion; Other Names: Cytoxan; Neosar; Drug: Filgrastim; Filgrastim 10 µg/kg/day to mobilize peripheral blood progenitor cells (PBPC) for autologous re-infusion (Auto-HCT); Filgrastim 5 µg/kg/day starting 6 days after melphalan (Day 4 after Auto-HCT); Filgrastim 16 µg/kg/day to mobilize donor peripheral blood progenitor cells (PBPC) for allogeneic transplant (Allo-HCT); Other Names: Neupogen; Granulocyte-colony stimulating factor (G-CSF); Drug: Melphalan; Melphalan 200 mg/m2 (high-dose) intravenously as conditioning for Auto-HCT; Other Names: Melphalan hydrochloride; Melphalan HCl; Radiation: Total body irradiation (TBI); 200 centigray (cGy) total body irradiation delivered on Day 0; Procedure: Cyclosporine (CSP); Cyclosporine administered twice-daily by mouth at a dose of 6.25 mg/kg from Day -3 through Day 56; Other Names: Cyclosporine A; Drug: Mycophenolate Mofetil (MMF); Mycophenolate mofetil will begin at 15 mg/kg twice-daily by mouth from Day 0 to Day 27; Other Names: CellCept

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free Survival (EFS)	Event-free survival (EFS) as determined for all participants who received the initial Auto-HCT treatment. "Event" was defined as any of the following within 3 years of the participant's last infusion of Auto-HCT or Allo-HCT: relapse; death; or last follow-up if there is no data to document the participant remained alive at 3 years.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse Rate	Relapse rate as determined for all participants who received the initial Auto-HCT treatment. Relapse was protocol-specified as progressive disease, indicated by an increase as compared to pre-Auto-HCT baseline, of serum or urine monoclonal protein >25%; bone marrow plasmacytosis >25%; or bone lesions on skeletal survey (any increase).	3 years
Overall Survival (OS)	Overall Survival (OS) as determined for all participants who received the initial Auto-HCT treatment, as assessed from the date of the last transplant.	3 years
Acute Graft-vs-Host-Disease (aGvHD)	Development of acute graft-vs-host-disease (aGvHD) within 6 months, for participants receiving Allo-HCT.	6 months
Chronic Graft-vs-Host-Disease (cGvHD)	Development of chronic graft versus host disease (cGvHD) within 3 years, for participants receiving Allo-HCT. Reported as "Extensive cGvHD;" "cGvHD, Not Extensive;" or "No cGvHD," as determined by investigator judgement (no protocol-specified criteria).	3 years

Collaborators and Investigators

• Sponsor: Wen-Kai Weng
• Investigators: Principal Investigator: Wen-Kai Weng, MD, Stanford University

Study record dates

Study Major Dates

• Study Start: August 1, 2000
• Primary Completion (Actual): April 1, 2009
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Actual): January 18, 2018
• Last Update Submitted That Met QC Criteria: January 16, 2018
• Last Verified: January 1, 2018

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; Neoplasms by Site; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hematologic Neoplasms; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Anti-Bacterial Agents; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Lenograstim; Melphalan; Mycophenolic Acid; Cyclosporine; Cyclosporins
• Other Study ID Numbers: IRB-13378; 75190 (Other Identifier: Stanford University Alternate IRB Approval No.); BMT109 (Other Identifier: OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No