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Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis

Primary Purpose

Anemia, ASXL1 Gene Mutation, EZH2 Gene Mutation

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Busulfan
Cyclophosphamide
Fludarabine
Hematopoietic Cell Transplantation
Laboratory Biomarker Analysis
Sponsored by
University of Utah
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Anemia

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Participants must have one of the following diagnoses of multiple myeloma (MM) or primary/secondary myelofibrosis (MF)

  • Participants must have histologically documented multiple myeloma (MM)

    • Participants in early relapse (less than 24 months from initiation of systemic anti-myeloma therapy which may include single or planned tandem autologous transplant) after primary therapy that included and autologous HSCT; OR
    • Later stage; OR
    • High risk factors defined by the presence of any one of the following detected at any time prior to enrollment: deletion of chromosome 13 by conventional cytogenetics, hypodiploidy, abnormality in chromosome 1 (1q amplification or 1p deletion), t(4;14), t(14;16), t(14;20) or deletion of 17p by fluorescence in situ hybridization (FISH) or conventional karyotyping; high risk criteria based on commercially available gene expression profiling; OR
    • Extramedullary disease, plasma cell leukemia or high lactate dehydrogenase (LDH)

  • Participants must have histologically documented myelofibrosis (MF)

    • Participants with Dynamic International Prognostic Scoring System (DIPSS) plus intermediate stage 2 or higher risk MF; OR

    • Subset of intermediate stage 1 participants; defined by:

      • Poor-risk molecular profile (triple negative: JAK2, CALR, MPL); OR
      • Presence of any of the following mutations: ASXL1, SRSF2, EZH2, IDH1/2; OR
      • Severe thrombocytopenia, severe anemia, high peripheral blood blasts percentage; OR
      • Unfavorable cytogenetic abnormalities (rearrangements of chromosome 5 or 7 or >= 3 abnormalities
  • Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines
  • DONOR: A related donor - fully matched
  • DONOR: A related donor - haploidentical
  • DONOR: An unrelated donor - fully matched
  • DONOR: An unrelated donor -9/10 matched

Exclusion Criteria:

  • Cardiac-left ventricular ejection fraction < 40%, symptomatic coronary artery disease, or uncontrolled arrhythmias
  • Pulmonary-forced expiratory volume at one second (FEV1) or diffusion capacity of lung for carbon dioxide (DLCO) < 40% or history of chronic use of supplemental oxygen. Temporary use of supplemental oxygen at the time of screening or registration is allowed if the investigator feels that the underlying cause of requiring oxygen is reversible by the time treatment begins.
  • Renal-calculated or measured glomerular filtration rate (GFR) < 30 ml/min, dialysis-dependent, or history of renal transplant
  • Hepatic-bilirubin > 2 X upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) > 2.5 X ULN or cirrhosis
  • Participants with active or uncontrolled bacterial, viral, or fungal infections requiring systemic therapy
  • Pregnant women, nursing mothers or women of child-bearing potential who are unwilling to use medically accepted methods of contraception
  • Male and female subjects not willing to agree to medically accepted methods of contraception

Sites / Locations

  • Huntsman Cancer Institute/University of Utah

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (busulfan, fludarabine, HSCT, cyclophosphamide)

Arm Description

Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo HSCT on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.

Outcomes

Primary Outcome Measures

Non-relapse Mortality (NRM) at Day 100
NRM is defined as death due to GVHD, infections, sepsis, organ (lung, liver, kidney) toxicity. Death from underlying disease (i.e. progression or relapse) is not considered NRM.

Secondary Outcome Measures

Non-relapse Mortality (NRM) at Day 365
NRM is defined as death due to GVHD, infections, sepsis, organ (lung, liver, kidney) toxicity. Death from underlying disease (i.e. progression or relapse) is not considered NRM.
Incidence of Acute Graft Versus Host Disease (GVHD)
Cases of acute graft versus host disease (GVHD) will be diagnosed by the treating physician and will be reported as a count of participants with acute GVHD.
Incidence of Chronic GVHD
Chronic GVHD will be assessed based on criteria established by the National Institutes of Health Consensus Development Project in 2005, and recently updated in 2014. This will be reported as a count of participants diagnosed with chronic GVHD
Overall Survival at One Year
Overall survival is defined as the number of participants remaining alive up to one year following stem cell transplant.
Disease Free Survival at One Year
Disease free survival is defined as an absence of disease relapse or progression up to one year following stem cell transplant.
Number of Participants With Different Clinical Responses
Clinical Responses were determined by disease-specific criteria taking into account multiple clinical and molecular markers. Multiple Myeloma (MM) response was determined using International Myeloma Working Group (IMWG) consensus criteria for response. Participants with MM had either Stringent Complete Response (sCR) or Very Good Partial Response (VGPR). Myelofibrosis (MF) response was determined using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus criteria. Participants with MF had either Complete Response (CR) or Stable Disease (SD) (also referred to in the protocol as no response).
Number of Participants With Minimal Residual Disease (MRD) Response
After bone marrow transplant, bone marrow was collected every 3-6 months (as clinically indicated per treating investigator) for up to one year after bone marrow transplant. Bone marrow was evaluated by a clinical pathologist for any evidence of multiple myeloma (MM) or myelofibrosis (MF). Evidence of MM or MF in the bone marrow is referred to as minimal residual disease (MRD). A participant with evidence of MRD is MRD-positive. A participant with no evidence of MRD is MRD-negative, which is considered an MRD response. This outcome reports the number participants with MRD responses any time between bone marrow transplant up to one year of follow-up.

Full Information

First Posted
October 2, 2017
Last Updated
May 3, 2022
Sponsor
University of Utah
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1. Study Identification

Unique Protocol Identification Number
NCT03303950
Brief Title
Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis
Official Title
Busulfan, Fludarabine, Donor Stem Cell Transplant, and Cyclophosphamide in Treating Participants With Multiple Myeloma or Myelofibrosis
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Terminated
Why Stopped
Slow accrual
Study Start Date
March 30, 2018 (Actual)
Primary Completion Date
May 14, 2019 (Actual)
Study Completion Date
February 19, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Utah

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial studies how well busulfan, fludarabine, donor stem cell transplant, and cyclophosphamide in treating participants with multiple myeloma or myelofibrosis. Drugs used in chemotherapy, such as busulfan, fludarabine, and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the participant they may help the participant's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving busulfan and fludarabine before and cyclophosphamide after donor stem cell may work better in treating participants with multiple myeloma or myelofibrosis.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate non-relapse mortality (NRM) up to day +100. SECONDARY OBJECTIVES: I. To evaluate non-relapse mortality (NRM) up to day +365. II. To evaluate the incidence of acute graft versus host disease (GVHD) and chronic GVHD up to day +365 post-transplant. III. To evaluate the overall survival and disease free survival up to 1 year. IV. To evaluate clinical response and molecular response (complete response and partial response) up to 1 year. OUTLINE: Participants receive busulfan intravenously (IV) over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic cell transplantation (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4. After completion of study treatment, participants are followed up for 1 year.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anemia, ASXL1 Gene Mutation, EZH2 Gene Mutation, IDH1 Gene Mutation, IDH2 Gene Mutation, Plasma Cell Myeloma, Primary Myelofibrosis, Recurrent Plasma Cell Myeloma, Secondary Myelofibrosis, Thrombocytopenia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (busulfan, fludarabine, HSCT, cyclophosphamide)
Arm Type
Experimental
Arm Description
Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo HSCT on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fluradosa
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Hematopoietic Cell Transplantation
Other Intervention Name(s)
HCT, Hematopoietic Stem Cell Transplantation, HSCT, stem cell transplantation
Intervention Description
Undergo HSCT
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Non-relapse Mortality (NRM) at Day 100
Description
NRM is defined as death due to GVHD, infections, sepsis, organ (lung, liver, kidney) toxicity. Death from underlying disease (i.e. progression or relapse) is not considered NRM.
Time Frame
Up to day 100
Secondary Outcome Measure Information:
Title
Non-relapse Mortality (NRM) at Day 365
Description
NRM is defined as death due to GVHD, infections, sepsis, organ (lung, liver, kidney) toxicity. Death from underlying disease (i.e. progression or relapse) is not considered NRM.
Time Frame
Up to day 365
Title
Incidence of Acute Graft Versus Host Disease (GVHD)
Description
Cases of acute graft versus host disease (GVHD) will be diagnosed by the treating physician and will be reported as a count of participants with acute GVHD.
Time Frame
Up to day 365
Title
Incidence of Chronic GVHD
Description
Chronic GVHD will be assessed based on criteria established by the National Institutes of Health Consensus Development Project in 2005, and recently updated in 2014. This will be reported as a count of participants diagnosed with chronic GVHD
Time Frame
Up to day 365
Title
Overall Survival at One Year
Description
Overall survival is defined as the number of participants remaining alive up to one year following stem cell transplant.
Time Frame
Up to 1 year
Title
Disease Free Survival at One Year
Description
Disease free survival is defined as an absence of disease relapse or progression up to one year following stem cell transplant.
Time Frame
Up to 1 year
Title
Number of Participants With Different Clinical Responses
Description
Clinical Responses were determined by disease-specific criteria taking into account multiple clinical and molecular markers. Multiple Myeloma (MM) response was determined using International Myeloma Working Group (IMWG) consensus criteria for response. Participants with MM had either Stringent Complete Response (sCR) or Very Good Partial Response (VGPR). Myelofibrosis (MF) response was determined using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus criteria. Participants with MF had either Complete Response (CR) or Stable Disease (SD) (also referred to in the protocol as no response).
Time Frame
Up to 1 year
Title
Number of Participants With Minimal Residual Disease (MRD) Response
Description
After bone marrow transplant, bone marrow was collected every 3-6 months (as clinically indicated per treating investigator) for up to one year after bone marrow transplant. Bone marrow was evaluated by a clinical pathologist for any evidence of multiple myeloma (MM) or myelofibrosis (MF). Evidence of MM or MF in the bone marrow is referred to as minimal residual disease (MRD). A participant with evidence of MRD is MRD-positive. A participant with no evidence of MRD is MRD-negative, which is considered an MRD response. This outcome reports the number participants with MRD responses any time between bone marrow transplant up to one year of follow-up.
Time Frame
Up to 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Participants must have one of the following diagnoses of multiple myeloma (MM) or primary/secondary myelofibrosis (MF) Participants must have histologically documented multiple myeloma (MM) Participants in early relapse (less than 24 months from initiation of systemic anti-myeloma therapy which may include single or planned tandem autologous transplant) after primary therapy that included and autologous HSCT; OR Later stage; OR High risk factors defined by the presence of any one of the following detected at any time prior to enrollment: deletion of chromosome 13 by conventional cytogenetics, hypodiploidy, abnormality in chromosome 1 (1q amplification or 1p deletion), t(4;14), t(14;16), t(14;20) or deletion of 17p by fluorescence in situ hybridization (FISH) or conventional karyotyping; high risk criteria based on commercially available gene expression profiling; OR Extramedullary disease, plasma cell leukemia or high lactate dehydrogenase (LDH) Participants must have histologically documented myelofibrosis (MF) Participants with Dynamic International Prognostic Scoring System (DIPSS) plus intermediate stage 2 or higher risk MF; OR Subset of intermediate stage 1 participants; defined by: Poor-risk molecular profile (triple negative: JAK2, CALR, MPL); OR Presence of any of the following mutations: ASXL1, SRSF2, EZH2, IDH1/2; OR Severe thrombocytopenia, severe anemia, high peripheral blood blasts percentage; OR Unfavorable cytogenetic abnormalities (rearrangements of chromosome 5 or 7 or >= 3 abnormalities Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines DONOR: A related donor - fully matched DONOR: A related donor - haploidentical DONOR: An unrelated donor - fully matched DONOR: An unrelated donor -9/10 matched Exclusion Criteria: Cardiac-left ventricular ejection fraction < 40%, symptomatic coronary artery disease, or uncontrolled arrhythmias Pulmonary-forced expiratory volume at one second (FEV1) or diffusion capacity of lung for carbon dioxide (DLCO) < 40% or history of chronic use of supplemental oxygen. Temporary use of supplemental oxygen at the time of screening or registration is allowed if the investigator feels that the underlying cause of requiring oxygen is reversible by the time treatment begins. Renal-calculated or measured glomerular filtration rate (GFR) < 30 ml/min, dialysis-dependent, or history of renal transplant Hepatic-bilirubin > 2 X upper limit of normal (ULN) Alanine aminotransferase (ALT) > 2.5 X ULN or cirrhosis Participants with active or uncontrolled bacterial, viral, or fungal infections requiring systemic therapy Pregnant women, nursing mothers or women of child-bearing potential who are unwilling to use medically accepted methods of contraception Male and female subjects not willing to agree to medically accepted methods of contraception
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Catherine Lee, MD
Organizational Affiliation
Huntsman Cancer Institute/ University of Utah
Official's Role
Principal Investigator
Facility Information:
Facility Name
Huntsman Cancer Institute/University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States

12. IPD Sharing Statement

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Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis

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