Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis

• Sponsor: University of Utah (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03303950
• Collaborator: (none)
• Enrollment: 6
• Location: 1
• Arm: 1
• Actual Duration (Months): 22.7
• Patients Per Site Per Month: 0.3

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Busulfan; Drug: Cyclophosphamide; Drug: Fludarabine; Procedure: Hematopoietic Cell Transplantation; Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate non-relapse mortality (NRM) up to day +100.

SECONDARY OBJECTIVES:

1. 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.

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Busulfan, Fludarabine, Donor Stem Cell Transplant, and Cyclophosphamide in Treating Participants With Multiple Myeloma or Myelofibrosis
• Actual Study Start Date: Mar 30, 2018
• Actual Primary Completion Date: May 14, 2019
• Actual Study Completion Date: Feb 19, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (busulfan, fludarabine, HSCT, cyclophosphamide) 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.

Drug: Busulfan; Given IV; Other Names: 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 ; Drug: Cyclophosphamide; Given IV; Other Names: (-)-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 ; Drug: Fludarabine; Given IV; Other Names: Fluradosa ; Procedure: Hematopoietic Cell Transplantation; Undergo HSCT; Other Names: HCT Hematopoietic Stem Cell Transplantation HSCT stem cell transplantation ; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Non-relapse Mortality (NRM) at Day 100 [Up to 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

1. Non-relapse Mortality (NRM) at Day 365 [Up to 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.

2. Incidence of Acute Graft Versus Host Disease (GVHD) [Up to day 365]

   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.

3. Incidence of Chronic GVHD [Up to day 365]

   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

4. Overall Survival at One Year [Up to 1 year]

   Overall survival is defined as the number of participants remaining alive up to one year following stem cell transplant.

5. Disease Free Survival at One Year [Up to 1 year]

   Disease free survival is defined as an absence of disease relapse or progression up to one year following stem cell transplant.

6. Number of Participants With Different Clinical Responses [Up to 1 year]

   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).

7. Number of Participants With Minimal Residual Disease (MRD) Response [Up to 1 year]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• University of Utah

Investigators

• Principal Investigator: Catherine Lee, MD, Huntsman Cancer Institute/ University of Utah

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 29, 2019

More Information

Publications

None provided.

• Responsible Party: University of Utah
• ClinicalTrials.gov Identifier: NCT03303950
• Other Study ID Numbers: HCI98381
• First Posted: Oct 6, 2017
• Last Update Posted: May 5, 2022
• Last Verified: May 1, 2022

• 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
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Thrombocytopenia; Primary Myelofibrosis; Cyclophosphamide; Busulfan; Fludarabine

Study Results

Participant Flow

Arm/Group Title	All Particpants - Treatment
Arm/Group Description	Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic stem cell transplant (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	All Participants - Treatment
Arm/Group Description	Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic stem cell transplant (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 83.3%
>=65 years	1 16.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.17 (6.97)
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54.5
Sex: Female, Male (Count of Participants)
Female	5 83.3%
Male	1 16.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 16.7%
Not Hispanic or Latino	5 83.3%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	6 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants - Treatment
Arm/Group Description	Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic stem cell transplant (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Measure Participants	6
Count of Participants [Participants]	1 16.7%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants - Treatment
Arm/Group Description	Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic stem cell transplant (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Measure Participants	6
Count of Participants [Participants]	2 33.3%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Particpants - Treatment
Arm/Group Description	Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic stem cell transplant (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Measure Participants	6
Count of Participants [Participants]	2 33.3%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Particpants - Treatment
Arm/Group Description	Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic stem cell transplant (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Measure Participants	6
Count of Participants [Participants]	1 16.7%

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Particpants - Treatment
Arm/Group Description	Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic stem cell transplant (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Measure Participants	6
Count of Participants [Participants]	3 50%

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Particpants - Treatment
Arm/Group Description	Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic stem cell transplant (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Measure Participants	6
Count of Participants [Participants]	3 50%

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

one participant was not evaluable due to failure to engraft (no response assessments performed)

Arm/Group Title	All Particpants - Treatment
Arm/Group Description	Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic stem cell transplant (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Measure Participants	5
Stringent Complete Response (sCR)	1 16.7%
Very Good Partial Response (VGPR)	1 16.7%
Complete Response (CR)	2 33.3%
Stable Disease (SD)	1 16.7%

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

one participant was not evaluable due to failure to engraft (no response assessments performed)

Arm/Group Title	All Particpants - Treatment
Arm/Group Description	Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic stem cell transplant (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Measure Participants	5
Count of Participants [Participants]	5 83.3%

Adverse Events

Time Frame	Adverse Events (AEs) and Serious Adverse Events (SAEs) were collected from Day -6 (6 days prior to stem cell transplant) to day +365 (365 days after stem cell transplant), approximately one year total.
Adverse Event Reporting Description	The occurrence of AEs was sought by non-directive questioning of the participant at each visit or phone contact, or when they were volunteered by the participant during or between visits, or through physical examination, laboratory test, or other assessments. Only G3-4 non-hematologic toxicities related to study treatment, engraftment failure, and SAEs were recorded and reported here. Relapse of disease or chronic or acute GVHD were not treated as AEs unless leading to a fatal outcome.
Arm/Group Title	All Participants - Treatment
Arm/Group Description	Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic stem cell transplant (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
All Cause Mortality
	All Participants - Treatment
	Affected / at Risk (%)	# Events
Total	3/6 (50%)
Serious Adverse Events
	All Participants - Treatment
	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)
Blood and lymphatic system disorders
Blood and lymphatic system disorders - Other	1/6 (16.7%)
Gastrointestinal disorders
Diarrhea	1/6 (16.7%)	2
General disorders
Death NOS	1/6 (16.7%)
Hepatobiliary disorders
Hepatobiliary disorders - Other	1/6 (16.7%)
Infections and infestations
Lung infection	2/6 (33.3%)
Sepsis	1/6 (16.7%)
Renal and urinary disorders
Acute kidney injury	1/6 (16.7%)	2
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/6 (16.7%)	3
Sinus disorder	1/6 (16.7%)
Other (Not Including Serious) Adverse Events
	All Participants - Treatment
	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)
Blood and lymphatic system disorders
Anemia	1/6 (16.7%)
Infections and infestations
Urinary tract infection	1/6 (16.7%)
Investigations
Blood bilirubin increased	1/6 (16.7%)
Creatinine increased	1/6 (16.7%)
Metabolism and nutrition disorders
Hypokalemia	2/6 (33.3%)	4
Hypophosphatemia	1/6 (16.7%)
Hypomagnesemia	1/6 (16.7%)
Nervous system disorders
Syncope	1/6 (16.7%)
Vasovagal reaction	1/6 (16.7%)
Psychiatric disorders
Insomnia	1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/6 (16.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.