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
Conditions
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.
Interventions
DRUGBusulfan
Given IV
DRUGCyclophosphamide
Given IV
DRUGFludarabine
Given IV
PROCEDUREHematopoietic Cell Transplantation
Undergo HSCT
OTHERLaboratory Biomarker Analysis
Correlative studies
Sponsors
University of Utah
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
| 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. |
| 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). |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants - Treatment 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. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | All Participants - Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 54.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 6 |
| other Total, other adverse events | 5 / 6 |
| serious Total, serious adverse events | 4 / 6 |
Outcome results
Primary
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.
Time frame: Up to day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants - Treatment | Non-relapse Mortality (NRM) at Day 100 | 1 Participants |
Secondary
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.
Time frame: Up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants - Treatment | Disease Free Survival at One Year | 3 Participants |
Secondary
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.
Time frame: Up to day 365
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants - Treatment | Incidence of Acute Graft Versus Host Disease (GVHD) | 2 Participants |
Secondary
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
Time frame: Up to day 365
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants - Treatment | Incidence of Chronic GVHD | 1 Participants |
Secondary
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.
Time frame: Up to day 365
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants - Treatment | Non-relapse Mortality (NRM) at Day 365 | 2 Participants |
Secondary
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).
Time frame: Up to 1 year
Population: one participant was not evaluable due to failure to engraft (no response assessments performed)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants - Treatment | Number of Participants With Different Clinical Responses | Stringent Complete Response (sCR) | 1 Participants |
| All Participants - Treatment | Number of Participants With Different Clinical Responses | Very Good Partial Response (VGPR) | 1 Participants |
| All Participants - Treatment | Number of Participants With Different Clinical Responses | Complete Response (CR) | 2 Participants |
| All Participants - Treatment | Number of Participants With Different Clinical Responses | Stable Disease (SD) | 1 Participants |
Secondary
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.
Time frame: Up to 1 year
Population: one participant was not evaluable due to failure to engraft (no response assessments performed)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants - Treatment | Number of Participants With Minimal Residual Disease (MRD) Response | 5 Participants |
Secondary
Overall Survival at One Year
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants - Treatment | Overall Survival at One Year | 3 Participants |