Multiple Myeloma, Relapsed, Multiple Myeloma, Refractory to Standard Treatment
Conditions
Keywords
Multiple Myeloma, Relapsed, Refractory, Progressive Disease, Symptomatic
Brief summary
In this phase I trial, patients with relapsed or refractory multiple myeloma will receive standard autologous stem cell transplant conditioned with high dose melphalan. In addition to Melphalan, the conditioning will include targeted total marrow irradiation (TMI). This is a conventional 3+3 phase I trial with increasing doses of TMI from minimum 3Gy to Maximum 9Gy.
Detailed description
In this phase I trial, patients with relapsed or refractory multiple myeloma will receive standard high dose melphalan with autologous stem cell rescue. In addition the pre-transplant conditioning will include targeted total marrow irradiation (TMI). This conventional 3+3 phase I trial will increase the dose of TMI until the maximum tolerated dose (MTD) is reached. Initial patients enrolled will receive the lowest possible dose of 3Gy. Maximum dose will be 9Gy.
Interventions
PROCEDUREAutologous transplant
Subjects will receive standard melphalan 200mg/m\^2 (100mg/m\^2 day-2 and day-1) conditioning with autologous stem cell rescue
RADIATIONTotal Marrow Irradiation
Subjects in this trial will receive total marrow irradiation 3Gy per day for up to four days and as little as one day
DRUGMelphalan
Subjects will receive standard melphalan 200mg/m\^2 (100mg/m\^2 day-2 and day-1) conditioning therapy prior to transplant
Subjects to begin GCSF 5 μg/kg/d SC or IV on Day 5 and continue until ANC \> 1000/mm\^3 over period of 3 days.
Sponsors
University of Illinois at Chicago
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Increasing doses of Total Marrow Irradiation (TMI), 3 Gy, 6 Gy, and 9 Gy.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Patients meeting criteria for symptomatic myeloma 2. Patients who have progressive myeloma following initial induction (patients may have received any number of treatment regimens including prior autologous transplant) 3. Patient age 18-75 years at time of enrollment 4. Karnofsky performance status of ≥70 5. Cardiac function: LVEF \>40% 6. Hepatic: Bilirubin \<2x upper limit of normal and ALT and AST \< 2.5x the upper limit of normal 7. Renal: Creatinine clearance of \>30mL/min, estimated or calculated 8. Pulmonary: DLCO, FEV1, FVC \>50% of predicted (after correction for hemoglobin)
Exclusion criteria
1. Patients with diagnosis of plasma cell leukemia 2. Patients with truly non secretory myeloma (patients with light chain disease are eligible) 3. Pregnant or breast-feeding 4. Uncontrolled viral, fungal or bacterial infection Note: Infection is permitted if there is evidence of response to medication. Eligibility of HIV infected patients will be determined on a case-by-case basis. 5. Patients who have undergone prior allogeneic stem cell transplant 6. Prior solid organ transplant 7. Patients receiving prior radiation to more than 20% of bone marrow containing areas
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Gy | Up to 60 days post-transplant. | Assessing MTD of TMI of 3Gy, 6Gy and 9Gy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) and in Patients With Multiple Myeloma (Relapsed or Refractory) Undergoing Autologous Stem Cell Transplant Using the Combination of High Dose Melphalan and Total Marrow Irradiation | Up to 1 year post-transplant. | The disease status of enrolled patients will be evaluated based on the International Myeloma Working Group Criteria. Response Criteria Stringent Complete Response (sCR) in addition to CR all of the following: 1. Normal free light chain ratio (FLC) 2. Absence of clonal cells in the bone marrow by immunohistochemistry if this is performed Complete Response (CR) requires all of the following: 1. Absence of the original monoclonal paraprotein in the serum or the urine by routine electrophoresis and by immunofixation. The presence of new monoclonal bands consistent with oligoclonal immune reconstitution does not exclude CR. 2. Less than 5% plasma cells in a bone marrow aspirate and bone marrow biopsy if this is performed. 3. No increase in size or number of lytic bone lesions on radiologic investigation (development of compression fracture does not exclude CR and radiographs are not required to document CR if not clinically indicated) 4. Disappearance of soft tissue plasmacytoma |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1Total Marrow Irradiation (TMI) 3Gy 3Gy with standard high dose melphalan prior to autologous stem cell rescue
Total Marrow Irradiation: Subjects in this trial will receive total marrow irradiation 3Gy per day for up to four days and as little as one day
Melphalan: Subjects will receive standard melphalan 200mg/m\^2 (100mg/m\^2 day-2 and day-1) conditioning therapy prior to transplant
Filgrastim (G-CSF): Subjects to begin GCSF 5 μg/kg/d SC or IV on Day 5 and continue until ANC \> 1000/mm\^3 over period of 3 days.
Autologous transplant: Subjects will receive standard melphalan 200mg/m\^2 (100mg/m\^2 day-2 and day-1) conditioning with autologous stem cell rescue | 3 |
| Cohort 2 Total Marrow Irradiation (TMI) 6Gy 6Gy with standard high dose melphalan prior to autologous stem cell rescue
Total Marrow Irradiation: Subjects in this trial will receive total marrow irradiation 6Gy per day for up to four days and as little as one day
Melphalan: Subjects will receive standard melphalan 200mg/m\^2 (100mg/m\^2 day-2 and day-1) conditioning therapy prior to transplant
Filgrastim (G-CSF): Subjects to begin GCSF 5 μg/kg/d SC or IV on Day 5 and continue until ANC \> 1000/mm\^3 over period of 3 days
Autologous transplant: Subjects will receive standard melphalan 200mg/m\^2 (100mg/m\^2 day-2 and day-1) conditioning with autologous stem cell rescue | 3 |
| Cohort 3 Total Marrow Irradiation (TMI) 9Gy 9Gy with standard high dose melphalan prior to autologous stem cell rescue
Total Marrow Irradiation: Subjects in this trial will receive total marrow irradiation 9Gy per day for up to four days and as little as one day
Melphalan: Subjects will receive standard melphalan 200mg/m\^2 (100mg/m\^2 day-2 and day-1) conditioning therapy prior to transplant
Filgrastim (G-CSF): Subjects to begin GCSF 5 μg/kg/d SC or IV on Day 5 and continue until ANC \> 1000/mm\^3 over period of 3 days
Autologous transplant: Subjects will receive standard melphalan 200mg/m\^2 (100mg/m\^2 day-2 and day-1) conditioning with autologous stem cell rescue | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Cohort 1Total Marrow Irradiation (TMI) 3Gy | Cohort 2 Total Marrow Irradiation (TMI) 6Gy | Cohort 3 Total Marrow Irradiation (TMI) 9Gy | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 0 Participants | 4 Participants | 6 Participants |
| Age, Continuous | 59 Years | 68 Years | 58 Years | 61 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 5 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 4 Participants | 6 Participants |
| Region of Enrollment United States | 3 Participants | 3 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 3 | 1 / 6 |
| other Total, other adverse events | 2 / 3 | 2 / 3 | 3 / 6 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 1 / 6 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Gy
Assessing MTD of TMI of 3Gy, 6Gy and 9Gy
Time frame: Up to 60 days post-transplant.
Population: 3 participants received 3Gy, 3 participants received 6Gy and 6 participants received 9Gy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm | Maximum Tolerated Dose (MTD) of Gy | NA Participants |
Secondary
Progression Free Survival (PFS) and in Patients With Multiple Myeloma (Relapsed or Refractory) Undergoing Autologous Stem Cell Transplant Using the Combination of High Dose Melphalan and Total Marrow Irradiation
The disease status of enrolled patients will be evaluated based on the International Myeloma Working Group Criteria. Response Criteria Stringent Complete Response (sCR) in addition to CR all of the following: 1. Normal free light chain ratio (FLC) 2. Absence of clonal cells in the bone marrow by immunohistochemistry if this is performed Complete Response (CR) requires all of the following: 1. Absence of the original monoclonal paraprotein in the serum or the urine by routine electrophoresis and by immunofixation. The presence of new monoclonal bands consistent with oligoclonal immune reconstitution does not exclude CR. 2. Less than 5% plasma cells in a bone marrow aspirate and bone marrow biopsy if this is performed. 3. No increase in size or number of lytic bone lesions on radiologic investigation (development of compression fracture does not exclude CR and radiographs are not required to document CR if not clinically indicated) 4. Disappearance of soft tissue plasmacytoma
Time frame: Up to 1 year post-transplant.
Population: There was no MTD reached for any Cohort
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm | Progression Free Survival (PFS) and in Patients With Multiple Myeloma (Relapsed or Refractory) Undergoing Autologous Stem Cell Transplant Using the Combination of High Dose Melphalan and Total Marrow Irradiation | 1 Participants |
| Cohort 2 Total Marrow Irradiation (TMI) 6Gy | Progression Free Survival (PFS) and in Patients With Multiple Myeloma (Relapsed or Refractory) Undergoing Autologous Stem Cell Transplant Using the Combination of High Dose Melphalan and Total Marrow Irradiation | 1 Participants |
| Cohort 3 Total Marrow Irradiation (TMI) 9Gy | Progression Free Survival (PFS) and in Patients With Multiple Myeloma (Relapsed or Refractory) Undergoing Autologous Stem Cell Transplant Using the Combination of High Dose Melphalan and Total Marrow Irradiation | 4 Participants |