Refractory Multiple Myeloma, Stage III Multiple Myeloma, Stage II Multiple Myeloma
Conditions
Brief summary
RATIONALE: Giving chemotherapy drugs, such as melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chemoprotective drugs, such as amifostine, may protect normal cells from the side effects of chemotherapy. Giving chemotherapy with a peripheral stem cell transplant once or twice, using stem cells from the patient or an identical brother or sister, may allow more chemotherapy to be given so more cancer cells are killed. Giving maintenance therapy after a stem cell transplant may kill any cancer cells that remain. It is not yet known which dose of melphalan is more effective in treating multiple myeloma (MM). PURPOSE: This randomized phase III trial is studying two different doses of melphalan to compare how well they work when given together with amifostine followed by one or two autologous or syngeneic stem cell transplants and maintenance therapy in treating patients with stage II-III MM
Detailed description
PRIMARY OBJECTIVES: I. Compare the complete response (CR) and near CR rate in patients undergoing autologous stem cell transplant (ASCT) using melphalan 280 mg/m\^2 or melphalan 200 mg/m\^2. SECONDARY OBJECTIVES: I. Compare toxicities between patients receiving amifostine and melphalan 280 mg/m\^2 or melphalan 200 mg/m\^2. OUTLINE: Patients are randomized to 1 of 2 treatment arms. INDUCTION THERAPY: ARM I (HIGH DOSE MELPHALAN AND AMIFOSTINE): Patients receive amifostine intravenously (IV) over 3-5 minutes on days -3 and -2 followed by high-dose melphalan IV over 15-30 minutes on day 2. ARM II (LOW DOSE MELPHALAN AND AMIFOSTINE): Patients receive amifostine as in arm I and melphalan as in arm I at a lower dose. AUTOLOGOUS OR SYNGENEIC PERIPHERAL BLOOD STEM CELL TRANSPLANTATION (PBSCT): At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0. Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT. Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy. After completion of study treatment, patients are followed up every 3 months for 5 years.
Interventions
DRUGmelphalan
Given IV
DRUGamifostine trihydrate
Given IV
PROCEDUREperipheral blood stem cell transplantation
Undergo PBSCT
GENETICfluorescence in situ hybridization
Correlative study
PROCEDUREbone marrow ablation with stem cell support
Undergo transplant
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients who have MM undergoing autologous or syngeneic hematopoietic transplantation * Patients must meet Salmon and Durie criteria for initial diagnosis of MM * Transplant will be offered to patients with stage II or III MM * Measurable disease, defined as serum monoclonal protein \>= 0.2 g/dl or Bence Jones protein \>= 200 mg/24 h * Karnofsky \>= 70 or Eastern Cooperative Oncology Group (ECOG) 0-2 * Life expectancy is not severely limited by concomitant illness * Left ventricular ejection fraction \>= 50% * No uncontrolled arrhythmias or symptomatic cardiac disease * Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and diffusion capacity of carbon monoxide (DLCO) \>= 50% * No symptomatic pulmonary disease * Human immunodeficiency virus (HIV) negative * Bilirubin \< 2 mg/dl * Serum glutamic pyruvate transaminase (SGPT) \< 2.5 x normal * Creatinine clearance \>= 60 cc/min, estimated or measured * Signed informed consent
Exclusion criteria
* Pregnant or lactating females * Uncontrolled infection * Planned tandem autologous/reduced intensity allograft * Insufficient PBSC for an autologous transplant (\< 3.0 x 10\^6 CD34+ cells/kg total) * Prior autologous transplant * Non-secretory myeloma and patients who are in a complete response or near complete response after conventional therapy * Patients unwilling to practice adequate forms of contraception if clinically indicated * Male patients on study need to be consulted to use latex condoms, even if they have had a vasectomy, every time they have sex with a woman who is able to have children * Patients with history of seizures * Patients receiving antihypertensive therapy that cannot be stopped for 24 hours preceding amifostine treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CR and Near CR Rates | Up to 120 days after transplant | Per modified European Group for Blood and Marrow Transplant (EBMT) response criteria for definition of response in patients with multiple myeloma treated by high-dose therapy and stem cell transplantation: Complete Response (CR): Complete disappearance of all clinically measurable disease, complete response requires negative tests for monoclonal proteins in serum and urine by immunofixation, no monoclonal plasma cells in marrow specimen by flow cytometry and no evidence of progressive bone disease by skeletal survey. Near Complete Response (nCR): Less than 0.1 gram/dL monoclonal protein detectable in serum by standard protein electrophoresis and less than 50 mg monoclonal protein detectable in urine on 24 hour collection. Less than 5% monoclonal plasma cells detectable in bone marrow by immunohistochemistry. No evidence of progressive bone disease by skeletal survey. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Toxicities Between Melphalan 280 mg/m^2 or Melphalan 200 mg/m^2 | Up to day 56 after transplant | Number of Grade 3-4 adverse events observed in each group from enrollment through the Day 80-120 evaluation. Grade 3-4 events are defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. |
Countries
United States
Participant flow
Recruitment details
This trial opened for enrollment September 2005 and completed enrollment in June 2012. Patients were enrolled at 4 centers: University of Washington, Seattle, WA; Veteran's Administration Puget Sound Healthcare Administration, Seattle, WA; Cedars Sinai Medical Center, Los Angeles, CA; and James Wilmot Cancer Center in Rochester, NY.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant) INDUCTION THERAPY:
Patients receive amifostine IV over 3-5 minutes on days -3 and -2 followed by high-dose melphalan IV over 15-30 minutes on day 2.
AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0.
Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT.
Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy. | 66 |
| Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant) INDUCTION THERAPY:
Patients receive amifostine as in arm I and melphalan as in arm I at a lower dose.
AUTOLOGOUS OR SYNGENEIC PBSCT: At least 20 hours after completion of melphalan, patients undergo autologous or syngeneic PBSCT on day 0.
Patients undergo restaging of the disease between days 80-90. Patients with progressive disease are removed from the study. Patients who achieve a CR or near-CR can proceed to optional maintenance therapy. Patients who do not achieve a CR or near-CR may undergo additional induction therapy as in arm I followed by a second autologous or syngeneic PBSCT.
Patients again undergo restaging of the disease 80-90 days later. Patients with progressive disease are removed from the study. Patients without progressive disease can proceed to maintenance therapy. | 64 |
| Total | 130 |
Baseline characteristics
| Characteristic | Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant) | Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 9 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 57 Participants | 55 Participants | 112 Participants |
| Region of Enrollment United States | 66 participants | 64 participants | 130 participants |
| Sex: Female, Male Female | 23 Participants | 23 Participants | 46 Participants |
| Sex: Female, Male Male | 43 Participants | 41 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 66 | 7 / 64 |
| serious Total, serious adverse events | 0 / 66 | 0 / 64 |
Outcome results
Primary
CR and Near CR Rates
Per modified European Group for Blood and Marrow Transplant (EBMT) response criteria for definition of response in patients with multiple myeloma treated by high-dose therapy and stem cell transplantation: Complete Response (CR): Complete disappearance of all clinically measurable disease, complete response requires negative tests for monoclonal proteins in serum and urine by immunofixation, no monoclonal plasma cells in marrow specimen by flow cytometry and no evidence of progressive bone disease by skeletal survey. Near Complete Response (nCR): Less than 0.1 gram/dL monoclonal protein detectable in serum by standard protein electrophoresis and less than 50 mg monoclonal protein detectable in urine on 24 hour collection. Less than 5% monoclonal plasma cells detectable in bone marrow by immunohistochemistry. No evidence of progressive bone disease by skeletal survey.
Time frame: Up to 120 days after transplant
Population: Per protocol, patients who completed the day 80-120 evaluation assessments.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant) | CR and Near CR Rates | 39 percentage of participants |
| Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant) | CR and Near CR Rates | 22 percentage of participants |
Secondary
Relative Toxicities Between Melphalan 280 mg/m^2 or Melphalan 200 mg/m^2
Number of Grade 3-4 adverse events observed in each group from enrollment through the Day 80-120 evaluation. Grade 3-4 events are defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Time frame: Up to day 56 after transplant
Population: Patients who were treated per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (High Dose Melphalan, Amifostine Trihydrate, Transplant) | Relative Toxicities Between Melphalan 280 mg/m^2 or Melphalan 200 mg/m^2 | 20 Grade 3-4 adverse events |
| Arm II (Low Dose Melphalan, Amifostine Trihydrate, Transplant) | Relative Toxicities Between Melphalan 280 mg/m^2 or Melphalan 200 mg/m^2 | 10 Grade 3-4 adverse events |