Multiple Myeloma
Conditions
Keywords
autologous stem cell transplantation
Brief summary
This is a research study for newly diagnosed multiple myeloma or multiple myeloma has returned (relapsed). Multiple myeloma is a type of cancer that begins in white blood cells called plasma cells. Plasma cells make proteins that help fight infections. Current therapy for multiple myeloma includes high dose chemotherapy and autologous (patient's own cells) stem cell transplantation. There will be two parts (or phases) to this study: The purpose of the first part is to find the highest dose of a drug called lenalidomide (Revlimid®) that can be given in combination with high dose melphalan without causing severe adverse events. The purpose of the second part is to find out the effects of this treatment (good and bad) on multiple myeloma patients.
Detailed description
Lenalidomide is a drug that interferes with the development of tiny blood vessels that help tumors grow. Lenalidomide in combination with dexamethasone is approved by the Food and Drug Administration (FDA) for the treatment of relapsed multiple myeloma. It is also approved for the treatment of specific types of myelodysplastic syndrome (MDS), another blood cancer. Other research studies using lenalidomide in combination with other drugs in subjects with newly diagnosed multiple myeloma also show good response rate. High dose melphalan is approved by the FDA and is commonly used in multiple myeloma treatment prior to stem cell transplantation. This combination of lenalidomide, high-dose melphalan and stem cell transplantation has not been studied in newly diagnosed and relapsed multiple myeloma, so it is considered experimental. In research studies, experimental refers to a drug or procedure that has undergone basic laboratory testing and received approval from the US Food and Drug Administration (FDA) to be tested in human subjects. A drug or procedure may be approved by the FDA for use in one disease or condition, but be considered experimental in other diseases or conditions. In this study, lenalidomide will be given together with melphalan (chemotherapy) with the hope that more disease will be killed before the stem cell transplant. Three months after the transplant, patients will take lenalidomide again with the hope that this will help prolong the time when the disease is in remission.
Interventions
DRUGLenalidomide plus Melphalan during autologous stem cell transplantation
Patients will receive a fixed dose of melphalan, while the dose of lenalidomide is escalated according to the protocol defined cohorts. Lenalidomide is given on day -7 to day +2, while intravenous melphalan is given on day -2 and -1. Lenalidomide dosing will be in the morning at approximately the same time each day.
Lenalidomide maintenance therapy will begin on Day +100 to Day +110 provided the protocol-defined criteria are met. The initial starting dose of lenalidomide during maintenance is 10 mg daily on Days 1-28 of each 28-day cycle.
Sponsors
Celgene
Attaya Suvannasankha
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All patients will receive melphalan 100 milligrams (mg) per meters squared (m2) intravenously day -2 and day -1. Phase I patients will be enrolled sequentially into one of dose levels below and administered the corresponding lenalidomide dose. The recommended phase II dose based on dose limiting toxicities observed in the phase I portion will be used for lenalidomide dosing in the phase II portion of the trial Dose level -1 Lenalidomide 25 mg daily day -7 to day +2, Dose level 1 Lenalidomide 50 mg daily day -7 to day +2, Dose level 2 Lenalidomide 75 mg daily day -7 to day +2, Dose level 3 Lenalidomide 100 mg daily day -7 to day +2, Dose level 4 Lenalidomide 150 mg daily day -7 to day +2,
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Phase I: Patients with diagnosis of multiple myeloma at any stage of disease undergoing high dose chemotherapy and stem cell transplantation. * Phase II: Patients with myeloma undergoing a first high dose chemotherapy and stem cell transplantation after achieving at least stable disease following induction therapy. Any induction regimen prior to transplantation is allowed. No more than 2 prior lines of therapy prior to transplantation are allowed. * All previous therapy not associated with peripheral blood stem cell transplant, including radiation, hormonal therapy, and surgery, must have been discontinued 4 weeks prior to treatment in this study. * ECOG performance status of \</= 2 at study entry * Laboratory test results within protocol-specified ranges * All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist® * Females of childbearing potential must have negative pregnancy test within 24 hours of first prescription for lenalidomide and must commit to either continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control. * Able to take aspirin daily as prophylactic anticoagulation * Subject must have the minimum stem cell dose of 5.0 x 10\^6 CD34+ cells/kg collected.
Exclusion criteria
* Pregnant or breast feeding females * History of intolerance or resistance to lenalidomide * Known hypersensitivity to thalidomide * The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. * Known seropositive for or active viral infection with human immunodeficiency vrus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis b virus vaccine are eligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Number of Patients With Dose Limiting Toxicity | up to 1 month | The number of patients who had a DLT during the dose finding portion (Phase I) of the trial for the safety of lenalidomide when used in combination with high dose melphalan in the setting of autologous stem cell transplantation in patients with multiple myeloma. |
| Phase II: Overall Response Rate | up to 5 years | Evaluate the overall response rate of patients receiving therapy. Patients are considered as having a response if their overall response is Partial Response or better (CR+sCR+VGPR+PR). The percentage of patients achieving this and the exact 95% confidence interval will be calculated. Responses will be defined using the response criteria determined by the International Working Group for Multiple Myeloma (CR= Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and 5% plasma cells in bone marrow; sCR=CR as defined above plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunoflurorescence; VGPR=Serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-component plus urine M-component\<100 mg per 24 h; PR=\>=50% reduction of serum M-protein and reduction in 24-h urinary M-protein by \>=90% or to \<200mg per 24 h). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Treatment-Related Adverse Events Grade 3 or Higher | up to 5 years | Number of unique patients who had a treatment-related (possible, probable or definite) adverse events that were graded 3 or higher. |
Countries
United States
Participant flow
Recruitment details
This protocol was based on enrolling up to 16 patients phase I and up to 46 patients in phase II. The study enrolled 60 patients with 16 in phase I and 44 in phase II.
Participants by arm
| Arm | Count |
|---|---|
| Phase I, Dose Level 1 All patients will receive Melphalan 100 mg/m2 intravenously day -2 and day -1 and Lenalidomide 50 mg given daily day -7 to day +2 | 3 |
| Phase I, Dose Level 2 All patients will receive Melphalan 100 mg/m2 intravenously day -2 and day -1 and Lenalidomide 75 mg given daily day -7 to day +2 | 4 |
| Phase I, Dose Level 3 All patients will receive Melphalan 100 mg/m2 intravenously day -2 and day -1 and Lenalidomide 100 mg given daily day -7 to day +2 | 3 |
| Phase I, Dose Level 4 All patients will receive Melphalan 100 mg/m2 intravenously day -2 and day -1 and Lenalidomide 150 mg given daily day -7 to day +2 | 6 |
| Phase II All patients will receive Melphalan 100 mg/m2 intravenously day -2 and day -1 and Lenalidomide 150 mg given daily day -7 to day +2 | 44 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 1 | 0 | 4 |
| Overall Study | Alternative Therapy | 0 | 1 | 1 | 0 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Disease Progression | 2 | 0 | 1 | 2 | 12 |
| Overall Study | Noncompliance | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Off Trt for other complicating disease | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 2 | 10 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 3 |
Baseline characteristics
| Characteristic | Phase I, Dose Level 1 | Phase I, Dose Level 2 | Phase I, Dose Level 3 | Phase I, Dose Level 4 | Phase II | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 10 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 3 Participants | 5 Participants | 34 Participants | 45 Participants |
| Age, Continuous | 62.3 years STANDARD_DEVIATION 7.3 | 63.0 years STANDARD_DEVIATION 11.7 | 56.1 years STANDARD_DEVIATION 10.8 | 56.6 years STANDARD_DEVIATION 9.1 | 58.6 years STANDARD_DEVIATION 8.4 | 58.7 years STANDARD_DEVIATION 8.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 3 Participants | 6 Participants | 43 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 3 Participants | 5 Participants | 38 Participants | 53 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 13 Participants | 16 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 2 Participants | 5 Participants | 31 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 3 / 3 | 6 / 6 | 44 / 44 |
| serious Total, serious adverse events | 0 / 3 | 1 / 4 | 2 / 3 | 3 / 6 | 11 / 44 |
Outcome results
Primary
Phase II: Overall Response Rate
Evaluate the overall response rate of patients receiving therapy. Patients are considered as having a response if their overall response is Partial Response or better (CR+sCR+VGPR+PR). The percentage of patients achieving this and the exact 95% confidence interval will be calculated. Responses will be defined using the response criteria determined by the International Working Group for Multiple Myeloma (CR= Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and 5% plasma cells in bone marrow; sCR=CR as defined above plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunoflurorescence; VGPR=Serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-component plus urine M-component\<100 mg per 24 h; PR=\>=50% reduction of serum M-protein and reduction in 24-h urinary M-protein by \>=90% or to \<200mg per 24 h).
Time frame: up to 5 years
Population: All Phase II patients who received at least one dose of study drug and had at least one evaluable post-baseline visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I, Dose Level 1 | Phase II: Overall Response Rate | 87.5 percentage of participants |
Primary
Phase I: Number of Patients With Dose Limiting Toxicity
The number of patients who had a DLT during the dose finding portion (Phase I) of the trial for the safety of lenalidomide when used in combination with high dose melphalan in the setting of autologous stem cell transplantation in patients with multiple myeloma.
Time frame: up to 1 month
Population: All Phase I patients receiving at least one dose of study drug and having at least one evaluable post-baseline visit (16 patients)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I, Dose Level 1 | Phase I: Number of Patients With Dose Limiting Toxicity | 0 Participants |
| Phase I, Dose Level 2 | Phase I: Number of Patients With Dose Limiting Toxicity | 0 Participants |
| Phase I, Dose Level 3 | Phase I: Number of Patients With Dose Limiting Toxicity | 0 Participants |
| Phase I, Dose Level 4 | Phase I: Number of Patients With Dose Limiting Toxicity | 0 Participants |
Secondary
Phase II: Treatment-Related Adverse Events Grade 3 or Higher
Number of unique patients who had a treatment-related (possible, probable or definite) adverse events that were graded 3 or higher.
Time frame: up to 5 years
Population: All Phase II patients who received treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I, Dose Level 1 | Phase II: Treatment-Related Adverse Events Grade 3 or Higher | 18 Participants |