Multiple Myeloma
Conditions
Brief summary
One of the complications that can occur after a stem cell transplant is called graft versus host disease (GVHD). Another complication is that multiple myeloma may come back (relapse). In this study, a drug called lenalidomide will be started 1-2 months after a transplant, or possibly later depending on recovery of your side effects. Lenalidomide and sirolimus have been shown to work together against multiple myeloma. Therefore, lenalidomide will be combined with sirolimus with the hope that this will help prolong the amount of time the disease is in remission. Researchers hope these steps will help prolong the amount of time the multiple myeloma is in remission and will decrease the chance of GvHD.
Interventions
DRUGSirolimus
Start on Day -3 and continue for 1 year
DRUGTacrolimus
Start on Day -3 and begin tapering on Day +100 until Day +180.
DRUGLenalidomide
Start between Day +30 and +120 and continue for 1 year.
Sponsors
Celgene Corporation
Sherif S. Farag
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Recipient Inclusion Criteria: * 1\. Understand and voluntarily sign an informed consent form. * 2\. Age 18-70 years at the time of signing the informed consent form. * 3\. Able to adhere to the study visit schedule and other protocol requirements. * 4\. Previously documented multiple myeloma (MM) with measurable monoclonal protein by either serum/urine protein electrophoresis or serum free light chains, or measurable plasmacytomas. * 5\. ECOG performance status of 0-2 at study entry (see Appendix 2). * 6\. Acceptable organ function as outlined in the protocol. * 7\. Otherwise fitting institutional criteria for allogeneic stem cell transplantation. * 8\. Presence of an HLA-matched (5/6 or 6/6 matched for HLA-A, B, and DR) sibling donor, or a HLA-matched (matched for at least HLA-A, B, C, and DRB1) unrelated donor by high-resolution testing. * 9\. Disease free of prior malignancies for \>/= 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma insitu of the cervix or breast. * 10\. All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®. * 11\. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test Recipient
Exclusion criteria
* 1\. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. * 2\. Pregnant or breast feeding females. * 3\. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. * 4\. Known hypersensitivity to thalidomide or Lenalidomide. * 5\. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. * 6\. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine or prior infection to which they are now immune (i.e., not carriers) are eligible. Donor Inclusion Criteria: The following categories of donor will be acceptable: * 1\. HLA-matched related donor (5/6 or 6/6 match): Minimal typing necessary is serologic typing for class I (A, B) and molecular typing for class II (DRB1). * 2\. HLA-matched Unrelated Donor (MUD): Molecular identity at least at HLA A, B, C, and DRB1 and DQB1 (8/10 match) by high resolution typing is required. * 3\. Syngeneic donors are not eligible. * 4\. The donor must be healthy and must be an acceptable donor as per institutional standards for marrow or stem cell donation. * 5\. Age ≥ 18 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Number of Participants With Dose Limiting Toxicity | 28 days | The number of patients who had a DLT during the dose finding/confirming portion (Phase I) of the trial for the safety of the combination of sirolimus, tacrolimus and lenalidomid. Patients will be monitored for 28 days (a cycle) to determine whether a DLT is experienced for the specific dose level. |
| Phase II: Percent of Patients Alive and Free of Progression at 12 Months Following Transplant | Transplant (Day 0) through 1 year post-transplant | Percent of patients and the 95% Binomial Confidence interval who were alive and free of progression at 12 months following transplant for the patients in Phase II. Progression will be based on International Myeloma Working Group criteria where patients may meet any one of the following criteria - increase of 25% or more in serum or urine M-protein from baseline, Serum M-protein and/or the absolute increase must be \>=0.5 g/dl, Urine M-protein and/or absolute increase must be \>=200 mg/24 hours, development of new bone lesions or soft tissue plasmacyomas or definite increase in the size of existing bone lesions or soft tissue plasmacyomas, or development of hypercalcemia (corrected serum Ca++\>11.5 mg/dl) that can be attributed solely to plasma cell proliferative disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II - Percent of Patients With Treatment-related Deaths at 100 Days | 100 days post transplant | Percent of patients and the 95% Binomial Confidence interval who had treatment-related deaths by 100 days for patients in Phase II. |
| Phase II - Percent of Patients With Treatment-related Deaths at 1 Year | Transplant (Day 0) through 1 year post-transplant | Percent of patients and the 95% Binomial Confidence interval who had treatment-related deaths by 1 year for patients in Phase II. |
| Phase II - Percent of Patients With Acute Graft Versus Host Disease (GvHD) | Day 0 through 1 year post transplantation | Percent of patients and the 95% Binomial Confidence interval who had any stage I-IV acute GvHD based on the modified Keystone Grading Scale for skin, liver and gastrointestinal symptoms for patients in Phase II. Zero means no acute GvHD was reported, and higher stages are worse outcomes (range of 0-4). For skin: 0=no rash; 1=erthematous macular rash over \<25% body surface; 2=over 25-50% of body surface; 4=bullae, exfoliation ulcerative dermatitis. For liver (bilirubin (mg/dL)): 0= \<2.0; 1= 2-\<2.9; 3= 3-\<5.9; 4= \>=15 . For gut changes (diarrhea\[ml/day\]): 0=none; 1= \>500-1000; 2= \>1000-1500; 3= \>1500; 4=severe abdominal pain with or without ileus. Overall grade 0: Skin=0; liver=0; gut changes=0. Overall grade 1: Skin with 1 or 2; liver=0; gut changes=0. Overall grade 2: Skin with 1, 2, or 3; liver=1; gut changes=1. Overall grade 3: Skin with 2 or 3; liver with 2 or 3; gut changes with 2 or 3. Overall grade 4: Patients with grade 4 toxicity in any organ system. |
| Phase II - Time to Platelet Engraftment | Transplant (Day 0) through 1 year post-transplant | Time to platelet engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of platelets is defined as the time from day 0 to the first of three consecutive Complete Blood Counts (CBCs) obtained on different days after transplantation during which the platelet count is at least 20 x109/l. The CBCs obtained should be at least seven days after the most recent platelet transfusion. Only patients who achieved engraftment of platelets will be included in the analysis. The median and 95% confidence intervals will be provided. |
| Phase II - Time to Neutrophil Engraftment | Transplant (Day 0) through 1 year post transplant | Time to neutrophil engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of neutrophils is defined as the time from day 0 to the date of the first of three consecutive days after transplantation during which the absolute neutrophils count (ANC) is at least 0.5 x109/l. Patients surviving at least 14 days after transplant will be evaluable for this endpoint. Patients who did not have neutrophil engraftment before death will be censored at the date of death. The median and 95% confidence intervals will be provided. |
| Phase II - Percent of Patients With Chronic Graft Versus Host Disease (GvHD) | Transplant (Day 0) through 1 year post-transplant | Percent of patients and the 95% Binomial Confidence interval who had any chronic GvHD reported based on Filipovich et al. consensus document (BB&MT 2005) and Akpek et al. chronic GvHD grading system (Blood 2003) for patients in Phase II. |
Countries
United States
Participant flow
Recruitment details
This protocol was a Phase I/II study. Phase I was based on a 3+3 design with the first cohort found to be safe with 3 patients. Phase II was based on a Simon Minimax two-stage design with the first interim analysis planned after 28 patients. The study was stopped at 11 patients in Phase II due to slow accrual.
Participants by arm
| Arm | Count |
|---|---|
| Phase I Dose Finding Standard treatment of sirolimus and tacrolimus as GvHD prophylaxis with sirolimus (target plasma drug level of 5-10 ng/ml) and lenalidomide (15 mg daily) as post-transplant maintenance | 3 |
| Phase II Standard treatment of sirolimus and tacrolimus as GvHD prophylaxis with sirolimus (target plasma drug level of 5-10 ng/ml) and lenalidomide (15 mg daily) as post-transplant maintenance | 11 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Death | 0 | 3 |
| Overall Study | Disease Progression | 1 | 6 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Phase I Dose Finding | Phase II | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 11 Participants | 14 Participants |
| Age, Continuous | 57.1 years STANDARD_DEVIATION 2.44 | 52.8 years STANDARD_DEVIATION 8.7 | 53.7 years STANDARD_DEVIATION 7.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 11 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 10 Participants | 13 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 11 / 11 |
| serious Total, serious adverse events | 2 / 3 | 8 / 11 |
Outcome results
Primary
Phase II: Percent of Patients Alive and Free of Progression at 12 Months Following Transplant
Percent of patients and the 95% Binomial Confidence interval who were alive and free of progression at 12 months following transplant for the patients in Phase II. Progression will be based on International Myeloma Working Group criteria where patients may meet any one of the following criteria - increase of 25% or more in serum or urine M-protein from baseline, Serum M-protein and/or the absolute increase must be \>=0.5 g/dl, Urine M-protein and/or absolute increase must be \>=200 mg/24 hours, development of new bone lesions or soft tissue plasmacyomas or definite increase in the size of existing bone lesions or soft tissue plasmacyomas, or development of hypercalcemia (corrected serum Ca++\>11.5 mg/dl) that can be attributed solely to plasma cell proliferative disease.
Time frame: Transplant (Day 0) through 1 year post-transplant
Population: All patients who received treatment and were followed after transplant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Finding | Phase II: Percent of Patients Alive and Free of Progression at 12 Months Following Transplant | 18.2 percentage of participants |
Primary
Phase I: Number of Participants With Dose Limiting Toxicity
The number of patients who had a DLT during the dose finding/confirming portion (Phase I) of the trial for the safety of the combination of sirolimus, tacrolimus and lenalidomid. Patients will be monitored for 28 days (a cycle) to determine whether a DLT is experienced for the specific dose level.
Time frame: 28 days
Population: All patients assigned to Phase I and received treatment medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Dose Finding | Phase I: Number of Participants With Dose Limiting Toxicity | 0 Participants |
Secondary
Phase II - Percent of Patients With Acute Graft Versus Host Disease (GvHD)
Percent of patients and the 95% Binomial Confidence interval who had any stage I-IV acute GvHD based on the modified Keystone Grading Scale for skin, liver and gastrointestinal symptoms for patients in Phase II. Zero means no acute GvHD was reported, and higher stages are worse outcomes (range of 0-4). For skin: 0=no rash; 1=erthematous macular rash over \<25% body surface; 2=over 25-50% of body surface; 4=bullae, exfoliation ulcerative dermatitis. For liver (bilirubin (mg/dL)): 0= \<2.0; 1= 2-\<2.9; 3= 3-\<5.9; 4= \>=15 . For gut changes (diarrhea\[ml/day\]): 0=none; 1= \>500-1000; 2= \>1000-1500; 3= \>1500; 4=severe abdominal pain with or without ileus. Overall grade 0: Skin=0; liver=0; gut changes=0. Overall grade 1: Skin with 1 or 2; liver=0; gut changes=0. Overall grade 2: Skin with 1, 2, or 3; liver=1; gut changes=1. Overall grade 3: Skin with 2 or 3; liver with 2 or 3; gut changes with 2 or 3. Overall grade 4: Patients with grade 4 toxicity in any organ system.
Time frame: Day 0 through 1 year post transplantation
Population: All patients who received treatment and were followed after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Finding | Phase II - Percent of Patients With Acute Graft Versus Host Disease (GvHD) | 36.4 percentage of participants |
Secondary
Phase II - Percent of Patients With Chronic Graft Versus Host Disease (GvHD)
Percent of patients and the 95% Binomial Confidence interval who had any chronic GvHD reported based on Filipovich et al. consensus document (BB&MT 2005) and Akpek et al. chronic GvHD grading system (Blood 2003) for patients in Phase II.
Time frame: Transplant (Day 0) through 1 year post-transplant
Population: All patients who received treatment and were followed after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Finding | Phase II - Percent of Patients With Chronic Graft Versus Host Disease (GvHD) | 18.2 percentage of participants |
Secondary
Phase II - Percent of Patients With Treatment-related Deaths at 100 Days
Percent of patients and the 95% Binomial Confidence interval who had treatment-related deaths by 100 days for patients in Phase II.
Time frame: 100 days post transplant
Population: All patients who received treatment and were followed after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Finding | Phase II - Percent of Patients With Treatment-related Deaths at 100 Days | 18.2 percentage of participants |
Secondary
Phase II - Percent of Patients With Treatment-related Deaths at 1 Year
Percent of patients and the 95% Binomial Confidence interval who had treatment-related deaths by 1 year for patients in Phase II.
Time frame: Transplant (Day 0) through 1 year post-transplant
Population: All patients who received treatment and were followed after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Finding | Phase II - Percent of Patients With Treatment-related Deaths at 1 Year | 36.4 percentage of participants |
Secondary
Phase II - Time to Neutrophil Engraftment
Time to neutrophil engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of neutrophils is defined as the time from day 0 to the date of the first of three consecutive days after transplantation during which the absolute neutrophils count (ANC) is at least 0.5 x109/l. Patients surviving at least 14 days after transplant will be evaluable for this endpoint. Patients who did not have neutrophil engraftment before death will be censored at the date of death. The median and 95% confidence intervals will be provided.
Time frame: Transplant (Day 0) through 1 year post transplant
Population: All patients who received treatment and survived at least 14 days after transplant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Finding | Phase II - Time to Neutrophil Engraftment | 11 days |
Secondary
Phase II - Time to Platelet Engraftment
Time to platelet engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of platelets is defined as the time from day 0 to the first of three consecutive Complete Blood Counts (CBCs) obtained on different days after transplantation during which the platelet count is at least 20 x109/l. The CBCs obtained should be at least seven days after the most recent platelet transfusion. Only patients who achieved engraftment of platelets will be included in the analysis. The median and 95% confidence intervals will be provided.
Time frame: Transplant (Day 0) through 1 year post-transplant
Population: All patients who received treatment and who achieved platelet recovery/engraftment of platelets
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Finding | Phase II - Time to Platelet Engraftment | 19 days |