Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Lenalidomide, Maintenance Therapy, Progression, Long-term, Anti-Myeloma Agents, Hematologic Disorders
Brief summary
This study is designed to compare long-term outcomes among patients randomized on the BMT CTN 0702 protocol (NCT01109004), A Trial of Single Autologous Transplant with or without Consolidation Therapy versus Tandem Autologous Transplant with Lenalidomide Maintenance for Patients with Multiple Myeloma. It is hypothesized that use of novel anti-myeloma agents will improve long-term progression-free survival (PFS) after high-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) as compared to a second autologous transplantation.
Detailed description
This study is designed to compare long-term outcomes among patients randomized on the BMT CTN 0702 protocol (NCT01109004). All patients who consent will be followed for death, progression, Second Primary Malignancies (SPMs), and Quality of Life (QOL). Patients who do not consent to the long-term follow-up mechanism or who have experienced progression on the BMT CTN 0702 study will be followed through the standard Center for International Blood and Marrow Transplant Research (CIBMTR) long-term follow-up mechanism. Additionally, patients who are eligible and are willing to continue with lenalidomide as maintenance therapy will be provided lenalidomide free of charge. These patients will continue to receive lenalidomide as maintenance therapy until disease progression or discontinuation due to toxicity, death, or withdrawal from the study. The endpoints assessed will include progression-free survival (PFS), overall survival (OS), event-free survival (EFS), incidence of second primary malignancies (SPM) and health quality of life (QOL).
Interventions
DRUGLenalidomide
In BMT CTN 0702, maintenance therapy with lenalidomide started at 10 mg daily for three months and increased to 15 mg daily. The duration of maintenance was three years in all treatment arms. Lenalidomide will be administered initially at the patient's last documented dose prior to discontinuation of BMT CTN 0702 lenalidomide maintenance therapy. Cycle duration is 28 days. Patients will continue lenalidomide until disease progression, or discontinuation due to toxicity, death, or withdrawal from the study.
Sponsors
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Patients fulfilling the following criteria will be eligible to provide continued long-term follow-up data as part of this study: 1. Enrolled and randomized on the BMT CTN 0702 protocol. 2. Alive at the completion of BMT CTN 0702 protocol specified follow-up defined as 4 years post-randomization. 3. Patients without evidence of disease progression at the completion of BMT CTN 0702 protocol specified follow up. 4. Signed Informed Consent Form. 5. Patients with the ability to speak English or Spanish are eligible to participate in the HQL component of this trial. Inclusion Criteria for Optional Long-term Lenalidomide Maintenance Therapy: Patients fulfilling the following criteria will be eligible to provide continued long-term follow-up data AND receive long-term lenalidomide maintenance therapy as part of this study: 1. Enrolled and randomized to BMT CTN 0702. 2. Completion of 3 years of maintenance therapy on BMT CTN 0702. 3. Registered in the mandatory Revlimid REMS® program (formerly the RevAssist® for Study Participants (RASP) program), and be willing and able to comply with the requirements of the Revlimid REMS® program, including counseling, pregnancy testing, and phone surveys. 4. Signed informed consent form. 5. Patients with the ability to speak English or Spanish are eligible to participate in the HQL component of this trial.
Exclusion criteria
Patients who meet any of the following criteria will be ineligible to receive long-term lenalidomide maintenance therapy as part of this study: 1. Patients who have evidence of disease progression prior to enrollment. 2. Patients who were discontinued from BMT CTN 0702 lenalidomide maintenance therapy, for any reason, prior to the completion of the 3 years of 0702 maintenance. 3. Female patients who are pregnant (positive - Beta Human Chorionic Gonadotropin) or breastfeeding. 4. Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use contraceptive techniques during the length of lenalidomide maintenance therapy. 5. Patients who experienced thromboembolic events while on full anticoagulation during prior therapy with lenalidomide. 6. Patients unwilling to take Deep Vein Thrombosis (DVT) prophylaxis. 7. Patients who developed a second primary malignancy, excluding non-melanoma skin cancers after initiation of lenalidomide maintenance therapy on BMT CTN 0702.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Progression-free Survival (PFS) | 5 years post-randomization in BMT CTN 0702 | This analysis includes all randomized subjects from the BMT CTN 0702 protocol classified according to their randomized treatment assignment (intention-to-treat). Progression-free survival is defined as survival without disease progression or initiation of non-protocol anti-myeloma therapy. To account for loss to follow-up, the Kaplan-Meier estimator was used to estimate progression-free survival during the 5 year post-randomization follow-up period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Survival (OS) | 5 years post-randomization in BMT CTN 0702 | This analysis includes all randomized subjects from the BMT CTN 0702 protocol classified according to their randomized treatment assignment (intention-to-treat). Overall survival is defined as survival of death from any cause. To account for loss to follow-up, the Kaplan-Meier estimator was used to estimate overall survival during the 5 year post-randomization follow-up period. |
| Percentage of Participants With Event-free Survival (EFS) | 5 years post-randomization in BMT CTN 0702 | This analysis includes all randomized subjects from the BMT CTN 0702 protocol classified according to their randomized treatment assignment (intention-to-treat). Event-free survival is defined as survival without disease progression, second primary malignancy, and death. To account for loss to follow-up, the Kaplan-Meier estimator was used to estimate event-free survival during the 5 year post-randomization follow-up period. |
| Percentage of Participants With Secondary Primary Malignancies (SPM) | 5 years post-randomization in BMT CTN 0702 | This analysis includes all randomized subjects from the BMT CTN 0702 protocol classified according to their randomized treatment assignment (intention-to-treat). SPM is defined as development of any second malignancy, excluding non-melanoma skin cancers. To account for loss to follow-up, the Aalen-Johansen estimator was used to estimate the cumulative incidence of SPM during the 5 year post-randomization follow-up period. The development of any SPMs excludes non-melanoma skin cancers. Death without SPMs will be considered a competing risk for this event. The cumulative incidence of SPMs will be compared between treatment arms. |
| Percentage of Participants With Disease Progression | 5 years post-randomization in BMT CTN 0702 | This analysis includes all randomized subjects from BMT CTN 0702, classified by their treatment assignment (intention-to-treat). Disease progression is defined as progression of multiple myeloma, including one or more of the following: * Reappearance of serum monoclonal paraprotein at a level \>= 0.5 g/dL * 24-hour urine protein electrophoresis of at least 200mg paraprotein/24 hours * Abnormal free light chain levels of \>10 mg/dl, only in patients without measurable paraprotein in serum and urine * At least 10% plasma cells in a bone marrow aspirate or trephine biopsy * Definite increase in the size of existing bone lesions or soft tissue plasmacytomas * Development of new bone lesions or soft tissue plasmacytomas * Development of hypercalcemia (corrected serum Ca \>11.5 mg/dL or \>2.8 mmol/L) not attributable to other causes To account for loss to follow-up, the Aalen-Johansen estimator was used to estimate the cumulative incidence of progression during the follow-up period. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tandem Auto Transplant Initial autologous transplant followed by a second autologous transplant and lenalidomide maintenance
Lenalidomide: In BMT CTN 0702, maintenance therapy with lenalidomide started at 10 mg daily for three months and increased to 15 mg daily. The duration of maintenance was three years in all treatment arms. Lenalidomide will be administered initially at the patient's last documented dose prior to discontinuation of BMT CTN 0702 lenalidomide maintenance therapy. Cycle duration is 28 days. Patients will continue lenalidomide until disease progression, or discontinuation due to toxicity, death, or withdrawal from the study. | 98 |
| RVD Consolidation Initial autologous transplant followed by lenalidomide, bortezomib and dexamethasone (RVD) consolidation and lenalidomide maintenance
Lenalidomide: In BMT CTN 0702, maintenance therapy with lenalidomide started at 10 mg daily for three months and increased to 15 mg daily. The duration of maintenance was three years in all treatment arms. Lenalidomide will be administered initially at the patient's last documented dose prior to discontinuation of BMT CTN 0702 lenalidomide maintenance therapy. Cycle duration is 28 days. Patients will continue lenalidomide until disease progression, or discontinuation due to toxicity, death, or withdrawal from the study. | 86 |
| Lenalidomide Maintenance Initial autologous transplant followed by lenalidomide maintenance
Lenalidomide: In BMT CTN 0702, maintenance therapy with lenalidomide started at 10 mg daily for three months and increased to 15 mg daily. The duration of maintenance was three years in all treatment arms. Lenalidomide will be administered initially at the patient's last documented dose prior to discontinuation of BMT CTN 0702 lenalidomide maintenance therapy. Cycle duration is 28 days. Patients will continue lenalidomide until disease progression, or discontinuation due to toxicity, death, or withdrawal from the study. | 89 |
| Total | 273 |
Baseline characteristics
| Characteristic | Tandem Auto Transplant | RVD Consolidation | Lenalidomide Maintenance | Total |
|---|---|---|---|---|
| Age, Continuous | 55 years | 56 years | 57 years | 56 years |
| Diseae Risk at BMT CTN 0702 Enrollment High | 25 Participants | 21 Participants | 17 Participants | 63 Participants |
| Diseae Risk at BMT CTN 0702 Enrollment Standard | 73 Participants | 65 Participants | 72 Participants | 210 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 5 Participants | 2 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 81 Participants | 77 Participants | 84 Participants | 242 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 4 Participants | 3 Participants | 13 Participants |
| Karnofsky Performance Score (KPS) 70-80 | 20 Participants | 26 Participants | 26 Participants | 72 Participants |
| Karnofsky Performance Score (KPS) 90-100 | 78 Participants | 60 Participants | 63 Participants | 201 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 5 Participants | 4 Participants | 11 Participants |
| Race/Ethnicity, Customized Black or African American | 22 Participants | 10 Participants | 16 Participants | 48 Participants |
| Race/Ethnicity, Customized Multiracial | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 68 Participants | 69 Participants | 68 Participants | 205 Participants |
| Sex: Female, Male Female | 40 Participants | 31 Participants | 34 Participants | 105 Participants |
| Sex: Female, Male Male | 58 Participants | 55 Participants | 55 Participants | 168 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 98 | 4 / 86 | 2 / 89 |
| other Total, other adverse events | 0 / 98 | 0 / 86 | 0 / 89 |
| serious Total, serious adverse events | 6 / 98 | 10 / 86 | 6 / 89 |
Outcome results
Primary
Percentage of Participants With Progression-free Survival (PFS)
This analysis includes all randomized subjects from the BMT CTN 0702 protocol classified according to their randomized treatment assignment (intention-to-treat). Progression-free survival is defined as survival without disease progression or initiation of non-protocol anti-myeloma therapy. To account for loss to follow-up, the Kaplan-Meier estimator was used to estimate progression-free survival during the 5 year post-randomization follow-up period.
Time frame: 5 years post-randomization in BMT CTN 0702
Population: All 754 randomized BMT CTN 0702 participants are included in this analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tandem Auto Transplant | Percentage of Participants With Progression-free Survival (PFS) | 47.7 percentage of participants |
| RVD Consolidation | Percentage of Participants With Progression-free Survival (PFS) | 44.1 percentage of participants |
| Lenalidomide Maintenance | Percentage of Participants With Progression-free Survival (PFS) | 45.0 percentage of participants |
Comparison: The null hypothesis is that the percentages of participants with PFS at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to Tandem auto transplant and RVD consolidation therapy.p-value: 0.6Log Rank
Comparison: The null hypothesis is that the percentages of participants with PFS at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to Tandem auto transplant and Lenalidomide maintenance therapy.p-value: 0.35Log Rank
Comparison: The null hypothesis is that the percentages of participants with PFS at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to RVD consolidation and Lenalidomide maintenance therapy.p-value: 0.68Log Rank
Secondary
Percentage of Participants With Disease Progression
This analysis includes all randomized subjects from BMT CTN 0702, classified by their treatment assignment (intention-to-treat). Disease progression is defined as progression of multiple myeloma, including one or more of the following: * Reappearance of serum monoclonal paraprotein at a level \>= 0.5 g/dL * 24-hour urine protein electrophoresis of at least 200mg paraprotein/24 hours * Abnormal free light chain levels of \>10 mg/dl, only in patients without measurable paraprotein in serum and urine * At least 10% plasma cells in a bone marrow aspirate or trephine biopsy * Definite increase in the size of existing bone lesions or soft tissue plasmacytomas * Development of new bone lesions or soft tissue plasmacytomas * Development of hypercalcemia (corrected serum Ca \>11.5 mg/dL or \>2.8 mmol/L) not attributable to other causes To account for loss to follow-up, the Aalen-Johansen estimator was used to estimate the cumulative incidence of progression during the follow-up period.
Time frame: 5 years post-randomization in BMT CTN 0702
Population: All 754 randomized BMT CTN 0702 participants are included in this analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tandem Auto Transplant | Percentage of Participants With Disease Progression | 48.8 percentage of participants |
| RVD Consolidation | Percentage of Participants With Disease Progression | 54.3 percentage of participants |
| Lenalidomide Maintenance | Percentage of Participants With Disease Progression | 54.2 percentage of participants |
Secondary
Percentage of Participants With Event-free Survival (EFS)
This analysis includes all randomized subjects from the BMT CTN 0702 protocol classified according to their randomized treatment assignment (intention-to-treat). Event-free survival is defined as survival without disease progression, second primary malignancy, and death. To account for loss to follow-up, the Kaplan-Meier estimator was used to estimate event-free survival during the 5 year post-randomization follow-up period.
Time frame: 5 years post-randomization in BMT CTN 0702
Population: All 754 randomized BMT CTN 0702 participants are included in this analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tandem Auto Transplant | Percentage of Participants With Event-free Survival (EFS) | 44.2 percentage of participants |
| RVD Consolidation | Percentage of Participants With Event-free Survival (EFS) | 42.1 percentage of participants |
| Lenalidomide Maintenance | Percentage of Participants With Event-free Survival (EFS) | 42.4 percentage of participants |
Comparison: The null hypothesis is that the percentages of participants with EFS at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to Tandem auto transplant and RVD consolidation therapy.p-value: 0.67Log Rank
Comparison: The null hypothesis is that the percentages of participants with EFS at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to Tandem auto transplant and Lenalidomide maintenance therapy.p-value: 0.2Log Rank
Comparison: The null hypothesis is that the percentages of participants with EFS at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to RVD consolidation and Lenalidomide maintenance therapy.p-value: 0.4Log Rank
Secondary
Percentage of Participants With Overall Survival (OS)
This analysis includes all randomized subjects from the BMT CTN 0702 protocol classified according to their randomized treatment assignment (intention-to-treat). Overall survival is defined as survival of death from any cause. To account for loss to follow-up, the Kaplan-Meier estimator was used to estimate overall survival during the 5 year post-randomization follow-up period.
Time frame: 5 years post-randomization in BMT CTN 0702
Population: All 754 randomized BMT CTN 0702 participants are included in this analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tandem Auto Transplant | Percentage of Participants With Overall Survival (OS) | 74.7 percentage of participants |
| RVD Consolidation | Percentage of Participants With Overall Survival (OS) | 75.4 percentage of participants |
| Lenalidomide Maintenance | Percentage of Participants With Overall Survival (OS) | 76.4 percentage of participants |
Comparison: The null hypothesis is that the percentages of participants with OS at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to Tandem auto transplant and RVD consolidation therapy.p-value: 0.57Log Rank
Comparison: The null hypothesis is that the percentages of participants with OS at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to Tandem auto transplant and Lenalidomide maintenance therapy.p-value: 0.38Log Rank
Comparison: The null hypothesis is that the percentages of participants with OS at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to RVD consolidation and Lenalidomide maintenance therapy.p-value: 0.77Log Rank
Secondary
Percentage of Participants With Secondary Primary Malignancies (SPM)
This analysis includes all randomized subjects from the BMT CTN 0702 protocol classified according to their randomized treatment assignment (intention-to-treat). SPM is defined as development of any second malignancy, excluding non-melanoma skin cancers. To account for loss to follow-up, the Aalen-Johansen estimator was used to estimate the cumulative incidence of SPM during the 5 year post-randomization follow-up period. The development of any SPMs excludes non-melanoma skin cancers. Death without SPMs will be considered a competing risk for this event. The cumulative incidence of SPMs will be compared between treatment arms.
Time frame: 5 years post-randomization in BMT CTN 0702
Population: All 754 randomized BMT CTN 0702 participants are included in this analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tandem Auto Transplant | Percentage of Participants With Secondary Primary Malignancies (SPM) | 10.8 percentage of participants |
| RVD Consolidation | Percentage of Participants With Secondary Primary Malignancies (SPM) | 7.9 percentage of participants |
| Lenalidomide Maintenance | Percentage of Participants With Secondary Primary Malignancies (SPM) | 7.2 percentage of participants |
Comparison: The null hypothesis is that the percentages of participants with SPM at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to Tandem auto transplant and RVD consolidation therapy.p-value: 0.43Gray's test
Comparison: The null hypothesis is that the percentages of participants with SPM at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to Tandem auto transplant and Lenalidomide maintenance therapy.p-value: 0.7Gray's test
Comparison: The null hypothesis is that the percentages of participants with SPM at 5 years post-randomization in BMT CTN 0702 are equal for those assigned to RVD consolidation and Lenalidomide maintenance therapy.p-value: 0.7Gray's test