A Trial of Single Autologous Transplant with or without Consolidation Therapy versus Tandem Autologous Transplant with Lenalidomide Maintenance for Patients with Multiple Myeloma

Summary

The study is a Phase III randomized clinical trial to evaluate three treatment strategies after a single autologous transplant for patients with multiple myeloma (MM): second autologous transplant with the same conditioning regimen followed by maintenance with lenalidomide; maintenance alone; or consolidation with lenalidomide, bortezomib and dexamethasone combination followed by lenalidomide maintenance. Patients will be randomized at time of enrollment, which should occur within 7 days prior to the first high-dose melphalan conditioning regimen. Maintenance therapy with lenalidomide will be given for 3 years to all patients. The endpoints assessed will include PFS, disease response at different time points according to the International Uniform Response Criteria, OS, incidence of toxicities and infections, TRM, rate of discontinuation of protocol therapy and quality of life. Analyses of outcomes will be stratified according to risk status defined by the presence of cytogenetic abnormalities and serum beta-2 microglobulin level.

Over a three year accrual period, the study will enroll 750 patients, allocated as 250 patients in each treatment arm. Around 10 patients will be enrolled at UTSW. Patients will be followed for 4 years from the time of randomization.

Participant Eligibility

Patient Eligibility
Patients must meet specified eligibility criteria to be registered on the study. Additional criteria must also be met to continue to successive stages of the protocol.

Initial Patient Eligibility Criteria

Patients fulfilling the following criteria will be eligible for entry into this study:
1. Patients meeting the criteria for symptomatic MM.
2. Patients who are 70 years of age, or younger, at time of enrollment.
3. Patients who have received at least two cycles of any regimen as initial systemic therapy and are within 2 - 12 months of the first dose of initial therapy.
4. Cardiac function: left ventricular ejection fraction at rest > 40%.
5. Hepatic: bilirubin < 2x the upper limit of normal and ALT and AST < 2.5x the upper limit of normal.
6. Renal: Creatinine clearance of >= 40 mL/min, estimated or calculated.
7. Pulmonary: DLCO, FEV1, FVC > 50% of predicted value (corrected for hemoglobin).
8. Patients with an adequate autologous graft defined as a cryopreserved PBSC graft containing >= 4 x 10 CD34+ cells/kg patient weight. The graft may not be CD34+ selected or otherwise manipulated to remove tumor or other cells. The graft can be collected at the transplanting institution or by a referring center. The autograft must be stored so that there are two products each containing at least 2 x 10 CD34+ cells/kg patient weight.
9. Signed informed consent form.

Patient Eligibility Criteria for Second Autologous Transplant (Treatment Arm A)
In order to be eligible to continue on protocol and receive their second transplant (preferably between 60-120 days, but at least 60 days or not longer than 180 days post first autologous transplant), patients must have recovered sufficiently from their first transplant. Conditioning therapy for the second transplant must not start sooner than 60 days after the first autologous transplant.

Eligibility criteria for a second transplant are as follows:
1. Mucositis and gastrointestinal symptoms resolved, off hyperalimentation and intravenous hydration.
2. Liver and renal function tests within the inclusion criteria for initial autograft.
3. Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungal therapy for the treatment of proven, probable or possible infections (defined in accordance with the EORTC/MSG criteria). Patients who have completed treatment for an infection but are continuing antibiotics or anti-fungal therapy for prophylaxis are eligible to continue on protocol with approval of the Medical Monitor or one of the Protocol Chairs.
4. Completed administration of any radiotherapy.
5. Cardiac and pulmonary function within the inclusion criteria for initial autograft. Evaluation is only required if clinically indicated.
6. Renal: Creatinine clearance of >= 40 mL/min, estimated or calculated.
7. Women who are pregnant (positive [lower beta]-HCG) or breastfeeding are ineligible to proceed to a second autologous transplant. Patients unable to meet criteria for a second transplant but are still eligible for maintenance therapy should proceed to maintenance.

Patient Eligibility Criteria to begin RVD Consolidation (Treatment Arm C)
Patients must have recovered sufficiently from their first transplant to be eligible for
consolidation therapy (preferably between 60-120 days, but at least 60 days or not longer than 180 days post first autologous transplant). Eligibility criteria for beginning consolidation therapy are as follows:

1. Mucositis and gastrointestinal symptoms resolved, off hyperalimentation and intravenous hydration.
2. Liver and renal function tests within the inclusion criteria for initial autograft.
3. Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungal therapy for proven, probable or possible infection. Patients who have been treated for an infection but are continuing antibiotics or anti-fungal therapy for prophylaxis are eligible to continue on protocol with approval of the Medical Monitor or one of the Protocol Chairs.
4. Completed administration of any radiotherapy.
5. Less than or equal to grade 2 sensory neuropathy within 14 days before start of consolidation.
6. Platelet count >=75 x109/L (without transfusion in previous 7 days).
7. Absolute neutrophil count (ANC) >= 1.5x109/L without filgrastim administration within 7 days, or pegfilgrastim within 14 days of starting consolidation.
8. Requirements prior taking lenalidomide: Females of childbearing potential (FCBP) must have a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL within 10 x 14 days prior to and again within 24 hours of beginning treatment with lenalidomide (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Women who are breastfeeding are ineligible to proceed to RVD Consolidation. Men must agree to use a latex condom during sexual contact with females of child bearing potential even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See Appendices D (Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods) and E-1 (RevAssist(RegisteredTM)for Study Participants (RASP) Program) and E-2 (CTEP Drug Distribution: Lenalidomide Education and Counseling Guidance Document).
9. Patients must be willing to begin DVT prophylaxis.
10. Patients unable to meet criteria for consolidation (NOTE: within 180 days of the first autologous transplantation) or who develop unacceptable toxicity during consolidation (see Section 2.4.3) should be started on maintenance therapy as per Section 2.3.5.
11. During the transition period beginning April 30, 2012 and by June 30, 2012 and through the duration of the study, all study participants must be registered into the mandatory RevAssist(RegisteredTM) for Study Participants (RASP) program, and be willing and able to comply with the requirements of the RASP program.
12. During the transition period beginning April 30, 2012 and by June 30, 2012 and through the duration of the study all study participants must receive counseling and complete phone surveys as required by the RASP program.

Patient Eligibility Criteria to Begin Maintenance Therapy (All Treatment Arms)
Patients must have recovered sufficiently from their first or second transplant (preferably between 60-120 days, but at least 60 days or not longer than 180 days post autologous transplant x Treatment Arms A and B) or completion of consolidation therapy (at least 84 days or less than 180 days from initiation of consolidation therapy or after completion of 4 cycles of RVD x Treatment Arm C) in order to initiate lenalidomide maintenance therapy.

Criteria for starting maintenance therapy with lenalidomide are as follows:
1. Mucositis and gastrointestinal symptoms resolved, off hyperalimentation and intravenous hydration.
2. Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungal therapy for treatment of proven, probable or possible infections (defined in accordance with the EORTC/MSG criteria34). Patients who completed treatment for an infection but are continuing antibiotics or anti-fungal therapy for prophylaxis are eligible to continue on protocol with approval of the Medical Monitor or one of the Protocol Chairs.
3. Completed administration of any radiotherapy.
4. Platelet count >=75 x109/L (without transfusion in previous 7 days).
5. Absolute neutrophil count (ANC) >= 1.5 x 109/L without filgrastim administration within 7 days, or pegfilgrastim within 14 days of measurement.
6. No contraindications to lenalidomide (patients who were previously exposed to lenalidomide and who either did not tolerate it or who developed severe adverse events that preclude future use of this medication).
7. Liver and renal function tests within the inclusion criteria for initial autograft.
8. During the transition period beginning April 30, 2012 and by June 30, 2012 and through the duration of the study, all study participants must be registered into the mandatory RevAssist(RegisteredTM) for Study Participants (RASP) program, and be willing and able to comply with the requirements of the RASP program.
9. During the transition period beginning April 30, 2012 and by June 30, 2012 and through the duration of the study, all study participants must receive counseling and complete phone surveys as required by the RASP program.

Females of childbearing potential (FCBP) must have a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL within 10 x 14 days prior to and again within 24 hours of beginning treatment with lenalidomide (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with females of child bearing potential even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See Appendices D (Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods) and E-1 (RevAssist(RegisteredTM)for Study Participants (RASP) Program) and E-2 (CTEP Drug Distribution: Lenalidomide Education and Counseling Guidance Document). Patients must be willing to begin DVT prophylaxis.