Lenalidomide in Treating Patients With Multiple Myeloma Undergoing Autologous Stem Cell Transplant

Study Overview
=================
Brief Summary
-----------------
This randomized phase III trial studies lenalidomide to see how well it works compared to a placebo in treating patients with multiple myeloma who are undergoing autologous stem cell transplant. Giving chemotherapy before a peripheral blood stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Biological therapies, such as lenalidomide, may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Giving lenalidomide after autologous stem cell transplant may be an effective treatment for multiple myeloma.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To determine the efficacy of CC-5013 (lenalidomide) in prolonging time to disease progression in patients with multiple myeloma after autologous stem cell transplant (ASCT). SECONDARY OBJECTIVES: I. To determine if CC-5013 will increase the complete response (CR) rate in patients with multiple myeloma following ASCT. II. To compare the progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma who have undergone ASCT and who then are randomized to either CC-5013 or placebo. III. To determine the feasibility of long-term administration of CC-5013 to multiple myeloma patients who have undergone ASCT. OUTLINE: PERIPHERAL BLOOD STEM CELL (PBSC) MOBILIZATION: Mobilization of autologous PBSC will be performed according to institutional guidelines. AUTOLOGOUS PBSC TRANSPLANTATION (PBSCT): Patients receive melphalan intravenously (IV) over 30-60 minutes on day -2 or -1 or over 2 days on days -3 and -2 or -2 and -1. Patients undergo autologous PBSCT on day 0. Patients are then randomized to 1 of 2 maintenance treatment arms. (Note: As of 12/17/09, no more patients will be randomized between lenalidomide and placebo. Patients who have not been randomized as of 12/17/09 will be assigned to lenalidomide.) ARM I: Beginning between day 100-110, patients receive lenalidomide orally (PO) once daily. ARM II: Beginning between day 100-110, patients receive placebo (PO) once daily. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months thereafter.

Official Title
-----------------
A Phase III Randomized, Double-Blind Study of Maintenance Therapy With CC-5013 (NSC # 703813) or Placebo Following Autologous Stem Cell Transplantation for Multiple Myeloma

Conditions
-----------------
DS Stage I Multiple Myeloma, DS Stage II Multiple Myeloma, DS Stage III Multiple Myeloma, Refractory Multiple Myeloma, Smoldering Multiple Myeloma

Intervention / Treatment
-----------------
* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Other: Laboratory Biomarker Analysis
* Drug: Lenalidomide
* Drug: Melphalan
* Procedure: Peripheral Blood Stem Cell Transplantation
* Other: Placebo Administration


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have active multiple myeloma requiring treatment (Durie-Salmon stage >= 1) and have stable disease or be responsive to at least 2 months of any induction therapy; patients with smoldering myeloma are not eligible unless the disease has progressed to >= stage 1 No more than 12 months of any prior therapy, including CC-5013 and thalidomide Within 12 months of initiation of induction therapy No prior progression after initial therapy; in addition, no more than two regimens will be allowed excluding dexamethasone alone No prior peripheral blood, bone marrow, or solid organ transplant Patients must have peripheral blood stem cell collection of >= 2 x 10^6 cluster of differentiation (CD)34+ cells/kg (patient body weight) and preferably 5 x 10^6 cells/kg (patient body weight); stem cells may be collected at any time prior to transplant; peripheral blood stem cell collection may occur before or after registration Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Patients must have diffusing capacity of the lung for carbon monoxide (DLCO) > 50% predicted with no symptomatic pulmonary disease Patients must have left ventricular ejection fraction (LVEF) >= 40% by multi gated acquisition scan (MUGA) or echocardiogram Patients must not have uncontrolled diabetes mellitus Patients must not have an active serious infection Patients must not be human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSag), or hepatitis (Hep) C positive Patients must be non-pregnant and non-nursing; women of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 10-14 days prior to registration and repeated within 24 hours prior to the first dose of lenalidomide; in addition, women of childbearing potential taking lenalidomide must have a pregnancy test performed by the doctor weekly during the first 4 weeks of treatment, and then every 4 weeks if menses are regular and every 2 weeks if menses are irregular, and then 30 days following the last dose of lenalidomide; women of childbearing potential must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control - one highly effective method (intrauterine device [IUD], hormonal, tubal ligation, or partner's vasectomy), and one additional effective method (latex condom, diaphragm, or cervical cap) - at the same time, at least 4 weeks before she begins lenalidomide therapy; women of childbearing potential is defined as a sexually mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months; men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking lenalidomide and for 4 weeks after therapy is stopped, even if they have undergone a successful vasectomy Absolute neutrophil count (ANC) >= 1000/uL Platelets >= 100,000/uL Creatinine clearance* >= 40 cc/min To be calculated by method of Cockcroft-Gault or after 24-hour urine collection Creatinine =< 2 mg/dL Total bilirubin =< 2 mg/dL Aspartate aminotransferase (AST) =< 3 x upper limits of normal Alkaline phosphatase =< 3 x upper limits of normal Urine (U)-human chorionic gonadotropin (HCG) or serum HCG negative (if patient of childbearing potential)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (melphalan, autologous PBSCT, lenalidomide)<br>Beginning between day 100-110, patients receive lenalidomide PO once daily. Treatment continues in the absence of disease progression or unacceptable toxicity. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous PBSCT<br>* Other names: Stem Cell Transplantation, Autologous;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo autologous PBSCT<br>* Other names: Peripheral Stem Cell Transplantation;|
| Placebo Comparator: Arm II (melphalan, autologous PBSCT, placebo)<br>Beginning between day 100-110, patients receive placebo PO once daily. Treatment continues in the absence of disease progression or unacceptable toxicity. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous PBSCT<br>* Other names: Stem Cell Transplantation, Autologous;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo autologous PBSCT<br>* Other names: Peripheral Stem Cell Transplantation;Other: Placebo Administration<br>* Given PO<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Time to progression (TTP) was defined as the date of transplant to date of progression or death due to any cause, whichever occurs first. TTP was estimated using the Kaplan Meier method. Progression was defined per the International Myeloma Working Group definition as one more of the following: 25% increase in serum M-component (absolute increase >= 0.5g/dl) 25% increase in urine M-component (absolute increase >= 200mg/24hour 25% increase in the difference between involved and uninvolved Free Light Chain levels (absolute increase >= 10mg/dl) 25 % increase in bone marrow plasma cell percentage (absolute increase of >=10%) Definite development of new bone lesion or soft tissue plasmacytomas Development of hypercalcemia | Duration of study (up to 10years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Autologous Hematopoietic Stem-cell Transplant (HSCT) at Day 100 | Response was defined according to International Myeloma Working Group criteria (2006) Complete Response: Complete disappearance of M-protein from serum & urine on immunofixation, normalization of Free Light Chain (FLC) ratio & <5% plasma cells in bone marrow (BM) Partial Response: >= 50% reduction in serum M-Component and/or Urine M-Component >= 90% reduction or <200 mg per 24 hours; or >= 50% decrease in difference between involved and uninvolved FLC levels Marginal Response: 25-49% reduction in serum M-component & urine M-component by 50-89% which still exceeds 200mg/24hour Progressive Disease: Defined in primary outcome measure Stable Disease: Not meeting any of the criteria above | Day 100 |