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Phase II Multicenter Trial of Single Autologous Hematopoietic Cell  
  
Transplant Followed by Lenalidomide Maintenance for Multiple Myeloma with or without Vaccination with Dendritic Cell /Myeloma Fusions
(Posted on clinincaltrials.gov as NCT02728102)
BMT CTN PROTOCOL 1401 Version 4.0 Study Co-Chairs David Avigan, MD1, Nina Shah, MD2, David Chung, MD3  
Protocol Team  
Devine, Steven4  
Fay, Joseph5  
Geller, Nancy6  
Holstein, Sarah7  
Lazarus, Hillard8  
| Protocol Team                                                                                  |                                                                                               |
|------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------|
| Logan, Brent9  Mendizabal, Adam10  Nelson, Courtney10  O'Brien, Kelly10  Pasquini, Marcelo9    | Poland, Nancy11  Rosenblatt, Jacalyn1  Rapoport, Aaron12  Soiffer, Robert13  Waller, Edmund14 |
| Manufacturing Team:  Reese, Jane8  Keever-Taylor, Carolyn16  Young, James3   Zurawski, Gerard5 | Uhl, Lynne1 Stroopinsky, Dina1  Herman, Michele1                                              |  
Manufacturing Team:  
Choi, Chris7 Copland, Ian14 Hematti, Peiman15  
O'Donnell, Lynn4  
Sponsored by the National Institutes of Health National Heart, Lung, and Blood Institute and National Cancer Institute FDA IND \# 16655 10 The EMMES Corporation 11 National Marrow Donor  
  
Program 12University of Maryland 13 Dana Farber Cancer Institute 14 Emory University 15 University of Wisconsin 16 Medical College of Wisconsin  
| 1  Beth Israel Deaconess Medical  Center  2 University of California- San  Francisco  3 Memorial Sloan-Kettering  Cancer Center  4 The Ohio State University  5 Baylor Institute for  Immunology Research, Baylor  Research Institute   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| 6  National Heart, Lung, and  Blood Institute  7  Roswell Park Cancer Institute  8  University Hospitals Case  Medical Center, Case Western  Reserve University  9 Center for International Blood  and Marrow Transplant  Research, Medical College of  Wisconsin   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
________________________________________ ________________________________________  
 Approval Signature (Protocol Chair/Officer) Approval Signature (Protocol Chair/Officer)
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core study participants affiliate study

University Hospitals Case Medical Center, Case Western Reserve University Emory University Fred Hutchinson Cancer Research Center Memorial Sloan Kettering Cancer Center Mount Sinai Medical Center Ohio State University Roswell Park Cancer Institute University of Minnesota University of Nebraska University of California-San Francisco Medical College of Wisconsin Beth Israel Deaconess Medical Center University of Maryland University of Wisconsin University of Texas, MD Anderson Cancer Center Thomas Jefferson University
protocol synopsis - bmt ctn
core study participants affiliate study

Phase II Multicenter Trial of Single Autologous Hematopoietic Cell Transplant Followed by Lenalidomide Maintenance for Multiple Myeloma with or without Vaccination with Dendritic Cell (DC)/Myeloma Fusions Co- **Principal Investigators:** David Avigan, MD, Nina Shah, MD, David Chung, MD Study Design: The study is designed as a Phase II, multicenter trial of vaccination with DC/myeloma fusions with granulocyte macrophage colony-stimulating factor (GM-CSF) adjuvant plus lenalidomide maintenance therapy versus maintenance therapy alone or with GM-CSF following autologous transplant as part of upfront treatment of multiple myeloma (MM).  
Primary Objective: The primary objective of this randomized trial is to compare the proportion of patients alive and in complete response (defined as CR or sCR) at one year post transplant (or approximately 10 months post randomization) between patients receiving DC/myeloma vaccine/GM-CSF with lenalidomide maintenance therapy to those receiving lenalidomide maintenance therapy with or without GM-CSF.  
Clinical Secondary Objectives:
To compare DC/myeloma vaccine/GM-CSF with lenalidomide maintenance therapy to lenalidomide maintenance therapy with or without GM-CSF with respect to: myeloma response (sCR, CR, VGPR, PR, and SD), conversion of partial to complete response, disease progression, treatment-related mortality, progression-free survival, overall survival, toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0, incidence of infections, and measures of minimal residual disease at one year post transplant (or approximately 10 months from randomization). Secondary exploratory analyses will also be conducted to compare in a pairwise fashion the vaccine arm, lenalidomide/GM-CSF arm, and lenalidomide alone arm, to describe the proportion of patients with collection of tumor cells who reach randomization, compliance with vaccine, and to describe the reproducibility of the vaccine manufacturing based on the release criteria.  
Immunologic Objectives: The primary immunologic endpoint is to compare the effect of DC/myeloma vaccine/GM-CSF with lenalidomide maintenance therapy to lenalidomide maintenance therapy alone or with GMCSF on treatment-induced expansion of myeloma-specific T cells, defined as a 2.4-fold increase from pre-therapy to peak post-treatment levels.  
Secondary immunologic endpoints will compare each of the treatment arms for: a) the percent of patients achieving at least a 10-fold expansion of myeloma-specific T cells; b) expansion of myeloma antigen-specific T cells by tetramer analysis; c) quantification of T cell subsets and PD-1 expressing lymphocytes; d) quantification of NK cells and identification of activation and inhibitory ligands; e) assessment of NK-mediated killing of myeloma targets; f) assessment of humoral response against whole myeloma cells and myeloma-associated antigens by SEREX and by characterizing myeloma-specific plasmablast responses.  
Eligibility: Patients must be considered transplant eligible by treating physician at the time of study. Patients will be enrolled prior to tumor cell collection for vaccine manufacturing. Eligible patients are ≥18.00 and < 71.00 years of age with symptomatic multiple myeloma requiring treatment, without history of prior disease progression or prior HCT, Karnofsky performance score ≥70%, evidence of at least 20% plasma cells in a bone marrow differential within 60 days of enrollment, and have received <1 cycle of systemic anti-myeloma therapy. If patient receives antimyeloma therapy treatment after bone marrow aspirate to assess eligibility and before bone marrow aspirate for tumor cell collection, a repeat bone marrow evaluation will be required to confirm > 20% plasma cells in the bone marrow aspirate differential prior to enrollment and tumor cell collection. Patients with prior auto or allo transplant are not eligible. Patients with active autoimmune diseases will be excluded.  
Treatment Plan: After meeting the initial eligibility criteria, patients will undergo harvesting of myeloma cells for assessment of immune response and for vaccine generation. Patients will have 30 mL of marrow harvested and cryopreserved after undergoing immunophenotypic analysis per the BMT CTN 1401 Manufacturing SOPs. Patients will then complete initial systemic anti-myeloma therapy and autologous hematopoietic stem cell mobilization and collection according to institutional practices. Approximately 2 months post-transplant, patients will undergo disease response assessment and will be randomized 2:1:1 to vaccine/GM-CSF plus lenalidomide maintenance, lenalidomide alone, or lenalidomide/GM-CSF. Patients randomized to the vaccine plus lenalidomide arm will undergo leukapheresis for dendritic cell generation for vaccine manufacturing. All patients will start lenalidomide maintenance Day 90-100 post transplant. Patients randomized to the vaccine arm will receive vaccine the first day of cycles 2, 3, and 4 of maintenance. Vaccine will be administered by subcutaneous injection with 100 ug GM-CSF given subcutaneously at the vaccine site on day of vaccination and daily for a total of 4 days. Patients randomized to lenalidomide/GM-CSF will receive 100 ug GM-CSF given subcutaneously daily for a total of 4 days starting the first day of cycles 2, 3 and 4 of maintenance. Lenalidomide maintenance will continue for 2 years for patients who continue free of progression.  
Vaccine Production and Characterization:
protocol synopsis - bmt ctn
vaccine production will consist of

1) Bone marrow aspiration of 30 mL, isolation of mononuclear cells by ficoll centrifugation, quantification of CD138+ or CD38+ cells by immunocytochemistry, and cryopreservation.  
2) Leukapheresis collection post transplant and after randomization.  
3) Mononuclear cells isolated by ficoll density centrifugation.  
Adherent cells segregated following 1 hour culture and then cultured for 5-7 days with GM-CSF and IL-4. Cultures are re-fed with cytokines after 3 days. Maturation with TNFα for 48-72 hours. DCs are harvested and undergo characterization by immunocytochemistry for expression of DR, CD86, and CD83.  
4) Tumor cells are thawed and re-characterized. 5) DC and tumor cells are pelleted and co-cultured in the presence of PEG at a ratio of 3:1.  
6) Fusion cells are quantified by determining the percentage of dual expressing cells by immunocytochemistry.
protocol synopsis - bmt ctn
vaccine release criteria

1) At least 20% of tumor cell prep must express CD38 or CD138 by staining 2) Tumor cell prep must yield >10 million plasma cells1 3) 50% of DC prep express CD86 4) Viability of DC prep > 50% 5) Fusion efficiency > 15% 6) Fusion viability > 50%  
| 7)                 | Sterility, mycoplasma, and endotoxin assays are negative                                                                                                                                                                                                                        |
|--------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Accrual Objective: | Target accrual is 132 patients randomized to vaccine/GM-CSF/ lenalidomide (n=66), lenalidomide alone (n=33), lenalidomide /GM-CSF (n=33), with an estimated total enrollment of 188,  assuming about 30% of patients are unable to proceed with  post-transplant immunotherapy. |
| Accrual Period:    | 36 months                                                                                                                                                                                                                                                                       |
| Study Duration:    | Patients will be followed for approximately 3 years after  maintenance initiation                                                                                                                                                                                               |
| Interim Analysis:  | There will be no interim analysis for efficacy or futility.                                                                                                                                                                                                                     |  
v
study schema
initial inclusion criteria

1. Transplant Eligible 2. Meet criteria for symptomatic multiple myeloma (Appendix A) 3. Age >18.00 - < 71.00 4. Karnofsky Performance of > 70% 5. 20% plasma cells in the bone marrow < 60 days prior to enrollment1 6. Received < 1 cycles of systemic anti-myeloma therapy2 7. Creatinine clearance > 40 mL/min (estimated or calculated)  
1 If patient receives anti-myeloma therapy treatment after bone  
marrow aspirate to assess eligibility and before bone marrow aspirate for tumor cell collection, a repeat bone marrow  
evaluation will be required to confirm > 20% plasma cells in the  
bone marrow aspirate differential prior to enrollment and tumor cell collection.  
2 Anti-myeloma therapy is defined as systemic treatment intended  
to treat the underlying myeloma disease. Treatments intended to alleviate pain and other symptoms of disease and/or administration of ≤160mg of dexamethasone or equivalent alternative steroid dose within a 30 day period are not considered anti-myeloma therapy.  
Inclusion Criteria for Randomization  
1. No disease progression since initiation of systemic antimyeloma therapy  
2. Received autologous transplant with melphalan 200mg/m2  
with a minimum cell dose of 2x106 CD34+ cells/kg <12  
months from enrollment onto BMT CTN 1401Tumor cell preparation must (1) Express > 20% CD38 or CD138 by staining (2) yield > 10 million plasma cells (Plasma cell count is determined by multiplying the total mononuclear cell yield by the percent of CD38 and CD138 staining reported on the Immunohistochemistry Report) (3) Have a negative microbiology assessment  
3. No evidence of uncontrolled infection requiring systemic  
therapy  
4. Platelet count ≥75,000/mm3 (without transfusion in previous  
7 days).  
5. Absolute neutrophil count (ANC) ≥ 1,500/mm3 without  
filgrastim administration within 7 days, or pegfilgrastim within 14 days of measurement.  
6. Bilirubin < 2x the upper limit of normal 7. ALT and AST < 2.5x the upper limit of normal  
8. Creatinine clearance of ≥ 40 mL/min. Patients with  
creatinine clearance >30 but < 40 will be considered with review/approval from the protocol chairs or officer if the cause of renal insufficiency is associated with multiple myeloma  
9. Patients must be willing to receive DVT prophylaxis 10. Patient must be willing to follow birth control and pregnancy  
testing practices outlined in the protocol
study schema
initial exclusion criteria

1. Prior Autologous or Allogeneic HCT
2. Non secretory multiple myeloma (defined as normal serum and urine immunofixation and normal serum free light chain assay).  
3. Patients with a history of Plasma Cell Leukemia at any time prior to enrollment 4. Patients with prior disease progression at any time prior to enrollment 5. Patients seropositive for the human immunodeficiency virus
(HIV).  
6. Patients receiving treatment with Daratumumab or other CD38 Monoclonal Antibodies.  
7. Patient receiving other investigational or anti-myeloma drugs within 14 days of enrollment.  
8. Patients with active clinically significant autoimmune disease 9. Patients who have received mid-intensity melphalan (>50 mg IV) as part of prior therapy.  
10. Additional exclusion criteria outlined in section 2.3.2
study schema
primary clinical endpoint

Complete response (CR or sCR) at one year between patients receiving DC/myeloma vaccine/GM-CSF with lenalidomide maintenance therapy to those receiving lenalidomide maintenance therapy with or without GM-CSF.  
| 7 days).   |                                                                                                                                                                                                                                              |    |
|------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|
| 5.         | Absolute neutrophil count (ANC) ≥ 1,500/mm3 without  filgrastim administration within 7 days, or pegfilgrastim  within 14 days of measurement.                                                                                               |    |
| 6.         | Bilirubin < 2x the upper limit of normal                                                                                                                                                                                                     |    |
| 7.         | ALT and AST < 2.5x the upper limit of normal                                                                                                                                                                                                 |    |
| 8.         | Creatinine clearance of ≥ 40 mL/min. Patients with  creatinine clearance >30 but < 40 will be considered with  review/approval from the protocol chairs or officer if the  cause of renal insufficiency is associated with multiple  myeloma |    |
| 9.         | Patients must be willing to receive DVT prophylaxis                                                                                                                                                                                          |    |
| 10.        | Patient must be willing to follow birth control and pregnancy  testing practices outlined in the protocol                                                                                                                                    | Overall Survival; Toxicity and rates of infection; Minimal Residual  Disease; CR and sCR rates will be compared between the vaccine arm  and each of the no-vaccine arms; proportion of patients with tumor cell  collection who reach randomization; compliance with vaccine; and  reproducibility of the vaccine. Immunologic:Secondary immunologic endpoint :a) the percent of  patients achieving at least a 10 fold expansion of myeloma specific Tcells cells; b) expansion of myeloma antigen-specific T cells by tetramer  analysis; c) quantification of T-cells subsets and PD-1 expressing  lymphocytes; d) quantification of NK cells and identification of  activation and inhibitory ligands; e) assessment of NK mediated killing  of myeloma targets; f) assessment of humoral response against whole  myeloma cells and myeloma associated antigens by SEREX and by  characterizing myeloma-specific plasmablast responses.    |
study schema
primary immunologic endpoint

Treatment-induced expansion of myeloma-specific T cells as defined by the 2.4-fold increase from pre-therapy to peak post-treatment levels comparing the vaccine arm with patients receiving lenalidomide maintenance therapy with and without GM-CSF.
study schema
secondary endpoints

Clinical: Myeloma Response; Rate of conversion to CR; Disease Progression; Treatment-Related Mortality; Progression-Free Survival; Overall Survival; Toxicity and rates of infection; Minimal Residual Disease; CR and sCR rates will be compared between the vaccine arm and each of the no-vaccine arms; proportion of patients with tumor cell collection who reach randomization; compliance with vaccine; and reproducibility of the vaccine.
study schema
outline of treatment plan

- Accrual targets 188 patients to be enrolled with a target of 132 patients to be randomized, assuming about 30% of patients are unable to proceed with post-transplant immunotherapy.  
o Arm A: Maintenance lenalidomide + vaccine + GM-CSF (n=66)
o Arm B: Maintenance lenalidomide + GM-CSF (n=33)
o Arm C: Maintenance lenalidomide alone (n=33)
- Patients will be stratified according to disease status at time of randomization between CR/
sCR and VGPR/PR/stable disease.
study schema
table of contents

| TABLE OF CONTENTS               |                                                                                                                                         |
|---------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|
| 1.                              | OVERVIEW                                                                                                                                |
| 1.1.                            | Background .                                                                                                                            |
| 1.1.1.                          | Vaccination with DC/Myeloma fusion cells following autologous transplant .......... 1-1                                                 |
| 1.1.2.                          | Post-transplant lenalidomide maintenance                                                                                                |
| Study Specific Information .    |                                                                                                                                         |
| 1.2.                            |                                                                                                                                         |
| 1.3.                            | Rationale for Study                                                                                                                     |
| 2.                              | STUDY DESIGN                                                                                                                            |
| 2.1.                            | Study Overview .                                                                                                                        |
| 2.2.                            | Hypotheses and Specific Objectives .                                                                                                    |
| 2.2.1.                          | Hypothesis                                                                                                                              |
| 2.2.2.                          | Study Objectives .                                                                                                                      |
| 2.2.3.                          | Clinical Secondary Objectives                                                                                                           |
| 2.2.4.                          | Immunologic Secondary Objectives ..............................................................................................2-2      |
| Patient Eligibility             |                                                                                                                                         |
| 2.3.                            |                                                                                                                                         |
| 2.3.1.                          | Initial Inclusion Criteria .                                                                                                            |
| 2.3.2.                          | Initial Exclusion Criteria .                                                                                                            |
| 2.3.3.                          | Patient Eligibility Criteria for Randomization ......................................................................2-4                |
| 2.4.                            | Treatment Plan                                                                                                                          |
| 2.4.1.                          | Treatment Prior to Enrollment                                                                                                           |
| 2.4.2.                          | T TUMOR CELL COLLECTION                                                                                                                 |
| 2.4.3.                          | Systemic Anti-myeloma Therapy ..............................................................................................2-6         |
| 2.4.4.                          | Stem Cell Mobilization .                                                                                                                |
| 2.4.5.                          | Autologous Stem Cell Transplantation ....................................................................................2-7            |
| 2.4.6.                          | Maintenance Therapy.................................................................................................................2-7 |
| 2.4.7.                          | Vaccine Manufacturing and Administration                                                                                                |
| 2.4.8.                          | GM-CSF Administration.                                                                                                                  |
| 2.5.                            | Supportive Care                                                                                                                         |
| 2.5.1.                          | Post Autologous Transplantation(s)                                                                                                      |
| 2.5.2.                          | Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) Prophylaxis ..........2-12                                                       |
| 2.6.                            | Risks and Toxicities .                                                                                                                  |
| 2.6.1.                          | T THE PROVIDES                                                                                                                          |
| 2.6.2.                          | Lenalidomide                                                                                                                            |
| 2.6.3.                          | DC/Fusion Vaccine - Manufacturing and Administration .......................................................2-13                        |
| 2.6.4.                          | GM-CSF .                                                                                                                                |
| 2.7.                            | Study Drug Supply.                                                                                                                      |
| 2.7.1.                          | Lenalidomide                                                                                                                            |
| 2.8.                            | Patient Withdrawal from Study and Off Study Criteria .....................................................2-18                          |
| STUDY ENDPOINTS AND DEFINITIONS |                                                                                                                                         |
| 3.                              |                                                                                                                                         |
| 3.1.                            | Definition of Disease Status........................................................................................................3-1 |
| 3.1.1.                          | Response Categories                                                                                                                     |  
| 3.1.2.   | Progressive Disease (PD) 3-2                                                               |
|----------|--------------------------------------------------------------------------------------------|
| 3.2.     | Primary Endpoint 3-3                                                                       |
| 3.3.     | Clinical Secondary Endpoints 3-3                                                           |
| 3.3.1.   | Response to treatment 3-3                                                                  |
| 3.3.2.   | Myeloma Progression 3-4                                                                    |
| 3.3.3.   | Minimal Residual Disease Assessment 3-4                                                    |
| 3.3.4.   | Treatment-related Mortality 3-4                                                            |
| 3.3.5.   | Incidence of Toxicities Grade ≥3 per CTCAE vesion 4.0 3-4                                  |
| 3.3.6.   | Incidence of Infections per BMT CTN Technical MOP 3-4                                      |
| 3.3.7.   | Progression-free survival 3-4                                                              |
| 3.3.8.   | Overall Survival 3-5                                                                       |
| 3.4.     | Primary Immunologic Endpoints 3-5                                                          |
| 3.4.1.   | Myeloma-Reactive T-cells 3-5                                                               |
| 3.5.     | Secondary Immunologic Endpoints: 3-5                                                       |
| 3.5.1.   | Myeloma-Reactive T-cells 3-5                                                               |
| 3.5.2.   | Assessment of antigen specific reactivity: 3-5                                             |
| 3.5.3.   | Quantification of T-cell subsets: 3-5                                                      |
| 3.5.4.   | Assessment of effect on NK cell populations: 3-6                                           |
| 3.5.5.   | Assessment of humoral immune response: 3-6                                                 |
| 4.       | PATIENT REGISTRATION, ENROLLMENT, AND EVALUATION 4-1                                       |
| 4.1.     | Enrollment Procedures 4-1                                                                  |
| 4.2.     | Study Monitoring 4-1                                                                       |
| 4.2.1.   | Follow - Up Schedule 4-1                                                                   |
| 4.3.     | Patient Evaluations 4-3                                                                    |
| 4.3.1.   | Pre- Enrollment Segment A Evaluations and Requirements 4-3                                 |
| 4.3.2.   | Tumor Cell Collection Evaluations and Requirements at Enrollment 4-4                       |
| 4.3.3.   | Pre- Randomization Evaluations and Requirements 4-4                                        |
| 4.3.4.   | Pre- Maintenance Evaluations and Requirements 4-5                                          |
| 4.3.5.   | Evaluations during Maintenance 4-6                                                         |
| 4.4.     | Data Reporting 4-11                                                                        |
| 4.4.1.   | Criteria for Forms Submission 4-11                                                         |
| 4.4.2.   | Reporting Patient Deaths 4-11                                                              |
| 4.4.3.   | Center for International Blood and Marrow Transplant Research (CIBMTR) Data Reporting 4-11 |
| 4.4.4.   | Adverse Event Reporting 4-11                                                               |
| 4.4.5.   | Pregnancy Reporting 4-13                                                                   |
| 4.4.6.   | Celgene Drug Safety Contact Information: 4-14                                              |
| 4.4.7.   | Reporting of other Special Events of Interest 4-14                                         |
| 4.5.     | Ancillary Correlative Laboratory Studies Procedures 4-14                                   |
| 4.5.1.   | Obtaining Informed Consent 4-14                                                            |
| 4.5.2.   | Data Entry Requirements 4-15                                                               |
| 5.       | STATISTICAL CONSIDERATIONS 5-1                                                             |  
| 5.1.   | Study Design 5-1                                            |
|--------|-------------------------------------------------------------|
| 5.1.1. | Accrual 5-1                                                 |
| 5.1.2. | Randomization 5-1                                           |
| 5.1.3. | Primary Endpoint 5-1                                        |
| 5.1.4. | Primary Hypothesis 5-1                                      |
| 5.1.5. | Duration of follow-up 5-2                                   |
| 5.2.   | Sample Size and Power Considerations 5-2                    |
| 5.2.1. | Primary Endpoint (Clinical) 5-2                             |
| 5.2.2. | Power Considerations for Primary Immunologic Endpoint 5-2   |
| 5.3.   | Interim Analysis and Stopping Guidelines 5-2                |
| 5.3.1. | Interim Analysis for Efficacy 5-2                           |
| 5.3.2. | Interim Analysis for Futility 5-2                           |
| 5.3.3. | Guidelines for Safety Monitoring 5-3                        |
| 5.4.   | Demographic and Baseline Characteristics 5-4                |
| 5.5.   | Analysis of Primary Clinical Endpoint 5-4                   |
| 5.6.   | Analysis of Secondary Clinical Endpoints 5-4                |
| 5.6.1. | Response to treatment 5-4                                   |
| 5.6.2. | Myeloma Progression 5-4                                     |
| 5.6.3. | Treatment-related Mortality 5-4                             |
| 5.6.4. | Progression-free survival 5-5                               |
| 5.6.5. | Overall survival 5-5                                        |
| 5.6.6. | Incidence of toxicities grade ≥ 3 per CTCAE version 4.0 5-5 |
| 5.6.7. | Incidence of infections 5-5                                 |
| 5.6.8. | Minimal Residual Disease assessment 5-5                     |
| 5.7.   | Analysis of Immunological Endpoints 5-5                     |
| 5.7.1. | Primary immunologic endpoint: Myeloma reactive T-cells 5-5  |
| 5.7.2. | Secondary immunologic endpoints: 5-6                        |
| 5.8.   | Endpoint Review Committee 5-6                               |  
| LIST OF APPENDICES APPENDIX A CRITERIA FOR SYMPTOMATIC MULTIPLE MYELOMA APPENDIX B1 INFORMED CONSENT FORM FOR BMT CTN 1401 APPENDIX B2 INFORMED CONSENT DOCUMENTS FOR BMT CTN 1401 OPTIONAL CORRELATIVE LABORATORY STUDY  PARTICIPANTION APPENDIX C LABORATORY PROCEDURES APPENDIX D LENALIDOMIDE RISKS OF FETAL EXPOSURE, PREGNANCY  TESTING GUIDELINES AND ACCEPTABLE BIRTH CONTROL  METHODS APPENDIX E Revlimid REMS® PROGRAM APPENDIX F HUMAN SUBJECTS APPENDIX G KARNOFSKY PERFORMANCE STATUS SCALE APPENDIX H NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION OF  CARDIAC DISEASE   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
x  
| APPENDIX I   | ADVERSE EVENTS                                   |
|--------------|--------------------------------------------------|
| APPENDIX J   | VCAN ANCILLARY STUDY                             |
| APPENDIX K   | T CELL/MYELOMA GENOMIC SIGNATURE ANCILLARY STUDY |
| APPENDIX L   | REFERENCES                                       |  
xi
chapter 1
1. overview 1.1.background

Immune therapy has emerged as a leading area of cancer therapeutics due to its potential to recruit multiple effectors that broadly target malignant cells and overcome mechanisms of resistance. Multiple myeloma (MM) is characterized by the loss of critical mediators of immune surveillance, resulting in the suppression of antigen-presenting and effector cell function and the development of an immunologic milieu that fosters disease progression1- 6. We have developed a tumor vaccine in which patient-derived myeloma cells are fused with autologous dendritic cells (DCs), such that a broad array of myeloma antigens are presented in the context of DC-mediated costimulation7- 10.  
In diverse tumor models that include MM, vaccination of animals with DC/tumor fusions results in protection from an otherwise lethal challenge of malignant cells and, more significantly, eradication of disease in the setting of advanced metastatic involvement11,12. In a phase I study, 17 patients with advanced myeloma (median of 4 prior regimens) underwent vaccination with DC/MM fusions in conjunction with 4 days of GM-CSF administered at the vaccine site. As previously described, MM cells were isolated from bone marrow aspirates and fused with autologous DCs generated from adherent mononuclear cells cultured with GM-CSF, IL-4, and TNFα13. Vaccine production was successful in all patients and was well-tolerated without evidence of clinically significant autoimmunity. Vaccination resulted in a mean 10-fold expansion of CD4 and CD8 myeloma-specific T cells, as determined by the percentage of cells expressing IFNγ in response to ex vivo exposure to autologous tumor lysate. Similarly, vaccination resulted in the development of myeloma-specific antibody responses as documented by SERAX analysis13.  
1.1.1. Vaccination with DC/Myeloma fusion cells following autologous transplant Vaccination with DC/Myeloma fusion cells following autologous transplant is associated with potent immune response and conversion from PR to CR in a subset of patients14. We completed a clinical trial in which MM patients were vaccinated with DC/MM fusion cells in conjunction with autologous transplantation (ASCT). In the first cohort of the study, twenty-four patients received serial vaccinations following post-transplant hematopoietic recovery. A second cohort of 12 patients received a pre-transplant vaccine followed by post-transplant vaccinations. Vaccine preparation was successful in all patients. Mean yield of the DC and MM cells was 1.74 x 108 and 6.5 x 107 cells, respectively. Mean fusion efficiency, as determined by the percentage of cells that co-expressed unique DC (CD80, CD86, and/or CD83) and MM (CD38 and/or CD138) antigens, was 38%. The mean dose administered was 3.6 x 106 fusion cells. Mean viability of the DC,
myeloma, and fusion preparations was 87%, 87%, 79%, respectively. The DC/MM fusion preparations exhibited potent antigen presenting capacity, as evidenced by their stimulation of allogeneic T cell proliferation, with a mean stimulation index of 36.6, similar to that observed with the DC preparation prior to fusion (mean stimulation index of 52.3). In contrast, the unfused myeloma cells demonstrated minimal capacity for T cell stimulation (mean stimulation index of 13.7). All vaccine-associated toxicities were of grade I-II intensity. The most common toxicity was erythema and induration at the vaccine injection site associated with T cell infiltration on biopsy. The other common side effects were transient pruritus, rash, fatigue, fever, and myalgias. One patient had a transiently elevated ANA level without clinical evidence of autoimmunity. One patient developed transient grade 2 leukopenia, but no evidence of graft compromise was observed following vaccination. Consistent with prior reports, the post-transplant period was associated with the relative suppression of general measures of cellular immunity as manifested by decreased T cell proliferative responses to mitogen or recall antigens. In contrast, the period of post-transplant lymphopoietic reconstitution was associated with the expansion of myeloma-specific T cells that was further boosted following vaccination, as determined by percentage of CD4+ and CD8+ T
cells expressing IFNγ in response to ex vivo exposure to autologous tumor lysate. In the first cohort that received only post-transplant vaccination, the mean log10 fold increase in myelomaspecific CD4+ T cells from pre-mobilization to post-transplant and from pre-mobilization to peak post-vaccination was 3.55 (95% CI 0.81;15.49) and 10.72 (95% CI 3.89;29.51), respectively. Similarly, the mean log10 fold increase in myeloma specific CD8+ T cells from pre-mobilization to post-transplant and from pre-mobilization to peak post-vaccination was 6.76 (95% CI 3.02;15.49) and 11.48 (95% CI 4.17;32.36), respectively. A smaller subset of patients underwent a single pre-transplant vaccination followed by post-transplant boosting. Of note, no difference in peak levels of CD4+ or CD8+ circulating myeloma-specific T cells was observed between the cohort receiving a pre-transplant vaccine and that undergoing post-transplant vaccination alone (p=0.185 and p=0.689, respectively). For the entire study population, the mean log10 fold increase in myeloma-specific CD4+ T cells from pre-mobilization to post-transplant and from premobilization to peak post-vaccination was 3.55 (95% CI 1.58;8.13) and 9.55 (95% CI 5.37;16.98),
respectively. The mean log10 fold increase in myeloma-specific CD8+ T cells from premobilization to post-transplant and from pre-mobilization to peak post-vaccination was 4.37 (95%
CI 2.40;7.76) and 8.32 (95% CI 4.68;15.14), respectively. Notably, vaccination was associated with the expansion of T cells targeting the myeloma-specific antigen, MUC1, as determined by tetramer analysis. In a cohort of patients who were HLA-A2, the median percentage of MUC1specific T cells was 0.12 pre-transplant and increased to 1.84 at 3 months after completion of vaccination (p<0.05), representing a median fold increase of 17.5. The expansion of T cells targeting MUC1 in response to vaccination is of particular interest, as we have identified a population of CD34+/MUC1+ cells in the bone marrow of patients with myeloma that demonstrate myeloma-initiating capacity.  
Seventy-eight percent of patients achieved a CR or VGPR (47% CR/nCR; 31% VGPR). Thirtyone percent achieved a CR/nCR in the early post-transplant period, whereas an additional 17% (6 patients: 4 from VGPR, 2 from PR) achieved CR/nCR as best response only after day 100 posttransplant and after undergoing vaccination. The presence of late responses several months after ASCT is consistent with an impact of vaccine therapy on post-transplant residual disease.  
1.1.2. Post-transplant lenalidomide maintenance Post-transplant lenalidomide maintenance prolongs disease-free and overall survival15. This is thought to be potentially due to its immunomodulatory characteristics. In pre-clinical studies, we demonstrated that lenalidomide potently enhances immune response to vaccination16. T cells were stimulated in vitro with DC/MM fusions in the absence or presence of lenalidomide. After 5–7 days of stimulation by the vaccine, the percentage of CD8+ T cells expressing IFNγ increased significantly in the presence of lenalidomide (from 6.37 to 9.9 %; n = 7, p = 0.03). A concomitant statistically significant decrease in the proportion of regulatory T cells was also observed (4.4 % in the lenalidomide group as opposed to 9.6 % in the control group; n = 3, p = 0.02). As determined by a flourochrome assay measuring granzyme B release in target cells, CTL-mediated lysis of autologous MM tumor targets was increased by 50% when T cells were stimulated by DC/MM fusions in the presence of lenalidomide, as compared to those cultured with fusions alone (mean 29.2% vs. 19.7%; n=3, p=0.004).
chapter 1
1.2.study specific information

Based on these encouraging data, the DC/MM fusion vaccine was chosen to be the first cellular immunotherapy to be evaluated in a multicenter cooperative group study involving several nationally prominent cancer centers (BMT CTN protocol 1401). We will conduct a multicenter phase II randomized study comparing post-transplant vaccination with DC/MM fusions/GM-CSF and lenalidomide maintenance to lenalidomide maintenance with and without GM-CSF, with vaccine manufacturing performed locally at each participating center. The primary objective is to assess the impact of post-transplant immunotherapy on the percentage of patients in CR at 1 year between the vaccine arm and both no-vaccine arms combined. Secondary endpoints include determining the effect of therapy on progression-free survival, myeloma response, minimal residual disease, toxicities, transplant-related mortality, and overall survival. Additionally, this study includes several immunologic endpoints to understand the effect of the vaccine on the antimyeloma immunity, the immune effects of lenalidomide, and general immune reconstitution after transplant. The primary immunologic endpoint is to compare the expansion of myeloma-specific T cells across all three arms.
chapter 1
1.3.rationale for study

MM is associated with immune suppression, including defects in antigen presentation and effector cell function that are thought to play a role in disease progression. Although the outcomes for myeloma patients have improved greatly over the past decade, the majority of patients relapse even after autologous stem cell transplant and post-transplant maintenance therapy with lenalidomide. Early phase clinical data demonstrate that post-transplant vaccination with a DC-MM fusion product with GM-CSF adjuvant increases the number of MM-specific T cells. Furthermore, it appears that lenalidomide can specifically augment vaccine-stimulated induction of MM-specific T cells. We are therefore interested in combining standard immunomodulatory therapy
(lenalidomide) with a potential immune stimulant (DC-MM vaccination) to increase posttransplant clinical response. Finally, pre-clinical data has suggested that immunomodulatory agents augment NK cell activity17 and that NK cells interact with and can be activated by DCs18.  
Thus, we are interested in further defining the NK immmunophenotype in the setting of posttransplant maintenance lenalidomide and the changes to this phenotype in the setting of DC-MM
fusion vaccination. We postulate that post-transplant lenalidomide maintenance will augment posttransplant anti-myeloma immunity, thus providing an ideal platform for DC/MM fusion vaccination. Additionally, to understand the effect of vaccine versus the adjuvant in the posttransplant setting, we split the non-vaccine arms into lenalidomide alone and lenalidomide plus GM-CSF, with GM-CSF administered in the exact same schedule and dosing as in the vaccine arm. Although there is no evidence that GM-CSF has an anti-myeloma effect, this additional control arm is important to understand whether any effect of the vaccine is due to its adjuvant and whether GM-CSF influences any of the immunologic outcomes. We further hypothesize that vaccination in this setting will effectively target post-transplant residual disease, increase the percentage of patients achieving CR, and create durable responses. The results of this trial will provide information on whether this patient-specific vaccine administered after transplant is promising for further comparison with current standard of care treatment. Furthermore, this trial will address several important aspects of anti-myeloma immunity, including how lenalidomide maintenance influences post-transplant recovery and myeloma control. Lastly, isolating the effect of the GM-CSF adjuvant will address whether any effect observed is related solely to the vaccine.
chapter 1
chapter 2 2. study design

The study is a three-arm, phase II randomized, open-labeled clinical trial to evaluate vaccination with DC/myeloma fusions/GM-CSF plus lenalidomide maintenance therapy compared to lenalidomide maintenance therapy with or without GM-CSF following autologous transplant as part of upfront treatment for patients diagnosed with multiple myeloma. Patients meeting initial eligibility will be enrolled, and tumor cells will be harvested. Patients will proceed or continue with systemic anti-myeloma therapy and stem cell mobilization according to institutional practices. Patients with available cryopreserved tumor cells who are eligible to proceed to transplantation will be randomized in the study around Day 56 post-transplant. Approximately 2 months post-transplant, patients will undergo their first disease response assessment and will be randomized 2:1:1 to the vaccine/GM-CSF plus lenalidomide arm, lenalidomide/GM-CSF arm, or lenalidomide alone arm. Patients assigned to vaccine plus lenalidomide maintenance will subsequently undergo leukapheresis for collection of dendritic cell precursors and vaccine production (DC/myeloma vaccine). For all patients, lenalidomide maintenance will start at Day 90-100 post-transplant and continue for two years or until disease progression, whichever comes first. Vaccines will be administered on the first day of cycles 2, 3, and 4 of lenalidomide maintenance, followed by four daily doses of GM-CSF for patients randomized to the vaccine arm. Patients randomized to lenalidomide/GM-CSF will receive GMCSF in the same schedule and dose as patients in the vaccine arm. Primary endpoint assessment will occur at 1 year post-transplant.
chapter 1
2.2.hypotheses and specific objectives 2.2.1.

Vaccination with DC/myeloma fusions plus lenalidomide maintenance therapy will result in improved responses in patients with multiple myeloma after autologous HCT.
chapter 1
2.2.2. study objectives

Compare the proportion of patients alive and in complete response (CR or sCR) at one year posttransplant, corresponding to 1 year post transplant (approximately 10 months after randomization)
between patients receiving DC/myeloma vaccine/GM-CSF with lenalidomide maintenance therapy to those receiving lenalidomide maintenance therapy with or without GM-CSF.
chapter 1
2.2.3. clinical secondary objectives

Compare myeloma response, rate of conversion to CR, myeloma progression, treatment-related mortality, progression-free survival, overall survival, incidence of grade > 3 toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0, incidence of infections, measures of minimal residual disease, between the vaccine and the combined no-vaccine treatment arms. A secondary pairwise analysis of the proportion of patients alive and in CR at one year posttransplant will also be conducted between the vaccine arm, lenalidomide/GM-CSF arm, and the lenalidomide alone arm. Additionally, the study will describe the proportion of patients with collection of tumor cells who reach randomization, compliance with vaccine, and the reproducibility of the vaccine manufacturing based on the release criteria.  
2.2.4. Immunologic Secondary Objectives Primary immunologic endpoints:
- Compare the expansion of treatment-induced myeloma-specific T cells, defined as a 2.4fold increase from pre-therapy to peak post-treatment levels between the vaccine arm and each of the no-vaccine arms separately.  
Secondary immunologic endpoints:
- Determine the percentage of patients achieving at least a 10-fold expansion of myelomaspecific T cells in each treatment arm.  
- Quantify myeloma antigen-specific T cells by tetramer analysis. - Quantify T cell subsets and PD-1 expressing lymphocytes. - Quantify NK cells and identify activation and inhibitory ligands. - Assess NK cell-mediated killing of myeloma targets. - Assess humoral response against whole myeloma cells and myeloma-associated antigens by SEREX and by characterizing myeloma-specific plasmablast responses.
chapter 1
2.3.patient eligibility

Patients must meet specified eligibility criteria outlined in section 2.3.1 and 2.3.2 to be registered on the study. Additional criteria must also be met to continue to successive stages of the protocol. All questions regarding eligibility criteria should be directed to the protocol coordinator at 301-251-1161.  
2.3.1. Initial Inclusion Criteria  
1. Patients must be considered transplant eligible by the treating physician at time of study entry.  
2. Patients must meet the criteria for symptomatic multiple myeloma (Appendix A) prior to initiating systemic anti-myeloma treatment.  
3. Age >18.00 years and < 71.00 years at the time of enrollment 4. Karnofsky Performance status of ≥ 70%
5. Patients must have > 20% plasma cells in the bone marrow aspirate differential <60 days prior to enrollment. If patient receives anti-myeloma therapy1 treatment after bone marrow aspirate to assess eligibility and before bone marrow aspirate for tumor cell collection, a repeat bone marrow evaluation will be required to confirm > 20% plasma cells in the bone marrow aspirate differential prior to enrollment and tumor cell collection.  
6. Patients must have received < 1 cycle of systemic anti-myeloma therapy1.  
7. Renal: Creatinine clearance of ≥ 40 mL/min, estimated or calculated.
2.3.2. Initial Exclusion Criteria 1. Patients with a prior autologous or allogeneic HCT  
2. Patients with purely non-secretory MM [absence of a monoclonal protein (M protein)
in serum as measured by electrophoresis and immunofixation and the absence of Bence Jones protein in the urine defined by use of conventional electrophoresis and immunofixation techniques and the absence of involved serum free light chain >100 mg/L]. Patients with light chain MM detected in the serum by free light chain assay are eligible.  
3. Patients with a history of Plasma Cell Leukemia at any time prior to enrollment. 4. Patients with disease progression at any time prior to enrollment (see Section 3.1.3 for disease progression definition).  
5. Patients seropositive for the human immunodeficiency virus (HIV). 6. Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure (see Appendix H), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening will be documented by the investigator as not medically relevant.  
7. Patients with active clinically significant autoimmune disease, defined as a history of requiring systemic immunosuppressive therapy and at ongoing risk for potential disease exacerbation. Patients with a history of autoimmune thyroid disease, asthma, or limited skin manifestations are potentially eligible.  
8. Patients receiving other investigational immunotherapy or anti-myeloma drugs within 14 days before enrollment.  
9. Patients receiving prior treatment with daratumumab, elotuzumab, and/or any other monoclonal antibody-based therapy at any time prior to enrollment.  
10. Patients with prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent < 5 years prior to enrollment will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.  
Cancer treated with curative intent > 5 years prior to enrollment is allowed.  
11. Female patients who are pregnant (positive β-HCG) or breastfeeding.  
12. Females of childbearing potential (FCBP)1 or men who have sexual contact with FCBP
unwilling to use contraceptive techniques (Appendix D) during the length of lenalidomide maintenance therapy.  
13. Patients who have received mid-intensity melphalan (>50 mg IV) as part of prior therapy.  
14. Prior organ transplant requiring immunosuppressive therapy. 15. Patients who previously received lenalidomide and have experienced toxicities resulting in treatment discontinuation.  
16. Patients who experienced thromboembolic events while on full anticoagulation during prior therapy with lenalidomide or thalidomide.  
17. Patients unwilling to take DVT prophylaxis. 18. Patients unable or unwilling to provide informed consent. 19. Patients unable or unwilling to return to the transplant center for their assigned treatments.
2.3.3. Patient Eligibility Criteria for Randomization  
1. No disease progression since initiation of systemic anti-myeloma therapy as determined ≤ 10 days prior to randomization/enrollment.  
2. Received an autologous cell transplant with melphalan 200mg/m2 with a minimum cell dose of 2x106 CD34+ cells/kg (actual body weight) < 12 months of enrollment onto BMT CTN 1401.  
3. Tumor cell preparation must:
a. Express > 20% CD38 or CD138 by staining b. Yield > 10 million plasma cells2 c. Have a negative microbiology assessment
4. Mucositis and gastrointestinal symptoms resolved, off hyperalimentation and intravenous hydration.  
5. No evidence of uncontrolled infection requiring systemic therapy. Patients who completed treatment for an infection but are continuing antibiotics, anti-viral, or antifungal therapy for prophylaxis are eligible to continue on protocol.  
6. Platelet count ≥75,000/mm3 (without transfusion in previous 7 days). 7. Absolute neutrophil count (ANC) ≥ 1,500/mm3 without filgrastim administration within 7 days, or pegfilgrastim within 14 days of measurement.  
8. Hepatic: bilirubin < 2x the upper limit of normal and ALT and AST < 2.5x the upper limit of normal. (Patients who have been diagnosed with Gilbert's Disease are allowed to exceed the defined bilirubin value of 2x the upper limit of normal.)
9. Renal: Creatinine clearance of ≥ 40 mL/min, estimated or calculated. Patients with creatinine clearance ≥30 but <40 will be considered with review/approval from the protocol chairs or officer if the cause of renal insufficiency is associated with multiple myeloma.  
10. All study participants must be registered into the mandatory Revlimid REMs program, and be willing and able to comply with the requirements.  
11. Females of childbearing potential (FCBP) as defined in section 2.7.1.1 must have a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days)
12. FCBP must either commit to abstain continuously from sexual intercourse or use 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, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of lenalidomide.  
13. FCBP must agree to ongoing pregnancy testing as required by the RevlimidREMs program.  
14. 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 while taking lenalidomide, during dose interruptions and for 28 days after discontinuing lenalidomide.  
15. Patients must be willing to receive DVT prophylaxis.
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2.4.treatment plan

2.4.1. Treatment Prior to Enrollment Patients must have < 1 cycle of anti-myeloma therapy prior to enrolling on the study. It is recommended whenever clinically feasible to minimize the treatment administered prior to enrollment to ensure adequate tumor cell collection and preparation for vaccine production. Patients receiving treatment with daratumumab or other CD38 monoclonal antibodies prior to enrollment should not be considered for this study. 2.4.2. Tumor Cell Collection An initial eligibility assessment will be performed at time of study entry prior to tumor collection for immune monitoring and subsequent vaccine production. Eligible patients will undergo aspiration of 30 mL of bone marrow from which myeloma cell preparations will be generated (Appendix C and BMT CTN 1401 Manufacturing, Clinical and Reference SOPs). Bone marrow will be aspirated into sterile heparinized syringes with approximately 5-8 mL aspirated per syringe to avoid significant hemodilution of bone marrow mononuclear cells. Bone marrow aspirate samples will be transferred in sterile syringes to the cell manipulation facility, and mononuclear cells will be isolated by ficoll density gradient centrifugation. Autologous plasma will be obtained by harvesting supernatant following centrifugation of 50 mL of peripheral blood. An aliquot of the tumor cells will be sent to BIDMC for centralized immunohistochemical staining as detailed in Appendix C. Tumor lysate will be prepared by freeze/thawing or sonication of an aliquot of tumor cells for immunological analysis. The remaining myeloma cells will be frozen in 10% DMSO/90% autologous plasma stored in liquid nitrogen for potential subsequent vaccine generation.
chapter 1
2.4.2.1.second tumor cell collection

If the initial bone marrow harvest does not yield a sufficient cell count as required by the BMT CTN 1401 Vaccine Product Release criteria, a second collection may be considered if the following items are completed *prior* to the second collection:
- Submission and review of an occurrence report in AdvantageEDC - Written approval from the BMT CTN 1401 Protocol Chairs/Officer and Medical Monitor is received
- All corrective actions are completed and appropriate documentation is submitted to the BMT CTN DCC
- Final written approval from the BMT CTN DCC is received by the site 2.4.3. Systemic Anti-myeloma Therapy Pre-transplant systemic anti-myeloma therapy will be administered per investigator discretion following enrollment and tumor cell collection.  
2.4.4. Stem Cell Mobilization Stem cell mobilization and collection should be done according to institutional guidelines. 2.4.5. Autologous Stem Cell Transplantation Autologous hematopoietic cell transplant will be done with high-dose melphalan (200mg/m2) at the schedule and timing according to institutional practices and must be within 12 months of enrollment on to the study 2.4.5.1.Peripheral blood stem cell infusion All patients will receive an autologous graft with a minimum cell dose of 2.0 x 106 CD34+ cells/kg patient actual body weight per autologous transplantation. The graft may not be CD34+ selected or otherwise manipulated to remove tumor or other cells. Cryopreservation and thawing of product will comply with FACT standards and local institutional practice. 2.4.6. Maintenance Therapy All patients who meet the eligibility criteria to proceed to randomization and who have completed the post-transplant disease response assessment will be randomized between day 53 and day 80 post-transplant and within 10 days of a disease response assessment. Patients will begin maintenance therapy with lenalidomide between 90 and 100 days after stem cell infusion. Lenalidomide will be administered initially at a dose of 10 mg per day continuously. Cycle duration during maintenance therapy is 28 days. Patients will continue lenalidomide for two years from initiation of therapy or until one of the criteria in section 2.8 applies. For patients receiving GM-CSF and/or Vaccine, lenalidomide is recommended to be taken in the evening at least 4 hours after vaccination to avoid confusion with immediate vaccine and/or GM-CSF site reactions. Patients who stop maintenance therapy for any reason prior to two years from initiation of maintenance will continue to be followed per protocol for 3 years post maintenance initiation. Upon completion of protocol specified maintenance therapy, patients will be treated at the investigator's discretion. However, it is recommended that patients continue receiving lenalidomide as per standard of care. 2.4.6.1.Lenalidomide maintenance dose modifications Lenalidomide dose will be adjusted for toxicity. Table 2.4.5B describes the dose reduction steps to be utilized during maintenance therapy. In the presence of lenalidomide-related toxicities (Table 2.4.5A), the study drug will be held until the toxicity resolves then restarted at a reduced dose as described in Table 2.4.5B. If lenalidomide is held for >8 weeks for any reason, study chair approval must be obtained prior to re-starting lenalidomide. Patients will be given DVT prophylaxis. DVT prophylaxis for patients will be given per institutional guidelines. See section 2.5.2 for suggested dose and more information.  
| for Non-Hematologic Toxicities                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                   |
|---------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade by NCI CTCAE# 1                                                                                                                       | Action                                                                                                                                                                                                                                                                                                                                                                            |
| Grade 3 neutropenia  associated with fever (temperature > 38. 5º C)  or Grade 4 neutropenia                                                 | Hold lenalidomide. Follow CBC weekly.  If the toxicity resolves to <grade 2 restart lenalidomide at next lower dose level.  If neutropenia is the only toxicity for which a dose reduction is required, granulocyte growth factors could be considered  at the discretion of the treating physician and the lenalidomide dose maintained. . Hold lenalidomide. Follow CBC weekly. |
| Thrombocytopenia                                                                                                                            | If the toxicity resolves to <grade 2 restart lenalidomide at next lower dose level.                                                                                                                                                                                                                                                                                               |
| (platelet count < 30,000/mm³) Non-blistering rash                                                                                           | Hold lenalidomide: Follow weekly. Treatment with antihistamine may be initiated at the discretion of the investigator.                                                                                                                                                                                                                                                            |
| Grade 3                                                                                                                                     | If the toxicity resolves to ≤ grade 1 restart lenalidomide at next lower dose level.                                                                                                                                                                                                                                                                                              |
| (Generalized rash ≥ 25% BSA) Non-blistering rash Grade 4                                                                                    | Discontinue lenalidomide permanently. Continue to follow the patient per-protocol                                                                                                                                                                                                                                                                                                 |
| Desquamating (blistering) rash any Grade                                                                                                    | Discontinue lenalidomide permanently. Continue to follow the patient per-protocol                                                                                                                                                                                                                                                                                                 |
| Venous thrombosis/embolism ≥ Grade 3                                                                                                        | Hold lenalidomide and start anticoagulation per institutional guidelines. Restart therapy and maintain dose level.                                                                                                                                                                                                                                                                |
| (DVT or cardiac thrombosis; intervention  indicated) Other non-hematologic toxicity                                                         | Hold lenalidomide.                                                                                                                                                                                                                                                                                                                                                                |
| assessed as Lenalidomide-related                                                                                                            | If the toxicity resolves to ≤ grade 2 restart lenalidomide at next lower dose level.                                                                                                                                                                                                                                                                                              |
| ≥ Grade 3                                                                                                                                   | Hold lenalidomide.                                                                                                                                                                                                                                                                                                                                                                |
| Hyperthyroidism or                                                                                                                          | Evaluate etiology, and initiate appropriate therapy.                                                                                                                                                                                                                                                                                                                              |
| Hypothyroidism                                                                                                                              | Restart lenalidomide at next lower dose level .                                                                                                                                                                                                                                                                                                                                   |
| Pregnancy3                                                                                                                                  | Discontinue lenalidomide study drug.                                                                                                                                                                                                                                                                                                                                              |
| 1 Please consult NCI CTCAE version 4 http://ctep.cancer.gov/reporting/ for complete Grade descriptions. The "≥ Grade 3" descriptions listed |                                                                                                                                                                                                                                                                                                                                                                                   |
chapter 1
table 2.4.6b - lenalidomide dose

| Lenalidomide Dose Reduction Steps for Non-Hematologic Toxicity   |                                        |
|------------------------------------------------------------------|----------------------------------------|
| Dose at Time of Toxicity                                         | Dose reduction                         |
| 10 mg daily                                                      | 5 mg daily                             |
| 5 mg daily                                                       | 5 mg daily for 21 days every 28 days   |
| 5 mg daily for 21 days every 28 days                             | 2.5 mg daily for 21 days every 28 days |
| 2.5 mg daily for 21 days every 28 days                           | Discontinue lenalidomide               |  
2.4.6.2. Lenalidomide maintenance dose re-escalation If a dose reduction has occurred and ANC ≥ 1000/µL and platelet count is ≥ 75,000/µL, the study drug dose may be re-escalated as shown on Table 2.4.5c, one step per cycle to a maximum of 10 mg daily.  
Current Patient Dose Dose Re-Escalation  
2.5 mg daily for 21 days every 28 days 5 mg daily for 21 days every 28 days  
| 5 mg daily for 21 days every 28 days   | 5 mg daily   |
|----------------------------------------|--------------|
| 5 mg daily                             | 10 mg daily  |  
10 mg daily No more dose escalations permitted  
2.4.7. Vaccine Manufacturing and Administration Vaccine preparation is outlined in detail in the BMT CTN 1401 SOPs and will be performed locally at each participating institution. Patients randomized to receive the DC/MM fusion vaccine will undergo leukapharesis for DC and vaccine generation per the BMT CTN 1401 manufacturing, clinical, and reference SOPs. Leukapheresis should occur by day 85 post-transplant to ensure sufficient time for vaccine production and sterility testing. The leukapheresis product will be transferred in a sterile container to the cell manipulation facility, and PBMC will be isolated from the leukapheresis product and cultured in the presence of autologous plasma for 1 hour and then cultured for 5-7 days with GM-CSF and IL-4. Cultures will be re-fed with cytokines, GM-CSF,
and IL-4 after 5-7 days. Twenty-five ng/mL of TNFαwill be added for 48-72 hours to induce DC
maturation after 5-7 days. An aliquot of the DC preparation will be sent to BIDMC for immunocytochemical staining for immunophenotypic analysis. Tumor cells and DC preparations will be co-cultured at ratio of 1:3 and washed in serum-free medium. After low-speed centrifugation, the cell pellet will be re-suspended in 50% solution of polyethylene glycol (PEG) and will be progressively diluted by the slow addition of serum-free medium. An aliquot of the DC, tumor, and fusion cell preparations will be sent to BIDMC for immunocytochemical analysis for vaccine characterization at the timepoints indicated in the BMT CTN 1401 manufacturing SOPs. The vaccine doses will be prepared per the Vaccine Dose Guidelines in section 2.4.7.1. The fusion cells will then be irradiated at 30 Gy, and frozen in 10% DMSO/90% autologous plasma in liquid nitrogen. An aliquot of the vaccine product will be sent for microbiological assessment consisting of endotoxin, mycoplasma and sterility testing as per the BMT CTN 1401 manufacturing SOPs. Release criteria for vaccine administration are:  
1) At least 20% of tumor cell prep must express CD38 or CD138 by staining 2) Tumor cell prep must yield >10 million plasma cells1 3) > 50% of DC prep express CD86 4) Viability of DC prep > 50% 5) Fusion efficiency > 15% 6) Fusion viability > 50% 7) Sterility, mycoplasma, and endotoxin assays are negative
At time of administration, fusion cells will be thawed. Patients randomized to the vaccine arm will receive the DC/myeloma fusion vaccine/GM-CSF (vaccine) on day 1 of cycles 2, 3, and 4 of lenalidomide maintenance. Vaccine will be administered by subcutaneous injection with 100 ug GM-CSF given subcutaneously at the vaccine site on day of vaccination and daily for a total of 4 days of each cycle. Patients who are randomized to the vaccine arm and are unable to receive vaccine for any reason, will receive lenalidomide alone for the duration of the study per section 2.4.6. All vaccine related procedures are detailed in the BMT CTN 1401 manufacturing, clinical, and reference SOPs which must be adhered to by all sites for each patient enrolled on the study. Patients who are unable to receive vaccine for any reason (i.e. toxicity, failure to meet release criteria, etc) should receive lenalidomide only for the duration of the study. 2.4.7.1.Vaccine Dose Guidelines The target dose is 3 x 106 fusion cells per vaccine. A minimum of 3 x 106 fusion cells will be required to proceed with vaccine administration. Patients who have < 3 x 106 fusion cells will not proceed with vaccination.  
| Table 2.4.7A - Vaccine Dose Guidelines                               |                                                                                          |                                                                                     |
|----------------------------------------------------------------------|------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------|
| Total Fusion Cell Yield                                              | Dose Guidance                                                                            |                                                                                     |
| -                                                                    | 3 doses of 3 x 106 fusion cells are cryopreserved  for patient administration            |                                                                                     |
| -                                                                    | Excess product should be cryopreserved in  aliquots of 3x106 fusion cells when possible. |                                                                                     |
| > 9 x 106 fusion cells > 3x106 fusion cells and < 9x106 fusion cells | -                                                                                        | Divide product in to 3 equal doses for  cryopreservation and patient administration |
| < 3x106 fusion cells                                                 | -                                                                                        | Patient will not receive vaccine.                                                   |  
2.4.7.2.Vaccine Production Occurrences Deviations from the manufacturing process outlined in the BMT CTN 1401 manufacturing, clinical, and reference SOPs will be documented on the Occurrence Report form in AdvantageEDC as per the Occurrence Report SOP (BMT 1401-RF 04). Following submission of an occurrence report, sites will be required to complete the following items *prior* to enrolling additional patients and proceeding with vaccine production:
- All queries and corrective actions associated with the report must be completed - The BMT CTN 1401 protocol chairs/officer and BMT CTN DCC will provide approval for continuing enrollment on the study. 2.4.7.2.1. Failure to Meet Release Criteria Sites experiencing difficulties with production as evidenced by failure to meet release criteria for 3 products will have vaccine production temporarily halted while undergoing onsite review of procedures by a member from the protocol team and central site. Additional training or guidance will be provided if needed.  
| Toxicities                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                              |
|----------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Toxicity                                                                                                                                     | Action Hold/delay vaccine. When lenalidomide is restarted, adjust date of vaccine administration to coincide  with Day 1 of cycles 2, 3 and 4 of lenalidomide maintenance.                                                                                                                                                                                                                                                                   |
| Discontinuation in                                                                                                                           | Administer vaccine at monthly intervals for a total of 3 doses                                                                                                                                                                                                                                                                                                                                                                               |
| lenalidomide therapy Hold/delay in  lenalidomide therapy Grade 4 toxicity  judged to be related to                                           | No additional vaccines.                                                                                                                                                                                                                                                                                                                                                                                                                      |
| vaccine alone Grade 3 toxicity  judged to be related to  vaccine alone                                                                       | Hold Vaccine Dose. If the toxicity resolves to ≤ grade 2 by time of subsequent vaccine administration,  vaccine may continue. Omit GM-CSF administration for subsequent vaccine injections or subsequent  scheduled administrations in the non-vaccine arm. Re-challenging GM-CSF  administrated when toxicity resolves to ≤ grade 2 can be considered at the discretion  of the treating investigator. Vaccine administration may continue. |
| Grade 3-4 toxicity  possibly related to  combination of  lenalidomide and  vaccine Grade 3-4 toxicity  judged to be related to  GM-CSF alone | Follow lenalidomide dose adjustments. Vaccine administration may continue.                                                                                                                                                                                                                                                                                                                                                                   |  
2.4.8. GM-CSF Administration For patients randomized to the vaccine and GM-CSF plus lenalidomide maintenance and lenalidomide maintenance plus GM-CSF arms, GM-CSF will be administered at cycles 2, 3, and 4 of maintenance therapy. 100 ug GM-CSF will be given subcutaneously (at the vaccine site for patients receiving vaccine) on days 1-4 of cycles 2, 3, and 4 per the BMT CTN 1401 manufacturing SOPs.  
On the first day of GM-CSF administration, the clinical research nurse will administer 100 ug of GM-CSF subcutaneously. The patient will be trained to inject the remaining three GM-CSF injections (100ug dose once a day at the vaccination site) for self-administration subcutaneously at home. Alternatively, if patients are unwilling or unable to self-administer the GM-CSF, they can return to the transplant center for subsequent injections. For patients receiving vaccine, tumor vaccine will be administered before the GM-CSF injection. GM-CSF is given on Day 1 at time of vaccination and around the same time of day (+/- an hour whenever feasible) for subsequent doses. If a patient experiences a grade 2 or higher (graded according to CTCAE v4.0) injection site reaction during the days when GM-SCF is administered, subsequent doses of GM-CSF may be held until the injection site reaction improves to grade 1 or less at the discretion of the treating investigator. For subsequent administrations, patients will receive pre-medication with diphenhydramine (Benadryl) 25-50 mg and/or acetaminophen (Tylenol) 650-1000 mg to minimize potential allergic-related symptoms.
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2.5.supportive care

2.5.1. Post Autologous Transplantation(s)
All supportive care will be given at the investigators discretion. 2.5.2. Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) Prophylaxis Prophylaxis for DVT/PE will be done according to institutional guidelines. Upon initiation of lenalidomide maintenance it is recommended that patients without a history of thromboembolic events should be on aspirin daily (81mg, 165mg or 350 mg); low molecular weight heparin or warfarin is usually administered in patients with a history of thromboembolic events or those that cannot tolerate aspirin.
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2.6.risks and toxicities

Recipients of autologous transplantation incur risks from pre-transplant conditioning and posttransplant therapy, which must be weighed against the risk of the disease for which the transplant is prescribed. Major risks following transplantation include: 1) Infection, which can be bacterial, viral, parasitic, or fungal. Often, these infections are life-threatening, particularly when caused by viral or fungal agents, and are associated with high mortality in the transplant population; 2) Graft Failure can occur and is associated with a high-risk of mortality; 3) End Organ Damage of one or more major organs may occur as a result of reactions to drugs (e.g., melphalan, antibiotics, antifungal medications, etc.), and as a result of destructive processes (e.g., infection, etc.) and may have a fatal outcome; 4) Progression of MM may occur; 5) Unknown Toxicities may occur in any individual patient due to multiple events and cumulative effects which may involve any and all organs, including the brain. Brain damage can result in severe loss of cognitive or neurologic function; and, 6) Death. These risks may or may not be increased by the post-transplant therapies to be evaluated in this protocol.
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2.6.1. therapy toxicities

All toxicities will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 with BMT CTN 1401 specific definitions when appropriate.  
2.6.2. Lenalidomide Common toxicities described for lenalidomide include:
- Neurologic: Somnolence, dizziness, headache, tremor, asthenia, paresthesia, and numbness  
- Hematologic: anemia, neutropenia, leucopenia, lymphopenia and thrombocytopenia; thromboembolic events (deep vein thrombosis and pulmonary embolism).  
- Gastrointestinal: Constipation, dehydration, dry mouth, diarrhea, dyspepsia, nausea, vomiting and stomatitis.  
- Constitutional: Weakness, insomnia, rigors, chills, sweating, weight loss and fever.  
- Reproductive: teratogenicity and miscarriage.  
- Musculoskeletal: arthralgia, back/neck pain, joint pain, muscle cramp and weakness.  
- Cardiac: hypotension.
- Dermatologic: rash, dry skin, itching.  
- Endocrine: hypothyroidism. - Infection.
- Pulmonary: cough, dyspnea.  
- Metabolic: hypokalemia, liver damage. - Renal: increased creatinine, renal failure. - Second Primary Malignancies
Pregnancy reporting: See Section 4.2.3, Adverse Event Reporting.
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other instructions related to lenalidomide

During maintenance, only one cycle (maximum 28-day supply) of therapy may be dispensed to the patient each month. If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day. If it is missed for the entire day, it should not be made up. Patients taking more than the prescribed dose of lenalidomide should be instructed to seek emergency medical care if needed and contact study staff immediately. See Section 2.7.1.1, Chapter 4, Appendices D (Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods) and E (Revlimid REMS program). 2.6.3. DC/Fusion Vaccine - Manufacturing and Administration 2.6.3.1. Tumor Collection All eligible patients will undergo a bone marrow biopsy and collection of 30 mL of bone marrow aspirate. The risks of this procedure are not different than bone marrow aspirates performed for diagnosis or disease status assessments. The risks include: bleeding, pain in the site of marrow collection, claudication and bruising. 2.6.3.2.Dendritic Cell Precursor Collection Collection of dendritic cell precursors will occur in patients randomized to receive vaccine posttransplant. Collection will be done through leukapheresis in a single session. Risks of this collection are related to placement of an intravenous leukapheresis catheter that can be associated with bleeding and pain. The leukapheresis procedure has a risk of hypocalcemia, thrombocytopenia, anemia, leukopenia and bleeding diathesis. 2.6.3.3.Vaccine Administration Vaccines will be administered at three time points approximately one month a part. GM-CSF will also be administered at the site of vaccine for 4 consecutive days. Toxicities related to the vaccine are:  
- Hematologic: Leucopenia, Neutropenia
- Neurologic: Headache, light headedness
- Gastrointestinal: Diarrhea, - Constitutional: Weakness, chills and fever. Pain at tumor site, fatigue, night sweats
- Musculoskeletal: arthralgia and myalgia. - Dermatologic: rash, itching, edema and local reaction in the site of infusion (swelling, pain, bruising, erythema, and pruritus).  
- Endocrine: elevated TSH.  
- Other: ANA positivity, candida infection
In prior studies, one participant with myeloma and a history of deep vein thrombosis developed a pulmonary embolus, which was determined to be serious and possibly related to the vaccine and GM-CSF.
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2.6.4. gm-csf

Potential side effects of GM-CSF treatment include fever, chills, nausea, vomiting, diarrhea, fatigue, weakness, headache, decreased appetite, facial flushing, bone and muscle pain, local reaction at the site of injections, rashes, low blood pressure, shortness of breath and low blood counts. Rarely patients may develop blood clots, rapid or irregular heartbeats, feeling of faintness, and allergic reactions or fluid retention, including potential fluid retention in lungs or around the heart.
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2.7.study drug supply

2.7.1. Lenalidomide Lenalidomide will be provided by Celgene and distributed by Biologics, Incorporated. Patients must be registered in the Revlimid REMS program in order to receive lenalidomide through the program (please see Appendix E).  
2.7.1.1.Lenalidomide (NSC 703813)
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note

Before lenalidomide is dispensed, patients must 1) have a negative pregnancy test (if applicable) and 2) study patients must be be counseled through the Revlimid REMS program. A maximum 28-day supply may be dispensed to a patient at one time. For more information please refer to www.revlimidrems.com. Only use the study specific drug request form per patient for ordering through Biologics.  
Chemical Name: 3-(4'-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione Other Names: CC-5013, Revlimid™, CDC-501 Classification: Immunomodulatory Agent CAS Registry Number: 191732-72-6 Molecular Formula: C13H13N303 **M.W.:** 259.25
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mechanism of action

Lenalidomide, a thalidomide analog, is an immunomodulatory agent with a spectrum of activity that is still under investigation. Some of its effects include inhibition of inflammation, inhibition of angiogenesis, inhibition of hematopoietic tumor cell proliferation, modulation of stem cell differentiation and up regulating responses of T cells and NK cells.
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drug supply and storage

Celgene supplies and Biologics, Inc. distributes lenalidomide 5 mg (size 2) and 2.5 mg hard gelatin capsules in tamper-evident, child-resistant, opaque, high density polyethylene (HDPE) bottles with HDPE caps. Bottles will contain a sufficient number of capsules per container for one cycle of dosing. The capsules also contain anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their participation in this trial at no charge to them or their insurance providers. Lenalidomide will be provided in accordance with the Revlimid REMSTM program of Celgene Corporation. Per standard Revlimid REMSTM requirements all physicians who prescribe lenalidomide for research subjects enrolled into this trial, and all research subjects enrolled into this trial, must be registered in and must comply with all requirements of the Revlimid REMSTM. Prescriptions must be filled within 7 days for FCBP and 14 days for all other risk categories.  
All study participants must be registered into the mandatory Revlimid REMSTM program, and be willing and able to comply with the requirements of the Revlimid REMSTM program. Any unused lenalidomide supplies distributed through the Revlimid REMSTM program must be returned to the clinical site and destroyed per institutional guidelines.
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administration

Take lenalidomide by mouth with or without food. Do not crush, chew or open capsules.  
Dispensing:
Only enough lenalidomide for one cycle may be dispensed at one time.
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patient care implications and counseling

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. An embryofetal development study in animals indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy. The teratogenic effect of lenalidomide in humans cannot be ruled out. Therefore, a risk minimization plan to prevent pregnancy must be observed. Definition of female of childbearing potential (FCBP) This protocol defines a female of childbearing potential as a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Before starting study drug:
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female subjects

- FCBP must have two negative pregnancy tests (minimum sensitivity of 50 mIU/mL) prior to prescribing study drug. The first pregnancy test must be performed within 10-14 days prior to prescribing study drug and the second pregnancy test must be performed within 24 hours prior to prescribing study drug (prescriptions must be filled within 7 days as required by Revlimid REMSTM). The subject may not receive study drug until the Investigator has verified that the results of these pregnancy tests are negative.  
- FCBP must commit either to abstain continuously from heterosexual intercourse or to use TWO methods of reliable birth control AT THE SAME TIME—one highly effective form of contraceptions and one additional effective contraceptive method as defined below. Contraception must begin 4 weeks prior to initiating treatment with lenalidomide, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of lenalidomide.  
o HIGHLY EFFECTIVE:
Tubal Litigations IUD Hormonal contraceptives (birth control pills, injections, hormonal patches, vaginal rings or implants)
Partners Vasectomy o EFFECTIVE:
Male latex or synthetic condom Diaphragm Cervical cap
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male subjects

- Must agree to use a latex or synthetic condom during sexual contact with females of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.
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all subjects

- Only enough lenalidomide for one cycle of therapy may be dispensed with each cycle of therapy.  
- If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a male study subject during study participation, lenalidomide must be immediately discontinued.
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potential drug interactions

Periodic monitoring of digoxin levels is recommended during co-administration with lenalidomide. Monitor patients receiving concomitant warfarin per standard practice guidelines. Lenalidomide is not a substrate of human CYP enzymes, nor is it an inhibitor or inducer.
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drug ordering and accountability

The REMs program provides education and counseling on the risks of fetal exposure, blood clots and reduced blood counts. Counseling will be provided by Biologics, Inc. prior to drug distribution. Please refer to Appendix E (Lenalidomide REMs program). The patient will be required to receive counseling every 28 days during treatment with lenalidomide, follow the pregnancy testing and birth control requirements of the program that are appropriate in order to take the telephone surveys regarding compliance with the program. All physicians must be registered prescribers of Revlimid® in the REMs program. Physician registration allows access to the REMs software to enroll patients in the REMs program. The prescriber should submit the Registration Form via fax number 919-256-0794 or REMsOnline *(RAO)*for Revlimid®) to Celgene Customer Care. Please reference Appendix E (REMsprogram) and follow the directions for submitting the registration. Biologics, the distributor of the lenalidomide, will not dispense or ship Revlimid® prior to Celgene's receipt of registration. Prescription information MUST BE entered using the REMs study specific electronic prescription form referenced in Appendix E (REMs program). An authorization **number** must be on the prescription form at the time of faxing. Prescriptions for Revlimid® must be sent to Biologics Clinical Trial Division at the following FAX number: 919-256-0794. A maximum of a 28-day supply of Revlimid® may be dispensed per cycle sent to the actual address noted on the REMs electronic prescription form. Biologics will verify the authorization number and complete the patient counseling. Patients will be provided with instructions from Biologics with each new dispense on the procedures for return of any unused Revlimid® capsules. Refer to Appendix E (REMsprogram).
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2.8.patient withdrawal from study and

Patients on the BMT CTN 1401 study have voluntarily agreed to the study and may withdraw at anytime. Additionally, the treating physician may discontinue therapy with reasonable justification. The following criteria would result in discontinuation of study therapy:  
- Disease progression
- Unacceptable adverse event(s)
- Participant decides to withdraw from the study - General or specific changes in the participant's condition render the participant unacceptable for further treatment in the opinion of the treating investigator.
After randomization, patients who stop therapy for any reason prior to two years from initiation will continue to be followed per protocol for 3 years post maintenance initiation unless the patient withdraws consent for study follow up. In the event of patient withdrawal, written documentation of the withdrawal must be provided to the BMT CTN.
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chapter 3 3. study endpoints

Patients' disease status at each data collection period will be evaluated based on the International Uniform Response Criteria19. Until disease progression, all disease classifications are relative to the patient's disease status prior to autologous transplant. At time of disease progression, disease classifications are relative to the patient's best response since time of study entry.  
3.1.1. Response Categories
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stringent complete response (scr)

sCR requires, in addition to CR (defined below), all of the following:
- Normal free light chain ratio (FLC).  
- Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.
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complete response (cr)

CR requires all of the following:  
- Absence of the original monoclonal paraprotein in serum and urine by routine electrophoresis and by immunofixation. The presence of new monoclonal bands consistent with oligoclonal immune reconstitution does not exclude CR.  
- Less than 5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy, if biopsy is performed.  
- No increase in size or number of lytic bone lesions on radiological investigations
(development of a compression fracture does not exclude CR)*.  
- Disappearance of soft tissue plasmacytomas.  
*If not clinically indicated, radiographs are not required to document CR.
Patients in whom some, but not all, the criteria for CR are fulfilled are classified as partial responses (see below), providing the remaining criteria satisfy the requirements for partial response. This includes patients in whom routine electrophoresis is negative but in whom immunofixation has not been performed.
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very good partial remission (vgpr)

VGPR requires, in addition to PR (defined below), all of the following:
- Serum or urine paraprotein detectable by immunofixation but not on electrophoresis.  
OR  
- Greater than or equal to 90% reduction in serum paraprotein plus urine paraprotein
<100 mg/24hrs.
- For free light chain only disease, VGPR requires a 90% reduction of involved light chain
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partial response (pr)

PR requires one of the following:  
- Greater than or equal to 50% reduction in the level of the serum monoclonal paraprotein and reduction in 24 hour urinary monoclonal paraprotein either by greater than or equal to 90% or to <200 mg/24 hours in light chain disease.  
- If the only measurable non-bone marrow parameter is FLC, greater than or equal to 50%
reduction in the difference between involved and uninvolved FLC levels or a 50% decrease in level of involved FLC with 50% decrease in ratio,
- If the bone marrow is the only measurable parameter, greater than or equal to 50% reduction in bone marrow plasma cells given that the baseline count was greater or equal to 30%,
- Greater than or equal to 50% reduction in the size of soft tissue plasmacytomas if present at baseline (by radiography or clinical examination).
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stable disease (sd)

- Patients who do not meet criteria for sCR, CR, VGPR, partial response or progressive disease (section 3.1.1.2) are considered to have stable disease (SD).  
3.1.2. Progressive Disease (PD)
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disease progression (pd)

Progression from CR or sCR requires one or more of the following:
- A reappearance of serum monoclonal paraprotein, with a level of at least 0.5 g/dL.  
- 24-hour urine protein electrophoresis with at least 200 mg paraprotein/24 hours. - Abnormal FLC levels of >10 mg/dl, only in patients without measurable paraprotein in the serum and urine.  
- At least 10% plasma cells in a bone marrow aspirate or on 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 any other cause.
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progressive disease (pd)

For patients not in CR or sCR, progressive disease requires one or more of the following measured from the time of randomization:
- >25% increase in the level of the serum monoclonal paraprotein, which must also be an absolute increase of at least 0.5 g/dL.  
- >25% increase in 24-hour urine protein electrophoresis, which must also be an absolute increase of at least 200 mg/24 hours.  
- Absolute increase in the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dl), only in patients without measurable paraprotein in the serum and urine.  
- >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10%.
- Definite increase in the size of existing bone lesions or soft tissue plasmacytomas.  
- Development of new bone lesions or soft tissue plasmacytomas.  
- Development of a compression fracture does not exclude continued response and may not indicate progression.  
- Development of hypercalcemia (corrected serum Ca >11.5 mg/dL or >2.8 mmol/L) not attributable to any other cause.
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3.2.primary endpoint

The primary objective of this randomized trial is to compare the proportion of patients alive and in complete response (CR or sCR) at one year post transplant between patients receiving DC/myeloma vaccine/GM-CSF with lenalidomide maintenance therapy to those receiving lenalidomide maintenance therapy with or without GM-CSF.
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3.3.clinical secondary endpoints

3.3.1. Response to treatment The trial will assess the rates of VGPR or better (VGPR, nCR, CR and sCR) responses) according to the International Uniform Response Criteria (Section 3.2) at specific time points in both arms from the time of randomization. Assessment of disease response will be done immediately prior to randomization, prior to cycles 3, 6, and then every 3 months until approximately 22 months from randomization or evidence of disease progression. Additionally, assessments of disease response will be conducted at 6, 12, and 24 months post-transplant. Rates of VGPR or better responses will be compared between the two arms. For patients not in CR at randomization, the rate of CR conversion (CR and sCR) will be compared between the vaccine and no-vaccine arms combined. A secondary pairwise analysis will compare the CR rates at 1 year between the vaccine arm, lenalidomide/GM-CSF arm and lenalidomide alone arm. 3.3.2. Myeloma Progression Myeloma progression defined according to Section 3.2 or initiation of off protocol anti-myeloma therapy is the event for this endpoint. Death without documentation of disease progression is the competing event. Patients alive without disease progression at last contact are considered censored for this event. The cumulative incidence of myeloma progression will be compared between vaccine and no-vaccine arms combined. A secondary pairwise analysis will compare the cumulative incidence of myeloma progression between the vaccine arm, lenalidomide/GM-CSF arm and lenalidomide alone arm.
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3.3.3. minimal residual disease assessment

Minimal residual disease (MRD) is defined as the presence of malignant plasma cells detected by multicolor flow cytometry among patients who are in complete remission. Multichannel flow cytometry will be used to establish MRD based on the presence of malignant plasma cells that are CD45 (-/dim), CD38+, CD138+, CD19-, CD56+ kappa or lambda restricted. The result will determine whether that patients has MRD (MRD +) or not (MRD -). The proportion of patients who are MRD negative at one year will be compared between vaccine and no-vaccine arms combined. A secondary pairwise analysis will be conducted comparing the proportion of patients who are MRD negative at one year between the vaccine arm, lenalidomide/GM-CSF arm and lenalidomide alone arm.
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3.3.4. treatment-related mortality

TRM is defined as death occurring in a patient from causes other than disease relapse or progression. Disease progression is the competing event for TRM. Patients alive without disease progression at last contact are considered censored for this event. TRM from time of randomization will be compared between vaccine and no-vaccine arms combined starting at time of randomization. A secondary pairwise analysis will compare TRM between the vaccine arm, lenalidomide/GM-CSF arm and lenalidomide alone arm.
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3.3.5. incidence of toxicities grade

All Grade ≥ 3 toxicities will be tabulated for treatment arms. The proportion of patients developing Grade ≥ 3 toxicity will be compared between the vaccine and no-vaccine arms combined until disease progression or end of follow up. A secondary pairwise analysis will compare the incidence of toxicities between the vaccine arm, lenalidomide/GM-CSF arm and lenalidomide alone arm.  
3.3.6. Incidence of Infections per BMT CTN Technical MOP
The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each patient. The proportion of patients in each treatment arm with these infections will be compared from randomization until disease progression or end of follow up.
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3.3.7. progression-free survival

Patients are considered a failure of this endpoint if they die or suffer from disease progression.  
The time to this event is the time from randomization to progression, death, initiation of nonprotocol anti myeloma therapy, loss to follow up or end of study whichever comes first and it will be compared between the vaccine and no-vaccine arms combined from time of randomization. A secondary pairwise analysis will compare progression-free survival between the vaccine arm, lenalidomide/GM-CSF arm and lenalidomide alone arm.
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3.3.8. overall survival

The event is death from any cause. The time to this event is the time from randomization to death, loss to follow-up or the end of the study, whichever comes first. Patients alive at the time of last observation are considered censored. Overall survival will be compared between the vaccine and no-vaccine arms combined from time of randomization. A secondary pairwise analysis will compare overall survival between the vaccine arm, lenalidomide/GM-CSF arm and lenalidomide alone arm.
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3.4.primary immunologic endpoints

3.4.1. Myeloma-Reactive T-cells The effect of DC/Myeloma Fusion Vaccine/GM-CSF with lenalidomide maintenance; lenalidomide maintenance; and lenalidomide maintenance with GM-CSF on levels of circulating myeloma reactive T cells will be quantified. Myeloma-reactive T cells, as defined by the percentage of circulating CD4+ and CD8+ T cells that express IFNγ following ex vivo exposure to autologous tumor lysate will be assess in both treatment arms. The percent of patients achieving at least a 2.4-fold increase in tumor reactive T cells will be compared between the vaccine and each of the no-vaccine arms separately.
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3.5.secondary immunologic endpoints

3.5.1. Myeloma-Reactive T-cells The percent of patients achieving at least a 10-fold increase in tumor-reactive T cells will be compared between the vaccine and no-vaccine arms separately as described above. 3.5.2. Assessment of antigen specific reactivity: The effect of DC/Myeloma Fusion Vaccine/GM-CSF + lenalidomide maintenance; lenalidomide maintenance; and lenalidomide maintenance + GM-CSF on immunologic responses directed against previously identified myeloma antigens will be assessed. In HLA-A2.1 patients, circulating CD8+ T cells binding tetramer constructed from MUC1, SOX2, NY-ESO, and XBP-1 will be quantified. At serial time points PBMC and BMMC will undergo dual staining for CD8 and the appropriate tetramer, and analyzed by multichannel flow cytometry. When cell yields allow, functional characteristics of the tetramer positive population will be determined by measuring IFNγ, granzyme B, IL-4, and IL-10 expression in the tetramer positive cells by intracellular staining.
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3.5.3. quantification of t-cell subsets

Quantification of regulatory T cells and activated memory effector cells will be performed at the serial time points (Appendix C). T cell subsets will be quantified with respect to the relative proportion of CD4 and CD8+ T cells and the presence of naïve, effector memory, and central memory cells will be determined by staining for CD45RA, and CD45RO, CD27, and CD62L by multichannel flow cytometry. Regulatory T cells will be quantified as CD4/CD25/FOXP3 cells. T cells expressing PD-1 will be quantified at the time points indicated above. Quantification of granulocytic and monocytic myeloid derived suppressor cells will be performed from peripheral blood and bone marrow samples undergoing multichannel flow cytometry for CD11b, HLA-DR,
CD14, CD15 and CD33. 3.5.4. Assessment of effect on NK cell populations: The effect of lenalidomide alone and in combination with DC/MM vaccination on the phenotype and function of circulating NK cell populations will be assessed as detailed in Appendix C. The expression of a panel of NK receptors including activating receptors (NKp30, NKp44, NKp46, NKG2D, NKG2C, DNAM1), inhibitory receptors (NKG2A and KIRs) and markers of NK function (CD16, CD25, CD132) will be assessed. The effector function of NK cells against MHC class I-deficient leukemia targets and primary MM cells (where available) from the recipient will be assessed by intracellular cytokine assay for interferon-gamma (IFN-γ) production, and cytotoxicity, including CD107a degranulation and 51chromium release assay. The expression of receptors important in the regulation of human NK cell trafficking and homing in vivo, including CD62L, CXCR4, CXCR3, CCR6 and CCR7 will be measured. The effect of treatment on NK function will be assessed by examining expression of the canonical transcription factors eomesodermin (Eomes) and T-bet prior to and serially following initiation of therapy. Surface expression of CD57 and KLRG1, both markers of mature NK cells, will be evaluated.  
3.5.5. Assessment of humoral immune response:
Serological Analysis of Recombinant cDNA Expression Library (SEREX) will be performed on serum samples to assess humoral response targeting myeloma antigens in patients treated with lenalidomide maintenance alone or in conjunction with DC/MM fusion vaccination as detailed in Appendix C. Peripheral blood will be transported for a cell based assay to assess the kinetics, magnitude and specificity of vaccine-induced myeloma specific plasmablast responses, as detailed in Appendix C.
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4. patient registration enrollment and

Patients are enrolled in to the Segment A prior to initial systemic therapy (<1 cycle) and first autologous transplant. At the time of enrollment, an authorized user at the clinical center completes the demographics and primary eligibility form which includes questions confirming that the patient signed the consent and meets the eligibility criteria for study entry. Patients must be successfully enrolled in Segment A prior the collection of tumor cells. Once the patient is enrolled in the study (Eligibility Form, Segment A competed):
1. A visit schedule based on enrollment date will be available for printing 2. Following enrollment and tumor cell collection the patient should proceed with initial systemic therapy and autologous transplant. Patients should be transplanted within one year of enrollment into Segment A.  
3. Patient will be seen 14 days or less prior to randomization for eligibility assessments prior to randomization/enrollment in Segment B. The pre-randomization disease response assessment must be performed < 10 days prior to randomization. Randomization should occur between day 53 and day 80 after the autologous HCT. An authorized user at the clinical center completes a checklist confirming that the patient is eligible to proceed to the next stage of treatment on the study.  
4. If the patient is eligible, they will be enrolled in Segment B and randomized to their treatment assignment and the treatment plan is continued.  
5. A visit schedule based on the date of randomization will be available for printing.
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4.2.study monitoring 4.2.1. follow -

The follow up schedule for study visits after Segment A enrollment and subsequently after randomization are outlined below in tables 4.2.1A and 4.2.1B, respectively. The follow up schedule is the intended schedule; however, the date of the follow up evaluations may vary due to delays in treatment or treatment interruption related to Adverse Events and toxicities. The visit window for the scheduled evaluations is included in each table. Patients will be followed for three years post maintenance initiation.  
| Study Visit                   | Target Day                                                         |
|-------------------------------|--------------------------------------------------------------------|
| Pre- Enrollment Screening     | < 8 weeks prior to enrollment                                      |
| Tumor cell collection         | 7 days post enrollment±7 days1                                     |
| Pre- Randomization  Screening | < 14 days prior to randomization                                   |
| Randomization                 | Day 53- Day 80 post transplant2                                    |
| Dendritic Cell Collection3    | < 14 days after randomization and prior to  Day 85 post transplant |
| Pre- Maintenance Screening    | < 14 days prior to maintenance initiation                          |
| Maintenance Start             | 90-100 days post transplant                                        |  
Dendritic Cell Collection3 < 14 days after randomization and prior to  
Day 85 post transplant  
Pre- Maintenance Screening < 14 days prior to maintenance initiation  
Maintenance Start 90-100 days post transplant  
1 Tumor cell collection by bone marrow aspirate can occur the same day of enrollment and up to 14 days  
after enrollment. 2 Randomization must also occur within 10 days of a disease response assessment. 3 Leukapheresis for dendritic cell collection is only required for patients randomized to the vaccine/GMCSF/Lenalidomide arm.
chapter 4
4.2.1a follow up schedule after

| Study Visit                                                                                   | Target Day Post Maintenance (+ 7 days)1   |
|-----------------------------------------------------------------------------------------------|-------------------------------------------|
| Baseline                                                                                      | < 14 days prior to randomization          |
| Prior to initiation of                                                                        | < 14 days prior to maintenance            |
| maintenance                                                                                   |                                           |
| Start of Maintenance2                                                                         | Day 1                                     |
| Cycle 1 Cycle 2                                                                               | 29 days                                   |
| Cycle 2 + 7 days                                                                              | 35 days                                   |
| Cycle 3                                                                                       | 57 days                                   |
| Cycle 4                                                                                       | 85 days                                   |
| Cycle 4 + 7 days                                                                              | 91 days                                   |
| Cycle 6                                                                                       | 141 days                                  |
| Cycle 9 (Start)                                                                               | 225 days                                  |
| Cycle 9 (End)                                                                                 | 253 days                                  |
| Cycle 12                                                                                      | 309 days                                  |
| Cycle 15                                                                                      | 393 days                                  |
| Cycle 18                                                                                      | 477 days                                  |
| Cycle 21                                                                                      | 561 days                                  |
| Cycle 24                                                                                      | 645 days                                  |
| 1 After 9 cycles of maintenance therapy, patients can be seen + 14 days from the target date. |                                           |  
| Endpoints                        | Days From Transplant   |
|----------------------------------|------------------------|
| 6 months post                    | Day 180 ± 14 days      |
| transplant (6T) 12 months post   | Day 365 + 14 days      |
| transplant (12T)2 24 months post | Day 730 + 14 days      |
| transplant (24T)3                |                        |
chapter 4
4.2.1c follow up schedule endpoint

1Endpoint assessments will occur at 6 months posttransplant and yearly post-transplant for 2 years or until disease progression. These assessments may be conducted at the required visits outlined in table 4.2.1B if they fall within 14 days of the target date for the post randomization visit. 2 The 6 month posttransplant visit should correspond to the start of the 4th cycle of maintenance unless the patient has been delayed for any reason.  
The 12 month posttransplant visit should correspond to the start of the 11th cycle of maintenance unless the patient has been delayed for any reason.  
3The 24 month post transplant visit should correspond to the start of the 24th cycle of maintenance unless the patient has been delayed for any reason.
chapter 4
4.3.patient evaluations

4.3.1. Pre- Enrollment Segment A Evaluations and Requirements The following evaluations must be determined < 8 weeks prior enrollment on BMT CTN 1401. See table 4.3.1A.  
1. History, physical examination, height and weight 2. Karnofsky Performance Score 3. CBC with differential, platelet count 4. Liver Functions and blood chemistries: Serum creatinine, total bilirubin, alkaline phosphatase, AST, ALT
5. Evaluation of creatinine clearance 6. Laboratory Disease Evaluation:
a. Quantitative serum immunoglobulin levels. b. Serum protein electrophoresis (SPEP). c. 24 hour urine collection to determine protein excretion,urine electrophoresis
(UPEP).  
d. Immunofixation of urine and serum protein regardless of SPEP and UPEP results. e. Serum free light chain ratios (FLC)  
7. Bone Marrow Evaluation: unilateral bone marrow biopsy and aspirate are required to assess plasma cell involvement in the marrow as per eligibility criteria outlined in section 2.3.1 8. Skeletal bone survey to include cranium, axial skeleton and proximal long bones or other imaging study to evaluate for bone involvement.
4.3.2. Tumor Cell Collection Evaluations and Requirements at Enrollment 1. Tumor Cell Collection1 a. Bone marrow aspiration (30mL) is required for vaccine production and eligibility validation.  
b. Peripheral Blood (50mL) collection 2. Protocol-required Samples for Correlative Studies (Table 4.3B)2 a. Bone marrow aspirate (4mL) for immunologic endpoints (see Appendix C for details)
b. Peripheral Blood (40mL) collection for immunologic endpoints (see Appendix C
for details)
3. Optional Samples for Future Research2 a. Bone marrow aspirate (3mL) (see Appendix C for details) b. Peripheral Blood (6mL) collection (see Appendix C for details)
4.3.3. Pre- Randomization Evaluations and Requirements The following evaluations to determine eligibility for randomization must be performed < 14 days prior to randomization unless otherwise noted below.  
1. History and physical examination 2. Assessment for toxicities 3. Laboratory Disease Evaluation (<10 days from randomization):
a. Quantitative serum immunoglobulin levels. b. Serum protein electrophoresis (SPEP). c. 24 hour urine collection to determine protein excretion, urine electrophoresis
(UPEP).  
d. Immunofixation of urine and serum protein regardless of SPEP and UPEP
results.  
e. Serum free light chain ratios (FLC)  
4. Bone Marrow Evaluation: unilateral bone marrow biopsy and aspirate are required only to confirm CR in patients unless required for BMT CTN 1401 correlative studies.  
5. Protocol-required Samples for Correlative Studies (Table 4.3B)3 a. Bone marrow aspirate (10mL) for immunologic endpoints (see Appendix C for details)
b. Peripheral Blood collection (30mL) for immunologic endpoints (see Appendix C for details)
6. Optional Samples for Future Research a. Bone marrow aspirate (3mL) (see Appendix C for details) b. Peripheral Blood (6mL) collection (see Appendix C for details)
7. Optional Samples for Ancillary Research: To be collected only on patients providing consent for ancillary research per Appendix J and/or K (see Appendix C for details)
a. Bone marrow aspirate (4mL) - additional sample volume collected at the time of required sample for immunologic endpoints b. Four (4) Paraffin Embedded Slides from Core Bone Marrow Biopsy required to confirm CR in some study patients prior to randomization 8. Skeletal bone survey to include cranium, axial skeleton and proximal long bones or other imaging study to evaluate for bone involvement.  
9. CBC with differential, platelet count 10. Liver Functions and blood chemistries: Serum creatinine, total bilirubin, alkaline phosphatase, AST, ALT
11. Evaluation of creatinine clearance 12. Pregnancy test, serum HCG (sensitivity of at least 50 mIU/mL) for FCBP.
4.3.4. Pre- Maintenance Evaluations and Requirements The following evaluations to determine eligibility for maintenance initiation must be performed <
14 days prior to the initiation of lenalidomide maintenance therapy unless otherwise noted below.  
1. History and Physical Exam  
2. Assessment for toxicities 3. CBC with differential, platelet count 4. Liver Functions and blood chemistries: Serum creatinine, total bilirubin, alkaline phosphatase, AST, ALT
5. Required evaluation prior Lenalidomide: Pregnancy test, serum HCG (sensitivity of at least 50 mIU/mL) for FCBP. Women are required to have 2 pregnancy tests prior to the initiation of lenalidomide as follows (Appendix D)
a. The first is required within 10 to 14 days prior to prescribing lenalidomide, b. The second is required within 24 hours of prescribing lenalidomide.  
4.3.5. Evaluations during Maintenance 1. The following evaluations will be done monthly for the first 4 cycles and then at cycles 6, 9, 12, 15, 18, 21, 24:
a. History and physical exam b. CBC with differential, platelet count4 c. Liver Functions and blood chemistries: Serum creatinine, total bilirubin, alkaline phosphatase, AST, ALT  
2. Assessment for Toxicities monthly for the first 4 cycles and then at cycles 6, 9, 15, 21, and 245.
3. Required evaluation for Lenalidomide: Pregnancy test, serum HCG (sensitivity of at least 50 mIU/mL) for female of childbearing potential (FCBP):
a. FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on therapy (including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide. Females with irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (Appendix D).  
b. The subject must follow the requirements of the Revlimid REMS® program of the Celgene Corporation. This program provides education and counseling on the risks of fetal exposure, blood clots and reduced blood counts. The patient will be required to receive counseling every 28 days during treatment with lenalidomide, follow the pregnancy testing and birth control requirements of the program that are appropriate in order to take the telephone surveys regarding compliance with the program.  
4. Laboratory Disease Evaluation at prior to cycles 3, and 6, and every 3 cycles thereafter.  
Disease evaluations will also be collected at 6 months, 1 and 2 years post-transplant:
a. Quantitative serum immunoglobulin levels. b. Serum protein electrophoresis (SPEP). c. 24 hour urine collection to determine protein excretion, urine electrophoresis
(UPEP).  
d. Immunofixation of urine and serum protein regardless of SPEP and UPEP results. e. Serum free light chain ratios (FLC)  
5. Bone Marrow Evaluation: unilateral bone marrow biopsy and aspirate are required only to confirm CR in patients
6. Skeletal bone survey to include cranium, axial skeleton and proximal long bones or other imaging study to evaluate for bone involvement at 1 and 2 years post transplant.  
7. Samples for Correlative Studies (Table 4.3B)
a. Bone marrow aspirate (10mL) just prior to the start of cycle 9 of maintenance for immunologic endpoints (see Appendix C for details).  
b. Peripheral Blood collection prior to cycles 1, 2, 3, 4, and 9 and at day 7 of cycles 2 and 4 for immunologic endpoints (see Appendix C for details).  
8. Optional Samples for Future Research a. Bone marrow aspirate (3mL) collection just prior to the start of cycle 9 of maintenance (see Appendix C for details)  
b. Peripheral Blood (6mL) collection just prior to the start of cycle 9 of maintenance
(see Appendix C for details)
9. Optional Samples for Ancillary Research: To be collected only on patients providing consent for ancillary research per Appendix K (see Appendix C for details)  
a. Bone marrow aspirate (4mL) (see Appendix C for details) - additional volume collected just prior to the start of cycle 9 of maintenance along with required research sample being collected for the primary trial, and a (5mL) marrow aspirate sample collected at time of disease progression determination.
b. Peripheral Blood Collection: additional volume of blood collected prior to cycles 1, 2, and 4 (10mL) along with the required research samples being collected for the primary trial, and (40mL) blood collected at the time of disease progression determination.  
*Myeloma Vaccine 1401* Version 4.0 dated *July 24, 2018*  
| maintenance                                                   | Cycles of maintenance   | Post-transplant   |     |    |    |    |    |    |    |    |    |     |     |    |    |    |
|---------------------------------------------------------------|-------------------------|-------------------|-----|----|----|----|----|----|----|----|----|-----|-----|----|----|----|
| Pre                                                           |                         |                   |     |    |    |    |    |    |    |    |    |     |     |    |    |    |
| Study Assessments                                             | Pre                         |                   |     |    |    |    |    |    |    |    |    |     |     |    |    |    |
| Enrollment                                                    | Pre                         |                   |     |    |    |    |    |    |    |    |    |     |     |    |    |    |
| Randomization                                                 | visits                  |                   |     |    |    |    |    |    |    |    |    |     |     |    |    |    |
| 1                                                             | 2                       | 3                 | 4   | 6  | 9  | 12 | 15 | 18 | 21 | 24 | 6T | 12T | 24T |    |    |    |
| History, physical exam, weight and height1                    | X                       | X                 | X   | X  | X  | X  | X  | X  | X  | X  | X  | X   | X   | X  | X  | X  |
| Karnofsky performance score                                   | X                       |                   |     |    |    |    |    |    |    |    |    |     |     |    |    |    |
| CBC, differential, platelet count, and blood  chemistries2    | X                       | X                 | X   | X  | X  | X  | X  | X  | X  | X  | X  | X   | X   |    |    |    |
| Evaluation of Creatinine Clearance                            | X                       | X                 |     |    |    |    |    |    |    |    |    |     |     |    |    |    |
| Pregnancy test3                                               | X                       | X                 | X   | X  | X  | X  | X  | X  | X  | X  | X  | X   |     |    |    |    |
| Quantitative serum immunoglobulins                            | X                       | X                 | X   | X  | X  | X  | X  | X  | X  | X  | X  | X   | X   |    |    |    |
| SPEP and immunofixation                                       | X                       | X                 | X   | X  | X  | X  | X  | X  | X  | X  | X  | X   | X   |    |    |    |
| 24 Hour Urine for UPEP, protein excretion  and immunofixation | X                       | X                 | X   | X  | X  | X  | X  | X  | X  | X  | X  | X   | X   |    |    |    |
| Serum free light chain ratio                                  | X                       | X                 | X   | X  | X  | X  | X  | X  | X  | X  | X  | X   | X   |    |    |    |
| Skeletal Survey or other imaging study                        | X                       | X                 | X   | X  |    |    |    |    |    |    |    |     |     |    |    |    |
| Bone marrow aspirate and biopsy                               | X4                      | X5                | X 5 | X5 | X5 | X5 | X5 | X5 | X5 | X5 | X5 | X5  | X5  |    |    |    |
| Toxicity assessment6                                          | X                       | X                 | X   | X  | X  | X  | X  | X  | X  | X  |    |     |     |    |    |    |
table 4.3a patient clinical assessments
4.3.patient evaluations

1Height and Weight are only required at pre-enrollment and pre-randomization visits. 2Blood chemistries include: serum creatinine, bilirubin, alkaline phosphatase, AST and ALT as required per protocol. 3 For female of childbearing potential: A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 4Bone Marrow aspirate and biopsy required within 60 days of enrollment; must be repeated if patient receives additional therapy between initial pre-treatment BM and enrollment 5Bone Marrow aspirate and biopsy required only to confirm CR in patients 6The toxicity assessment will include a review of all toxicities and appropriate lab evaluations experienced **during the entire assessment period** and the **highest grade** for each toxicity during the assessment period will be recorded on the Toxicity form in AdvantageEDC using CTCAE version 4.  
*Myeloma Vaccine 1401* Version 4.0 dated *July 24, 2018*
table 4.3a patient clinical assessments
table 4.3b sample collection time

| Tumor Cell  Collection (At  Enrollment)4                                                                                                                           | Cycles of maintenance   |       |         |               |     |    |     |    |    |    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|-------|---------|---------------|-----|----|-----|----|----|----|
| Pre                                                                                                                                                                    |                         |       |         |               |     |    |     |    |    |    |
| Randomization6                                                                                                                                                     | 2  +7d8                 | 37    | 47      | 4             | 97  |    |     |    |    |    |
| 17                                                                                                                                                                 | 27                      | + 7d8 | (prior) | Progression10 |     |    |     |    |    |    |
| Sample Collection Bone Marrow Aspirate Bone marrow aspirate for tumor collection (30mL)                                                                            | X1                      |       |         |               |     |    |     |    |    |    |
| MRD Assessment (6 mL)2                                                                                                                                             | X                       | X     |         |               |     |    |     |    |    |    |
| Myeloma Reactive T Cells (4 mL)                                                                                                                                    | X1                      | X     | X       |               |     |    |     |    |    |    |
| T Cell/Genomic Signature Study (4mL unless  otherwise noted)                                                                                                       | X                       | X     | X (5mL) |               |     |    |     |    |    |    |
| VCAN Assessment9                                                                                                                                                   | X                       |       |         |               |     |    |     |    |    |    |
| Optional Repository Sample for Future Research                                                                                                                     | X1                      | X     | X       |               |     |    |     |    |    |    |
| (3mL) Total Maximum Marrow Volume (mL)5                                                                                                                            | 37                      | 17    | 17      | 5             |     |    |     |    |    |    |
| Peripheral Blood Plasma for Vaccine Production (50mL)                                                                                                              | X5                      |       |         |               |     |    |     |    |    |    |
| Plasmablast Responses (30mL)                                                                                                                                       | X                       | X3    | X3      | X3            | X   |    |     |    |    |    |
| Myeloma Reactive T Cells (40mL)                                                                                                                                    | X5                      | X     | X       | X             | X   | X  |     |    |    |    |
| NK cell reconstitution (30mL)                                                                                                                                      | X                       | X     | X       | X             | X   |    |     |    |    |    |
| T Cell/Genomic Signature Study (10mL unless                                                                                                                        | X                       | X     | X       | X (40mL)      |     |    |     |    |    |    |
| otherwise noted) Optional Repository Sample for Future Research                                                                                                    | X5                      | X     | X       |               |     |    |     |    |    |    |
| (6mL) Total Maximum Blood Volume (mL)                                                                                                                              | 965                     | 36    | 80      | 803           | 603 | 70 | 803 | 60 | 76 | 40 |
| 1 Bone marrow aspirate for collection of tumor cells should be done with 1-2 pull(s) per site until the total volume is achieved. The first 30mL will be dedicated |                         |       |         |               |     |    |     |    |    |    |  
1 Bone marrow aspirate for collection of tumor cells should be done with 1-2 pull(s) per site until the total volume is achieved. The first 30mL will be dedicated for vaccine production, which will be cryopreserved at the transplant center. The remainder volume (7mL) will be aliquoted into two samples, which will be shipped to the BMT CTN repository and to BIDMC.  
2 Minimal residual disease (MRD) assessment will be done at the center and centrally at RPCI, the MRD sample will be aliquot in two 3 mL samples, one will be sent to RPCI and the other for analysis at the transplant center. Patients with overt evidence of disease progression are not required to submit sample for MRD assessment.  
3 Assessment for plasmablast only applies to patients who were randomized to the vaccine arm. 4 The Tumor Cell Collection Visit should occur < 14 days post enrollment in Segment A. 5 Blood collection at study entry can be collected over a 10 day period to avoid collection of excessive volumes in a single day.  
*Myeloma Vaccine 1401* Version 4.0 dated *July 24, 2018* 6The Pre-Randomization collection should be collected + 14 days from date of randomization however, randomization samples are preferred to be collected after a patient is randomized. If samples(s) need to be collected prior to randomization, contact the protocol coordinator. 7Samples should be collected < 3 days from target date (If target date is a Friday, Saturday or Sunday, collect the previous Thursday) 8Samples should be collected -2 days to +1 day from target (If target date is a Friday or, Saturday, collect the previous Thursday. If Sunday, collect Monday.) 9No additional sample is required. Four (4) Paraffin embedded slides prepared at the clinical site from the core biopsy required for clinical assessment prior to randomization. 10Collected at the time of confirmation of disease progression per Chapter 3.
table 4.3a patient clinical assessments
4.4.data reporting

4.4.1. Criteria for Forms Submission Forms that are not entered into AdvantageEDCSM within the specified time will be considered delinquent. A missing form will continue to be requested either until the form is entered into the AdvantageEDCSM and integrated into the Data and Coordinating Center's (DCC) master database, or until an exception is granted and entered into the Missing Form Exception File. 4.4.2. Reporting Patient Deaths Recipient death information must be entered into AdvantageEDCSM within 24 hours of knowledge of the patient's death. If the cause of death is unknown at that time, it need not be recorded at that time. However, once the cause of death is determined, the form must be updated in AdvantageEDCSM.  
4.4.3. Center for International Blood and Marrow Transplant Research (CIBMTR) Data Reporting Centers participating in BMT CTN trials must register pre- and post-transplant outcomes on all consecutive hematopoietic stem cell transplants done at their institution during their time of participation to the Center for International Blood and Marrow Transplant Research (CIBMTR). Registration is done using procedures and forms of the Stem Cell Transplant Outcomes Database (SCTOD). (Note: Federal legislation requires submission of these forms for all US allotransplant recipients.) Enrollment in BMT CTN 1401 must be indicated on the SCTOD pre-transplant registration form. Additionally, CIBMTR pre- and post- transplant Comprehensive Report Forms must also be submitted for all patients enrolled on this trial. CIBMTR forms will be submitted directly to the CIBMTR at the times specified on the Form Submission Schedule.  
4.4.4. Adverse Event Reporting Reporting of adverse events on the BMT CTN 1401 protocol has unique requirements due to the addition of lenalidomide as part of the protocol. Adverse event reporting requirements are summarized below and further described in Appendix I.
table 4.3a patient clinical assessments
4.4.4.1.definitions

Adverse Event: An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that develops or worsens in severity after starting the first dose of study treatment or any procedure specified in the protocol, even if the event is not considered to be related to the study.  
Expectedness: An adverse event can be Expected or Unexpected
- Expected adverse **events** are those that have been previously identified as resulting from administration of the agent. For the purposes of this study, an adverse event is considered expected when it appears in the current adverse event list, the Investigator's Brochure, the package insert or is included in the informed consent document as a potential risk.  
- **Unexpected adverse events** are those that vary in nature, intensity or frequency from information in the current adverse event list, the Investigator's Brochure, the package insert, or when it is not included in the informed consent document as a potential risk.
table 4.3a patient clinical assessments
4.4.4.2. bmt ctn adverse event

It is BMT CTN policy that AEs must be reported even if the investigator is unsure whether a relationship exists between the adverse event and the use of the study treatment. Reporting of AEs for BMT CTN 1401 will be consistent with the BMT CTN Administrative Manual of Procedures. Additional requirements specific to this protocol are outlined below and in Appendix I. In BMT CTN studies, expected adverse events are reported via the web-based electronic data capture system, AdvantageEDC. Events are captured on calendar-driven case report forms (e.g., Toxicity) or event-driven case report forms (e.g., Progression, and Death). From the time of enrollment until randomization, only deaths, secondary primary malignancies and progressions are required to be reported. From time of randomization until 3 years post maintenance initiation, unexpected, grades 3-5 AEs, irrespective of the attribution of the event to the study drug /procedure/treatment, will be reported through the expedited AE reporting system via AdvantageEDC, and will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. The BMT CTN 1401 protocol has two distinct interventions: transplant and maintenance therapy. Determination of expectedness for events occurring post-transplant and/or post-maintenance therapy will be at the discretion of the investigator as described in Appendix I. Unexpected, grades 4-5 AEs must be reported within 24 hours of knowledge of the event. Unexpected, grade 3 AEs must be reported within three business days of knowledge of the event. The NHLBI Data and Safety Monitoring Board will receive summary reports of all adverse experiences at least twice yearly. Since this study is under an FDA Investigational New Drug, all suspected and unexpected fatal or life-threatening adverse events are reported to the FDA within seven calendar days after receipt of the information, following FDA guidelines. All suspected and unexpected Grade 3 serious adverse events are reported to the FDA via a written report within fifteen days of receipt of the information (21 CFR
312.32). If the Medical Monitor assesses the event to be unrelated to the study, then the event will not require expedited reporting but will be included in a summary report issued annually. All expected adverse events (i.e., those listed in the informed consent, product inserts, or study materials) not covered under the above requirements need not be reported via the AE Form. They will be captured on other CRFs. Although death and graft failures are not considered unexpected post-transplant events, they are reported to the FDA via annual reports. Safety reporting to the FDA
will be done by the BMT CTN based upon date of initial entry on the Adverse Event Forms and requires no additional action from the participating site.  
All second primary malignancies (SPM), excluding non-melanoma skin cancers, experienced by patients enrolled on the study will be reported using the expedited AE reporting system in AdvantageEDC and must be reported within three business days of knowledge of the event. The Event Description entered in AdvantageEDC should include histologic type. 4.4.4.3. Additional Adverse Event Reporting Celgene Corporation (Celgene) is supplying lenalidomide for this study and a description of additional reporting requirement for this study is detailed in **Appendix I**. The additional adverse event reporting period for lenalidomide begins with the first dose and continues until 28 days after permanent discontinuation of lenalidomide. 4.4.4.4.Adverse Event Reporting Following Progression If a patient meets the protocol defined definition of progression (Chapter 3), Unexpected Grade 35 Adverse Events and events listed in Appendix I are no longer required to be reported on the Adverse Event Form once the patient is more than 28 days from their last dose of lenalidomide. However, SPMs should continue to be reported within three business days of the knowledge of the event through 3 years post-maintenance initiation. 4.4.4.5.Adverse Event Reporting Following an SPM Adverse Event reporting following an SPM is dependent on the treatment received for the reported SPM.  
- If a patient experiences an SPM resulting in permanent discontinuation of lenalidomide and initiation of non-protocol systemic therapy, Unexpected Grade 3-5 Adverse Events and events listed in Appendix I are no longer required to be reported on the Adverse Event Form once the patient is more than 28 days from their last dose of lenalidomide.  
- If a patient experiences an SPM that does *not* result in permanent discontinuation of lenalidomide, Adverse Events will continue to be reported as per section 4.2.3 and appendix I of the protocol.  
- Requests to discontinue Adverse Event Reporting for events that do not meet the criteria above will be considered on a case by case basis.
table 4.3a patient clinical assessments
4.4.5. pregnancy reporting

Pregnancies, suspected exposure of a pregnant woman (including female partner of a male patient and exposure to lenalidomide while dispensing) and suspected pregnancies (including a positive pregnancy test regardless of age or disease state) of a female subject occurring while the subject is on lenalidomide, or within 28 days of the subject's last dose of lenalidomide, are considered immediately reportable events. Lenalidomide is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy test must be reported through the expedited AE
reporting system in AdvantageEDC. The female subject should be referred to an obstetriciangynecologist, preferably one experienced in reproductive toxicity for further evaluation and counseling. The Investigator will follow the female subject until completion of the pregnancy, and must notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal outcome) using the expedited AE reporting system in AdvantageEDC. If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should report the abnormal outcome as an AE. All neonatal deaths that occur within 28 days of birth should be reported, without regard to causality through the expedited AE reporting system in AdvantageEDC. In addition, any infant death after 28 days that the Investigator suspects is related to the inutero exposure to lenalidomide should also be reported through the expedited AE reporting system within 24 hours of the Investigator's knowledge of the event
table 4.3a patient clinical assessments
male subjects

If a female partner of a male subject taking investigational product becomes pregnant, the male subject taking lenalidomide should notify the Investigator, and the pregnant female partner should be advised to call her healthcare provider immediately. 4.4.6. Celgene Drug Safety Contact Information: Celgene Corporation Global Drug Safety and Risk Management Connell Corporate Park 300 Connell Dr. Suite 6000 Berkeley Heights, NJ 07922 Fax: (908) 673-9115 E-mail: drugsafety@celgene.com 4.4.7. Reporting of other Special Events of Interest There are other special events of interest to Celgene that require reporting through the AE expedited reporting system in AdvantageEDC. If any of the following events occur, they are required to be reported within 3 business days of the site's knowledge of the event:  
- overdose, abuse and misuse that meets one of the criteria of a serious adverse event
- medication errors that meets one of the criteria of a serious adverse event - occupational exposure of any kind - public health emergency
- Celgene product technical complaint that leads to an adverse event
table 4.3a patient clinical assessments
4.5. ancillary correlative laboratory studies

Selected study patients will be presented with the opportunity to participate in the ancillary studies outlined in Appendix J and K. This section describes procedures associated with the ancillary studies including data entry and obtaining informed consent. Additional details including eligibility requirements for each ancillary study can be found in the protocol appendices. 4.5.1. Obtaining Informed Consent The Optional Research Sample Consent form should be presented to eligible patients ≤ 30 days prior to randomization on BMT CTN 1401. The following 3 documents are provided for documentation of informed consent to participate on the ancillary studies in appendix J and K:
- Informed Consent Form to Participate in Optional Ancillary Correlative Laboratory Research: The purpose of this document is to obtain consent to participate in the Optional Ancillary Research for BMT CTN 1401. This consent provides an overview of the required components required to obtain informed consent. However, it must be presented in conjunction with at least one of the two supplementary consent documents.  
- Supplementary Consent Document for the VCAN Study: The purpose of this document is to be presented alongside the Informed Consent Form to Participate in Optional Ancillary Research. This consent document should be presented to patients eligible for the VCAN study per appendix J. Patients must sign this Supplementary Consent Document along with the Informed Consent Form to Participate in Optional Ancillary Research in order to move forward with providing the required sample for the VCAN Study.  
- Supplementary Consent Document for T Cell/Genomic Signature Study: The purpose of this document is to be presented alongside the Informed Consent Form to Participate in Optional Ancillary Research. This consent document should be presented to patients eligible for the T Cell/Genomic Signature Study per appendix K Patients must sign this Supplementary Consent Document along with the Informed Consent Form to Participate in Optional Ancillary Research in order to move forward with providing the required samples for the T Cell/Genomic Signature Study.
4.5.2. Data Entry Requirements Consent and Eligibility for ancillary research participation will be documented on the BMT CTN 1401 Segment B Enrollment Form. Sample collection and shipment will be documented in GlobalTrace and on the Specimen Acquisition Form in AdvantageEDC. Further information regarding sample collection, shipment, and documentation can be found in the Research Sample Information Guide and the BMT CTN 1401 Forms Guide. Additional information on the data entry and laboratory procedures are outlined in appendix J and K.
chapter 5
5. statistical considerations 5.1.study design

The study is designed as a Phase II randomized, open label, multicenter trial to evaluate the use of vaccination with DC/myeloma fusions/GM-CSF plus lenalidomide maintenance therapy compared to lenalidomide maintenance therapy with and without GM-CSF following autologous transplant as part of upfront treatment for patients diagnosed with multiple myeloma. Patients meeting initial eligibility will be enrolled for the purpose of harvesting tumor cells. Randomization will then occur approximately 2 months after autologous transplant and within 10 days of disease assessment. The target enrollment is 132 patients randomized; assuming that 30% will drop out between tumor collection and randomization, the study will target 188 patients for initial enrollment. As the impact of GM-CSF without vaccine on clinical outcomes is expected to be minimal, analysis of clinical outcomes will focus on comparing the vaccine arm vs. the combined no-vaccine arms. This will help maintain power for these primary analyses. Further randomization of the no-vaccine arms into maintenance vs. maintenance +GM-CSF is done to isolate the effect of the GM-CSF adjuvant on immunological outcomes and address whether any observed effect of vaccine is truly related to the vaccine.
chapter 5
5.1.1. accrual

It is estimated that 36 months of accrual will be necessary to enroll the targeted sample size. Accrual will be reported by race, ethnicity, gender, and age.
chapter 5
5.1.2. randomization

Randomization will occur approximately 2 months after autologous transplant and within 10 days of disease assessment. Randomization will be performed in a 2:1:1 ratio using random block sizes for the vaccine/GM-CSF (n=66), lenalidomide/GM-CSF (n=33) and lenalidomide alone (n=33) treatment arms, respectively. Randomization will be stratified according to disease response at time of randomization between sCR/CR and VGPR/PR/Stable disease.
chapter 5
5.1.3. primary endpoint

The primary endpoint is the proportion of patients alive and in CR or sCR at one year post transplant, corresponding to approximately 10 months post randomization. The primary analysis will be performed using the intent-to-treat principle so that all randomized patients will be included in the analysis.
chapter 5
5.1.4. primary hypothesis

The primary objective of the study is to determine whether vaccination with DC/myeloma fusions/GM-CSF in combination with lenalidomide maintenance therapy increases the proportion of patients alive and in CR or sCR at one year compared to the combined maintenance groups without vaccine. Letting P denote the proportion of patients alive and in CR and sCR at one year, the hypotheses of interest are: H0: PVACCINE/GMCSF +MAINT = PMAINT±GMCSF vs. Ha: PVACCINE/GMCSF +MAINT > PMAINT±GMCSF. 5.1.5. Duration of follow-up All patients will be followed for approximately 3 years post-maintenance initiation for primary and secondary endpoints.
chapter 5
5.2.sample size and power considerations

5.2.1. Primary Endpoint (Clinical) Based on the prior cooperative group studies, we anticipate approximately 40% of patients will achieve CR and sCR at 1 year. In the prior phase II study of patients undergoing post-transplant vaccination in the absence of lenalidomide maintenance, CR was achieved in 29% and 54% of patients at 100 days and 1 year post-transplant respectively. Given that we anticipate that lenalidomide maintenance will enhance vaccine efficacy, we will consider the experimental arm of vaccine/GM-CSF + maintenance promising if the CR rate at 1 year is improved from 40% to 60%. A sample size of 66 patients (132 total) randomized to the vaccine arm and the combined no-vaccine arms will have 85% power to detect this improvement in the CR rate at 1 year from 40% to 60%, using a two-sample comparison of proportions with a one-sided type I error of 10%. Because randomization occurs post collection of tumor sample and post-transplant, we anticipate needing to enroll 188 at the time of initial tumor collection pre-transplant assuming that 30% will drop out between tumor collection and randomization. Secondary comparisons of CR rate at 1 year post HCT between the vaccine/GM-CSF arm vs. either lenalidomide/GM-CSF or lenalidomide alone separately will have 80% power to detect a 23% increase in the CR rate, using the same one-sided alpha level of 10%. Comparison between the two no-vaccine arms will have 80% power to detect a 26% improvement in the CR rate.  
5.2.2. Power Considerations for Primary Immunologic Endpoint The primary immunologic endpoint will be to quantify the expansion of myeloma reactive T cells as determined by the pretreatment and peak post-treatment levels. The anticipated standard deviation of the log 10 peak change in tumor reactive T cells from baseline is 0.61, based on prior studies. Assuming 15% of patients will not be evaluable for immune reconstitution studies, the expected evaluable sample sizes will be 56 for the vaccine group and 28 for each of the no-vaccine groups. Comparisons between the vaccine group and either of the no-vaccine groups will have 80% power to detect a log 10 fold change of 0.4, corresponding to a 2.5 fold expansion of myeloma specific T cells, using a two-sample t-test with a 5% two-sided significance level. Comparisons between the two no-vaccine groups will have 80% power to detect a log 10 fold change of 0.46, corresponding to a 2.9 fold expansion of myeloma specific T cells. Note that a stricter alpha level is used for immunologic endpoints to reduce the risk of type I errors while still being adequately powered to detect larger quantitative differences likely to translate into clinical improvements.
chapter 5
5.3.interim analysis and stopping guidelines

5.3.1. Interim Analysis for Efficacy There will be no interim analyses for efficacy.  
5.3.2. Interim Analysis for Futility There will be no interim analyses for futility. 5.3.3. Guidelines for Safety Monitoring Monitoring of a key safety endpoint will be conducted monthly, and if rates significantly exceed pre-set thresholds, the NHLBI will be notified in order that the DSMB can be advised. Policies and composition of the DSMB are described in the BMT CTN's Manual of Procedures. The stopping guideline serves as trigger for consultation with the DSMB for additional review. The key safety endpoint for this study is treatment limiting toxicity (TLT) within the first month of combined therapy, defined as any grade V event regardless of attribution to combined therapy, grade IV hematologic (lasting greater than 7 days) and grade III-IV non-hematologic toxicity judged to be related to combined therapy. At least three events must be observed in order to trigger review. The rate of TLT within the first month is expected to be no higher than 25%. Each month, the null hypothesis that the 1 month TLT rate is 25% will be tested. This outcome will be monitored using a truncated Sequential Probability Ratio Test (SPRT) for binary data as described below. The SPRT conserves type I error at 5% across all of the monthly examinations. The SPRT can be represented graphically. At each interim analysis, the total number of patients enrolled and started combined therapy is plotted against the total number of patients who have experienced treatment limiting toxicities. The continuation region of the SPRT is defined by two decision boundaries. Only the upper boundary will be used for monitoring the study to protect against high incidences of TLT. If the graph falls above the upper boundary, the SPRT rejects the null hypothesis, and concludes that the TLT incidence is higher than predicted by the observed number of patients enrolled on study. Otherwise, the SPRT continues until enrollment reaches the target goal. The SPRT for TLT was developed from the following SPRT: A SPRT contrasting 25% versus 40% 1 month incidence, with nominal type I and II errors of 12% and 15%, respectively, which results in decision boundaries with a common slope of 0.322 and an upper intercept of 2.824. The actual operating characteristics of this truncated test, shown in Table 5.3.3, were determined in a simulation study that assumed uniform accrual of 66 individuals over a three-year time period.
chapter 5
table 5.3.3 operating characteristics of

| True 1 month Incidence      | 25%   | 35%   | 40%   | 45%   |
|-----------------------------|-------|-------|-------|-------|
| Probability Reject Null     | 0.100 | 0.595 | 0.836 | 0.957 |
| Mean Month Stopped          | 34.8  | 25.0  | 18.3  | 13.5  |
| Mean # Endpoints in 1 month | 15.5  | 15.4  | 13.1  | 10.6  |
| Mean # Patients Enrolled    | 62.1  | 43.8  | 32.7  | 23.7  |  
For example, the testing procedure rejects the null hypothesis in favor of the alternative 10% of the time when the true 1 month TLT rate is 25%, and 84% of the time when the rate is 40%. This corresponds to a type I error rate of α = 0.1 and a type II error rate of β = 0.16. When the true 1 month TLT rate is 40%, on average, the DSMB will be consulted 18 months after opening, when 13 events have been observed in 33 patients.
chapter 5
5.4.demographic and baseline characteristics

Demographics and baseline characteristics will be summarized for all patients. Characteristics to be examined are: age, gender, race/ethnicity, performance status, pre-randomization disease response. Between group comparisons will be performed for continuous variables via a KruskalWallis test and for categorical variables, via the chi-square test.
chapter 5
5.5.analysis of primary clinical endpoint

The intent-to-treat principle will be followed, so that all patients who are randomized will be included in the analysis. The proportion of patients alive and in CR/sCR at 1 year post transplant will be described in the vaccine and no vaccine groups with 80% confidence intervals and compared between groups using a two-sample Z test comparing binomial proportions. A onesided significance level of 0.1will be used for this comparison to indicate whether the vaccine plus maintenance treatment is promising compared to the combined no-vaccine groups in this phase II trial. An 80% two-sided confidence interval (consistent with one-sided significance level of 0.1) will be constructed for the difference in proportions. A secondary analysis stratified on disease response prior to randomization will be conducted using a Cochran-Mantel-Haenszel test, and a stratified odds ratio along with 80% confidence intervals will be estimated. A secondary pairwise analysis of CR rates comparing the vaccine arm, lenalidomide/GM-CSF arm and the lenalidomide alone arm will also be conducted.
chapter 5
5.6.analysis of secondary clinical endpoints

5.6.1. Response to treatment The distribution of disease response will be tabulated at each time point. The proportion of patients alive and with a response of VGPR or better will be compared between the vaccine arm with the no-vaccine arms combined at 6 months, 1 year, and 2 years post-transplant using a chi-square test. A secondary pairwise analysis of response to treatment comparing the vaccine arm, lenalidomide/GM-CSF arm and the lenalidomide alone arm will also be conducted. Rates of conversion to CR will also be compared using a chi-square test among the subset of patients who are not in CR at the time of randomization.
chapter 5
5.6.2. myeloma progression

Incidence of myeloma progression will be estimated using cumulative incidence function, treating death as a competing risk. Incidence of myeloma progression will be compared between the vaccine arm with the no-vaccine arms combined using Gray's test. A secondary pairwise analysis of myeloma progression comparing the vaccine arm, lenalidomide/GM-CSF arm and the lenalidomide alone arm will also be conducted.
chapter 5
5.6.3. treatment-related mortality

Incidence of TRM will be estimated using the cumulative incidence function, treating myeloma progression as a competing risk. Incidence of TRM will be compared between the vaccine arm with the no-vaccine arms combined using Gray's test. A secondary pairwise analysis of TRM comparing the vaccine arm, lenalidomide/GM-CSF arm and the lenalidomide alone arm will also be conducted.  
5.6.4. Progression-free survival Progression-free survival curves will be estimated using the Kaplan-Meier estimator, and compared between the vaccine arm with the no-vaccine arms combined using the log-rank test. Hazard ratios, along with confidence intervals, will be estimated from a Cox model with treatment group as a covariate. A secondary pairwise analysis of PFS comparing the vaccine arm, lenalidomide/GM-CSF arm and the lenalidomide alone arm will also be conducted.
chapter 5
5.6.5. overall survival

Overall survival curves will be estimated using the Kaplan-Meier estimator, and compared between the vaccine arm with the no-vaccine arms combined using the log-rank test. Hazard ratios, along with confidence intervals, will be estimated from a Cox model with treatment group as a covariate. A secondary pairwise analysis of overall survival comparing the vaccine arm, lenalidomide/GM-CSF arm and the lenalidomide alone arm will also be conducted.  
5.6.6. Incidence of toxicities grade ≥ 3 per CTCAE version 4.0 All Grade ≥ 3 toxicities will be tabulated by grade for each treatment arm, by type of toxicity as well as the peak grade overall. Toxicity frequencies will be described for each time interval as well as cumulative over time.
chapter 5
5.6.7. incidence of infections

The number of infections and the number of patients experiencing infections will be tabulated by type of infection, severity, and time period after transplant. The cumulative incidence of infections, treating death as a competing event, will be compared between the vaccine arm with the no-vaccine arms combined using Gray's test. A secondary pairwise analysis of the incidence of infections comparing the vaccine arm, lenalidomide/GM-CSF arm and the lenalidomide alone arm will also be conducted. 5.6.8. Minimal Residual Disease assessment The proportions of patients with MRD present (MRD+) will be described using frequencies at each timepoint and compared between the vaccine arm with the no-vaccine arms combined using the chi-square test. A secondary pairwise analysis of MRD comparing the vaccine arm, lenalidomide/GM-CSF arm and the lenalidomide alone arm will also be conducted.
chapter 5
5.7.analysis of immunological endpoints

5.7.1. Primary immunologic endpoint: Myeloma reactive T-cells Log transformations will be used to induce normality in quantitative measurements, and if still non-normal, then nonparametric tests will be used. The primary endpoint of log 10 peak change in tumor reactive T cells from baseline will be compared across the 3 groups using analysis of variance, and if significant then two-sample t-tests will be conducted for each pairwise comparison to determine which groups are different from one another. A secondary analysis of peak change in tumor reactive T cells will be done by comparing the proportions of patients who experience
>10-fold increase in IFNγ expression, using a chi-squared test. Myeloma reactive T-cell response profiles over time will be compared between the treatment groups using linear mixed models for repeated measures data. Peak immune response as well as most recent immune response will be compared between those in CR and those not in CR at each assessment, using a two-sample t-test, to assess the relationship between immune response and clinical response. Peak and most recent immune response will also be considered as time-dependent covariates in a Cox proportional hazards model to assess their impact on progression-free survival.
chapter 5
5.7.2. secondary immunologic endpoints

Additional exploratory analyses will be conducted in a similar fashion to examine a number of secondary immunologic endpoints, including: 1) antigen specific reactivity by tetramer analysis, 2) quantification of T-cell subsets and PD-1 expressing lymphocytes by flow cytometry 3) quantification of NK cell populations with inhibitor and activating markers, 4) NK-cell cytotoxic function as measured by IFNγ and CD107a degranulation in response to ex vivo exposure to autologous MM cells, and 5) humoral response against autologous MM cells and myeloma associated antigens such as MUC1, and vaccine-induced myeloma-specific plasmablast responses. In each case, log transformations will be considered to induce normality, and if still non-normal then nonparametric tests will be used. Profiles of these secondary immunologic endpoints will be described at each time point for each group using summary statistics and compared between the groups using mixed models for repeated measures data. The correlation between the immune environment measures and the myeloma specific T-cell response will be assessed and reported using Spearman rank correlation at each time point.
chapter 5
5.8.endpoint review committee

An Endpoint Review Committee of appointed physicians will convene to adjudicate the primary endpoint of complete response as defined by a protocol endpoint review charter. The charter outlines the primary and secondary endpoints to be evaluated and details the endpoints to be adjudicated, process for adjudication, procedures for discrepancy resolution, and recording of results. This review will be done in a blinded manner.
appendix a criteria for symptomatic
all three required

1. Monoclonal plasma cells in the bone marrow ≥ 10% and/or presence of a biopsy-proven plasmacytoma 2. Monoclonal protein present in the serum and/or urinea 3. Myeloma defining events (1 or more)
a. Myeloma- related organ dysfunctionb:
i. Calcium elevation in the blood (serum calcium > 10.5 mg/l or upper limit of normal)
ii. Renal insufficiency (serum creatinine > 2mg/dl)
iii. Anemia (hemoglobin <10 g/dL)
iv. Lytic bone lesions or osteoporosisc b. Any one or more of the following biomarkers of malignancy:
i. Clonal bone marrow plasma cell percentage > 60%
ii. Involved: uninvolved serum free light chain ratio >100 iii. >1 focal lesion of MRI
*Note: These criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA becomes smoldering or indolent myeloma.  
a If no monoclonal protein is detected (nonsecretory disease), then ≥30% monoclonal bone marrow plasma cells and/or a biopsy-proven plasmacytoma required.  
b A variety of other types of end organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related. c If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the sole defining criteria, then ≥ 30% plasma cells are required in the bone marrow.  
*Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. The Hematology Journal (2003) 4, 379–398
appendix b informed consent documents
bmt ctn 1401 v4.0

Phase II Multicenter Trial of Single Autologous Hematopoietic Cell Transplant Followed by Lenalidomide Maintenance for Multiple Myeloma with or without Vaccination with Dendritic Cell /Myeloma Fusions  
| Your Name:               | __________________________                                                                                                                                                                                      |
|--------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Study Title:             | Phase II Multicenter Trial of Single Autologous Hematopoietic Cell  Transplant Followed by Lenalidomide Maintenance for Multiple Myeloma  with or without Vaccination with Dendritic Cell /Myeloma Fusions      |
| Protocol:                | BMT CTN 1401 v4.0                                                                                                                                                                                               |
| Principal  Investigator: | Insert local PI information                                                                                                                                                                                     |
| Sponsor:                 | The National Institutes of Health (NIH) is sponsoring this study by  providing financial support for the coordination of this study through the  Blood and Marrow Transplant Clinical Trials Network (BMT CTN). |
appendix b informed consent documents
1. introduction

We invite you to join this clinical trial, also known as a research study. You are being asked to join because:
- You're >18 and <71 years old
- You have multiple myeloma (MM)
- Your doctor thinks an **autologous transplant** is a possible treatment option for you.  
The standard of care for patients with MM is an autologous transplant and **maintenance**
treatment. Maintenance treatment is chemotherapy after transplant. There's no cure for MM, so patients get maintenance treatment to slow the return of MM after a transplant. We're doing this study to learn if maintenance treatment works better alone or with a vaccine made from your own blood cells. This study will take at least 3 years and will include 203 participants. Your participation will last for a **maximum of 4 years from when you are enrolled.** This consent form will tell you about the purpose of the study, the possible risks and benefits, other options available to you, and your rights as a participant in the study.  
Everyone who takes part in research at [*insert facility name*] should know that:
- Being in any research study is voluntary.  
- You may or may not benefit from being in the study. Knowledge we gain from this study may benefit others.
- If you join the study, you can quit the study at any time.  
- If you decide to quit the study, it will not affect your care at [insert name of facility or institution].  
- Please ask the study staff questions about anything that you do not understand, or if you would like to have more information.  
- You can ask questions now or any time during the study.  
- Please take the time you need to talk about the study with your doctor, study staff, and your family and friends. It is your decision to be in the study. If you decide to join, please sign and date the end of the Consent Form.
You and your doctor will discuss other treatment choices if you do not want to participate in this study.
appendix b informed consent documents
2. study background

The National Institutes of Health (NIH), through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), are providing staff support and money for this research study. The BMT CTN and the NIH will make decisions about how to manage the study.  
For this study, you will receive an **autologous transplant** (transplant). An autologous transplant uses blood-forming cells that are collected from your blood stream. After they are collected and frozen, you will get a high dose of chemotherapy. Chemotherapy before a transplant is called the "conditioning regimen". The goal of chemotherapy is to kill as many cancer cells in your body as possible. It also destroys most of the normal cells in your bone marrow. To restore your marrow, your frozen blood-forming cells are thawed and transplanted back into your blood stream. The cells find their way into the bone marrow where they start making healthy blood-forming cells. The standard of care for patients with MM is an autologous transplant and maintenance treatment. Maintenance treatment is chemotherapy after transplant. There's no cure for MM, so patients get maintenance treatment to slow the return of MM after a transplant.  
Some patients may receive a vaccine, and/or GM-CSF **(also known as Leukine)** with their maintenance therapy. GM-CSF helps your body make new white blood cells after transplant.  
The vaccine is made from dendritic cells and MM tumor cells in a laboratory. We will collect a sample of your cells through your central line (or catheter). This process is called leukapheresis. If the vaccine is made successfully, it will be frozen and stored to give to you later. We're doing this study to learn if maintenance treatment works better alone, or with a vaccine made from your own blood cells.
appendix b informed consent documents
3. study purpose

We are inviting you to take part in this study because you have multiple myeloma (MM) and an autologous transplant is a treatment option for you. We are doing this study to learn more about ways to prevent or slow the return of MM after transplant. We will use 3 treatments to see which one works best to prevent or slow the return of MM. See Table 1 for information on each treatment group.  
| Treatment Group A  (maintenance treatment with  GM-CSF and vaccines)   | Treatment Group B  (maintenance treatment with  GM-CSF)   | Treatment Group C (only  maintenance treatment)   |                                       |    |                                       |
|------------------------------------------------------------------------|-----------------------------------------------------------|---------------------------------------------------|---------------------------------------|----|---------------------------------------|
| -                                                                      | Melphalan (chemotherapy  drug)                            | -                                                 | Melphalan (chemotherapy drug)         | -  | Melphalan (chemotherapy  drug)        |
| -                                                                      | Autologous transplant                                     | -                                                 | Autologous transplant                 | -  | Autologous transplant                 |
| -                                                                      | Lenalidomide (maintenance treatment)                      | -                                                 | Lenalidomide  (maintenance treatment) | -  | Lenalidomide (maintenance  treatment) |
| -                                                                      | GM-CSF                                                    | -                                                 | GM-CSF                                | -  |                                       |
| -                                                                      | Vaccine                                                   |                                                   |                                       |    |                                       |
appendix b informed consent documents
table 1. study treatment groups

This study will help doctors make the best choice about treatment after transplant for patients with MM. See section 5: Study Tests **and Treatments** for information on how your treatment group will be determined and for information about the drugs listed in **Table 1**.
appendix b informed consent documents
4. rights to ask questions

You have the right to ask questions about the study at any time. If you have questions about your rights as a participant or you want to leave the study, please contact:
appendix b informed consent documents
[insert contact info]

Being in this study is voluntary. You can choose not to be in this study or leave this study at any time. If you choose not to take part or leave this study, it will not affect your regular medical care in any way. Your study doctor and study staff will be available to answer any questions that you may have about taking part in or leaving this study.
appendix b informed consent documents
5. study treatment and tests

We will check your health before you start treatment, during your treatment, and for 3 years after you begin your maintenance treatment.
appendix b informed consent documents
before you start your treatment

You will need to have several check-ups and tests to see if you can be in the study. These checkups and tests are part of your regular cancer care and would be done even if you were not part of this study. These tests include:  
- Medical history and physical exam
- Blood tests for cell counts
- Liver and kidney function tests
- Tests to measure your disease - Bone marrow tests - Skeletal survey
- A pregnancy test (if you are a woman able to have children)
appendix b informed consent documents
during your treatment tumor cell

After you join the study, we will collect about 30mL (approximately 2 tablespoons) of bone marrow and 50mL (approximately 3 tablespoons) of blood. The bone marrow and blood samples will be frozen until it is determined if you will receive the vaccine as part of your treatment. This tumor cell collection is not part of your standard of care treatment If you are assigned to Treatment Group A after your transplant, your bone marrow will be thawed and used to make your vaccine. If you are assigned to Treatment Group B or C, your bone marrow sample will not be used in this study. Your doctor may talk to you about other uses for your stored bone marrow samples not related to this study.  
We will also talk with you about giving extra blood and marrow samples for future research (see section **17: Blood and Marrow Samples for Future Research**). The extra blood and marrow samples are also completely optional.
appendix b informed consent documents
initial treatment for multiple myeloma

The first step (initial) is standard chemotherapy treatment (chemo). Chemo lowers the number of MM cells in your body. Different chemotherapy drugs can be used to treat MM. Your doctor will decide which drug or combination of drugs is best for you. You will be asked to sign a separate consent form that will explain the side effects of whichever drug your doctor chooses. This step may last several months.
appendix b informed consent documents
blood-forming cell collection

Next, we'll collect blood-forming cells from your blood stream. This is known as apheresis. These cells will be frozen and stored until your transplant day.
appendix b informed consent documents
conditioning regimen before transplant

The third step is the conditioning regimen, or the chemotherapy, you will get before your transplant. The conditioning regimen helps the blood-forming cells start to grow and make new cells in your bone marrow (engraft). The regimen includes a chemo drug called **melphalan**, given by intravenous infusion (IV) in your arm. Your doctor will decide when you are ready to get melphalan. You will start this treatment step no more than 12 months after you start on this study. Melphalan works better for some patients than it does for others. If the drug does not work well for you, you may not be able to have a transplant. Your doctor will talk to you about other treatment options.
appendix b informed consent documents
infusion of blood forming cells

On your transplant day (Day 0), your cells will be given to you through your catheter. The cells will travel to your bone marrow where they will start to make healthy, new blood cells (engraft).
appendix b informed consent documents
your treatment group

Approximately 2 months after transplant, we will check to see if you're healthy enough to start maintenance treatment. If you are found healthy enough, we will randomize you to 1 of the 3 treatment groups. **"Randomize"** means that you will be put in one or another group by chance, just like flipping a coin. We will use a computer program to assign you by chance to Treatment Group A, B, or C. You won't be able to choose your group. Once you are assigned to a group, you can't change to another group. The study doctor can't change your group either.  
Half of the patients on this study (about 66), will be assigned to Treatment Group A. One-fourth of the patients (about 33) will be assigned to Treatment Group B; and one-fourth of patients (about 33) will be assigned to Treatment Group C. See the section below, Your Maintenance Treatment After Transplant, for a description of the treatments.  
Once all these tests are done, you will be randomized to Treatment Group A, B or C. See **Table**
2 for a schedule of these tests.  
If you're not healthy enough after transplant, you won't be randomized. If this happens, your Follow up on this study is complete
appendix b informed consent documents
your maintenance treatment after transplant

You will start maintenance treatment about 3 months after your transplant.
appendix b informed consent documents
treatment group a lenalidomide vaccine

If you are assigned to Treatment Group A, you will get: lenalidomide, vaccines, and GM-CSF injections. We will collect extra blood samples to make the vaccine. We will insert a catheter into a large vein in your neck or chest. The catheter will collect some blood cells and the rest are returned to your body. This process is called leukapheresis. We will use the blood cells and the marrow that was collected and frozen to create your vaccine. The vaccine will be made in a laboratory and frozen until you're ready for maintenance treatment. You will take lenalidomide as a pill every day for 2 years or until your disease returns. You will receive enough pills for 1 cycle (28 days in each cycle) at a time. It's important to take the pill at the same time every day. Be sure to talk with your doctor to figure out a good time to take the pill every day.  
You will also receive 3 doses of the vaccine. This will be given to you on the first day of your 2nd, 3rd, and 4th cycle of lenalidomide. The vaccine is the part of the treatment we are testing in this study. This is also called the research treatment. With each vaccine, you will also get an injection of GM-CSF in your upper thigh. GM-CSF helps to boost the effect of the vaccine. You will receive the GM-CSF injection on the day you get the vaccine and every day for 3 days after the vaccine. This will either be given to you in the clinic or you will be taught to give the injections to yourself at home. See **Table 2** for a timeline of the drugs for Treatment Group A.  
| Timeline for Maintenance Treatment Drugs   |                               |              |    |    |    |    |    |    |    |    |    |    |
|--------------------------------------------|-------------------------------|--------------|----|----|----|----|----|----|----|----|----|----|
| Cycle: (28 days  in each  cycle)           | 1                             | 2            | 3  | 4  | 6  | 9  | 12 | 15 | 18 | 21 | 24 |    |
| Treatment  Group A  drugs:                 | Amount:                       |              |    |    |    |    |    |    |    |    |    |    |
| Lenalidomide                               | 1 dose every day for  2 years | X            | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  |
| Vaccine                                    | 3 doses total                 | X            | X  | X  |    |    |    |    |    |    |    |    |
| X  (+3  days)                              | X  (+3  days)                 |              |    |    |    |    |    |    |    |    |    |    |
| GM-CSF                                     | 12 doses total                | X (+3  days) |    |    |    |    |    |    |    |    |    |    |
table 2 treatment group a
treatment group b lenalidomide and

If you are assigned to Treatment Group B, you will get: lenalidomide and GM-CSF injections. You will take lenalidomide every day for 2 years or until your disease returns. You will receive the enough pills for 1 cycle (28 days in each cycle) at a time. It's important to take the pill at the same time every day. Be sure to talk with your doctor to figure out a good time to take the pill every day.  
You will also get an injection of GM-CSF in upper thigh. You will get the GM-CSF injection every day for 4 days starting the first day of cycles 2, 3 and 4. This will either be given to you in the clinic or you will be taught to give the injections to yourself at home.  
See **Table 3** for a timeline of the drugs for Treatment Group B.  
| Timeline for Maintenance Treatment Drugs   |                               |             |                |                |    |    |    |    |    |    |    |    |
|--------------------------------------------|-------------------------------|-------------|----------------|----------------|----|----|----|----|----|----|----|----|
| Treatment  Group B drugs:                  | Amount:                       | Cycle:      |                |                |    |    |    |    |    |    |    |    |
| (28 days in  each cycle)                   | 1                             | 2           | 3              | 4              | 6  | 9  | 12 | 15 | 18 | 21 | 24 |    |
| Lenalidomide                               | 1 dose every day for 2  years | X           | X              | X              | X  | X  | X  | X  | X  | X  | X  | X  |
| X                                          |                               |             |                |                |    |    |    |    |    |    |    |    |
| GM-CSF                                     | 12 doses total                | (+ 3  days) | X  (+ 3  days) | X  (+ 3  days) |    |    |    |    |    |    |    |    |
table 2 treatment group a
treatment group c lenalidomide

If you are assigned to Treatment Group C, you will take lenalidomide every day for 2 years or until your disease returns. You will receive enough pills for 1 cycle (28 days in each cycle) at a time. It's important to take the pill at the same time every day. Be sure to talk with your doctor to figure out a good time to take the pill every day.
table 2 treatment group a
maintenance treatment dose (all treatment

Lenalidomide is available only from a certified pharmacy through the Revlimid REMS® program. During maintenance therapy, only a 28-day supply (1 cycle) will be given to you at a time. If this is the first time you've taken lenalidomide, you'll have to sign-up, or register, for the program. This will include a separate consent process, which calls out the reproductive risks of taking this medicine. You'll have to give your name, address, phone number, birth date, and social security number to sign-up for the program. This information will be provided to Celgene Corporation and Biologics Incorporated to show you're taking part in this study. After you're registered, you'll be counseled at the site or through the program:
- When you're first given the drug
- At least every 28 days while you're taking it, and
- When you stop taking it You will be counseled about:
- Side effects
- Not sharing lenalidomide (or other study drugs)  
- Risks of exposing a fetus (unborn baby)
- Donating blood  
- How to take the pills
We'll give you the, "Lenalidomide Information Sheet for Patients Enrolled in Clinical Research Studies" with each new supply of lenalidomide to remind you of these safety issues.
table 2 treatment group a
how to take the lenalidomide

- Swallow the whole lenalidomide pill with water at the same time each day. Do not break, chew or open the capsules.  
- If you miss a dose, take it as soon as you remember on the same day. If you miss taking your dose for the entire day, take your regular dose the next scheduled day (do not take a double dose to make up for the missed dose).  
- If you take more than the prescribed dose you should seek emergency medical care if needed and contact study staff right away.  
- Women who can become pregnant that care for you should wear gloves whenever they need to touch the lenalidomide pills or bottles.
table 2 treatment group a
checking your health

We will watch your health closely during your maintenance treatment, including how well your organs work. We will lower your dose if your organs don't handle the treatment well. We won't start a new cycle until your organs work well again. If we lower your dose and then your organs start working normally, we may raise your dose again. We will stop the maintenance treatment if you:
- Have a serious side effect
- Have low blood cell counts - Are a woman and become pregnant, or there is a chance that you are pregnant
- Go more than 56 days before starting a new maintenance treatment cycle - Don't follow the study directions, or
- Choose to leave the study.  
You will need to visit your clinic for several check-ups and tests during your maintenance treatment. These tests are shown in Table 4. These assessments are standard of care for patients receiving lenalidomide maintenance therapy. Table 4. Timeline of Tests Before and During Your Maintenance Treatment  
| Timeline for Maintenance Treatment Tests (CYCLES)          | Timeline for   |    |    |    |    |    |    |    |    |    |    |    |     |     |
|------------------------------------------------------------|----------------|----|----|----|----|----|----|----|----|----|----|----|-----|-----|
| Post-Transplant  Tests (Months)                            |                |    |    |    |    |    |    |    |    |    |    |    |     |     |
| Before  you're  Random ized                                |                |    |    |    |    |    |    |    |    |    |    |    |     |     |
| Tests                                                      | 1              | 2  | 3  | 4  | 6  | 9  | 12 | 15 | 18 | 21 | 24 | 6T | 12T | 24T |
| Physical  exam,  height, and  weight                       | X              | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X   | X   |
| Tests for  toxicities,  and  infections                    | X              | X  | X  | X  | X  | X  | X  | X  | X  | X  |    |    |     |     |
| Blood tests  for cell  counts, liver  and kidney  function | X              | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  |     |     |
| Tests to see  how much  cancer you  still have             | X              | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  |     |     |
| Pregnancy  test (women  able to have  children)            | X              | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  |     |     |