Randomized Phase II Study of Autologous Stem Cell Transplantation With Tadalafil and Lenalidomide Maintenance With or Without Activated Marrow Infiltrating Lymphocytes (MILs) in High Risk Myeloma
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

 
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TITLE:  A Randomized Phase II Study of Autologous Stem Cell Transplantation with  
  
Tadalafil and Lenalidomide Maintenance with or without Activated Marrow  
 
Infiltrating Lymphocytes (MILs) in High Risk Myeloma   
  
  
Coordinating Center:  
Sidney Kimmel Comprehensive Cancer Center (SKCCC) 
  
Johns Hopkins University 550 Building, Suite 802  
  
Baltimore, MD 21205  
  
  
  
  
  
  
  
  
  
onc-coordcnt@jhmi.edu  
  
  
  
IND Sponsor/Protocol Chair: Kenneth R. Cooke, MD  
Sidney Kimmel Comprehensive Cancer Center  
1650 Orleans Street, Room 207  
Baltimore, MD 21287   
410-502-7223   
  
NCT01858558  
  
IND Number:  
BB IND 14117  
  
Protocol Number:  
J1343  
  
Original Protocol Date:  
28 May 2013  
  
Amendment 9  
15 January 2020    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
This study will be conducted in compliance with the protocol and all other applicable regulatory requirements.  
CONFIDENTIALITY STATEMENT  

 
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Your acceptance and use of this document is subject to the condition that no information contained herein will be 
published or disclosed without first obtaining written approval from Sidney Kimmel Comprehensive Cancer Center. If 
you do not agree to this condition, please return the document to Sidney Kimmel Comprehensive Cancer Center at the 
above address.  
Statistician:  
  
Statistician:   
 
Gary Rosner, Ph.D.  
Marianna Zahurak, M.S.  
 
550 N. Broadway, Suite 1103  
550 N. Broadway, Suite 1103  
 
Baltimore, MD 21205  
Baltimore MD 21205  
 
410-955-4884  
410-955-4219  
 
grosner1@jhmi.edu  
 
Responsible Research Nurse/  
mzahura1@jhmi.edu  
Coordinating Center Contact:  
Responsible Data Manager:  
 
Laura Cucci, Ph.D., R.N.   
Dmitry Kololo    
 
201 N. Broadway  
201 N. Broadway, Viragh Bldg M2101-06   
 
Viragh Building M2101-29  
 Baltimore, MD 21287  
 
Baltimore, MD 21287  
410-502-6058   
 
410-614-5407   
 Fax: 410-614-2449  
 
 lcucci1@jhmi.edu  
 dkololo1@jhmi.edu   
 
  
  
Regulatory Coordinator:  
 M. Amanda Stevens MD CCRA  
201 N. Broadway  
Viragh Building M2101-27  
Baltimore, MD 21287    443-287-
0180   
   msteve35@jhmi.edu  
  
Participating Sites:  
  
Philip Imus, MD  
Sidney Kimmel Comprehensive Cancer Center  
1650 Orleans Street, Suite 310   
Baltimore, MD 21231   
410-955-8873 Pimus1@jhmi.edu   
  
Frederick Locke, M.D.  
Department of Blood and Bone Marrow Transplantation   
Moffitt Cancer Center  
12902 Magnolia Drive  
Tampa, FL 33612 813-745-
2557   
frederick.locke@moffitt.org  

 
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Sikander Ailawadhi, MD  
Division of Hematology/Oncology  
Department of Medicine  
Mayo Clinic Florida  
4500 San Pablo Road  
Jacksonville, FL 32224  
904 953 7290 ailawadhi.sikander@mayo.edu  
  
Lawrence E. Morris, Jr  
Blood and Marrow Transplant Group of Georgia  
5670 Peachtree Dunwoody Rd  
Atlanta, GA 30342 404 
255 1930 
lemorris@bmtga.com 
TABLE OF 
CONTENTS  
  
PROTOCOL APPROVAL PAGE ...................................................................................................7  
TRIAL SYNOPSIS  8  
SCHEMA  
10  
STUDY OVERVIEW ........................................................................................................11  
1. 
STUDY OBJECTIVES ......................................................................................................11  
1.1 
Primary Objective ..................................................................................................11  
1.2 
Secondary Objectives.............................................................................................11  
2. 
BACKGROUND ...............................................................................................................12  
2.1 
Multiple Myeloma .................................................................................................12  
2.2 
Current Therapies for Multiple Myeloma ..............................................................13  
2.3 
Overview of Cell-mediated Immunity ...................................................................13  
2.4 
Immune Defects in Patients with Cancer Including Multiple Myeloma ...............14  
2.5 
Rationale for Immunotherapy of Multiple Myeloma .............................................14  
2.6 
Rationale for the Use of CD3xCD28 Bead-Activated T Cells ..............................15  
2.7 
Rationale for the Use of Activated MILs in Myeloma ..........................................16  
2.8 
Results from the First MILs Trial ..........................................................................18  
2.9 
Phosphodiesterase-5 (PDE-5) Inhibition ...............................................................19  
2.10 
Rationale for Study Design ....................................................................................20  
3. 
PATIENT SELECTION ....................................................................................................21  
3.1 
Eligibility Criteria for Enrollment .........................................................................21  

 
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3.2 
Eligibility Criteria for Bone Marrow Transplant ...................................................22  
3.3 
Confirmation of Eligibility ....................................................................................23  
4. 
REGISTRATION ON STUDY AND RANDOMIZATION .............................................23  
5. 
MULTICENTER GUIDELINES .......................................................................................23  
5.1 
Registration Guidelines ..........................................................................................23  
5.2 
Registration Process ...............................................................................................24  
5.3 
Responsibilities ......................................................................................................24  
6. 
BASELINE EVALUATIONS ...........................................................................................25  
7. 
MARROW INFILTRATING LYMPHOCYTES (MILs) COLLECTION .......................25  
7.1 
MILs Collection Procedure ....................................................................................26  
8. 
MILs ACTIVATION PROCESS, CELL DOSE & PRODUCTION FORMULATION ..26  
8.1 
MILs Activation Process........................................................................................26  
8.2 
Formulation Storage and Dose of Activated MILs T Cells ...................................26  
8.3 
Shipping and Storage of Activated MILs ..............................................................26  
9. 
MOBILIZATION AND COLLECTION OF PERIPHERAL BLOOD STEM CELLS ....27  
9.1 
Mobilization Regimen ...........................................................................................27  
9.2 
Peripheral Blood Stem Cell Collection ..................................................................27  
9.3 
Nomenclature for Numbering of Days ..................................................................27  
9.4 
Day -2 and Day -1: Melphalan...............................................................................27  
9.5 
Peripheral Blood Stem Cell Transplant (Day 0) ....................................................27  
9.6 
Supportive Care .....................................................................................................28  
9.7 
Post-Transplant Filgrastim .....................................................................................28  
9.8 
Tadalafil .................................................................................................................28  
10. 
ADMINISTRATION OF ACTIVATED MILs (~DAY 3 & 4) ........................................28  
10.1 
Evaluations Prior to Activated MILs T Cell Infusion ............................................28  
10.2 
Timing of Infusion of Activated MILs (aMILs) ....................................................28  
10.3 
Pre-Medication Prior to Infusion of aMILs ...........................................................29 
10.4 Procedure for Administering aMILs 
......................................................................29  
 
10.5  Safety Monitoring During Administration of aMILs .............................................29  
11. 
OBSERVATION, EVALUATION, AND MANAGEMENT AFTER TREATMENT  
WITH aMILs 30  
11.1 
Evaluations from Day 5 Through Day 28 after Peripheral Blood Stem Cell  
Transplant ..............................................................................................................30  
11.2 
Evaluations from Day 28-360 after Peripheral Blood Stem Cell Transplant ........30  
11.3 
Initiation of Lenalidomide Maintenance Therapy .................................................31  
11.4 
Discontinuation of Evaluations after Treatment ....................................................31  

 
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11.5 
Contraindicated Medications .................................................................................32  
12. 
TADALAFIL 32  
13. 
MANAGEMENT OF PROGRESSIVE DISEASE ...........................................................33  
13.1 
Documentation of Progressive Disease .................................................................33  
14. 
RISK AND TOXICITY ASSESSMENT ..........................................................................33  
14.1 
Risks of Venous Access .........................................................................................33  
14.2 
Risks of MILs Bone Marrow Harvest ....................................................................33  
14.3 
Microbial Contamination of Activated MILs ........................................................34  
14.4 
Potential Toxicity of Storage Solutions .................................................................34  
14.5 
Potential Adverse Effects of Tadalafil ...................................................................34  
14.6 
Potential Adverse Effects Associated with Activated MILs..................................35  
14.7 
Potential Adverse Events Associated with Peripheral Blood Stem Cell  
Transplant ..............................................................................................................36  
14.8 
Lenalidomide .........................................................................................................37  
15. 
ADVERSE EVENTS .........................................................................................................37  
15.1 
Definitions..............................................................................................................37  
15.2 
Adverse Event Assessment and Recording............................................................38  
15.3 
Grading of Adverse Events and Toxicities ............................................................39  
15.4 
Attribution of Causality .........................................................................................39  
15.5 
Serious Adverse Event Capture and Reporting .....................................................40  
15.6 
Definitions of Response (IMWG Criteria) ............................................................42  
15.7 
Survival Endpoints .................................................................................................45  
15.8 
Definitions of Engraftment and Graft Failure ........................................................45  
16. 
STATISTICAL CONSIDERATIONS...............................................................................46  
16.1 
Sample Size ............................................................................................................46  
16.2 
Statistical Analysis .................................................................................................46  
16.3 
Safety Data Monitoring..........................................................................................49  
16.4 
Plan for Statistical Summaries and Analyses.........................................................49  
17. 
ETHICAL, REGULATORY, AND ADMINISTRATIVE CONSIFERATIONS ............51  
17.1 
Informed Consent...................................................................................................51  
17.2 
Institutional Review ...............................................................................................51  
17.3 
Tissue Use for Research Purposes .........................................................................52  
18. 
STUDY MONITORING AND DATA COLLECTION....................................................52  
18.1 
Study Monitoring ...................................................................................................52  
18.2 
Maintenance of Study Documentation ...................................................................53  
18.3 
Final Study Report .................................................................................................53  
18.4 
Investigational Product Labeling and Accountability............................................53  

 
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19. 
REFERENCES ..................................................................................................................55  
20. 
Appendices  60  
20.1 
APPENDIX A DIAGNOSTIC CRITERIA FOR MULTIPLE MYELOMA ........60  
20.2 
APPENDIX B       DURIE-SALMON STAGING OF MULTIPLE  
MYELOMA ...........................................................................................................61  
20.3 
APPENDIX C ECOG PERFORMANCE STATUS .............................................62  
20.4 
APPENDIX D. NEW YORK HEART ASSOCIATION CLASSIFICATION  
OF   PATIENTS WITH DISEASES OF THE HEART ........................................63  
20.5 
APPENDIX F SKCCC DATA AND SAFETY MONITORING PLAN ..............66  
20.6 
APPENDIX G:  STANDARD EXPECTED TRANSPLANT RELATED  
TOXICITIES..........................................................................................................67  
20.7 
APPENDIX H:   NCI CTCAE V4.0 ......................................................................68  
20.8 
APPENDIX I. A Randomized Phase II Study of Autologous Stem Cell 
Transplantation with Tadalafil and Lenalidomide Maintenance with or  
without Activated Marrow Infiltrating Lymphocytes (MILs) in High Risk  
Myeloma ................................................................................................................69  
20.9 
Appendix J. Adverse Event assessment Chart .......................................................70  
20.10 Appendix K:  Revised Statistical Plan ................... Error! Bookmark not defined.  
  
  
  
PROTOCOL APPROVAL PAGE  
  
Signature of Principal Investigator  
A Randomized Phase II Study of Autologous Stem Cell Transplantation with Tadalafil and 
Lenalidomide Maintenance with or without Activated Marrow  Infiltrating Lymphocytes 
(MILs) in High Risk Myeloma   
I, the undersigned, have reviewed this protocol and I agree to conduct this protocol in accordance 
with all applicable laws and requirements, and any conditions required by a regulatory authority 
and/or Institutional Review Board (IRB).   
I understand that the protocol may not be modified without written approval of the sponsor. All 
changes to the protocol must be submitted to the applicable regulatory authority and IRB, and must 
be approved by the IRB prior to implementation except when necessary to eliminate immediate 
hazards to the subjects or when the change(s), as deemed by the sponsor, involve(s) only logistical 
or administrative changes. Documentation of IRB approval must be sent to the sponsor immediately 
upon receipt.  
Signature and date:  
 
 
 
  
  
  
  
  
  

 
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Name and Title:  
 
 
 
  
  
  
  
  
  
Address:  
  
 
 
  
  
  
  
  
  
  
 
  
 
 
  
  
  
  
  
  
Telephone number:  
  
 
 
  
  
  
  
  
Site/Center Number (if available):   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
TRIAL SYNOPSIS  
Patient Population:  
Patients with active myeloma (Durie-Salmon Stage II/III) that have high risk features, have 
completed induction therapy and are eligible for an autologous peripheral stem cell transplant.  
  
High risk features are defined by any one of the following criteria:  
• 
High risk chromosomal translocations by FISH: t(4;14), t(14;16), t(14;20), del(17p), 1p del, 
1q amplification;  
• 
MyPRS GEP-70 high risk signature;  
• 
LDH at baseline >300U/L;  
• 
Relapse within 12 months from prior therapy.  
  

 
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Number of Patients:  
Will treat a total of 90 evaluable patients. More patients may be consented such that the target of 90 
evaluable patients can be met. There will be a 2:1 randomization of patients to MILs vs no MILs.  
  
Study Objectives:  
Primary Objective  
• 
Progression free survival.  
  
Secondary Objective  
• 
Toxicity;  
• 
Overall survival;  
• 
Subset analysis of immune responsiveness:  
o Quantification of anti-myeloma immunity; o 
Validation of immune responsive phenotype.  
  
Eligibility Criteria:  
Inclusion  
• 
Patient age 18 - 80 years old;  
• 
Patients with active myeloma requiring systemic treatment;  
• 
Newly diagnosed patients.  Relapsed myeloma patients that have not previously had a 
transplant;  
• 
Patients who meet the criteria for high-risk disease;  
• 
Measurable serum and/or urine M-protein from prior to induction therapy documented and 
available.  A positive serum free lite assay is acceptable;  ECOG performance status of 0 – 
2 (see Appendix C).  
• 
Meet all institutional requirements for autologous stem cell transplantation;  
• 
The patient must be able to comprehend and have signed the informed consent;  
• 
Patients must have had > than PR after last therapy in order to proceed to transplant (MILs 
can be harvested prior to treatment)  
  
  
Exclusion  
• 
Diagnosis of any of the following cancers:  
o POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein [M-protein] and skin changes);  
o Non-secretory myeloma (no measurable protein on Serum Free Lite Assay);  
• 
Diagnosis of amyloidosis;  
• 
Previous hematopoietic stem cell transplantation;  
• 
Use of corticosteroids (glucocorticoids) within 21 days of bone marrow collection;  
• 
Use of any myeloma-specific therapy within 21 days of bone marrow collection;  
• 
Infection requiring treatment with antibiotics, antifungal, or antiviral agents within seven  
days of registration;  

 
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• 
Participation in any clinical trial within 21 days of bone marrow collection involving an 
investigational drug or device;  
• 
History of malignancy other than multiple myeloma within five years of registration, except 
adequately treated basal or squamous cell skin cancer;  
• 
History of an autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic 
lupus erythematosis) requiring active systemic treatment. Hypothyroidism without evidence 
of Grave’s disease or Hashimoto’s thyroiditis is permitted.  
• 
HTLV 1 or 2 positive;  
• 
Contraindication to phosphodiesterase-5 inhibitors (e.g. currently on nitrates).  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
SCHEMA  
  
                              MILs Bone Marrow Harvest  
 
  
  
Randomization (2:1)  
  
 
  
 
 
  

 
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Mel-200 AutoSCT  
Mel-200 AutoSCT  
 
 
Tadalafil 10mg days 2-11  
 
Tadalafil 10mg days 2-11  
  
MILs days 3,4  
  
  
  
  
  
  
    Lenalidomide 5 mg qd   
                                                 (~day 60 until disease progression)  
  
 
  
Follow for progression-free survival  
         
______________________________________________________________________ STUDY 
OVERVIEW  
  
This randomized Phase II clinical study is designed to examine the clinical efficacy of 
antiCD3/CD28 activated marrow infiltrating lymphocytes (aMILs), an activated, autologous bone 
marrow derived T cell product, in the study of myeloma patients with high risk disease undergoing 
their first autologous bone marrow transplant.  Additional screening will be performed on those 
eligible patients to determine whether they meet the criteria for exclusion based on immune 
unresponsiveness.  This will be accomplished by analysis of blood that will be sent to the Borrello 
Lab and run for a panel of parameters.  The PI or patient will be informed of these results.  
  
A bone marrow aspiration will be performed to collect ~200ml of marrow. During the in vitro 
expansion process, T cells will be activated and expanded ex vivo by co-stimulation with anti-CD3 
and anti-CD28 monoclonal antibodies covalently attached to super-paramagnetic microbeads. 
Patients will be treated with standard high-dose chemotherapy regimen for multiple myeloma 
consisting of single agent melphalan (200mg/m2).  Patients will then receive peripheral blood stem 
cells. For patients randomized to MILs arm, activated MILs will be infused on two consecutive 
days between days 2 and 5 following the stem cell infusion. Because of the potential negative 
impact of G-CSF on T cell trafficking to the bone marrow, patients will not receive post-transplant 
G-CSF.  Tadalafil will be administered to all patients from day 2- 11post-transplant.  The rationale 
is to both reduce the immune-suppressive myeloid-derived suppressor cells (MDSCs) as well as to 
increase the bone marrow infiltration of MILs which will hopefully increase the anti-tumor efficacy 
of the adoptive T cell therapy approach.  Lenalidomide will be started as per standard of care 
around day 60.  
  

 
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The primary objective of the study is progression free survival.  Additional secondary endpoints in 
the study include: overall survival and toxicity of MILs.    
  
  
1. STUDY OBJECTIVES  
  
1.1  
Primary Objective  
  
Determine the progression free survival (PFS) of autologous stem cell transplant (ASCT) alone vs 
ASCT plus MILs.  
  
1.2  
Secondary Objectives  
  
1.2.1 Evaluate Toxicity  
Toxicities according to the NCI Common Toxicity Criteria will be tabulated by body 
system, grade, and attribution of causality only for those felt to be related to MILs.  
Expected transplant related toxicities will not be recorded.  
  
1.2.2 Evaluate Overall Survival  
Patients will be monitored for progression/relapse on Days 60, 180, and 360, and as  
clinically indicated. Following one year follow-up, patients will be followed quarterly for 
the next five years.  
  
1.2.3 Determine Immune Responses  
Immune responses will be determined only in a subset of patients in certain sites for whom 
samples can be obtained.  
  
1.2.4 Anti-Tumor Immune Responses  
Lymphocytes from patients will be collected and banked at several time points during the 
study. Tumor specific anti-tumor immunity will be determined by analysis of samples 
obtained throughout the study.  
  
  
2. BACKGROUND  
  
2.1  
Multiple Myeloma  
  
Multiple myeloma is a plasma cell dyscrasia that is the most common cancer of the bone marrow.1, 
2  The American Cancer Society estimates that over 14,000 new cases of multiple myeloma will 
occur and that over 10,000 people will die of this disease in the United States in 2002.3  
  
Multiple myeloma is most often diagnosed in middle aged and elderly individuals. The most 
common sites of disease are the bone and bone marrow. Malignant plasma cells arise from clonal 

 
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expansion and accumulate in the bone marrow in masses known as plasmacytomas. These plasma 
cells produce large amounts of monoclonal immunoglobulins, most commonly IgG (50-60%) and 
IgA (20-25%) and occasionally IgD, IgM and IgE.4 Patients often suffer from bone pain and 
skeletal fragility.5  Plasmacytomas are osteolytic in nature and often confined to the central 
skeleton, skull, and femur.  Bone destruction is usually localized but can be present throughout the 
skeleton.6  
  
The etiology remains unknown, but risk factors are thought to include chronic immune stimulation, 
autoimmune disorders, exposure to ionizing radiation, occupational exposure to pesticides or 
herbicides, occupational exposure to dioxin, and perhaps prolonged use of certain hair coloring 
products. 7,8  
  
The diagnosis is made using several criteria including results of radiographic skeletal survey, bone 
marrow examination, and measurement of serum and/or urine monoclonal protein (M-protein).9,10 
Patients are also classified by stage (Stage I, II, III) according to the status of bone lesions, 
hemoglobin, serum calcium, -2 microglobulin, C-reactive protein and M-protein.11 The M-protein 
is often used to monitor response to treatment via measurement of serum and/or urine analysis of 
Bence-Jones protein, the light chain component of the M-protein.  
  
Multiple myeloma is a largely incurable disorder and most patients will die of their disease.  A 
variety of chemotherapy agents have been used to treat the disease but few patients experience 
long-term disease-free survival with current therapeutic approaches. There is an urgent need for 
more effective therapies to treat this challenging disease.  
  
2.2  
Current Therapies for Multiple Myeloma  
  
Treatment for multiple myeloma is dependent on the stage of the disease. Patients with Stage I 
disease are often monitored without treatment.  Patients with Stage II and III disease are usually 
treated with chemotherapy until a response is achieved. A variety of different combination 
chemotherapy regimens have been developed in an attempt to improve on these results.  
Unfortunately, regardless of the type of initial treatment, the disease will recur and the 5-year 
survival is less than 30%.12,13  
  
Dose intensification using high-dose chemotherapy followed by autologous stem cell 
transplantation has recently been used to increase the response rate and improve the outcome of 
patients with multiple myeloma.14-25 In 1996, the French Myeloma Intergroup reported the results 
of a randomized clinical trial, which compared high-dose chemotherapy supported by autologous 
bone marrow support to conventional chemotherapy in patients with previously untreated multiple 
myeloma.21 The study demonstrated the superiority of high-dose therapy in terms of response rate, 
event-free survival and overall patient survival.  This pivotal study has led to the widespread use of 
high-dose chemotherapy with autologous stem cell support as standard of care in multiple myeloma 
patients with good performance status.  
  

 
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More recently, the addition of lenalidomide maintenance in two multi-center randomized trials has 
resulted in a significant improvement in progression free survival from 23 months with no 
maintenance to 45 months with maintenance26, 27. These data confirm the difficulty of eradicating 
the disease.  Interestingly, the benefits observed with chronic lenalidomide are likely related to two 
attributes, continuous suppression of the malignant clone and immunomodulation resulting in 
priming of myeloma-specific immunity.  
  
In the allogeneic transplant setting, long-term responses have been demonstrated.  However, this 
treatment is associated with severe graft versus host disease (GVHD) and substantial mortality, 
which has limited its use.28  However, the presence of long-term remissions in patients developing 
GVHD points to an immune-mediated response.  
  
A major goal of newer studies has been to increase the overall efficacy of autologous stem cell 
transplantation without added toxicity.  Clearly, the ability to impart a myeloma-specific immune 
response without the toxicity seen with allogeneic transplants offers significant appeal. Recent 
studies attempting to utilize vaccine approaches alone or in combination with adoptive 
immunotherapy have shed significant light into the potential efficacy of these approaches.  More 
importantly, these studies underscore the profound limitations of the current interventions and 
enabled the development of novel strategies with greater anti-tumor specificity.  
  
2.3  
Overview of Cell-mediated Immunity  
  
The human immune system is made up of many kinds of cells responsible for eliminating harmful 
invaders such as viruses or cancer from the body.  One type of lymphocyte, the T cell, plays a 
central role in orchestrating most immune responses.  T cells become activated when they 
recognize antigens, specific elements of microbes or tumor cells, as foreign to the body.  This 
occurs when antigens are taken up, processed and presented by an antigen-presenting cell (APC) to 
a molecular complex on the T cell.  This molecular complex contains the T cell receptor (TCR) 
associated with the CD3 signaling complex. 28  
The primary signal for activating a T cell takes place when the TCR expressed on its surface binds 
to a processed antigen present on the surface of an APC.  Each individual T cell only expresses a 
single TCR capable of recognizing a specific antigen.  However, the many billions of T cells found 
in the human body express millions of different TCRs, thereby enabling recognition of millions of 
distinct antigens.  Only a specific T cell that recognizes a particular antigen will become activated 
during a normal immune response.  
  
APCs must deliver a second signal in order to activate T cells.  This co-stimulatory signal occurs 
when receptors on APCs bind to CD28 receptors on T cells.  Activation of T cells takes place when 
APCs bind to the TCR/CD3 complex and CD28 receptor.  These activated T cells are exquisitely 
sensitive to further stimulation and also secrete a variety of chemical messengers called cytokines.  
This process further augments the immune response both by driving continued activation and 
proliferation of T cells and recruiting and stimulating other cells of the immune system.  This 
cascade of events ultimately leads to destruction of pathogens such as tumor cells and viruses.  
  

 
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2.4  
Immune Defects in Patients with Cancer Including Multiple Myeloma  
  
The inability of a patient's own immune system to respond to and control cancer may be due to a 
number of problems.  Defects in both the afferent (responding) as well as efferent (acting) arms of 
the immune system are well documented in cancer patients.  Deficits in the afferent arm of 
immunity include zeta chain defects in the TCR, which contribute to signaling problems in T cells.  
In addition, patients with hematological malignancies including chronic lymphocytic leukemia and 
multiple myeloma demonstrate significant narrowing of the broad spectrum of T cell receptors 
present in healthy individuals.29-31 This narrow T cell receptor repertoire may limit the patient’s 
ability to recognize and respond to tumor cells as well as other pathogens.  This may contribute not 
only to cancer progression, but also to the infections that are often observed in patients with 
hematological malignancies. These defects are both a result of the malignancy itself as well as 
cytotoxic therapy that can damage T cells.  Additionally, ineffective induction of CD40L (CD154) 
on T cells has been demonstrated in cancer patients.32 Without CD40L signaling, APCs are not 
capable of being activated or presenting antigen to T cells.  Poor co-stimulation by APCs due to 
non-responsive elements or defects in the co-stimulatory pathway has been observed in cancer 
patients.28  Problems with the effector arm of the immune system in cancer patients include the 
presence of relatively low numbers of cytotoxic T lymphocytes (CTL), which are required to kill 
the tumor cells.  Additionally, some cancers including multiple myeloma produce cytokines that 
inhibit the function of normal T cells or APCs.33 The deficits in immunity may limit the ability of 
the patients' own T cells to mount an effective immune response to their own cancers.  
  
2.5  
Rationale for Immunotherapy of Multiple Myeloma  
  
Immunotherapy is one approach to improving the outcome of patients with multiple myeloma.  As 
noted above, defects in the host’s immune system are present in patients with cancer including 
multiple myeloma.  These deficits are thought to play a role in the patient’s inability to generate an 
anti-tumor response and control the disease.  A variety of therapeutic approaches are now being 
developed that stimulate the patient’s immune system.  Several groups are using idiotype vaccines 
to stimulate T cell-mediated responses to the patient’s tumor cells.34,35 Using this approach, patients 
are typically treated with an autologous transplant followed by vaccination with their own idiotype, 
which is derived from their unique M-protein.  Promising clinical results have been observed in 
some of these clinical trials.  However, many patients have weakened immune systems after the 
transplant and have been unable to respond to the vaccine36  
  
We have recently completed a clinical study utilizing autologous tumor vaccines in the autologous 
transplant setting.  In this study, newly diagnosed patients undergo a bone marrow harvest to 
collect autologous tumor that will be combined with the K562/GM-CSF producing bystander cell 
line in the final vaccine formulation 37. Patients are administered the vaccine pre-transplant in an 
effort to prime tumor-specific T cell responses in vivo.  The lymphocytes are then collected and 
infused at the time of transplantation in an attempt to impart an early anti-tumor effect.  The 
posttransplant vaccinations start 6 weeks post-transplant and are administered every 3 weeks for a 
total of 8 post-transplant vaccines.  The rationale for starting vaccinations this early post-transplant 
is based on murine data demonstrating the existence of an early endogenous tumor-specific 

 
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lymphocyte expansion that can then be maintained with vaccinations in the post-transplant setting 
38. While this study shows evidence of the generation of tumor-specific T cell responses, the degree 
of lymphopenia post-transplantation is greater than initially predicted with absolute CD4 numbers 
considerably below normal up to one year post-transplant.  One attempt to increase vaccine efficacy 
is the ability to enhance T cell reconstitution and utilize vaccines at a time when maximal T cell 
responsiveness can be guaranteed.  
  
Recently, several investigators have documented the potent anti-tumor effects of donor 
lymphocyte infusions (DLI) administered to patients who relapse after allogeneic stem cell 
transplantation.39-43 Unfortunately, the limited availability of suitable donors coupled to the high 
incidence of GVHD observed with DLI has significantly limited its therapeutic application.  
  
Investigators have documented that T cells with anti-tumor activity are present in the blood of 
patients with multiple myeloma.44 If sufficient numbers of the patient’s own T cells could be 
activated and expanded, they could be used in combination with an autologous stem cell transplant.  
This would provide a potentially safer therapeutic alternative to DLI.  Patients would avoid the 
risks of GVHD as well as the substantial morbidity and mortality (up to 40%) that has been 
documented in multiple myeloma patients undergoing allogeneic stem cell transplantation. 45  
  
Additionally, recent clinical data provide further rationale for the administration of autologous T 
cells in patients undergoing autologous bone marrow transplantation.  Several clinical studies have 
documented improved therapeutic outcome in patients with multiple myeloma (as well as 
nonHodgkin’s lymphoma, breast cancer, and ovarian cancer), who experience more rapid and/or 
complete recovery of their peripheral blood lymphocytes after autologous stem cell 
transplantation.46-48  
  
2.6  
Rationale for the Use of CD3xCD28 Bead-Activated T Cells  
  
Carl June and colleagues developed technology to activate T cells of the immune system outside of 
the body (ex vivo)49.  This procedure is based on the roles of the CD3 signaling complex and CD28 
receptor in the activation of T cells.  In the manufacturing process, T cells are stimulated ex vivo 
using monoclonal antibodies that bind to the CD3 and CD28 molecules expressed on the surface of 
T cells.  The antibodies are attached to microscopic beads, thereby creating artificial APCs.  As a 
result, a universal reagent can be developed to activate all T cells.  Single beads, which coordinate 
CD3 and CD28 signals, optimize T cell activation and allow rapid expansion of T cells.  Preclinical 
studies have shown that T cells can be generated ex vivo using these beads from patients with 
human immunodeficiency virus (HIV) or cancer. 50,51  
  
Studies have demonstrated that T cells can be activated and expanded more than one hundred fold 
in less than 10-12 days with anti-CD3/CD28 bead activation with a predominant expansion of CD4 
over CD8 T cells.  Further studies have shown that the patients’ activated T Cells express high 
levels of CD154 (CD40L), CD137 (4-1BB) and other key effector molecules such as CD134 
(OX40), CD54 (ICAM) as well as important receptors such as CD25 (IL-2 receptor).  Finally, this 
process generates T cells that display a Th1 phenotype secreting high levels of IL-2 and 

 
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interferongamma that are known to play essential roles in activating both helper T cells as well as 
cytolytic T cells.   These features demonstrate the ability to reverse tolerance in cancer patients and 
restore T cell responsiveness that may enable these T cells to restore anti-tumor immunity.  
  
A number of independent clinical trials have been conducted in which patients have been treated 
with T cells activated ex vivo using a CD3/CD28 bead-based technology. T cells activated in this 
manner have previously been tested in patients undergoing a peripheral blood stem cell transplant 
for relapsed or refractory Non-Hodgkin’s lymphoma52. T cells were collected prior to high-dose 
chemotherapy. Fourteen days following the peripheral blood stem cell infusion, activated and 
expanded T cells were administered.  Three patients were treated at a median cell dose of 0.4 x 109, 
twelve patients were treated at a median cell dose of 1.6 x 109, and two patients were treated with a 
median cell dose of 9.8 x 109. Infusion related toxicities experienced by the two patients at the 
highest dose level included transient fever, dyspnea, rigors and pulmonary edema. Maximal 
responses included five patients with complete responses, seven patients with partial responses, and 
five patients with stable disease.  
  
We recently completed a Phase I/II study in multiple myeloma in which 32 patients were 
administered anti-CD3/CD28 activated T cells.  T cells were effectively expanded in all patients 
with an average fold-increase of 268 (± 101).  T cells were then infused on day + 3 following an 
autologous stem cell transplant.  Interestingly, in addition to the in vitro expansion, patients 
experienced an additional in vivo expansion reaching maximal expansion on day +21 that far 
exceeded the T cell numbers seen in a non-transplanted healthy individual.  However, despite the 
feasibility, safety and evidence of both in vitro and in vivo expansion, the overall clinical response 
showed CR 6%, PR 34% with an overall response rate of 40% which is no better than standard 
autologous stem cell transplants.  There were no significant toxicities related to the infusion of 
activated T cells and the majority of adverse events related to T-cells were mild in severity and 
included fever (19%), chills (17%), asthenia (10%), headache (10%), and nausea (10%).  
  
  
  
2.7  
Rationale for the Use of Activated MILs in Myeloma  
  
From the above-mentioned clinical studies, we have shown the ability of this technology to 
effectively overcome the inherent unresponsiveness seen in T cell from tumor-bearing hosts and to 
expand upon anti-CD3/CD28 stimulation.  This data also underscores a significant limitation of the 
polyclonal expansion - the lack of antigen specificity.  To this effect, we have developed a strategy 
aimed at increasing the tumor specificity of this approach.  Specifically, we discovered that marrow 
infiltrating lymphocytes (MILs) can be effectively activated and expanded with properties 
suggestive of an effector/memory population.  More importantly, they possess several critical  

 
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features required for effective anti-tumor adoptive 
immunotherapy:  
1) they can be activated and expanded to reasonable 
numbers; 2) they demonstrate significant specificity 
against  mature plasma cells; 3) the possess surface 
unique surface markers that increase their likelihood 
of trafficking to the marrow upon re-infusion; and 4) 
that possess a memory phenotype that increases their 
likelihood of persisting over  
Figure 1: aMILs exhibit marked anti- 
myeloma activity.  T cells from blood or marrow 
were either activated with anti-CD3/CD28 beads 
or left unstimulated.  Tumor specificity was 
determined by incubating the cells either with 
autologous plasma cells (CD138), autologous 
non-malignant myeloid cells (CD33) or nothing 
and determining H-thymidine incorporation.  
time. As shown in Figure 1, whereas activated 
PBLs (aPBLs) failed to show measurable 
tumor specificity, activated MILs (aMILs) 
exhibited marked tumor reactivity.   
Interestingly, no reactivity was appreciated 
against normal hematopoietic elements. In 
addition to their significant activity against 
mature plasma cells, aMILs were also capable 
of significantly limiting the outgrowth of 
clonogenic myeloma precursors suggesting a 
broad range of tumor antigen recognition.  
  
Another critical aspect of effective adoptive immunotherapy is the ability of T cells to traffic to the 
tumor microenvironment.  SDF-1 (stromal derived factor -1) and its cognate chemokine receptor, 
CXCR4 are critical factors in cell trafficking in the marrow.  We have shown that a significantly 
higher percentage of MILs express CXCR4 as compared to PBLs thus increasing the likelihood of 
trafficking of these cells to the appropriate compartment.  53.  To confirm this, we performed an 
experiment utilizing NOD/SCID mice.  Mice were irradiated and challenged with the H929 
myeloma cell line and then 18 days later either given activated MILs, activated PBLs or no T cells.  
The T cell doses used corresponded to doses ranging from 3 – 20 x 107 CD3/kg (doses easily 
achievable in humans).  As shown below in Figure 2, activated PBLs imparted no measurable anti-
tumor effect compared to no T cells whereas the mice receiving activated MILs demonstrated 
100% survival with no evidence of detectable tumor.  Furthermore, T cells were detectable in the 
marrows of mice having received aMILs whereas no T cells but CD138+ plasma cells were seen in 
the bone marrows of mice treated with HBSS or aPBLs.  These findings confirm our in vitro data 
and suggest the overall efficacy and durability of this approach.  

 
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Fig 2: aMILs confer significant tumor-free survival 
advantage.  NOD/SCID mice were challenged with 
the human myeloma cell line, H929.  18 days later 
they either received HBSS, aPBLs, or aMILs at doses 
ranging from 1-5 x 106 /mouse and were followed for 
tumor-free survival.  
  
2.8 Results from the First MILs Trial  
  
The first trial was conducted in patients that 
had never undergone an autologous stem cell 
transplant (ASCT) and that were not in a 
complete remission at the time of transplant.  
Patients underwent a standard Mel-200 
ASCT with the infusion of aMILs on day +3.  
To monitor the ability of T cells to 
adoptively transfer vaccine-primed 
immunity, patients were administered the 
polyvalent  
pneumococcal vaccine conjugate, Prevnar 
(PCV) prior to MILs harvest and on day 
+21 post-transplant. We were able to grow 
MILs on all patients, the median T cell dose 
infused was 1.96 x10e9 total cells.  We 
observed a 38% incidence of graft vs host 
disease which was mostly limited to the 
skin  
and resolved spontaneously. No grade 3 or 4 toxicities were appreciated that could be related to the 
infusion of MILs.  Interestingly, the median number of prior therapies for patients on this study 
was 2.3 (range 1-6).  Considering that the greatest predictor of CR post-transplant is entering 
transplant in a CR54 and that patients in CR were excluded from the trial, we feel the overall 
response rate seen of 72% with a CR rate of 27% was possibly better than anticipated in this 
pretreated relatively high risk patient population.    
  
One of the major aspects of this study was the demonstration of persistence of MILs and evidence 
of induction of measurable myeloma-specific 
immunity.  To accomplish this, we performed 
immune monitoring only within the tumor 
microenvironment utilizing MILs obtained at harvest 
and at various time points post-transplant.  PCV 
immunity and tumor specificity is shown below in 
Fig 3.  Patients showed evidence of PCV immunity 
with the harvest T cells (collected 2 weeks after the 
pre-transplant vaccine).  This immunity was 
transferred post-transplant, peaked at 6 months but  
Fig 3: PCV and tumor specificity.  BM was analysed was still 
measurable one –year post-transplant. With at harvest and post-SCT.  CRM-197 antigen specificity regards to 
myeloma-specific immunity, there was no was appreciable early and preserved.  Tumor specificity evidence of 
tumor specific immunity at harvest (as was generated and maintained over time. expected).  However, 
measurable anti-tumor Fig 4: Tumor specific immunity immunity was detectable in the post-transplant 
setting correlates with clinical response.  that peaked at 6 months but was still present at the 1-year  

 
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Tumor specificity of MILs was time-point.  Taken together atients showed evidence of PCV determined 
at the indicated time immunity with the harvest T cells (collected 2 weeks after  
the pre-transplant vaccine).  This immunity was transferred post-transplant, peaked at 6 months but 
was still measurable one –year post-transplant. With regards to myeloma-specific immunity, there 
was no evidence of tumor specific immunity at harvest (as expected).  However, measurable 
antitumor immunity was detectable in the post-transplant setting that peaked at 6 months but was 
still present at the 1-year time-point.  Taken together these data 
prove that MILs were able to impart a MM-specific immune 
response and that these cells persisted over time.  We also 
observed a range in tumor-specific immunity and upon further 
investigation were able to show a direct correlation between the 
ability to achieve a significant response with the ability to enter 
into complete remission (Fig 4). This correlation was 
subsequently lost with patients that achieved a PR or less.   
Taken together, these data suggest that, at least in this study, 
achieving a CR was in part mediated by the ability to induce 
and maintain of a vigorous anti-myeloma immune response.  
  
  
 
2.9  
Phosphodiesterase-5 (PDE-5) Inhibition  
  
  
A major obstacle to the achieving clinically meaningful results  
with immunotherapy is largely due to the multitude of immunosuppressive mechanisms in place in 
a tumor bearing-host.  Myeloid derived suppressor cells (MDSCs) are one population associated 
with tumor-induced immunosuppression that has been implicated.  It exerts its immunosuppressive 
function through the production of nitric oxide (NO) and up-regulation of arginase-1 (Arg-1).  We 
have previously shown that the use of PDE-5 inhibitors such as tadalafil can significantly 
downregulate production of NO and Arg-1 and restore tumor-specific T cell immunity.55  
  
There is also extensive data to suggest that improved clinical outcomes are associated with a 
higher degree of tumor infiltrating lymphocytes as shown in both colon and ovarian cancers. 56, 57  
As such, strategies that increase the ability of T cells to infiltrate the tumor potentially increase 
the ability to augment anti-tumor efficacy.  In our original 
murine studies, we observed an increased in anti-tumor 
efficacy when T cells were adoptively transferred in the 
conjunction with PDE5 inhibition. 55 This data was 
subsequently confirmed in a recent clinical trial in head and 
neck squamous cell carcinoma in which tadalafil (Cialis) or 
placebo was administered in the neo-adjuvant setting.  We 
observed a significant increase in activated tumor 
infiltrating lymphocytes as defined as CD8+ CD69+ 
compared to the placebo treated group (Fig 5).  We already  
pretreatment 
posttreatment believe that a major therapeutic benefit of MILs compared to 
peripheral T cells rests with their increased tumor specificity and increased tropism for the bone 
# of CD8 
+ 
CD69 
+ 
/field (average) 
0 
5 
10 
15 
20 
25 
Arm 1 
placebo 
Arm 2 

 
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marrow.  However, we have also shown that granulocytic MDSCs in our earlier study correlated 
with worse clinical outcomes.  As such, any strategy that could increase the ability of these tumor 
specific T cells to traffic to the tumor site immediately following T cell transfer would likely 
increase our therapeutic benefit of the study.  
  
2.10  
Rationale for Study Design  
  
Current treatments for high-risk multiple myeloma are unsatisfactory. Data obtained from the 
Arkansas group utilizing a 70-gene expression panel has demonstrated that this subgroup fails to 
achieve a meaningful response despite high dose chemotherapy regimens such as Total Therapies  
2 and 3 as manifest by depth of response, progression free survival or overall survival. 58, 59   
 
Fig 5.  Tadalafil increases the percentage of  
Similar poor outcomes were also observed in the ECOG  
activated TILs.  Patients with head and neck cancer  
were treated with either tadalafil 10 or 20mg or Lenalidomide high vs low-dose dexamethasone trial as well placebo for 
21 days.  Tumor specimens obtained as in IFM studies. 60 Taken together, these results underscore pre- and post-treatment 
were stained for CD8 and  
 
CD69.    
the lack of effective therapies for this poor risk group.   
Interestingly, This GEP-70 is now commercially available as  
the MyPRS that can be run as a send-out test by Signal Genetics.  Interestingly, it represents 
approximately 18% of newly diagnosed, untreated patients and this percentage has been shown to 
increase with subsequent relapses.  
  
Other parameters associated with high risk disease and worse overall prognosis include poor risk 
chromosomal rearrangements identified by FISH such as t(4;14), t(14;16), t(14;20), del(17p) as 
well as ISS stage III and an elevated LDH at diagnosis. 61 In this protocol, we will extend the 
inclusion criterion to these other high-risk features.  The rationale for this is based on the fact that 
we are attempting to demonstrate the clinical efficacy of this approach in a high risk disease 
setting, would also like to assure that the protocol can be enrolled in a relatively short period of 
time without requiring an extensive number of screen failures, and that with the randomized nature 
of the study we will be able to still determine the clinical efficacy of this approach.  From a 
practical stand point, tertiary referral centers usually see patients at the time of consultation for 
transplant and most will not have had the GEP-70 profile done.  This is further complicated by the 
fact that the induction regimens have increased their overall efficacy to the point that an 
increasingly larger percentage of patients are able to achieve a complete remission prior to 
transplant – a factor that makes obtaining GEP-70 even more difficult.  However, FISH and ISS 
from diagnosis is generally known which will enable us to determine eligibility criteria for the 
patients.  
  
The first MILs trials has shown a significantly high response rate for patients with several high 
risk features including ISS III and poor risk chromosomal translocations by FISH.  
Immunotherapy offers the possibility to kill tumors with mechanisms very different from those 
utilized by conventional cytotoxic chemotherapy. 62 Taken together, there is both significant 
biologic as well as clinical rationale for the proposed study.  
  

 
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Lenalidomide is included in the study for two major reasons: 1) two studies examining its role as 
maintenance in the post-transplant setting have demonstrated its significant clinical efficacy in 
terms of its ability to significantly increase progression free survival (PFS) in patients undergoing 
an autologous SCT; and 2) it has significant immunomodulatory effects including its ability to 
enhance T cell co-stimulation, 63 increase NK function, 64 and overall enhance tumor specific 
immunity. 65  
  
The PDE-5 inhibitor, tadalafil, is being used early post-transplant to increase the possibility of 
trafficking of the aMILs to the tumor site.  We have previously shown that this drug was able to 
increase the therapeutic efficacy of adoptive T cell therapy in a murine model and also to increase 
the percentage of tumor infiltrating lymphocytes in a recently conducted head and neck cancer 
trial.  As such, administration of tadalafil in association with the infusion of MILs should enhance 
their therapeutic efficacy.  
  
  
  
3. PATIENT SELECTION  
  
3.1  
Eligibility Criteria for Enrollment  
  
Patient eligibility for the study will be determined when patients are deemed eligible to proceed to 
transplant.  To determine patient eligibility, evaluations for inclusion and exclusion criteria must 
be performed prior to patient registration. Patients who meet these criteria can then be registered 
on the trial. All evaluations for inclusion and exclusion criteria must be performed within 30 days 
prior to registration unless otherwise noted.  Please refer to Patient Study Calendars, Appendix E.  
  
At the time of study registration, patients will be eligible if they meet all of the following inclusion 
criteria:  
• 
Previous diagnosis of multiple myeloma based on standard criteria as defined in 
Appendix A (Diagnostic Criteria for Multiple Myeloma). Tests need not be performed 
within 30 days of registration;  
• 
Active myeloma as defined as the presence of CRAB criteria: hypercalcemia, renal 
insufficiency, anemia and/or bone disease;  
• 
Measurable serum and/or urine M-protein from prior to induction therapy documented 
and available.  A positive serum free lite assay is acceptable;  
• 
Presence of at least one of the features defining high risk.  These include:  
o High risk chromosomal translocations by FISH: t(4;14), t(14;16), t(14;20), 
del(17p), del(1p), amplification 1q.;  
o MyPRS GEP-70 high risk signature either from diagnosis or at time of 
registration for the study;  
o LDH > 300 U/L at diagnosis; o Relapse from prior therapy within 12 months.  
• 
Patient age 18 - 80 years old;  
• 
ECOG performance status of 0 - 2  
• 
Life expectancy  6 months;  

 
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• 
Corrected serum calcium < 11 mg/dL, and no evidence of symptomatic hypercalcemia. 
(Corrected serum calcium is calculated by adding 0.8 mg/dL to the measured serum 
calcium for every 1 g/dL that the serum albumin falls below 4.0 g/dL.);  
• 
Serum total bilirubin and SGPT (ALT) < 2.0 times the upper limit of normal;  
• 
Serum creatinine < 2.0 mg/dL;  
• 
The patient must be able to comprehend and have signed the informed consent.  
  
At the time of study registration, patients will be ineligible if any of the following exclusion 
criteria apply:  
• 
Diagnosis of any of the following cancers:  
o POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein [M-protein] and skin changes); o Non-
secretory myeloma (no measurable protein on Serum Free Lite Assay); o Plasma 
cell leukemia; o HTLV1 / HTLV2 positive.  
• 
Diagnosis of amyloidosis;  
• 
Previous hematopoietic stem cell transplantation.  Patients can have had prior relapsed 
disease as long as they have never been previously transplanted;  
• 
Known history of HIV infection;  
• 
Use of corticosteroids (glucocorticoids) within 21 days of the MILs collection;  
• 
Use of any myeloma-specific therapy within 21 days of the MILs collection;  
• 
Systemic infection requiring treatment with antibiotics, antifungal, or antiviral agents 
within seven  days of registration;  
• 
Patients should be excluded if they are known to be positive test for hepatitis B virus 
surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) 
indicating acute or chronic infection.   
• 
Participation in any clinical trial, within four weeks prior to registration on this trial, 
which involved an investigational drug or device;  
• 
History of malignancy other than multiple myeloma within five years of registration, 
except adequately treated basal or squamous cell skin cancer;  
• 
Active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic 
lupus erythematosis) requiring active systemic treatment. Hypothyroidism without 
evidence of Grave’s Disease or Hashimoto’s thyroiditis is permitted;  
• 
Known contraindication to phosphodiesterase-5 inhibitors (e.g. currently on nitrates).  
  
3.2  
Eligibility Criteria for Bone Marrow Transplant  
  
Prior to transplant, patients will be eligible if they meet all of the following inclusion criteria:  
• 
Myeloma specific therapy with a minimum of 3 cycles;  
• 
Achieved at least a partial response (PR) to therapy  
• 
Institutional criteria for and have institutional approval to undergo autologous 
peripheral blood stem cell transplantation;  
• 
Females of child-bearing potential must have a negative serum HCG test and be 
willing to use effective contraception (i.e. a hormonal contraceptive, intra-uterine 

 
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device, diaphragm with spermicide, or condom with spermicide, or abstinence) up to 
Day 180.  
  
Prior to transplant, patients will be ineligible if any of the following exclusion criteria apply: 
 Evidence of spinal cord compression;  
• 
Major organ system dysfunction including (but not limited to): New York Heart  
Association Class III or IV (Appendix D), pulmonary disease requiring the use of  
inhaled steroids or bronchodilators, renal, hepatic, gastrointestinal, neurologic, or 
psychiatric dysfunction which would impair patient’s ability to participate in the trial;  
HIV infection.  
  
  
  
3.3  
Confirmation of Eligibility  
  
Data collected from time of diagnosis, prior to induction therapy must be available for eligibility:  
• 
M-protein results from the time of diagnosis, prior to induction therapy;  
• 
ISS which includes -2 microglobulin and serum albumin;  
• 
Myeloma FISH bone marrow results (if available);  
• 
Baseline LDH (if available);  
• 
Durie-Salmon Stage;  
• 
Date of diagnosis;  
• 
Duration of induction;  
• 
Type of prior therapy(s);  GEP-70 MyPRS (if available).  
  
  
4. REGISTRATION ON STUDY AND RANDOMIZATION  
  
At registration, patients will have the baseline evaluations listed in Section 7. Once eligibility 
requirements are met, the patient will proceed to bone marrow collection to obtain MILs.  
  
Randomization will occur after the bone marrow has been collected for MILs expansion.  The 
following criteria will be utilized:  
• 
Newly diagnosed vs. relapsed;  
• 
Presence of high risk GEP-70 signature.  For patients with an indeterminate or 
unavailable GEP-70 profile, they will be assigned to the “low-risk” group.  
  
  
5. MULTICENTER GUIDELINES  
  
5.1  
Registration Guidelines  
  

 
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Eligible patients will be entered on study centrally at the Sidney Kimmel Comprehensive Cancer 
Center at the Johns Hopkins University by the Lead Study Coordinator.    
  
To verify eligibility and coordinate MILs collection all sites should contact:  
  
• 
lead study coordinator Dmitry Kololo (dkololo1@jhmi.edu)    
• 
lead research nurse Laura Cucci, RN (lcucci1@jhmi.edu )   
• 
Coordinating Center mailbox (onc-coordcnt@jhmi.edu)   
  
The Registration Form and Eligibility Worksheet will be supplied to each participating site.  
  
Following registration, patients are eligible to begin protocol treatment. Issues that would cause 
treatment delays should be discussed with Dr.Imus .  If a patient does not receive protocol therapy 
following registration, the patient’s registration on the study may be canceled.  The Study 
Coordinator should be notified of cancellations as soon as possible.  
  
5.2  
Registration Process  
  
To register a patient, the following documents should be completed by the site’s Register Nurse or 
Study Coordinator and emailed to all the addresses provided above:  
• 
Registration Form;  
• 
Signed patient consent form;  
• 
HIPAA authorization form;  Eligibility screening checklist;  
• 
Copy of required screening tests.  
  
5.3  
Responsibilities  
  
  
Protocol Chair  
  
The Protocol Chair is responsible for performing the following tasks:  
• 
Coordinating, developing, submitting, and obtaining approval for the protocol as well 
as its subsequent amendments.  
• 
Assuring that all participating institutions are using the correct version of the protocol.  
• 
Taking responsibility for the overall conduct of the study at all participating institutions 
and for monitoring the progress of the study.  
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAE)  Reviewing data 
from all sites.  
  
  
Coordinating Center  
  
The Coordinating Center is responsible for performing the following tasks:  
• 
Ensuring that IRB approval has been obtained at each participating site prior to the first 
patient registration at that site, and maintaining copies of IRB approvals from each site.  
• 
Managing central patient registration.  
• 
Collecting and compiling data from each site.  

 
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• 
Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties.  
• 
Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites.  
  
  
Participating Sites  
  
Participating sites are responsible for performing the following tasks:  
• 
Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
 Submitting data to the Coordinating Center.  
• 
Registering all patients with the Coordinating Center by submitting patient registration 
form, and signed informed consent promptly.  
• 
Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct a collaborative trial according to the protocol.  
• 
Maintaining regulatory binders on site and providing copies of all required documents 
to the Coordinating Center.  
• 
Collecting and submitting data according to the schedule specified by the protocol.  
  
  
6. BASELINE EVALUATIONS  
  
Harvest Consent:  
After the patient has been registered in the study at the time of initial consent, the following 
evaluations will be performed to determine the patient’s baseline status. All tests must be 
completed within 30 (±_7 days) of the MILs bone marrow harvest:  
• 
Complete clinical exam, including complete medical history, review of systems, ECOG 
performance status, vital signs, and physical examination.   
• 
Current medications;  
• 
Serum chemistries: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
calcium, ALT, AST, total bilirubin, alkaline phosphatase, albumin;  
• 
CBC with differential and platelet count;  
• 
HTLV-1, HTLV-2 (tests must all be negative).  
The following myeloma labs should be obtained on the day of the MILs harvest:  
• 
M-protein, serum:  
o Protein electrophoresis; o 
Immunofixation;  
o Freelite (sensitive assay 
for kappa and lambda 
light chains) only if most 
recent immunofixation 
result showed no 
evidence of M-protein.  
• 
M-protein, urine (24 hour collection) for:  

 
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o Total protein; o Protein 
electrophoresis; o 
Immunofixation.  
• 
Quantitative immunoglobulins (IgG, IgM, IgA);  
• 
-2 microglobulin;  
• 
MyPRS GEP-70 from Signal Genetics (if not previously obtained)  
  
Transplant Consent:  
Prior to proceeding to autologous stem cell transplantation, patients should undergo the routine 
testing to meet the institution requirements for autologous stem cell transplantation for myeloma.  
This should include myeloma labs (SPEP, UPEP, quantitative immunoglobulins, serum free light 
chains)  
  
7. MARROW INFILTRATING LYMPHOCYTES (MILs) COLLECTION  
  
The bone marrow harvest will be performed to obtain the marrow infiltrating lymphocytes (MILs) 
required for the in vitro activation. The patient’s treatment schedule is summarized in Appendix E, 
Patient Study Calendar.  Patient should undergo MILs collection within 30 of consent.  If outside 
the window, the infectious serologies need to be repeated.  
  
7.1  
MILs Collection Procedure  
  
Each eligible patient will have approximately 200cc of bone marrow collected in syringes 
containing 2ml of 10,000 units/ml heparin under steady state conditions. The marrow will be 
collected in 60cc syringes and transferred into a 300ml transfer pack.  Sedation and analgesia will 
be administered per standard institutional practices.  
  
• Patients should also have 20ml of blood collected in heparinized tubes.  
• 15ml of bone marrow should be collected in green top (heparinized tubes) For 
patients on the immune sub-study (Hopkins only), 100ml of blood will be collected in  
heparinized syringes instead of the 20ml and 20 ml of aspirate will be collected in a 
heparinized syringe instead of 15 ml in a green top tube.  
The marrow and blood will be shipped overnight at room temperature between Monday and 
Thursday (NO PRODUCTS SHOULD BE SHIPPED ON FRIDAY) to:  
Johns Hopkins Cell Therapy Lab  
401 N Broadway  
Weinberg Building, Rm 2450  
Baltimore, MD 21287  
Tel: 410 955 2354  
Fax: 410 502 6749  
  
  

 
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8. MILs ACTIVATION PROCESS, CELL DOSE & PRODUCTION FORMULATION  
  
8.1  
MILs Activation Process  
  
The MILs bone marrow product will undergo ex vivo activation and expansion of T cells in the 
Johns Hopkins Cell Therapy Laboratory (CTL). In the activation process, the T cells are activated 
and expanded by co-stimulation of T cells with anti-CD3 and anti-CD28 antibodies conjugated to 
super-paramagnetic microbeads (Dynabeads M-450 CD3/CD28 T).  The super-paramagnetic 
microbeads are removed at the completion of the process.  The product will not be released, unless 
acceptance criteria have been met.  
8.2  
Formulation Storage and Dose of Activated MILs T Cells  
  
The activated MILs will be formulated in cryopreservation bags in a final volume of up to 50 ml.   
Each bag will contain aMILs formulated in a cryoprotectant consisting of Hetastarch  [6%  
Hetastarch in 0.9% sodium chloride injection] supplemented with 2% Human Serum Albumin 
(HSA) and 5% dimethylsulfoxide (DMSO),  The aMILs T Cell product will be frozen in a 
controlled-rate freezer until it reaches –80ºC.  The product will then be stored in the vapor phase 
of a liquid nitrogen freezer at less than -135ºC.  
  
8.3  
Shipping and Storage of Activated MILs  
  
Shipment of the aMILs will be coordinated between the Johns Hopkins CTL and the receiving site.   
Upon receipt, the product will be stored in the vapor phase of a liquid nitrogen freezer at less than 
1350 C.  
  
  
9. MOBILIZATION AND COLLECTION OF PERIPHERAL BLOOD STEM CELLS  
  
Following MILs collection, the patient may begin the mobilization regimen, which should be 
performed according to institutional standards.  
  
9.1  
Mobilization Regimen  
  
The mobilization regimen will occur as per institutional standards.  The procedure used for 
mobilization will be recorded.  
  
9.2  
Peripheral Blood Stem Cell Collection  
  
Peripheral blood stem cell leukapheresis will be performed per standard institutional practice. 
Leukapheresis will be performed to obtain a minimum of 2.0 x 106 CD34+ cells/kg.  Standard 
leukapheresis will be performed according to institutional guidelines for the collection of 
peripheral blood stem cells.  
  

 
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Should patients fail to mobilize, they will be able to proceed as per institutional guidelines which 
could include: bone marrow harvest or mobilization with other agents including but not limited to 
plerixafor.  
  
9.3  
Nomenclature for Numbering of Days  
  
The day of infusion of the peripheral blood stem cells is called Day 0.  Days following peripheral 
blood stem cell transplant are numbered accordingly, e.g., the first day after transplant is 
designated as Day 1. Days before the transplant are designated in the negative, e.g., the day prior 
to transplant is referred to as Day –1.  
  
9.4  
Day -2 and Day -1: Melphalan  
  
Melphalan 200mg/m2 will be administered per institutional standard of care: either on two 
consecutive days (Day –2 and Day –1) at a dose of 100 mg/m2/day intravenously in sterile water 
(5mg/ml) over 20-30 minutes or all in one day. Current medications will be documented.  
  
CBC with differential will be obtained on Day –2 and Day –1 prior to Melphalan infusion.  
  
9.5  
Peripheral Blood Stem Cell Transplant (Day 0)  
  
A CBC with differential and platelets will be obtained prior to stem cell infusion.  
  
A minimum of 2.0 x 106 CD34+ cells/kg stem cells will be infused. The infusion will occur the day 
after the last dose of melphalan. Corticosteroids may have an adverse effect on the activity of T 
cells contained in the stem cell product and should, therefore, be avoided.    
See Section 12.7, Contraindicated Medications.  
  
9.6  
Supportive Care  
  
All patients will receive supportive care according to institutional clinical guidelines for 
autologous peripheral blood stem cell transplantation. This may include but not be limited to 
allopurinol, menstrual suppression, prophylactic antibiotics, empiric antibiotics, intravenous 
immunoglobulin (IVIG), transfusion of blood products, hyperalimentation, and erythropoietin.  
  
9.7  
Post-Transplant Filgrastim  
  
Post-transplant filgrastim (Neupogen; G-CSF) will not be permitted on this trial because of the 
known ability of this agent to down-regulate CXCR4 which may negatively impact on the ability 
of aMILs to traffic to the bone marrow following infusion.  
  
9.8  
Tadalafil  
  

 
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Tadalafil 10mg po will be administered to all patients starting on day +2 and given through day 
+11 to both cohorts of patients.   Should patients demonstrate unacceptable hypotension, the 
tadalafil will be discontinued and restarted once the blood pressure has normalized.    
  
  
10. ADMINISTRATION OF ACTIVATED MILs (~DAY 3 & 4)  
  
10.1  
Evaluations Prior to Activated MILs T Cell Infusion  
  
The following evaluations will be made prior to infusion of activated MILs:  
• 
Clinical assessment: review of systems, vital signs;  
• 
CBC with differential and platelet count;  
• 
Serum chemistries: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
calcium,  ALT, AST, total bilirubin, alkaline phosphatase, albumin;  
• 
Serum separator for cytokine measurement (only for immune monitoring substudy)  
Concurrent medication documentation;  
• 
Adverse event documentation.  
  
10.2  
Timing of Infusion of Activated MILs (aMILs)  
  
Activated MILs T Cell infusions will be infused on two consecutive days.  One third of the total 
product will be infused on Day 3  -/+ 1 day and the remainder of the product on the next day. 
Infusion may be delayed if required by cell processing issues or if warranted by the patient’s 
clinical condition.  
  
Date and time of each infusion must be documented.  
  
Infusion should be given on two consecutive days.  
  
NOTE: If medically unstable, the MILs infusion(s) will be delayed until those issues have 
been resolved.  
  
aMILs will not be infused if:  
 Temperature >38.5oC;  
 Oxygen saturation < 90% on room air;  
 Patient is felt to be clinically unstable by the medical team.  
  
Infusion can be given once these symptoms have resolved and the patient is felt to be medically fit 
to receive it after discussion with protocol chair.  
  
10.3  
Pre-Medication Prior to Infusion of aMILs  
  

 
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The patient will be pre-medicated with acetaminophen 650 mg by mouth and diphenhydramine 
hydrochloride 25-50 mg by mouth or IV, no greater than 30 minutes prior to the infusion of 
activated MILs. These medications may be repeated every six hours as needed. A course of 
nonsteroidal anti-inflammatory medication may be prescribed if the patient continues to have a 
high fever not relieved by acetaminophen.  
  
Intravenous diphenhydramine hydrochloride, epinephrine, hydrocortisone and supplemental 
oxygen will be available at the patient’s bedside in the event of anaphylaxis or an infusion 
reaction.  
  
Other medications may also be prescribed to treat additional side effects during the course of 
treatment.  However, there are some medications and therapies that may have adverse effects on 
the activity of activated MILs T Cell therapy and therefore are contraindicated (see Section 12.7, 
Contraindicated Medications). In particular, patients should not receive systemic 
corticosteroids such as hydrocortisone, prednisone, prednisolone (Solu-Medrol) or 
dexamethasone (Decadron) at any time, except in the case of a life-threatening emergency, since 
this may have an adverse effect on activated MILs. If steroids are required for an acute infusional 
reaction, an initial dose of hydrocortisone 100 mg is recommended.  
  
10.4  
Procedure for Administering aMILs  
  
For the administrating of the activated MILs, the patient will be hydrated with D5½NS at 
approximately 200 ml per hour for at least one hour. If the activated MILs product appears to have 
a damaged or leaking bag, or otherwise to be compromised, it will not be infused. Otherwise the 
activated MILs will be thawed and infused through standard blood tubing containing a 170-260 
micron filter without an additional leukoreduction filter into a central IV site. Each of the bags 
will be infused at a rate of approximately 10 ml per minute. Following aMILs infusion, the patient 
will be hydrated with D5W½NS at approximately 200 ml per hour for two hours.  
  
10.5  
Safety Monitoring During Administration of aMILs  
  
During the infusion of activated MILs, the patient’s blood pressure, heart rate, respiratory rate, 
temperature, and peripheral oxygen saturation will be monitored at the following time intervals:  
Immediately prior to infusion of first bag of activated MILs;  
• 
15 minutes after initiation of first bag of activated MILs;  
• 
30 minutes after initiation of first bag of activated MILs;  
• 
1 hour after initiation of first bag of activated MILs;  
• 
2 hours after initiation of first bag of activated MILs;  
  
In the event of a severe allergic reaction (e.g., anaphylaxis, bronchospasm, hypotension) or other 
serious adverse reaction (i.e., cardiac failure, respiratory failure, severe nausea and vomiting) to 
the, activated MILs the infusion of the activated MILs will be stopped immediately and the patient 
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The reaction should be noted as a serious adverse event, and the IRB, the Cell Therapy Lab as well 
as the Protocol chair,Philip Imus, , should be notified within 24 hours.  
  
  
11. OBSERVATION, EVALUATION, AND MANAGEMENT AFTER TREATMENT  
WITH aMILs  
  
Follow-up evaluation of the patient will be carried out according to standard institutional 
guidelines for autologous peripheral blood stem cell transplantation.  In addition, the patient 
will have a limited number of tests performed specifically for this protocol.  Any toxicity felt to 
be related to the infusion of aMILs will be reported as adverse events. See Appendix E, Patient 
Study Calendar  
  
11.1  
Evaluations from Day 5 Through Day 28 after Peripheral Blood Stem Cell Transplant  
  
The following tests will be performed from Day 4 until the day of confirmed engraftment for 
both neutrophils and platelets as clinically indicated (See section 15.8 for definition of 
engraftment):  
• 
CBC with differential and platelet count (differential will only be performed if the total 
WBC > 100/µl);  
• 
Adverse event documentation related to the infusion of aMILs will continue until 
resolution of those events.  
  
The following tests will be performed on Day 7, 11, 14 and 28 (± 2 days):  
• 
Serum chemistries: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
calcium,  ALT, AST, total bilirubin, alkaline phosphatase, albumin;  
• 
Serum separator for measurement of cytokines (only for immune monitoring substudy)  
• 
Adverse event documentation – in any way related to the infusion of aMILs or tadalafil.  
  
11.2  
Evaluations from Day 28-360 after Peripheral Blood Stem Cell Transplant  
  
The patients will be evaluated post transplant on Day 28  2 days, 60 ± 7 days, Day 180 ± 30 days, 
and Day 360 ± 30 days for:  
• 
Clinical assessment: review of systems, ECOG performance status, vital signs;  CBC 
with differential and platelet count;  
• 
Serum chemistries: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
calcium, ALT, AST, total bilirubin, alkaline phosphatase, albumin;  M-protein, serum 
and urine:  
o Protein electrophoresis;  
o Immunofixation (if no measurable M-spike in serum or urine);  
o Freelite (sensitive assay for kappa and lambda light chains) only if most recent 
immunofixation result showed no evidence of M-protein. o Urine eletropheresis 

 
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can be done with a spot urine if the patient has no measurable disease in the urine 
at diagnosis  
• 
Quantitative immunoglobulins (IgG, IgM, IgA);  
• 
Disease response/progression/relapse assessment;  
• 
Adverse event assessment in any way related to either the administration of tadalafil or 
administration of MILs as appropriate  
• 
Concurrent medication documentation;  
• 
Bone marrow aspirate and biopsy.  The bone marrow examination will be performed on 
days 28± 2 days, 60 ± 7 days, 180 ±  30 days and 360 30 days only for patients 
enrolled on the immune sub-study.  In addition to aspirate and biopsy, additional bone 
marrow (at least 20ml) will be obtained in a heparinized syringe only for the immune 
monitoring sub-study;  
• 
Study Blood 100ml in heparinized syringe only for the immune monitoring sub-study.  
  
11.3  
Initiation of Lenalidomide Maintenance Therapy  
  
• 
5mg to start around day 60 once the following parameters are met:  
o Absolute neutrophil count >1500/ l; 
o Platelets > 50,000/ l; o Hemoglobin 
> 10.5g/dL.  
• 
Up to 10mg from approximately 6 months to be continued until disease progression or 
as long as medically tolerated;  
• 
Dose can be adjusted up or down as medically indicated; but cannot be increased above 
10mg.  
• 
Dose of lenalidomide will be recorded  
• 
Those subjects with revlimid dose higher than 10mg will be considered off study.  
  
  
If lenalidomide needs to be discontinued because of toxicity, it should be restarted once the 
toxicities have been resolved.  The interval off drug and dose upon reinstitution of the drug should 
be recorded.  
  
  
11.4  
Discontinuation of Evaluations after Treatment  
  
There are several reasons that a patient may be discontinued from the post-treatment protocol 
evaluations. These include, but are not limited to:  
• 
Patient decision to withdraw from the study;  
• 
Protocol non-compliance;  
• 
Patient lost to follow-up;  
• 
Activated MILs product failed to meet specifications;  Activated MILs product was 
not infused.  
• 
Revlimid dose exceeds 10mg  

 
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The reason for discontinuation of the protocol evaluations will be documented.  The patient should 
continue to be followed annually for survival when possible.  
  
11.5  
Contraindicated Medications  
  
There are some medications that may have adverse effects on the activity of activated MILs.  
These medications and/or therapies should NOT be given to patients at any time during the entire 
study unless indicated in the protocol or to treat life-threatening conditions.  Patients should not be 
placed on any maintenance therapy following transplant. Contraindicated medications and 
therapies include:  
• 
Corticosteroids (e.g., hydrocortisone, prednisone, prednisolone 66, dexamethasone 
(Decadron), etc.). Inhaled steroids for the use of allergic rhinitis or pulmonary disease 
is allowed and not contraindicated;  
• 
Thalidomide;  
• 
Interferon;  
• 
Nitrates;  
• 
Growth factors, interleukins, or other cytokines (except filgrastim as outlined in the 
protocol, or erythropoietin);  
• 
Cytotoxic agents (except cyclophosphamide for stem cell mobilization, fludarabine and 
high-dose melphalan as outlined in the protocol);  Other immunosuppressive drugs;  
Other experimental therapies.  
  
After disease progression, use of corticosteroids and other medications are not dictated by the 
protocol.  
  
NOTE: Corticosteroids treatment may have an adverse effect on the activity of activated  
MILS. Each patient’s hospital and clinic chart will be labeled “NO STEROID 
MEDICATIONS EXCEPT FOR EMERGENCIES” on the cover.  
  
  
12. TADALAFIL  
  
Tadalafil is currently FDA approved for the use of erectile dysfunction and pulmonary 
hypertension with an extensive clinical track record.  In this study we propose to utilize this agent 
in the early post-transplant period in an effort to alter the tumor microenvironment and thereby 
increase the likelihood of maximizing trafficking of T cells.  In an effort to maximize our ability to 
determine the clinical efficacy of MILs, tadalafil will be administered to both groups. Tadalafil 
administration will be recorded by patient on drug diary (Appendix I) and/or by the nurse in 
medical records.  
  
  
  

 
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13. MANAGEMENT OF PROGRESSIVE DISEASE  
13.1  
Documentation of Progressive Disease  
  
Patients with disease progression/relapse shall have this documented.   
  
Disease relapse for patients needs to be documented with:  
• 
SPEP   
• 
Quantitative immunoglobulins  
• 
UPEP (if the patients have light chain disease)  
• 
Serum free light chain  
• 
CBC with differential  
• 
Chemistries: Na, K, Cl, CO2, BUN, creatinine, total protein, albumin, calcium, alkaline 
phosphatase, AST, ALT  
• 
Bone marrow biopsy and aspirate to include the MyPRS (if available).  Hopkins 
patients should also have 20ml of marrow collected in a heparinized syringe for 
research purposes.  
  
At relapse,   patients are eligible to proceed with an alternative acceptable myeloma regimen.   
  
  
14. RISK AND TOXICITY ASSESSMENT  
  
If the Protocol Chair or Site Principal Investigator determines that an adverse event is sufficiently 
severe to remove the patient from the study, an assessment should be performed and the patient 
should be given appropriate treatment under medical supervision.  
  
Patients will be subject to the risks associated with high-dose chemotherapy and peripheral blood 
stem cell transplant.  Because autologous stem cell transplantation is considered a standard 
treatment option in multiple myeloma, this section will focus on the risks associated with the 
infusion of activated MILs, as well as unforeseen adverse events that could result from the 
interaction of activated MILs with the stem cell transplantation therapy.  
  
14.1  
Risks of Venous Access  
  
Complications associated with venous access for leukapheresis of stem cells, infusion of stem cells 
and activated MILs include discomfort, bruising, and/or bleeding at the catheter insertion site, 
thrombosis of the accessed vessel, and infection. Complications from placement of a central line 
required for the high-dose chemotherapy and stem cell transplantation procedure and activated  
MILs include increased risk and severity of the above complications, as well as pneumothorax.  
  
14.2  
Risks of MILs Bone Marrow Harvest  
  

 
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The patients will undergo a standard bedside bone marrow aspiration with conscious sedation and 
sterile technique to collect the marrow infiltrating lymphocytes for subsequent T cell activation. 
There is a potential risk of excessive pain that will be handled with analgesia as needed.  There is 
also the possibility of local and/or systemic infection.  
  
14.3  
Microbial Contamination of Activated MILs  
  
There is the potential that microorganisms inadvertently introduced during cell collection and 
processing could cause an infection in the patient following infusion of the activated MILs.  All 
precautions to maintain sterility will be taken.  Cultures will be obtained prior to and after 
completing the T cell activation process.  
  
14.4  
Potential Toxicity of Storage Solutions  
  
14.4.1 Dimethyl Sulfoxide (DMSO)  
The activated MILs product is cryopreserved in a solution containing approximately 5% 
DMSO.  DMSO is a cryoprotectant used to store a variety of infused cell products 
including peripheral blood stem cells and bone marrow.  After cells are thawed, DMSO 
contained in the freezing solution is infused along with the cells.  Toxicity associated with 
DMSO infusion is usually limited to minor changes in heart rate, blood pressure, fever, 
chills, sweats, nausea, vomiting and headaches.  These are usually self-limited, lasting no 
more than a few hours.  The most notable effect is a garlicky odor due to exhalation of a 
DMSO metabolite that may last up to one day.  More severe adverse effects include severe 
acute allergic reactions including anaphylactoid reactions, pulmonary embolism, 
respiratory failure, renal failure, cardiac arrhythmias, seizures, and death. 68,69These side 
effects are rarely observed and occur primarily in patients receiving much higher volumes 
of cryopreserved cell products than being infused in the present study.  Nevertheless, 
patients will be carefully monitored for any adverse effects as outlined in Section 15, 
Adverse Events.   
  
14.4.2 Human Serum Albumin (HSA)  
The aMILs are formulated in a cryopreservative supplemented by 2% human serum 
albumin.  Albumin solutions are FDA approved for volume resuscitation (treatment of 
hypovolemia, shock, and burns).  Although hypersensitivity reactions are possible, 
reactions are not anticipated to the small amount of albumin administered.  
  
14.4.3 Hetastarch  
The cryopreservative for the aMILs will also contain 6% hetastarch.  Hetastarch is FDA 
approved for hypovolemia and as a volume expander administered during leukapheresis.  
Hypersensitivity reactions have occurred but are not common.  Considering the small 
amount of hetastarch to be administered to the patient, adverse reactions are not 
anticipated.  
  

 
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14.5  
Potential Adverse Effects of Tadalafil  
  
Tadalafil has been evaluated extensively for safety. Initial safety was evaluated in doses up to 20 
mg daily for 12 weeks (n=258), with a 3% discontinuation rate70  and did not demonstrate any 
gender related differences in pharmacokinetics or adverse effects. A recent meta-analysis did not 
demonstrate any higher cardiovascular risk compared to placebo.71  Non-arterial anterior ischemic 
optic retinopathy has been proposed as a rare side effect of PDE-5 inhibitors, but definitive data 
have not been provided due to the rarity of this phenomenon in both the population and subject 
using PDE-5 inhibitors, as well as the widespread use of PDE-5 inhibitors.72  
  
The most common side effects of tadalafil at a dose of 20mg are headache (15%), dyspepsia 
(10%), back pain (6%), myalgia (3%), flushing (3%), limb pain (3%) and nasal congestion (3%). 
These side effects usually go away after a few hours. Men who get back pain and muscle aches 
usually get it 12-24 hours after taking tadalafil. Back pain and muscle aches usually go away 
within 2 days. Some uncommon side effects include priapism, color vision changes, sudden 
decrease or loss of vision in one or both eyes, sudden loss or decrease in hearing, sometimes with 
tinnitus and dizziness.  
  
Drug interactions:  
• 
Nitrates: Administration of tadalafil to patients who are using any form of nitrate is 
contraindicated. Tadalafil has been shown to potentiate the hypotensive effect of 
nitrates;  
• 
Alpha blockers: Tadalafil and alpha adrenergic blockers are vasodilators with blood 
pressure lowering effects and when used in combination an additive effect on blood 
pressure may be anticipated;  
• 
Cytochrome P450 inhibitors: Tadalafil is a substrate of and predominantly metabolized 
by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole and ritonavir can 
increase tadalafil exposure;  
• 
Cytochrome P450 inducers: Drugs that induce CYP3A4 such as rifampin can decrease 
tadalafil exposure.  
  
Contraindications:  
• 
Known hypersensitivity to tadalafil;   
• 
Concurrent use of organic nitrates in any form.  
  
14.6  
Potential Adverse Effects Associated with Activated MILs  
  
Previous clinical trials using CD3xCD28 bead-activated and expanded peripheral blood T cells 
were described above. Eighty-nine HIV patients have been treated, with the most common 
toxicities being fevers, chills, fatigue, rash, sinusitis, asthenia, headaches, and nausea. 73-76Grade 3 
and 4 toxicities were predominantly associated with IL-2, which was infused in some of the 
patients in these trials.  T cells activated with CD3xCD28 beads have also been administered to 
patients undergoing peripheral blood stem cell transplantation for relapsed or refractory 
NonHodgkin’s lymphoma.52 T cells were collected prior to high-dose chemotherapy. Fourteen 

 
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days following peripheral blood stem cell infusion, activated and expanded T cells were 
administered.  Three patients were treated at a median cell dose of 0.4 x 109, twelve patients were 
treated at a median cell dose of 1.6 x 109, and two patients were treated with a median cell dose of 
9.8 x 109.  The latter two patients experienced infusion related toxicities including transient fever, 
dyspnea, rigors and pulmonary edema (one patient).  
  
It is possible that activated T cells could attack the patient’s own tissues, resulting in autoimmune 
disorders.  However, this was thought to be due to high-dose IL-2, a known cause of this disorder, 
which was given with the cell therapy.  Autoimmune disease has not been observed in previous 
studies using CD3xCD28 bead-activated T cells. Considering that in this case, the lymphocytes are 
obtained from the marrow microenvironment, it is possible that an immune response could 
develop towards normal hematopoietic elements.  For this reason, hematologic engraftment will be 
closely monitored throughout the trial.  
  
To date, over 50 patients have been treated with activated MILs.  No Grade 2 or greater toxicity 
was observed in any of the patients.  Patients did not have any infusion related toxicities.  We 
have, however, noticed a 35% incidence of acute Grade 1 or 2 skin graft vs host disease (GVHD) 
that was self-limiting and required no local or systemic treatment.  
  
14.7  
Potential Adverse Events Associated with Peripheral Blood Stem Cell Transplant  
  
Patients will be at risk for all of the complications associated with the peripheral blood stem cell 
transplant procedure. The Investigator is responsible for discussing these risks in detail with the 
patient. The following is a brief overview of the major risks associated with peripheral blood stem 
cell transplantation, and is not intended to be comprehensive.  An extensive list of the expected 
complications associated with an autologous peripheral stem cell transplant is listed in Appendix 
G.  
  
14.7.1 Peripheral Blood Stem Cell Mobilization Chemotherapy Regimen  
Patients receive cyclophosphamide chemotherapy and filgrastim to mobilize peripheral 
blood stem cells for collection.  Cyclophosphamide can cause alopecia, nausea, vomiting, 
bladder irritation and hemorrhage, and myelosuppression including anemia, leukopenia, 
and thrombocytopenia.  Patients are at risk of bleeding and infection.  
  
14.7.2 Administration of Filgrastim (G-CSF)  
Filgrastim is given in the peripheral blood stem cell mobilization regimen and can cause 
significant bone pain in many patients.  
  
14.7.3 Melphalan  
High doses of melphalan can cause nausea, vomiting, fatigue, anemia, and alopecia. 
Patients are at significant risk of serious and life-threatening infections during the 
neutropenic period, which usually lasts for approximately two weeks.  Patients will likely 
require red blood cell and platelet transfusions, both of which are associated with infectious 
risks such as hepatitis and HIV.  

 
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14.7.4 Leukapheresis  
Patients will require leukapheresis to collect the peripheral blood stem cells.  
  
14.7.5 Peripheral Blood Stem Cell Infusion  
  
The peripheral blood stem cells may become contaminated with microbes during their 
collection or processing.  Infusion of peripheral blood stem cells contaminated with 
microbes such as bacteria could cause an infection.  The peripheral blood stem cells are 
stored in DMSO.  Similar to the administration of activated MILs, the DMSO is infused 
along with the cells.  
  
14.8  
Lenalidomide  
  
Lenalidomide can commonly cause myelosuppression, skin rashes, and fatigue.  The drug will not 
be initiated until the patients meet the required hematologic criteria as specified by the protocol.  
However, because of our desire to increase the immunostimulatory effects of lenalidomide on the 
MILs, we will attempt to start treatment around 60 days post-transplant and to start with the low 
dose of 5mg.  
  
Lenalidomide has been associated with a significant improvement in progression free survival and 
possibly also overall survival.  It has also been associated with a 3-5% incidence of secondary 
malignancies when administered either in association with melphalan or following high dose 
melphalan in the post-transplant setting.  
  
  
15. ADVERSE EVENTS  
  
15.1  
Definitions  
  
15.1.1 Adverse Event (AE)  
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening 
of a pre-existing medical condition in a patient or clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of investigational product, whether or not considered 
related to the investigational product (refer to ICH E6 GCP Guidance – section 1.2).  
  
15.1.2 Serious Adverse Event (SAE)  
A Serious AE (SAE) is any untoward medical occurrence that at any dose produces any 
of the following outcomes (refer to ICH E6 GCP Guidance – section 1.50):  Results in 
death;  

 
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• 
Is life threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe);  
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below for exceptions);  
• 
Results in persistent or significant disability/incapacity;  
• 
Is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth defects 
must also be reported on the Pregnancy Supplemental Form);  
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
intervention [e.g., medical, surgical] to prevent one of the other serious outcomes listed 
in the definition above.). Examples of such events include, but are not limited to, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization).  
• 
Transplant-related complications that are expected but exceed the severity and are felt 
to be related to either tadalafil or the MILs need to be reported as SAEs.  Examples 
include but are not limited to: prolonged aplasia, excessive fevers, excessive diarrhea  
• 
Although pregnancy, overdose, and cancer are not always serious by regulatory 
definition, these events must be handled as SAEs.  
  
  
NOTES:   
  
1. The following hospitalizations are not considered SAEs:  
 Admissions as per protocol for a planned medical/surgical procedure;  
 Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy);  
 Medical/surgical admission for purpose other than remedying ill health state and 
was planned prior to entry into the study. Appropriate documentation is required 
in these cases;  
 Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of 
housing, economic inadequacy, care-giver respite, family circumstances, 
administrative).  
  
15.1.3 Non-serious Adverse Event  
A non-serious adverse event is any adverse events not classified as serious (as described in 
previous section).  
  
15.2  
Adverse Event Assessment and Recording  
  

 
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15.2.1  Collection and Assessment of AEs/SAEs   
  
The process of reviewing of all AEs by the PI will be documented on the “Adverse event 
assessment chart” (Appendices J). Source documentation, including all available clinic notes, will 
be reviewed from the time of bone marrow collections of MILs through Day 360/disease 
progression post-transplant. AEs/SAEs that occur after Day 360 or disease progression/relapse 
would likely reflect the disease process, and not the activated MILs or tadalafil.    
  
 All toxicities, abnormal laboratory results and/or potential adverse events experienced by accrued 
subjects during this time will be assessed by the PI. These assessments are to occur regularly for 
the time periods specified in Appendices K and confirmed by the PI based on attribution to study 
intervention(s).  
• 
Only Adverse Events considered in any way related to the either infusion of aMILs or 
Tadalafil are recorded on the AE Log in database.   
• 
Only clinically significant laboratory results considered in any way related to either aMILs 
or Tadalafil and not at all related to bone marrow transplant are recorded on the AE Log.  
  
For purposes of this study, clinical significance is defined as any laboratory result that is outside 
the range of normal, as defined by each laboratory’s recorded reference range and is deemed 
clinically significant by the Principal Investigator.  
  
This assessment chart does not pertain to SAEs. Each SAE is individually assessed by the PI at 
the time of the event. All SAEs will be recorded on the AE Log in database.  
  
  
  
15.3  
Grading of Adverse Events and Toxicities  
  
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for all AE reporting.  
  
Attribution of AE’s:  
• 
Mild (Grade 1) – near the lowest intensity (or within the lower one-third) typically seen 
with the observed sign or symptom;  
• 
Moderate (Grade 2) – average intensity typically seen with the observed sign or 
symptom;  
• 
Severe (Grade 3) – near the highest intensity (or within the top third) typically seen 
with the observed sign or symptom;  
• 
Life-threatening or disabling (Grade 4) – any AE that places the patient, in the view of 
the investigator, at immediate risk of death from the reaction as it occurred.  It does not 
refer to an event which hypothetically might have caused death if it were more severe; 
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Note:  These terms are used to describe intensity of a specific event; the event itself may be of 
relatively minor medical significance (such as severe headache).  
  
15.4  
Attribution of Causality  
  
The association or relationship of the AEs to activated MILs or tadalafil will be defined according 
to the NCI Common Toxicity Criteria guidelines as follows:  
• 
Definite – The AE is clearly related to the study product, e.g., an event that follows a 
reasonable temporal sequence from administration of the drug or in which the drug 
level has been established in body fluids or tissues, that follows a known or expected 
response pattern to the suspected drug, and that is confirmed by improvement on 
stopping or reducing the dosage of drug;  
• 
Probable – The AE is likely related to the study product, e.g., an event that follows a 
reasonable temporal sequence from administration of the drug, that follows a known or 
expected response pattern to the suspected drug, that is confirmed by stopping or 
reducing the dosage of the drug, and that could be reasonably explained by the known 
characteristics of the subject’s clinical state;  
• 
Possible – The AE may be related to the study product, e.g., an event that follows a 
reasonable temporal sequence from administration of the drug, that follows a known or 
expected response pattern to the suspected drug, but that could readily have been 
produced by a number of other factors;  
• 
Unlikely – The AE is doubtfully related to the study product;  
• 
Unrelated – The AE is clearly not related to the study product;  
• 
Not applicable – The AE occurred prior to administration of the study product;  
Unknown – No evaluation for causality can be made.  
  
15.5  
Serious Adverse Event Capture and Reporting  
  
The Sponsor/Investigator is obligated to report to the FDA suspected adverse reaction that is both 
serious and unexpected. (see 21 CRF, part 312.32):  
• 
Serious Adverse Event - any adverse experience which is fatal or life-threatening, 
permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, 
cancer, or overdose;  
• 
Unexpected Adverse Event - any adverse experience that is not identified in nature, 
severity or frequency in the current Investigator Brochure.  
  
ALL serious adverse events, regardless of causality must be reported to the following entities:  
• 
IND Sponsor – Dr.Cooke ;  
• 
Study PI – Dr Imus;  
• 
IRB (per the IRB’s reporting requirements);  
  
15.5.1 Investigator Reporting Responsibilities  

 
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The conduct of the study will comply with all FDA safety reporting requirements. All 
adverse experience reports must include the patient number, age, sex, weight, severity of 
reaction (mild, moderate, severe), relationship to study drug (probably related, unknown 
relationship, definitely not related), date and time of administration of test medications and 
all concomitant medications, and medical treatment provided.   The investigator is 
responsible for evaluating all adverse events to determine whether criteria for “serious” and 
“unexpected” as defined above are present.  
This SKCCC clinical trial requires all study sites to maintain a study-specific master 
adverse event log and a protocol deviation log in Excel format. Templates will be provided 
by the Coordinating Center.   
  
  
15.5.2 SAE Reporting to the IND Sponsor  
SAEs that meet the definition of an unanticipated event must be reported to the IND 
Sponsor, Dr. Cooke within 24 hours of the event. Subsequently each participating site must  
document such an SAE using MedWatch form (FDA 3500A) and send it to the 
coordinating center’s study research nurse Laura Cucci at Johns Hopkins and to 
onccoordcnt@jhmi.edu within 7 calendar days of the event.  
  
15.5.3 Sponsor SAE Reporting to the FDA  
All SAEs are reported to the FDA via the IND annual report per 21 CFR 312.33. SAEs 
deemed unexpected and related to the investigational product qualify for expedited 
reporting and must be submitted by the IND Sponsor to the FDA per 21 CFR 312.32 as 
shown immediately below.  
  
15.5.3.1  
7 Calendar-Day Telephone or Fax IND Safety Report to FDA  
The Sponsor is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the Sponsor Investigator to be possibly related to the 
use of activated MILs or tadalafil within 7 calendar-days of first learning of the event. 
An unexpected adverse event deemed possibly related to the use of an investigational 
study drug is defined as any adverse drug experience of which the specificity or 
severity is not consistent with the current investigator brochure, the general 
investigational plan, or elsewhere in the current application, as amended.  
  
Such reports are to be telephoned or faxed to the FDA and Laura Cucci, R.N. at Johns 
Hopkins (tel: 410 614 5407 or fax 410 502 9690) within 7 calendar-days of first 
learning of the event. Each telephone call or fax transmission should be directed to the 
FDA new drug review division in the Center for Drug Evaluation and Research or in 
the product review division for the Center for Biologics Evaluation and Research, 
whichever department is responsible for the review of the IND.  
  
15.5.3.2  
15 Calendar-Day Written IND Safety Report to FDA  
The IND Sponsor is required to notify the FDA, and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected adverse event considered by the 

 
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IND Sponsor to be possibly related to the use of activated MILs and tadalafil within 15 
calendar-days of first learning of the event. If applicable, the IND Sponsor must also 
notify the FDA, and all participating investigators of any finding from tests in 
laboratory animals that suggests a significant risk for human subjects including reports 
of mutagenicity, teratogenicity, or carcinogenicity within 15 calendar-days of first 
learning of the event.  
  
A serious, unexpected adverse event deemed possibly related to the use of an 
investigational study drug is any adverse drug experience of which the specificity or 
severity is not consistent with the current investigator brochure, the general 
investigational plan, or elsewhere in the current application, as amended, and results in 
any of the following outcomes:  
• 
Death (reported first as a 7-day telephone/fax report);  
• 
Life-threatening adverse drug experience (reported first as a 7-day phone/fax 
report);  
• 
Inpatient hospitalization or prolongation of existing hospitalization;  
• 
A persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect;  
Or is an important medical event that may not result in death, be life-threatening, or 
require hospitalization but is considered a serious adverse drug experience when, 
based upon appropriate medical judgment, it may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  
  
Note: Aggregate reporting of hospitalizations due to neutropenic fever   
  
Stem cell transplant is the background regimen in the study. Admissions during the 
period of aplasia associated with the transplant are expected complications of the 
transplant. An occurrence of such an event is not an adequate basis to conclude that the 
event is a suspected adverse reaction to the investigational products tadalafil and MILs. 
Therefore, neutropenic fevers will not be reported individually as they occur because 
they are uninformative as single cases. These SAEs will be monitored and assessed for 
causality to investigational products, and the numbers of events in each arm will be 
compared. An IND safety report based on data in the aggregate will be submitted as a part 
of annual report.  
  
All written IND Safety Reports should include an Analysis of Similar Events in 
accordance with 21 CFR 312.32. All safety reports previously filed with the IND 
concerning similar events should be analyzed. The new report should contain 
comments on the significance of the new event in light of the previous, similar reports 
and be submitted to the FDA, and all participating investigators within 15 calendardays 
of first learning of the event. The FDA prefers these reports be documented on a 
MedWatch 3500A Form, but alternative formats are acceptable (e.g., summary letter).  
  

 
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The address of the Food and Drug Administration is:  
Center for Biologics Evaluation and Research  
Food and Drug Administration  
HFM-99, Room 200  
1401 Rockville Pike  
Rockville, MD  20852-1448  
  
15.5.3.3  
Follow-up Reports to FDA  
All follow-up information concerning IND Safety Reports should be submitted to the 
FDA as soon as possible (and no later than 15 calendar days after receiving an FDA 
request for more information).  
  
15.6  
Definitions of Response (IMWG Criteria)  
  
Definitions of response are adapted from the combined criteria developed for patients with 
multiple myeloma treated by high-dose chemotherapy and hematopoietic stem cell transplantation  
(Blade’s Criteria) and are updated based upon the consensus report of the International Myeloma 
Working Group (IMWG) criteria.77 If confirmation of a measurement is required, the date of 
response/progression/relapse will be the date at which the M-protein measurement first meets the 
required criterion. M-protein measurements by serum protein electrophoresis (SPEP) will take 
precedence over quantitative immunoglobulins for determining response. The date of 
response/progression/relapse will be determined by the date when the relevant tests were obtained, 
and not by the date when the investigator reviews the test results.  
  
Criteria for Evaluation and Endpoint Definitions:  
• 
The serum and urine M-protein levels obtained at baseline will be used as the reference 
baseline for calculation of increases or decreases in the M-protein level. The M-protein 
levels from the time of diagnosis will also be obtained for the patients that proceed 
directly from induction chemotherapy to transplant.  For patients with relapsed 
myeloma, the M-protein level baseline will be considered the highest value prior to the 
last chemotherapy given leading up to the transplant.  The response calculations using 
those respective values as baseline will also be performed in secondary analyses.  
  
15.6.1 Complete Response (CR) Requires 
all of the following:  
• 
Absence of the original M-protein in serum by immunofixation, maintained for a 
minimum of 6 weeks.  Presence of M-protein by Freelite assay does not exclude CR. 
The presence of oligoclonal bands consistent with oligoclonal immune reconstitution 
does not exclude CR. Normalization of serum concentrations of normal 
immunoglobulins is not required;  
• 
If a urine M-protein is present at baseline or other prior evaluation, absence of this 
Mprotein in urine by immunofixation, maintained for a minimum of 6 weeks;  
• 
< 5% plasma cells in a bone marrow aspirate and on bone biopsy (must be performed)  

 
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• 
No increase in the size or number of lytic bone lesions on skeletal x-rays, if performed.  
Development of a compression fracture does not exclude response; 
 Disappearance of any soft tissue plasmacytomas.  
  
15.6.2 Stringent Complete Response (sCR)  
Requires all of the criteria for CR to be met, plus all of the following:  
• 
Normal FLC ratio (0.26 to 1.65); and  
• 
Absence of clonal plasma cells in the bone marrow, defined by 2-4 color flow 
cytometry OR immunohistochemistry  
  
15.6.3 Very Good Partial Response (VGPR) Requires 
all of the following:  
• 
A decrease in the serum M-protein by  90%, maintained for a minimum of 6 weeks;  
• 
If a urine M-protein is present at baseline or other prior evaluation, the urine M 
component must be less that 100mg per 24 hours;  
• 
No increase in the size or number of lytic bone lesions on skeletal x-rays, if performed.  
Development of a compression fracture does not exclude response; 
 Disappearance of any soft tissue plasmacytomas.  
  
15.6.4 Partial Response (PR) Requires 
all of the following:  
• 
A decrease in the serum M-protein by  50%, maintained for a minimum of 6 weeks;  
• 
If a urine M-protein is present at baseline or other prior evaluation, a > 90% reduction 
in this protein, or a decrease to less than 200 mg in a 24 hour urine collection. This 
response must be maintained for a minimum of 6 weeks;  
• 
No increase in the size or number of lytic bone lesions on skeletal x-rays, if performed.  
Development of a compression fracture does not exclude response;  
• 
Decrease of  50% in the size of any soft tissue plasmacytomas (by radiography or 
clinical examination)  
  
15.6.5 Minimal Response (MR) Requires 
all of the following:  
• 
A decrease in the serum M-protein by  25%, maintained for a minimum of 6 weeks;  
• 
If a urine M-protein is present at baseline or other prior evaluation, a > 50% reduction 
in this protein in a 24 hour urine collection. This response must be maintained for a 
minimum of 6 weeks;  
• 
No increase in the size or number of lytic bone lesions on skeletal x-rays, if performed.  
Development of a compression fracture does not exclude response;  
• 
Decrease of  25% in the size of any soft tissue plasmacytomas (by radiography or 
clinical examination).  
  
15.6.6 Stable Disease  

 
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Not meeting the criteria of CR, VGPR, PR, MR, progression, or relapse from CR  
  
15.6.7 Relapse from CR (NB this is not distinguished in new IMWG criteria) Requires 
one or more of the following:  
• 
Reappearance of serum or urinary M-protein on immunofixation or routine 
electrophoresis, confirmed by at least one further investigation, and excluding 
oligoclonal immune reconstitution;  
• 
> 5% plasma cells in a bone marrow aspirate or on bone biopsy;  
• 
Development of new lytic bone lesions or soft tissue plasmacytomas or definite 
increase in the size of residual bone lesions. Development of a compression fracture 
does not exclude continued response and may not indicate progression;  
• 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.8 mmol/L) 
not attributable to any other cause.  
  
15.6.8 Progression  
Requires one or more of the following:  
• 
A > 25% increase in the level of serum M-protein, which must also be an absolute 
increase of at least 5 g/L and confirmed by at least one repeat investigation;  
• 
A > 25% increase in the 24 hour urinary light chain excretion, which must also be an 
absolute increase of at least 200 mg/24 hours and confirmed by at least one repeated 
investigation;  
• 
Only in subjects with no measurable serum or urine M spike: a >25% increase in the 
difference between involved and uninvolved FLC levels (absolute increase must be > 
10 mg / dL)  
• 
Only in subjects without meausurable serum and urine M protein levels AND without 
measurable disease by FLC levels: a > 25% increase in plasma cells in a bone marrow 
aspirate or on 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 at any time since 
baseline. Development of a compression fracture does not exclude continued response 
and may not indicate progression;  
• 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.8 mmol/L) 
at any time since baseline, which is not attributable to any other cause. (Corrected 
serum calcium is calculated by adding 0.8 mg/dL to the measured serum calcium for 
every 1 g/dL that the serum albumin falls below 4.0 g/dL.).  
  
Reference level for increase in M-protein, plasma cells, or lesion sizes is the lowest level 
documented since (and including) baseline evaluation.  
  
  
15.6.9 Response Criteria for serum free light chain responses  
  

 
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Minimum 
deemed 
measurable  
PR  
CR  
sCR  
Progression  
MM without 
measurable 
serum or urine 
M‐ protein  
iFLC >/= 
100mg/l and 
rFLC abnormal  
50% reduction of 
dFLC  
ND  
Normal rFLC & 
CR by IFE and 
bone marrow  
50% increase of 
iFLC to > 100 
mg/l  
MM with 
measurable 
disease  
Use of FLC not 
recommended  
Use of FLC not 
recommended  
Use of FLC not 
recommended  
Normal rFLC & 
CR by IFE and 
bone marrow  
Use of FLC not 
recommended  
Abbreviations: iFLC, inv-restricted disease; dFLC, difference between iFLC and uninvolved FLC; rFLC, free light 
chain ratio; ND, not defined. Measurable M protein includes serum M protein of at least 1 g per 100 ml or a urine 
Mprotein of at least 200 mg/24 h for myeloma patients (100 mg/24 h for AL patients).  
  
15.7  
Survival Endpoints  
  
15.7.1 Overall Survival  
Measured as the time from Day 0 to death from any cause.  
  
15.7.2 Progression-Free Survival  
Measured as the time from initial registration Day 0 to progression/relapse of disease or death 
from any cause, whichever occurs first.  
  
15.8  
Definitions of Engraftment and Graft Failure  
  
15.8.1 Engraftment  
Neutrophil engraftment is defined as the day post-transplant when the absolute neutrophil 
count is > 500/mm3 for two consecutive days post-transplant (note: bands as well as 
neutrophils are included in calculations).  The first day on which this criterion is met is 
considered the day of neutrophil engraftment.  
  
Platelet engraftment is defined as the first of three consecutive counts post-transplant when  
the platelet count is > 20,000/mm3 without platelet transfusion support.  The first day on 
which this criterion is met is considered the day of platelet engraftment.  
  
15.8.2 Failure of Engraftment  
Primary graft failure is defined as failure to recover an absolute neutrophil count > 
500/mm3 or platelet count > 20,000/mm3 by Day 28 post-transplant.  Secondary graft 
failure is defined as a fall to less than these levels for three or more consecutive days after 
Day 28 without another cause.  
  
  

 
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16. STATISTICAL CONSIDERATIONS  
  
NOTE:  The original statistical plan is noted here in Section 16.  Due to protocol violations that 
were discovered in the conduct of the study, this statistical plan is no longer valid.  The current 
statistical plan is noted in Appendix K.  The original statistical plan is left in the protocol for 
historical reference only, and will not be followed.  
  
16.1  
Sample Size  
  
Ninety patients will be treated in this clinical trial. If patients are registered but do not proceed to 
transplant for any reason, then additional patients will be registered such that the target of 90 
patients treated can be achieved.  
  
16.2  
Statistical Analysis  
  
This is a prospective, randomized clinical trial in multiple myeloma (MM) patients with high risk 
disease undergoing their first autologous bone marrow transplant.  In this study patients 
randomized to the MILs arm will receive a post-transplant infusion of anti-CD3/CD28 activated 
marrow infiltrating lymphocytes (aMILs) in an attempt to induce durable myeloma-specific 
immune responses.  The primary endpoint will assess the impact of infusing aMILs on progression 
free survival (PFS). Patients will be random ized in a 2:1 ratio to receive aMILs (Arm A) or not 
(Arm B) following ASCT.  All patients will be given tadalafil from days 2-21.  Lenalidomide will 
be started on day +60 post ASCT.  Randomization will be stratified by relapse status prior to 
transplant and high-risk phenotype based on the GEP-70 profile – if available.78  
  
Primary Objective:  Determine the efficacy of aMILs in prolonging PFS in patients with high 
risk multiple myeloma followed by ASCT.  Relapse for patients in CR prior to transplant is 
defined in section 16.6.6.  Progression for patients not in CR prior to transplant is defined in 
section 16.6.7.  PFS will be defined as the time from ASCT to documented progression/relapse, 
death from any cause or last follow-up.  Assessment of progression will be made by the treating 
physician and confirmed through laboratory biochemical analyses.  
  
The time-to-event in both arms of this study will be assumed to follow an exponential distribution.  
We hypothesize that the median PFS is 15 months for the control (Arm B) and 33.3 months for the 
aMILs treated group (Arm A).  The stratification factors for randomization will consist of relapse 
status prior to transplant and the presence or absence of high risk GEP-70 profile. A randomized 
block procedure will be used.  
  
Secondary Objectives:  
1. Evaluate hematopoietic and infusional toxicities associated with this treatment;  
2. Evaluate progression-free survival at 2 years;  
3. Evaluate overall survival;  
4. Quantify anti-myeloma immunity in the subset participating on the immune study;  
5. Validate immune response phenotype identified in previous MILs trial.  

 
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Sample Size: The median PFS in high-risk MM patients on the study arm not receiving aMILs 
(Arm B) is expected to be 15 months.  Hazard rates over four time intervals were estimated based 
on the TT2 PFS curve for MyPRS-defined high-risk patients1.  Simple linear regressions were 
used to fit the natural logarithm of the Kaplan-Meier product limit estimate of the PFS function as 
a function of time in four intervals: from 1 to 7 weeks, 7 to 15, 15 to 21, and 21 to 23 weeks.  
These estimated hazard rates: 0.0072, 0.0136, 0.0058, and 0.0009 per person week were used in 
simulations to evaluate power for this study.  We hypothesize that the addition of aMILs will 
translate into a relative improvement of 46% on the 15 month PFS (15 month PFS improved from 
50% to 73%).  Patients will be randomized to the aMILs (Arm A) and no aMILs arms (Arm B) in 
a 2:1 ratio.  Using a one sided 5% type I error allowance, accrual of 36 patients per year for 2.5 
years (Arm A and B target sample sizes of 60 and 30 respectively) with an additional 2 years of 
follow up, this study will provide sufficient events to have 83% power to detect an improvement 
of the median PFS from 15 months to 33.3 months, i.e. a hazard ratio of 0.45.  
  
Futility monitoring plan:  We will monitor the study for futility using a non-parametric Bayesian 
predictive probability approach79,80,81.  This monitoring plan is based on calculations of the 
posterior distribution of the survival distribution and simulations to determine the probability that 
the PFS at two years on the treatment arm will be greater than that on the control arm at the end of 
the study.  When the trial is monitored, Gibbs sampling is used to generate samples from the 
posterior distribution of the survival distribution via Monte Carlo simulation, given the data and a 
Dirichlet process prior.  Censored observations are treated as random quantities and PFS event 
times are simulated for each censored observation.  This is repeated many times and ultimately 
converges to a realization of the parameters drawn from the posterior distribution.  The algorithm 
is that reported in Kuo and Smith.80 If the probability that the treatment 2 year PFS is greater than 
the control PFS at 2 years is very low, less than 33.3%, the study will be stopped for futility.  
  
The reference hazard rates were estimated based on the TT2 PFS curve for MyPRS-defined high 
risk patients78.  Simple linear regressions were used to fit the natural logarithm of the KaplanMeier 
product limit estimate of the survival function as a function of time in four intervals: from 1 to 7 
weeks, 7 to 15, 15 to 21, and 21 to 23 weeks.  Survival times were then generated using a 
piecewise exponential distribution with these estimated hazard rates: 0.0072, 0.0136, 0.0058, and 
0.0009 per person week.  For simulation purposes, the effect of treatment was assumed to multiply 
these hazard rates by factors of 1.0 (no difference), 0.805 0.75, 0.65, 0.55, 0.50, and 0.45.  The 
randomization ratio for these simulated studies was 2:1 and a single interim analysis, evaluating 2 
year PFS, was performed after 50% of the patients were enrolled, i.e. n=30 in Arm A (aMils) and 
n=15 in Arm B (no aMils).  A one-sided 0.05 alpha level log-rank test was used for the final 
analysis.  Plots of the reference curve (black) and six scenarios of treatment effects (red) are 
shown in figure 1.  In scenario one, the reference and treatment hazard rates are equal.  Table 1 
gives operating characteristics of this monitoring plan for these scenarios.  Column 4 in table 1 is 
the proportion of studies rejecting the null hypothesis out of the number of studies that did not stop 
for futility.  Column 5 is the overall proportion of studies with a positive result.  
  
  

 
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Table 1.  Operating characteristics of monitoring rule from 500 simulated studies with interim 
analysis on 4 month PFS and final analysis based on the log-rank test.  
  
Scenario  
Control 
hazard rate  
(λ) 
multiplier  
Stop for 
Futility %  
Rejected at 
final analysis  
%*  
Overall 
studies 
rejecting Ho  
%  
1  
1.00  
10.4%  
6.5%  
5.8%  
2  
0.85  
3.2%  
9.7%  
9.4%  
3  
0.75  
2.0%  
20.4%  
20.0%  
4  
0.65  
1.0%  
40.6%  
40.2%  
5  
0.55  
0.0%  
62.6%  
62.6%  
6  
0.50  
0.0%  
77.4%  
77.4%  
7  
0.45  
0.0%  
83.4%  
83.4%  
*Denominator is the number of simulations that do not stop early for futility.  
  
Primary analysis:  The primary analysis will be intent to treat analysis of all patients treated on 
protocol, regardless of treatment modification or discontinuation.  The PFS event time 
distributions for patients receiving aMILs (Arm A) and patients not receiving aMILs (Arm B) will 
be estimated with the method of Kaplan and Meier and compared using the log-rank statistic.  The 
primary analysis will use a two sided 0.05 alpha-level test.  
  
Secondary analyses:  
1. The time to neutrophil and platelet engraftment (absolute neutrophil count >500/mm3 and 
platelet >20,000/mm3) will be summarized using cumulative incidence curves with death as 
the competing risk.  The rate of primary graft failure will be estimated and reported with 95% 
exact binomial confidence intervals.  Any adverse events appreciated during the infusion of 
aMILs or felt to be related to the infusion will be summarized and reported.  
2. Overall survival event time distributions for the two arms of the study will be estimated with 
the method of Kaplan and Meier and compared using the log-rank statistic.  
3. Lymphocytes from the peripheral blood and marrow will be collected and banked at the 
indicated time points during the study: blood on days +7, +14, +28, +60, +180 and +360; and 
bone marrow, on days +28, +60, +180 and +360 for the patients participating in this substudy 
(Hopkins only). Tumor-specific assays will be performed in these patients. We expect tumor 
specific responses post-transplant.  Results will be summarized and correlated with clinical 
responses.   For patients receiving the aMILs following disease relapse, blood will be 
collected and banked on days +7, +14, +28, +60, +180 and +360; and bone marrow, on days 
+28, +60, +180 and +360 following the administration of cyclophosphamide for the patients 
participating in this sub-study (Hopkins only).  For patients with ongoing responses, bone 
marrow samples (and possibly blood) will be obtained and stored whenever the patient is 
getting a bone marrow as part of the standard clinical care.  It is routine at Hopkins to have 
patients undergo annual bone marrow biopsies for up to 5 years post-transplant assuming the 
patients are still in remission.  

 
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4. Data from the first MILs trial suggests that high endogenous CD8/IFN  and an increased 
percentage of effector as well as effector memory CD8 cells at baseline was associated with 
progressive disease.  These parameters will be correlated with progression free and overall 
survival.  
  
  
  
  
16.3  
Safety Data Monitoring  
  
16.3.1 Review of Safety Data  
The Investigators will review safety data on an ongoing basis. Clinical research meetings 
are held at least monthly via teleconference with participating sites in which all the patient 
data is reviewed including adverse events and safety.  The trial may be prematurely 
terminated should the occurrence of adverse events warrant such action.  
  
16.3.2 Premature Termination of the Study  
If at any time four patients die of treatment related causes or experience Grade 4 pulmonary 
or hepatic toxicity, the study will be terminated. The study will also be terminated if there 
are two or more deaths, which are definitely or probably attributable specifically to the 
activated MILs or vaccination.  
  
16.4  
Plan for Statistical Summaries and Analyses  
  
16.4.1 Subject Accountability  
The following data will be summarized:  
• 
Number (%) of subjects registered;  
• 
Number (%) of subjects undergoing autologous stem cell transplant;  
• 
Number (%) of subjects who receive activated MILs.  
  
16.4.2 Demographic and Baseline Analysis  
Demographic, disease, and baseline characteristics will be summarized for each of the 
study groups specified above.  
  
For continuous variables, the analysis will include mean, median, standard deviation, and 
range. For categorical variables, number and percentages of subjects possessing a 
characteristic will be provided.  The data will include, but will not be limited to:  
• 
Subject age;  
• 
Subject gender;  
• 
Subject disease history and relevant concomitant medical conditions.  
  
16.4.3 Protocol Compliance  
The registered study subject population will be described in reference to the study criteria.   

 
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At a minimum, the following tabulations will be provided:  
• 
Number of subjects with violations of inclusion/exclusion criteria;  Number of 
subjects with major on-study deviations or violations.  
  
16.4.4 Primary Endpoint  
The primary endpoint of the study is progression free survival.  
Evaluate Response Rates  
Inclusion of patients into the efficacy analysis data sets is secondary to meeting entrance 
criteria and receiving activated MILs and vaccination. Overall event free survival and 
relapsed rates will be determined.  
Exact methods will be used to compute a 95% confidence interval for the estimated 
proportion of CR and overall response (CR, VGPR, PR, MR). Additional analyses may be 
carried out to examine the significance of baseline prognostic variables.  
  
The Kaplan-Meier method will be used to estimate duration of response. This is defined as  
the date of response to the first date when the patient meets the criteria for 
progression/relapse as defined in Section 13.5, Definitions of Response.  
  
16.4.5 Secondary Endpoint  
Evaluate Toxicity  
Hematopoietic Toxicity:  
The mean and median time to neutrophil and platelet engraftment (absolute neutrophil 
count >500/mm3 and platelet >20,000/mm3) will be summarized among those with 
successful engraftment, along with the rate of primary graft failure.   It should be 
remembered that in the absence of post-transplant G-CSF, we would expect neutrophil 
engraftment to be slightly delayed.  However, should red cell, platelet and neutrophil 
engraftment all show evidence of significant delay in more than 2 patients, the study will 
be placed on hold until a more formal evaluation can be performed.  
  
Infusional Toxicity:  
This will include any adverse appreciated during the infusion of aMILs or felt to be related 
to the infusion.  
  
Evaluate Overall Survival  
Patients will be monitored for overall survival during and following the study. The 
KaplanMeier method will be used to estimate the overall survival as defined in Section 
16.7, Survival Endpoints.  
  
Evaluate Anti-Tumor Immune Responses  
Lymphocytes from the peripheral blood and marrow will be collected and banked at the 
indicated time points during the study for the patients participating in this substudy. 

 
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Tumor-specific assays will be performed in these patients. Results will be summarized and 
correlated with clinical responses.  
  
Correlate Baseline Immune Function with Clinical Outcomes  
Data from the first MILs trial suggests that high endogenous CD8/IFN  and an increased 
percentage of effector as well as effector memory CD8 cells at baseline was associated 
with progressive disease.  These parameters will be examined and will be correlated with 
clinical outcomes.  
  
16.4.6 Results of Activated MILs Manufacturing Process  
T cell activation and expansion will be summarized using descriptive statistics. A table will 
be generated to summarize the activated MILs product profiles for all the patient samples 
processed.  The variables may include: Total cell count,  %CD3+, Total CD3+ Count, 
%CD3+CD4+, %CD3+CD8+, CD4:CD8 Ratio, %Viability, Sterility, Mycoplasma, 
Endotoxin.  
  
  
17. ETHICAL, REGULATORY, AND ADMINISTRATIVE CONSIFERATIONS  
  
17.1  
Informed Consent  
  
The principles of informed consent are described in the Code of Federal Regulations 21 CFR, part 
50.  
  
Patients or their legal guardians must be made aware of the investigational nature of this treatment 
protocol, and have the possible risks, hazards and benefits of the protocol explained to them.  The 
information that is given shall be in a language understandable to the patient.  No informed 
consent, whether oral or written, may include any exculpatory language through which the patient 
is made to waive or appear to waive any of their legal rights, or releases or appears to release the 
Principal Investigator, the institution, or its agents from liability for negligence.  
  
The patient, or legal guardian, must be able to comprehend the informed consent and must sign the 
document prior to registration on study.  The patient will receive a copy of the respective signed 
consent form.  
  
17.2  
Institutional Review  
  
The principles of Institutional Review Board (IRB) are described in the Code of Federal 
Regulations 21 CFR, part 56.  
  
The Principal Investigator will obtain approval for the study from the IRB. The Principal 
Investigator must notify the IRB within 5 days of protocol deviations in emergency situations 
regarding patient safety. The Principal Investigator will be responsible for obtaining annual IRB 

 
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renewal through the duration of the study, or more frequently if required by the IRB.  Copies of 
the Principal Investigator's report and copies of the IRB’s continuance of approval must be 
maintained in the regulatory binder located at the clinical site.  
  
  
17.3  
Tissue Use for Research Purposes  
  
A portion of the MILs bone marrow product and/or final activated MILs product may remain 
unused at the conclusion of the study. Patients will have the option on the study consent form to 
allow this tissue to be used for further research purposes by the Principal Investigator, or to be 
destroyed one year after collection.  
  
In addition, various patient tissues, including peripheral blood and bone marrow will be collected 
from patients during the course of the study expressly for research assays. Baseline bone marrow 
specimens with adequate tumor involvement may be used to develop primers required for a PCR 
based assay for minimal residual tumor in the final activated MILs product. Quantification of 
minimal residual disease will also be performed in bone marrow from patients in complete 
remission for whom primers can be developed. Peripheral blood and tumor containing marrow 
specimens may also be used in immune assays.  
  
Results from assays performed for research purposes will not be provided to patients. At the 
conclusion of the study and follow-up period (some of this tissue may remain unused. Patients will 
have the option in the study consent form to allow this tissue to be used for further research 
purposes or to be destroyed.  
  
  
18. STUDY MONITORING AND DATA COLLECTION  
  
18.1  
Study Monitoring  
  
This is a DSMP Level II study under the SKCCC Data Safety Monitoring Plan (12/6/2012). Data 
Monitoring of this protocol will occur on a regular basis with the frequency dependent on the rate 
of subject accrual and the progress of the study. The protocol will be monitored internally at 
SKCCC by the Principal Investigator and the SKCCC CRO, as well as, by a CRO contracted by 
the Leukemia Lymphoma Society (sponsor of this study) in accordance with SKCCC guidelines. 
The SKCCC Safety Monitoring Committee requires all DSMP Level I-IV study teams to maintain 
a study-specific master adverse event log and a protocol deviation log in Excel format. Templates 
available here: http://cro.onc.jhmi.edu/.  External participating sites are required to maintain 
updated versions of these logs, and submit them to the CC team upon request Trial monitoring at 
Johns Hopkins site will be done through the Safety Monitoring Committee (SMC) at SKCCC. 
Additionally, Leukemia and Lymphoma Society will monitor the study at all sites.  
  
Authorized representatives of the Coordinating Center may visit participating sites to perform 
audits or inspections, including source data verification.  The purpose of these audits or 

 
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inspections is to systematically and independently examine all trial related activities and 
documents to determine whether these activities were conducted and data were recorded, analyzed, 
and accurately reported according to the protocol, Good Clinical Practice (GCP), and any 
applicable regulatory requirements.  
  
18.1.1 Completion of electronic Case Report Forms (eCRFs)  
The Principal Investigator/sub-investigator or his designee will be responsible for 
completing, in a timely manner, a eCRF for each patient who is registered to participate in 
this study.  eCRFs should be completed within 10 days after the date of study visit, or as 
information becomes available.  
  
 Master Adverse Event Log located in the study database will be utilized for AEs/SAEs 
collection. Master Adverse Event Log should be sign in database by the PI at least 
monthly. Master Adverse Event Log can be converted into Excel file if needed.  
  
18.1.2 Cell Therapy Lab (CTL) Cell-Processing Facility  
The Cell Therapy Lab (CTL) is the processing lab for all cellular products (bone marrow, 
vaccines, and adoptive T cell products) administered in the Cancer Center at Johns 
Hopkins.  It operates according to Good Tissue and Manufacturing Practices and is fully 
accredited by FACT.  
  
The results of cell processing using the activated T cell process will be recorded on CRFs 
or in the Batch Production Records at the Johns Hopkins CTL facility.  CRFs and other 
study records will be reviewed in detail by the CRA, or designee, who will have access to 
all patient medical records, laboratory data, and other source documentation to verify the 
accuracy of the data recorded on these documents.  
  
  
18.2  
Maintenance of Study Documentation  
  
It is the responsibility of the Principal Investigator and study staff to maintain a comprehensive 
and centralized filing system of all study-related documentation. This filing system must be 
suitable for inspection at any time by the CRO or Quality Assurance (QA) designee of Johns 
Hopkins and the FDA.  Elements should include:  
• 
Subject Files - containing the completed patient CRFs, supporting source 
documentation, and a signed and dated Informed Consent;  
• 
Regulatory Binder - containing the protocol with all amendments, current Consent 
Form, the Investigator Brochure, clinical site logs, accountability records and 
laboratory documents (e.g., certification, norms/ranges, etc.).  
  
18.2.1 Retention of Records  
The FDA requires that each Principal Investigator retain records for a period of two (2) 
years from the date of FDA approval to market the product for this indication, or two (2) 
years from the date that the Sponsor withdraws the application for approval.  

 
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18.3  
Final Study Report  
  
Upon completion of the study, the Principal Investigator is required to submit a final study 
summary report to the Institution.  This report must also be submitted to the IRB.  
  
18.4  
Investigational Product Labeling and Accountability  
  
18.4.1 Investigational Product Labeling  
The activated MILs product will be labeled with the patient name, history number, unique 
product number and the volume within the bag.  
  
18.4.2 Investigational Product Accountability  
The Investigator should take adequate precautions, including storage of the investigational 
products, to prevent theft or diversion of the products into unauthorized channels of 
distribution.  The processing of each product will be documented on a Batch Production 
Record.  Release test results will be summarized on the Product Specification Report.  
  
  
 

 
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45. Gahrton G. Allogeneic bone marrow transplantation in multiple myeloma. Pathol Biol (Paris) 
1999;47:188-91.  
46. Porrata LF, Gertz MA, Inwards DJ, et al. Early lymphocyte recovery predicts superior 
survival after autologous hematopoietic stem cell transplantation in multiple myeloma or non- 
Hodgkin lymphoma. Blood 2001;98:579-85.  
47. Pierelli L, Perillo A, Ferrandina G, et al. The role of growth factor administration and T-cell 
recovery after peripheral blood progenitor cell transplantation in the treatment of solid tumors: 
results from a randomized comparison of G-CSF and GM-CSF. Transfusion 2001;41:157785.  
48. Porrata LF, Ingle JN, Litzow MR, Geyer S, Markovic SN. Prolonged survival associated with 
early lymphocyte recovery after autologous hematopoietic stem cell transplantation for 
patients with metastatic breast cancer. Bone Marrow Transplant 2001;28:865-71.  
49. Levine BL, Bernstein WB, Connors M, et al. Effects of CD28 costimulation on long-term 
proliferation of CD4+ T cells in the absence of exogenous feeder cells. J Immunol 
1997;159:5921-30.  
50. Levine BL, Cotte J, Small CC, et al. Large-scale production of CD4+ T cells from HIV-
1infected donors after CD3/CD28 costimulation. J Hematother 1998;7:437-48.  
51. Liebowitz DN, Lee KP, June CH. Costimulatory approaches to adoptive immunotherapy. 
Curr Opin Oncol 1998;10:533-41.  
52. Laport GG, Liebowitz DN, Williams SF, et al. Adoptive transfer of CD3/CD28 ex vivo 
costimulated T cells in patients with relapsed/refractory Non-Hodgkin's lymphoma (NHL) 

 
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following high dose chemotherapy (HDC) with CD34-selected peripheral blood stem cell 
(PBSC) support. Blood 2000;96.  
53. Noonan K, Matsui W, Serafini P, et al. Activated marrow-infiltrating lymphocytes effectively 
target plasma cells and their clonogenic precursors. Cancer Res 2005;65:2026-34.  
54. Lahuerta JJ, Mateos MV, Martinez-Lopez J, et al. Influence of pre- and post-transplantation 
responses on outcome of patients with multiple myeloma: sequential improvement of 
response and achievement of complete response are associated with longer survival. J Clin 
Oncol 2008;26:5775-82.  
55. Serafini P, Meckel K, Kelso M, et al. Phosphodiesterase-5 inhibition augments endogenous 
antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 
2006;203:2691-702.  
56. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within 
human colorectal tumors predict clinical outcome. Science 2006;313:1960-4.  
57. Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival 
in epithelial ovarian cancer. N Engl J Med 2003;348:203-13.  
58. Zhan F, Hardin J, Kordsmeier B, et al. Global gene expression profiling of multiple myeloma, 
monoclonal gammopathy of undetermined significance, and normal bone marrow plasma 
cells. Blood 2002;99:1745-57.  
59. Shaughnessy JD, Jr., Haessler J, van Rhee F, et al. Testing standard and genetic parameters in 
220 patients with multiple myeloma with complete data sets: superiority of molecular 
genetics. Br J Haematol 2007;137:530-6.  
60. Kumar SK, Uno H, Jacobus SJ, et al. Impact of gene expression profiling-based risk 
stratification in patients with myeloma receiving initial therapy with lenalidomide and 
dexamethasone. Blood 2011;118:4359-62.  
61. Terpos E, Katodritou E, Roussou M, et al. High serum lactate dehydrogenase adds prognostic 
value to the international myeloma staging system even in the era of novel agents. Eur J 
Haematol 2010;85:114-9.  
62. Ravi R, Fuchs EJ, Jain A, et al. Resistance of cancers to immunologic cytotoxicity and 
adoptive immunotherapy via X-linked inhibitor of apoptosis protein expression and coexisting 
defects in mitochondrial death signaling. Cancer Res 2006;66:1730-9.  
63. LeBlanc R, Hideshima T, Catley LP, et al. Immunomodulatory drug costimulates T cells via 
the B7-CD28 pathway. Blood 2004;103:1787-90.  
64. Chang DH, Liu N, Klimek V, et al. Enhancement of ligand-dependent activation of human 
natural killer T cells by lenalidomide: therapeutic implications. Blood 2006;108:618-21.  
65. Neuber B, Herth I, Tolliver C, et al. Lenalidomide enhances antigen-specific activity and 
decreases CD45RA expression of T cells from patients with multiple myeloma. J Immunol 
2011;187:1047-56.  
66. Boon T, Old LJ. Cancer Tumor antigens. Curr Opin Immunol 1997;9:681-3.  
67. Noonan K, Rudraraju L, Ferguson A, et al. Lenalidomide-induced immunomodulation in 
multiple myeloma: impact on vaccines and antitumor responses. Clin Cancer Res 
2012;18:1426-34.  
68. Shpall EJ, LeMaistre CF, Holland K, et al. A prospective randomized trial of buffy coat 
versus CD34-selected autologous bone marrow support in high-risk breast cancer patients 
receiving high-dose chemotherapy. Blood 1997;90:4313-20.  

 
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69. Davis J, Rowley SD, Santos GW. Toxicity of autologous bone marrow graft infusion. Prog 
Clin Biol Res 1990;333:531-40.  
70. Schulman CC, Shen W, Stothard DR, Schmitt H. Integrated analysis examining first-dose 
success, success by dose, and maintenance of success among men taking tadalafil for erectile 
dysfunction. Urology 2004;64:783-8.  
71. Kloner RA, Jackson G, Hutter AM, et al. Cardiovascular safety update of Tadalafil: 
retrospective analysis of data from placebo-controlled and open-label clinical trials of 
Tadalafil with as needed, three times-per-week or once-a-day dosing. Am J Cardiol 
2006;97:1778-84.  
72. Danesh-Meyer HV, Levin LA. Erectile dysfunction drugs and risk of anterior ischaemic optic 
neuropathy: casual or causal association? Br J Ophthalmol 2007;91:1551-5.  
73. Mitsuyasu RT, Anton PA, Deeks SG, et al. Prolonged survival and tissue trafficking 
following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells 
in human immunodeficiency virus-infected subjects. Blood 2000;96:785-93.  
74. Walker RE, Bechtel CM, Natarajan V, et al. Long-term in vivo survival of receptor-modified 
syngeneic T cells in patients with human immunodeficiency virus infection. Blood 
2000;96:467-74.  
75. Levine BL, Bernstein WB, Aronson NE, et al. Adoptive transfer of costimulated CD4+ T 
cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV 
infection. Nat Med 2002;8:47-53.  
76. Deeks SG, Wagner B, Anton PA, et al. A phase II randomized study of HIV-specific T-cell 
gene therapy in subjects with undetectable plasma viremia on combination antiretroviral 
therapy. Mol Ther 2002;5:788-97.  
77. Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in 
patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell 
transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and 
Marrow Transplant. Br J Haematol 1998;102:1115-23.  
78. Shaughnessy JD, Jr., Zhan F, Burington BE, et al. A validated gene expression model of 
highrisk multiple myeloma is defined by deregulated expression of genes mapping to 
chromosome 1. Blood 2007;109:2276-84.  
79. Susarla V, Vanryzin J. Nonparametric Bayesian Estimation of Survival Curves from 
Incomplete Observations. J Am Stat Assoc 1976;71:897-902.  
80. Kuo L, Smith AFM, Maceachern S, West M. Bayesian Computations in Survival Models Via 
the Gibbs Sampler. Nato Adv Sci I E-App 1992;211:11-24.  
81. Rosner GL. Bayesian monitoring of clinical trials with failure-time endpoints. Biometrics 
2005;61:239-45.  
  
  
  
  
  
  

 
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20. APPENDICES  
  
  
20.1  
APPENDIX A  
DIAGNOSTIC CRITERIA FOR MULTIPLE MYELOMA  
  
Major criteria:  
1. Plasmacytomas on tissue biopsy;  
2. Bone marrow plasmacytosis (>30% plasma cells);  
3. Monoclonal immunoglobulin spike on serum electrophoresis IgG >3.5 g/dL or IgA >2.0 g/dL; 
kappa or lambda light chain excretion > 1 g/day on 24 hour urine protein electrophoresis.  
  
Minor criteria:  
1. Bone marrow plasmacytosis (10 to 30% plasma cells);  
2. Monoclonal immunoglobulin present but of lesser magnitude than given under major criteria; 
3. Lytic bone lesions;  
4. Normal IgM <50 mg/dL, IgA <100 mg/dL or IgG <600 mg/dL.  
  
Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:  
1. Any two of the major criteria;  
2. Major criterion 1 plus minor criterion b, c, or d; 3. Major criterion 3 
plus minor criterion a or c; 4. Minor criterion a, b and c or a, b and d.  
  
  
Reference: Durie, B. G. 1986. Staging and kinetics of multiple myeloma. Semin.Oncol. 13[3], 
300- 
309.  
  
  
  
  
  
  

 
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20.2  APPENDIX B       DURIE-SALMON STAGING OF MULTIPLE MYELOMA  
  
Stage I  
  
All of the following must be present:  
1. Hemoglobin > 10.5 g/dL or hematocrit > 32%;  
2. Serum calcium level normal;  
3. Low serum myeloma protein production rates as evidenced by all of the following:  
• 
IgG peak < 5g/dL;  
• 
IgA peak < 3g/dL;  
• 
Bence Jones protein < 4g/24 h.  
4. No bone lesions.  
  
Stage II  
  
All patients who do not meet criteria for Stage I or III are considered to be Stage II.  
  
Stage III  
  
One of the following abnormalities must be present:  
1. Hemoglobin < 8.5 g/dL, hematocrit < 25%;  
2. Serum calcium > 12 mg/dL;  
3. Very high serum or urine myeloma protein production rates as evidenced by one or more of the 
following:  
• 
IgG peak > 7g/dL;  
• 
IgA peak > 5g/dL;  
• 
Bence Jones protein > 12 g/24 h;  
4. 3 lytic bone lesion on bone survey (bone scan not acceptable).  
  
Sub-classification  
  

 
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A: Serum creatinine < 2.0 mg/dL  
B: Serum creatinine > 2.0 mg/dL  
  
  
Adapted from: Durie BGM, Salmon SE. A clinical staging system for multiple myeloma.  
Correlation of measured myeloma cell mass with presenting clinical features, response to 
treatment and survival. Cancer 1975;36:842-54.  
  
  
  
  
  
  
  
  
20.3  
APPENDIX C  
ECOG PERFORMANCE STATUS  
  
  
Grade  
ECOG  
0  
Fully active, able to carry on all pre-disease performance without 
restriction  
1  
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light house 
work, office work  
2  
Ambulatory and capable of all self care but unable to carry out any 
work activities. Up and about more than 50% of waking hours  
3  
Capable of only limited self care, confined to bed or chair more 
than 50% of waking hours  
4  
Completely disabled. Cannot carry on any self care. Totally 
confined to bed or chair   
5  
Dead  
  
AS PUBLISHED IN AM. J. CLIN. ONCOL. (CCT) 5:649-655, 1982  
  
  
  
  
  
  
  
  

 
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20.4  
APPENDIX D. NEW YORK HEART ASSOCIATION CLASSIFICATION OF  
 
  
  
PATIENTS WITH DISEASES OF THE HEART  
  
  
Functional Classification:  
Class l  
 
 
 
Class ll  
 
 
 
Class lll  
 
 
 
Class lV  
Patient with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.  
 
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.  
 
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain.  
 
Patients with cardiac disease resulting in inability to carry on any physical  
activity without discomfort. Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased.  
(New York Heart Association Criteria Committee: Diseases of the Heart and Blood Vessels: Nomenclature and  
Criteria for Diagnosis, 6th ed. Boston, Little, Brown, & Co. 1964)  
  
  

 
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APPENDIX E  
PATIENT STUDY CALENDAR FOR TRANSPLANT PATIENTS  
  
   
 
 
 
 
 
 
 
 
   
Therapy  
  
Follow-
u 
p  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent  
X  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
Inclusion/Exclusion criteria  
X  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
Clinical Assessment1  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
X  
X  
  
  
Bone marrow examination2  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
X  
X  
  
X  
PRS GEP-70  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
  
X  
Skeletal survey/PET3  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
  
  
Beta2-microglobulin  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
  
  
CBC w/diff, platelets  
X  
X  
  
  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
Serum Chemistries4  
X  
  
  
  
  
  
  
  
  
  
X  
  
  
X  
X  
X  
X  
X  
X  
X  
  
X  
HTLV-1, 2, HIV-1, 2  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
M-protein, serum5  
  
X  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
X  
X  
X  
M-protein, urine6  
  
X  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
X  
X  
X  
Quantitative immunoglobulins  
  
X  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
X  
X  
X  
Tadalafil7  
  
  
  
  
  
  
  
  
  
X  
X  
X  
X  
X  
X  
  
  
  
  
  
  
  
Study Registration  
Eligibility 
Marrow Harvest 
Baseline 
Stem Cell Mobilization  
Stem  Cell Collection 
Day  
- 
2 
(Melphalan 
) 
Day  
- 
1 
(Melphalan 
Day 0 (Stem Cell  
Infusion) 
Day 1  Day 2  
Day 3   aMILs  
Infusion 
10 
Day 4   
aMILs  
Infusion 
10 
Day 5 Day 7 Day  
11 
Day  
14 
Day 28 (±2 days) 
15 
Day 60 (±7 days) 
15 
Day 180 (± 30 days) 
Day 360 (± 30 days) 
Quarterly until  
disease progression   
Off Study 
14 
16 ,  

 
 
Lenalidomide8  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
X  
X  
  
Study Blood 9  
  
X  
  
  
  
  
  
  
  
  
Xa  
  
  
X  
  
X  
X  
X  
X  
X  
  
  
Disease Response/Progression11  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
X  
X  
X  
Survival Status12  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
X  
X  
X  
X  
Current meds  
X  
  
  
X  
X  
  
  
  
X  
  
  
  
  
  
X  
X  
X  
X  
X  
X  
X  
  
Adverse events13  
  
X  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
  
 
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 APPENDIX E  
PATIENT STUDY CALENDAR FOR TRANSPLANT PATIENTS (CONTINUED)  
  
  
 
1 
Clinical assessment: history, review of systems, weight, vital signs, physical exam  
2 
Collect 20ml of marrow in a heparinized 60 ml syringe For Hopkins patients on the immune sub-study: 100ml of blood will be collected in the heparinized syringes  (Hopkins only) instead of the 20ml and 20 ml of aspirate will be collected in a 
heparinized syringe instead of 15 ml in a green top tube..  
3 
Skeletal survey/PET scan is optional but recommended for patients with extensive bone involvement before transplantation and on Day 360  
4 
Chemistries: sodium, potassium, chloride, bicarbonate, BUN, creatinine, calcium, AST, ALT, alk. phosph., total bili, albumin  
5 
M-protein, serum: serum protein electropheresis & immunofixation, Freelite (sensitive assay for kappa and lambda light chains)  
6 
M-protein, urine: 24 hour urine collection for total protein, protein electropheresis & immunofixation  should be done at marrow harvest. For patients that do not have Bence-Jones proteinuria, 24-hour urine will only be collected to document 
complete remission.  
7 
Tadalafil will be given from days 2-11  
8 
Lenalidomide: start at 60 days as clinically indicated at 5mg 21 out of 28 days. Other dose adjustments per clinical practice a 
9 
100ml of blood will be collected in heparinized syringes, and an additional tiger top tube.  Days1, 7, 11 and 14 should only be a tiger top tube and 2 EDTA (lavender tubes).. Only for patients participating on the substudy at Hopkins o 
10 For aMILs infusion, patients must have T<38.5 C and room air O2 saturation of >90%. If T cell infusion is delayed, perform Day 7 evaluations on second day following T cell infusion  
11 Disease progression will be captured at every visit for the first year and quarterly thereafter  
12 Survival and disease status will be follow-up for 5 years from Day 0 of transplant  
13 Captured adverse events are those felt to be in any way related to the infusion of aMILs and/or tadalafil.  Standard stem cell transplant toxicities will not be captured  
14 Attempts should be made for annual bone marrow biopsies.  Biopsy done at relapse needs to have the MyPRS repe as well as Myeloma labs, CBC w/diff, Platelets, Serum Chemistries  
15 For Clinical Assessment, Disease Response/Progression and Survival Status Assessment, Current meds and AEs collection allowed window is ±14 days   
16 Upon relapse, the visit documenting relapse can serve as the end of study visit  
  
  

 
 
 
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20.5 
APPENDIX F  
SKCCC DATA AND SAFETY MONITORING PLAN  
  
http://cro.onc.jhmi.edu/pageData/dsmp.pdf  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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20.6 
APPENDIX G:  STANDARD EXPECTED TRANSPLANT RELATED  
TOXICITIES  
   
Toxicity  
Up to Grade  
 
Investigations  
 
White blood cell decreased  
4  
Anemia  
3  
Platelet count decreased  
4  
Alanine aminotransferase increased  
3  
Aspartate aminotransferase increased  
3  
Blood and lymphatic system disorders  
 
Febrile neutropenia  
3  
Metabolism and nutrition disorders  
 
Anorexia  
3  
Hypo- or hypercalcemia  
4  
Hypo- or hyperkalemia  
4  
Hypo- or hyperphosphatemia  
4  
Hypo- or hypermagnesemia  
4  
Hypo- or hypernatremia  
4  
Skin and subcutaneous tissue disorders  
 
Rash maculo-papular  
2  
Alopecia  
2  
Gastrointestinal disorders  
 
Nausea  
3  
Vomiting  
3  
Oral mucositis  
3  
Diarrhea  
3  
Renal and urinary disorders  
 
Acute kidney injury  
3  
Infections and infestations  
 
Lung infection  
3  
Other infections and infestations  
3  
Respiratory, thoracic and mediastinal disorders  
 

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Pulmonary edema  
3  
General disorders  
 
Fatigue  
3  
Musculoskeletal and connective tissue disorders  
 
Muscle weakness  
3  
Nervous system disorders  
 
Seizure  
2  
Reproductive system disorders  
 
Irregular menstruation  
3  
  
  
20.7 
APPENDIX H:   NCI CTCAE V4.0  
  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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20.8 APPENDIX I. A Randomized Phase II Study of Autologous Stem Cell 
Transplantation with Tadalafil and Lenalidomide Maintenance with or 
without Activated Marrow Infiltrating Lymphocytes (MILs) in High Risk 
Myeloma   
  
Tadalafil Diary  
  
Site Number  
  
Patient’s Initials    
Patient’s Number  
  
Patient’s MRN  
  
  
  
Instructions for patient:  
Please indicate the date and time you took Tadalafil 10 mg PO. If dose is missed please add 
comments. Please sign, date and return at the end of the treatment.  
  
Study Day  
Date  
Time  
Comments  
Day +2  
  
:  
  
Day +3  
  
:  
  
Day +4  
  
:  
  

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Day +5  
  
:  
  
Day +6  
  
:  
  
Day +7  
  
:  
  
Day +8  
  
:  
  
Day +9  
  
:  
  
Day +10  
  
:  
  
Day +11  
  
:  
  
  
  
Research Nurse’s Comments (if Tadalafil doses were missed, treatment was interrupted or 
discontinued, please provide all related information): 
___________________________________  
_____________________________________________________________________________
_  
  
  
Research Nurse Signature: ____________________         
Date: ___________________         
Patient Signature: ___________________________                        Date: ___________________  

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20.9  Appendix J. Adverse Event assessment Chart  
  
A Randomized Phase II Study of Autologous Stem Cell  
Transplantation with Tadalafil and Lenalidomide  
Maintenance with or without Activated Marrow Infiltrating 
Lymphocytes (MILs) in High Risk Myeloma.   
  
  
Adverse Event Assessment Chart  
  
  
Site Number  
  
Patient’s Initials  
  
Patient’s Number  
  
Patient’s MRN  
  
  
Source documentation, including all available clinic notes, is reviewed from the time of bone 
marrow collections of MILs through Day 360/disease progression.  All toxicities, abnormal 
laboratory results and/or potential adverse events experienced by accrued subjects during this 
time are assessed by the PI. These assessments are to occur for each of the following time 
periods and confirmed by the PI based on attribution to study intervention(s).  
  
• 
Only Adverse Events considered in any way related to the either infusion of aMILs or 
Tadalafil are recorded on the AE Log.   
• 
Only clinically significant laboratory results considered in any way related to either 
aMILs or Tadalafil, and not at all related to bone marrow transplant, were also recorded 
on the AE Log.  
• 
Serious Adverse Events are defined per protocol section 15.1.2 and this assessment chart 
does not pertain to those events (SAEs are individually assessed by PI on the AE Log).  
  
  
  
Study Visits  
PI signature  
Assessment Date  
Comments  
BM Harvest – Day 1    
  
  
Day 2 – Day 14  
  
  
  
Day 14 – Day 28  
  
  
  

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Day 28 – Day 60  
  
  
  
Day 60 – Day 180  
  
  
  
Day 180 – Day 360  
  
  
  
  
  
20.10   Appendix K:  Revised Statistical Plan  
  
Overview  
  
The following describes a plan to analyze the data from study J1343 (“A Randomized Phase II 
Study of Autologous Stem Cell Transplantation with Tadalafil and Lenalidomide Maintenance 
with or without Activated Marrow Infiltrating Lymphocytes (MILs) in High Risk Myeloma”) in light 
of reported lenalidomide dosing deviations. Briefly, these deviations occurred when on-study 
patients received doses of lenalidomide greater than 10 mg per day prior to disease progression 
during the time such higher doses were not allowed by the protocol.   
  
 This study’s original design sought to evaluate the possible ability of activated marrow 
infiltrating lymphocytes (aMILs) to delay disease progression after autologous stem-cell 
transplant (ASCT). The study’s primary endpoint is progression-free survival, defined in the 
protocol as “the time from ASCT to documented progression/relapse, death from any cause or 
last follow-up.” The higher dose  of  lenalidomide prior to progression could serve to delay 
disease progression. Because these deviations occurred predominantly within one treatment 
arm (i.e., those receiving aMILs), the two treatment groups in J1343 did not receive the same 
care in all respects except for aMILs. A higher percentage of one group than the other appears to 
have received higher doses of lenalidomide treatment than the protocol prescribed, and these 
higher doses could affect the study’s primary endpoint.  
  
These dosing violations have compromised the randomization; therefore, we will not perform 
comparative analyses of efficacy. There is no simple way to salvage the analysis of a 
randomized clinical trial to reduce bias completely once the randomization has been 
compromised in a manner that affects the primary endpoint as in this case. Any straightforward 
comparison of the outcomes in the two treatment groups in our study will provide a biased 
estimate of the effect of adding aMILs to ASCT, keeping all other aspects of patient care the 
same.    
  
Therefore, our primary analysis will focus on safety and feasibility of using MILs to treat 
patients with high-risk myeloma (as defined in the protocol) in the context of a multi-center 
study. There will not be a comparison of efficacy (progression-free survival) between the two 
treatment groups.  Instead, the primary endpoint will be feasibility, defined below.  A key 
secondary endpoint will be safety, which will be evaluated in the interval between transplant and 
60 days after transplant.    
  

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Analysis Populations  
The last subject on trial reached 60 days on May 3, 2019 and thus the data collection for the 
primary and key secondary endpoint was complete on that date.  No new data were collected 
after that date. We will consider May 3, 2019 as the last possible date for follow-up times 
relating to time-to-event data (e.g., overall survival and progression-free survival).   
  
Safety population  
The safety population consists of all registered subjects who underwent MILs harvest. Any 
patient in the MILs arm who does not receive MILs will be so identified but will remain in that 
arm for analysis in order to provide an unbiased comparison to the control arm for safety.  
  
Feasibility  
Feasibility is defined as the ability to harvest, expand, and infuse the MILs product within 120 
days, which is a typical timeframe between BMT referral and stem cell infusion.  Based on our 
experience using MILs, we expect that MILs will be feasible for 90% of patients. We will 
declare the use of MILs not to be feasible if there is high probability that no more than 75% of 
patients can feasibly receive MILs. A priori our best guess is that MILs will be feasible for 90% 
of patients, and we think there is only 5% probability that the proportion for whom it is feasible 
is 75% or less. This assessment corresponds to a prior beta (23, 3.4) distribution for the 
proportion of patients for whom MILs is feasible. After treating 60 patients with MILs, we will 
declare MILs not feasible if we can only harvest, expand, and deliver MILs to 40 or fewer 
patients. If we are only successful with 40 of 60 patients, the probability that MILs is feasible for 
at most 75% of patients is 0.46 (i.e., less than even odds in favor of feasibility).  
  
Safety Analyses  
Safety and tolerability will be assessed, where applicable, by incidence and grade for adverse 
events (AEs) and deaths.  
  
Adverse events (AEs)  
  
The number and percentage of patients experiencing AEs of grade three or higher will be 
summarized.  The incidence of AEs will be presented by treatment arm for those occurring from 
MILs harvest through 60 days after transplant. A patient who experiences repeated episodes of 
the same AE will be counted only once, with the highest severity grade used in tabulations of 
incidence.  
  
A summary of the number of deaths, cause of death (progressive disease vs. other), and time of 
death (from the date of the MILs harvest) will be provided.  
  

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Efficacy Analysis  
Efficacy analyses will be conducted on the population of all patients randomized to the MILs 
arm.    
  
Progression-Free Survival (PFS) and Overall Survival (OS)  
  
PFS time will be calculated from the time of randomization (in months) until disease 
progression, death due to any cause, or protocol deviation with respect to lenalidomide dosing 
(above 10mg), whichever occurs first. Subjects still at risk for one of the PFS events at the time 
of the analysis will be censored at the date last known to be at risk for one of these events. OS 
time will be calculated from time of randomization until death due to any cause. The last 
possible follow-up date for the study is May 3, 2019. Patients whose follow-up data indicate that 
they were alive without progressive disease (PFS) or known to be alive after having progressed  
(OS) at the time of last contact will be censored at the date of last contact in the analyses. If the 
patient’s last contact occurs after May 3, 2019, then the patient’s follow-up time will be 
censored on May 3, 2019.   
  
Any presentation of the data will include a description of the protocol violations (dosing above 
10mg of lenalidomide per day), the number of patients affected, and our assigning the timing of 
each violation as the occurrence of an event in the analysis of progression-free survival.  
  
ORR  
Best response on study will be reported according to IMWG criteria.  The associated 95% CI 
will be estimated using the Clopper Pearson method (Clopper and Pearson, 1934).