Conditions: Multiple Myeloma
Keywords: Lenalidomide M-spike negative GVax GM-CSF secreting myeloma vaccine MRD positive
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
This study seeks to determine whether addition of an allogeneic myeloma vaccine can augment clinical responses to lenalidomide in patients with near complete remission (nCR), or complete remission (CR) leading to a significant improvement in progression-free survival.This main objective of this study is to compare the 2-year progression free survival of patients with multiple myeloma in CR or nCR, treated with lenalidomide plus an allogeneic myeloma vaccine in combination with lenalidomide (with or without Prevnar vaccine) or versus placebo in combination with lenalidomide (control arm).

Detailed description:
This is a single institution, three- arm, randomized controlled, Phase II study examining the clinical efficacy of an allogeneic GM-CSF secreting myeloma vaccine in combination with lenalidomide (with or without Prevnar) compared to lenalidomide and placebo (control arm).

Patients enrolled in the study must have two disease measurements (including the last one) consistent with a near complete remission (M-spike negative with persistence of immunofixation), or complete remission (M-spike negative, negative immunofixation, and \<5% clonal plasma cells on bone marrow) per criteria for response in a 3 month period. All patients must be minimal residual disease (MRD) positive by NGS sequencing at enrollment.

Prior to enrollment, patients will have been treated with a lenalidomide containing regimen for a minimum of 6 cycles. All patients will continue on a standard dose of lenalidomide as a single agent until progression, or treatment limiting toxicity, following enrollment.

Patients will be randomized to receive either an allogeneic myeloma vaccine and Prevnar vaccine in combination with lenalidomide, or allogeneic myeloma vaccine without Prevnar vaccine in combination with lenalidomide, or lenalidomide in combination with placebo. Patients will receive allogeneic myeloma vaccine or placebo injections on day 14 (+/-3 days) of cycles 1, 2, 3 and 6 from enrollment, and then annually thereafter for up to 3 years. If assigned to allogeneic myeloma vaccine plus Prevnar vaccine arm, Prevnar-13 will be administered with each allogeneic myeloma vaccine. If assigned to either of the two arms that do not include Prevnar, then patients will receive a placebo in lieu of Prevnar on the same schedule. All patients will be followed for a minimum of 3 years.

Arms:
arm 1: Patients will continue on a standard dose of lenalidomide as a single agent until progression, or treatment limiting toxicity, following enrollment.

Patients assigned to vaccine therapy will receive injections on day 14 (+/-3 days) of cycles 1, 2, 3 and 6 from enrollment, and then annually thereafter. Prevnar vaccine will be administered with the GM-CSF vaccine administration. arm 2: Patients will continue on a standard dose of lenalidomide as a single agent until progression, or treatment limiting toxicity, following enrollment. Patients will also get placebo GM-CSF vaccine and placebo prevnar13. Placebo will be saline. arm 3: Patients will continue on a standard dose of lenalidomide as a single agent until progression, or treatment limiting toxicity, following enrollment.

Patients assigned to vaccine therapy will receive injections on day 14 (+/-3 days) of cycles 1, 2, 3 and 6 from enrollment, and then annually thereafter. Patients will also be administered a placebo prevnar13 vaccination. Placebo will be saline.

Interventions: intervention 1: GM-CSF vaccine intervention 2: Lenalidomide intervention 3: Prevnar13 intervention 4: Placebo Prevnar13 intervention 5: Placebo GM-CSF Vaccine
Intervention descriptions: intervention 1: Each vaccination will consist of three total intra-dermal injections, on day 14 of cycles 1, 2, 3, 6 and annually for a minimum of 36 months in the right and left anterior upper thighs, and one in the non-dominant upper arm (unless contraindicated). In the event that the specified limb is contraindicated, the dominant arm may be used. Vaccine injection sites shall be at least 5 cm at needle entry from the nearest neighbor. The approximate volume of each vaccination injection is approximately 0.7-0.8ml. intervention 2: Patients will be continued on the same dose of lenalidomide as they were prior to being enrolled in the study. Doses of lenalidomide for investigation can vary from 5-25 mg/day, orally on days 1 - 21 followed by 7 days rest (28 day cycle). intervention 3: Prevnar will be administered at the same time points as the GM-CSF vaccine (day 14 of cycles 1, 2, 3, 6 and annually for a minimum of 36 months), but on the opposite arm from GM-CSF vaccine. intervention 4: Saline will be used for placebo. Placebo prevnar will be administered at the same time points as the GM-CSF vaccine or Placebo GM-CSF Vaccine (day 14 of cycles 1, 2, 3, 6 and annually for a minimum of 36 months), but on the opposite arm from GM-CSF vaccine or placebo GM-CSF vaccine. intervention 5: Saline will be used for placebo. Each placebo vaccine will consist of three total intra-dermal injections on day 14 of cycles 1, 2, 3, 6 and annually for a minimum of 36 months in the right and left anterior upper thighs, and one in the non-dominant upper arm (unless contraindicated). In the event that the specified limb is contraindicated, the dominant arm may be used. Placebo injection sites shall be at least 5 cm at needle entry from the nearest neighbor. The approximate volume of each injection is approximately 0.7-0.8ml.

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version: October 6, 2021 
CC-5013
1 
A Randomized, Double-blind, Placebo-Controlled Phase II Trial of an 
Allogeneic Myeloma GM-CSF Vaccine With Lenalidomide in Multiple 
Myeloma Patients in Complete or Near Complete Remission 
P.I.
Co-Investigators: 
IND Sponsor: 
Research Nurse: 
Data Manager: 
Regulatory: 
Statisticians: 
Version: 
Protocol #: 
Syed Abbas Ali, MD 
Carol Ann Huff, MD 
Philip Imus, MD 
Syed Abbas Ali, MD 
Adrienne Holmes, RN 
Katherine Sawyer 
M. Amanda Stevens, MD CCRA
Elizabeth A Sugar 
Joshua Betz 
October 6, 2021 
J16118 
NCT03376477
Celgene tracking #:  RV-CL-MM-PI-005749 


Protocol Version: October 6, 2021 
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2 
 
 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Principal Investigator: 
Signature of Investigator 
Date 
Syed Abbas Ali, M.D.  
Printed Name of Investigator 
By my signature, I agree to personally supervise the conduct of 
this study and to ensure its conduct in compliance with the 
protocol, informed consent, IRB/EC procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the 
United States Code of Federal Regulations or local regulations 


Protocol Version: October 6, 2021 
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3 
 
 
 
 
 
 
 
 
STUDY PERSONNEL 
 
Supporter: 
Celgene 
Corporation 86 
Morris Ave, 
Summit, NJ 
07901 
1-800-742-3107 
Study Location: 
Johns Hopkins University 
Principal 
Investigator/Sponsor 
Syed Abbas Ali, 
M.D. 1650 Orleans 
St., Rm. 242 
Study Coordinator: 
Katherine Sawyer 
Adrienne Holmes, RN 
Research Nurse: 
Other Investigators: 
Carol Ann Huff, MD 
Philip Imus, MD 


Protocol Version: October 6, 2021 
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4 
 
 
Contents 
Table of Contents 
Title Page ................................................................................................................................................................................ 1 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ......................................................................................................... 2 
1. PROTOCOL SYNOPSIS ............................................................................................................................................ 7 
STUDY OBJECTIVES AND ENDPOINTS: ................................................................................................................. 8 
Secondary ........................................................................................................................................................................ 8 
2. SCHEDULE OF STUDY ASSESSMENTS ............................................................................................................. 11 
3. GLOSSARY OF ABBREVIATIONS ...................................................................................................................... 14 
4 
BACKGROUND AND RATIONALE ..................................................................................................................... 17 
4.1 
Multiple Myeloma: .......................................................................................................................................... 17 
4.3 Lenalidomide augments responses to Prevnar vaccination .................................................................................. 19 
4.4 
Allogeneic Myeloma GVAX with Lenalidomide in Near Complete Remission Enhances Progression Free 
Survival...................................................................................................................................................................... 21 
4.5 K562/GMCSF vaccine: ........................................................................................................................................ 23 
4.6 K562/GM-CSF as a universal GM-CSF producing Bystander Cell: ................................................................... 24 
4.7 Allogeneic myeloma vaccine preparation ............................................................................................................ 24 
4.8 Rationale for Allogeneic Myeloma Vaccine ........................................................................................................ 24 
5 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................................ 26 
5.1    Study objectives: ........................................................................................................................................................ 26 
Primary .......................................................................................................................................................................... 26 
Secondary ...................................................................................................................................................................... 26 
6 
INVESTIGATIONAL PLAN ................................................................................................................................... 27 
6.1 Overall design ....................................................................................................................................................... 27 
SCHEMA....................................................................................................................................................................... 28 
6.1.1 Registration on Study and Randomization ................................................................................................. 29 
6.1.2 Minimal Residual Disease Testing ............................................................................................................. 29 
6.2 Administration of Allogeneic Myeloma Vaccine or Placebo .............................................................................. 30 
6.2.1 Administration Parameters ......................................................................................................................... 31 
6.2.2 Vaccine Formulation................................................................................................................................... 31 
6.2.3 Vaccine Administration .............................................................................................................................. 31 
6.2.4 Potential Vaccine Toxicities ....................................................................................................................... 32 
6.2.5 Availibility .................................................................................................................................................. 33 
6.3 PREVNAR-13 ................................................................................................................................................... 33 
6.4 LENALIDOMIDE................................................................................................................................................ 34 
6.4.1 Other names: Revlimid ® ........................................................................................................................... 34 
6.4.4 Mode of action ............................................................................................................................................ 35 
6.4.5 Adverse effects ............................................................................................................................................ 35 
6.4.6 Storage: ....................................................................................................................................................... 36 


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     6.4.7 Prescribing Lenalidomide ................................................................................................................................ 36 
6.4.8.2  Pharmacokinetic Parameters ............................................................................................................................ 36 
Metabolism and Excretion ............................................................................................................................................. 36 
6.4.9 Supplier(s) ................................................................................................................................................... 37 
6.4.10 
Packaging .................................................................................................................................................. 37 
6.4.11 
Dosage forms ............................................................................................................................................ 37 
6.4.12 
Dosing regimen and dose reductions ........................................................................................................ 37 
6.4.13 
Dose adjustments/modifications can be made if needed based on toxicity .................................................... 38 
6.4.14 
Concomitant therapy ................................................................................................................................. 38 
6.4.15 
Prohibited Concomitant Therapy ............................................................................................................. 38 
6.4.16 
Anticoagulation Considerations ............................................................................................................... 39 
6.4.17 
General Concomitant Medication and Supportive Care Guidelines ........................................................ 39 
6.5 Duration of Follow-up .......................................................................................................................................... 39 
6.6 Dose delay/Dose modifications ............................................................................................................................ 39 
7 
SCREENING AND ELIGIBILITY........................................................................................................................... 41 
7.1 Inclusion Criteria: ............................................................................................................................................... 42 
7.2 Exclusion Criteria: .............................................................................................................................................. 43 
7.3 Visit Schedule And Assessments ....................................................................................................................... 44 
7.4 Follow-Up........................................................................................................................................................... 44 
7.5 Serious Adverse Event (SAE) Definition ........................................................................................................... 44 
7.6 Adverse Drug Reaction Reporting ..................................................................................................................... 44 
7.6.1 Adverse events not listed in the NCI Common Terminology Criteria ....................................................... 46 
7.6.2 Relationship of the Adverse Event to the Investigational Drug ................................................................. 46 
7.7 Expedited Reporting By Investigator To Celgene ............................................................................................... 47 
7.9 Celgene Drug Safety Contact Information ........................................................................................................... 48 
7.10 Investigator Reporting Responsibilities ............................................................................................................. 48 
7.11 Report Of Adverse Events To The Institutional Review Board ........................................................................ 49 
7.12 Investigator Reporting To The FDA .................................................................................................................. 49 
7.13 Adverse Event Updates/Ind Safety Reports ....................................................................................................... 49 
8 
RESPONSE CRITERIA............................................................................................................................................ 50 
9 
PROTOCOL AMENDMENTS/DEVIATIONS ....................................................................................................... 50 
9.1 Protocol amendments............................................................................................................................................ 50 
9.2 Protocol deviations ............................................................................................................................................... 51 
10 DATA MANAGEMENT .......................................................................................................................................... 51 
10.1 Analyses and Reporting ...................................................................................................................................... 51 
10.2 Study monitoring and Auditing .......................................................................................................................... 51 
10.2.1 
Investigator Responsibilities..................................................................................................................... 51 
10.2.2 
Data Safety Monitoring Board (DSMB) .................................................................................................. 52 
11 BIOSTASTICAL ANALYSIS .................................................................................................................................. 52 
11.1 Sample Size Considerations ............................................................................................................................... 52 
11.2 Statistical Analyses ............................................................................................................................................. 53 


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 11.3    Toxicity Stopping Guidelines .................................................................................................................................. 54 
12 REGULATORY CONSIDERATIONS .................................................................................................................... 56 
12.1 Institutional Review Board/Ethics Committeeapproval .................................................................................... 56 
12.2 Informed consent ................................................................................................................................................ 57 
12.3 Subject confidentiality ........................................................................................................................................ 57 
12.4 Study records requirements ................................................................................................................................ 57 
12.5 Premature discontinuation of study .................................................................................................................... 57 
13 RESPONSIBILITIES ................................................................................................................................................ 58 
13.1 Primary Investigator ........................................................................................................................................... 58 
14 PATIENTS WITH PROGRESSIVE DISEASE ON THE CONTROL ARM ......................................................... 58 
APPENDICES...................................................................................................................................................................... 59 
APPENDIX 2: TUMOR CLASSIFICATION ..................................................................................................................... 59 
APPENDIX 3: CRITERIA FOR DISEASE EVALUATION ............................................................................................. 61 
APPENDIX 4: NCI CTC VERSION 4.03........................................................................................................................... 63 
APPENDIX 5: RISKS OF FETAL EXPOSURE, PREGNANCY TESTING GUIDELINES AND ACCEPTABLE 
BIRTH CONTROL METHODS.......................................................................................................................................... 64 
APPENDIX 6: SKCCC DATA SAFETY MONITORING PLAN ..................................................................................... 67 
REFERENCES:.................................................................................................................................................................... 68 


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1. PROTOCOL SYNOPSIS 
 
 
 
PROTOCOL TITLE: A Randomized, Double-blind, Placebo-Controlled Phase 
II Trial of an Allogeneic Myeloma GM-CSF Vaccine With Lenalidomide in 
Multiple Myeloma Patients in Complete or Near Complete Remission 
PROTOCOL NUMBER: 
JHU Protocol #: J16118 
Celgene Tracking #: RV-CL-MM-PI-005749 
DATE PROTOCOL FINAL: 
June 16, 2020 
STUDY DRUG: 
Allogeneic myeloma GM-CSF vaccine, 
Revlimid ® (lenalidomide) 
INDICATION: 
Augmenting clinical response with vaccine 
plus lenalidomide 
STUDY PHASE: 
Randomized Phase II 
BACKGROUND AND RATIONALE: This study seeks to determine whether 
addition of an allogeneic myeloma vaccine can augment clinical responses to 
lenalidomide in patients with near complete remission (nCR), complete remission 
(CR) leading to a significant improvement in progression-free survival. 


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STUDY OBJECTIVES AND ENDPOINTS: 
Primary: 
• To compare the 2-year progression free survival of patients with multiple 
myeloma in a complete remission (CR), or near complete remission 
(nCR), treated with lenalidomide plus an allogeneic myeloma vaccine in 
combination with lenalidomide (with or without Prevnar vaccine) or 
versus placebo in combination with lenalidomide (control arm). 
Secondary: 
• To compare the 2-year progression free survival for those treated with 
or without Prevnar in addition to an allogeneic myeloma vaccine and 
lenalidomide 
• To determine the rate of conversion from near CR (immunofixation 
positive) to true CR (immunofixation negative) 
• To determine the rate of conversion from MRD (Minimal Residual 
Disease) positive status to MRD negative status by NGS (next 
generation sequencing). 
• Determine time to response 
• Determine progression free survival at 3 and 5 years 
• Determine the toxicity of the allogeneic myeloma vaccine in combination 
with lenalidomide 
• Measure tumor specific immunity and correlate with systemic immunity 


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STUDY DESIGN: 
This is a single institution, three- arm, randomized controlled, Phase II study 
examining the clinical efficacy of an allogeneic GM-CSF secreting myeloma 
vaccine in combination with lenalidomide (with or without Prevnar) compared to 
lenalidomide and placebo (control arm). Patients enrolled in the study must have 
two disease measurements (including the last one) consistent with a near complete 
remission (M-spike negative with persistence of immunofixation), or complete 
remission (M-spike negative, negative immunofixation, and <5% clonal plasma 
cells on bone marrow) per criteria for response in a 3 month period. All patients 
must be minimal residual disease (MRD) positive at 10-4 by NGS sequencing at 
enrollment. Prior to enrollment, patients will have been treated with a lenalidomide 
containing regimen for a minimum of 6 cycles. All patients will continue on a 
standard dose of lenalidomide as a single agent until progression, or treatment 
limiting toxicity, following enrollment. Patients will be randomized to receive either 
an allogeneic myeloma vaccine and Prevnar vaccine in combination with 
lenalidomide, or allogeneic myeloma vaccine without Prevnar vaccine in 
combination with lenalidomide, or lenalidomide in combination with placebo. 
Patients will receive allogeneic myeloma vaccine or placebo injections on day 14 
(+/-3 days) of cycles 1, 2, 3 and 6 from enrollment, and then annually thereafter for 
up to 3 years. If assigned to allogeneic myeloma vaccine plus Prevnar vaccine 
arm, Prevnar-13 will be administered with each allogeneic myeloma vaccine. If 
assigned to either of the two arms that do not include Prevnar, then patients will 
receive a placebo in lieu of Prevnar on the same schedule. All patients will be 
followed for a minimum of 3 years. 
STUDY DURATION:  3-5 years 
TOTAL SAMPLE SIZE: 54 (18 per arm) 


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DOSING REGIMEN(S): 
Lenalidomide: Patients will continue 
on a stable dose of lenalidomide on 
days 1 – 21 of a 28 day cycle until 
progression 
Allogeneic myeloma vaccine 
consisting of 3 cell lines: 
H929 5x107 cells/ vaccine 
U266 5x107 cells/ vaccine 
K562/GM-CSF 5x106 cells/ vaccine 
Prevnar-13 administered with each 
myeloma vaccine 
STUDY DRUG SUPPLIES: 
Allogeneic myeloma vaccine consisting of 3 
cell lines to be manufactured by Aduro 
Biotech, and dispensed by the Cell Therapy 
Lab (CTL) at Johns Hopkins Sidney Kimmel 
Comprehensive Cancer Center (SKCCC). 
Myeloma vaccine placebo injections will be 
prepared by the CTL at Johns Hopkins 
SKCCC. 
Prevnar, and Prevnar placebo, will be 
prepared 
by 
the 
Pharmacy 
and 
Investigational Drug Service (IDS) at the 
Johns Hopkins Hospital. 
All placebo will be made with saline. 
For study participants, lenalidomide will be 
administered as a commercial drug. 


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y 
ud 
St 
 
2. SCHEDULE OF STUDY ASSESSMENTS* 
 
Procedure 
Screen/Baseline9 
(Cycel 1 D 1 (28 days 
before) 
Cycle 1 D 14 (+/- 3 days) 
Cycle 2 D 14(+/- 3 days) 
Cycle 3 D 14(+/- 3 days) 
Cycle 6 D 14(+/-3 days) 
1 year (+/-7 days)/Off- 
Study
18 months (+/-7 
days)/Off-Study
2 years (+/-7 days)/Off- 
30 months (+/-7 
days)/Off-Study
3 years (+/-7 days)/Off- 
Study
Informed Consent 
X 
Eligibility 
X 
Complete medical history 
X 
Interval history and review of patient vaccine 
reaction diary1 
X X X 
X 
X 
X 
X 
X 
X 
Review of systems1 
X 
X X X 
X 
X 
X 
X 
X 
X 
Confirm diagnosis and stage 
X 
Performance Status (ECOG)1 
X 
X X X 
X 
X 
X 
X 
X 
X 
Concomitant Therapy1 
X 
X X X 
X 
X 
X 
X 
X 
X 
Myeloma Vaccine or placebo2 
X X X 
X 
X 
X 
X 
Prevnar Vaccine or placebo3 
X X X 
X 
X 
X 
X 
Research Blood4 
X 
X 
X 
X 
X 
Bone Marrow Aspiration & Biopsy5 
X 
X 
X 
X 
X 
Safety Assessments: 
Adverse event query 
- 
X X X 
X 
X 
X 
X 
X 
X 
Physical Examination, vital signs, weight 
X 
X X X 
X 
X 
X 
X 
X 
X 
CBC with differential 
X 
X X X 
X 
X 
X 
X 
X 
X 
Comprehensive panel 
X 
X X X 
X 
X 
X 
X 
X 
X 
Pregnancy Testing6,7 
X6 
X X X 
X 
X 
X 
X 
X 
X 
Disease Measurements: 
Minimal Residual Disease (MRD) testing8 
X10
X 
X 
X 
X 
Protein electrophoresis (serum and 24 hr 
urine) or M-spike quantification (serum and 
24hr urine) 
X 
X X X 
X 
X 
X 
X 
X 
X 
Free light chain assay 
X 
X X X 
X 
X 
X 
X 
X 
X 
Quantitative Immunoglobulins 
X 
X X X 
X 
X 
X 
X 
X 
X 
Immunofixation studies (serum and 24 hour 
urine) 
X 
X X X 
X 
X 
X 
X 
X 
X 
Beta-2 microglobulin 
X 
Assessment of response1 
X 
X X X 
X 
X 
X 
X 
X 
X 
 
In addition to the regularly scheduled study visits, an unscheduled visit can occur at any time during the 
study. Investigators may also assess participants via telemedicine at any point the investigator, local health 
or government authorities and/or other Hopkins authorities deem it appropriate. In these cases, an 
assessment may not include a physical exam or samples collection. All efforts should be made to perform in 
person visits if possible.  Source documents must be maintained for these remote visits and unscheduled 


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visits. The date for the visit and any data generated must be recorded on the appropriate CRF. 


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If physical examination, vital signs, weight and ECOG performance status were done within 7 days of Day 
1, they do not need to be repeated at Study Day 1. 
 
*  A variation of +/- 3 days of a scheduled visit is permitted. 
1 Needs to be documented with the cycle in which patients are getting the vaccine. Can also occur on 
day 1 of each cycle. 
2 Myeloma Vaccine consists of 3 cell lines admixed, irradiated and administered over 3 limbs.Placebo 
administration will occur along the same schedule in the same limbs in the placebo arm 
3 Prevnar-13 Vaccine or placebo will be administered together with the myeloma vaccine. It will be 
injected intramuscularly in one arm. 
4 100ml of blood in heparinized syringes and 10cc tiger top tube and 2 green top tubes will be collected. 
5 Collect 20 ml of bone marrow in a heparinized 20 ml syringe. Includes cytogenetic and FISH analysis. 
6 Pregnancy tests for females of childbearing potential. A female of childbearing potential (FCBP) is a 
sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has 
not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time 
in the preceding 24 consecutive months). 
7 Pregnancy tests must occur within 10 – 14 days prior to prescribing lenalidomide, and again within 24 
hours prior to prescribing lenalidomide (prescriptions must be filled within 7 days).  A FCBP with regular 
or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while 
on therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 28 post the last 
dose of lenalidomide. Females with irregular menstruation must have a pregnancy test weekly for the first 
28 days and then every 14 days while on therapy (including breaks in therapy), at discontinuation of 
lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix 5: Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods) 
8 MRD testing by NGS. Patients who are MRD negative will not proceed with the clinical trial 
9Screening and baseline assessments can be completed within 28 days from consent and prior to C1D1 
10MRD assessments resulted within 60 days prior to consent are acceptable for screening at PI’s 
discretion 
Patients may continue treatment with lenalidomide provided there is evidence of clinical efficacy. 


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3. GLOSSARY OF ABBREVIATIONS 
AE 
Adverse event 
Alanine transaminase (serum glutamate pyruvic 
ALT (SGPT) 
transaminase) 
 
ANC 
Absolute neutrophil count 
AST (SGOT) 
BiRD 
Aspartate transaminase (serum glutamic oxaloacetic 
transaminase) 
Biaxin, Revlimid and dexamethasone 
 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTC 
Common toxicity criteria 
DSMB 
Data Safety Monitoring Board 
DTIC 
Dacarbazine 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMEA 
European Agency for Evaluation of Medicinal Products 
FDA 
Food and Drug Administration 
FCBP 
Females of child bearing potential 
G-CSF 
Granulocyte colony stimulating factor, filgrastim (Neupogen) 
GM-CSF 
Granulocyte/macrophage colony stimulating factor 
GCP 
Good clinical practice 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IDS 
Investigational Drug Service 
IFN 
Interferon 
IL-2 
Interleukin-2 
IND 
IP 
Investigational New Drug 
Investigational Product 
 
 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 


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IVRS 
KRd 
Interactive Voice Response System 
Carfilzomib, Revlimid and dexamethasone 


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LD 
Longest diameter 


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LDH 
Lactate dehydrogenase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
MRD 
NGS 
Medical Dictionary for Regulatory Activity 
Minimal Residual Disease 
Next Generaion Sequencing 
 
 
 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
OS 
Overall survival 
PCV 
Pneumococcal Conjugate Vaccine 
PD 
PFS 
Progressive disease 
Progression Free Survival 
 
 
 
PR 
Partial response 
RBC 
RD 
Red blood cell 
Revlimid and dexamethasone 
 
 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
SMC 
Safety Monitoring Committee 
TPP 
Therapeutics Product Program 
TTP 
VRD 
Time to progression 
Velcade, Revlimid and dexamethasone 
 
 
WBC 
White blood cell 
WHO 
World Health Organization 


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4 BACKGROUND AND RATIONALE 
4.1 
Multiple Myeloma: 
 
Multiple myeloma (MM) is the second most frequent malignancy of the blood in the USA 
after non-Hodgkin lymphoma 1. It accounts for about 1% of neoplastic diseases and 13% 
of hematological malignancies 2. Multiple myeloma is most often diagnosed in middle 
aged and elderly individuals with a median age at diagnosis of about 69 years 3. Only 
about 2% of patients are younger than 40 years 4. The annual incidence is a little over 6 
per 100,000, and a little over 26,000 new cases are estimated to occur in the USA in 2015 
3. Multiple myeloma is a neoplasm arising from clonal expansion of malignant plasma 
cells, and is characterized by renal insufficiency, hypercalcemia, and destructive lytic 
bone lesions 5. Malignant plasma cells can produce large amounts of monoclonal 
immunoglobulins, most commonly IgG (50-60%) and IgA (20-25%) and occasionally IgD, 
IgM and IgE.6 Patients often suffer from bone pain and skeletal fragility.7 
 
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.8,9 
 
The diagnosis is made using several criteria including results of radiographic skeletal 
survey or magnetic resonance imaging (MRI), bone marrow examination, measurement 
of serum and/or urine monoclonal protein (M-protein), and free light chain assay. 10,11 
Disease stage and extent of tumor burden is determined by one of two staging systems, 
the International Staging System (ISS), or the Durie-Salmon Staging system (both stage 
I, II, and III). The ISS incorporates data from levels of β-2 microglobulin and serum 
albumin, while Durie-Salmon Staging system includes subjective measures such as tumor 
cell density in the bone marrow, as well as measures of end-organ damage such as 
hemoglobin, serum calcium,renal insufficiency, immunoglobulin burden and status of lytic 
bone lesions. 12,13 The lack of subjectivity and the simplicity of the ISS have led to its 
becoming the preferred staging system. 
 
The therapy of patients with newly diagnosed multiple myeloma (NDMM) is based on a 
combination of features including cytogenetic risk stratification, age and eligibility for 
autologous stem cell transplantation (ASCT). Several recent randomized trials have 
evaluated the addition of a novel agent to oral melphalan and prednisone in older patients, 
while novel agents have been incorporated before, during and after ASCT, in younger 
individuals. Newer investigational approaches that are not age-dependent include 
continuous myeloma suppression with dexamethasone plus an immunomodulatory 
derivative, or the use of multiple cycles of combination regimens followed by a treatment 
break or maintenance therapy. Survival prospects in MM have improved during the last 
decade with the introduction of new drug regimens, including immunomodulatory drugs 
(IMiDs; such as lenalidomide, thalidomide), and pomalidomide and proteasome inhibitors 
(such as bortezomib and carfilzomib). 14 However, despite the use of novel agents and 
immunotherapies,  Multiple  Myeloma  largely remains an incurable disease in the  vast 


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majority of patients with a median survival of 4 to 6 years.15 Most patients relapse with 
few experiencing long-term disease-free survival with current therapeutic approaches.14 
There is an urgent need for more effective therapies to treat this challenging disease. 
 
Long-term responses have been demonstrated in the allogeneic transplant setting. 
However, this treatment is associated with severe graft versus hostdisease (GVHD) and 
substantial mortality, which has limited its use.16 A major goal of newer studies has been 
to increase the overall clinical efficacy 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. 
 
4.2 
Clinical responses to Lenalidomide and Dexamethasone 
In patients with relapsed refractory myeloma, responses to lenalidomide and 
dexamethasone were compared to that of dexamethasone and placebo in a large 
randomized North American study.17 Patients were enrolled from February 27th, 2003, to 
April 14th, 2004. Results were presented for response and time to progression were based 
on data before unblinding, and the results for safety were based on data obtained prior to 
December 31st, 2005. Median follow-up was 17.6 months. Complete, near-complete, or 
partial responses occurred in 108 patients (61.0%) in the lenalidomide and 
dexamethasone group and in 35 patients (19.9%) in the control group treated with 
dexamethasone alone (P<0.001); complete responses occurred in 14.1% and 0.6%, 
respectively (P<0.001). The median time to progression was 11.1 months in the 
lenalidomide group and 4.7 months in the control group (P<0.001). Median overall survival 
times in the two groups were 29.6 months and 20.2 months, respectively (P<0.001). 
Grade 3 or 4 adverse events were reported in 85.3% of the lenalidomide group and in 
73.1% of the control group; these events resulted in study discontinuation in 19.8% and 
10.2%, respectively. Grade 3 or 4 neutropenia and venous thromboembolism were more 
common in the lenalidomide group than in the control group (41.2% vs. 4.6% and 14.7% 
vs. 3.4%, respectively; P<0.001 for both comparisons). 
 
In newly diagnosed patients, the combination of lenalidomide and dexamethasone was 
tested in 34 patients at the Mayo Clinic.18 Overall, thirty-one patients achieved an 
objective response, defined as a partial response or better (91%; 95% confidence interval, 
79%-98%), with a complete response plus very good partial response rate of 56%. The 
complete response plus very good partial response among the 21 patients who received 
Rev-Dex without SCT was 67%. The 2-year progression-free survival rates for patients 
proceeding to SCT and patients remaining on Rev-Dex were 83% and 59%, respectively; 
the OS rates were 92% and 90% at 2 years and 92% and 85% at 3 years, respectively. 
An IFM/DFCI 2009 study with two arms, Velcade-Revlimid-dexamethasone (VRd) plus 
transplant vs VRd with no transplant, followed by Revlimid maintenance (without steroids) 
in the post transplant setting, demonstrated a 3-year OS rate for the whole cohort in both 


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arms of 88%, and showed significant improvement in the sCR/CR rate.19 In Phase III 
multicenter randomized trial lenalidomide maintenance (without steroids) was compared 
to no maintenance after melphalan, prednisone, lenalidomide (MPR). Lenalidomide 
maintenance improved clinical responses and progression free survival when compared 
to no maintenance.20 In a CALGB study, lenalidomide maintenance (without steroids) was 
compared to placebo after autologous stem cell transplant. A 58% decreased risk in 
disease progression was noted in the patients who were on maintenance lenalidomide.21 
A recent meta-analysis of three major trials presented at the annual ASCO meeting in 
June 2016 concluded that lenalidomide maintenance significantly prolonged OS in the 
post-autologous stem cell transplant (ASCT) setting. There was an estimated 2.5 year 
improvement in OS (HR = 0.74, 95% CI: 0.62-0.89, p = 0.001). The benefit gained 
outweighed the risk of secondary primary malignancies, and thus lenalidiomide 
maintenance following ASCT can be considered standard of care. 
4.3 
Lenalidomide augments responses to Prevnar vaccination 
In preclinical models lenalidomide has been shown to augment immune responses in vitro 
while the in vivo immunomodulatory properties of this drug are unknown. We previously 
conducted a clinical trial in relapsed myeloma patients examining the ability of 
lenalidomide to augment both endogenous, as well as vaccine-specific cellular and 
humoral immune responses to the pneumococcal vaccine, Prevnar 22. Prevnar was given 
either before or during administration of lenalidomide in two cohorts of patients. Cohort A 
received their first vaccination prior to administration of Lenalidomide, and the second 
vaccine on cycle 2, day 15 of Lenalidomide. Cohort B received both vaccines after 
initiation of Lenalidomide: cycle 2, day 15 and cycle 4, day 15. Pneumococcal serotype 
titres as well as CRM-197 T cell responses quantified the B and T cell responses, 
respectively, to Prevnar vaccination and were correlated with lenalidomide administration. 
Systemic immune responsiveness was determined by DTH responses to candida and by 
flow cytometric analysis of immune cell subsets. 24 patients were enrolled. 17 patients 
were evaluable with 10 in Cohort A and 7 in Cohort B. 


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Fig 1: 
 
 
Lenalidomide augments Prevnar-specific Vaccine responses: Cohort A received Prevnar prior and on day 14, cycle 2 
whereas Cohort B received Prevnar on day 14 of Cycles 2 and 4. Antibody responses to Prevnar were increased in Cohort B 
compared to Cohort A (Fig B vs. A). T cell responses to CRM-197 were also greater in Cohort B when measured in both blood 
(Fig C) as well as bone marrow (Fig D). 
 
 
7 patients with progressive disease while on study were not evaluable. All patients had 
measurable T cell and antibody responses to Prevnar. T cell responses to CRM-197 
demonstrated significantly higher responses in Cohort B with a peak 5.8 fold-increase 
above baseline compared to 1.5 in Cohort A in the blood. The bone marrow T cells 
showed a greater response which persisted longer in Cohort B (15.5 fold to 4.5 at 6 
months) vs. A (12.5 fold to 1.8 at 6 months). A tendency owards better T cell responses 
were observed in patients with better clinical responses to lenalidomide. Vaccination 
primed serotype responses in both groups. While the second Prevnar vaccine in Cohort 
B further augmented antibody titres, no subsequent increase was observed in Cohort 
A. As a measure of systemic immunity, DTH responses to Candida were examined. 
Cohort B demonstrated up to a 78-fold increase in induration compared to no change in 
Cohort A. Flow cytometric analyses showed increased NK (1.2 fold) and CD8 (2.5 fold) 
in Cohort B. Furthermore, T cell subset analyses revealed an increase of activation 
markers as well as an increase in the central memory and effector memory phenotypes 
in both peripheral blood and bone marrow. Interestingly, greater myeloma clinical 
responses were observed in Cohort B (57% ORR) vs Cohort A (10% ORR). 


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This is the first in vivo demonstration of the immunomodulatory properties of lenalidomide, 
and lenalidomide-mediated augmentation of both cellular and humoral responses in 
myeloma patients. These data suggest a synergy between the immunomodulatory effects 
of lenalidomide and vaccines. Surprisingly, the increased anti-tumor effect observed in 
Cohort B suggests the possibility of lenalidomide-induced vaccine-mediated epitope 
spreading. 
 
This pilot study established the scientific rationale for utilizing lenalidomide as an immune 
adjuvant with vaccines. Implications of the use of lenalidomide as a vaccine adjuvant 
apply to both cancer vaccines as well as infectious disease vaccines. 
 
4.4 
Allogeneic Myeloma GVAX with Lenalidomide in Near Complete 
Remission Enhances Progression Free Survival 
 
As the depth of response to therapy in MM correlates with improved progression free 
survival, we extended the above research to examine whether vaccinating patients on 
lenalidomide in a near complete remission (nCR) (negative M-spike, IFE positive), could 
further deepen the clinical response and generate measurable myeloma specific 
immunity.23 
 
Patients on a Len-containing regimen (VRD, Rd, BiRD or R) that achieved and maintained 
a nCR for 4-6 months were eligible for the study. Patients continued only on single agent 
Len and received 4 GVAX vaccinations consisting of two allogeneic MM lines: H929, 
U266 admixed with K562 transduced to express GM-CSF as well as PCV. Patients 
received 3 monthly vaccines and a boost at 6 months. Immune monitoring was performed 
on BM samples obtained at baseline, 6 months and 1 year. 
 
To date 32 patients have been screened. 17 patients initially in a nCR were ineligible for 
vaccination: 3 (18%) had disease progression, 7 (42%) entered into an IFE negative CR, 
and 7 (42%) maintained a nCR during the observation period but opted not to enroll. 15 
patients have been enrolled and completed their vaccinations. Patient characteristics are 
shown in the Table. Of note, none possessed high-risk features by ISS or FISH. Median 
follow-up for the study is 34.0 months. Median progression free survival (PFS) of the 
cohort of vaccinated patients has not been reached whereas the PFS in the observation 
arm that remained on the multidrug Len-containing therapy was 17.9 months (p<0.001) 
(figure 2). Vaccination in the setting of a rising M-spike was less likely to induce a durable 
remission with a median PFS of 14.3 months (p<0.003) (figure 3). Laboratory analysis 
showed that the patients achieving a CR had greater expression of PD-1 on CD4 and 
CD8 cells at baseline in the BM. Furthermore, durable responses were associated with 
the development and persistence of MM-specific immunity. 
 
Patient charateristics: 
 
Vaccination 
(n=15) 
Observation 
(n=16) 
Age 
69 (55-81) 
66 (40-83) 


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FISH (high risk) 
0% 
0% 
ISS Stage III 
2 (13%) 
3 (19%) 
IFE negative 
0 (0%) 
7 (42%) 
Prior Therapies 
1.8 (1-4) 
1.8 (1-3) 
 
 
 
 
 
Figure 3. Presence of Disease Reduces Vaccine Efficacy 
Figure 2. GVAX significantly prolong PFS in patients in a nCR 


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Vaccination with a poly-antigenic approach such as GVAX in combination with 
lenalidomide induced immunomodulation in patients with minimal residual disease 
generates potent MM-specific immunity, and appears to significantly extend the PFS. The 
promising early clinical activity has led us to design a randomized phase II trial to further 
explore this approach as a means to maintaining durable clinical remissions. 
 
4.5 
K562/GMCSF vaccine: 
 
Tumor cell-based vaccine strategies seek to enhance the immunogenicity of tumor cells 
by modifying them in vitro to express immunomodulatory cytokines.24-27 Our group and 
many others have demonstrated the generation of T-cell mediated systemic anti-tumor 
immunity capable of eradicating a small, pre-established tumor burden in certain murine 
models following vaccination. The vaccination site has been shown to contain an influx of 
eosinophils, activated macrophages, 26 and dendritic cells (DCs),28 with complete 
destruction of the vaccinating tumor cells within three to five days.29 GM-CSF producing 
tumor vaccines act by recruiting and activating professional antigen presenting cells 
(APCs) which process antigens liberated from the irradiated tumor cells at the vaccine 
site and migrate to the draining lymph nodes.30 Here, processed antigen is presented to 
tumor-specific T-cells leading to their activation. 
 
APCs are critical in the priming phase of this response. This is underscored by 
demonstration that tumor-specific CD8+ cytotoxic T- lymphocytes (CTL) are actually 
primed by bone marrow derived APCs that have processed exogenous tumor antigen in 
response to vaccination (“cross-priming”), rather than by tumor presentation of 
endogenous antigen.31 Significantly, this provides a rationale for the use of allogeneic 
tumor cells as a source of antigen in clinical settings where collection of autologous tumor 
is not feasible. Many tumor-associated antigens identified to date are not patient specific, 
but rather are common to the type of tumor. Since host APCs initiate the T-cell response 
to such vaccines, it is not necessary to “match” the HLA of the allogeneic tumor cell with 
that of the patient; instead antigens are liberated from the irradiated cell lines, captured, 
processed, and presented by host APCs in an autologous HLA-restricted fashion to host 
T-cells. 
 
The efficacy of GM-CSF transduced tumor vaccines has been demonstrated in multiple 
animal models of melanoma, lung cancer, colon cancer, renal cell cancer,26 as well as 
prostate cancer, acute leukemia, and B-cell lymphoma.32-34 In addition, early clinical trials 
with GM-CSF expressing vaccines have tested patients with renal cell carcinoma, 
prostate cancer, melanoma, non-small cell lung cancer and pancreatic cancer.35-38 The 
clinical data available to date reveal minimal toxicities (local swelling and tenderness at 
the vaccine site) at doses as high as 5x108 cells per injection, with tumor cells secreting 
up to 1000 ng GM-CSF/106 cells/24 hours (i.e. up to 500 micrograms of GM-CSF/day), 
with serum GM-CSF levels peaking 3 days post vaccine and becoming undetectable by 


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7 days. In vitro assays have demonstrated the induction of tumor-specific cytotoxic 
lymphocyte activity,37 and the appearance of high titer antibody to the vaccinating cell 
population.36 
 
4.6 
K562/GM-CSF as a universal GM-CSF producing Bystander Cell: 
 
K562, a cell line, derived from a CML patient in blast crisis was transfected with a plasmid 
vector encoding human GM-CSF. K562/GM-CSF grows well in serum-free media, stably 
expresses > 1000 ng of GM-CSF / 106 cells/ 24 hours, and is easily expanded to large 
numbers for vaccine production. 
 
Clinical trials performed at Johns Hopkins initially used the K562/GM-CSF vaccine as a 
“bystander” cell together with irradiated autologous tumor in patients with multiple 
myeloma and acute myeloid leukemia. In those studies, analysis of vaccine biopsy sites, 
serum GM-CSF levels, and serial white blood cell counts indicate that GM-CSF 
production is sustained for at least 3-5 days post vaccination. 
 
 
 
4.7 
Allogeneic myeloma vaccine preparation: 
We have developed an allogeneic myeloma vaccine which consists of 3 cell lines: 
1. H929 – is an unaltered myeloma cell line grown in serum-free medium. This is an IgA 
cell line isolated from the pleural effusion of a patient with end-stage myeloma. The cell 
line possesses the t(4; 14) as well as the N-13 ras mutation. It also expresses MAGE-A2 
and NY-ESO-1. 
 
2. U266 – is an unaltered myeloma cell line isolated from a patient with plasma cell 
leukemia. The line contains the t(11;14), overexpression of cyclin D1 and amplification of 
bcl-2.  It also expresses NY-ESO-1 and GAGE-3. 
 
3. K562/GM-CSF – is a CML cell line modified to express stable, high levels of GM-CSF 
to be used as the GM-CSF-producing bystander. This cell line was chosen in that it lacks 
surface HLA expression. The cell line produces approximately 1500ng/106 cells/24hrs of 
GM-CSF. 
 
4.8 
Rationale for Allogeneic Myeloma Vaccine 
 
In multiple myeloma, donor lymphocyte infusions (DLI) have been able to induce 
prolonged remissions in patients who relapsed after allogeneic transplantation.39 This 
approach demonstrates the efficacy of immune mediated anti-tumor effect in myeloma. 
We have been able to measure tumor specific T cell responses in a recent trial using an 
autologous vaccine in the setting of a stem cell transplant. However, significant barriers 
still exist that prevent us from maximizing vaccine-mediated anti-tumor efficacy. Results 
from both pre-clinical and clinical studies have demonstrated that tumor vaccines  work 


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best in the setting of minimal residual disease. A possible explanation for these findings 
is the immunosuppressive effects of advanced tumors in tumor-bearing hosts. 
Specifically, the increase in VEGF levels that result in impaired dendritic cell function, 
changes in -chain signaling on the T cell receptor resulting in global immunosuppression, 
the induction of myeloid suppressor cells exerting an inhibitory immune effect via nitric 
oxide and arginase-dependent pathways and the development of antigen-specific 
tolerance induction resulting in a skewing from a positive Th1 CD4 response to an 
inhibitory Th2 response. 
 
These findings have enabled us to identify putative targets to improve the underlying 
immune responsiveness of the host in an effort to augment the efficacy of tumor-specific 
vaccine strategies in an immune responsive host, and to impart an immune-mediated 
anti-tumor effect on chemo-resistant tumors, that underscore the ability of active 
immunotherapy to exert its anti-tumor effect through non-cross-reactive mechanisms. 
Taken together, these findings provide a strong rationale for studies that integrate tumor 
vaccines into a setting in which prior therapy achieved its maximal anti-tumor benefit. 
 
We have tested the immunomodulatory role of lenalidomide on pneumococcal vaccine 
(Prevnar) responses in arecently conducted clinical trial (described above) in patients with 
relapsed myeloma 22. Ultimately the data demonstrated that lenalidomide augments in 
vivo immune responses in patients with advanced/relapsed multiple myeloma, which 
provides the rationale for utilizing this drug in combination with cancer vaccines to 
augment anti-tumor efficacy. 
 
Most patients achieving a CR still go on to relapse14. However, the depth and duration of 
CR may play an important role in disease prognosis, and higher CR has been shown to 
correspond with improved survival. The potential benefit of tumor vaccine may be best 
seen in the setting of minimal residual disease (MRD), where tumor induced tolerogenic 
mechanisms may be less relevant, and may be an effective mechanism of achieving a 
deeper remission such as stringent CR when not already in stringent CR, or molecular 
CR. 
 
We will study the effect of the tumor vaccine in patients achieving at least a near complete 
remission (nCR), as well as a complete remission (CR) with a lenalidomide based 
regimen. The goal of the study will be to improve the clinical responses in patients with 
near complete remission (nCR) or complete remission who are also minimal residual 
disease positive (MRD+), and to determine whether the allogeneic myeloma vaccine 
confers a PFS advantage upon patients treated with allogeneic myeloma vaccine in 
combination with lenalidomide (with or without Prevnar vaccine) as compared to a non- 
vaccine control arm with patients on lenalidomide alone. The effect of adding Prevnar to 
the allogeneic myeloma vaccine and lenalidomide combination will also beexplored. 
 
Since administration of corticosteroids can dampen immune responses, patients will 
discontinue dexamethasone or other steroids at least one month prior to receiving the first 
vaccine, and must not show evidence of progressive disease as defined by the 
International Uniform Response criteria 47, prior to being started on the trial. The adverse 


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effects and significant morbidity from long term use of corticosteroids are well described, 
and this trial will give us an excellent opportunity to explore novel treatment strategies in 
a ‘steroid free’ regimen with a goal to improve the depth of response and have a low 
toxicity profile. 
 
The incorporation of the Prevnar vaccination in our earlier study had a dual purpose. We 
were able to measure the efficacy of the vaccine by examining both the humoral, as well 
as cellular responses to Prevnar; and we uncovered a potential therapeutic effect of 
Prevnar vaccine in our earlier study. Specifically, the ability of Prevnar to prime T cell 
responses targeting HB-EGF (heparin binding epidermal growth factor), a cell adhesion 
molecule expressed on a significant percentage of myeloma cells. 22, 23 
 
We believe that the data support the efficacy of lenalidomide in augmenting in vivo 
immune responses in patients with multiple myeloma, and thus warrant the investigation 
of lenalidomide in combination with the allogeneic myeloma vaccine without the 
potentially confounding effect of Prevnar. However, to confirm that clinical benefits are 
primarily due to the effect of allogeneic myeloma vaccine alone, there is an additional 
comparison arm consisting of allogeneic myeloma vaccine along with Prevnar, in 
combination with lenalidomide which was the composition of the vaccine in our Phase I 
trial. 
 
 
5 STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Study objectives: 
Primary: 
• To compare the 2-year progression free survival of patients with multiple 
myeloma in a near complete remission (nCR) or complete remission (CR) 
who are also minimal residual disease positive (MRD+), treated with an 
allogeneic myeloma vaccine in combination with lenalidomide (with or without 
Prevnar vaccine) versus placebo in combination with lenalidomide. 
 
Secondary: 
• To compare the 2-year progression free survival for those treated with or 
without Prevnar in addition to an allogeneic myeloma vaccine and lenaliodmide 
• Determine rate of conversion of nCR to true CR 
• Determine rate of conversion of MRD positivity to MRD negativity 
• Determine time to response 
• Determine the progression free survival at 3 and 5 years 
• Evaluate toxicity of the allogeneic myeloma vaccine 
• Measure tumor specific immunity and correlate with systemic immunity 


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6 INVESTIGATIONAL PLAN 
 
6.1 
Overall design: 
Patients with newly diagnosed or relapsed/refractory multiple myeloma (NDMM or 
RMM) in CR or nCR who meet appropriate criteria will be eligible for enrollment. 
Specifically: 
• Patients with NDMM who have completed 6 cycles of treatment with any 
lenalidomide containing regimen (e.g. KRD, VRD, Rd, BiRD or R alone) and who 
have been in CR or nCR for ≥ 3 months. 
• Patients with MM who have undergone ASCT will only become eligible ≥ 12 
months following date of cell infusion, will have been on lenalidomide 
maintenance for ≥ 6 cycles prior to enrollment, and continue to meet criteria for 
CR or nCR for ≥ 3 months. 
• Patients with RMM will need to have completed at least 6 cycles of current 
therapy with a lenalidomide containing regimen, and be in CR or nCR for ≥ 3 
months. 
• All patients must be MRD positive at 10-4 by NGS sequencing at enrollment 
Eligible patients who go on to enroll will be randomized in a 1:1:1 fashion to one of three 
arms. All patients will continue on a standard dose of lenalidomide (15mg daily, to be 
adjusted as clinically necessary), given on days 1 – 21 of a 28 day cycle. Patients on 
the myeloma vaccine arm will receive injections with an allogeneic myeloma vaccine 
administered intradermally on day 14 of cycles 1, 2, 3, 6 and annually for a minimum of 
36 months in addition to lenalidomide unless otherwise clinically indicated, or until 
progression. Patients on myeloma plus Prevnar vaccine arm will receive injections of 
both allogenic myeloma vaccine, intradermally, and Prevnar vaccine, intramuscularly, 
on day 14 of cycles 1, 2, 3, 6, and annually for a minimum of 36 months in addition to 
lenalidomide unless otherwise clinically indicated, or until progression. Patients on the 
myeloma vaccine placebo arm will receive myeloma vaccine placebo on the same 
schedule as allogeneic myeloma vaccine. If assigned to either of the two arms that do 
not include Prevnar, then patients will receive placebo in lieu of Prevnar on the same 
schedule. The placebo will be saline. The study schema is shown below: 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination Schedule 
Randomization 1:1:1 
Allogeneic 
Myeloma Vaccine 
+ 
Prevnar Vaccine 
Placebo 
+ 
Lenalidomide – 
single agent 
Allogeneic Myeloma 
Vaccine 
+ 
Prevnar Vaccine 
+ 
Lenalidomide – 
single agent 
Allogenic Myeloma 
Vaccine Placebo 
+ 
Prevnar Vaccine 
Placebo 
+ 
Lenalidomide – 
single agent 
Follow for Progression-Free Survival  (and secondary end-points) 
Multiple Myeloma 
NDMM or RRMM 
nCR or CR ≥ 3 months 
Len containing regimen, min. 6 cycles 
≥ 12 mo since ASCT 
MRD+ at 10-4 by NGS 
Eligibility and Screening 
Lenalidomide – standard dose till progression 
1   2  3 
12 
24 
36 
 
Allogeneic Myeloma Vaccine or placebo administration – in months: 1, 2, 3, 6, 12, 24, and 36 
Prevnar or Prevnar placebo administration – concurrent with myeloma vaccine administration 
MRD testing – enrollment, 6 mo, 12 mo, annually for the duration of study 


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6789 
 
 
6.1.1 Registration on Study and Randomization 
 
At registration, patients will have the baseline evaluations listed in Sections 2 and 7. 
Once eligibility requirements are met, the patients will proceed to bone marrow biopsy 
with cytogenetics and FISH analysis, and/or GEP assessment via myPRS, if this 
information is not already available at diagnosis, or on recent testing. Randomization in 
a 1:1:1 fashion will occur after screening and eligibility requirements have been met, 
and bone marrow biopsy obtained if needed. The primary criteria for stratification will 
be: 
 
• Near Complete Remission vs Complete Remission (nCR v CR) 
• Prior autologous stem cell transplant vs no prior autologous stem cell transplant 
 
 
6.1.2 Minimal Residual Disease Testing 
 
Outcomes for patients with MM have improved significantly over the past decade, with 
improvements in both progression-free survival and overall survival.44 Many patients are 
now achieving a complete response to treatment, and consequently highly sensitive 
assays are needed for detection of minimal residual disease (MRD) in patients with 
MM.44 Results of multicolour flow cytometry and deep-sequencing studies suggest that 
among patients achieving a complete response, MRD-negative status is associated with 
substantial improvements in progression-free, and overall survival.44  MRD status 
seems, therefore, to be an important prognostic factor in patients with MM. The 
prognostic value of sequencing based MRD testing was demonstrated in a publication 
by Hiroyuki Takamatsu et al at the 57th Annual ASH Meeting, 2015.45 One hundred and 
twenty-three Japanese patients with newly diagnosed MM who received various 
induction regimens prior to ASCT were retrospectively analyzed. All patients received 
ASCT and were followed between June 15, 2004 and April 25, 2015. All patients had 
achieved a partial response (PR) or better after ASCT. Analyzed samples included: (1) 
BM slides from 96 MM patients at diagnosis, (2) fresh/frozen BM cells from 27 MM 
patients at diagnosis, (3) autografts and/or (4) post-ASCT BM cells obtained at the time 
of best response based on serum and urine tests. IGH-based ASO-PCR was performed 
as described previously 46. NGS-based (Next Generation Sequencing-based) MRD 
assessment was performed using the immunosequencing platform (Adaptive 
Biotechnologies, South San Francisco, CA) 47. Patients whose autografts were negative 
by NGS-based MRD assessment (N=19) had 100% PFS and OS at 5 years post ASCT 
irrespective of whether or not they received post ASCT treatment. Conversely, post 
ASCT treatment had a significant effect on the outcome of patients whose autografts 


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were MRD positive by NGS. Specifically, the NGS-based MRD positive patients who 
received post ASCT treatment (N=45) had a significantly better PFS. 
 
 
 
 
 
To be able to study the interaction between allogeneic vaccine and MRD negativity on 
outcomes in our study, we plan to incorporate NGS-based MRD testing for all patients 
at enrollment, six months, one year and annually thereafter. 
 
6.2 
Administration of Allogeneic Myeloma Vaccine or Placebo 
 
Treatment will be administered on an outpatient basis. Reported adverse events and 
potential risks for allogeneic myeloma/K562/GM-CSF vaccine and lenalidomide, as well 
as appropriate dose modifications for lenalidomide, are described below. No dose 
modification exists for the allogeneic myeloma K562/GM-CSF vaccine. No investigational 
or commercial agents or therapies other than those described below may be administered 
with the intent to treat the patient's malignancy. 


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6.2.1 Administration Parameters 
 
At time of enrollment all patients will be on a stable, standard dose of lenalidomide given 
on days 1 – 21 of a 28 day cycle. 
 
The following parameters must be present for each dose of the vaccine to be 
administered: 
• No systemic infections requiring treatment 
• Hemoglobin  8g/dL 
• Platelets > 20,000 
• ALT/AST  3X upper limit of normal 
• Patient must be receiving lenalidomide on the day of thevaccine 
• Missed vaccine doses can be made up within 2 weeks of the missed dose, 
with a delay by an equal number of days for the next dose (and the 
remaining doses), for the first 4 vaccine doses (there wil be a minimum of 
one month between doses). 
• Vaccine doses that are missed beyond the 4th dose of vaccine, can be 
made up within 1 month of the original date of administration.Subsequent 
doses do not need to be delayed. 
 
 
6.2.2 Vaccine Formulation 
 
The cell lines used for the vaccine preparation were manufactured and released by the 
Cell Processing and Gene Therapy Facility, a cGMP compliant facility, at the Sidney 
Kimmel Comprehensive Cancer Center at Johns Hopkins.. The vaccine cells are 
irradiated prior to cryopreservation and stored frozen in the vapor phase of liquid nitrogen 
until the day of use. The details of production, irradiation, freezing, and preparation for 
administration have been discussed in detail in the Investigational New Drug (IND) 
submission. Equal numbers (5 x 107 each) of the myeloma cell lines H929 and U266 cells 
will be combined with the bystander cell line K562/GM-CSF (5x106) to prepare the 
vaccine. Vaccine cells frozen in an injectable formulation Pentaspan® (10% Pentastarch 
in 0.9% sodium chloride with 2% human serum albumin and 5% DMSO) will be thawed 
on the day of vaccination in a 37ºC water bath, mixed, and then taken up into three labeled 
syringes prior to administration. .The cells are kept at 2-8ºC with gel packs until 
administration Injections should be started within 60 minutes of the thaw. Myeloma 
vaccine placebo injections will be saline solutions and will be prepared by the CTL at 
Johns Hopkins SKCCC in accordance with standard policies in order to maintain blinding. 
 
6.2.3 Vaccine Administration 
 
Each vaccination will consist of three total intra-dermal injections, one each in the right 
and  left  anterior  upper  thighs,  and  one  in  the  non-dominant upper arm 
(unless 


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contraindicated). In the event that the specified limb is contraindicated, the dominant arm 
may be used. Vaccine injections sites shall be at least 5 cm at needle entry from the 
nearest neighbor. The approximate volume of each vaccination injection is approximately 
0.7 – 0.8 mL 
 
Application of a lidocaine based topical anesthetic (may include but is not limited to EMLA 
or ELA-MAX) cream at each injection site approximately 1-2 hours prior to vaccination will 
be recommended to diminish the discomfort associated with the intra-dermal injections. 
The topical anesthetic is optional and participants are allowed to decline its use. Self- 
application of the topical anesthetic is allowed after the research participant receives 
instruction. If the research participant is does not comply with application instructions, the 
topical anesthetic may be applied by the research nurse. If the subject is allergic to 
lidocaine, the topical anesthetic will not be used. All research participants will be seen in 
the oncology outpatient center for vaccine administration and monitoring for at least 30 
minutes after vaccination is completed. Those administrating the vaccine will record: 
a. Clinical lot number. Record of this will be kept by CTL in order to maintain blinding 
b. Date of vaccine administration 
c. Number of syringes dispensed 
d. Total vaccine dose. Record of this will be kept by CTL in order to maintain blinding 
e. Vaccination sites 
 
Vaccinations will occur on Day 14 (±3 days) of cycles 1, 2, 3 and 6 and then annually 
from enrollment thereafter through 36 months. 
 
Treatment will be discontinued if any of the following occur: 
 
a. Intercurrent illness that prevents further administration of treatment, 
b. Unacceptable adverse events(s), 
c. The patient decides to withdraw from the study, or 
d. General or specific changes in a patient's condition render further treatment 
inappropriate in the clinical judgment of the investigator. 
 
 
6.2.4 Potential Vaccine Toxicities 
 
Toxicities associated with the intravenous administration of Pentaspan® include 
circulatory overload, abnormalities of coagulation (prolonged prothrombin, partial 
thromboplastin and clotting times), and hypersensitivity reactions characterized by 
wheezing, urticaria, hypotension, and anaphylactic/anaphylactoid reactions. Additionally, 
patients who are allergic to corn can also develop hypersensitivity to Pentaspan®. 
 
The experience with K562/GM-CSF to date has shown it to be safe and well tolerated 48. 
Elevated levels of GM-CSF can be detected in the serum for 3-5 days post vaccination, 
and this is accompanied by a transient rise in the white blood cell, neutrophil, and absolute 


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eosinophil counts. Toxicity is generally limited to myalgias and grade 1-2 injection site 
erythema, induration, tenderness, and localized pruritus. Most patients experience local 
vaccine site reactions that last for approximately 1 week; induration has ranged from 0.5 
cm to as great as 20 cm. In other trials of GM-CSF producing vaccines, systemic reactions 
have included fever, headache, rash, generalized pruritus, andmalaise. 
 
As with any vaccine, there is a possibility of a serious allergic reaction although to date 
this has not been observed with any of the GM-CSF based vaccines administered here 
at Johns Hopkins. As with any investigational drug, other adverse reactions may develop 
that have not yet been described. 
 
There is a theoretical risk of autoimmune disease reactivation or development with GM- 
CSF producing vaccines. In a previous multiple myeloma vaccine trial, induction of 
immune responses to autologous tumor cells has been demonstrated in vitro. Importantly, 
all multiple myeloma patients who had undergone autologous stem-cell transplant 
followed by vaccination have had normal kinetics of engraftment. There has been no 
serological or clinical evidence of autoimmune disease to date arising in recipients of the 
K562/GM-CSF vaccine in the previous AML, CML and myeloma trials. 
 
6.2.5 Availibility 
The vaccine is derived from the three master banks for K562/GM-CSF, H929 and U266. 
The master cell banks are the source material for all working clinical lots.The clinical grade 
allogeneic myeloma K562/GM-CSF vaccine will be manufactured by the GMP facilities 
operated by Aduro Biotech, and shipped to Johns Hopkins. 
 
 
6.3 
PREVNAR-13 
Other names: Pneumococcal 13-Valent Conjugate Vaccine 
 
Classification: Infectious vaccine 
 
Supplier: Prevnar-13 will be purchased from Wyeth Pharmaceuticals. 
 
 
Dosage: 
Prevnar-13 will be administered at 0.5ml dose by intramuscular injection. This dose will 
thus contain serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F and 
approximately 20µg of CRM197 carrier protein; and 0.125mg of aluminum phosphate. 
Since the product is a suspension containing an adjuvant, shake vigorously immediately 
prior to use to obtain a uniform suspension in the vaccine container. The vaccine should 
not be used if it cannot be resuspended or if particulate matter or discoloration is found. 
 
Storage: 


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Vaccine is to be stored refrigerated at 2OC to 8OC (36OF to 46OF). It should not be frozen. 
 
Contraindications: 
Hypersensitivity to any component of the vaccine, including diphtheria toxoid, is a 
contraindication to use of this vaccine. 
 
Warnings: 
Healthcare professionals should prescribe and/or administer this product with caution to 
patients with a possible history of latex sensitivity since the packaging contains dry natural 
rubber. 
 
Precautions: 
Prevnar®
 is for intramuscular use only. Prevnar 
SHOULD UNDER  NO 
CIIRCUMSTANCES  BE ADMINISTERED INTRAVENOUSLY. The  safety and 
immunogenicity for other routes of administration (e.g., subcutaneous) have not been 
evaluated. 
 
6.4 
LENALIDOMIDE: 
6.4.1 Other names: Revlimid ® 
 
6.4.2 Classification: Immunomodulatory drug 
 
6.4.3 Description: 
Revlimid® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with 
anti-angiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H- 
isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure: 
 
 
Chemical Structure of Lenalidomide: 
O 
 
N 
O 
 
NH2 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3. 
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in 
organic solvents and low pH solutions. Solubility was significantly lower in less acidic 
buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric  carbon 


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atom and can exist as the optically active forms S(-) and R(+), and is produced as a 
racemic mixture with a net optical rotation of zero. 
 
 
6.4.4 Mode of action: 
The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide 
possesses immunomodulatory and antiangiogenic properties. Lenalidomide inhibited the 
secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory 
cytokines from peripheral blood mononuclear cells. Lenalidomide inhibited cell 
proliferation with varying effectiveness (IC50s) in some but not all cell lines. Of cell lines 
tested, lenalidomide was effective in inhibiting growth of Namalwa cells 49 (a human B cell 
lymphoma cell line with a deletion of one chromosome 5) but was much less effective in 
inhibiting growth of KG-1 cells (human myeloblastic cell line, also with a deletion of one 
chromosome 5) and other cell lines without chromosome 5 deletions. Lenalidomide 
inhibited the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro. 
 
Lenalidomide is a proprietary IMiD™ compound of Celgene Corporation. IMiD™ 
compounds have both immunomodulatory and anti-angiogenic properties which could 
confer antitumor and antimetastatic effects. 50 Lenalidomide has been demonstrated to 
possess anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha 
induced endothelial cell migration, due at least in part to inhibition of Akt phosphorylation 
response to bFGF. In addition, lenalidomide has a variety of immunomodulatory effects. 
Lenalidomide stimulates T cell proliferation and the production of IL-2, IL-10 and IFN- 
gamma, inhibits IL-1 beta and IL-6 and modulates IL-12 production. Upregulation of T cell 
derived IL-2 production is achieved at least in part through increased AP-1 activity. 
 
Although the exact antitumor mechanism of action of lenalidomide is unknown, a number 
of mechanisms are postulated to be responsible for lenalidomide’s activity against 
multiple myeloma. Lenalidomide has been shown to increase T cell proliferation, which 
leads to an increase in IL-2 and IFN-gamma secretion. The increased level of these 
circulating cytokines augment natural killer cell number and function, and enhance natural 
killer cell activity to yield an increase in multiple myeloma cell lysis. In addition, 
lenalidomide has direct activity against multiple myeloma and induces apoptosis or 
G1growth arrest in multiple myeloma cell lines and in multiple myeloma cells of patients 
resistant to melphalan, doxorubicin and dexamethasone. 
 
6.4.5 Adverse effects: 
The most frequently reported adverse events reported during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of presumed 
relationship to study medication, include: anemia, neutropenia, thrombocytopenia and 
pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, rash, itching, 
infections, sepsis, pneumonia, UTI, Upper respiratory infection, cellulites, atrial fibrillation, 
congestive heart failure, myocardial infarction, chest pain, weakness, hypotension, 
hypercalcemia, hyperglycemia, back pain, bone pain, generalized pain, dizziness, mental 


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status changes, syncope, renal failure, dyspnea, pleural effusion, pulmonary embolism, 
deep vein thrombosis, CVA, convulsions, dizziness, spinal cord compression, syncope, 
disease progression, all cause death and fractures. Complete and updated adverse 
events are available in the FDA label. 
 
6.4.6 Storage: 
Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold. 
 
6.4.7 Prescribing Lenalidomide: 
Lenalidomide (Revlimid®) will be supplied commercially to research subjects for the 
duration of their participation in this trial by their insurance providers. Lenalidomide will be 
provided in accordance with Celgene Corporation’s Revlimid REMS® program. Per 
standard Revlimid REMS® program requirements, all physicians who prescribe 
lenalidomide for research subjects enrolled into this trial, and all research subjects 
enrolled into this trial, must be registered in, and must comply with, all requirements of 
the Revlimid REMS®program. Prescriptions must be filled within 7 days. Only enough 
lenalidomide for one cycle of therapy will be supplied to the patient during each cycle. 
Further    information    about    the    Revlimid    REMS®    program    is    available  at 
www.celgeneriskmanagement.com. 
 
6.4.8 Pharmacokinetics and Drug Metabolism: 
 
6.4.8.1 
Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with 
maximum plasma concentrations (Cmax) occurring between 0.625 and 1.5 hours post- 
dose. Co-administration with food does not alter the extent of absorption 51, but does 
reduce the Cmax by 36%. The pharmacokinetic disposition of lenalidomide is linear, i.e. 
Cmax and AUC increase proportionately with increases in dose. Multiple dosing at the 
recommended dose-regimen does not result in drug accumulation. 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the 
phase I studies. Absorption was found to be rapid on both Day 1 and Day 28 with time to 
maximum blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, 
and 50mg). No plasma accumulation was observed with multiple daily dosing. Plasma 
lenalidomide declined in a monophasic manner with elimination half-life ranging from 2.8 
to 6.1 hours on both Day 1 and 28 at all 4 doses. Peak and overall plasma concentrations 
were dose proportional over the dosing range of 5mg to 50mg.51 Exposure in multiple 
myeloma patients is 57% higher than in healthy male volunteers. 
 
6.4.8.2 
Pharmacokinetic Parameters: 
Distribution: 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
Metabolism and Excretion: 


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The metabolic profile of lenalidomide in humans has not been studied. In healthy 
volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through 
urinary excretion. The process exceeds the glomerular filtration rate and therefore is 
partially or entirely active.  Half-life of elimination is approximately 3 hours. 
6.4.9 Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) commercially to study 
participants. 
 
6.4.10 Packaging 
Lenalidomide will be shipped directly to patients. Each bottle will contain a sufficient 
number of capsules for one cycle of dosing. 
 
6.4.11 Dosage forms: 
5, 10, 15 and 25 mg capsules. 
 
 
6.4.12 Dosing regimen and dose reductions: 
Patients will need to be on a maintenance dose of lenalidomide upon being enrolled in 
the study. Doses of lenalidomide for investigation can vary from 5-25 mg/day, orally on 
days 1 - 21 followed by 7 days rest (28 day cycle). Patients may be kept on whichever 
regimen of Revlimid they were taking at the time of enrollment, or changed to an adjusted 
dose at the PI’s discretion. 
Prescriptions must be filled within 7 days. 
If a patient is on a 10mg dose of lenalidomide upon enrollment into the study, they can 
be dose reduced to 5mg and remain on study. If a patient requires a dose reduction to 
less that 5mg, further continuation on study must be approved by the principal 
investigator. 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same 
day.  If it is missed for the entire day, it should not be made up. 
Patients who take more than the prescribed dose of lenalidomide should be instructed to 
seek emergency medical care if needed and contact study staff immediately. 


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6.4.13 Dose adjustments/modifications can be made if needed based on toxicity: 
 
Table 1: LENALIDOMIDE Dose Reduction Steps 
 
Starting Dose 
Dose Reduction 
15 mg daily on Days 1-21 every 28 days 
10 mg daily on Days 1-21 every 28 days 
10 mg daily on Days 1-21 every 28 days 
5 mg daily on Days 1-21 every 28 days 
 
 
Overdose 
Overdose, as defined for this protocol, refers to Revlimid® dosing only. 
 
 
On a per dose basis, an overdose is defined as the following amount over the protocol- 
specified dose of Revlimid® assigned to a given patient, regardless of any associated 
adverse events or sequelae. 
PO 
any amount over the protocol-specified dose 
IV 
10% over the protocol-specified dose 
SC      10% over the protocol-specified dose 
 
 
On a schedule or frequency basis, an overdose is defined as anything more frequent than 
the protocol required schedule or frequency. 
On an infusion rate basis, an overdose is defined as any rate faster than the protocol- 
specified rate. Complete data about drug administration, including any overdose, 
regardless of whether the overdose was accidental or intentional, should be reported in 
the case report form. 
 
6.4.14 Concomitant therapy: 
Subjects should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, and antiemetics when appropriate. Considering that all patients will 
be on lenalidomide for several cycles prior to enrolling on the study, they will be kept on 
whichever regimen they were taking at the time of enrollment. 
 
6.4.15 Prohibited Concomitant Therapy 
Concomitant use of other anti-cancer therapies, corticosteroids, G-CSF, including 
radiation, thalidomide, or other investigational agents is not permitted while subjects are 
receiving protocol therapy during the treatment phase of the study. Topical, ophthalmic 
and inhaled corticosteroids are excluded. 


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6.4.16 Anticoagulation Considerations 
Lenalidomide increases the risk of thrombotic events in patients who are at high risk or 
with a history a thrombosis particularly when combined with steroids (e.g. dexamthasone, 
prednisone), or other anticancer drugs known to cause thrombosis (e.g. anthracyclines 
[Doxil, Adriamycin] and erythropoietin). 
Consideration should be given to use of aspirin (81 or 325 mg) or some other form of 
prophylactic antipcoagulant as deemed appropriate. Low molecular weight heparin may 
be utilized in patients that are intolerant to ASA. Coumadin should be used with caution 
and close monitoring of INR. If prophylaxis is used, it should be held when platelet counts 
< 50,000, and then restarted when platelet counts are above this level. 
 
6.4.17 General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of lenalidomide with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other 
drugs, over-the-counter medications, or alternative therapies. 
 
The allogeneic myeloma K562/GM-CSF vaccine is an immune based treatment. As such, 
immunosuppressants in the form of steroids, cyclosporine, imuran, cellcept, sirolimus, 
tacrolimus and others should not be administered during this clinical trial. For questions, 
address the Primary Investigator. 
 
6.5 
Duration of Follow-up 
Patients will be followed for a minimum of 36 months after enrollment in the study or until 
relapse or death, whichever occurs first. Patients removed from study treatment for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. 
 
6.6 
Dose delay/Dose modifications 
There are no dose modifications for the vaccine. Lenalidomide dose adjustments as 
noted in section 6.4.13. 


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NCI CTC Toxicity Grade 
(CTC AE 4.0) 
Dose Modification Instructions 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia 
• 
Hold (interrupt) lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If neutropenia has resolved to ≤ grade 2, restart lenalidomide at next 
lower dose level and continue through the scheduled end of the 
cycle. Otherwise, omit for remainder of cycle and reduce the dose of 
lenalidomide by 1 dose level at the start of the next cycle. Omitted 
doses are not made up. 
Thrombocytopenia 
≥Grade 3 (platelet count 
< 50,000/mm³) 
• 
Hold (interrupt) lenalidomide dose. 
• 
Follow CBC weekly. 
• 
NOTE: Consider criteria (perhaps based on platelet count) forholding 
and then resuming prophylactic anti-coagulation, if applicable. 
• 
If thrombocytopenia resolves to ≤ grade 2, restart lenalidomide at 
next lower dose level and continue through scheduled end of the 
cycle. Otherwise, omit for remainder of cycle and reduce the dose of 
lenalidomide by 1 dose level at start of next cycle. Omitted doses are 
not made up. 
Non-blistering rash 
Grade 3 
Grade 4 
• 
If Grade 3, hold (interrupt) lenalidomide dose.  Follow weekly. 
• 
If the toxicity resolves to ≤ grade 1, restart lenalidomide at nextlower 
dose level and continue through the scheduled end of the cycle. 
Otherwise, omit for remainder of cycle and reduce the dose of 
lenalidomide by 1 dose level at the start of the next cycle. Omitted 
doses are not made up. 
• 
If Grade 4, discontinue lenalidomide. Remove patient from study. 
Desquamating 
(blistering) rash- any 
Grade 
• 
Discontinue lenalidomide. Remove patient from study. 
Neuropathy 
Grade 3 
Grade 4 
• 
If Grade 3, hold (interrupt) lenalidomide dose. Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to Day 21, restart 
lenalidomide at next lower dose level and continue through the 
scheduled end of the cycle. Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at the start of the 
next cycle. Omitted doses are not made up. 
• 
If Grade 4, discontinue lenalidomide. Remove patient from study. 
Venous 
thrombosis/embolism 
≥ Grade 3 
• 
Hold (interrupt) lenalidomide and start anticoagulation; restart 
lenalidomide at investigator’s discretion (maintain dose level). 
• 
Omit lenalidomide for remainder of cycle. See Anticoagulation 
Consideration (Section 5.6.1.2) 
Hyperthyroidism or 
hypothyroidism 
• 
Omit lenalidomide for remainder of cycle, evaluate etiology, and 
initiate appropriate therapy. 
• 
See Instructions for Initiation of a New Cycle and reduce the dose of 
lenalidomide by 1 dose level. 
other non-hematologic 
toxicity ≥ Grade 3 
• 
Hold (interrupt) lenalidomide dose. Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 2 prior to Day 21, restart 
lenalidomide and continue through the scheduled end of the cycle. 
Otherwise, omit for remainder of cycle. Omitted doses are not made 
up. For toxicity attributed to lenalidomide, reduce the lenalidomide 
dose by 1 dose level when restarting lenalidomide. 


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7 SCREENING AND ELIGIBILITY 
Subjects must meet the following inclusion/exclusion criteria to be eligible for the study. 


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7.1 Inclusion Criteria: 
• Myeloma eligibility criteria are the following: 
• Near complete remission (nCR) for ≥ 3 months defined as no measurable 
M-spike, and a positive serum immunofixation 
▪ For patients with a light chain only myeloma, they will be in deemed 
to be in a CR if they meet criteria for CR by International Myeloma 
Working Group (IMWG) consensus criteria 2016. 
▪ For patients with a light chain only myeloma that meet criteria for 
Very Good Partial Response (VGPR) by IMWG consensus 
criteria 2016 and are IFE –ve (negative serum immunofixation), 
they will be considered to be in a near complete remission 
(nCR). 
• Or complete remission (CR) (no measurable M-spike, immunofixation 
negative and bone marrow clonal plasma cells <5%) 
• NDMM or RMM in nCR or CR having completed a minimum of 6 cycles of 
a lenalidomide based regimen for a minimum of ≥ 3 months 
• NDMM or RMM a patients who have been off corticosteroids for ≥ 4 weeks 
• Patients with NDMM or RMM who have had autologous stem cell 
transplant are eligible, but must be ≥ 12 months from transplant 
• All patients must be MRD positive at 10-4 or greater by NGS sequencing at 
enrollment 
• All patients must be currently taking Revlimid at screening. 
• Age >18 years 
• ECOG performance scores 0-2 
• History of measurable serum or urine M protein or free light chains 
• Life expectancy greater than 12 months 
• Corrected serum calcium < 11 mg/dL, and no evidence of symptomatic 
hypercalcemia 
• Serum creatinine< 2 mg/dl 
• ANC >1000/µL 
• Platelet >100,000/µL 
• Total bilirubin  1.5 x ULN 
• AST (SGOT) and ALT (SGPT)  3 x ULN. 
• Ability to comprehend and have signed the informed consent. 
• Have previously agreed to continue on maintenance therapy with lenalidomide 
concurrent with vaccine administration until disease progression, or clinical 
indication to cease therapy. 
• All patients must be willing and able to comply with the requirements of the 
REMS® program as directed by their providers. 
• All study participants will have been registered into the mandatory Revlimid 
REMS® program as per standard of care, prior to enrollment. 
• Females of reproductive potential must adhere to the scheduled pregnancy 
testing as required in the Revlimid REMS® program. 


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• Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior 
to starting lenalidomide with each cycle (prescriptions must be filled within 7 
days) and must either commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth control, one highly 
effective method and one additional effective method AT THE SAME TIME, at 
least 28 days before taking lenalidomide, as per standard of care. FCBP must 
also agree to ongoing pregnancy testing. Men must agree to use a latex condom 
during sexual contact with a FCBP even if they have had a successful 
vasectomy. See Appendix 5: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods. 
• Able to take prophylactic anticoagulation (aspirin 81 or 325 mg/daily or, for 
patients intolerant to ASA, warfarin or low molecular weight heparin). 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
 
7.2 Exclusion Criteria: 
 
• Disease progression after stopping corticosteroids as defined as the appearance 
of a detectable serum or urine M-spike, or an absolute increase of >10 mg/dl 
between involved and uninvolved light chains, in the absence of measurable 
serum or urine M-protein. 
• Patients who are MRD negative by NGS at screening. 
• Patients with a known diagnosis of POEMS syndrome, plasma cell leukemia, 
CNS involvement, non-secretory myeloma and amyloidosis 
• High-risk myeloma defined by presence of at least one of the following defining 
features on initial diagnostic, or most recent bone marrow biopsy: 
• High risk chromosomal translocations by FISH: t(4;14), t(14;16), t(14;20), 
• del(17p), del(1p), amplification 1q.; 
• MyPRS GEP-70 or SkylineDx high risk signature either from diagnosis or 
at time of registration for the study; 
• LDH > 300 U/L at diagnosis; 
• Relapse from prior therapy within 12 months. 
• HIV disease, active infection requiring treatment with antibiotics, anti-fungal or 
anti-viral agents within 2 weeks of enrollment would be excluded from the study. 
• History of a pre-existing malignancy other than myeloma within the last 5 years 
with exception of treated basal cell or squamous cell carcinoma of the skin, or 
carcinoma “in situ” of the uterus, cervix or breast. 
• Patients who have participated in any clinical trial, within the last four weeks, 
which involved an investigational drug. 
• Autoimmune disease requiring active treatment. 
• Known contra-indication to any component of allogeneic myeloma vaccine 
• History of an allogeneic transplant 


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7.3 Visit Schedule And Assessments 
Screening assessments and procedures to be performed on study scheduled visits are 
outlined in Section 2 Table of Study Assessments. All screening assessments should be 
completed within 28 days from consent and prior to Cycle 1 Day 1. The day 14 visit can 
occur ± 3 days. 
An unscheduled visit can occur at any time during the study. For all unscheduled visits, 
source documents must be maintained and the date for the visit and any data generated 
must be recorded on the appropriate CRF. 
Investigators may also assess participants via telemedicine at any point the investigator, 
local health or government authorities and/or other Hopkins authorities deem it 
appropriate. In these cases, an assessment may not include a physical exam or samples 
collection.  All efforts should be made to perform in person visits if possible. 
 
7.4 Follow-Up 
Subjects who discontinue study treatment for any reason will undergo a safety 
assessment approximately 30 days post the last dose of study drug. 
 
7.5 Serious Adverse Event (SAE) Definition 
A serious adverse event (SAE) is one that at any dose (including overdose): 
• Results in death 
• Is life-threatening1 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity2 
• Is a congenital anomaly or birth defect 
• Is an important medical event3 
• Pregnancy 
1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused 
death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred. Important medical 
events that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above should also usually be considered serious. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. A new diagnosis of cancer during the course of a treatment should be considered as 
medically important. 
 
 
7.6 Adverse Drug Reaction Reporting 
Toxicity will be scored using CTC Version 4.0 for toxicity and adverse event reporting. A 


45 
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Protocol 
copy of the CTC Version 4.0 can be downloaded from the CTEP homepage 
(http://ctep.info.nih.gov). All appropriate treatment areas have access to a copy of the 
CTC Version 4.0.        All adverse events (AEs), whether observed by the investigator or 


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reported by the patient, must be recorded with details about the duration and intensity of 
each episode, the action taken with respect to the test drug, and the patient’s outcome. 
The investigator must evaluate each adverse experience for its relationship to the test 
drug and for its seriousness. 
The principal investigator is responsible for evaluating all adverse events, obtaining 
supporting documents, and determining that documentation of the event is adequate. The 
principal investigator is responsible for determining the severity and relationship of the 
adverse event to the investigational drug. The principal investigator may delegate these 
duties to sub-investigators and must assure that these sub-investigators are qualified to 
perform these duties under the supervision of the principal investigator. 
 
All adverse events will be recorded in the subject’s Case Report Form and in the study 
data base. The detailed description of the event will include appropriately graded severity 
of the adverse event and its relationship to the studydrug. 
Severity of adverse events will be categorized by toxicity grade according to the NCI 
Common Terminology Criteria for Adverse Events version 5.0 available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
7.6.1 Adverse events not listed in the NCI Common Terminology Criteria 
Adverse events not listed in the NCI Common Terminology Criteria for Adverse Events 
will be evaluated using the following criteria: 
 
Grade 1, Mild: Awareness of symptom, but easily tolerated; usually transient requiring no 
special treatment; does not interfere with usual status oractivities 
Grade 2, Moderate: May be ameliorated by simple therapeutic measures; may interfere 
with usual activities 
Grade 3, Severe: Incapacitating, inability to perform usual activities 
Grade 4, Life-threatening/Disabling: Subject was at risk of death or significant disability 
at the time of the event 
Grade 5, Death related to AE 
 
 
7.6.2 Relationship of the Adverse Event to the Investigational Drug 
Relationship of the adverse event to the investigational drug will be determined by the 
principal investigator, and will be categorized as: 
 
Not Related: The adverse event is clearly related to other factors such as the subject’s 
clinical state, environmental factors, or other modes of therapy or concomitant drugs 
administered to the subject. 


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Possible: The adverse event follows a reasonable temporal sequence from 
administration of the study drug, and/or follows a known response pattern to the study 
drug, but could readily have been produced by the subject’s clinical state, environmental 
factors, or other modes of therapy or concomitant drugs administered to the subject. 
Probable: The adverse event follows a reasonable temporal sequence from 
administration of the study drug and follows a known response pattern to the study drug, 
and cannot readily have been produced by the subject’s clinical state, environmental 
factors, or other modes of therapy or concomitant drugs administered to the subject. 
 
The investigator must appraise all abnormal clinical laboratory results for their clinical 
significance. In accordance with FDA requirements and guidelines, we shall report the 
most frequent and most serious adverse events (SAEs) suffered by subjects on the 
clinical trial. 
If any abnormal laboratory result is considered clinically significant and possibly drug 
related, the investigator must provide details about the action taken with respect to the 
study drug and about the patient’s outcome. 
 
 
7.7 
Expedited Reporting By Investigator To Celgene 
 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the 
expectedness of events of being related to lenalidomide based on the Investigator 
Brochure. In the United States, all suspected unexpected serious adverse reactions 
(SUSARs) will be reported in an expedited manner in accordance with 21 CFR 312.32. 
Serious adverse events (SAE) are defined above. The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 
hours of being aware of the event. The written report must be completed and supplied to 
Celgene by facsimile within 24 hours. The initial report must be as complete as possible, 
including an assessment of the causal relationship between the event and the 
investigational product(s). Information not available at the time of the initial report (e.g., 
an end date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up report. A final report to document resolution of the SAE is 
required. The Celgene tracking number (RV-CL-MM-PI-005749) and the institutional 
protocol number should be included on SAE reports (or on the fax cover letter) sent to 
Celgene. A copy of the fax transmission confirmation of the SAE report to Celgene should 
be attached to the SAE form, and retained with the patient records. 
 
7.8 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless 
of age or disease state) of a female subject occurring while the subject is on IP, or within 
28 days of the subject’s last dose of IP, are considered immediately reportable events. IP 


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is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by facsimile, or 
other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form. The female subject may be referred to an obstetrician-gynecologist (not 
necessarily one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation. 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either 
normal or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved 
equivalent form. 
IF THE OUTCOME OF THE PREGNANCY WAS ABNORMAL (E.G., SPONTANEOUS 
OR THERAPEUTIC ABORTION), THE INVESTIGATOR SHOULD REPORT THE 
ABNORMAL OUTCOME AS AN AE. IF THE ABNORMAL OUTCOME MEETS ANY OF 
THE SERIOUS CRITERIA, IT MUST BE REPORTED AS AN SAE TO CELGENE DRUG 
SAFETY IMMEDIATELY BY FACSIMILE, OR OTHERAPPROPRIATE METHOD, 
WITHIN 24 HOURS OF THE INVESTIGATOR’S KNOWLEDGE OF THE EVENT USING 
THE SAE REPORT FORM, OR APPROVED EQUIVALENT FORM. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death after 28 days that the Investigator 
suspects is related to the in utero exposure to the IP should also be reported to Celgene 
Drug Safety immediately by facsimile, or other appropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form, or approved equivalent 
form. 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, 
the male subject taking lenalidomide should notify the Investigator, and the pregnant 
female partner should be advised to call their healthcare provider immediately. 
 
7.9 
Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ 07922 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
 
7.10 Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements. If the 
FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date. 21 CRF 312.33 


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provides the data elements that are to be submitted in the report. The Annual Report 
should be filed in the study's Regulatory Binder, and a copy provided to 
Celgene Corporation as a supporter of this study as follows: 
Celgene Corporation 
Attn: Medical Affairs Operations 
Connell Corporate Park 
400 Connell Drive, Suite 700 
Berkeley Heights, NJ 07922 
Tel: (908) 673-9000 
All adverse experience reports must include the patient number, age, sex, weight, severity 
of reaction (e.g. mild, moderate, severe), relationship to drug (e.g. 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 as defined above are present. The investigator is responsible for 
reporting adverse events to Celgene as described below. 
 
7.11 Report Of Adverse Events To The Institutional Review Board 
The Principal Investigator is required to notify the Institutional Review Board (IRB) by 
facsimile using the serious adverse experiences CRF within 7 calendar days of observing 
or learning of a serious and unexpected adverse event. A mailed hard copy to the IRB 
(with a copy to the study monitor) must be submitted within 15 calendar days of observing 
or learning of the event. The written report should identify all safety reports previously 
filed with the IND concerning a similar adverse reaction and should analyze the 
significance of the adverse reaction in light of the previous, similar reports. 
 
7.12 Investigator Reporting To The FDA 
Adverse drug reactions that are Serious, Unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
Brochure, or reference safety information documents should be reported promptly to the 
Food and Drug Administration (FDA) in writing by the Primary Investigator (PI) engaged 
in clinical research. A clear description of the suspected reaction should be provided along 
with an assessment as to whether the event is drug or disease related. 
 
The PI must notify the FDA by telephone or fax of any unexpected, fatal or life threatening 
experience associated with the use of the drug as soon as possible but no later than 7 
days of the sponsors initial receipt of the information. 
 
7.13 Adverse Event Updates/Ind Safety Reports 
Celgene shall notify the Primary Investigator via an IND Safety Report of the following 
information: 


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• Any AE associated with the use of study drug in this study or in other studies that 
is both serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
The Primary Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. 
 
The Primary Investigator must keep copies of all AE information, including 
correspondence with Celgene and the IRB/EC, on file. 
 
8 RESPONSE CRITERIA 
Baseline tumor assessments must occur within  28 days of initiation of the study as 
indicated in Section 2, Schedule of Study Assessments. 
Measurements of anti-myeloma efficacy will occur prior to the initiation of each cycle of 
lenalidomide. Myeloma response assessments will be based on the International Uniform 
Criteria. 52 
Patients with confirmed progressive disease will be eligible to cross over on to the vaccine 
arm based on clinical judgement, available response data, and the PI’s discretion, or be 
removed from study treatment. 
Research blood and marrow will be used to assess responses during the trial. This will 
likely include but are not limited to: 
1. Tumor specific immunity 
2. Assessment of myeloid derived suppressor cell (MDSC) numbers and function by 
flow cytometry and T cell proliferation assays. 
3. Activation markers on T cells by flow cytometry 
4. Clonogenic myeloma precursors by flow cytometry. 
5. Minimal Residual Disease (MRD) testing 
The major purpose of this study is to determine whether the addition of an allogeneic 
myeloma vaccine can augment clinical responses to Lenalidomide. 
 
9 PROTOCOL AMENDMENTS/DEVIATIONS 
9.1 
Protocol amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and 
reviewed by Celgene. Amendments should only be submitted to IRB/EC after 
consideration of Celgene review. Written verification of IRB/EC approval will be obtained 
before any amendment is implemented. 


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9.2 
Protocol deviations 
When an emergency occurs that requires a deviation from the protocol for a subject, a 
deviation will be reported only for that subject. A decision will be made as soon as possible 
to determine whether or not the subject (for whom the deviation from protocol was 
effected) is to continue in the study treatment. The subject’s medical records will 
completely describe the deviation from the protocol and state the reasons for such 
deviation. In addition, the Investigator will notify the IRB/EC in writing of such deviation 
from protocol. 
Non-emergency minor deviations from the protocol will be permitted with approval of the 
Principal Investigator. 
 
10 DATA MANAGEMENT 
10.1 Analyses and Reporting 
Patients will be considered evaluable for safety and efficacy once they have initiated any 
study treatment (lenalidomide, vaccine and/or Prevnar vaccine). 
Safety will be monitored continuously throughout the trial. Efficacy will be analyzed upon 
trial completion.  No interim efficacy analyses are planned. 
 
 
10.2 Study monitoring and Auditing 
The protocol will be monitored internally by the Principal Investigator and externally via 
the SKCCC Compliance Monitoring Program which provides external monitoring for JHU- 
affiliated sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019). The 
Institution’s Safety Monitoring Committee (SMC) Subcommittee will determine the level 
of patient safety risk and level/frequency of monitoring. 
 
10.2.1 Investigator Responsibilities 
The Primary Investigator’s responsibilities are set out in the ICH guideline for Good 
Clinical Practice (GCP) and in the US Code of Federal Regulations. 
Study data will be entered onto a dedicated GVAX database. The Primary Investigator 
will permit study-related monitoring visits and audits by Celgene or its representatives, 
IRB/IEC review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct 
access to the facilities where the study took place, to source documents, to CRFs, and to 
all other study documents. 
The Primary Investigator, or a designated member of the Investigator’s staff, must be 
available during monitoring visits to review data, to resolve any queries and to allow direct 


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access to the subject’s records (e.g., medical records, office charts, hospital charts, and 
study related charts) for source data verification. The data collection must be completed 
prior to each monitoring visit and be made available to the Celgene representative so that 
the accuracy and completeness may be checked. 
 
10.2.2 Data Safety Monitoring Board (DSMB) 
The role of the DSMB will be to monitor the study for safety and toxicity issues regarding 
the combination of Lenalidomide with a cellular myeloma vaccine. Interim analysis of 
toxicity, outcome, and ongoing scientific investigations will be performed at least annually 
by the Sidney Kimmel Comprehensive Cancer Center Data Safety Monitoring Board 
(SKCCC DSMB). The SKCCC DSMB Recommendation letter will state the timeline for 
the next required review. The SKCCC DSMB will review aspects of this trial that are 
outlined in the responsibilities section of the Data and Safety Monitoring Board (DSMB) 
Guidance. If the committee decides that amendments should be made to this trial, 
recommendations will be made in writing to the study Principal Investigator. The study 
team will submit modifications to the IRB within 60 days of receipt from the DSMB. The 
Associate Director of Clinical Research will arbitrate any disagreements between the 
DSMB and the study Principal Investigator. These changes may include early termination 
of accrual if deemed appropriate. 
 
 
11 BIOSTASTICAL ANALYSIS 
11.1 Sample Size Considerations 
The primary endpoint of this phase II study is progression free survival (PFS). The primary 
analysis will compare the control arm (lenalidomide plus placebo) versus the pooled 
allogenic myeloma vaccine arms (with and without Prevnar) In a prior study, the median 
PFS for patients on Len containing therapy was 17.9 months. Patients will be accrued 
over the course of 2 years with a minimum follow-up of 3 years (i.e. all patients will have 
3-5 years of follow-up). A sample size of 54 patients (18 placebo vs 36 allogenic myeloma) 
would provide 80% power to detect an increase in the median PFS from 18 months in the 
control arm to 42.8 months in the pooled vaccine arm (HR = 0.4199) based upon a log- 
rank test assuming a two-sided type I error rate of 10% and a loss to follow- up rate of 1% 
per year (5% overall). The accrual rate is expected to be 2.3 per month. Due to the small 
sample size, no interim efficacy analysis is planned at this time. 
 
 
Our principal secondary endpoints will be conversion from “near CR” (M-spike at or below 
0 but IFE positive), to “true CR” (IFE negative), and conversion from MRD positive status 
to MRD negative status. The trial will accrue patients for a total n=18 per arm at single 
center for a period two years, while trial duration for every patient enrolled will be 3 years. 
The analysis will be performed on the intention to treat population. 


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11.2 Statistical Analyses 
The efficacy and safety analysis populations will include all patients that received at least 
one dose of their assigned treatment. The primary analyses will compare the control arm 
with the pooled vaccine arm. Secondary analyses will compare the two vaccine arms to 
one another and to the control arm. 


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Demographic and disease characteristics will be summarized overall and within each 
treatment group using medians and ranges for continuous variables and counts and 
proportions for categorical variables. 
 
The primary outcome (PFS) is defined as the time from randomization until progression 
or death. Individuals who do not have an event will be censored at the date of last 
assessment. Kaplan-Meier estimates of the survival function will be used to compare the 
two treatment groups graphically as well as to provide estimates of the median PFS and 
the proportion who have progressed at key time points (e.g. 1-, 2-, and 3-years) with 90% 
confidence intervals. Log-rank tests will be used to compare the treatment groups and 
Cox proportional hazards models will be used to examine the effects of specific risk 
factors of interest and their interaction with treatment (e.g. vaccine by MRD status 
interactions). If the proportional hazards assumption is violated, the piecewise 
proportional hazards models or other semi-nonparametric approaches will be used. Key 
secondary endpoints include conversion from “near CR” (M-spike at or below 0 but IFE 
positive), to “true CR” (IFE negative), and conversion from MRD positive status to MRD 
negative status. These and other time to event outcomes including will be analyzed in a 
similar manner to the primary outcome as well as with competing risk models to account 
for death or progression. 
 
Tumor immunology assessments will be made at baseline and on day 14 of cycles 3, 6, 
and 12 (the 1-year assessment). At each time point, graphical (e.g. boxplots over time, 
spaghetti plots) and numeric (e.g. median, range, proportion) summaries will be used to 
explore the continuous (e.g. T cell populations) and binary (e.g. tumor specific immunity) 
outcomes. If appropriate, transformations (e.g. log) will be used to address skewness in 
the data. Cross-sectional comparisons will be made using t-tests, Kruskal-Wallis tests, or 
linear regression and Chi-squared tests, Fisher’s exact test, or logistic regression for 
continuous and categorical outcomes, respectively. Generalized estimating equations 
and mixed effects models will be used to formally model the behavior over time and 
compare treatment groups and/or risk factors while adjusting for repeated measurements 
within each individual. The association between baseline tumor measuarement as well as 
changes in tumor measurements over time and clinical outcomes will be assessed using 
Cox proportional hazards models. 
 
Toxicity will be scored using NCI CTC Version 4.0 for toxicity and adverse events. All 
toxicities will be summarized overall, by treatment group, and within subgroups of interest 
(e.g. true CR status, MM type). The number of toxicities and number of affected patients 
will be tabulated by type, grade, and relatedness to study treatment (overall and for each 
treatment). In addition to counts and proportions, the toxicity rates will be modeled and 
compared between treatment groups and subgroups of interest using Poisson regression 
or Negative Binomial regression, as appropriate. 
 
11.3 Toxicity Stopping Guidelines: 


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The proportion of unacceptable toxicities will be continuously monitored in each arm 
separately. Unacceptable toxicities include hematologic toxicities of lenalidomide: low 
neutrophils (ANC <1000) and low platelets (<50K), for which we would hold the vaccine 
administration, as well as vaccine related toxicities which include: grade 3/4 local 
reactions (erythema, swelling, pain) and systemic symptoms (fevers, rash) (Refer to 7.6.1 
and 7.6.2 for guidelines on attribution of toxicities). 
 
Unacceptable toxicities as scored using NCI CTCAE V5.0 include: 
• Any laboratory or clinical organ dysfunction ≥ Grade 3 
• Abnormalities of coagulation (prolonged prothrombin, partial thromboplastin and 
clotting times ≥ Grade 3 
• Autoimmune disease reactivation or development ≥ Grade 2 
• Immune system disorders including myalgias or headaches ≥ Grade 3 
• Immune system disorders including allergic or hypersensitivity reactions such as 
rash, or fever ≥ Grade 3 
• Immune system disorders including anaphylaxis or anaphylactoid reactions (eg. 
Wheezing, urticarial, hypotension) ≥ Grade 3 
• General disorders and administration site conditions including injection site 
reactions such as tenderness with or without associated symptoms (e.g., warmth, 
erythema, itching, and malaise) ≥ Grade 3 
• Any other undefined or unanticipate adverse event ≥ Grade 3 
• Any death on study 
 
If the levels of uacceptable toxicitiy is too high (i.e. a high probability that they exceed the 
maximum threshold of 30%), then enrollment will be suspended pending review by the 
PI, DSMB, and Celgene. Any death on study within 30 days of GVAX administration will 
lead to suspension of enrollment pending review by the PI, DSMB, and Celgene. 
 
A Bayesian stopping guideline will be used to assess the level of unacceptable toxicity. 
We expect the rate of unacceptable toxicities to be 25%. Hence a Beta(1, 3) prior was 
used. After the first three patients are recruited, toxicity will be monitored continuously. 
Accrual will be suspended if the probability that the unacceptable toxicity rate exceeds 
30% is 0.70 or higher. Table 11.1 shows the number of toxicities needed to halt accrual. 
 
Table 11.1. The number of toxicities needed to trigger stopping guidelines throughout the 
course of the study. 
 
Number of Subjects Per 
Treatment Arm 
Number of toxicities 
needed to trigger 
re-evaluation 
3-4 
3 
5-7 
4 
8-10 
5 
11-13 
6 
14-16 
7 
17-18 
8 


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The operating characteristics of these stopping guidelines were generated based upon 
5000 simulations (Table 11.1). 
 
Table 11.2. Probability of triggering stopping guidelines based upon range of underlying 
toxicity rates. 
 
True Toxicity 
(DLT) Risk 
Prob. Declare 
Treatment Too 
Toxic 
Avg. Sample 
Size 
0.05 
<0.1% 
18.0 
0.10 
0.4% 
18.0 
0.15 
2.7% 
17.7 
0.20 
7.6% 
17.2 
0.25 
15.2% 
16.5 
0.30 
27.7% 
15.4 
0.35 
44.0% 
13.8 
0.40 
59.5% 
12.3 
  
0.45 
74.2% 
10.7 
 
 
 
 
 
12 REGULATORY CONSIDERATIONS 
12.1 Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki. The review of this protocol by the IRB/EC 
and the performance of all aspects of the study, including the methods used for obtaining 
informed consent, must also be in accordance with principles enunciated in the 
declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), 
Part 50 Protection of Human Subjects and Part 56 Institutional ReviewBoards. 
The Primary Investigator will be responsible for preparing documents for submission to 
the relevant IRB/EC and obtaining written approval for this study. The approval will be 
obtained prior to the initiation of the study. 
The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by 
the Investigator to the IRB/EC for approval. The Investigator is also responsible for 
notifying the IRB/EC of any serious deviations from the protocol, or anything else that 
may involve added risk to subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved 
by the IRB/EC prior to use. 


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12.2 Informed consent 
The Primary Investigator must obtain informed consent of a subject or his/her designee 
prior to any study related procedures as per GCPs as set forth in the CFR and ICH 
guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study 
and the informed consent process should be recorded in the subject’s source documents. 
The original consent form, signed and dated by the subject and by the person consenting 
the subject prior to the subject’s entry into the study, must be maintained in the 
Investigator’s study files. 
 
12.3 Subject confidentiality 
The Primary Investigator and Celgene affirms the subject’s right to protection against 
invasion of privacy. In compliance with United States federal regulations, Celgene 
requires the Primary Investigator to permit Celgene’s representatives and, when 
necessary, representatives of the FDA or other regulatory authorities to review and/or 
copy any medical records relevant to the study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Primary 
Investigator to obtain such permission in writing from the appropriate individual. 
 
12.4 Study records requirements 
The Primary Investigator must ensure that the records and documents pertaining to the 
conduct of the study and the distribution of the study drug be retained for as long as 
needed to comply with national, international and site specific regulations (generally 2 
years after discontinuing clinical development or last marketing approval. This applies to 
copies of CRFs and source documents including but not limited to hospital records; 
clinical and office charts; laboratory notes; memoranda; subject’s diaries or evaluation 
checklists; SAE reports; pharmacy dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; 
microfiches; photographic negatives, microfilm, or magnetic media; x-rays; subject files; 
and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical study; documents regarding subject treatment and 
study drug accountability; and original signed informed consents. The Investigator agrees 
to adhere to the document/records retention procedures by signing theprotocol. 
 
12.5 Premature discontinuation of study 
The Primary Investigator as well as Celgene have the right to discontinue this study at 
any time for reasonable medical or administrative reasons in any single center. Possible 
reasons for termination of the study could be but are not limited to: 
• Unsatisfactory enrollment with respect to quantity or quality. 
• Inaccurate or incomplete data collection. 


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• Falsification of records. 
• Failure to adhere to the study protocol. 
Any possible premature discontinuation would be documented adequately with reasons 
being stated, and information would have to be issued according to local requirements 
(e.g., IRB/EC, regulatory authorities, etc.). 
 
 
13 RESPONSIBILITIES 
13.1 Primary Investigator 
The Primary Investgator is responsible for performing the following tasks: 
• Coordinating, developing, submitting, and obtaining approval for the protocol as 
well as its subsequent amendments. 
• Taking responsibility for the overall conduct of the study, andand for monitoring 
the progress of the study. 
• Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
 
 
14 PATIENTS WITH PROGRESSIVE DISEASE ON THE CONTROL ARM 
Patients on the placebo control arm without GVAX vaccine with evidence of progressive disease by 
criteria defined in this protocol, who were in CR (defined as no measurable M-spike, immunofixation 
negative and bone marrow plasma cells <5%) but no longer meet the criteria for CR, or patients who were 
in nCR (no measurable M-spike, and a positive serum immunofixation) who develop measurable M- 
protein or free light chains in the serum or urine, or patients who were MRD negative who subsequently 
become MRD positive, can be evaluated, and potentially considered for roll over to the vaccine arm, 
provided they meet criteria for enrollment, and at the clinical discretion of the PI. 


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APPENDICES 
APPENDIX 1: ECOG PERFORMANCE STATUS SCALE 
 
 
SCORE 
DESCRIPTION 
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. 
For list of Treatment Assignment Stratification prognostic indicators, see Appendix IV. 
 
APPENDIX 2: TUMOR CLASSIFICATION 
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: 
• Any two of the major criteria 
• Major criterion 1 plus minor criterion b, c, or d 


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• Major criterion 3 plus minor criterion a or c 
• Minor criterion a, b and c or a, b and d 
International Staging System for Multiple Myleoma 
Stage I 
• Albumin ≥3.5 g/dl AND 
• Beta-2-microglobulin <3.5 mg/L 
 
Stage II 
Neither stage I nor stage III 
 
Stage III 
• Beta-2-microglobulin >5.5 mg/L 
Durie-Salmon Staging of Multiple Myeloma 
Stage I 
All of the following must be present: 
• Hemoglobin  10.5 g/dL or hematocrit32% 
• Serum calcium level normal 
• 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 
• No bone lesions 
 
Stage II 
All patients who do not meet criteria for Stage I or III are considered Stage II. 
 
Stage III 
One of the following abnormalities must be present: 
• Hemoglobin  8.5 g/dL, hematocrit 25% 
• Serum calcium 12 mg/dL 
• Very high serum or urine myeloma protein production rates as evidenced byone 
or more of the following: 
• IgG peak  7g/dL 
• IgA peak  5g/dL 
• Bence Jones protein  12g/24 h 
•  3 lytic bone lesion on bone survey (bone scan not acceptable) 
Subclassification 
A: 
Serum creatinine 2.0 mg/dL 
B: 
Serum creatinine>2.0 mg/dL 


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APPENDIX 3: CRITERIA FOR DISEASE EVALUATION 
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, and response calculations using 
that value as baseline will also be performed in secondary analyses. 
 
Definitions of Response 
 
Responses will be defined as per the modified International Uniform Response Criteria 
for myeloma.52 
 
Response sub 
category 
Response criteriaa 
sCR 
CR as defined below plus normal FLC ratio and absence of 
clonal cells in bone marrowb by immunohistochemistry or 
immunofluorescencec 
CR 
Negative immunofixation on the serum and urine and 
disappearance of any soft tissue plasmacytomas and <5% 
plasma cells in bone marrowb 
nCR 
Serum and urine M-protein undetectable. Immunofixation 
positive. 
VGPR 
Serum and urine M-protein detectable by immunofixation but 
not on electrophoresis or 90% or greater reduction in serum M- 
protein plus urine M-protein level <100mg per 24 h. 
PR 
>50% reduction of serum M-protein and reduction in 24-h 
urinary M-protein by >90% or to <200mg per 24 h. If the serum 
and urine M-protein are unmeasurable,d a >50% decrease in 
the difference between involved and uninvolved FLC levels is 
required in place of the M-protein criteria. If serum and urine M- 
protein are unmeasurable, and serum free light assay is also 
unmeasurable, X50% reduction in plasma cells is required in 
place of M-protein, provided baseline bone marrow plasma cell 
percentage was >30%. In addition to the above listed criteria, if 
present at baseline, a >50% reduction in the size of soft tissue 
plasmacytomas is also required. 
SDe 
Not meeting criteria for CR, VGPR, PR or progressive disease 
PD 
Any one or more of the following criteria: 
Increase of 25% from lowest confirmed response value in one 
or more of the following criteria: 
• Serum M-protein (absolute increase must be ≥0.5 g/dL) 
• Serum M-protein increase ≥1 g/dL, if the lowest M component 
was ≥5 g/dL 
• Urine M-protein (absolute increase must be ≥200 mg/24 h) 


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• In patients without measurable serum and urine M-protein 
levels, the difference between involved and uninvolved FLC 
levels (absolute increase must be >10 mg/dL) 
• In patients without measurable serum and urine M-protein 
levels and without measurable involved FLC levels, bone 
marrow plasma-cell percentage irrespective of baseline status 
(absolute increase must be ≥10%) 
• Appearance of a new lesion(s), ≥50% increase from nadir in 
SPD of >1 lesion, or ≥50% increase in the longest diameter of 
a previous lesion >1 cm in short axis 
≥50% increase in circulating plasma cells (minimum of 200 cells 
per μL) if this is the only measure of disease 
Relapse from CR 
Any of the following criteria: 
• Reappearance of serum or urine M-protein by immunofixation 
or electrophoresis 
• Development of ≥5% plasma cells in the bone marrow 
Appearance of any other sign of progression (ie, new 
plasmacytoma, lytic bone lesion, or hypercalcemia) 
Relapse from MRD- 
negative CR 
Any one or more of the following criteria: 
• Loss of MRD negative state (evidence of clonal plasma cells 
on NGF or NGS, or positive imaging study for recurrence of 
myeloma) 
• Reappearance of serum or urine M-protein by immuno xation 
or electrophoresis 
Development of ≥5% clonal plasma cells in the bone marrow; 
Appearance of any other sign of progression (ie, new 
plasmacytoma, lytic bone lesion, or hypercalcemia) 
Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, 
stable disease; sCR, stringent complete response; VGPR, very good partial response; 
PD, progressive disease; MRD, minimal residual disease. 
a. All response categories require two consecutive assessments made at any time 
before the institution of any new therapy; all categories also require no known 
evidence of progressive or new bone lesions if radiographic studies were performed. 
Radiographic studies are not required to satisfy these response requirements. 
b. Confirmation with repeat bone marrow biopsy not needed. 
c. Presence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 
plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone 
is k/l of 44:1 or 1:2. 
d. Refer to “Practical details of response evaluation” for definitions ofmeasurable 
disease. 
e. SD is not recommended for use as an indicator ofdisease. 
 
Practical details of response evaluation 


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Definitions of measurable disease 
 
Response criteria for all categories and subcategories of response except CR are 
applicable only to patients who have ‘measurable’ disease defined by at least one of the 
following three measurements: 
1. Serum M-protein >1 g/dl (>10 gm/l)[10 g/l] 
2. Urine M-protein >200 mg/24 h 
3. Serum FLC assay: Involved FLC level >10 mg/dl (>100 mg/l) provided serum 
FLC ratio is abnormal 
 
 
 
APPENDIX 4: NCI CTC VERSION 4.03 
Toxicity will be scored using NCI CTC Version 4.03 for toxicity and adverse event 
reporting. A copy of the NCI CTC Version 4.03 can be downloaded from the CTEP 
homepage: (http://ctep.info.nih.gov). All appropriate treatment areas have access to a 
copy of the CTC Version 4.0. 


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APPENDIX 5: RISKS OF FETAL EXPOSURE, PREGNANCY TESTING 
GUIDELINES AND ACCEPTABLE BIRTH CONTROL METHODS 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied 
nor has the effect of the lenalidomide on human eggs and sperm. Lenalidomide is 
structurally related to thalidomide. Thalidomide is a known human teratogenic active 
substance that causes severe life-threatening birth defects.  An embryofetal 
development study in animals indicates that lenalidomide produced malformations in the 
offspring of female monkeys who received the drug during pregnancy. The teratogenic 
effect of lenalidomide in humans cannot be ruled out.  Therefore, a risk minimization 
plan to prevent pregnancy must be observed. 
All study participants must be registered into the mandatory RevAssist® program, and be 
willing and able to comply with the requirements of RevAssist®. 
 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female 
who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been 
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at 
any time in the preceding 24 consecutive months). 
 
 
The investigator must ensure that: 
• Females of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that she has an adequate level of 
understanding 
• Females NOT of childbearing potential acknowledge that she understands the 
hazards and necessary precautions associated with the use oflenalidomide 
• Male patients taking lenalidomide acknowledge that he understands that traces of 
lenalidomide have been found in semen, that he understands the potential 
teratogenic risk if engaged in sexual activity with a female of childbearing potential, 
and that he understands the need for the use of a condom even if he has had a 
vasectomy, if engaged in sexual activity with a female of childbearing potential. 
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence 
from 


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heterosexual intercourse during the following time periods related to this study: 1) for at 
least 28 days before starting lenalidomide; 2) throughout the entire duration of 
lenalidomide treatment; 3) during dose interruptions; and 4) for at least 28 days after 
lenalidomide discontinuation. 
The two methods of reliable contraception must include one highly effective method and 
one additional effective (barrier) method. FCBP must be referred to a qualified provider 
of contraceptive methods if needed. The following are examples of highly effective and 
additional effective methods of contraception: 
• Highly effective methods: 
• Intrauterine device (IUD) 
• Hormonal (birth control pills, injections, implants) 
• Tubal ligation 
• Partner’s vasectomy 
• Additional effective methods: 
• Male condom 
• Diaphragm 
• Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are 
not recommended. If a patient is currently using combined oral contraception the patient 
should switch to one of the effective method listed above. The risk of venous 
thromboembolism continues for 4−6 weeks after discontinuing combined oral 
contraception. The efficacy of contraceptive steroids may be reduced during co-treatment 
with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding. 
Prophylactic antibiotics should be considered particularly in patients with neutropenia. 
 
 
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing 
potential who commit to complete abstinence, as outlined below. 


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Before starting lenalidomide 
Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
prescribing lenalidomide. The first pregnancy test must be performed within 10-14 days 
prior to prescribing lenalidomide and the second pregnancy test must be performed within 
24 hours prior to prescribing lenalidomide. The patient may not receive lenalidomide until 
the Investigator has verified that the results of these pregnancy tests are negative. 
Male Patients: 
Must agree to practice complete abstinence or agree to use a condom during sexual 
contact with pregnant females or females of childbearing potential throughout the entire 
duration of lenalidomide treatment, during dose interruptions and for at least 28 days 
following lenalidomide discontinuation, even if he has undergone a successful vasectomy. 
 
 
During study participation and for 28 days following lenalidomide discontinuation 
Female Patients: 
• FCBP with regular or no menstrual cycles must agree to have pregnancy tests 
weekly for the first 28 days of lenalidomide treatment, including dose interruptions 
and then every 28 days throughout the remaining duration of lenalidomide 
treatment, including dose interruptions, at lenalidomide discontinuation, and at Day 
28 following lenalidomide discontinuation. If menstrual cycles are irregular, the 
pregnancy testing must occur weekly for the first 28 days of lenalidomide 
treatment, including dose interruptions, and then every 14 days throughout the 
remaining duration of lenalidomide treatment, including dose interruptions, at 
lenalidomide discontinuation, and at Day 14 and Day 28 following lenalidomide 
discontinuation. 
• At each visit, the Investigator must confirm with the FCBP that she is continuing to 
use two reliable methods of birth control at each visit during the time that birth 
control is required. 
• If pregnancy or a positive pregnancy test does occur in a study patient, 
lenalidomide must be immediately discontinued. 
• Pregnancy testing and counseling must be performed if a patient misses her period 
or if her pregnancy test or her menstrual bleeding is abnormal. Lenalidomide 
treatment must be temporarily discontinued during this evaluation. 


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• Females must agree to abstain from breastfeeding during study participation and 
for at least 28 days after lenalidomide discontinuation. 
Male Patients: 
• Must practice complete abstinence or use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire 
duration of lenalidomide treatment, during dose interruptions and for at least 28 
days following lenalidomide discontinuation, even if he has undergone a 
successful vasectomy. 
• If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 
Additional precautions 
• Patients should be instructed never to give lenalidomide to anotherperson. 
• Female patients should not donate blood during therapy and for at least 28 days 
following discontinuation of lenalidomide. 
• Male patients should not donate blood, semen or sperm during therapy or for at 
least 28 days following discontinuation of lenalidomide. 
• Only enough lenalidomide for one cycle of therapy may be prescribed with each 
cycle of therapy. 
 
 
 
APPENDIX 6: SKCCC DATA SAFETY MONITORING PLAN 
 
https://oassrv3.onc.jhmi.edu/cro/pageData/SKCCC%20Data%20and%20Safety%20 
Monitoring%20Plan.Posted%202019.03.25.pdf 
 
 
 
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