Clinical trial NCT02492750
Conditions: Indolent Plasma Cell Myeloma Plasma Cell Myeloma Smoldering Plasma Cell Myeloma
Sponsor: Mayo Clinic
Start date: 2016-04-01; Completion date: 2019-09-13
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This partially randomized phase I/II trial studies the side effects and best dose of anakinra when given together with lenalidomide and dexamethasone in treating patients with early stage multiple myeloma. Biological therapies, such as lenalidomide and anakinra, may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether lenalidomide and dexamethasone are more effective with or without anakinra in treating patients with multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD)/maximum allowable dose (MAD) of anakinra that can be combined with lenalidomide and dexamethasone. (Phase I) II. To compare the time to progression of the standard treatment arm (lenalidomide/dexamethasone) to the experimental arm (lenalidomide/dexamethasone + anakinra). (Phase II)

SECONDARY OBJECTIVES:

I. To compare the response rate of the standard treatment arm (lenalidomide/dexamethasone) to the experimental arm (lenalidomide/dexamethasone + anakinra).

II. To compare the toxicity of the standard treatment arm (lenalidomide/dexamethasone) to the experimental arm (lenalidomide/dexamethasone + anakinra).

III. To compare the overall survival of the standard treatment arm (lenalidomide/dexamethasone) to the experimental arm (lenalidomide/dexamethasone + anakinra).

OUTLINE: This is a phase I, dose-escalation study of anakinra followed by a phase II study.

PHASE I: Patients receive lenalidomide orally (PO) on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Patients also receive anakinra subcutaneously (SC) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Patients also receive anakinra SC on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive lenalidomide and dexamethasone as in Arm A. Patients also receive placebo SC on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Arms: arm 1: Patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Patients also receive anakinra SC on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity arm 2: Patients receive lenalidomide and dexamethasone as in Arm A. Patients also receive placebo SC on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Anakinra intervention 2: Dexamethasone intervention 3: Laboratory Biomarker Analysis intervention 4: Lenalidomide intervention 5: Placebo
Intervention descriptions: intervention 1: Given SC intervention 2: Given PO intervention 3: Correlative studies intervention 4: Given PO intervention 5: Given SC

Protocol documents:
Prot_SAP_000.pdf: 




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Table of Contents 
Protocol Resources.......................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
Schema: Phase I Dose Escalation ................................................................................................... 4 
Schema: Phase II ............................................................................................................................. 5 
1.0 
Background ........................................................................................................... 6 
2.0 
Goals ...................................................................................................................... 8 
3.0 
Patient Eligibility ................................................................................................... 9 
4.0 
Test Schedule ...................................................................................................... 11 
5.0 
Grouping/Stratification Factors: .......................................................................... 12 
6.0 
Registration/Randomization Procedures ............................................................. 13 
7.0 
Protocol Treatment .............................................................................................. 15 
8.0 
Dosage Modification Based on Adverse Events ................................................. 18 
9.0 
Ancillary Treatment/Supportive Care ................................................................. 23 
10.0 
Adverse Event (AE) Reporting and Monitoring ................................................. 24 
11.0 
Treatment Evaluation .......................................................................................... 33 
12.0 
Descriptive Factors .............................................................................................. 36 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient .................................... 36 
14.0 
Body Fluid Biospecimens: None ......................................................................... 37 
15.0 
Drug Information ................................................................................................. 38 
16.0  
Statistical Considerations and Methodology ....................................................... 47 
17.0  
Pathology Considerations/Tissue Biospecimens: None ...................................... 54 
18.0 
Records and Data Collection Procedures ............................................................ 55 
19.0  
Budget ................................................................................................................. 57 
20.0 
References ........................................................................................................... 58 
Appendix I 
ECOG Performance Status Scale ........................................................................ 60 
Appendix II 
Mayo Risk Stratification ..................................................................................... 61 
Appendix III 
NYHA Classification .......................................................................................... 62 
Appendix IV 
Multiple Myeloma Diagnostic Criteria ............................................................... 63 
Appendix V 
PATIENT MEDICATION DIARY .................................................................... 64 
Appendix VI 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods .................................................................................................. 66 
 
 


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Schema: Phase I Dose Escalation 
 
Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office 
for dose level and to insure that a place on the protocol is 
open to the patient.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NOTE (Phase I Only): As of Addendum 5, Anakinra will no longer be provided and all 
patients will go off study treatment.  Event monitoring will no longer be required.  Patients 
may obtain Anakinra commercially and be treated off study. 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13.0 for follow-up 
information. 
Cycle length=28 days 
 
Generic name: Lenalidomide 
Brand name(s): Revlimid® 
Mayo Abbreviation: CC5013 
Availability: via Revlimid REMS 
Generic name: Anakinra  
Brand name(s): Kineret® 
Mayo Abbreviation: ANAKIN 
Availability:  
As of October 31, 2018: 
Commercially available  
(Previously provided by SOBI, AB) 
Generic Name: Dexamethasone 
Brand Name: 
Decadron® 
Mayo Abbreviation: DXM 
Availability: Commercial 
 
 
 
 
 
 
Len/Dex + Anakinra 
Early Stage MM 
Monotypic Plasma Cell S-phase ≥0.3% 
PD at any time 
Unacceptable adverse events 
Event Monitoring (per Section 18.0) 
Patient refusal 


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Schema: Phase II 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13.0 for follow-up 
information. 
Cycle length=28 days 
 
Generic name: Lenalidomide 
Brand name(s): Revlimid® 
Mayo Abbreviation: CC5013 
Availability: via Revlimid REMS 
Generic name: Anakinra 
Brand name(s): Kineret® 
Mayo Abbreviation: ANAKIN 
Availability: TBD 
Generic Name: Dexamethasone 
Brand Name: 
Decadron® 
Mayo Abbreviation: DXM 
Availability: Commercial 
 
 
 
Event Monitoring 
(per Section 18.0) 
Len/Dex + Placebo 
Randomization 
Len/Dex + Anakinra 
Early Stage MM 
Monotypic Plasma Cell S-phase ≥0.3% 
PD at any time 
Unacceptable adverse Events  
Event Monitoring 
Patient Refusal 




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myeloma21. Although many cytokines can stimulate IL-6 production, in myeloma 
interleukin-1β (IL-1β) appears to be one of the major cytokines responsible for the 
paracrine production of IL-6 by marrow stromal cells22-25. The aberrant IL-1β produced 
by the myeloma cells induces IL-6 production by bone marrow stromal cells which in 
turn supports the growth and survival of the myeloma cells22. The results of a recent 
clinical trial using IL-1 receptor antagonist (IL-1Ra) confirmed that IL-1Ra in vivo 
targeted the myeloma proliferative component. The median progression free survival 
(PFS) for the entire group of 47 patients was 37 months. The median PFS for patients 
without (n=22) and with (n=25) a decrease in their baseline hsCRP was 11 months and 
103 months respectively (p<0.0001). The median overall survival (OS) for the 47 patients 
was 9.5 years. The median OS for patients without and with a decrease in their baseline 
hsCRP was 7.9 years and has not been reached, respectively (p=0.001). In SMM/IMM 
patients at high risk for progression to active myeloma, treatment with IL-1 inhibitors (IL-
1Ra ± Dex) results in an increased PFS and OS in patients that demonstrate a ≥40% 
reduction in the baseline CRP compared to those who do not show this decrease. Toxicity 
included injection site reactions during the first month of therapy and asymptomatic 
neutropenia26. The importance of IL-1 lies in the fact that small amounts of IL-1β can induce 
large amounts of IL-6 in a paracrine fashion22,27. Since IL-6 is a central myeloma growth 
factor, it appears that the myeloma proliferative component can be inhibited with IL-1Ra in 
early stage disease.  
 
1.4 
Patient and physicians desire a way to delay progression in patients with early stage MM. 
Patients with ≥10% BMPCs and ≥3 g/dL M-protein have a median time to progression to 
active MM of 2 years and patients with a high growth rate have an even shorter time to 
progression28. Lenalidomide and dexamethasone (len/dex) are useful at targeting the non-
proliferative myeloma compartment however patients with a high growth rate often 
relapse quickly on lenalidomide/dexamethasone. Since IL-1R inhibitors are effective at 
inhibiting the proliferative myeloma subset, early stage myeloma patients with an 
elevated growth rate (≥1%) may benefit from a combination of 
lenalidomide/dexamethasone and IL-1 receptor antagonist which is the focus of this trial. 
 
1.5 
There is a large body of literature describing the dosing of lenalidomide with 
dexamethasone and one publication describing the dosing of anakinra with 
dexamethasone26 however the use of all three in a clinical trial has not been previously 
reported. Therefore, we will perform a Phase I Safety Run increasing doses of anakinra 
with lenalidomide and dexamethasone. 
 
1.6 
This study will be conducting in accordance with the Declaration of Helsinki and Good 
Clinical Practices Guidelines (GCP). 
 
 
 


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2.0 
Goals 
 
2.1 
Primary Objective 
 
2.11 
Phase I: To determine the MTD/MAD of anakinra that can be combined with 
lenalidomide and dexamethasone. 
 
2.12 
Phase II: The primary goal of this trial is to compare the time to progression of 
the standard treatment arm (lenalidomide/dexamethasone) to the experimental 
arm (lenalidomide/dexamethasone + anakinra). 
 
2.2 
Secondary Objectives 
 
2.21 
To compare the response rate of the standard treatment arm 
(lenalidomide/dexamethasone) to the experimental arm 
(lenalidomide/dexamethasone + anakinra). 
 
2.22 
To compare the toxicity of the standard treatment arm 
(lenalidomide/dexamethasone) to the experimental arm 
(lenalidomide/dexamethasone + anakinra). 
 
2.23 
To compare the overall survival of the standard treatment arm 
(lenalidomide/dexamethasone) to the experimental arm 
(lenalidomide/dexamethasone + anakinra). 
 
 
 
 


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3.0 
Patient Eligibility 
Phase I only: Prior to discussing protocol entry with the patient, call the MCCC 
Registration Office 
)for dose level and to insure that a place on the protocol is 
open to the patient. 
 
3.1 
Inclusion Criteria  
 
3.11 
Age ≥18 years. 
3.12 
The following laboratory values obtained ≤7 days prior to registration. 
• 
Absolute neutrophil count (ANC) ≥1700/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Hemoglobin ≥8.0 g/dL 
• 
SGOT (AST) ≤3 x upper limit of normal (ULN) 
• 
Creatinine clearance ≥30 mL/min (as determined by Cockroft-
Gault equation*) 
*Cockcroft-Gault Equations: 
Creatinine clearance for males = (140 - age)(actual body weight in kg) 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females = (140 - age)(actual body weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 
Example: A woman aged 75, weight 50 kg and creatinine of 1.35 mg/dL has a calculated clearance 
of 28. 
 
3.13 
Diagnosis of multiple myeloma according to International Myeloma 
Working Group criteria and one of the following: 
• SMM 
• IMM 
• newly diagnosed MM 
Note: Patients with lytic disease and anemia are eligible 
 
3.14 
High risk disease defined by all of the following: 
• ≥10% bone marrow plasma cells 
AND 
• Abnormal serum free light chain (FLC) ratio (<0.26 or >1.65) by 
serum FLC assay 
AND 
• Monotypic Plasma Cell S-phase ≥0.3% 
 
3.15 
Measureable level of M-protein >1 g/dL on serum protein electrophoresis or 
>200 mg of M-protein on a 24 hour urine protein electrophoresis. 
 
3.16 
Negative tuberculosis (TB) testing (Quantiferon – TB blood test or skin test) 
≤7 days prior to registration. 
 
3.17 
ECOG performance status (PS) 0, 1 or 2 (Appendix I).  


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3.18 
Provide signed informed consent. 
 
3.19a 
Negative (serum or urine) pregnancy test done ≤7 days prior to registration, 
for women of childbearing potential only. 
NOTE: A second pregnancy test must be performed within 24 hours prior to the 
start of lenalidomide. The subject may not receive lenalidomide until the study 
doctor has verified that the results of these pregnancy tests are negative. 
3.19b Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.19c 
Willing and able to comply with the requirements of the Revlimid REMS™ 
program. 
3.19d Females of childbearing potential must be willing to adhere to the scheduled 
pregnancy testing as required by the Revlimid REMS™ program. 
 
3.2 
Exclusion Criteria 
 
3.21  
Prior treatment with any other agent that may affect M-protein ≤30 days prior to 
registration. 
 
3.22  
Acute/chronic infections, open wounds, or any active infection requiring 
intravenous antibiotic therapy ≤12 weeks prior to registration. 
 
3.23 
Other active malignancy (≤3 years) prior to registration. 
Exceptions: Basal cell skin cancer or carcinoma-in-situ of the cervix or low-risk 
prostate cancer after curative therapy 
 
3.24 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown:  
• 
Pregnant women 
• 
Nursing women  
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.25 
NYHA Class 3 or 4 CHF symptoms 
 
3.26 
Other concurrent chemotherapy, radiotherapy, or any ancillary therapy 
considered investigational. 
 
NOTE: Bisphosphonates are considered to be supportive care rather than 
therapy, and are thus allowed while on protocol treatment. 
 


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4.0 
Test Schedule  
Tests and Procedures 
Active Monitoring 
≤7 Days 
Prior to 
Registration 
End of Cycles 1-3 
then end of every 
third cycle and 
end of treatment7 
Pre-
treatment  
every 
cycle5 
Mid-
cycle 
eyery 
cycle10 
End of 
Cycle 6 and 
Cycle 12, 
then yearly 
Complete medical history 
X 
 
 
 
 
Adverse Event monitoring 
X 
X9 
X 
 
 
Physical exam, including weight and vital 
signs 
X 
X 
 
 
 
Height 
X 
 
 
 
 
Performance status (ECOG scale)  
X 
X 
 
 
 
EKG 
X 
 
 
 
 
Hematology group (WBC, ANC, Hgb, 
PLT) 
X 
X10 
X5 
X 
 
Chemistry group (glucose, alkaline 
phosphatase; total bilirubin; SGOT 
(AST); serum creatinine, creatinine 
clearance, calcium, LDH and TSH6) 
X 
X 
 
 
 
Beta2-microglobulin, high sensitivity C-
reactive protein  
X 
X 
 
 
 
SPEP and  
UPEP (24 hours collection) 
X 
X 
 
 
 
Circulating plasma cells (PBLI/PCLI) 
X 
X 
 
 
 
Immunofixation serum and urine 
X2 
X4 
 
 
 
Immunoglobulin free light chain (MML) 
X 
X 
 
 
 
Involved Immunoglobulin (IgA, IgG, 
IgM) 
X 
X3 
 
 
 
X-ray skeletal survey (incl long bones) or 
low dose full body CT 
X2 
 
 
 
X 
Bone marrow aspirate and biopsy, 
myeloma FISH, metaphase cytogenetics, 
Plasma cell proliferation assay and flow 
cytometry 
X2 
X4 
 
 
X 
Serum or urine pregnancy test 
X1 
X1 
X1,5 
 
 
Tuberculosis testing (Quantiferon blood 
test or skin testing) 
X 
 
 
 
 
Register patient into Revlimid REMS® 
program 
X 
 
 
 
 
Prescribe lenalidomide via Revlimid 
REMS 
 
X5,8 
X 
 
 
Research per IRB 521-93, optionalR 
XR 
 
 
 
XR 
1) 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). Pregnancy tests must occur ≤7 days prior to registration and again within 24 hours 
prior to initiation of lenalidomide. FCBP with regular or no menstruation must have a pregnancy test weekly for 
the first 4 weeks 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 


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Addendum 5 
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pregnancy test weekly for the first 4 weeks 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 VI: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).  
2) ≤30 days prior to registration 
3) Specific testing required only if used to assess disease response 
4) Required to document complete response; if response, repeat (mail-in acceptable) to confirm response at 
≥4weeks. Bone marrow biopsy does not need confirmation. (Bone marrow biopsy will occur one time as 
clinically indicated.) 
5) Only enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle. After the first 3 
months, the drug may be mailed out to the patient if clinical evaluation and blood tests can be obtained per test 
schedule and mailed/faxed to Mayo Clinic, and patient can return at least every 3 months for follow up to Mayo 
Clinic. In place of physical exam, RNs will phone patient for adverse event assessment. All unused study drug 
must be returned to Mayo Clinic and all study drug must be accounted for. CBC and pregnancy testing may be 
done at local clinic. 
6) TSH to be repeated every three months, for patients on active treatment. 
7) ±7 days 
8) Lenalidomide must be prescribed through and in compliance with Celgene’s Revlimid REMS program. 
Prescriptions must be filled within 7 days. 
9) The patient should be contacted by a nurse 30 days (±2 days) after the last dose of study treatment (or at the 
time of initiation of subsequent treatment if started before 30 days) to check if the patient has experienced any 
late adverse events. Grade 3 or higher adverse events and all serious adverse events (SAEs) at least possibly 
related to study treatment and deaths due to any cause should be reported as a late adverse event on the event 
monitoring form if they were not already reported on the nadir/AE form for the last cycle and they occurred 
prior to any subsequent treatment. 
10) CBC should be done weekly during Cycle 1. After Cycle 1, CBC should be done pre-treatment and mid-cycle 
every cycle. CBC should also be done at the end of treatment. CBC testing may be done at local clinic. 
R 
Research funded (see Section 19.0). Will be charged to study and not to patient’s account. 
 
5.0 
Grouping/Stratification Factors: 
 
5.1 
Grouping Factors 
 
5.11 
Phase:  I vs. II 
 
5.2 
Stratification Factors (Phase II Only) 
 
5.21 
Diagnosis of Active Myeloma:  Yes vs. No 
 
5.22 
Presence of Myeloma Bone Lesions:  Yes vs. No 
 
5.23 
Disease Stage (ISS Staging System) > 1:  Yes vs. No 
 
 
 


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6.0 
Registration Procedures 
6.1 
Phase I Registration Procedures 
Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office 
 for dose level and to insure that a place on the protocol is 
open to the patient.  
To register a patient, fax (507-284-0885) a completed eligibility checklist to the Mayo 
Clinic Cancer Center (MCCC) Registration Office between 8 a.m. and 4:30 p.m. central 
time Monday through Friday. 
6.2 
Phase II Registration Procedures 
 
6.21 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration/randomization application. The registration/ 
randomization application is available 24 hours a day, 7 days a week.  Back up 
and/or system support contact information is available on the Web site.  If unable 
to access the Web site, call the MCCC Registration Office at (507) 284-2753 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
The instructions for the registration/randomization application are available on 
the MCCC web page 
and detail the 
process for completing and confirming patient registration.  Prior to initiation of 
protocol treatment, this process must be completed in its entirety and a MCCC 
subject ID number must be available as noted in the instructions.  It is the 
responsibility of the individual registering the patient to confirm the process has 
been successfully completed prior to release of the study agent.  Patient 
registration via the registration/randomization application can be confirmed in 
any of the following ways: 
• 
Contact the MCCC Registration Office
  If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.22 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
.  If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
6.3 
Phase I and II 
6.31 
Prior to accepting the registration, the registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 


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• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.32 
Treatment on this protocol must commence at Mayo Clinic Rochester under 
supervision of a hematologist 
6.33 
Treatment cannot begin prior to registration. 
6.34 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
6.35 
All required baseline symptoms (see Section 10.6) must be documented and 
graded. 
6.36 
Study drug is available on site 
 
6.4 
Phase II Randomization Procedures 
6.41 
The factors defined in Section 5.0, together with the registering membership, will 
be used as stratification factors. 
 
6.42  
After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups using the Pocock and Simon dynamic allocation procedure 
which balances the marginal distributions of the stratification factors between the 
treatment groups  
• 
Len/Dex + Placebo 
• 
Len/Dex +Anakinra 
 
6.5 
Procedures for Double-Blinding the Treatment Assignment 
6.51 
After the treatment assignment has been ascertained by the 
registration/randomization application, the patient’s study medication code 
number will be displayed on the confirmation of registration screen 
6.52 
The data manager/nurse/pharmacist at the patient’s institution must contact the 
MCCC Registration Office for a code number when additional study product is 
needed for the patient. 
6.53 
The number of the syringe will be recorded on the dosing form. 
6.54 
MCCC Registration Office personnel will monitor the supply of coded bottles at 
each participating institution  
 
 


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7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule - Cycle length = 28 days  
 
7.11 
Phase I - Dose Escalation 
 
Agent 
Dose 
Route 
Days 
Lenalidomide 
25 mg 
PO 
Days 1-21 
Dexamethasone 
20 mg (SMM and IMM);  
40 mg (Active MM) 
PO 
Days 1, 8, 15, and 22 
Anakinra  
As assigned by MCCC 
Registration Office  
SQ 
Days 1-28 
Aspirin  
325 mg/day with food 
PO 
Days 1-28 
 
7.12 
Phase II Study at MTD/MAD 
 
Agent 
Dose 
Route 
Days 
Lenalidomide 
25 mg 
PO 
Days 1-21 
Dexamethasone 
20 mg (SMM and IMM);  
40 mg (Active MM) 
PO 
Days 1, 8, 15, and 22 
Anakinra or 
Placebo 
Based on phase I results 
SQ 
Days 1-28 
Aspirin  
325 mg/day with food 
PO 
Days 1-28 
 
7.2 
Determination of Maximum Tolerated Dose (MTD)/Maximum Allowable Dose (MAD)  
 
7.21 
Dose Escalation 
Dose Level 
Dose of anakinra 
1* 
100 mg SQ every 3rd day 
2 
100 mg SQ every other day 
3 
100 mg SQ daily 
*Starting dose 
 
7.211 For this protocol, the patient must return to the consenting institution for 
evaluation at least every 28 days during treatment (Active Monitoring 
Phase). 
 
7.212 Treatment by a local medical doctor (LMD) is not allowed. 
 
7.213 Three patients will be treated at each dose level and observed for a 
minimum of 4 weeks (i.e. one full cycle), to assess toxicities, before new 
patients are treated. Doses will not be escalated in any individual patient. 
 
7.214 Investigators are to contact the Study Chair as soon as any dose-limiting 
toxicity (DLT) occurs. 
 
 


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7.22 
Definition of DLT – See Section 16.22 for additional information 
For this protocol, DLT will be defined as an adverse event during Cycle 1 of 
treatment at least possibly related to the study medication and meeting the 
following criteria: 
Toxicity* 
DLT Definition 
Blood and lymphatic system 
disorders 
Grade 3 Febrile neutropenia: ANC <1000/mm3 
with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of 
≥38 degrees C (100.4 degrees F) for more than one 
hour 
Investigations 
Grade 4 neutropenia (ANC <500/mm3) for ≥7 days 
or Grade 4 thrombocytopenia  (<25,000/mm3) for 
≥7 days 
Infection and infestations 
Grade 4 
Other Non-hematologic 
Grade 4 as per NCI Common Terminology Criteria 
for Adverse Events v 4.0**  
Dose Delay 
Any toxicity that causes a dose delay of >2 weeks 
of the next intended dose.*** 
Dose Reduction 
Any dose reduction within cycle 1.*** 
*Adverse event at least possibly related to the study medication. 
**Grade 4 vomiting or diarrhea with maximal supportive treatment(s) will be considered 
dose limiting.   
***Except dose reductions and delays due to rash associated with lenalidomide. These 
patients will be replaced with another study patient. 
 
7.3 
Lenalidomide supply 
Patients will receive lenalidomide every 28 days. All unused study drug must be returned 
to Mayo Clinic to be recorded. Study drug is to be handed back to the patient to return as 
per Revlimid REMS. Only enough lenalidomide for one cycle of therapy will be 
supplied to the patient each cycle. 
 
7.4 
Stem cell collection 
Treatment can be interrupted for the purpose of collecting stem cells. Patients can 
be restarted on protocol therapy after stem cell collection as long as criteria for 
initiation of a next cycle are met at the time of therapy initiation (Section 8.11). 
 
7.5 
Stable plateau 
Patients that achieve a stable plateau after 2 years of therapy may be tapered to 
lower doses of lenalidomide and/or dexamethasone at the discretion of the 
treating physician  
When the patient discontinues all study medication, the MCCC Registration Office must 
be called (507-284-2753) to find out which study therapy the patient was receiving. 
Appropriate procedures for gradually reducing the doses of lenalidomide and/or 
dexamethasone should then be followed. 
 
7.6 
Return to Mayo Clinic 
For this protocol, the patient must return to the Mayo Clinic for evaluation for Cycles 1-3 
and then at least every 3 cycles. After the first 3 cycles, clinical evaluation and blood tests 


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can be obtained per test schedule and mailed/faxed to Mayo Clinic and patient can return 
at least every 3 cycles for follow up to Mayo Clinic. Adverse events will be collected at 
the end of each cycle by telephone call.  
Only enough lenalidomide for one cycle of therapy will be supplied to the patient each 
cycle. All study participants must be registered into the mandatory REVLIMID REMS™ 
program, and be willing and able to comply with the requirements of REVLIMID 
REMS™. 
After the first 3 cycles, lenalidomide and anakinra may be mailed out monthly to the 
patient if clinical evaluation and blood tests can be obtained per test schedule. Patient 
can return at least every 3 cycles for follow up to Mayo. Prescription for 
dexamethasone will be provided.  
 
7.7 
Breaking Codes in Double–Blinded Studies 
 
Situations requiring codes to be broken:  There are three distinct situations in which it 
is appropriate to break the codes for individual patients enrolled in double-blind trials: 
 
(1) 
In the event of an emergency for an individual patient. 
 
(2) 
In the event that it would be helpful for the future clinical care of an 
individual patient after she/he has completed participation in the trial. 
 
(3) 
When it is necessary to know the specific treatment assignment of each 
patient in the trial in order to manage them all appropriately after they 
have completed participation in the trial.  Example:  There is a blinded 
arm that contains a steroid, narcotic, or other medication that must be 
carefully reduced in order to prevent physiological damage.  [This one is 
rare--there are no currently active protocols of this type.] 
 
In the event of an emergency, call the MCCC Registration Office at 
 to break the code on Monday through Friday, 8:00 a.m. 
to 4:30 p.m. Central Time. If the code must be broken after hours, 
assume the patient was assigned to active treatment and treat 
accordingly. Place a call to the MCCC Registration Office and leave a 
message informing them of the need to un-blind a patient. Provide your 
contact information so that MCCC Registration Office personnel can 
return the call the next business day. 
 
If, in the judgment of the attending physician, it would be helpful for the 
future clinical care of the individual patient, the code may be broken 
after the patient has completed the study. That is, after the patient has 
been fully evaluated and all evaluation information has been recorded by 
the attending physician and the patient (if appropriate), the MCCC 
Registration Office may be called 
to find out which 
study therapy the patient was receiving. 
 
 


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8.0 
Dosage Modification Based on Adverse Events  
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained.  Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects.  If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed.  
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1 
Dose Levels (Based on Adverse Events in Tables 8.2) 
Dose Level 
Lenalidomide 
Starting Dose 
25 mg days 1-21 every 28 days 
-1 
15 mg days 1-21 every 28 days 
-2 
10 mg days 1-21 every 28 days 
-3 
5 mg days 1-21 every 28 days 
 
Dose Level 
Anakinra 
Starting Dose 
100 mg SQ daily 
-1 
100 mg SQ every other day 
-2* 
100 mg SQ every 3rd day 
*If patients unable to tolerate -2 they will go off treatment to event monitoring 
 
8.11 
Instruction for initiation of a new cycle of therapy  
A new course of treatment may begin on the scheduled day 1 of a new cycle if: 
• 
The ANC is ≥1,500/μL; 
• 
The platelet count is ≥75,000/μL; 
• 
Any drug-related injection site reaction or peripheral sensory neuropathy that 
may have occurred has  resolved to ≤Grade 1 severity; 
• 
Any other drug-related adverse events that may have occurred have resolved 
to ≤Grade 2 severity;  
• 
If these conditions are not met on Day 1 of a new cycle, the subject will be 
evaluated weekly and a new cycle of treatment will not be initiated until the 
toxicity has resolved as described above. If lenalidomide dosing was halted 
during the previous cycle and was restarted with a one-level dose reduction 
without requiring an interruption for the remainder of the cycle, then that 
reduced dose level will be initiated on Day 1 of the new cycle. If 
lenalidomide dosing was omitted for the remainder of the previous cycle 
or if the new cycle is delayed due to toxicity newly encountered on the 
scheduled Day 1, then the new cycle will be started with a one-level 
dose reduction of lenalidomide. 
 
 


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8.2 
Dose Modifications of Lenalidomide during a Cycle of Therapy 
Dose reductions of one drug and not the other may be done at the investigators 
discretion based on attribution of adverse events except neutropenia in which 
lenalidomide should be decreased first before anakinra. 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION** Days 2-
14 of cycle 
ACTION** 
Day ≥15 of cycle 
Blood and 
lymphatic system 
disorders 
Febrile neutropenia 
associated with fever 
(temperature ≥38.5ºC) 
Lenalidomide Omit lenalidomide 
dose. 
Follow CBC weekly. 
If neutropenia has 
resolved to ≤Grade 2 
prior to Day 21, restart 
lenalidomide at next 
lower dose level and 
continue the cycle 
through Day 21.  
If neutropenia is the 
only toxicity for which 
a dose reduction is 
required, G-CSF may 
be used and the 
lenalidomide dose 
maintained 
Omit lenalidomide for 
remainder of cycle. 
See Section 8.11 for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level. 
If neutropenia is the 
only toxicity for which 
a dose reduction is 
required, G-CSF may be 
used and the 
lenalidomide dose 
maintained for the next 
cycle at the 
investigator’s 
discretion. 
Investigations 
Platelet count 
decreased 
≥ Grade 3 (platelet 
count <50,000/mm³) 
Lenalidomide Omit lenalidomide 
dose 
Follow CBC weekly 
Hold anticoagulation 
until platelets >50,000 
If thrombocyte-penia 
resolves to ≤Grade 2 
prior to Day 21, restart 
lenalidomide at next 
lower dose level and 
continue the cycle 
through Day 21 
Omit lenalidomide for 
remainder of cycle 
See Section 8.11, 
Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level 


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Addendum 5 
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CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION** Days 2-
14 of cycle 
ACTION** 
Day ≥15 of cycle 
Skin and 
subcutaneous tissue 
disorders 
Rash maculo papular  
Grade 2 or 3. 
Lenalidomide Omit lenalidomide 
dose 
Follow weekly 
If the event resolves to 
≤Grade 1 prior to Day 
21, restart 
lenalidomide at next 
lower dose level and 
continue the cycle 
through Day 21 
Omit lenalidomide for 
remainder of cycle 
See Section 8.11, 
Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level 
Any rash  
Grade 4 
Lenalidomide Discontinue 
lenalidomide 
Discontinue 
lenalidomide 
Nervous System 
Disorders 
Peripheral sensory 
neuropathy 
Grade 3 
Lenalidomide Omit lenalidomide 
dose 
Follow at least weekly 
If the event resolves to 
≤Grade 1 prior to 
Day 21, restart 
lenalidomide at next 
lower dose level and 
continue the cycle 
through Day 21 
Omit lenalidomide for 
the remainder of the 
cycle. 
See Section 8.11 
Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level 
Peripheral sensory 
neuropathy  
Grade 4 
Lenalidomide Discontinue 
lenalidomide 
Discontinue 
lenalidomide 
Immune system 
disorders 
Allergic reaction  
Grade 2-3 
Lenalidomide Omit dose 
Follow at least weekly 
If the toxicity resolves 
to ≤Grade 1 prior to 
Day 15 restart at next 
lower dose level and 
continue the cycle 
until Day 21 
Omit lenalidomide for 
the remainder of the 
cycle 
If the adverse event 
resolves to ≤Grade 1, 
reduce dose 1 level in 
next cycle 
If adverse event recurs, 
discontinue therapy 
Grade 4 
Lenalidomide Discontinue 
lenalidomide 
Discontinue 
lenalidomide 
Vascular disorders 
Thromboembolic 
event 
≥Grade 3 
Lenalidomide Omit dose and start 
anticoagulation; restart 
at investigator’s 
discretion (maintain 
dose level) 
Omit lenalidomide for 
remainder of cycle and 
start anticoagulation. 
Maintain dose level in 
next cycle 


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Addendum 5 
Protocol version date:  25Oct2018 
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION** Days 2-
14 of cycle 
ACTION** 
Day ≥15 of cycle 
Endocrine disorders Hyperthyroidism or 
Hypothyroidism 
≥Grade 2 
Lenalidomide -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 
Omit lenalidomide for 
remainder of cycle, 
evaluate etiology, and 
initiate appropriate 
therapy.  
See Section 8.11, 
Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level 
Other non-
hematologic adverse 
event 
Other non-
hematologic toxicity 
≥Grade 3 
Lenalidomide -Omit lenalidomide 
dose. Follow at least 
weekly. If the toxicity 
resolves to ≤Grade 2 
prior to Day 21, restart 
lenalidomide at next 
lower dose level and 
continue the cycle 
through Day 21 
Omit lenalidomide for 
remainder of cycle.  
See Section 8.11, 
Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level. 
 
8.3 
Dose Modifications of Anakinra/Placebo during a Cycle of Therapy 
Dose reductions of one drug and not the other may be done at the investigators 
discretion based on attribution of adverse events except neutropenia in which 
lenalidomide should be decreased first before anakinra. 
CTCAE 
System/organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION ** (each cycle) 
Blood and lymphatic 
system disorders 
Febrile Neutropenia 
≥Grade 3 
Anakinra/ 
Placebo 
For ANC <1000, omit 
anakinra/placebo until ANC ≥1500. 
Then restart anakinra or placebo with 
the dose reduced one dose level. 
Infections and 
Infestations 
Infection/Febrile 
Neutropenia ≥Grade 2 
Omit until infection resolved; then 
restart at same dose 
Infection/Febrile 
Neutropenia ≥Grade 3 
Omit until infection resolved; then 
restart anakinra or placebo with the 
dose reduced one dose level 
Other non-
hematologic adverse 
event 
Any adverse event 
≥Grade 3 
Omit until toxicity reduces to ≤grade 
2; then restart anakinra or placebo 
with the dose reduced one dose level 
 
 
 
 


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Addendum 5 
Protocol version date:  25Oct2018 
8.4 
Dose Modifications of Dexamethasone during a Cycle of Therapy 
CTCAE 
System/organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION ** (each cycle) 
Gastrointestinal 
Disorders 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grade 1-2 
(Symptomatic; altered GI 
function; medical intervention 
indicated; limiting 
instrumental ADL ) 
Dexamethasone Treat with H2 blockers, sucralfate, or 
omeprazole 
If symptoms persist despite above 
measures, decrease dexamethasone 
dose  by 50% 
Dyspepsia, gastric or duodenal 
ulcer, gastritis ≥Grade 3 
(Severely altered GI function; 
TPN indicated; elective 
operative or endoscopic 
intervention indicated; 
limiting self-care ADL; 
disabling) 
Omit dexamethasone until symptoms 
adequately controlled 
Restart one dose level below along 
with concurrent therapy with H2 
blockers, sucralfate, or omeprazole 
If symptoms persist despite above 
measures, decrease dex by 50% 
Pancreatitis 
≥Grade 3 (severe pain; 
vomiting; medical intervention 
indicated (e.g., analgesia, 
nutritional support)) 
Discontinue dex, and begin event 
monitoring 
General Disorders 
Edema 
≥Grade 3 (limiting function 
and unresponsive to therapy or 
anasarca) 
Decrease dex by 50%; use diuretics 
prn 
Psychiatric Disorders 
Confusion or Mood alteration 
≥Grade 2 (Severe 
disorientation; limiting self-
care ADL) 
Omit until symptoms resolve; 
Decrease dex by 50% 
Musculoskeletal and 
connective tissue 
disorders 
Muscle weakness 
≥Grade 2  
Weakness limiting self-care 
ADL; disabling 
Decrease dex by 50%; if symptoms 
persist then decrease 50% prn 
Eye Disorders 
Blurred vision  
≥Grade 3 
Decrease dex by 50%; if symptoms 
persist then decrease 50% prn 
Metabolism and 
nutrition disorders 
Hyperglycemia Grade 3 or 
higher, (>250 - 500 mg/dL; 
>13.9 - 27.8 mmol/L); 
hospitalization indicated 
Treat with oral hypoglycemic agent or 
insulin prn; decrease by 50% prn 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The patient 
does not make up the omitted dose(s) at a later time 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
NOTE:  If the patient experiences a significant adverse event requiring a dose reduction at the start 
of the next cycle, then the dose will remain lowered for that entire subsequent cycle.  If that cycle is 


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Addendum 5 
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completed with no further adverse events >Grade 2, then the dose may be increased, at the 
investigator’s discretion, one level at a time, in the following cycles.  
NOTE:  Adverse events requiring a dose-reduction step for any or all drugs beyond the two dose-
reduction steps (levels –1 and –2) will be at the discretion of the treating physician, if the decision 
is made for the patient to be kept on study.  These dose reductions must be clearly recorded in 
reported clinical data.  
NOTE: Patients in whom one or more of the study treatment agents have been discontinued will 
remain on study unless all study treatment agents are discontinued. Patients in whom all study 
treatment agents were discontinued will proceed to event monitoring (see Section 18.0). 
 
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Patients may receive concurrent treatment with a bisphosphonate.  
9.2 
Patients may continue on low level/stable steroid doses for replacement or inhalation 
therapy. 
9.3 
The following medications are not permitted during the trial: 
• 
Any other investigational treatment  
• 
Any cytotoxic chemotherapy 
• 
Any other systemic anti-neoplastic therapy including, but not limited to, 
immunotherapy, hormonal therapy or monoclonal antibody therapy. 
• 
Any external beam radiotherapy 
9.4 
Antiemetics may be used at the discretion of the attending physician. 
9.5 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  ASCO 2006 Update of 
Recommendations for the Use of White Blood Cell Growth Factors:  An Evidence-Based 
Clinical Practice Guidelines Journal of Clinical Oncology 2006; 24:3187-3205. 
9.6 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records. 
9.7 
Diarrhea:  This could be managed conservatively with loperamide. The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
9.8 
Use of colony stimulating factors is allowed as detailed in the dose modification table for 
lenalidomide 
 
 


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Addendum 5 
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10.0 
Adverse Event (AE) Reporting and Monitoring 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm) 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4).  Important: Expedited adverse 
event reporting requires submission of a MedWatch 3500A report(s). Expedited 
reports are to be completed within the timeframes and via the mechanisms 
specified in Sections 10.4. All AEs reported via expedited mechanisms must also 
be reported via the routine data reporting mechanisms defined by the protocol 
(see Sections 10.52 and 18.0). 
10.12 Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).  Grade is an essential element of the Guidelines and, in 
general, relates to severity for the purposes of regulatory reporting to NCI. 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same 
as serious AE which is defined in the table in Section 10.4. 
10.2 
Expected vs. Unexpected 
• 
The determination of whether an AE is expected is based on the agent-specific 
information provided in Section 15.0 of this protocol. 
• 
Unexpected AEs are those not listed in the agent-specific information provided in 
Section 15.0 of this protocol. 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  








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Addendum 5 
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10.52 Death 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 
24-hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
Reportable categories of Death: 
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal:  A disorder characterized by cessation of life during the 
first 28 days of life. 
• 
Death NOS:  A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS:  A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
– Other (Progressive Disease)” under the system organ class (SOC) of 
the same name.  Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted. 
10.53 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A secondary malignancy is not considered a metastasis of the 
initial neoplasm. 
All secondary malignancies that occur following treatment with an agent under an 
IND/IDE must be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting. 
10.55 Pregnancy 
Females of reproductive potential must adhere to scheduled pregnancy testing as 
required in the Revlimid REMS™ program. 






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Addendum 5 
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10.6 
Required Routine Reporting 
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
SYSTEM ORGAN 
CLASS 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Investigations 
Creatinine increased 
X 
X 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
Lymphocyte count decreased 
X 
X 
White blood cell decreased 
X 
X 
Anemia 
X 
X 
General disorders and 
administration site 
conditions 
Fatigue  
X 
X 
Injection site reaction 
 
X 
Gastrointestinal 
Disorders 
Nausea 
X 
X 
Vomiting 
X 
X 
Diarrhea 
 
X 
Constipation 
 
X 
Number of stools 
X 
 
Renal and urinary 
disorders 
Chronic kidney disease (decreased 
creatinine clearance) 
X 
X 
Skin and 
subcutaneous tissue 
disorders 
Rash, maculopapular 
X 
X 
Nervous system 
disorders 
Peripheral sensory neuropathy  
X 
X 
Constitutional 
Symptoms 
Insomnia 
X 
X 
Vascular Disorders 
Thromboembolic event 
X 
X 
 
10.61 Submit via appropriate MCCC Case Report Forms (i.e., paper or 
electronic, as applicable) the following AEs experienced by a patient and 
not specified in Section 10.6 (above): 
10.611 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.612 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.613 Grade 5 AEs (Deaths) 
10.6131 Any death within 30 days of the patient’s last study treatment 
or procedure regardless of attribution to the study treatment or 
procedure. 


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Addendum 5 
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10.6132 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, with 
a CTCAE type and attribution assigned. 
 
10.62 Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
10.7 
All serious adverse events (SAEs) will be followed until resolution or death. 
 
 
 


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Addendum 5 
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11.0 
Treatment Evaluation 
The International Myeloma Working Group (IMWG) uniform response criteria (Rajkumar et al, 
2011) will be used to assess response to therapy  
11.1 
Terms and definitions 
• 
M-protein: synonyms include M-spike, monoclonal protein and myeloma protein, 
paraprotein, M-component. 
 
Serum M-protein level is quantitated using densitometry on SPEP except in cases 
where the SPEP is felt to be unreliable.   
• M-proteins migrating in the β-region (usually IgA M-proteins)  
• Cases in which the M-protein is so large and narrow on agarose (some 
specimens >4 g/dL) that they underestimate the actual immunoglobulin level 
(by greater than 1500 mg/dL) due to technical staining properties of the 
agarose gel. 
• Cases in which there are multiple peaks of same M-protein (aggregates or 
dimers) 
 
If SPEP is not available or felt to be unreliable (above examples) for routine M-
protein quantitation, then quantitative immunoglobulin levels derived from 
nephelometry or turbidometry can be accepted. However, this must be explicitly 
reported at baseline, and only nephelometry can be used for that patient to assess 
response. SPEP derived M-protein values and quantitative nephelometric 
immunoglobulin values cannot be used interchangeably.   
 
Urine M-protein measurement is estimated using 24-h UPEP only. Random or 24 h 
urine tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended. 
 
FLC estimation is currently carried out using the serum FLC assay (Freelite, The 
Binding Site Limited, UK).  Patients with kappa/lambda FLC ratio <0.26 are defined 
as having monoclonal lambda FLC and those with ratios >1.65 as having a 
monoclonal kappa FLC.  The monoclonal light chain isotype is considered the 
involved FLC isotype, and the opposite light chain type as the uninvolved FLC type.  
 
• 
Response terms: The following response terms will be used: stringent Complete 
Response (sCR), complete response (CR), very good partial response (VGPR), partial 
response (PR), Minimal Response (MR), stable disease (SD), and progressive disease 
(PD).  
 
In addition, for each response category, there will be an “unconfirmed” response 
category, which will be for internal use, for the purpose of guiding decision making 
and test ordering. These designations will applied at the time of the first measurement 
at which the quantitative aspect of the response category has been satisfied without 
the confirmation step having been satisfied. The designation “u” will precede the 
standard abbreviations, and will include usCR, uCR, uVGPR, uPR, uMR, uPD.  
 
• 
Measurable disease: Patients who have a measurable serum or urine M-protein.  
o serum M-protein >1 g/dL OR urine M-protein >200 mg/24 hr 


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Addendum 5 
Protocol version date:  25Oct2018 
 
11.2  
Clarification of test indications 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study. 
 
Table 11.2 
Tests Required To Assess Response (Must Be Done At Each Disease Measurement Visit 
except as indicated1,2) 
On Study Baseline Value 
SPEP3 
24 hr 
UPEP2 
Ig 
FLC 
BM Bx 
Serum M-protein ≥3 g/dl, and urine M-protein 
≥500 mg/24 hrs 
X 
X 
 
 
Serum M-protein ≥3 g/dl, but urine M-protein 
<500 mg/24 hrs 
X 
 
 
 
Serum M-protein <3 g/dl, and urine M-protein 
≥500 mg/24 hrs 
 
X 
 
 
1  SPEP, UPEP, Immunofixation studies of both serum and urine, and Bone marrow 
biopsy are required to document CR regardless of registration values, and in addition 
FLC measurement and bone marrow immunophenotyping is required to document 
sCR. SPEP and UPEP are required to document VGPR regardless of registration 
values. 
2  For serum measurable patients, 24 hour urine does not need to be confirmed (i.e. 
repeated after documented response) for any response category 
3 If serum M-protein is being followed by quantitative immunoglobulin levels derived 
from nephelometry or turbidometry, quantitative immunoglobulins are required.  SPEP 
is only required to document CR or VGPR.  
 
11.3 
Confirmed response  
In order to be classified as a hematologic response, confirmation of serum M- protein, 
serum immunoglobulin free light chain (when primary determinant of response) and 
urine M- protein (when primary determinant of response) results must be made by 
verification on two consecutive determinations.   
• 
Bone marrow aspirate and biopsy are only required to document CR or sCR, 
except for patients with evaluable disease only, where a bone marrow is required 
to document all response categories including progression. However, a second 
confirmatory bone marrow is not required to confirm response in any case. 
• 
Radiographic studies are not required to satisfy these response requirements; 
however, if radiographic studies were performed there should be no evidence of 
progressive or new bone lesions. 
Appropriate tests required to document and confirm response are listed in Table 11.2 
 
11.4 
Bone progression  
Caution must be exercised to avoid rating progression on the basis of variation of 
radiologic technique alone.  Compression fracture does not exclude continued response 
and may not indicate progression.  When progression is based on skeletal disease alone, it 
should be discussed with the Study Chair before removing the patient from the study.  
 
 
 


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11.5 
Response and Progression 
Criteria for response and progression are listed in Table 11.5. Progressive disease for all 
patients as defined in Table 11.5.  
 
Table 11.5 
CATEGORY 
RESPONSE CATEGORY a 
Stringent Complete 
Response (sCR) b 
• CR as defined plus 
• Normal FLC ratio and 
• Absence of clonal PCs by immunohistochemistry or 2- to 4- color 
flow cytometry h 
Complete Response 
(CR) b 
• Negative immunofixation of serum and urine c and 
• Disappearance of any soft tissue plasmacytoma and 
<5% PCs in Bone Marrow 
Very Good Partial 
Response (VGPR)  
• Serum and urine M-protein detectable by immunofixation but not 
on electrophoresis c or 
• ≥90% reduction in serum M-protein and urine M-protein <100 
mg/24 h c 
Partial Response (PR) 
• If present at baseline, ≥ 50% reduction of serum M-protein and 
reduction in 24-hour urinary M-protein by ≥90% or to <200 
mg/24hrs c 
• If present at baseline, ≥ 50% reduction in the size of soft tissue 
plasmacytomas 
Minor Response (MR)  
• If present at baseline, ≥25% but ≤ 49% reduction of serum M 
protein and reduction in 24-hour urine M-protein by 50-89% 
which still exceeds 200mg/24 hours c and 
• If present at baseline, 25-49% reduction in the size of soft tissue 
plasmacytoma and 
• No increase in the size or number of lytic bone lesions 
(development of compression fracture does not exclude response) 
Progressive Disease 
(PD) b, g 
 
Increase of 25% from lowest value in any of the following e, f: 
• Serum M-protein (absolute increase must be ≥ 0.5 g/dL) and/or 
• Urine M-protein (absolute increase must be ≥ 200 mg/24 hrs) 
and/or 
Or any one or more of the following: 
• Development of new bone lesion or soft tissue plasmacytoma or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytoma 
• Development of hypercalcemia (corrected serum calcium > 
11.5mg/dL) that can be attributed solely to the PC proliferative 
disorder 
Stable Disease (SD) 
Not meeting criteria for sCR, CR, VGPR, PR, MR or PD 
a All response categories require two consecutive assessments (sCR, CR, VGPR, PR, MR, PD) made at any time 
before the institution of any new therapy; sCR, CR, VGPR, PR, MR and SD 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. Bone marrow assessments need not be confirmed. Each category, 
except for stable disease, will have a working subcategory of “unconfirmed” [prefix ‘u”] to designate first time point 
at which response category MAY have been achieved if confirmed. 
b CR patient will need to progress at the same level as VGPR and PR patients to be considered a PD.  A positive 
immunofixation alone is not sufficient. 
c If more than one M protein spike meets the criteria for measurable disease at baseline, then both need to be 
followed for response.  Otherwise, only follow the measurable M protein spike for response.   


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Addendum 5 
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d In patients in whom the only measurable disease is by serum FLC levels: CR in such patients indicates a normal 
FLC ratio of 0.26-1.65 in addition to the CR criteria listed above.  
e A "25% increase" refers to M protein, FLC and bone marrow results and does not refer to bone lesions, soft tissue 
plasmacytoma or hypercalcemia.  The lowest value does not need to be a confirmed value.  If the lowest serum M-
protein is ≥ 5 g/dL, an increase in serum M-protein of ≥ 1 g/dL is sufficient to define disease progression. 
f In the case where a value is felt to be a spurious result per physician discretion (for example, a possible lab error), 
that value will not be considered when determining the lowest value. 
g Progressive disease should be confirmed.  However, treatment may be discontinued for progressive disease that is 
unconfirmed per physician discretion.  In this case, an objective status of PD should be entered on the measurement 
form and progressive disease should be reported on the event monitoring form. 
h Presence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by immunohistochemistry 
requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is 
k/l of 4:1 or 1:2.  
 
12.0 
Descriptive Factors  
12.1 
Prior treatment: Yes vs. no. 
12.2 
Durie Salmon Stage of myeloma at diagnosis:  I vs. II vs. IIIa vs. IIIb 
12.3 
ISS Stage of myeloma at diagnosis: I vs. II vs. III 
12.4 
Parameters followed for hematologic response (pick one): serum M- protein >1 g/dL and 
urine M-protein >200 mg/24 hours vs. serum M-protein >1 g/dL only vs. urine M-protein 
>200 mg/24 hours only.  
NOTE: Distinguish between SPEP measurements versus quantitative IgA measurements 
for serum M-protein 
12.5 
Diagnosis:  Smoldering multiple myeloma (SMM) vs. indolent multiple myeloma (IMM) 
vs. newly diagnosed multiple myeloma 
12.6 
Dose Level:  1 vs. 2 vs. 3 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
NOTE (Phase I Only): As of Addendum 5, Anakinra will no longer be provided and all 
patients will go off study treatment.  Event monitoring will no longer be required.  Patients 
may obtain Anakinra commercially and be treated off study 
 
13.1 
Responding to treatment 
Patients who are sCR, CR, VGPR, PR, or SD (or usCR, uCR, uVGPR, uPR) will 
continue treatment per protocol. 
13.2 
Treatment continuation 
In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies: 
13.21 Progression requiring treatment for active myeloma  
13.22 Unacceptable toxicity and ineligibility for retreatment. 
13.23 Patient refusal of continued treatment. 
All attempts should be made to complete the End of Study procedures if a patient 
withdraws from the trial early.  The patient will then go to event monitoring per 
Section 18.0. 


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13.3 
Ineligible patients 
A patient is deemed ineligible if at the time of registration, the patient did not satisfy each 
and every eligibility criteria for study entry. The patient may continue treatment off 
protocol at the discretion of the physician as long as there are no safety concerns, and the 
patient was properly registered. The patient will go directly to the event-monitoring phase 
of the study. 
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per section 18.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 
is necessary. 
13.4 
Major Violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
Cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. Event 
monitoring will be required per Section 18.0 of the protocol.  
The patient may continue treatment with lenalidomide and dexamethasone off-protocol at 
the discretion of the physician as long as there are no safety concerns, and the patient was 
properly registered. Event monitoring will be required per Section 18.0 of the protocol. 
13.5 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. 
13.6 
Phase I only: Failure to complete the first cycle of treatment 
If a patient fails to complete the first cycle of treatment for reasons other than toxicity, 
the patient will be regarded as inevaluable and will be replaced. If a patient has a dose 
reduction to <70% of the expected dose or dose delay of more than 3 weeks during Cycle 
1 for reasons other than DLT, the patient will be replaced by an additional patient. 
 
14.0 
Body Fluid Biospecimens: None 
 
 
 


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15.0 
Drug Information 
15.1 
Lenalidomide (Revlimid, CC-5013, CDC-501) 
Please consult the most current Investigator’s Brochure and package insert for 
complete drug information. 
15.11 Background: Lenalidomide has a wide range of effects, including the inhibition 
of hematopoietic tumor cell proliferation, the enhancement of T cells and natural 
killer (NK) cell activity, the modulation of stem cell differentiation, the inhibition 
of angiogenesis, and the inhibition of inflammation. 
15.12 Formulation: For clinical study, lenalidomide is provided as 10, 15, and 25 mg 
as capsules for oral administration. Each capsule contains lenalidomide as the 
active ingredient and the following inactive ingredients: anhydrous lactose, 
microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. 
The lenalidomide capsules are supplied in push-through blister foil or tamper-
evident, child-resistant, opaque, high-density polyethylene (HDPE) containers 
with HDPE caps. 
15.13 Preparation and storage: Lenalidomide should be stored at room 
temperature, between 59 and 86ºF (15-30ºC).  Store drug away from direct 
sunlight. 
15.14 Administration:  Capsules are administered by mouth daily with water. Patients 
should not break, chew or open the capsules. 
15.15 Pharmacokinetic information: 
a)  Absorption – Lenalidomide is rapidly absorbed following oral administration 
to subjects with multiple myeloma or MDS, with maximum plasma 
concentrations occurring between 0.5 and 1.5 hours post-dose. Co-administration 
with a high-fat and high-calorie meal in healthy subjects reduced the extent of 
absorption, resulting in an approximately 20% decrease in AUC and 50% 
decrease in Cmax in plasma.   
In the pivotal MM and MDS registration trials where the efficacy and safety were 
established for lenalidomide, the drug was administered without regard to food 
intake. Thus, lenalidomide can be administered with or without food. 
Multiple dosing (up to 100 mg BID) did not cause marked drug accumulation.   
b)  Distribution – In vitro (14C)-lenalidomide binding to plasma proteins is 
approximately 30%. 
c)  Metabolism – Lenalidomide undergoes limited metabolism. Unchanged 
lenalidomide is the predominant circulating component in humans. Two 
identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each 
constitutes less than 5% of parent levels in circulation. 
d)  Excretion – Elimination is primarily renal.  Approximately 65% to 85% of 
lenalidomide is eliminated unchanged through urinary excretion in subjects with 
normal renal function. The half-life of elimination is approximately 3 to 4 hours 
(2 to 3 hours in patients 5 to 21 years) at the clinically relevant doses (5 to 50 
mg/day). Steady-state levels are achieved within 4 days. 
 


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Addendum 5 
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15.16 Potential Drug Interactions:  In vitro studies demonstrate that lenalidomide is 
not a substrate of CYP enzymes. In addition, lenalidomide shows little inhibitory 
or induction potential towards the CYP enzymes in vitro. Hence, 
coadministration of CYP substrates, inhibitors, or inducers with lenalidomide is 
not likely to result in clinically relevant drug-drug interactions in humans.  
In vitro, lenalidomide is not a substrate of BCRP, MRP1, MRP2, MRP3, OAT1, 
OAT3, OATP1B1, OCT1, OCT2, MATE1, OCTN1, or OCTN2. Thus, it is 
unlikely that substrates or inhibitors of these transporters would affect 
lenalidomide disposition in humans. 
Lenalidomide is not an inhibitor of BSEP, BCRP, MRP2, OAT1, OAT3, 
OATP1B1, OATP1B3, or OCT2. Thus, lenalidomide is not anticipated to cause 
any significant drug-drug interactions due to inhibition of these transporters. 
Lenalidomide is not an inhibitor of UGT1A1 and is not anticipated to cause any 
significant drug-drug interactions due to UGT1A1 inhibition. 
In vitro, lenalidomide is a weak substrate, but not an inhibitor of P-glycoprotein 
(P-gp). 
Erythropoietic agents or other agents that may increase the risk of thrombosis, 
such as hormone replacement therapy and oral contraceptives, should be used 
with caution in patients with multiple myeloma receiving lenalidomide with 
dexamethasone. 
Periodic monitoring of digoxin plasma levels is recommended due to increased 
Cmax and AUC with concomitant lenalidomide therapy.  Close monitoring of PT 
and INR is recommended in multiple myeloma patients taking concomitant 
warfarin. 
 
15.17 Known potential toxicities:   
Pregnancy Warning: Lenalidomide, a thalidomide analogue, caused limb 
abnormalities in a developmental monkey study similar to birth defects caused by 
thalidomide in humans. If lenalidomide is used during pregnancy, a teratogenic 
effect of lenalidomide in humans cannot be ruled out. Pregnancy must be 
excluded before start of treatment. Prevent pregnancy during treatment by the use 
of two reliable methods of contraception. 
Very Common AEs (≥10%): anemia, febrile neutropenia, granulocytopenia, 
leukopenia, lymphopenia, neutropenia, thrombocytopenia, cataracts, blurred 
vision, abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, 
asthenia, chills, edema including peripheral, fatigue, pyrexia, abnormal liver 
function tests, bronchitis, gastroenteritis, influenza, nasopharyngitis, sinustitis, 
pneumonia, rhinitis, upper respiratory tract infection, urinary tract infection 
weight decreased, decreased appetite, hyperglycemia, hypocalcemia, 
hypokalemia, arthralgia, back pain, bone pain, muscle spasms, musculoskeletal 
pain, myalgia, pain in extremity, dizziness, dysgeusia, headache, hypoesthesia, 
neuropathy peripheral, neuropathy, paresthesia, tremor, depression, insomnia, 
renal failure, cough, dyspnea, epistaxis, pharyngitis, pulmonary embolism, dry 
skin, pruritus, rash, and deep vein thrombosis. 
Common (≥1% and <10%): hemolytic anemia, pancytopenia, acute myocardial 
infarction, atrial fibrillation, cardiac failure, congestive heart failure, myocardial 


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Addendum 5 
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ischemia, tachycardia, vertigo, upper abdominal pain, dry mouth, toothache, 
chest pain, fall, cholestasis, arthritis infective, bacteremia, cellulitis, erysipelas, 
herpes simplex, herpes zoster, lower respiratory infection, lung infection, 
meningitis, ophthalmic herpes zoster, respiratory infection, sepsis, contusion, 
alanine aminotransferase increased, c-reactive protein increased, gamma-
glutamyltransferase increased, dehydration, diabetes mellitus, gout, 
hypercalcemia, hyperuricemia, hypophosphatemia, hypomagnesemia, 
hyponatremia, iron overload, muscular weakness, acute myeloid leukemia, basal 
cell carcinoma, myelodysplastic syndrome, squamous cell carcinoma of skin, T-
cell type acute leukemia, tumor flare, tumor lysis syndrome, cerebrovascular 
accident, lethargy, peripheral sensory neuropathy, syncope, mood altered, 
respiratory distress, erythema, hyperhidrosis, night sweats, hematoma, 
hypertension, hypotension, thrombosis, and vasculitis. 
Uncommon, limited to important or life-threatening (< 1%): appendicitis, 
bursitis infective, clostridium difficile colitis, infective exacerbation of chronic 
obstructive airways disease, pyelonephritis, hypersensitivity, Graft vs Host 
Disease, viral reactivation (such as hepatitis B virus or herpes zoster), DRESS. 
The following additional adverse reactions have been reported in Celgene-
sponsored clinical studies and are considered by the company to be at least 
possibly related to the administration of lenalidomide: pneumonitis, transient 
abnormal liver laboratory tests, hyperthyroidism, hypothyroidism, viral 
reactivation (such as hepatitis B virus or herpes virus) acute graft-versus-host 
disease following allogeneic transplant, solid organ rejection, TLS, TFR, and 
allergic conditions (including angioedema, SJS, TEN, and DRESS).  These 
reactions are reported voluntarily from a population of uncertain size, so it is not 
possible to reliably estimate their frequency. 
Lenalidomide may have minor or moderate influence on the ability to drive and 
use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have 
been reported with the use of lenalidomide. Therefore, caution is recommended 
when driving or operating machines. 
Please refer to the Investigator’s Brochure for a more comprehensive list of 
treatment-emergent adverse events. 
15.18 Drug procurement:  Lenalidomide (Revlimid®) will be provided directly to 
research subjects for the duration of their participation in this trial at no charge to 
them or their insurance providers in accordance with the 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 Celgene REVLIMID REMS® program. Drug will be 
shipped on a per patient basis by the contract pharmacy to the clinic site for IND 
studies. Prescriptions must be filled within 7 days. Only enough lenalidomide 
for one cycle of therapy will be supplied to the patient each cycle. 
Any unused lenalidomide should be returned for disposition in accordance with 
the REVLIMID REMS®   program. 
15.19 Nursing Guidelines:  
15.191 
Myelosuppression is dose-dependent and reversible with treatment 
interruption and/or dose reduction. Monitor CBC w/diff regularly. 


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Addendum 5 
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Instruct patient to report any unusual bruising or bleeding 
(thrombocytopenia); signs and symptoms of infection (neutropenia); 
and energy conserving lifestyle (anemia). 
15.192 
Lenalidomide can have thrombotic adverse events (i.e DVT and PE). 
Instruct patient to report any limb swelling or pain, and to seek medical 
attention for shortness of breath or chest pain. 
15.193 
Because of the potential for birth defects patients should be instructed 
in effective methods of birth control. Female patients should use 2 
forms of birth control during treatment and for 4 weeks after 
discontinuing therapy. Males must be instructed to use a latex condom 
during any sexual contact with a woman of child bearing potential 
(even if they have had a vasectomy), because it is unknown if 
lenalidomide is present in semen. 
15.194  
Patents may experience pruritus, rash and dry skin. Because of the rare 
risk of Steven’s Johnson Syndrome, patients should immediately report 
any rash to their provider. 
15.195 
Drug may cause hyperglycemia. Patients with diabetes or impaired 
fasting glucose may need to have their glucose levels monitored more 
closely. 
15.196 
Gastrointestinal side effects (diarrhea, constipation, nausea, dyspepsia, 
anorexia, etc) are commonly seen. Manage patent symptomatically and 
monitor for effectiveness. 
15.197 
Patients may experience myalgias, arthralgias, parasthesias, and other 
generalized pain. Administer analgesics as ordered and monitor for 
their effectiveness. Rarely infective bursitis and arthritis have been 
reported. Instruct patients to report and joint pain or redness to study 
team immediately 
15.198 
Upper respiratory symptoms (nasopharyngitis, cough, epistaxis, etc.) 
can be seen. Manage symptomatically and monitor for effectiveness 
15.199a Agent may cause fatigue, dizziness, vertigo or blurred vision. Instruct 
patients to use caution when driving or operating machines.  
15.199b Monitor LFT’s and report any elevations to the study team. Instruct 
patient to report abdominal pain and/or jaundice to the study team. 
15.199c All prescribers and patients must be enrolled into the REVLIMID 
REMS program. Only enough Lenalidomide for one cycle of therapy 
will be supplied to the patient each cycle. 
15.199d Rarely secondary malignancies have been seen after lenolidamide 
therapy, including MDS, squamous/basal cell carcinomas of the skin, 
T-cell type acute leukemia. 
15.199e Monitor Renal function, renal failure has been reported. 
 
15.2 
Dexamethasone for Oral Administration (DXM) 
15.21 Background: Dexamethasone is an adrenal corticosteroid compound. 
Dexamethasone decreases inflammation by suppression of neutrophil migration, 
decreased production of inflammatory mediators, and reversal of increased 
capillary permeability; suppresses normal immune response. Dexamethasone’s 
mechanism of antiemetic activity is unknown. 


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Addendum 5 
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15.22 Formulation: Commercially available for oral administration as:  
Tablets [scored]: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg,  
15.23 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral tablets at room 
temperature between 20ºC to 25ºC (60ºF to 77ºF). Protect from moisture. 
Dispense in a well-closed, light-resistant container as defined in the 
USP/NF. Store oral liquid at room temperature, do not freeze. Do not use 
if solution contains a precipitate. Refer to commercial package for drug 
expiration date. 
15.24 Administration:  Refer to the treatment section for specific administration 
instructions. May be taken with meals to decrease GI upset.  
15.25 Pharmacokinetic information: 
Onset of action: Prompt 
Duration of metabolic effect: 72 hours 
Metabolism: Hepatic 
Half-life elimination: Normal renal function: 1.8-3.5 hours; Biological 
half-life: 36-54 hours 
Time to peak, serum: Oral: 1-2 hours 
Excretion: Urine and feces 
15.26 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CYP3A4 (major); Induces 
CYP2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 3A4 (strong) 
Increased Effect/Toxicity: Aprepitant, azole antifungals, calcium channel 
blockers, cyclosporine, estrogens, and macrolides may increase the serum 
levels of corticosteroids. Corticosteroids may increase the hypokalemic 
effects of amphotericin B or potassium-wasting diuretics (loop or 
thiazide); monitor. Refer to the package insert for a listing of other drugs. 
Decreased Effect: Antacids and bile acid sequestrants may reduce the 
absorption of corticosteroids; may reduce the absorption of corticosteroids; 
separate administration by 2 hours. Aminoglutethimide, barbiturates, and 
CYP3A4 inducers may reduce the serum levels/effects of dexamethasone 
and dexamethasone may decrease the levels/effects of other CYP3A4 
substrates. Serum concentrations of isoniazid may be decreased by 
corticosteroids. Corticosteroids may lead to a reduction in warfarin effect. 
Corticosteroids may suppress the response to vaccinations. 
Ethanol/Nutrition/Herb Interactions:  
Ethanol: Avoid ethanol (may enhance gastric mucosal irritation). 
Food: Dexamethasone interferes with calcium absorption. Limit caffeine. 
Herb/Nutraceutical: Avoid cat’s claw, Echinacea (have immunostimulant 
properties) 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
Common known potential toxicities, frequency not defined:   
Fluid and electrolyte disturbances, congestive heart failure in susceptible 
persons, hypertension, euphoria, personality changes, insomnia, 
exacerbation of infection, exacerbation or symptoms of diabetes, 
psychosis, muscle weakness, osteoporosis, vertebral compression 
fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, 


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Addendum 5 
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convulsions, vertigo and headache, endocrine abnormalities, ophthalmic 
changes, and metabolic changes. Some patients have experienced itching 
and other allergic, anaphylactic or hypersensitivity reactions. Withdrawal 
from prolonged therapy may result in symptoms including fever, myalgia 
and arthralgia. 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
15.29 Nursing Implications: 
15.291 
Monitor regularly for hypertension, CHF and other evidence of fluid 
retention. 
15.292 
Advise patient of possible mood or behavioral changes, i.e., 
depression, euphoria, insomnia, even psychosis.  Instruct patient to 
report any suspected changes to healthcare team. 
15.293 
Assess for symptoms of gastric ulcer, heartburn, or gastritis.  Suggest 
antacids.  Instruct patient to report symptoms to healthcare team if 
unable to control. 
15.294 
Evaluate signs of infection, particularly local candidal infections and 
treat appropriately. 
15.295 
Monitor blood glucose frequently. 
15.296 
Instruct patient to report frequent, unrelenting headaches or visual 
changes to healthcare team. 
15.297 
Advise patient that easy bruising is a side effect. 
 
 


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15.3 
Anakinra (Kineret®) or Placebo 
15.31 Background: Anakinra is an interleukin-1 (IL-1) receptor agonist. Interleukin-1 
(IL-1) is a key mediator of immune and inflammatory responses. This cytokine 
promotes fever, hypotension, and anorexia as well as mediates inflammation by 
increasing neutrophils, activating macrophages, and initiating T-cell and B-cell 
growth and differentiation.  Production of IL-1 is induced in response to 
inflammation, immunologic reactions, microbial invasion, and tissue injury and 
may lead to acute or chronic inflammation. Acute and chronic inflammatory 
diseases that have been linked to IL-1 activity include rheumatoid arthritis (RA), 
osteoarthritis (OA), multiple sclerosis (MS), Lyme arthritis, graft-versus-host 
disease, acute and chronic myelogenous leukemia (AML and CML, 
respectively), multiple myeloma, stroke, head trauma, ulcerative colitis, Crohn’s 
disease, septic shock or sepsis syndrome, asthma, and diabetes mellitus. 
15.32 Formulation: Injection: 100 mg/0.67 mL solution in a single-use prefilled 
syringe for subcutaneous injection. Graduated syringe allows for doses between 
20 mg and 100 mg. 
Placebo is provided as 0.67 mL 0.9% NaCL in a single-use syringe for 
subcutaneous injection. 
15.33 Preparation and storage:  Kineret is supplied in single-use preservative free, prefilled 
glass syringes with 29 gauge needles. Each prefilled glass syringe contains 100 mg of 
anakinra per 0.67 mL. The full syringe contains 100 mg anakinra. Kineret is dispensed in 
a 4 x 7 syringe dispensing pack containing 28 syringes. Kineret is also dispensed in a 1 x 
7 syringe dispensing pack containing 7 syringes.  
Storage: Kineret should be stored in the refrigerator at 2ºC to 8ºC (36ºF to 46ºF). DO 
NOT FREEZE OR SHAKE. Protect from light.. 
15.34 Administration: Instructions on appropriate use should be given by the 
healthcare provider to the patient or caregiver. The prescribed dose of anakinra or 
placebo should be administered according to the instructions for use and any 
unused portions discarded. After administration of anakinra or placebo it is 
essential to follow the proper procedure for disposal of syringes and any residual 
drug. Rotate injection sites between areas including the thigh, abdomen, upper 
arm, buttocks. The injection should be given at least 1 inch away from the 
previous injection site. Allow solution to warm to room temperature prior to use 
(60-90 minutes); do not shake. 
15.35 Pharmacokinetic information: The absolute bioavailability of Kineret after a 
70 mg subcutaneous bolus injection in healthy subjects (n = 11) is 95%. In 
subjects with RA, maximum plasma concentrations of Kineret occurred 3 to 7 
hours after subcutaneous administration of Kineret at clinically relevant doses (1 
to 2 mg/kg; n = 18); the terminal half-life ranged from 4 to 6 hours. In RA 
patients, no unexpected accumulation of Kineret was observed after daily 
subcutaneous doses for up to 24 weeks. The influence of demographic covariates 
on the pharmacokinetics of Kineret was studied using population 
pharmacokinetic analysis encompassing 341 patients receiving daily 
subcutaneous injection of Kineret at doses of 30, 75, and 150 mg for up to 24 
weeks. The estimated Kineret clearance increased with increasing creatinine 
clearance and body weight. After adjusting for creatinine clearance and body 
weight, gender and age were not significant factors for mean plasma clearance. 
Patients With Renal Impairment: The mean plasma clearance of Kineret in 


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Addendum 5 
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subjects with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine 
clearance 30-49 mL/min) renal insufficiency was reduced by 16% and 50%, 
respectively. In severe renal insufficiency and end stage renal disease (creatinine 
clearance <30 mL/min1), mean plasma clearance declined by 70% and 75%, 
respectively. Less than 2.5% of the administered dose of Kineret was removed by 
hemodialysis or continuous ambulatory peritoneal dialysis. Based on these 
observations, a dose schedule change should be considered for subjects with 
severe renal insufficiency or end stage renal disease.  
Patients with Hepatic Dysfunction: No formal studies have been conducted 
examining the pharmacokinetics of Kineret administered subcutaneously in 
patients with hepatic impairment. 
15.36 Potential Drug Interactions (USPI Section Drug Interactions):  
Warnings and Precautions 
Serious Infections – Kineret has been associated with an increased incidence of 
serious infections (2%) vs Placebo (<1%) in clinical trials in RA.  
Administrations of anakinra should be discontinued if a patient develops a 
serious infection.  Treatment should not be initiated in patients with active 
infections.  The safety and efficacy of anakinra in immunosuppressed patients or 
in patients with patients with chronic infections have not been evaluated.   
Drugs that affect the immune system by blocking TNF have been associated with 
an increased risk of reactivation of latent tuberculosis (TB).  It is possible that 
taking drugs such as anakinra that blocks IL-1 increases the risk of TB or other 
atypical or opportunistic infections.  (Section 5.1 of the USPI) 
Hypersensitivity reactions – Hypersensitivity reactions, including anaphylactic 
reactions and angioedema have been reported with anakinra.  If a severe 
hypersensitivity reaction occurs, administration of anakinra should be 
discontinued and appropriate therapy initiated. (Section 5.3 of the USPI) 
Immunosuppression – The impact of treatment with anakinra on active and / or 
chronic infections and the development of malignancies is not known. (Section 
5.4 of the USPI) 
 
15.37 Known potential toxicities: 
>10% of patients: 
Local: Injection site reaction (majority mild, typically lasting 14-28 days, 
characterized by erythema, ecchymosis, inflammation, and pain). Infection  
(Upper respiratory infections were 14% in the combined studies while serious 
infections were only 2%). 
1% to 10% of patients: Hematologic: neutropenia 
Miscellaneous: Headache, Immunogenicity to Anakinra.  
<1% of patients (limited to important or life-threatening): 
Hypersensitivity reactions (including anaphylaxis, angioedema, pruritus, rash, 
urticarial) 
 
15.38 Drug procurement: As of October 31, 2018.   Avavailable from commercial 
supply.  Note:  Previously provided by SOBI, AB.   
 
 
 


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15.39 Nursing Guidelines:  
15.391 
Instruct patients on self-administration of anakinra and monitoring of 
injection sites. Be sure to instruct patient on rotating injection sites - 
injection sites should be at least 1 inch away from previous injections.  
15.392 
Allow solution to warm to room temperature over 60-90 minutes. Do 
not shake. 
15.393 
Patients should not receive live vaccines while on agent. 
15.394 
Instruct patient about injection site reactions which can last anywhere 
from 14-28 days. Instruct patient to contact PI if they have concerns 
about injection site reactions. 
15.395 
Warn patients of infection risk. Instruct patients to report any fever, or 
other signs/symptoms of infection to the study team. 
15.396 
Patients may experience headache. Treat symptomatically and monitor 
for effectiveness. 
15.397 
Although less common, gastrointestinal side effects (diarrhea and 
nausea), may be seen. Treat symptomatically and monitor for 
effectiveness. 
15.398 
Neutropenia may be seen. Monitor CBC w/diff as per protocol and 
instruct patients to report signs and symptoms of infection to the study 
team. 
 
 
 


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16.0  
Statistical Considerations and Methodology  
16.1 
Overview 
This is a phase I/II study. The phase I portion is designed to determine the maximally 
tolerated dose (MTD) and toxicity profile of lenalidomide in combination with 
dexamethasone plus anakinra in patients with high risk SMM, IMM, or newly diagnosed 
multiple myeloma using the standard cohort 3+3 design. The MTD may not be reached 
and therefore the maximum administered dosage (MAD) will be obtained. The phase II 
portion is a randomized study designed to compare time to disease progression (TTP) of 
lenalidomide and dexamethasone plus placebo (standard treatment arm) versus 
lenalidomide and dexamethasone plus anakinra (experimental arm) in patients with high 
risk (monotypic plasma cell S-phase≥0.3%) SMM, IMM, or newly diagnosed multiple 
myeloma. Approximately one third of newly diagnosed multiple myeloma patients are 
expected to be high risk. 
16.11 Primary Endpoint 
The primary endpoint of the phase I portion is toxicity, and more specifically, 
MTD determination. The primary endpoint of the phase II portion of this study is 
time to disease progression (TTP), which will be compared between the two 
arms. Time to progression is defined as the time from registration until the 
earliest date of documentation of disease progression. If a patient dies without a 
documentation of disease progression, the patient will be considered to have had 
disease progression at the time of their death unless there is sufficient 
documented evidence to conclude no progression occurred prior to death. If a 
patient receives subsequent treatment before disease progression, they will be 
censored on the date of the last disease assessment. All patients meeting the 
eligibility criteria who have signed a consent form and have begun treatment will 
be evaluable for the primary endpoint. 
16.12 Sample Size 
The phase I portion of the trial is expected to require at least 12 patients and as 
many as 18 patients to determine the MTD. The phase II portion of this study is 
expected to accrue a maximum of 45 evaluable patients in each arm unless undue 
toxicity is encountered. We anticipate accruing 12 additional patients (2 phase I, 
5 phase II in each arm) to account for ineligibility, cancellation, major treatment 
violation, or other reasons. Therefore, this study is expected to accrue a 
maximum of 120 patients overall. 
16.13 Accrual Rate and Study Duration 
The anticipated accrual rate is 4 patients per month assuming that approximately 
one third of newly diagnosed patients will be high risk. At this rate, it will likely 
take about 2.5 months to enroll, treat, and evaluate each cohort in the phase I 
portion of this study. The phase I portion is expected to take between 10 and 
15 months. The phase II portion of this study is expected to accrue in 2 years. 
The total study duration is expected to be approximately 5.5 years, or until the 
last patient accrued has been observed for at least 2 years. 
Phase I Portion  
16.2 
Study Design 
The phase I study is designed to determine the maximally tolerated dose (MTD) and 
toxicity profile of lenalidomide in combination with dexamethasone and anakinra in 
patients with high risk SMM, IMM, or newly diagnosed multiple myeloma using the 


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Addendum 5 
Protocol version date:  25Oct2018 
standard cohort 3+3 design. Three patients will be treated at each dose level and observed 
for a minimum of four weeks (i.e. one full cycle) before new patients are treated. Doses 
will not be escalated in any individual patient. 
16.21  MTD Definition 
MTD is defined as the dose level below the lowest dose that induces dose-
limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum 
of 6 new patients). A total of 6 patients treated at the MTD will be sufficient to 
identify common toxicities at the MTD. For instance, those toxicities with an 
incidence of at least 25% will be observed with a probability of at least 82%  
(1-(1-0.25)6). 
If all dose levels are determined to be safe, then the maximum administered 
dosage (MAD) will be the dose level selected to be brought forward to the phase 
II portion of the study. 
Refer to Section 7.22 for definition of dose-limiting toxicity (DLT). 
16.22 MTD Determination 
Dose Escalation: The phase I portion of this study will utilize a standard cohort-
of-three design. The dose levels to which patients will be assigned in sequential 
cohorts are described in Section 7.21. The first cohort of three patients will be 
treated at dose level 1. Decisions on when and how to dose escalate are described 
below. 
16.221 
Three patients will be treated at a given dose level combination and 
observed for one (1) cycle to assess toxicity. 
16.222 
If DLT is not seen in any of the 3 patients, 3 new patients will be 
accrued and treated at the next higher dose level. If DLT is seen in 2 or 
3 of 3 patients treated at a given dose level, then the next 3 patients 
will be treated at the next lower dose level, if only 3 patients were 
enrolled and treated at this lower dose level. 
16.223 
If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level. 
If DLT is seen in at least one of these additional three patients (≥2 of 
6), the MTD will have been exceeded and further accrual will cease to 
this cohort. If dose-limiting toxicity (DLT) is not seen in any of the 
three additional patients, 3 new patients will be accrued and treated at 
the next higher dose level.  
16.224 
After enrolling 6 patients on a specific dose level, if DLT is observed 
in at least 2 of 6 patients, then the MTD will have been exceeded and 
defined as the previous dose unless only 3 patients were treated at the 
lower dose level. In that case, 3 additional patients will be treated at 
this lower dose level such that a total of 6 patients are treated at the 
MTD to more fully assess the toxicities associated with the MTD. 
16.225 
Dose de-escalation: If dose-limiting toxicity meets the stopping 
boundaries set by the above dose escalation algorithm at dose level 1 
(for example, more than 1 out of 3 patients or more than 1 out of 6 
patients), the study will be temporarily closed. Further dose re-
escalation will depend on the toxicity profile observed, and re-
evaluation of the regimen by the study team may be done. 
16.226 
If a patient fails to complete the first cycle of treatment for reasons 
other than toxicity, the patient will be regarded as inevaluable and will 


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Addendum 5 
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be replaced. If a patient has a dose reduction to <70% of the expected 
dose or dose delay of more than 3 weeks during Cycle 1 for reasons 
other than DLT, the patient will be replaced by an additional patient. 
 
16.227 
Operating Characteristics for standard cohort of 3 design: The 
following table gives the probability of dose escalation at a single dose 
level as a function of the true probability of DLT at that level using the 
cohorts of 3 design described above. 
True Rate 
of DLT (%) 
Probability of Dose Escalation 
10 
0.91 
20 
0.71 
30 
0.49 
40 
0.31 
50 
0.17 
16.23 Analysis Plans 
All the relevant results pertaining to toxicity, MTD, response, timed endpoints 
and laboratory correlates will be examined in an exploratory and hypothesis-
generating fashion. The small sample size and the heterogeneous patient 
population associated with phase I studies restricts the generalizability of the 
results. Any notable statistical result should only be viewed as preliminary 
evidence for further study in Phase II trials rather than a definitive finding in and 
of itself. Data will continue to be collected on patients as long as they are trial 
participants. 
16.231 
Adverse Events Profile 
The number and severity of all adverse events (overall and by dose-
level) will be tabulated and summarized in this patient population. The 
Grade 3+ adverse events will also be described and summarized in a 
similar fashion. This will provide an indication of the level of tolerance 
for this treatment combination in this patient group.  
16.232 
Toxicity Profile 
The term toxicity is defined as adverse events that are classified as 
either possibly, probably, or definitely related to study treatment.  Non-
hematologic toxicities will be evaluated via the ordinal CTC standard 
toxicity grading. Hematologic toxicity measures of thrombocytopenia, 
neutropenia, and leukopenia will be assessed using continuous 
variables as the outcome measures (primarily nadir) as well as 
categorization via CTC standard toxicity grading. 
Overall toxicity incidence as well as toxicity profiles by dose level, 
patient and tumor site will be explored and summarized. Frequency 
distributions, graphical techniques and other descriptive measures will 
form the basis of these analyses. 
16.233 
Response Profile 
A response is defined to be a sCR, CR, VGPR, or PR noted as the 
objective status.  Response will be evaluated using all cycles of 
treatment.  All patients meeting the eligibility criteria who have signed 


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Addendum 5 
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a consent form and have begun treatment will be evaluable for 
response. 
Responses will be summarized by simple descriptive summary 
statistics delineating complete and partial responses as well as stable 
and progressive disease in this patient population. 
Phase II Portion  
16.3 
Statistical Considerations 
16.31 Study Design: 
In a study of consecutive patients treated with lenalidomide and dexamethasone 
as initial therapy for symptomatic multiple myeloma at Mayo Clinic, the TTP for 
16 high risk patients (defined as presence of hypodiploidy, del(13q) by 
metaphase cytogenetics, del(17p), IgH translocations [t(4; 14), or t(14;16)] or 
PCLI ≥3%) was approximately 18 months (Kapoor et al, 2009). However, that 
definition of high risk may not be inclusive of all patients that will be accrued to 
this study.  In addition, a second study of patients treated with lenalidomide and 
dexamethasone at Mayo Clinic estimated that 29 high risk patients (defined as 
PCLI ≥1%) had a median TTP of approximately 29 months (unpublished). This 
study will define high risk as monotypic plasma cell S-phase≥0.3%. PCLI and 
monotypic plasma cell S-phase are both assays that measure plasma cell 
proliferation, where a cutoff of ≥0.3% for monotypic plasma cell S-phase would 
give a similar patient population as using a cutoff of ≥1% for PCLI. Thus, 
estimates of TTP from previous studies that defined high risk using PCLI would 
still be relevant. However, due to the small sample sizes and inconsistency in 
TTP estimates for high risk patients in these prior studies, the lenalidomide and 
dexamethasone arm of this study will be used to better estimate TTP in high risk 
myeloma patients (defined as monotypic plasma cell S-phase≥0.3% for this 
study).  We estimate that the median TTP in the lenalidomide and 
dexamethasone plus placebo arm will be 20 months. We are interested in testing 
the alternative hypothesis that the median TTP in the lenalidomide and 
dexamethasone plus Anti-IL-1 antibody arm will be at least 40 months. This 
translates into an improvement in the 2-year TTP from 43% to 66% assuming an 
exponential survival model. 
The primary goal of this trial is to compare the time to progression of the 
standard treatment arm (Arm A) to the experimental arm (Arm B). We will 
conduct a randomized trial comparing the experimental arm against the standard 
treatment arm. We will enter 45 evaluable patients to each arm of the study using 
a 1:1 randomization scheme (Pocock et al, 1975). The stratification factors that 
will be used are listed in Section 5.0.  The primary analysis will be a comparison 
of Arm A to Arm B using a one-sided log-rank test between the two Kaplan-
Meier curves. This final analysis will take place after an approximate 24-month 
accrual period and after 52 total progressions have occurred or the last patient has 
been followed for at least 2 years (whichever occurs first). Additionally, we 
assume a constant accrual rate over the course of the study and that we will not 
have a significant lost to follow-up issue, as historically lost to follow-up rates in 
Mayo clinic trials have been <1%. A sample size of 45 evaluable patients per arm 
(90 total) provides 80% power to detect an improvement in median time to 
progression from 20 months to 40 months (a hazard ratio of 2.0), using a 1-sided 
log-rank test at a significance level of 0.05. A final decision regarding the level 


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Addendum 5 
Protocol version date:  25Oct2018 
of promise for the experimental regimen will take all factors into account 
including TTP, response rate, OS, adverse events, and other relevant factors. All 
patients meeting the eligibility criteria who have signed a consent form and have 
begun treatment will be evaluable for the primary endpoint. 
16.32 Interim Monitoring 
An interim analysis with a futility rule will be performed to permit the decision 
regarding inactivity if there is strong evidence that the proposed treatment is 
inactive. The interim analysis will be performed after one-half of the required 
number of events for the primary analysis, or specifically, after 26 events 
(progressions) are observed on study. At the interim analysis, we will compare 
the distribution of TTP in the experimental arm (Arm B) to the standard 
treatment arm (Arm A). If the observed hazard rate of Arm B divided by the 
observed hazard rate on Arm A ≥1, we will conclude that an advantage for Arm 
B has not been established and the trial will be terminated early for futility. 
Termination of the trial for futility at the interim analysis using this rule results in 
minimal loss of power (<2%) (Wieand et al, 1994). 
16.33 
Secondary Outcome Analyses 
The secondary endpoints listed below will be evaluated in each arm 
independently and will also be compared between the two arms in an exploratory 
manner. 
16.331 
Survival time is defined as the time from registration to death due to 
any cause. The distribution of survival time will be estimated using the 
method of Kaplan-Meier within each arm and compared between the 
arms using a one-sided log-rank test. 
16.332 
Overall response rate: The overall response rate will be estimated by 
the number of patients with an objective status of sCR, CR, VGPR, or 
PR divided by the total number of evaluable patients. All evaluable 
patients will be used for this analysis. Exact binomial 95% confidence 
intervals for the true overall response rate will be calculated within 
each arm and compared between the arms using Fisher’s exact test. 
16.34 Adverse Events 
All eligible patients that have intitiated treatment will be considered evaluable for 
assessing adverse event rate(s). The maximum grade for each type of adverse 
event will be recorded for each patient, and frequency tables will be reviewed to 
determine patterns. Additionally, the relationship of the adverse event(s) to the 
study treatment will be taken into consideration. 
16.35 Over Accrual 
If more than the target number of patients are accrued, the additional patients will 
not be used to evaluate the stopping rule or used in any decision making 
processes; however, they will be included in final point estimates and confidence 
intervals. 
16.36 Data & Safety Monitoring: 
16.361 
The principal investigator(s) and the study statistician will review the 
study at least twice a year to identify accrual, adverse event, and any 
endpoint problems that might be developing. The Mayo Clinic Cancer 
Center (MCCC) Data Safety Monitoring Board (DSMB) is responsible 


MC138B 
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Addendum 5 
Protocol version date:  25Oct2018 
for reviewing accrual and safety data for this trial at least twice a year, 
based on reports provided by the MCCC Statistical Office. 
16.362 
Adverse Event Stopping Rules (These rules apply to Arm A and Arm 
B independently for patients in the randomized phase II portion of the 
study):  The stopping rules specified below are based on the knowledge 
available at study development.  We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-
opening to accrual or (2) at any time during the conduct of the trial and 
in consideration of newly acquired information regarding the adverse 
event profile of the treatment(s) under investigation.  The study team 
may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
Accrual will be temporarily suspended to both arms if at any time we 
observe events considered at least possibly related to study treatment 
(i.e. an adverse event with attribute specified as  “possible”, 
“probable”, or “definite”) that satisfy either of the following: 
• 
if 3 or more patients in the first 12 treated patients experience 
a grade 4 or higher non-hematologic adverse event at least 
possibly related to treatment. 
• 
if after the first 12 patients have been treated, 25% of all 
patients experience a grade 4 or higher non-hematologic 
adverse event at least possibly related to treatment 
We note that we will review Grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
16.4 
Results Reporting on ClinicalTrials.gov 
At study activation, this study will have been registered within the “ClincialTrails.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on ClinicalTrials.gov. For purposes of timing of the Results 
Reporting, the initial estimated completion date for the Primary Endpoint of this study is 
5.5 years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time the last patient registered has been 
followed for at least 2 years. 
16.5 
Inclusion of Women and Minorities 
16.51 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
16.52 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
16.53 The geographical region served by MCCC has a population which includes 
approximately 5% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 5% of patients will be classified as minorities by 


MC138B 
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Addendum 5 
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race and about 45% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 
 
 


MC138B 
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Addendum 5 
Protocol version date:  25Oct2018 
Accrual Estimates by Gender/Ethnicity/Race for All Phase 2 and 3 Studies 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
1 
1 
0 
2 
Not Hispanic or Latino 
53 
65 
0 
118 
Unknown 
0 
0 
0 
0 
Ethnic Category: Total of all subjects 
54 
66 
0 
120 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
2 
2 
0 
4 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
52 
64 
0 
116 
More than one race 
0 
0 
0 
0 
Unknown 
0 
0 
0 
0 
Racial Category: Total of all subjects 
54 
66 
0 
120 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
17.0  
Pathology Considerations/Tissue Biospecimens: None 
 
 


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18.0 
Records and Data Collection Procedures 
NOTE (Phase I Only): As of Addendum 5, Anakinra will no longer be provided and all patients will 
go off study treatment.  Event monitoring will no longer be required.  Patients may obtain 
Anakinra commercially and be treated off study. 
 
18.1 
Submission Timetables 
18.11 Initial Material(s) 
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study 
≤14 days after registration 
Adverse Event  - Baseline 
Measurement – Baseline 
SPEP, UPEP, FLC, Immunofixation, 
FISH, Cytogenetics, PCLI reports  
Bone marrow biopsy report 
Skeletal survey report 
End of Active Treatment/Cancel 
Notification  
Submit ≤14 days after registration if 
withdrawal/refusal occurs prior to beginning 
protocol therapy 
 
 
18.12 Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation during 
treatment 
At end of treatment 
Evaluation/Treatment  
X 
X 
Nadir/Adverse Event  
X 
X 
Hematology Interval Laboratory 
X 
 
Measurement  
X 
X 
End of Active Treatment/Cancel Notification  
 
X 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
SPEP, UPEP, FLC, Immunofixation, FISH, 
Cytogenetics, PCLI reports  
X2 
X2 
Bone marrow biopsy report 
X1 
X1 
Skeletal survey report 
X1 
X1 
Stem Cell Harvest (optional) 
X3 
 
1. Only when required by the Test Schedule (see Section 4.0). 
2. Submission of these reports is only required for documentation of CR (including sCR) or 
progression. For documentation of CR, submit all of these reports at the first confirmation of CR. 
For documentation of progression, submit one report for one of the measures where progression 
was seen. Submit reports to the QAS for MC138B. 
3. May interrupt therapy for stem cell collection at any time per Section 7.4. Submit the Stem Cell 
Harvest Form after stem cell collection has been completed. 
 


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MC138B 
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Addendum 5 
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18.13 Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
q. 6 
months 
until PD2 
At PD2 
After 
PD q. 
12 mos. 
Death 
New Primary 
Event Monitoring  
X 
X 
X 
X 
At each 
occurrence 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
2. Submit copy of documentation of response or progression to the MCCC Operations Office, 
Attention: QAS for MC138B. 
 
 
19.0  
Budget 
 
19.1 
Costs charged to patient: Routine clinical care 
 
19.2 
Tests to be research funded: Lenalidomide will be provided by Celgene. As of  October 31, 2018  
Anakinra  will no longer be provided (previously provided by SOBI, AB.     . 
 
 
 


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20.0 
References 
 
1. Kyle RA, Vincent Rajkumar S. Treatment of multiple myeloma: an emphasis on new 
developments. Annals of Medicine. 2006;38(2):111-115. 
2. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and 
the impact of novel therapies. Blood. 2008;111(5):2516-2520. 
3. Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance and 
smoldering multiple myeloma. Hematology - Oncology Clinics of North America. 
2007;21(6):1093-1113. 
4. International Myeloma Working G. Criteria for the classification of monoclonal 
gammopathies, multiple myeloma and related disorders: a report of the International 
Myeloma Working Group. British Journal of Haematology. 2003;121(5):749-757. 
5. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering 
(asymptomatic) multiple myeloma. New England Journal of Medicine. 2007;356(25):2582-
2590. 
6. Weber DM, Dimopoulos MA, Moulopoulos LA, Delasalle KB, Smith T, Alexanian R. 
Prognostic features of asymptomatic multiple myeloma. British Journal of Haematology. 
1997;97(4):810-814. 
7. Dimopoulos MA, Moulopoulos A, Smith T, Delasalle KB, Alexanian R. Risk of disease 
progression in asymptomatic multiple myeloma. American Journal of Medicine. 
1993;94(1):57-61. 
8. Facon T, Menard JF, Michaux JL, et al. Prognostic factors in low tumour mass asymptomatic 
multiple myeloma: a report on 91 patients. The Groupe d'Etudes et de Recherche sur le 
Myelome (GERM). American Journal of Hematology. 1995;48(2):71-75. 
9. Wisloff F, Andersen P, Andersson TR, et al. Incidence and follow-up of asymptomatic 
multiple myeloma. The myeloma project of health region I in Norway. II. European journal 
of haematology. 1991;47(5):338-341. Prepublished on 1991/11/01 as DOI. 
10. Mateos M-V, Hernandez M-T, Giraldo P, et al. Lenalidomide plus dexamethasone for high-
risk smoldering multiple myeloma. New England Journal of Medicine. 2013;369(5):438-447. 
http://dx.doi.org/10.1056/NEJMoa1300439. 
11. Greipp PR, Witzig TE, Gonchoroff NJ, et al. Immunofluorescence labeling indices in 
myeloma and related monoclonal gammopathies. Mayo Clinic Proceedings. 
1987;62(11):969-977. 
12. Greipp PR, Katzmann JA, O'Fallon WM, Kyle RA. Value of beta 2-microglobulin level and 
plasma cell labeling indices as prognostic factors in patients with newly diagnosed myeloma. 
Blood. 1988;72(1):219-223. 
13. Greipp PR, Kyle RA. Clinical, morphological, and cell kinetic differences among multiple 
myeloma, monoclonal gammopathy of undetermined significance, and smoldering multiple 
myeloma. Blood. 1983;62(1):166-171. 
14. Greipp PR, Lust JA, O'Fallon WM, Katzmann JA, Witzig TE, Kyle RA. Plasma cell labeling 
index and beta 2-microglobulin predict survival independent of thymidine kinase and C-
reactive protein in multiple myeloma [see comments]. Blood. 1993;81(12):3382-3387. 
15. Greipp PR, Lust JA. Pathogenetic relation between monoclonal gammopathies of 
undetermined significance and multiple myeloma. Stem Cells. 1995;13(Suppl 2):10-21. 
16. Huff CA, Matsui W, Smith BD, Jones RJ. The paradox of response and survival in cancer 
therapeutics. Blood. 2006;107(2):431-434. 


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Protocol version date:  25Oct2018 
17. Kawano M, Hirano T, Matsuda T, et al. Autocrine generation and requirement of BSF-2/IL-6 
for human multiple myelomas. Nature. 1988;332(6159):83-85. 
18. Schwab G, Siegall CB, Aarden LA, Neckers LM, Nordan RP. Characterization of an 
interleukin-6-mediated autocrine growth loop in the human multiple myeloma cell line, 
U266. Blood. 1991;77(3):587-593. 
19. Klein B, Zhang XG, Jourdan M, et al. Paracrine rather than autocrine regulation of myeloma-
cell growth and differentiation by interleukin-6. Blood. 1989;73(2):517-526. 
20. Portier M, Rajzbaum G, Zhang XG, et al. In vivo interleukin 6 gene expression in the 
tumoral environment in multiple myeloma. European Journal of Immunology. 
1991;21(7):1759-1762. 
21. Hilbert DM, Kopf M, Mock BA, Kohler G, Rudikoff S. Interleukin 6 is essential for in vivo 
development of B lineage neoplasms. Journal of Experimental Medicine. 1995;182(1):243-
248. 
22. Xiong Y, Donovan KA, Kline MP, et al. Identification of two groups of smoldering multiple 
myeloma patients who are either high or low producers of interleukin-1. Journal of 
Interferon & Cytokine Research. 2006;26(2):83-95. 
23. Donovan KA, Lacy MQ, Kline MP, et al. Contrast in cytokine expression between patients 
with monoclonal gammopathy of undetermined significance or multiple myeloma. Leukemia. 
1998;12(4):593-600. 
24. Lust JA, Donovan KA. The role of interleukin-1 beta in the pathogenesis of multiple 
myeloma. Hematology - Oncology Clinics of North America. 1999;13(6):1117-1125. 
25. Lacy MQ, Donovan KA, Heimbach JK, Ahmann GJ, Lust JA. Comparison of interleukin-1 
beta expression by in situ hybridization in monoclonal gammopathy of undetermined 
significance and multiple myeloma. Blood. 1999;93(1):300-305. 
26. Lust JA, Lacy MQ, Zeldenrust SR, et al. Induction of a Chronic Disease State in Patients 
With Smoldering or Indolent Multiple Myeloma by Targeting Interleukin 1Î²-Induced 
Interleukin 6 Production and the Myeloma Proliferative Component. Mayo Clinic 
Proceedings. 2009;84(2):114-122. 10.4065/84.2.114. 
27. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996;87(6):2095-2147. 
28. Kyle RA, Remstein ED, Therneau TM, et al. Clinical Course and Prognosis of Smoldering 
(Asymptomatic) Multiple Myeloma. N Engl J Med. 2007;356(25):2582-2590. 
10.1056/NEJMoa070389. 
29. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed 
multiple myeloma. Mayo Clinic Proceedings. 2003;78(1):21-33. 
30. Kapoor P, Kumar S, Fonseca R, et al. Impact of risk stratification on outcome among patients 
with multiple myeloma receiving initial therapy with lenalidomide and dexamethasone. 
Blood. 2009;114(3):518-521. 10.1182/blood-2009-01-202010. 
31. Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design issues of 
randomized phase II trials and a proposal for phase II screening trials. Journal of Clinical 
Oncology. 2005;23(28):7199-7206. 
32. Pocock, SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors 
in the controlled clinical trial. Biometrics. 1975;31(1):103-115, 1975 Mar. 
 
 


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Appendix I 
 
Page 1 of 1 
Protocol version date:  25Oct2018 
Appendix I 
ECOG Performance Status Scale 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis, 
MD, Group Chair. 
From http://www.ecog.org/general/perf_stat.html 
 
 
 


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Appendix II 
 
Page 1 of 1 
 
Protocol version date 25Jul2018 
 
Appendix II 
Mayo Risk Stratification 
 
 
High Risk 
FISH deletion 17p 
FISH t(4:14) 
FISH t(14:16) 
Metaphase cytogenetic del 13 
Hypodiploidy 
PCLI >3% 
 


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Appendix III 
 
Page 1 of 1 
Protocol version date 25Jul2018 
 
Appendix III NYHA Classification 
 
Class I:  
NO Symptoms with ordinary activity  
Class II:  
Symptoms with ordinary activity  
Class III:  
Symptoms with minimal activity 
Class IV:  
Symptoms at rest 
 
 


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Appendix IV 
 
Page 1 of 1 
Protocol version date 25Jul2018 
Appendix IV Multiple Myeloma Diagnostic Criteria 
 
Standard criteria for a diagnosis of multiple myeloma are as follows (Kyle et al British Journal 
of Haematology. 121(5):749-57, 2003)  
 
Multiple Myeloma 
Monoclonal protein present in serum ≥ 3 g/dl 
and/or 
Bone marrow clonal plasma cells ≥ 10% 
 
Myeloma-related organ or tissue impairment (ROTI) 
Calcium 1 mg/dL (0.25 mmol/L) above the upper limit of normal 
Creatinine > 2 mg/dL (173 mmol/L) 
Lytic bone lesions or osteoporosis 
 
Asymptomatic myeloma 
Multiple myeloma and absence of ROTI 
 
Symptomatic myeloma 
Multiple myeloma and presence of any ROTI that can be attributed to myeloma. 
 




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Appendix V 
 
Page 1 of 1 
Protocol version date:  25Oct2018 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please call: ______________________ 
Bring all bottles and any unused study medication along with this diary  
when you return for your next appointment. 
 
Other Medications: 
 
 
Comments: 
 
 
 
 
 
Area Below Only to be Completed by Coordinator 
 
Number of pills returned_____ 
 
Study Coordinator Initials________ 
Number of vials returned_____ 
Date
 
 
Discrepancy Yes
 No
 
 
 


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Appendix VI 
 
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Protocol version date:  25Oct2018 
Appendix VI 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.  The risks to a fetus are not known.  
However, because lenalidomide is related to thalidomide, and thalidomide is known to cause 
severe birth defects, the following requirements must be observed. 
Females of childbearing potential (FCBP)† must agree to use two reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual intercourse during the 
following time periods related to this study: 1) for at least 28 days before starting study drug; 2) 
while participating in the study; and 3) for at least 28 days after discontinuation from the study. 
The two methods of reliable contraception must include one highly effective method (i.e. 
intrauterine device (IUD), hormonal [birth control pills, injections, or implants], tubal ligation, 
partner’s vasectomy) and one additional effective (barrier) method (i.e. latex condom, 
diaphragm, cervical cap).  FCBP must be referred to a qualified provider of contraceptive 
methods if needed.   
Before starting study drug: 
Female Subjects: 
• FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
starting lenalidomide.  The first pregnancy test must be performed within 10-14 days 
prior to the start of lenalidomide and the second pregnancy test must be performed within 
24 hours prior to the start of lenalidomide.  The subject may not receive study drug until 
the Investigator has verified that the results of these pregnancy tests are negative. 
• Will be warned that sharing study drug is prohibited and will be counseled about 
pregnancy precautions and potential risks of fetal exposure.. 
• Must agree to abstain from donating blood during study participation and for at least 28 
days after discontinuation from the study. 
Male Subjects:   
• Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following 
discontinuation from the study even if he has undergone a successful vasectomy.  
• Will be warned that sharing study drug is prohibited and will be counseled about 
pregnancy precautions and potential risks of fetal exposure,  
                                                 
† 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). 
 


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Appendix VI 
 
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• Must agree to abstain from donating blood, semen, or sperm during study participation 
and for at least 28 days after discontinuation from the study. 
During study participation and for 28 days following discontinuation from the study: 
All Subjects: 
• Only enough lenalidomide for one cycle of therapy may be dispensed with each cycle of 
therapy.  
• If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a 
male study subject during study participation, lenalidomide must be immediately 
discontinued. 
Female Subjects:   
• FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, at study 
discontinuation, and at day 28 following discontinuation from the study. If menstrual 
cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and 
then every 14 days while on study, at study discontinuation, and at days 14 and 28 
following discontinuation from the study.   
• In addition to the required pregnancy testing, the Investigator must confirm with FCBP 
that she is continuing to use two reliable methods of birth control at each visit.   
• Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days. During counseling, subjects must be reminded 
to not share study drug and to not donate blood, . 
 
Pregnancy testing and counseling must be performed if a subject misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal.  Study drug treatment must be 
discontinued during this evaluation. 
• Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after discontinuation from the study. 
Male Subjects: 
Counseling about the requirement for latex condom use during sexual contact with females of 
childbearing potential and the potential risks of fetal exposure must be conducted at a minimum 
of every 28 days. During counseling, subjects must be reminded to not share study drug and to 
not donate blood, sperm, or semen