Clinical trial NCT02516696
Conditions: Multiple Myeloma
Sponsor: Weill Medical College of Cornell University
Start date: 2016-02-01; Completion date: 2022-07-22
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, open-label, phase III study to investigate the efficacy of combination therapy with an induction phase utilizing a combination clarithromycin (Biaxin®), lenalidomide (Revlimid®), dexamethasone (Decadron®), in multiple myeloma patients who are newly diagnosed and require treatment when compared to patients who receive lenalidomide and dexamethasone alone.

Detailed description:
This research study is for men and women with newly diagnosed, previously untreated multiple myeloma. The purpose of this study is to observe the how well the different combinations of study drugs work as therapy for patients with newly diagnosed, transplant ineligible, previously untreated multiple myeloma.

The study will be done in two arms:

BiRd Arm:

* Clarithromycin 500mg PO twice daily on days 1-28 for a 28-day cycle
* Lenalidomide 25mg PO daily on days 1-21 of a 28-day cycle
* Dexamethasone 40mg PO will be given on days 1, 8, 15, 22 of a 28-day cycle

Rd Arm:

* Lenalidomide 25mg PO daily on days 1-21 of a 28-day cycle
* Dexamethasone 40mg PO will be given on days 1, 8, 15, 22 of a 28-day cycle

Subjects will be treated in 28-day cycles and may continue treatment as long as they are responding to therapy and not experiencing unacceptable side effects or disease progression. There will be an evaluation at the end of each cycle. Participants will be in the study until disease progression or unacceptable toxicity.

Arms: arm 1: Subjects on the BiRD arm will receive clarithromycin, lenalidomide, and dexamethasone in 28-day cycles. arm 2: Subjects on the Rd arm will receive lenalidomide and dexamethasone in 28-day cycles.
Interventions: intervention 1: Clarithromycin intervention 2: Lenalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: 500mg PO twice daily on days 1-28 for a 28-day cycle. intervention 2: 25 mg PO days 1-21 followed by a 7 day rest period for each 28-day cycle intervention 3: 20 mg PO on Days 1, 8, 15, and 22 for each cycle for subjects 75 years and younger.

Protocol documents:
Prot_SAP_000.pdf: 
 
IRB Protocol Number: 1411015662 
 
Version Date: A(4) dated 22 JUN 2021 
 
 
 
 
 
 
 
 
TITLE:  Lenalidomide and Dexamethasone (Rd) versus Clarithromycin [Biaxin®] / 
Lenalidomide [Revlimid®] / Dexamethasone (BiRd) as Initial Therapy in Multiple 
Myeloma.  
 
WCM IRB #: 1411015662 
NCT#: 02516696 
Celgene’s Reference #: RV-CL-MM-PI-004078 
 
 
Principal Investigator: 
 
 
Jorge Monge, MD 
 
 
 
 
 
 
Weill Cornell Medical College 
 425 E. 61st Street, Suite 800 
 New York, NY 10021 
 Phone: (646) 962-6500    
 Fax: (212)-746-8961 
 Email: jum9127@med.cornell.edu 
 
Participating Principal Investigator  
(University of Colorado - Denver):  
 
 
Tomer Mark, MD 
 
 
1665 Aurora Court, MS F754 
Aurora, CO 80045 
 
 
Ph: (720) 848 0414 
 
 
Email: tomer.mark@ucdenver.edu 
 
 
 
Statistician:  
Paul J. Christos, DrPH, MS 
Weill Cornell Medical College 
402 E. 67th Street / Room 241 
New York, NY 10065 
Phone: (646) 962-8018 
Fax: (646)-962-0281 
pac2001@med.cornell.edu  
 
 
 


Amendment 4 dated 22 JUN 2021 
 
2
Table of Contents 
 
 
1.0  
STUDY SCHEMA .................................................................................................. 4 
1.1       BiRd medication schedule (one cycle) ............................................................. 4 
1.1       Rd medication schedule (one cycle) ................................................................. 4 
1.3 
Schedule of Assessments...................................................................................... 5 
2.0      OBJECTIVES AND SCIENTIFIC AIMS ........................................................... 7 
2.1 
   Study Objectives ............................................................................................... 7 
2.2 
Study Endpoints ................................................................................................... 7 
3.0 
BACKGROUND AND RATIONALE ................................................................... 9 
3.1 
Disease Information ............................................................................................. 9 
3.2 
Prognosis ............................................................................................................... 9 
3.3 
Treatment ............................................................................................................. 9 
3.4 
Dexamethasone .................................................................................................. 10 
3.5 
Clarithromycin (Biaxin®) .................................................................................. 10 
3.6 
Biaxin®, Low-dose Thalidomide and Dexamethasone .................................... 11 
3.7 
Lenalidomide (Revlimid®)................................................................................. 11 
3.8 
Rationale for BiRD Combination in Multiple Myeloma ................................ 12 
4.0 
INVESTIGATIONAL PLAN ............................................................................... 13 
4.1 
Study Design ....................................................................................................... 13 
4.2 
Recruitment Plan ............................................................................................... 14 
5.0 
CRITERIA FOR PATIENT ELIGIBILITY ...................................................... 15 
5.1 
Inclusion Criteria ............................................................................................... 15 
5.2  Exclusion Criteria ............................................................................................. 16 
6.0 
PRETREATMENT EVALUATION ................................................................... 17 
7.0 
THERAPUTIC AGENTS ..................................................................................... 18 
7.1 
Clarithromycin (Biaxin®) .................................................................................. 18 
7.2 
Lenalidomide (Revlimid®)................................................................................. 18 
7.3 
Dexamethasone (Decadron®) ............................................................................ 21 
8.0 
Toxicities and Side Effects .................................................................................... 21 
8.1 
Clarithromycin (Biaxin®) .................................................................................. 21 
8.2 
Lenalidomide (Revlimid®)................................................................................. 21 
8.3 
Dexamethasone (Decadron®) ............................................................................ 22 
9.0 
Therapeutic Plan ................................................................................................... 22 
9.1 
Treatment ........................................................................................................... 22 
9.2 Early Termination of Study ................................................................................ 24 
9.3 
Supportive Care and Concurrent Treatments ................................................ 24 
9.4 
Day One Dosing Guidelines .............................................................................. 25 
9.5 
Instruction for initiation of a new cycle ........................................................... 25 
9.6 
Dose Modification .............................................................................................. 26 
10.0 
STUDY EVALUATIONS ................................................................................... 32 


Amendment 4 dated 22 JUN 2021 
 
3
10.1 
Day 1, Cycle 1 ................................................................................................... 32 
10.2 
Days 8, 15, 22 Cycle 1 ...................................................................................... 32 
10.3 
Day 1 (starting cycle 2) and End of Study ..................................................... 32 
10.4 
Post Study Follow-up ...................................................................................... 33 
10.5  Treatment Compliance ................................................................................... 33 
10.11 
Criteria for removal from study .................................................................. 34 
11.0 
ADVERSE EVENTS GRADING AND REPORTING ................................... 35 
11.1 
Adverse Events ................................................................................................. 35 
11.2  Serious Adverse Events (SAE) ....................................................................... 35 
 
11.3 
Investigator Reporting Responsibilities ........................................................ 37 
11.3.4 Reporting of Secondary Primary Malignancies ............................................ 39 
11.4 
Adverse event updates/IND safety reports .................................................... 39 
11.5 
Provisions for Adverse Events ........................................................................ 39 
12.0  PROTOCOL AMENDMENTS AND DEVIATIONS ........................................ 39 
12.1 
Amendments .................................................................................................... 39 
12.2  Protocol Deviations ......................................................................................... 39 
13.0  
DATA MANAGEMENT ................................................................................... 40 
13.1 
Analyses and Reporting .................................................................................. 40 
13.2 
Data Safety Monitoring Board. ...................................................................... 40 
13.3 
Study Monitoring and Auditing ..................................................................... 41 
14.0 STATISTICAL CONSIDERATIONS .................................................................. 41 
15.0 
REGULATORY CONSIDERATIONS ............................................................ 43 
15.1 
Institutional Review Board/Ethics Committee approval ............................. 43 
15.2 
Informed Consent Procedures ........................................................................ 44 
15.3 
Protecting Privacy and Confidentiality ......................................................... 44 
15.4 
Study records requirements ........................................................................... 45 
15.5 
Protection of Human Rights ........................................................................... 45 
15.6 
Premature Discontinuation of Study ............................................................. 45 
15.7 
Benefits of the Protocol ................................................................................... 46 
15.8 
Risks in Relation to Anticipated Benefit........................................................ 46 
15.8 
Alternative Treatments ................................................................................... 46 
15.9 
Incentives .......................................................................................................... 46 
15.10 
Costs ................................................................................................................ 46 
References ........................................................................................................................ 47 
APPENDIX I: Criteria for Response ............................................................................ 49 
APPENDIX II: Diagnostic and Staging Criteria for Multiple Myeloma ................... 50 
APPENDIX III:  Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods ............................................................................... 52 
APPENDIX VI: New York State Association Classification of Cardiac Disease...... 59 
 
 


Amendment 4 dated 22 JUN 2021 
 
4
1.0  
STUDY SCHEMA 
 
1.1       BiRd medication schedule (one cycle) 
 
 
 
 
 
 
 
 
1.1       Rd medication schedule (one cycle) 
 
 
 
 
 
 
 
 
 
 
 
 
   1                         8                          15                          21       22 28 
Day 
Dex* 
 40mg PO 
Dex 
 40mg PO 
Dex 
 40mg PO 
Dex 
 40mg PO 
Lenalidomide 25mg PO 
Clarithromycin  500mg PO BID 
   1                         8                          15                          21       22 28 
Day 
Dex* 
 40mg PO 
Dex 
 40mg PO 
Dex 
 40mg PO 
Dex 
 40mg PO 
Lenalidomide 25mg PO 
Lenalidomide will be given for days 1-21 followed by a 7 day rest period for each 28-day cycle. 
*Dexamethasone at a dose of 20mg on Days 1, 8, 15, 22 will be used for subjects  ≤75 years old.  
Lenalidomide will be given for days 1-21 followed by a 7 day rest period for each 28-day cycle. 
*Dexamethasone at a dose of 20mg on Days 1, 8, 15, 22 will be used for subjects  ≤75 years old.  


Amendment 4 dated 22 JUN 2021 
 
5
 
 
 
1.3 
Schedule of Assessments  
Procedure 
Screening 
<28 days 
prior to start 
date (unless 
otherwise 
indicated) 
Cycle 
1 
Day 
1 
Cycle 
1 
Days  
8, 15, 
22 
All 
Other 
Cycles 
Day 1 
End 
of 
Study9 
Follow-
Up Phase 
(Every 6 
months) 
Complete medical 
history with quality of 
life assessment. 
X 
X 
 
X 
 
 
Physical exam, KPS, 
vital signs, height and 
weight 
X 
X 
 
X 
 
 
CBC with differential 
X 
X 
X 
X 
X 
 
Complete metabolic 
profile1,2 
X 
X 
X 
X2 
X 
 
Generate / review new 
drug diary 
 
X 
 
X 
 
 
Collect / review prior 
drug diary 
 
 
 
X 
X 
 
SPEP, IF, quantatative 
immunoglobulins3  
X 
X 
 
X 
X 
 
Serum free light 
chains3 
X 
X 
 
X 
X 
 
24-hour urine for UTP, 
UPEP, UIF3 
X 
X 
 
X 
X 
 
β2M3 
X 
 
 
 
 
 
CRP 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
Pregnancy test4 
X 
X 
 
X 
X 
 
Register patient into 
RevAssist® program5  
X 
 
 
 
 
 
Skeletal survey, MRI, 
or whole body PET/CT 
scan 
X6 
 
 
X8 
X8 
 
Bone marrow biopsy 
and aspirate7 
X6 
 
 
X8 
X8 
 
Concurrent medication 
use survey 
X 
X 
 
X 
 
 
Electrocardiogram 
X 
 
 
 
 
 
Drug dispensation6 
 
Continuous 
Adverse event 
 
Continuous  


Amendment 4 dated 22 JUN 2021 
 
6
monitoring  
Obtain Follow-Up anti-
cancer treatments  
 
 
 
 
 
X 
Obtain disease status, 
physical status, 
survival information, 
and if any occurrence 
of secondary primary 
malignancies  
 
 
 
 
 
X 
1. Includes sodium, potassium, chloride, CO2, calcium, blood urea nitrogen (BUN), 
serum creatinine and calculated creatinine clearance, glucose, albumin, total 
protein, alkaline phosphatase, total bilirubin, SGOT/AST, SGPT/ALT, LDH, Uric 
Acid.  Phosphorus and magnesium are performed at screening and Cycle 1 Day 1. 
2. To include Thyroid Stimulating Hormone (TSH) at screening, and every 3 months 
beginning with cycle 4 (more often if clinically indicated). 
3. UTP = urine total protein; UPEP = urine protein electrophoresis; UIF = urine 
immunofixation; SPEP = serum protein electrophoresis; IF = serum 
immunofixation; β2M = beta-2 microglobulin. 
 
4. Pregnancy test for females of child-bearing potential (FCBP).  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 (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (i.e., has had menses at 
any time in the preceding 24 consecutive months).  Pregnancy tests must occur 
within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide 
(prescriptions must be filled within 7 days).  FCBP with regular or no 
menstruation must have a pregnancy test weekly for the first 28 days and then 
every 28 days while on therapy (including breaks in therapy), at discontinuation 
of lenalidomide (whichever comes later) and at Day 28 post the last dose of 
lenalidomide (whichever comes later).  FCBP with irregular menstruation must 
have a pregnancy test weekly for the first 28 days and then every 14 days while 
on therapy (including breaks in therapy), at discontinuation of lenalidomide 
(whichever comes later) and at Day 14 and Day 28 post the last dose of 
lenalidomide (whichever comes later) (see Appendix III: Risks of Fetal Exposure, 
Pregnancy Testing Guidelines and Acceptable Birth Control Methods). 
5. Lenalidomide must be prescribed through and in compliance with Celgene’s 
RevAssist® program. Prescriptions of lenalidomide must be filled within 7 days. 
6. To occur within 6 weeks of treatment 
7. Iliac crest bone marrow aspirate for cytological review, including cytogenetics, 
FISH studies, flow cytometry (when available), and core biopsy for 
immunohistochemistry. 
8. To confirm complete remission, progression, or when clinically indicated 
9. An additional safety assessment will be done 30 days (+/- 7 days) following the 
last dose of study drug. 
 
 


Amendment 4 dated 22 JUN 2021 
 
7
2.0      OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 
   Study Objectives 
2.1.1 To evaluate the efficacy of clarithromycin (Biaxin), lenalidomide 
(Revlimid), and dexamethasone (Decadron) combination therapy (BiRd), 
compared to lenalidomide and dexamethasone (Rd) alone as an induction 
therapy for patients with newly diagnosed, transplant ineligible, previously 
untreated multiple myeloma (MM). 
2.1.2 To determine the progression free survival (PFS) of the BiRd regimen 
compared to Rd.  
2.1.3 To compare objective response rate (ORR) of BiRd versus Rd. 
2.1.4 To determine and compare duration of response (DOR), event free 
survival (EFS), time to progression (TTP), and overall survival (OS) of 
BiRd versus Rd. 
2.1.5 To assess safety and drug toxicity in each arm. 
2.1.6 To determine relative dose intensity for each component of protocol 
medication prescribed.  
2.1.7 To evaluate and compare minimal residual disease following therapy of 
BiRd versus Rd. 
2.18 
To determine and compare the PFS2 (time from study entry until 2nd 
instance of disease progression) of BiRd versus Rd.  
2.19 
To assess determine and compare quality of life assessments for BiRd vs 
Rd. 
2.2 
Study Endpoints 
• Progression free survival 
• Response rate by IMWG criteria (see Appendix I) 
• Event free survival (an event is defined by coming off protocol for any 
reason, including progression of disease, lack of disease response, regimen 
intolerability, or death). 
• Overall survival 
• Duration of response 
• Time to progression 
• Progression free survival 2: time from study entry until 2nd instance of 
disease progression 


Amendment 4 dated 22 JUN 2021 
 
8
• Quality of life: as measured by Functional Assessment of Chronic Illness 
Therapy – Fatigue (FACIT-Fatigue) Scale (Appendix IX) as part of a 
quality of life assessment. 
• Regimen toxicities, as defined by CTCAE V4.0  
 
 


Amendment 4 dated 22 JUN 2021 
 
9
3.0 
BACKGROUND AND RATIONALE 
3.1 
Disease Information 
Multiple Myeloma (MM) is a neoplastic disorder of unknown etiology characterized by 
an abnormal proliferation of plasma cells producing excess quantities of a single 
immunoglobulin protein isotype (M-protein). Malignant plasma cells expand and 
accumulate in the bone marrow, leading to cytopenias, imbalance of bone formation and 
resorption, and the production of monoclonal protein.1 It is estimated that over 21,000 
new cases of myeloma are diagnosed in the US each year accounting for approximately 
1% of all cancers and 10-15% of all hematological malignancies.2 The disease is twice as 
common in persons of African descent as compared to Caucasians. MM usually occurs in 
older individuals with a median age of 69 years old.3 There is currently no cure, and 
available therapies are only able to slow disease progression, prolong survival, and 
minimize symptoms.  
 
3.2 
Prognosis 
The overall median survival for patients with MM is 36 months, with International 
Staging System stage I, II, and III patients surviving a median of >60, 41, and 23 months 
respectively.4 Several prognostic factors have been identified. An elevated serum level of 
beta-2 micro-globulin (ß2M), a component of the class I HLA molecule, is a powerful 
prognostic indicator of shortened survival.5 Since ß2M is excreted by the kidney, renal 
insufficiency will increase serum levels of ß2M. The plasma cell labeling index (PCLI) 
identifies the percentage of proliferating plasma cells in S phase of the cell cycle and is 
powerful independent predictor of progression and survival.6 Chromosomal 
abnormalities, such as translocations t(4;14), del 17p, and t(14;16) confer poor 
prognosis.7,8  Investigators have found that achieving a complete remission early on in the 
disease may be important in predicting long-term survival.9,10 Indeed, Kyle et. al 
suggested that an objective response to standard therapy is by far the most important 
feature of long-term survivors.11 Major controlled trials have confirmed this seminal 
observation even in the context of high-dose chemotherapy.12 Based on those 
observations, the goal of achieving an early complete remission should allow patients to 
sustain long-term survival and perhaps lead to a cure. 
 
Myeloma is still an incurable disease and obtaining an initial long disease-free interval 
prior to relapse is important to prolong patient survival and improve quality of life. At the 
present time, there is still a need for new and effective induction therapies for the newly 
diagnosed multiple myeloma patients to achieve this goal.  
3.3 
Treatment 
Oral dexamethasone and intermittent oral melphalan and prednisone (MP) were widely 
used standard conventional therapies for MM for many years.  Responses, defined as a 
50% or greater decrease in paraprotein (aka M-protein or M-spike), were seen in 
approximately 30-60% of patients.  Duration of response to these agents is generally 1.5 
to 2 years, with median survival from time of initiation of therapy of approximately 24 to 


Amendment 4 dated 22 JUN 2021 
 
10
30 months. Cures are not achieved. Relapses are often marked by the development of 
drug resistance and by a more aggressive clinical course.  Thus, subsequent remissions 
are more difficult to achieve and are progressively shorter.13 
Various combination chemotherapy regimens have been developed in an attempt to 
improve remission rates and duration. These include vincristine, melphalan, 
cyclophosphamide, carmustine, and prednisone (M2), , vincristine, doxorubicin, and 
dexamethasone (VAD), vincristine, melphalan, cyclophosphamide, and prednisone 
alternating with vincristine, carmustine, doxorubicin, and prednisone (VMCP/VBAP), 
doxorubicin, carmustine, cyclophosphamide, and melphalan (ABCM), amongst other 
regimens. 14 15 16 17Although these regimens may produce higher response rates and in 
some cases more rapid tumor mass reduction, a survival advantage has not been 
demonstrated. Those eligible are often recommended to undergo autologous stem cell 
transplant, though age and other factors render the majority of patients unable to undergo 
a successful transplant.  
With the advent of novel agents such as thalidomide, lenalidomide and bortezomib there 
has been a marked improvement in outcomes particularly in younger and fit patients.18 
These agents are discussed more fully below.  
3.4 
Dexamethasone 
Dexamethasone is a synthetic steroid with anti-inflammatory, anti-proliferative, 
immunomodulatory abilities found to cause apoptosis of myeloma cells.19 The benefit of 
VAD (vincristine, doxorubicin, and dexamethasone) over high-dose dexamethasone is 
marginal (overall response rate 50-55%). A study by the Dutch Hematology-Oncology 
Group HOVON reports equal overall response rates of 68% when VAD was administered 
as an IV push and when dexamethasone was given at 40 mg PO QD x 4 only.20 These 
results suggest that the concurrent administration of VA (vincristine and doxorubicin) 
does not add major cytoreduction.  The results of the 91-155 study at Memorial Sloan-
Kettering Cancer Center in which dexamethasone was comparatively intensified show a 
much higher response rate despite the poor prognostic characteristics of the cohort.9 
These results indicate that the intensification of dexamethasone is an important factor in 
determining responses, providing compelling evidence that dexamethasone is by far the 
most important component in this combination.  
3.5 
Clarithromycin (Biaxin®) 
Biaxin®, or clarithromycin, is a semi-synthetic macrolide antibiotic indicated for the 
treatment of mild to moderate infections caused by susceptible strains of microorganisms.  
Pre-clinical studies have shown that Biaxin® has an immunomodulatory effect and may 
have antineoplastic properties mediated in part by suppression of Interleukin-6 and other 
cytokines.21 Biaxin® has also been shown to modulate the serum half-life of a number of 
corticosteroids and concurrent biaxin / corticosteroid administration may increase total 
time of corticosteroid exposure.22 Based upon these properties, the group at Cedars Sinai 
Comprehensive Cancer Center began a trial using Biaxin® 500mg PO BID for the 
treatment of newly diagnosed and relapsed/refractory MM patients.23 Of the 30 patients 


Amendment 4 dated 22 JUN 2021 
 
11
treated, 6 patients achieved a complete response, 7 achieved a partial response, 6 patients 
had stable disease, 4 had a mixed response and 7 patients were too early to evaluate. 
Follow up studies by other groups in Canada and France have failed to duplicate these 
promising results.24  
 
3.6 
Biaxin®, Low-dose Thalidomide and Dexamethasone 
Prior experience at the New York Presbyterian Hospital using the combination of 
Biaxin®, low-dose thalidomide and dexamethasone (BLTD) for the treatment of patients 
with newly diagnosed and relapsed/refractory MM and Waldenstrom’s 
macroglobulinemia have revealed impressive results.25 Of 40 evaluable patients, 37 
(93%) achieved a response.  Five patients (13%) achieved a complete remission defined 
by complete disappearance of M-spike and no serologic evidence of disease.  Complete 
(normalization of Ig spike), major (>75% reduction of Ig spike), and partial (>50% 
reduction of Ig spike) response rates were 40%, 13%, and 27% respectively.  A subset of 
responding patients had been previously resistant to Thalidomide, Dexamethasone, or a 
combination of the two.  These results suggest a synergistic effect amongst the three 
agents. The response criteria defined above are substantially more stringent than the 
widely used SWOG criteria.  Using the latter, we have obtained a near CR rate (> 75% 
reduction in Ig spike) of 66%.  In order to further our understanding of these findings we 
have completed a trial randomizing newly diagnosed multiple myeloma patients to 
receive either low-dose thalidomide or dexamethasone. Patients without a satisfactory 
response (<50% drop in tumor mass) after 8 weeks of treatment had Biaxin® added to 
their regimen.  Results showed that the addition of Biaxin® to either regimen seem to 
dramatically improve both response rate and time to response, even in patients who were 
previously unresponsive to low-dose thalidomide or dexamethasone. [unpublished 
results]. Using BLTD as a foundation, we sought new approaches to achieve an increase 
the CR rate, specifically in the form of BiRd therapy (discussed below). 
 
3.7 
Lenalidomide (Revlimid®) 
Lenalidomide (Revlimid®) is an oral analog of thalidomide with greater potency to 
activate immunomodulatory effects and inhibit angiogenesis when compared to 
thalidomide. Both lenalidomide and thalidomide are members of Celgene’s proprietary 
class of compounds called IMiDs® which are characterized by their immunomodulatory 
and anti-angiogenic activity. In vitro studies comparing the effects of IMiDs® on the 
production of cytokines and multiple myeloma cell proliferation activity found that 
lenalidomide was 50 to 2000 fold more potent than thalidomide.26 In addition, 
lenalidomide’s toxicity profile is unique, with fewer non-hematologic side-effects when 
compared to thalidomide with more predictable and manageable toxicities.  
Two phase I studies of heavily pretreated subjects with relapsed or refractory multiple 
myeloma were conducted to identify the MTD and to evaluate the safety of oral 
lenalidomide.27 Myelosupression was found to be the DLT and the MTD was determined 
to be 25 mg/day.  No significant somnolence, constipation, or neuropathy was observed.  
The first phase I study, 17 (71%) of 24 evaluable patients achieved >25% reduction of the 
myeloma paraprotein and in the second study, 20% of patients achieved a > 50% 


Amendment 4 dated 22 JUN 2021 
 
12
paraprotein reduction (responders received 25-50 mg/day).  The results from phase II 
trials of lenalidomide given at 30 mg per day for 21 days every 28 days suggest that oral 
lenalidomide is active in advanced multiple myeloma and is well tolerated.  Of 46 
evaluable subjects with relapsed or refractory MM, 39 (85%) achieved at least stable 
disease, including 2 subjects with complete resolution of paraprotein.28  
 
Thus, early studies suggest that lenalidomide is active against advanced multiple 
myeloma and is well tolerated.  Currently it is approved in combination with 
dexamethasone for treatment of relapsed multiple myeloma after a phase III study 
investigating the effectiveness of lenalidomide with high dose dexamethasone compared 
to high dose dexamethasone alone in newly diagnosed patients found response for the 
combination therapy was superior (61% vs. 20%).29 In addition, in vitro analysis 
determining the effect of low dexamethasone on the anti-myeloma properties of 
lenalidomide found that dexamethasone works synergistically in antagonizing 
lenalidomide’s immunostimulatory effects and enhancing its antiproliferative properties 
while independently inhibiting myeloma cell proliferation. 
3.8 
Rationale for BiRD Combination in Multiple Myeloma 
While new anti-myeloma therapies such as bortezomib and immunomodulatory drugs 
have been developed, multiple myeloma remains an incurable malignancy. Given that 
obtaining a complete remission with therapy will allow patients with newly diagnosed 
multiple myeloma to enjoy a higher quality of life and longer duration of freedom from 
disease symptoms, finding an optimally effective and well-tolerated regimen is 
imperative.     
Based on the immunodulatory effect of biaxin, the unique anti-myeloma activity of 
lenalidomide, and the synergistic properties of dexamethasone, the combination of BiRd 
has demonstrated to be highly effective in the treatment of multiple myeloma, and is 
anticipated to provide superior outcomes when compared to lenalidomide and 
dexamethasone therapy alone. A phase II study of clarithromycin (500mg twice daily), 
lenalidomide (25mg daily for 21 days out of a 28 day cycle), and low dose 
dexamethasone (40mg weekly) called the BiRd regimen was conducted. 30 By replacing 
thalidomide with lenalidomide into our former BLTD treatment platform, we achieved an 
overall response rate of 90.3%, and a higher CR rate compared with the earlier BLTD 
data, 30% vs. 13%. Retrospective case matched analysis comparing patients induced with 
BiRd vs Rd found that the addition of clarithromycin to Rd significantly increased 
patient’s rate of response, with 90.3% vs 79.1% of patients achieving PR or greater, and 
45.8% vs 13.9% of patients achieving CR.31 While promising, randomized phase III 
studies are needed to confirm the superiority of BiRd compared with RD in terms of 
response rates and survival.   
This study is intended to investigate the efficacy of combination therapy with an 
induction phase utilizing a combination clarithromycin (Biaxin®), lenalidomide 
(Revlimid®), dexamethasone (Decadron®), in multiple myeloma patients who are newly 
diagnosed and require treatment when compared to patients who receive lenalidomide 


Amendment 4 dated 22 JUN 2021 
 
13
and dexamethasone alone.  Randomized phase III studies are needed to confirm the 
superiority of BiRd compared with Rd in terms of response rates and survival. We 
anticipate the addition of lenalidomide and biaxin will lead to a greater CR rate, shorter 
times to response, and less toxicity. The primary endpoints of this trial include best 
response rate, toxicities, progression free survival, event free survival, and overall 
survival.   
4.0 
INVESTIGATIONAL PLAN 
4.1 
Study Design 
This phase III study, open-label, randomized study investigating lenalidomide and 
dexamethasone with and without biaxin in subjects with newly diagnosed, previously 
untreated multiple myeloma. Eligible subjects will be randomized in a 1:1 ratio to receive 
a regimen consisting of either biaxin, lenalidomide, and low dose dexamethasone (BiRd 
arm), or lenalidomide and low dose dexamethasone (Rd arm). Up to 306 patients will be 
enrolled.   
BiRd Arm 
Subjects on the BiRD arm will receive biaxin, revlimid, and dexamethasone in 28-day 
cycles. Dosing is as follows:  
• Clarithromycin 500mg PO twice daily on days 1-28 for a 28-day cycle. If a dose of 
clarithromycin is missed, it should be taken as soon as possible on the same day. If 
it is missed for the entire day, it should not be made up. Vomited doses will not be 
made up. 
• Lenalidomide 25mg PO daily on days 1-21 of a 28-day cycle for patients with a 
calculated creatinine clearance of >60 cc/min. Patients with a calculated creatinine 
clearance of <60 cc/min will receive 15 mgs PO daily on days 1-21 of a 28 cycle. 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the 
same day. If it is missed for the entire day, it should not be made up. Vomited doses 
will not be made up. 
• Dexamethasone 40mg PO will be given on days  1, 8, 15, 22 of a 28-day cycle. 
Missed or vomited doses will not be made up. If subject cannot tolerate oral 
dexamethasone, it will be given intravenously.  
Rd Arm 
Subjects on the Rd arm will receive revlimid, and dexamethasone in 28-day cycles. 
Dosing is as follows:  
• Lenalidomide 25mg PO daily on days 1-21 of a 28-day cycle for patients with a 
calculated creatinine clearance of >60 cc/min. Patients with a calculated clearance 
of <60 cc/min will receive 15 mgs PO daily on days 1-21 of a28 cycle. If a dose of 
lenalidomide is missed, it should be taken as soon as possible on the same day. If it 


Amendment 4 dated 22 JUN 2021 
 
14
is missed for the entire day, it should not be made up. Vomited doses will not be 
made up. 
• Dexamethasone 40mg PO will be given on days  1, 8, 15, 22 of a 28-day cycle. 
Missed or vomited doses will not be made up. If subject cannot tolerate oral 
dexamethasone, it will be given intravenously.  
Correlative studies: Relative dose intensity: Projected total dose per cycle of each 
component of assigned drug will be divided by the actual dose received  and a ratio will be 
assessed for each cycle delivered.  
MRD: Minimal residual disease testing will be performed in subjects who achieve 
complete response.  MRD testing may be performed either by flow cytometry or PCR, 
whichever is more readily available at the study institution.  
Subjects will continue their randomized treatment assignment until disease progression or 
unacceptable toxicity (whichever occurs first). In case toxicity precludes dosing of one 
agent (i.e dexamethasone, clarithromycin, lenalidomide), treatment regimen will continue 
with the remaining agents. Subjects unable to receive ALL the components of the 
assigned treatment arms will be removed from study after reasonable attempts to dose 
reduce and manage side effects. Subjects with elevations of AST/ALT greater than three 
times the upper limit of normal, with concomitant elevation of bilirubin 2 times the upper 
limit of normal, not attributable to disease, should be discontinued from treatment. 
Subjects can also be removed from study at investigator’s discretion, or if they withdraw 
consent. At completion or early discontinuation of treatment, subjects will be followed 
for 30 additional days or up to the initiation of subsequent treatment (whichever occurs 
first), after which they will be off the active treatment phase of the study. Long term 
follow up for disease status and survival will proceed until the subject has withdrawn 
consent, is lost to follow up, or has died.  
 
4.1.4 Disease Assessment 
At the end of every cycle (which may coincide with day 1 of the new cycle), response 
and toxicity will be evaluated.  During cycle 1, patients will have lab work done weekly 
(CBC with differential and blood electrolytes) and female of childbearing potential will 
have their pregnancy testing done on Day 1, (see Appendix III).  All patients will remain 
on study until disease progression or side effects become excessive.   
4.2 
Recruitment Plan 
A reasonable estimate for accrual of patients for this study is 10-15 patients per month.  
The anticipated time for completion of this trial is about 2-3 years. Detailed informed 
consent in plain language will be given to patients for review in either the inpatient or 
outpatient setting and sufficient time will be given to answer all the questions related to 
the study.  After consent has been signed, pretreatment evaluations will be completed and 
as outlined in Table 1, Schedule of Assessments, patients will start treatment. 


Amendment 4 dated 22 JUN 2021 
 
15
5.0 
CRITERIA FOR PATIENT ELIGIBILITY 
5.1 
Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to be eligible to participate 
in this study: 
• Subject must voluntarily sign and understand written informed consent. 
• Subject is ≥65 years at the time of signing the consent form. 
• Subject has histologically confirmed multiple myeloma that has never before 
been treated (see Appendix II).    
• Subject has no prior anti-myeloma treatment therapy within 14 days prior to 
initiation of study treatment except for corticosteroids with a maximum 
allowed dosage equivalent to three pulses of dexamethasone (40mg daily for 4 
days equals one pulse).  Patients may have received prior adjuvant 
antiresorptive therapy (i.e., pamidronate or zoledronic acid) as routine care, or 
radiation therapy as palliation for pain and/or spinal cord compression. 
• Subject has measurable disease as defined by > 0.5 g/dL serum monoclonal 
protein, >10 mg/dL involved serum free light chain (either kappa or lambda) 
provided that the serum free light chain ratio is abnormal, >0.2 g/24 hrs 
urinary M-protein excretion, and/or measurable plasmacytoma(s) of at least 
1cm in greatest dimension as measured by either CT scanning or MRI.    
• Subject has a Karnofsky performance status ≥60% (>50% if due to bony 
involvement of myeloma (see Appendix IV). 
• Subject is able to take prophylactic anticoagulation as detailed in section 9.1 
(patients intolerant to aspirin may use warfarin or low molecular weight 
heparin). 
• Subject is registered into the mandatory RevAssist® program, and is willing and 
able to comply with the requirements of RevAssist® program. 
• If subject is a female of childbearing potential (FCBP),0F† she must have a 
negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 
within 10 – 14 days prior to and again within 24 hours of prescribing 
lenalidomide (prescriptions must be filled within 7 days) and must either 
commit to continued abstinence from heterosexual intercourse or begin TWO 
acceptable methods of birth control, one highly effective method and one 
additional effective method AT THE SAME TIME, at least 28 days before she 
starts taking lenalidomide.  FCBP must also agree to ongoing pregnancy testing.  
Men must agree to use a latex condom during sexual contact with females of 
child bearing potential even if they have had a successful vasectomy. See 
 
† 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). 
  


Amendment 4 dated 22 JUN 2021 
 
16
Appendix III: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods. 
• Subject has a life expectancy ≥ 3 months  
• Subjects must meet the following laboratory parameters: 
o Absolute neutrophil count (ANC) ≥1000 cells/mm3 (1.0 x 109/L) 
o Hemoglobin ≥ 7 g/dL 
o Platelet count ≥ 50,000/mm3 (50 x 109/L) 
o Serum SGOT/AST <3.0 x upper limits of normal (ULN) 
o Serum SGPT/ALT <3.0 x upper limits of normal (ULN) 
o Serum total bilirubin  <2.0 mg/dL (34 µmol/L) 
o Creatinine clearance ≥ 45 cc/min 
 
5.2  
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not eligible to participate in 
this study: 
• Subject has immeasurable MM (no measurable monoclonal protein, free light 
chains in blood or urine, or measurable plasmacytoma on radiologic 
scanning). 
• Subject has a prior history of other malignancies unless disease free for ≥ 5 
years, except for basal cell or squamous cell carcinoma of the skin, carcinoma 
in situ of the cervix or breast, or localized prostate cancer with Gleason score 
< 7 with stable prostate specific antigen (PSA) levels.  
• Subject has had myocardial infarction within 6 months prior to enrollment , or 
NYHA(New York Hospital Association) Class III or IV heart failure (see 
APPENDIX VI), Ejection Fraction < 35%, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, electrocardiographic evidence of  acute  
ischemia or active conduction system abnormalities. 
• Female subject who is pregnant or lactating.   
• Subject has known HIV infection  
• Subject has known active hepatitis B or hepatitis C infection.  
• Subject has active viral or bacterial infections or any coexisting medical 
problem that would significantly increase the risks of this treatment program. 
• Subject is unable to reliably take oral medications 
• Subject has known hypersensitivity to dexamethasone, clarithromycin, 
lenalidomide, or thalidomide 
• Subject has a history of thromboembolic event within the past 4 weeks prior 
to enrollment. 
• Subject has any clinically significant medical or psychiatric disease or 
condition that, in the Investigator’s opinion, may interfere with protocol 
adherence or a subject’s ability to give informed consent.  
• Subject has previously been treated for multiple myeloma  
 


Amendment 4 dated 22 JUN 2021 
 
17
6.0 
PRETREATMENT EVALUATION 
6.1 Should be done within four weeks prior to starting treatment, unless otherwise 
indicated: 
6.1.1 Complete medical history and physical exam with particular attention to 
prior transfusions, prior treatment, and radiotherapy. Vital signs, KPS, weight, 
and height should be recorded 
6.1.2 Complete Blood Count (CBC) with differential and platelet count.  
6.1.3 Complete metabolic profile including sodium, potassium, chloride, CO2, 
calcium, magnesium, phosphorus, blood urea nitrogen (BUN), serum 
creatinine and calculated creatinine clearance, glucose, albumin, total protein, 
alkaline phosphate, total bilirubin, SGOT/AST. SGPT/ALT 
6.1.4 Lactate dehydrogenase (LDH) 
6.1.5 Uric Acid 
6.1.6 TSH 
6.1.7 Serum protein electrophoresis, serum immunofixation, serum quantitative 
immunoglobulins, and free serum light chain studies 
6.1.8 24 hour urine collection for total protein, protein electrophoresis, and 
immunofixation 
6.1.9 Beta-2-microglobulin (B2M) 
6.1.10 C-reactive protein (CRP) 
6.1.11 Urinalysis including microscopic analysis 
6.1.12 Serum or urine pregnancy for women in childbearing potential 10 – 14 
days and within 24 hours of initiation of treatment  
6.2 Within six weeks prior to starting treatment 
6.2.1 Complete skeletal survey including all long bones, AP pelvis, C-T-L 
spine, chest, ribs and lateral skull films OR whole body PET/CT scan. 
6.2.2 Unilateral iliac crest bone marrow aspirate for cytological review, 
cytogenetics, FISH studies, flow cytometry (when available) and core biopsy 
for immunohistochemistry. 
6.2.3 Electrocardiogram 


Amendment 4 dated 22 JUN 2021 
 
18
 
7.0 
THERAPUTIC AGENTS 
7.1 
Clarithromycin (Biaxin®) 
Clarithromycin, is a semi-synthetic macrolide antibiotic and is active in vitro against a 
variety of aerobic and anaerobic gram-positive and gram-negative microorganisms.  
Biaxin® is indicated for the treatment of mild to moderate infections caused by 
susceptible strains of microorganisms.  It is administered as 500 mg tablets (Abbott 
Laboratories) to be taken orally.  It is rapidly absorbed after oral administration and 
distributes widely into most body tissue with the exception of the central nervous system.  
Serum concentrations peak within 2 hours, with a Tmax of 2 to 4 hours.  The elimination 
half-life is about 3 to 4 hours and has primarily renal excretion, however it is also an 
inhibitor of cytochrome p450 isozyme CYP3A4.  There is potential for drug interaction 
with other substrates of CYP3A4, as listed in APPENDIX VII. The administration of 
other substrates for CYP3A4 should be avoided if possible. If unavoidable, such drugs 
should be used with caution.   Commercial clarithromycin will be used. Subjects will 
receive a prescription from the investigator for 500 mg tablets for oral administration, 
which will be obtained from the subject’s local pharmacy. Subjects experiencing adverse 
event may need study treatment modifications. 
7.2 
Lenalidomide (Revlimid®) 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent 
with anti-angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -
2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:  
 
Chemical Structure of Lenalidomide: 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight 
is 259.3.  
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in 
organic solvents and low pH solutions. Solubility was significantly lower in less acidic 
buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon 
N
N
H
O
O
O
NH2


Amendment 4 dated 22 JUN 2021 
 
19
atom and can exist as the optically active forms S(-) and R(+), and is produced as a 
racemic mixture with a net optical rotation of zero. 
REVLIMID® (lenalidomide) is available in 5 mg, 10 mg, 15 mg and 25 mg capsules for 
oral administration. Each capsule contains lenalidomide as the active ingredient and the 
following inactive ingredients: lactose anhydrous, microcrystalline cellulose, 
croscarmellose sodium, and magnesium stearate.  
7.2.1  Clinical Pharmacology: 
The mechanism of action of lenalidomide remains to be fully characterized. 
Lenalidomide possesses immunomodulatory and antiangiogenic properties.  
Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the 
secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells.  
Lenalidomide inhibited cell proliferation with varying effectiveness (IC50s) in some but 
not all cell lines.  Of cell lines tested, lenalidomide was effective in inhibiting growth of 
Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) 
but was much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell 
line, also with a deletion of one chromosome 5) and other cell lines without chromosome 
5 deletions.  Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) but not 
COX-1 in vitro.   
7.2.2  Pharmacokinetics and Drug Metabolism: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration 
with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. 
Co-administration with food does not alter the extent of absorption (AUC) but does 
reduce the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic 
disposition of lenalidomide is linear. Cmax and AUC increase proportionately with 
increases in dose. Multiple dosing at the recommended dose-regimen does not result in 
drug accumulation. 
Pharmacokinetic sampling in myelodysplastic syndrome (MDS) patients was not 
performed. In multiple myeloma patients maximum plasma concentrations occurred 
between 0.5 and 4.0 hours post-dose both on Days 1 and 28.  AUC and Cmax values 
increase proportionally with dose following single and multiple doses. Exposure (AUC) 
in multiple myeloma patients is 57% higher than in healthy male volunteers.  
7.2.3 Pharmacokinetic Parameters: 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
Metabolism and Excretion: 
The metabolic profile of lenalidomide in humans has not been studied. In healthy 
volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through 
urinary excretion. The process exceeds the glomerular filtration rate and therefore is 
partially or entirely active.  Half-life of elimination is approximately 3 hours 


Amendment 4 dated 22 JUN 2021 
 
20
7.2.4 Drug Supply and Dosage:  Subjects will obtain commercially available Revlimid® 
(lenalidomide) as 5 mg and 25 mg capsules for oral administration through Celgene 
Corporation’s RevAssist® program. 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 Celgene’s RevAssist® program. 
The planned dose of lenalidomide for investigation is 25 mg/day, orally on days 1-21 
followed by a 7-day rest period (28 day cycles).  Subjects experiencing adverse events 
may need study treatment modifications.   
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same 
day.  If it is missed for the entire day, it should not be made up. 
Patients who take more than the prescribed dose of lenalidomide should be instructed to 
seek emergency medical care if needed and contact study staff immediately. 
7.2.5 Packaging: Lenalidomide will be shipped directly to patients.   Bottles will 
contain a sufficient number of capsules to last for one cycle of dosing. 
 
7.2.6 Storage and Special Handling Instructions: Lenalidomide should be stored at 
room temperature away from direct sunlight and protected from excessive heat and cold.  
Females of child bearing potential should not handle or administer the clinical dosage 
forms unless they are wearing gloves.   
7.2.7 Prescribing Information: Lenalidomide will be prescribed in accordance with the 
RevAssist® program of Celgene Corporation.  Per standard RevAssist® 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 Celgene’s RevAssist® program.  Prescriptions must be filled within 
14 days unless the patient is a female of childbearing potential, in which case the 
prescription must be filled within 7 days.  Only enough lenalidomide for one cycle of 
therapy will be supplied to the patient each cycle.  
7.2.8 Record of Administration: Accurate records will be kept of all study drug 
administration, including dispensing and dosing, in the source documents. 
7.3 
Dexamethasone (Decadron®) 
Dexamethasone is a synthetic adrenocortical steroid primarily used for its potent anti-
inflammatory effects.  In addition, it modifies the body’s immune response to diverse 
stimuli.  In the treatment of multiple myeloma, dexamethasone has been widely used as a 
single agent, as well as in combination, for newly diagnosed, relapsed and refractory 
disease. Pharmacokinetics are characterized by liver metabolism, time to peak serum 
concentration within 1-2 hours, duration of metabolic effect up to 72 hours and 
elimination in the urine. Dexamethasone (Decadron®) will be used as 4 mg tablets to be 
taken orally.  Subjects experiencing adverse events may need dosage modification.  


Amendment 4 dated 22 JUN 2021 
 
21
8.0 
Toxicities and Side Effects 
Toxicities and adverse events will be scored using CTCAE version 4.0 for toxicity and 
adverse event reporting.  A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP homepage (http://ctep.info.nih.gov).  All appropriate treatment areas must have 
access to a copy of the CTCAE version 4.0. 
8.1 
Clarithromycin (Biaxin®)  
Possible common side effects associated with clarithroymycin are headaches, diarrhea, 
nausea, abnormal taste, heartburn and abdominal pain. Possible rare side effects are 
irregular blood counts, shortness of breath, hypoglycemia, anxiety, hallucinations, 
anxiety, fast heartbeat, and tremors.  
8.2 
Lenalidomide (Revlimid®)  
In clinical trials conducted to date, lenalidomide appears to be well tolerated and has an 
acceptable safety profile. In Phase I/II trials of lenalidomide, the drug was well tolerated 
and had a manageable side effect profile.  Common side effects of lenalidomide include 
rash, fatigue, itching, diarrhea, fever, constipation, light-headedness, and leg cramps, 
which generally are very mild. The most common side effects are mostly related to a drop 
in platelet or neutrophil counts.  Severe side effects which include Stevens-Johnson’s 
syndrome, tumor lysis syndrome, and irregular blood counts are rare. These side effects 
tend to be the dose limiting toxicities when attempting to achieve a full dose. The 
teratogenic effects of lenalidomide have not been tested in humans. However because 
lenalidomide is a derivative of thalidomide, all subjects are instructed to use effective 
contraception prior to study entry and for the duration of study participation. 
Secondary Primary Malignancies 
Patients treated with lenalidomide (Revlimid) may be at an increased risk of developing 
secondary primary malignancies than patients who were not treated with lenalidomide. 
Preliminary data derived from evaluation of outcomes after longer-term exposure to 
Lenalidomide (Revlimid) and from controlled clinical trials conducted inside and outside 
the Unites States shows an increased incidence of some second primary malignancies, 
particularly acute myelogenous leukemia (AML) , myelodysplastic syndromes, B- cell 
malignancies, and Hodgkin lymphoma when compared to controls.36 
8.3 
Dexamethasone (Decadron®) 
Possible common side effects of dexamethasone are fluid retention, weight gain, stomach 
upset or ulcers, and insomnia and mood changes.  Possible side effects of dexamethasone 
that are less common include hyperglycemia, hypertension, muscle weakness, vertigo, 
headaches, osteoporosis, manifestation of latent diabetes, increased requirements for 
insulin or oral hypoglycemic agents in diabetics, cataracts, skin changes, necrosis of the 
hip, and susceptibility to infections. 
 


Amendment 4 dated 22 JUN 2021 
 
22
8.5 
Thrombosis Risk 
Lenalidomide and thalidomide increase the risk of thrombotic events in patients who are 
at high risk or with a history a thrombosis, in particular when combined with other drugs 
known to cause thrombosis. When lenalidomide or thalidomide is combined with other 
agents such as steroids (e.g. dexamethasone, prednisone), anthracyclines (Doxil, 
Adriamycin) and erythropoietin the risk of thrombosis is increased.  All patients enrolled 
into this study will take aspirin therapy as outlined in the treatment plan, section 9.1. 
Concurrent use of recombinant erythropoietin is discouraged due to reports of increased 
thromboembolic events in patients receiving lenalidomide with erythropoietin. 32 
Concurrent use of erythropoietin requires full anticoagulation of patients with therapeutic 
doses of LMWH or coumadin.  Anticoagulation should be held for platelet counts 
<50,000/mm3.  Anti-microbial prophylaxis is not required and is left to the discretion of 
the treating physician.   
 
9.0 
Therapeutic Plan 
9.1 
Treatment 
Patients who sign informed consent will be seen in clinic or in the hospital at New York 
Presbyterian Hospital-Weill Cornell Medical College, by their physician for pretreatment 
testing as outlined in section 6.0. All prescribers must be registered in the Celgene 
RevAssist® program in order to prescribe lenalidomide (Revlimid®). Subjects who 
complete pretreatment evaluations and meet all eligibility criteria may start treatment. All 
patients will be started on BiRd in 28-day cycles according to the following schedule:  
For all subjects, Dexamethasone (Decadron®) will be given orally at a dose of 40 mg on 
days 1, 8, 15, and 22 for each subsequent cycle 
For subjects on the BiRd arm only, Clarithromycin (Biaxin®) will be given orally at a 
dose of 500 mg twice a day, beginning on day 1 of cycle 1. 
For all subjects, Lenalidomide (Revlimid®) will be given orally at a dose of 25 mg/day 
beginning on day 3 and ending on day 21 of cycle 1, and on days 1-21 of each subsequent 
cycle. 
Due to the risk of thrombosis (see Section 8.5), all patients will begin thromboembolic 
prophylaxis with aspirin 81mg daily throughout treatment, starting on cycle 1 day 1.  
Aspirin-intolerant patients, or patients with a prior history of venous thrombosis, 
should receive prophylactic doses of daily low molecular weight heparin (LMWH). For 
patients who are unable to take aspirin or LMWH, other antithrombotic agents may be 
used at the investigators discretion.  If warfarin is used, the INR should be monitored 
frequently to maintain within the goal range of 2-3. Concurrent use of recombinant 
erythropoietin to treat anemia is discouraged due to reports of increased 
thromboembolic events in patients receiving lenalidomide with erythropoietin. 
Concurrent use of erythropoietin requires full anticoagulation of patients with 


Amendment 4 dated 22 JUN 2021 
 
23
therapeutic doses of LMWH or coumadin.  Anticoagulation should be held for platelet 
counts <50,000/mm3.   
Monitoring for Secondary Primary Malignancies 
Due to the potential increased risk of developing secondary primary malignancies 
associated with lenalidomide treatment, patients will be advised to undergo regular 
cancer screenings as part of standard of care. Monitoring for development of acute 
leukemia and Hodgkin's lymphoma will be performed by review of regular blood work, 
chemistry panel, and LDH at each visit including during follow-up.  Particular attention 
will be paid to the complete blood count differential with a low threshold to investigate 
emerging cytopenias or altered differential with either bone marrow biopsy or PET 
scanning if clinically indicated. In addition, men and women will be advised to have a 
yearly skin exam by a dermatologist and regular colonoscopy screening (every 5 years or 
earlier, depending on GI recommendations). Women will also be advised to have yearly 
mammograms and regular cervical cancer screening.  Men will also be advised  to 
undergo yearly Prostate-Specific Antigen (PSA) testing.  
For information on the risk of venous thromboembolism with combined oral 
contraception see Appendix III: Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods. 
Cycles will be repeated every 28 days. Patient will return to clinic every 28 days for 
evaluation of toxicity and response and will remain on study until progression of disease, 
toxicities become excessive, or until discontinuation for another reason (see Section 9.2).  
Doses may be modified due to side effects.   
Patients who achieve a resolution of monoclonal gammopathy as detected on serum 
immunofixation or achieve a plateau of disease (no change in quantitative M-spike or 
free light chains) for > 2 cycles will be transitioned to maintenance therapy. Maintenance 
therapy will consist of dexamethasone at a dose of 20mg weekly (given on days 1, 8, 15, 
and 22 of a 28 day cycle) and lenalidomide at a dose of 25 mg/day on days 1-21 of a 28 
day cycle (a dose of 15mg/day days 1-21 of a 28 day cycle will be given to patients with 
a creatinine clearance of < 60 cc/min).  
9.2 
Early Termination of Study 
Study-terminating events are listed below (to include?): 
• Early death (defined by death within 30 days of beginning therapy) deemed to be 
related to study treatment of more than 1 of the first 10 subjects. 
• Early need for hospitalization (defined by hospitalization within 30 days of 
beginning therapy) of more than 5 of the first 10 subjects.  
• If there is an unacceptable rate of Grade 4 toxicities (according to CTCAE 
version 4.0), as deemed by the research team, Celgene, or the Data Safety 
Monitoring Board.  


Amendment 4 dated 22 JUN 2021 
 
24
• If >5% of patients develop a secondary primary malignancy on maintenance 
lenalidomide, the study will be halted and reviewed by the Investigator and Data 
Safety Monitoring Board before a decision will be made to proceed.  
9.3 
Supportive Care and Concurrent Treatments 
9.3.1  Treatments: Prophylactic medications should be routinely administered in 
combination with Dexamethasone.  Individualization is required, as some patients require 
no prophylaxis therapy, while other patients require intensive therapy.  The particular 
choice of prophylactic therapy will be at the discretion of the treating physician 
investigator. We recommend patients receive omeprazole 20 mg once daily as gastritis 
prophylaxis, docusate 100mg tablet twice daily for constipation prophylaxis, Bactrim DS 
1 tablet once daily for Pneumocystis carinni pneumonia prophylaxis beginning with cycle 
2 of either BiRd or Rd therapy, and mycelex troches 10mg four to five times daily as 
needed for oral thrush prophylaxis.  See Section 9.1 for thromboembolic prophylaxis 
using aspirin, warfarin or coumadin. 
9.3.2   Lytic Bone Lesions: Patients with lytic bone lesions, if able to, should receive 
standard of care treatment in routine multiple myeloma management, such as IV 
bisphosphonates, as determined by the investigator. It is preferred that investigators use 
the same route of bisphosphonate therapy for all subjects at their sites (if applicable). 
9.3.3 Hematopoeitic support: Thrombocytopenia should be treated conservatively.  In 
the absence of bleeding, platelet transfusions should only be given for a platelet count 
below 10,000.  If the patient develops bleeding, platelet transfusions should be 
administered in accordance with standard of practice, usually maintaining a platelet count 
≥ 50,000/mm3.  Febrile neutropenia is a life-threatening complication requiring 
hospitalization and urgent broad-spectrum antibiotics.  Hematopoietic growth factors may 
be used according to Table 2: Dose Modification Instructions. Such cases will be 
evaluated individually to determine the toxicity grade. Symptomatic anemia should be 
treated with appropriate red blood cell support and transfusion is recommended if the 
hemoglobin falls below 8 g/dl.  Recombinant erythropoietin may be used with concurrent 
anticoagulation, as described above in section 9.1, if desired by the patient’s local 
physician. 
9.3.4 Radiotherapy: Patients who require localized external beam radiotherapy or 
surgery at the time of protocol screening should receive it before study entry.  Patients 
may receive radiotherapy or surgery during the study if required to treat a pathological 
fracture, cord compression, or associated pain that was present prior to study entry.  
Patients who require radiotherapy or surgery to treat pathological fractures related to a 
new growth of myeloma, cord compression, or associated pain will be considered to have 
progression of disease and will be removed from study.  Patients may receive radiation 
therapy or surgery for the treatment of a plasmacytoma that was present prior to study 
entry only if the plasmacytoma is not considered a target lesion to assess response. 
9.3.5 Prohibited Concomitant Therapy: Concomitant use of sargramostim (GM-CSF), 
other anti-cancer therapies, or other investigational agents is not permitted while subjects 


Amendment 4 dated 22 JUN 2021 
 
25
are receiving study drug during the treatment phase of the study.  Agents that alter the 
QTc will be discouraged particularly in patients receiving clarithromycin. See Appendix 
VII 
9.4 
Day One Dosing Guidelines  
A new cycle of treatment may begin on a scheduled Day 1 if any therapy related adverse 
events have resolved to an acceptable grade (see Section 9.3, Dose Modifications). If not, 
the patient should be evaluated at least at weekly intervals until resolution of toxicities. If 
start of new cycle is delayed more than 4 weeks, the patient will be removed from the 
protocol.  The patient will also be directed to take the following prophylactic medicines: 
1) omeprazole at a dose of 20mg once daily; 2) Bactrim at a dose of one DS tab once 
daily (or equivalent Pneumocystis jiroveci prophylaxis; patients may start at cycle 2 if 
preferred by treating physician); 3) aspirin at a dose of 81 mg once daily (or other 
equivalent anti-thrombotic therapy).   
9.5 
Instruction for initiation of a new cycle  
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
• Absolute neutrophil count (ANC) ≥750 cells/mm³  
• Platelets count ≥ 50,000/mm³  
• 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 the toxicity does not resolve within four weeks, the patient will be 
taken off the study.  If the dosing of clarithromycin, lenalidomide or dexamethasone 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 
will be initiated on Day 1 of the new cycle. If the dosing of clarithromycin, lenalidomide 
or dexamethasone 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 dose modifications as described in Section 9.6 and Table 2. 
If the start of a new cycle is delayed more than 4 weeks, the patient will be removed from 
the protocol. 
9.6 
Dose Modification 
Doses of study medications will be modified for toxicity as listed below in Tables 1, 2a, 
and 2b.  Doses must be adjusted for adverse events deemed related to study drug by the 
investigator.  Doses may be adjusted for adverse events related to study medications not 
listed below at the discretion of the investigator. 


Amendment 4 dated 22 JUN 2021 
 
26
Unless otherwise noted, other drugs in the regimen should be continued when the dosing 
of one or more drugs is delayed due to toxicity.   
During BiRd therapy, if toxicity occurs that would indicate an interruption in treatment, 
the toxicity should be attributed to one or more drugs in the BiRD regimen and dose 
modifications instituted as instructed in the “Action” column of the table below based on 
attribution. During maintenance therapy, if toxicity occurs that would indicate a 
lenalidomide dose modification, toxicity should be attributed to lenalidomide and dose 
modifications instituted as instructed in the “Action” column of the table below based on 
attribution. 
 
 
Table 1: Dose Reduction Steps: 
Lenalidomide Dose Reduction 
Starting Dose 
Lenalidomide PO 25mg/day on days 1-21 
of a 28 day cycle 
Dose Level -1 
Lenalidomide PO 15mg/day on days 1-21 
of a 28 day cycle 
Dose Level -2 
Lenalidomide PO 10 mg/day on days 1-21 
of a 28 day cycle 
Dose Level -3 
Lenalidomide PO 5 mg/day on days 1-21 
of a 28 day cycle 
Dose Level -4 
Lenalidomide PO 5 mg every other day 
for on days 1-21 of a 28 day cycle  
 
Dexamethasone Dose Reduction 
Starting Dose 
40 mg PO on days 1, 8, 15 and 22 of a 28 
day cycle 
Dose Level -1  
20 mg PO on days 1, 8, 15 and 22 of a 28 
day cycle 
Dose Level -2  
8 mg PO on days 1, 8, 15 and 22 of a 28 
day cycle 
Dose Level -3  
8 mg PO on days 1 and 15 of a 28 day 
cycle 
Dose Level -4  
4 mg PO on days 1 and 15 of a 28 day 
cycle 
 
Clarithromycin Dose Reduction 
Starting Dose 
500 mg BID PO days 1-28 of a 28 day 
cycle 
Dose Level -1 
250 mg BID PO days 1-28 of a 28 day 
cycle 


Amendment 4 dated 22 JUN 2021 
 
27
Dose Level -2 
250 mg PO daily on days 1-28 of a 28 day 
cycle 
Dose Level -3 
250 mg PO daily on days odd days of a 28 
day cycle 
Dose Level -4 
Discontinue drug 
 
 
Table 2a:  RD Dose Modification Instructions 
 
Toxicity 
NCI Toxicity 
Grade 
Action 
Neutropenia 
≥ Grade 3 
with fever 
(temperature 
≥ 38.5º C) 
• Hold (interrupt) lenalidomide. 
• Follow CBC weekly. 
• If neutropenia has resolved to ≤ 
grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue 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. 
Neutropenia 
Grade 4 
• Hold (interrupt) lenalidomide. 
• Follow CBC weekly.  
• If neutropenia has resolved to ≤ 
grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue 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. 
Thrombocytopenia 
≥ Grade 3 
(platelet 
count < 
50,000/mm³) 
• Hold (interrupt) lenalidomide and 
anti-coagulation dosing.  
• Follow CBC weekly.  
• If thrombocytopenia has resolved 
to ≤ grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and restart anti-coagulation.   


Amendment 4 dated 22 JUN 2021 
 
28
Toxicity 
NCI Toxicity 
Grade 
Action 
Rash 
(non-blistering) 
≥ Grade 3 
• Hold (interrupt) lenalidomide for 
remainder of cycle 
• Reduce lenalidomide by 1 dose 
level and restart next cycle. 
Rash  
Grade 4 non-
blistering or 
desquamating 
(blistering) 
any Grade 
• Discontinue lenalidomide and take  
patient off study 
Erythema 
multiforme 
≥ Grade 3 
• Discontinue lenalidomide and take  
patient off study 
Hyperthyroidism or 
Hypothyroidism 
Any grade 
• Omit lenalidomide remainder of 
cycle 
• Evaluate etiology and initiate 
appropriate therapy  
• Restart lenalidomide at same dose 
level.  
Sinus bradycardia/ 
other cardiac 
arrhythmia 
Grade > 2 
• Hold (interrupt) lenalidomide for 
remainder of cycle.  Follow at least 
weekly. 
• Reduce lenalidomide by 1 dose 
level and restart next cycle.  
Sinus bradycardia/ 
other cardiac 
arrhythmia 
 > Grade 3 
• Discontinue lenalidomide and take 
patient off study 
Allergic reaction or 
hypersensitivity 
 
≥ Grade 2 
• Hold (interrupt) lenalidomide for 
remainder of cycle.  Follow at least 
weekly. 
• Reduce lenalidomide by 1 dose 
level and restart next cycle. 
Allergic reaction or 
hypersensitivity 
 
≥ Grade 3 
• Discontinue lenalidomide and take 
patient off study 
Venous 
thrombosis/embolism 
 
≥ Grade 3 
• Hold (interrupt) lenalidomide and 
Start anticoagulation; restart 
lenalidomide at investigator’s 
discretion (maintain dose level). 
Gastritis, gastric or 
duodenal ulcer 
≥ Grade 3 
• Hold (interrupt) dexamethasone 
until ≤ grade 1 
• Reduce dexamethasone by 1 dose 
level and restart 


Amendment 4 dated 22 JUN 2021 
 
29
Toxicity 
NCI Toxicity 
Grade 
Action 
Edema 
≥ Grade 3 
• Reduce dexamethasone by 1 dose 
level 
• Use diuretics as needed 
Confusion or mood 
alternations 
≥ Grade 2 
• Hold (interrupt) dexamethasone 
until ≤ grade 1 
• Reduce dexamethasone by 1 dose 
level and restart 
Muscle weakness 
≥ Grade 3 
• Reduce dexamethasone by 1 dose 
level 
• If symptoms persist continue to 
reduce dexamethasone by 1 dose 
level as needed. 
Hyperglycemia 
≥ Grade 3 
• Reduce dexamethasone by 1 dose 
level 
• Treat with insulin or oral 
hypoglycemics as needed 
Acute pancreatitis 
≥ Grade 3 
• Discontinue dexamethasone and 
patient off study. 
Other non-
hematologic 
toxicity assessed 
as treatment-
related 
≥ Grade 3 
• Attribute toxicity to one or more 
drugs.  Hold drug(s) attributed to 
toxicity for remainder of cycle.  
Reduce drug(s) attributed to 
toxicity by 1 dose level.* 
 
Table 2b:  BiRD Dose Modification Instructions 
Toxicity 
NCI Toxicity 
Grade 
Action 
Neutropenia 
≥ Grade 3 
with fever 
(temperature 
≥ 38.5º C) 
• Hold (interrupt) lenalidomide. 
• Follow CBC weekly. 
• If neutropenia has resolved to ≤ 
grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue 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. 


Amendment 4 dated 22 JUN 2021 
 
30
Toxicity 
NCI Toxicity 
Grade 
Action 
Neutropenia 
Grade 4 
• Hold (interrupt) lenalidomide. 
• Follow CBC weekly.  
• If neutropenia has resolved to ≤ 
grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue 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. 
Thrombocytopenia 
≥ Grade 3 
(platelet 
count < 
50,000/mm³) 
• Hold (interrupt) lenalidomide and 
anti-coagulation dosing.  
• Follow CBC weekly.  
• If thrombocytopenia has resolved 
to ≤ grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and restart anti-coagulation.   
Rash 
(non-blistering) 
≥ Grade 3 
• Hold (interrupt) lenalidomide for 
remainder of cycle 
• Reduce lenalidomide by 1 dose 
level and restart next cycle. 
Rash  
Grade 4 non-
blistering or 
desquamating 
(blistering) 
any Grade 
• Discontinue lenalidomide and take  
patient off study 
Erythema 
multiforme 
≥ Grade 3 
• Discontinue lenalidomide and take  
patient off study 
Hyperthyroidism or 
Hypothyroidism 
Any grade 
• Omit lenalidomide remainder of 
cycle 
• Evaluate etiology and initiate 
appropriate therapy  
• Restart lenalidomide at same dose 
level.  
Sinus bradycardia/ 
other cardiac 
arrhythmia 
Grade > 2 
• Hold (interrupt) lenalidomide for 
remainder of cycle.  Follow at least 
weekly. 
• Reduce lenalidomide by 1 dose 
level and restart next cycle.  
Sinus bradycardia/ 
other cardiac 
arrhythmia 
 > Grade 3 
• Discontinue lenalidomide and take 
patient off study 


Amendment 4 dated 22 JUN 2021 
 
31
Toxicity 
NCI Toxicity 
Grade 
Action 
Allergic reaction or 
hypersensitivity 
 
≥ Grade 2 
• Hold (interrupt) lenalidomide for 
remainder of cycle.  Follow at least 
weekly. 
• Reduce lenalidomide by 1 dose 
level and restart next cycle. 
Allergic reaction or 
hypersensitivity 
 
≥ Grade 3 
• Discontinue lenalidomide and take 
patient off study 
Venous 
thrombosis/embolism 
 
≥ Grade 3 
• Hold (interrupt) lenalidomide and 
Start anticoagulation; restart 
lenalidomide at investigator’s 
discretion (maintain dose level). 
Diarrhea 
≥ Grade 3 
• Hold (interrupt) clarithromycin 
until ≤ grade 1, then reduce dose to 
250 mg twice daily 
Dyspepsia 
≥ Grade 3 
• Hold (interrupt) clarithromycin and 
dexamethasone dosing until ≤ 
grade 1 
• Reduce dexamethasone OR 
clarithromycin by 1 dose level 
based on attribution and restart 
dexamethasone and clarithromycin 
Anaphylaxis or 
Hepatic failure 
≥ Grade 3 
• Discontinue clarithromycin and 
patient is off study 
Loss of appetite 
or Nausea 
≥ Grade 3 
• Hold (interrupt) clarithromycin 
until ≤ grade 1, then reduce dose to 
250 mg twice daily 
Gastritis, gastric or 
duodenal ulcer 
≥ Grade 3 
• Hold (interrupt) dexamethasone 
until ≤ grade 1 
• Reduce dexamethasone by 1 dose 
level and restart 
Edema 
≥ Grade 3 
• Reduce dexamethasone by 1 dose 
level 
• Use diuretics as needed 
Confusion or mood 
alternations 
≥ Grade 2 
• Hold (interrupt) dexamethasone 
until ≤ grade 1 
• Reduce dexamethasone by 1 dose 
level and restart 
Muscle weakness 
≥ Grade 3 
• Reduce dexamethasone by 1 dose 
level 
• If symptoms persist continue to 
reduce dexamethasone by 1 dose 
level as needed. 


Amendment 4 dated 22 JUN 2021 
 
32
Toxicity 
NCI Toxicity 
Grade 
Action 
Hyperglycemia 
≥ Grade 3 
• Reduce dexamethasone by 1 dose 
level 
• Treat with insulin or oral 
hypoglycemics as needed 
Acute pancreatitis 
≥ Grade 3 
• Discontinue dexamethasone and 
patient off study. 
Other non-
hematologic 
toxicity assessed 
as treatment-
related 
≥ Grade 3 
• Attribute toxicity to one or more 
drugs.  Hold drug(s) attributed to 
toxicity for remainder of cycle.  
Reduce drug(s) attributed to 
toxicity by 1 dose level.* 
 
 
 
10.0 
STUDY EVALUATIONS 
Patients will be followed in clinic every week for the first cycle and on Day 1 (+/- 7 days) 
for subsequent cycles.  Females of childbearing potential (FCBP) must have a pregnancy 
test done by the doctor as outlined in Appendix III prior to and during lenalidomide-
containing cycles.  During scheduled study visits patients will undergo the following 
evaluations for assessment of response and toxicity (depicted in Table 1, section 1.0):  
10.1 
Day 1, Cycle 1  
• Physical evaluation: A complete medical evaluation including medical history, 
concomitant medications, physical exam, vital signs, KPS, height and weight. 
• Complete Blood Count (CBC) with differential and platelet count 
• Complete metabolic profile (including sodium, potassium, chloride, CO2, 
calcium,  blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, 
alkaline phosphatase, total bilirubin, SGOT/AST, and SGPT/ALT) 
• Lactate dehydrogenase  (LDH)  
• Uric Acid 
• Magnesium 
• Phosphorus 
• Drug diary generated and reviewed with patient (See Appendix VIII)  
• Serum protein electrophoresis, serum immunofixation, serum quantitative 
immunoglobulins 
• Serum free light chain studies 
• 24-hour urine collection for total protein, protein electrophoresis, and 
immunofixation 
• Serum pregnancy test, if applicable 
• Quality of Life Assessment (See Appendix IX) 


Amendment 4 dated 22 JUN 2021 
 
33
 
10.2 
Days 8, 15, 22 Cycle 1 
• Complete Blood Count (CBC) with differential and platelet count 
• Complete metabolic profile (including sodium, potassium, chloride, CO2, 
calcium, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, 
alkaline phosphatase, total bilirubin, SGOT/AST, and SGPT/ALT, LDH, uric 
acid) 
 
10.3 
Day 1 (starting cycle 2) and End of Study 
• Physical evaluation: A complete medical evaluation including medical history, 
adverse events, concomitant medications, physical exam, vital signs, KPS, height 
and weight. 
• Complete Blood Count (CBC) with differential and platelet count. 
• Complete metabolic profile (including sodium, potassium, chloride, CO2, 
calcium, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, 
alkaline phosphatase, total bilirubin, SGOT/AST, SGPT/ALT 
• LDH 
• Uric Acid 
• TSH every 3 months beginning with cycle 4 (more often if clinically indicated) 
• Serum protein electrophoresis, serum immunofixation, serum quantitative 
immunoglobulins  
• Serum free light chains studies 
• 24-hour urine collection for total protein, protein electrophoresis, and 
immunofixation. 
• Prior cycle drug diary will be collected.  New drug diary will be generated and 
reviewed with the patient.  
• Serum pregnancy test, if applicable 
• Bone marrow aspiration and biopsy to confirm a CR, or when clinically indicated. 
• Skeletal survey, MRI, or whole body PET/CT scan when clinically indicated (i.e., 
to evaluate for disease response in non-secretory myeloma or to investigate for 
disease progression).  
• All subjects will be followed for survival. Cause of death is to be recorded in the 
subject’s medical record. 
• Quality of Life assessment (Appendix IX) 
• Second primary malignancies will be monitored as events of interest and should 
be included as part of the assessment of adverse events throughout the course of 
the study.   
 
10.4 
Post Study Follow-up 
All attempts will be made to follow patients until progression or death.  Subjects who 
have been discontinued from study will still be followed in a clinic setting to the fullest 
extent possible on a monthly to bi-monthly basis.  Those who choose not to resume 
regular clinic follow-up will be contacted every 6 months by telephone or electronically 


Amendment 4 dated 22 JUN 2021 
 
34
to collect post study information.  The post-study collection information will consist of a 
telephone interview between the clinical investigator and the discontinued patient.  The 
information requested will be current disease status including information about the 
development of secondary primary malignancies, current treatment use, and physical 
status of the patient.  
10.5  Treatment Compliance 
At all times research center personnel will review the dosing instructions with subjects. 
Subjects will be asked to maintain a drug diary to record the drug administration. If doses 
of clarithromycin or lenalidomide are missed, the dose should be taken as soon as 
possible on the same day. If the dose is missed for the entire day, it should not be made 
up. Missed doses of dexamethasone will not be made up. Vomited doses of 
clarithromycin, lenalidomide and dexamethasone will not be made up. Patients who take 
more than the prescribed dose of clarithromycin, lenalidomide or dexamethasone should 
be instructed to seek emergency medical care if needed and contact study staff 
immediately. Subjects will be asked to bring any unused study drug to the research center 
at their next visit.  Research personnel will count and record the number of used and 
unused study drug capsules at each visit. 
10.11 Criteria for removal from study 
Rules for termination of the study for the individual subject are listed below: 
• Subjects may withdraw consent and stop participation at any time. 
• Any Grade 4 skin toxicity (i.e. Stevens Johnson syndrome) or Grade 4 
hypersensitivity (i.e. anaphylaxis). 
• Progression of multiple myeloma, as defined by the International Myeloma 
Working Group Criteria (Appendix 1 of the protocol).  
• Development of any co-morbid condition or excessive toxicity that would make 
further participation in the protocol unsafe. 
• The development of any comorbid condition of excessive toxicity that would 
make further participation in the protocol unsafe. 
• Non-compliance or refusal of the patient to continue treatment and/or evaluation.  
• Major violation of the study protocol. 
• Any adverse event(s) that, in the judgment of an Investigator, may cause severe or 
permanent harm if the study medications are continued.  
• At the discretion of the principal investigator and/or Celgene Pharmaceuticals, 
Inc. for any reason. 
• Loss to follow up. 
• Death of patient 
 
Any possible premature discontinuation would be documented adequately with reasons 
being stated, and information would have to be issued according to local requirements 
(e.g., IRB/EC, regulatory authorities, etc.). 


Amendment 4 dated 22 JUN 2021 
 
35
10.11.2     The responsible Clinical Investigator as well as Celgene Pharmacuticals, Inc. 
have the right to discontinue this study at any time for reasonable medical or 
administrative reasons in any single center.  Possible reasons for termination of the study 
could be but are not limited to: 
• Unsatisfactory enrollment with respect to quantity or quality. 
• Inaccurate or incomplete data collection. 
• Falsification of records. 
• Failure to adhere to the study protocol. 
 
11.0 
ADVERSE EVENTS GRADING AND REPORTING 
11.1 
Adverse Events 
An adverse event is any sign, symptoms, illness, or diagnosis (either observed or 
volunteered) that appears or worsens during the course of the study. Toxicity will be 
scored using CTCAE version 4.0 for toxicity and adverse event reporting.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP homepage 
http://ctep.info.nih.gov.  All appropriate treatment areas must have access to a copy of the 
CTCAE version 4.0.  All adverse clinical experiences, whether observed by the 
investigator or reported by the patients, must be recorded with details about the duration 
and intensity of each episode, the action taken with respect to the test drug, and the 
patient’s outcome.  The investigator must evaluate each adverse experience for its 
relationship to the test drug and for its seriousness.  
The investigator must appraise all abnormal laboratory results for their clinical 
significance.  If any abnormal laboratory result is considered clinically significant, the 
investigator must provide details about the action taken with respect to the test drug and 
about the patient’s outcome. 
11.2  Serious Adverse Events (SAE) 
A serious adverse event is one that at any dose (including overdose): 
• Results in death 
• Is life-threatening1 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity2 
• Is a congenital anomaly or birth defect 
• Is an important medical event3 
• Suspected or positive pregnancy 
 


Amendment 4 dated 22 JUN 2021 
 
36
 1“Life-threatening” means that the subject was at immediate risk of death at the time of 
the serious adverse event; it does not refer to a serious adverse event that hypothetically 
might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred.  
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above should also usually be considered 
serious.  Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse.  
A new diagnosis of cancer during the course of a treatment should be considered as 
medically important.  
Second primary malignancies will be monitored as events of interest and must be 
reported as serious adverse events regardless of the treatment arm the subject is in.  This 
includes any second primary malignancy, regardless of causal relationship to any of the 
study drugs, occurring at any time for the duration of the study, from the time of signing 
the informed consent up to the time all patients have been followed for at least 5 years 
from randomization or have died.  Events of second primary malignancy are to be 
reported using the SAE report form and must be considered an “Important Medical 
Event” even if no other serious criteria apply; these events must also be documented in 
the appropriate page(s) of  the CRF and subject’s source documents.   
Documentation on the diagnosis of the second primary malignancy must be provided at 
the time of reporting as a serious adverse event (eg., any confirmatory histology or 
cytology results, X-rays, CT scans, etc.). 
11.2.1 Pregnancies: 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject 
is on lenalidomide, or within at least 28 days of the subject’s last dose of 
lenalidomide, are considered immediately reportable events. Lenalidomide is to 
be discontinued immediately. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, 
or approved equivalent form. The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for 
further evaluation and counseling. 
The Investigator will follow the female subject until completion of the pregnancy, 
and must notify Celgene Drug Safety immediately about the outcome of the 


Amendment 4 dated 22 JUN 2021 
 
37
pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up 
Report Form, or approved equivalent form. If the outcome of the pregnancy was 
abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the 
serious criteria, it must be reported as an SAE to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 1 business day of 
the Investigator’s knowledge of the event using the SAE Report Form, or 
approved equivalent form. 
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to lenalidomide should 
also be reported to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, within 1 business day of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form. 
Male Subjects 
If a female partner of a male subject taking lenalidomide becomes pregnant, the 
male subject taking lenalidomide should notify the Investigator, and the pregnant 
female partner should be advised to call their healthcare provider immediately. 
11.2.2 Celgene Drug Safety Contact Information for Pregnancy Reporting: 
Celgene Corporation 
Drug Safety  
86 Morris Avenue 
Summit, NJ 07901 
 
Toll Free: 
800-640-7854 
Phone:  
908-673-9667 
Fax: 
 
908-673-9115 
Email:  
clinicaldrugsafety@celgene.com 
 
11.3 
Investigator Reporting Responsibilities: 
The conduct of the study will comply with all FDA safety reporting requirements.   
All adverse experience reports must include the patient number, age, sex, weight, severity 
of reaction (mild, moderate, severe), relationship to study drug (probably related, 
unknown relationship, definitely not related), date and time of administration of test 
medications and all concomitant medications, and medical treatment provided.   The 
investigator is responsible for evaluating all adverse events to determine whether criteria 
for “serious” and “unexpected” as defined above are present.  The investigator is 
responsible for reporting adverse events to Celgene as described below. 
11.3.1 Expedited reporting by investigator to Celgene  


Amendment 4 dated 22 JUN 2021 
 
38
Serious adverse events (SAE) are defined in Section 11.2 above.  The investigator should 
inform Celgene Pharmaceuticals, Inc. of any SAE within 1 business day of being aware 
of the event. The date of awareness should be noted on the report.  This must be 
documented on the Onyx Therapeutics, Inc. SAE forms or a FDA 3500 or MEDWATCH 
form.  This form must be completed and supplied to Onyx Therapeutics, Inc. within 24 
hours / 1 business day at the latest on the following working day.  The initial report must 
be as complete as possible, including details of the current illness and (serious) adverse 
event, and an assessment of the causal relationship between the event and the 
investigational product(s).  Information not available at the time of the initial report (e.g., 
an end date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up MEDWATCH.  A final report to document resolution of the 
SAE is required.  The Celgene protocol number should be included on the SAE reports.  
A copy of the fax transmission confirmation of the SAE report to Celgene should be 
attached to the SAE and retained with the patient records.  
Celgene Drug Safety Contact Information  
Celgene Corporation 
Drug Safety  
86 Morris Avenue 
Summit, NJ 07901 
 
Toll Free: 
800-640-7854 
Phone:  
908-673-9667 
Fax: 
 
908-673-9115 
Email:  
drugsafety@celgene.com 
11.3.2 Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) 
of a serious adverse event according to institutional policy.  
11.3.3 Investigator Reporting to the FDA 
Adverse drug reactions that are Serious, Unlisted/Unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the 
Food and Drug Administration (FDA) in writing by Dr. Ruben Niesvizky (the principal 
sponsor-investigator).  A clear description of the suspected reaction should be provided 
along with an assessment as to whether the event is drug or disease related.   
The principal sponsor-investigator shall notify the FDA by telephone or by fax of any 
unexpected fatal or life threatening experience associated with the use of the drug as soon 
as possible but no later than 7 calendar days after the sponsors initial receipt of the 
information.    Each phone call or fax shall be transmitted to the FDA new drug review 
division in the Center for Drug Evaluation and Research or the product review division in 
the Center for Biologics Evaluation and Research that has responsibility for review of the 
IND. 


Amendment 4 dated 22 JUN 2021 
 
39
The principal sponsor-investigator must also call the FDA as soon as an adverse reaction 
occurs.  The phone number is (301) 594-5778.  A recorder is available after hours.  
Report these reactions to the FDA within ten (10) working days both verbal and written. 
The address of the FDA is: 
FDA 
 
 
 
 
Division of Oncology  
 
 
 
 
HFD-150 
 
 
 
 
1451 Rockville Pike 
 
 
 
 
Rockville, MD  20852-1448 
 
The phone number of the FDA is:  
(301) 594-5778 
 
Please ask to speak with the Division of Oncology. 
 
11.3.4 Reporting of Secondary Primary Malignancies 
Secondary primary malignancies will be reported to the FDA, Celgene Pharmaceuticals, 
and the Weill Cornell Medical College Data Safety Monitoring Board at the time of 
annual renewal. Additional information regarding secondary primary malignancies listed 
in Section 11.2. 
11.4 
Adverse event updates/IND safety reports 
Celgene Pharmaceuticals, Inc. shall notify the Investigator via an IND Safety Report of 
the following information: 
• Any AE associated with the use of study drug in this study or in other studies that 
is both serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. 
The Investigator must keep copies of all AE information, including correspondence with 
Celgene and the IRB/EC, on file (see Section 15.4 for records retention information). 
11.5 
Provisions for Adverse Events 
Necessary prophylaxis will be administered.  Anti-emetics and will be prescribed if 
necessary.  Blood and platelet transfusions will be given as clinically indicated.  
Pamidronate or Zoledronic acid may be given monthly as part of standard care. 


Amendment 4 dated 22 JUN 2021 
 
40
12.0  PROTOCOL AMENDMENTS AND DEVIATIONS 
12.1 
Amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and 
reviewed by Celgene.  Amendments should only be submitted to IRB/EC after 
consideration Celgene Pharmaceuticals, Inc. review.  Written verification of IRB/EC 
approval will be obtained before any amendment, which affects subject safety or efficacy, 
is implemented.  Amendments that are administrative in nature do not require IRB/EC 
approval but will be submitted to the IRB/EC for information purposes. 
12.2  Protocol Deviations 
When an emergency occurs that requires a deviation from the protocol for a subject, a 
deviation will be made only for that subject.  A decision will be made as soon as possible 
to determine whether or not the subject (for whom the deviation from protocol was 
effected) is to continue in the study.  The subject’s medical records will completely 
describe the deviation from the protocol and state the reasons for such deviation.  In 
addition, the Investigator will notify the IRB/EC in writing of such deviation from 
protocol.   
Non-emergency minor deviations from the protocol will be permitted with approval of 
the Principal Investigator. 
13.0  DATA MANAGEMENT 
13.1 
Analyses and Reporting 
This study will be conducted at The New York Presbyterian Hospital at the Weill Cornell 
Medical College.  Clinical data will be collected under the supervision of one of the study 
investigators.  Clinical data will be organized and recorded with the help of data 
managers located at the Cornell campus.  Study design and data analysis will be 
implemented in collaboration with our biostatistician at Weill Cornell Medical College 
and data will be collected and tabulated on a monthly basis.  
13.2 
Data Safety Monitoring Board. 
The Data Safety Monitoring Board (DSMB) at Weill-Cornell Medical Center will be 
composed of medical and statistical independent reviewers and will meet to review the 
efficacy and safety data and determine a risk/benefit analysis in this subject population.  
The purpose of the DSMB is to advise on serious safety considerations, lack of efficacy 
and any other considerations within the charge to the Committee.  The DSMB may 
request additional meetings or safety reports as deemed necessary upon discussion with 
Celgene and its representatives.  The PI, Dr. Jorge Monge, will be the safety contact for 
all DSMB related analysis outcomes. 


Amendment 4 dated 22 JUN 2021 
 
41
Dr. Monge’s office is located at: 
NYPH-WCMC 
425 East 61st Street, Suite 800 
New York, NY  10065 
The phone number to Dr. Monge’s office is: +1-646-962-6500  
The DSMB may stop the study following review of results from each interim analysis.  
The first interim analysis will take place 3 months after the study begins subject accrual 
or after 10 patients have been enrolled, whichever occurs first, and will examine only 
safety information.  A subsequent interim analysis will take place 6 months after the 
study begins subject accrual, and every six months thereafter, and will examine both 
safety and efficacy.  The DSMB will also review the study after 66 PFS events have 
occurred across both arms for futility, (as outlined in the Statistical Considerations 
Section 14) including toxicity data, protocol adherence, and protocol deviations and 
enforce stopping rules if necessary. Efficacy and safety data summaries will be provided 
to the DSMB after each interim analysis. 
“13.3 Study Monitoring and Auditing 
13.3.1 Investigator Responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice 
(GCP) and in the US Code of Federal Regulations. Investigators must enter study data 
onto CRFs or other data collection system.  The Investigator will permit study-related 
monitoring visits and audits by Celgene Corporation or its representatives, IRB/EC 
review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to 
the facilities where the study took place, to source documents, to CRFs, and to all other 
study documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available at 
some time during monitoring visits to review data and resolve any queries and to allow 
direct access to the subject’s records (e.g., medical records, office charts, hospital charts, 
and study related charts) for source data verification.  The data collection must be 
completed prior to each visit and be made available to the Celgene Pharmaceuticals, Inc. 
representative so that the accuracy and completeness may be checked. 
 
14.0  STATISTICAL CONSIDERATIONS 
14.1 
Study Design/Primary Endpoint 
 
The study is a randomized phase III design, and the primary endpoint in both treatment 
arms is median PFS.  PFS will be defined as the time from randomization day until 
objective progression or death from any cause.  The PFS distributions of the two 
treatment arms will be estimated by Kaplan-Meier survival analysis and the PFS 
distributions will be compared by an unstratified log-rank test.  Ninety-five percent 
confidence intervals for the Kaplan-Meier PFS estimates will be calculated using 


Amendment 4 dated 22 JUN 2021 
 
42
Greenwood’s formulae.  The primary comparison will be made using the intent-to-treat 
(ITT) patient population.  Patients will be analyzed based on their randomization 
assignments, regardless of therapy initiation or compliance.  A secondary analysis will be 
performed comparing “evaluable” patients as patients who met eligibility requirements, 
have initiated therapy, and were not removed from the study for non-compliance or 
patient withdrawal. 
 
The median PFS for MM patients receiving Revlimid /dexamethasone chemotherapy 
(Rd) (Arm A) is expected to be approximately 25.5 months, as reported in the MM-010 
study of continuous Rd vs Rd for 18 months (Facon T, Dimopoulos M, Dispenzieri A, et 
al: Initial phase 3 results of the FIRST trial in newly diagnosed multiple myeloma 
patients ineligible for stem cell transplant. 2013 ASH Annual Meeting. Abstract 2. 
Presented December 8, 2013.).  Therefore, the target median PFS for patients receiving 
Revlimid/dexamethasone/Clarithromycin (BiRd) (Arm B) is hypothesized to be 44.6 
months (target hazard ratio = 1.75).   
 
14.2 
Sample Size/Accrual Rate 
 
To achieve 90% power to detect a 75% increase in median PFS (44.6 vs. 25.5 months), at 
the two-sided 0.05 significance level, will require 306 patients total, accrued over 
approximately 3.0 years (assuming an accrual rate of approximately 9 patients/month), 
with an additional 12 months of follow-up subsequent to termination of accrual.  
  
When the sample size in each group is 153 patients, with a total number of PFS events 
required of 133, an exponential maximum likelihood test of equality of survival curves 
with a 0.05 two-sided significance level will have 90% power to detect the difference 
between an Arm A (Rd) median PFS of 25.5 months and an Arm B (BiRd) median PFS 
of 44.6 months (a constant hazard ratio of 1.75); this assumes an accrual period of 3.0 
years, a maximum follow-up time of 4.0 years, and no dropouts.  The exponential 
assumption is for planning purposes only, actual analysis will employ nonparametric 
methods for estimation and testing of survival distributions.  Assuming a 10% dropout 
rate, approximately 337 patients will be accrued to the study. 
  
A futility analysis will be conducted after 50% of the total PFS events required for final 
analysis has occurred (i.e., 66 of the 133 required PFS events).  No accrual suspension is 
required to conduct the futility analysis.  If at this point (i.e., after accumulation of 66 
PFS events) the hazard ratio of the control arm over the experimental arm is 1.0 or less, 
the study will be stopped for futility. 
 
14.3 
Analysis of Progression-Free Survival 
 
Because the analysis of PFS can be difficult, especially in the presence of missing data 
and lost-to-follow-up, sensitivity analyses can be helpful in determining whether the PFS 
analysis is robust.  As suggested by the alternative PFS definitions recommended in the 
FDA’s Guidance for Industry, “Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics (May, 2007), the following three types of PFS analyses will be 


Amendment 4 dated 22 JUN 2021 
 
43
conducted: 
 
Table A. PFS #1 (includes documented progression only) (Primary PFS Analysis): 
 
Situation  
Date of Progression or 
Censoring  
Outcome  
No baseline tumor assessments  
Randomization  
Censored  
Progression documented between scheduled 
visits  
Earliest of:  
• Date of hematological 
assessment showing progression; 
or 
• Date of radiological assessment 
showing progression; or 
• Date of urine assessment 
showing progression 
Progressed  
No progression  
Date of last hematological, 
radiological, or urine assessment 
Censored  
Treatment discontinuation for undocumented 
progression  
Date of last hematological, 
radiological, or urine assessment 
Censored  
Treatment discontinuation for toxicity or other 
reason  
Date of last hematological, 
radiological, or urine assessment 
Censored  
New anticancer treatment started  
Date of last hematological, 
radiological, or urine assessment 
Censored  
Death before first PD assessment  
Date of death  
Progressed  
Death between adequate assessment visits  
Date of death  
Progressed  
Death or progression after more than one missed 
visit  
If progression: 
• Date of hematological 
assessment showing progression; 
or 
• Date of radiological assessment 
showing progression; or 
• Date of urine assessment 
showing progression 
 
OR, if not progression: 
 
Date of last hematological, 
radiological, or urine assessment  
Censored  
 
Table A represents the primary PFS analysis that only includes well-documented and 
verifiable progression events.  Other data are censored.  In Table A, the progression dates 
are 1) based only on radiological assessments verified by an IRC (clinical progression 
will not be considered a progression endpoint), 2) assigned to the first time when disease 
progression is noted, and 3) the date of death when the patient is closely followed.  
However, deaths occurring after two or missed visits will be censored at the last visit. 
 
 
 
 
 
 


Amendment 4 dated 22 JUN 2021 
 
44
 
Table B. PFS #2 (uniform progression and assessment dates) (PFS Sensitivity 
Analysis #1): 
 
Situation  
Date of Progression or 
Censoring  
Outcome  
No baseline tumor assessments  
Randomization  
Censored  
Progression documented between scheduled visits  Date of next scheduled visit  
Progressed  
No progression  
Date of last visit with adequate 
assessment  
Censored  
Treatment discontinuation for undocumented 
progression  
Date of last visit with adequate 
assessment  
Censored  
Treatment discontinuation for toxicity or other 
reason  
Date of last visit with adequate 
assessment  
Censored  
New anticancer treatment started  
Date of last visit with adequate 
assessment  
Censored  
Death before first PD assessment  
Date of death  
Progressed  
Death between adequate assessment visits  
Date of death  
Progressed  
Death or progression after more than one missed 
visit  
Date of last visit with adequate 
assessment  
Censored  
 
Table B presents a sensitivity analysis for PFS that helps to correct for potential bias in 
follow-up schedules for tumor assessment by assigning the dates of censoring and events 
only at scheduled visit dates.  This approach can introduce bias if the progression 
occurred closer to the last visit, particularly in an open-label study. 
 
 
Table C. PFS #3 (includes investigator claims) (PFS Sensitivity Analysis #2): 
 
Situation  
Date of Progression or 
Censoring  
Outcome  
No baseline assessment  
Randomization  
Censored  
Progression documented between scheduled 
visits  
Next scheduled visit  
Progressed  
No progression  
Date of last visit with 
adequate assessment  
Censored  
Investigator claim of clinical progression  
Scheduled visit (or next 
scheduled visit if between 
visits)  
Progressed  
Treatment discontinuation for toxicity or 
other reason  
Date of last visit with 
adequate assessment  
Censored  
New anticancer treatment started with no 
claim of progression  
Date of last visit with 
adequate assessment  
Censored  
Death before first PD assessment  
Date of death  
Progressed  
Death between adequate assessment visits or 
after patient misses one assessment visit  
Date of death  
Progressed  
Death after an extended lost-to-follow-up 
time (two or more missed assessments)  
Last visit with adequate 
assessment  
Censored  
 


Amendment 4 dated 22 JUN 2021 
 
45
Table C presents a sensitivity analysis for PFS that evaluates PFS according to the 
investigator’s assessment.  This approach can introduce bias if the progression occurred 
closer to the last visit, particularly in an open-label study. 
 
Although the above PFS analyses will initially censor patients who died or progressed 
after more than one missed visit (Tables A/B/C), these analyses will also be redone to 
classify the patients as progression events, and the date of death will be used as the date 
of progression.  Counting such deaths as progression events may overestimate PFS, but 
also minimizes bias.  
 
Lastly, a comparison of the adequacy of follow-up and the number of scheduled 
assessments in each treatment arm will be performed to evaluate potential bias resulting 
from missing data.  Because the trial is unblinded, there is always the potential for bias 
(i.e., evaluation-time bias) between the treatment arms because of the subjective aspects 
of the progression endpoint.  To evaluate the impact of any evaluation-time bias in the 
assessment of PFS, we will use the approach of Freidlin and Korn when comparing PFS 
between the two treatment arms (Freidlin B, Korn EL, Hunsberger S, Gray R, Saxman S, 
Zujewski J. Proposal for the use of progression-free survival in unblinded randomized 
trials. Journal of Clinical Oncology. 2007;25:2122-2126).  The method of Freidlin and 
Korn will not be the primary analysis.  The primary analysis will be performed as 
discussed in section 14.2, first two paragraphs.  The Freidlin/Korn method will be 
performed to assess the extent of any evaluation-time bias that may have resulted 
from comparison of the two treatment arms in the primary analysis (i.e., primary 
analysis using the actual reported progression times; progression-free survival 
curves). 
 
14.3 
Stratification Factors 
 
Patients will be stratified based on enrolling institution. 
 
Blocked randomization will be performed at all participating sites.  A series of 
randomized blocks will be generated for each participating site with a 1:1 allocation ratio. 
This will provide assurance that there will be an equal patient allocation to both treatment 
arms at any given participating site. 
 
 
14.4 
Analysis of Secondary Endpoints 
 
Secondary endpoints include objective response rate (CR+PR) and complete response 
rate (CR) (estimated via binomial proportions), and Kaplan-Meier overall survival.  
Overall survival will be defined as the time from randomization day until death.  Ninety-
five percent confidence intervals will be calculated for the objective response proportion 
in each group via binomial proportions.  Comparison of the objective response rate and 
complete response rate between the treatment groups will be performed by the chi-square 
test.  The comparison of the overall survival distributions between the treatment groups 
will be performed by the log-rank test.  Analysis of these three secondary endpoints will 


Amendment 4 dated 22 JUN 2021 
 
46
be considered hypothesis-generating only and will be adjusted for multiplicity of 
outcomes by the Bonferroni method.  In the event that no significant result is observed 
for the primary endpoint (PFS), significant findings for the secondary endpoints (even 
after correction for multiplicity of outcomes) will not result in efficacy claims for 
labeling purposes.  Similarly, if a significant finding is observed for the primary endpoint, 
significant findings for the secondary endpoints will still not result in efficacy claims for 
labeling purposes.  All other secondary endpoints (i.e., event-free survival, duration of 
response, time to progression, progression-free survival 2, and quality of life measures) 
will only be descriptively presented for each treatment group and no formal statistical 
comparison will be made between treatment arms.  Confidence intervals for the 
secondary endpoints of objective response rate, complete response rate, and overall 
survival will be Bonferroni-corrected.  The frequency of subjects experiencing toxicities 
will be tabulated.  Toxicities will be assessed and graded according to CTCAE v. 4.0 
terminology.  Exact 95% confidence intervals around the toxicity proportions will be 
calculated to assess the precision of the obtained estimates. 
 
All p-values will be two-sided with statistical significance evaluated at the 0.05 alpha 
level.  P-values will be Bonferroni-corrected for the secondary endpoints of objective 
response rate, complete response rate, and overall survival.  All analyses will be 
performed in SAS Version 9.4 (SAS Institute, Inc. Cary, NC) and Stata Version 14.0 
(StataCorp, College Station, TX). 
 
15.0 
REGULATORY CONSIDERATIONS 
15.1 
Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki.  The review of this protocol by the 
IRB/EC and the performance of all aspects of the study, including the methods used for 
obtaining informed consent, must also be in accordance with principles enunciated in the 
declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations 
(CFR), Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to the 
relevant IRB/EC and obtaining written approval for this study.  The approval will be 
obtained prior to the initiation of the study. 
The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted for 
approval by the Investigator to the IRB/EC.  The Investigator is also responsible for 
notifying the IRB/EC of any serious deviations from the protocol, or anything else that 
may involve added risk to subjects. 


Amendment 4 dated 22 JUN 2021 
 
47
Any advertisements used to recruit subjects for the study must be reviewed and approved 
by the IRB/EC prior to use. 
15.2 
Informed Consent Procedures 
The Investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedure as per GCP’s as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study 
and the informed consent process should be recorded in the subject’s source documents.  
The original consent form, signed and dated by the subject and by the person consenting 
the subject prior to the subject’s entry into the study, must be maintained in the 
Investigator’s study files.   At the pre-admission consultation, patients will be fully 
informed as to the purposes and potential risks and benefits involved in this study. 
Patients will have ample opportunity to ask questions before consenting. Legal guardians 
will sign informed consent for legally incompetent patients in accordance with hospital 
policy. 
15.3 
Protecting Privacy and Confidentiality 
Confidentiality will be maintained within the limits of the law. Patient names or any other 
identifying information will not be used in reports or publications resulting from this 
study. Only qualified staff from New York Presbyterian Hospital, Weill Medical College 
of Cornell University, the Food and Drug Administration, or other study support such as 
the National Cancer Institute will be able to review patient medical records. 
Celgene Pharmaceuticals, Inc. affirms the subject’s right to protection against invasion of 
privacy.  In compliance with United States federal regulations, Celgene requires the 
Investigator to permit Celgene’s representatives and, when necessary, representatives of 
the FDA or other regulatory authorities to review and/or copy any medical records 
relevant to the study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Investigator to 
obtain such permission in writing from the appropriate individual. 
15.4 
Study records requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of 
the study and the distribution of the study drug, that is copies of CRFs and source 
documents (original documents, data, and records [e.g., hospital records; clinical and 
office charts; laboratory notes; memoranda; subject’s diaries or evaluation checklists; 
pharmacy dispensing records; recorded data from automated instruments; copies or 
transcriptions certified after verification as being accurate copies; microfiches; 
photographic negatives, microfilm, or magnetic media; x-rays; subject files; and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical study; documents regarding subject treatment and study drug accountability; 
original signed informed consents, etc.]) be retained by the Investigator for as long as 


Amendment 4 dated 22 JUN 2021 
 
48
needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval).  The 
Investigator agrees to adhere to the document/records retention procedures by signing the 
protocol. 
15.5 
Protection of Human Rights 
Participation in this trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to Weill Cornell Medical College IRB guidelines.  
Patients will be eligible for this trial regardless of gender or racial/ethnic background.  
All patients must follow the guidelines for pregnancy testing, birth control and 
counseling related to the risk of fetal exposure to lenalidomide as outlined in Appendix 
III. 
15.6 
Premature Discontinuation of Study 
The responsible local clinical investigator, as well as Celgene, has the right to discontinue 
this study at any time for reasonable medical or administrative reasons in any single 
center.  Possible reasons for termination of the study could be but are not limited to: 
• Unsatisfactory enrollment with respect to quantity or quality. 
• Inaccurate or incomplete data collection. 
• Falsification of records. 
• Failure to adhere to the study protocol. 
 
15.6.1 Study as a whole 
Celgene reserves the right to terminate this clinical study at any time for reasonable 
medical or administrative reasons. 
Any possible premature discontinuation would be documented adequately with reasons 
being stated, and information would have to be issued according to local requirements 
(e.g. IRB/EC, regulatory authorities, etc.). 
15.7 
Benefits of the Protocol 
The potential benefit of this study is the development of a safe and effective treatment 
program for newly diagnosed MM patients.  Knowledge will be acquired about this 
treatment program, its tolerability, and the effectiveness of clarithromycin (Biaxin®), 
lenalidomide (Revlimid®), and dexamethasone (Decadron®) in the treatment of newly 
diagnosed MM. If effective, this treatment plan may improve remission rates in newly 
diagnosed MM patients and hopefully prolong the disease survival. 
15.8 
Risks in Relation to Anticipated Benefit 
The risks associated with participation in this trial are commensurate with the expected 
risks of other potential therapies and are reasonable given the potential benefit to patients 


Amendment 4 dated 22 JUN 2021 
 
49
with newly diagnosed MM. If the combination of Car-BiRD is as effective against newly 
diagnosed MM as anticipated, this regimen could become standard of care leading to 
improved survival.   
15.8 
Alternative Treatments 
Patients who refuse to participate in the study or decided to withdrawal from the study 
will be given the option to choose standard chemotherapy, other investigation studies, 
supportive care, or no anti-cancer treatment at all.  Some patients treated with standard 
chemotherapy do benefit.  Treatment with thalidomide, lenalidomide, bortezomib, or 
other cytotoxic chemotherapy alone or in combination with corticosteroids has prior 
proven efficacy. (While the results of this therapy have been encouraging, long-term 
remissions are rare, no patients are cured and none of the drugs used in these standard 
treatments are free of side effects.  We believe that this novel regimen will improve 
response rates and duration of remission. 
15.9 
Incentives 
No incentives will be offered to patients/subjects for participation in the study.  
Participation is voluntary. 
15.10 Costs 
Patients and/or their medical insurance coverage will be responsible for paying for their 
hospitalization, doctor visits, diagnostic tests, chemotherapy drugs, and other medicines 
used in their care directly. Patients and/or their medical insurance coverage will also be 
responsible for payment for clarithromycin and dexamethasone as used in this study and 
are freely available in local pharmacies.  These costs are expected to be equivalent to 
those of standard treatment. Commercially available Lenalidomide (Revlimid®) will be 
prescribed to research subjects for the duration of their participation in this trial in 
accordance with the RevAssist® program.  Lenalidomide will be shipped directly to 
patients.  
 


Amendment 4 dated 22 JUN 2021 
 
50
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31. Gay, F. et al. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone 
(BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed 
myeloma. Am J Hematol 85, 664-669 (2010). 
32. Knight, R., DeLap, R. J. & Zeldis, J. B. Lenalidomide and venous thrombosis in 
multiple myeloma. N Engl J Med 354(19), 2079-2080 (2006). 
33. Rajkumar, S Vincent et al. International Myeloma Working Group updated criteria 
for the diagnosis of multiple myeloma. The Lancet Oncology 15(12), e538 - e548 
(2014). 
 


Amendment 4 dated 22 JUN 2021 
 
52
APPENDIX I: Criteria for Response 
 
Table 1: Criteria for Response, Disease plateau, and Disease Relapse as adopted from 
the EBMT and the international uniform response criteria35 
Stringent Complete Response (sCR) requires all of the following: 
 All of the criteria of complete response  
 Normal serum free light chain ratio 
 Absence of monoclonal cells on bone marrow aspirate by immunohistochemistry or 
immunofluorescence 
Complete Response (CR) requires all of the following: 
 Absence of the original monoclonal protein in serum and urine by immunofixation. The presence 
of oligoclononal bands consistent with oligoclonal immune reconstitution does not exclude CR. 
  ≤5% plasma in a bone marrow aspirate and also on trephine bone biopsy, if biopsy is performed. 
If absence of monoclonal protein is sustained for 6 weeks it is not necessary to repeat the bone 
marrow, except in patients with non-secretory myeloma where the marrow examination must be 
repeated after an interval of at least 6 weeks to confirm CR. 
 No increase in size or number of lytic bone lesions (development of a compression fracture does 
not exclude response) 
 Disappearance of soft tissue plasmacytoma. 
Very Good Partial Response (VGPR) requires all of the following: 
 Negative serum and urine protein electrophoeresis with persistence of monoclonal protein 
detectable on immunofixation OR 
 ≤90% reduction in serum monoclonal protein level with urine monoclonal protein level < 100mg 
in 24 hour collection.  
Partial Response (PR) requires all of the following: 
 ≥50% reduction in the level of the serum monoclonal paraprotein. 
 Reduction in 24h urinary light chain excretion either by ≥90% or to <200mg. 
 For patents with  light chain only disease, then a 50% reduction in the difference between the 
involved and uninvolved free light chain level may be substituted for the M-protein 
measurement.  
 For patients with non-secretory myeloma only, ≥50% reduction in plasma cells in a bone marrow 
aspirate and on trephine bone biopsy, if biopsy is performed. 
 ≥50% reduction in the size of soft tissue plasmacytomas (by radiography or clinical 
examination). 
 No increase if size or number of lytic bone lesion (development of a compression fracture does 
not exclude response)             
Stable Disease (SD) requires the following: 
 Not meeting the criteria stringent complete response (sCR), complete response (CR), very good 
partial response (VGPR), or partial response (PR) 
Plateau: 
 Stable values (within 25% above or below value at the time response is addressed) 
Patients in which no significant change (<50% decrease or <25% increase from baseline) in the 
production rate of the monoclonal serum protein or Bence-Jones protein excretion and no new 
lytic lesions and/or plasmacytomas are detected. 
Relapse from CR requires at least one of the following: 


Amendment 4 dated 22 JUN 2021 
 
53
 Reappearance of serum or urinary paraprotein on immunofixation or routine electrophoresis, 
confirmed by at least one further investigation and excluding oligoclonal immune reconstitution. 
 ≥5% plasma in a bone marrow aspirate or trephine bone biopsy. 
 Development of new lytic lesions of soft tissue plasmacytomas or definite increase in the size 
of residual bone lesions (development of a compression fracture does not exclude continued 
response and may not indicate progression). 
 Development of hypercalcemia (corrected serum calcium >11.5mg/dl or 2.8 mmol/l) not 
attributable to any other cause. 
Progressive disease (PD) for patients not in CR requires one or more of the following: 
 >25 increase in the level of the serum monoclonal paraprotein, which must also be an absolute 
increase of at least 5g/L and confirmed by at least one repeated investigation. 
 >25 increase in the 24h urinary light chain excretion, which must also be an absolute increase 
of at least 200mg/24h and confirmed by at least one repeated investigation. 
 >25% increase in plasma cells in a bone marrow aspirate and on trephine bone biopsy, which 
must also be an absolute increase of at least 10%. 
 Definite increase in the size of excisting bone lesions or soft tissue plasmacytomas. 
 Development of new bone lesions or soft tissue plasmacytomas (development of a compression 
fracture does not exclude continued response and may not indicate progression). 
 Development of hypercalcemia (corrected serum calcium >11.5mg/dl or 2.8 mmol/l) not 
attributable to any other cause. 
 
 


Amendment 4 dated 22 JUN 2021 
 
54
Appendix II: Diagnostic and Staging Criteria for Multiple Myeloma33 
 
International Myeloma Working Group (IMWG) Guidelines for the diagnosis of 
Multiple Myeloma 
 
 
Definition of multiple myeloma 
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary 
plasmacytoma* and any one or more of the following myeloma defining events: 
• Myeloma defining events: 
o Evidence of end organ damage that can be attributed to the underlying 
plasma cell proliferative disorder, specifically: 
 Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher 
than the upper limit of normal or >2.75 mmol/L (>11 mg/dL) 
 Renal insufficiency: creatinine clearance <40 mL per min† or 
serum creatinine >177 μmol/L (>2 mg/dL) 
 Anaemia: haemoglobin value of >20 g/L below the lower limit of 
normal, or a haemoglobin value <100 g/L 
 Bone lesions: one or more osteolytic lesions on skeletal 
radiography, CT, or PET-CT‡ 
o Any one or more of the following biomarkers of malignancy: 
 Clonal bone marrow plasma cell percentage* ≥60% 
 Involved:uninvolved serum free light chain ratio§ ≥100 
 >1 focal lesions on MRI studies¶ 
 
Definition of smoldering multiple myeloma 
Both criteria must be met: 
 Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein 
≥500 mg per 24 h and/or clonal bone marrow plasma cells 10–60% 
 Absence of myeloma defining events or amyloidosis 
 
PET-CT=1⁸F-fluorodeoxyglucose PET with CT. *Clonality should be established by showing κ/λ-light-chain 
restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage 
should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core 
biopsy, the highest value should be used. †Measured or estimated by validated equations. ‡If bone marrow has less 
than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with 
minimal marrow involvement. §These values are based on the serum Freelite assay (The Binding Site Group, 
Birmingham, UK). The involved free light chain must be ≥100 mg/L. ¶Each focal lesion must be 5 mm or more in size. 
 
 
 
 
 
 
 
 


Amendment 4 dated 22 JUN 2021 
 
55
 
 
Diagnosis   
Diagnostic Criteria: All Three Required 
Symptomatic multiple 
myelomaa 
• 
Monoclonal plasma cells in the bone marrow 
>/=10% and/or presence of a biopsy-proven 
plasmacytoma 
• 
Monoclonal protein present in the serum 
and/or urineb 
• 
Myeloma-related organ dysfunction (>/=1)c  
[C] Calcium elevation in the blood 
(serum calcium >10.5 mg/l or upper 
limit of normal 
[R] Renal insufficiency (serum 
creatinine >2mg per 100 ml) 
[A] Anemia (hemoglobin <10 g per 
100 ml or 2 g <normal) 
[B] Lytic bone lesions or osteoporosisd  
Monoclonal gammopathy of 
undetermined significance 
(MGUS) 
• 
Serum monoclonal protein lowe 
• 
Monoclonal bone marrow plasma cells <10% 
• 
No evidence of end-organ damage attributable 
to the clonal plasma cell disorder: 
o Normal serum calcium, hemoglobin 
level and serum creatinine 
o No bone lesions on full skeletal X-ray 
survey and/or other imaging if 
performed 
o No clinical or laboratory features of 
amyloidosis or light chain deposition 
disease 
Smoldering or indolent 
myelomaf 
• 
Monoclonal protein present in the serum 3 g 
per 100 ml or higher or 
• 
Monoclonal plasma cells 10% or greater 
present in the bone marrow and/or a tissue 
biopsy 
• 
No evidence of end-organ damage attributable 
to the clonal plasma cell disorder: 
o Normal serum calcium, haemoglobin 
level and serum creatinine 
o No bone lesions on full skeletal X-ray 
survey and/or other imaging if 
performed 


Amendment 4 dated 22 JUN 2021 
 
56
o No clinical or laboratory features of 
amyloidosis or light chain deposition 
disease 
Solitary plasmacytoma of 
bone  
• 
Biopsy-proven plasmacytoma of bone in a 
single site only. X-rays and magnetic 
resonance imaging and/or 
• 
FDG PET imaging (if performed) must be 
negative outside the primary site.  
• 
The primary lesion may be associated with a 
low serum and/or urine M-component 
• 
The bone marrow contains no monoclonal 
plasma cells 
• 
No other myeloma-related organ dysfunction 
Adapted with permission from Kyle and Rajkumar, Criteria for diagnosis, staging, risk stratification and 
response assessment of multiple myeloma..Leukemia 2009; 23: 3–9. 
aThese criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA 
becomes smoldering or indolent myeloma. 
bIf no monoclonal protein is detected (non-secretory disease), then >/= 30% monoclonal bone marrow 
plasma cells and/or a biopsy-proven plasmacytoma required. 
cA variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy. 
Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related. 
dIf a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) is the sole defining 
criteria, then >/= 30% plasma cells are required in the bone marrow. 
eLow is defined as serum M protein <3.0 g per 100 ml. 
fThese criteria identify Stage IA myeloma by Durie/Salmon stage. 
 
 
Salmon-Durie Staging System 
Stage 
Criteria 
    I 
All of the following present: 
 
   Hemoglobin > 10 g/dL 
 
   Serum IgG < 5 g/dL 
 
   Serum IgA < 3 g/dL 
 
   Normal serum calcium 
 
   Urine monoclonal protein excretion < 4 g/day 
 
   No lytic bone lesions 
    II 
Fulfills neither stage I nor stage III criteria 
    III 
One of more of the following present 
 
   Hgb < 8.5 g/dL 
 
   Serum IgG > 7g/dL 
 
   Serum IgA > 5 g/dL 
 
   Serum calcium > 12mg/dL (3mmol/L) 


Amendment 4 dated 22 JUN 2021 
 
57
 
   Urine monoclonal protein excretion > 12g/day 
 
   Multiple lytic bone lesions 
Subcategory 
 
    A 
Serum creatinine < 2mg/dL (177 μmol/L) 
    B 
Serum creatinine ≥ 2mg/dL 
 
International Staging System (ISS) 
Stage 
Criteria 
    I 
β2-microglobulin < 3.5 mg/dL 
 
Serum albumin ≥ 3.5 g/dL  
    II 
Neither stage I nor stage II 
    III 
β2-microglobulin ≥ 5.5 mg/dL 
 


Amendment 4 dated 22 JUN 2021 
 
58
APPENDIX III:  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 human teratogenic active substance that causes severe life-threatening birth 
defects.  An embryofetal development study in animals indicates that lenalidomide 
produced malformations in the offspring of female monkeys who received the drug 
during pregnancy.  The teratogenic effect of lenalidomide in humans cannot be ruled out.  
Therefore, a risk minimization plan to prevent pregnancy must be observed. 
All study participants must be registered into the mandatory RevAssist® program, and be 
willing and able to comply with the requirements of RevAssist®. 
Females of childbearing potential (FCBP)1F† 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.   
Counseling 
For a female of childbearing potential, lenalidomide is contraindicated unless all of the 
following are met (i.e., all females of childbearing potential must be counseled 
concerning the following risks and requirements prior to the start of lenalidomide study 
therapy):  
• She understands the potential teratogenic risk to the unborn child 
• She understands the need for effective contraception, without interruption, 4 
weeks before starting study treatment, throughout the entire duration of study 
treatment, dose interruption and 28 days after the end of study treatment 
• She should be capable of complying with effective contraceptive measures 
 
 
† 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). 
  


Amendment 4 dated 22 JUN 2021 
 
59
• She is informed and understands the potential consequences of pregnancy and 
the need to notify her study doctor immediately if there is a risk of pregnancy 
• She understands the need to commence the study treatment as soon as study 
drug is dispensed following a negative pregnancy test 
• She understands the need and accepts to undergo pregnancy testing based on 
the frequency outlined in this protocol  
• She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
The investigator must ensure that for females of childbearing potential: 
• Complies with the conditions for pregnancy risk minimization, including 
confirmation that she has an adequate level of understanding 
• Acknowledge the aforementioned requirements 
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of 
the following are met (i.e., all females NOT of childbearing potential must be counseled 
concerning the following risks and requirements prior to the start of lenalidomide study 
therapy):  
• She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
Traces of lenalidomide have been found in semen.  Male patients taking lenalidomide 
must meet the following conditions (i.e., all males must be counseled concerning the 
following risks and requirements prior to the start of lenalidomide study therapy): 
• Understand the potential teratogenic risk if engaged in sexual activity with a 
pregnant female or a female of childbearing potential 
• Understand the need for the use of a condom even if he has had a vasectomy, 
if engaged in sexual activity with a pregnant female or a female of 
childbearing potential.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence from 
heterosexual contact 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; 3) dose 
interruptions; and 4) for at least 28 days after study treatment discontinuation.  
The two methods of reliable contraception must include one highly effective method and 
one additional effective (barrier) method. FCBP must be referred to a qualified provider 
of contraceptive methods if needed. The following are examples of highly effective and 
additional effective methods of contraception:   
• Highly effective methods: 
− Intrauterine device (IUD) 


Amendment 4 dated 22 JUN 2021 
 
60
− Hormonal (birth control pills, injections, implants) 
− Tubal ligation 
− Partner’s vasectomy 
• Additional effective methods: 
− Male condom 
− Diaphragm 
− Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are 
not recommended. If a patient is currently using combined oral contraception the patient 
should switch to one of the effective method listed above. The risk of venous 
thromboembolism continues for 4 to 6 weeks after discontinuing combined oral 
contraception. The efficacy of contraceptive steroids may be reduced during co-treatment 
with dexamethasone 
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding. 
Prophylactic antibiotics should be considered particularly in patients with neutropenia.  
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing 
potential who commit to complete abstinence, as outlined below. 
Before starting study drug:   
Female Subjects:   
• FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) 
prior to prescribing lenalidomide.  The first pregnancy test must be performed 
within 10-14 days prior to prescribing lenalidomide and the second pregnancy test 
must be performed within 24 hours prior to prescribing lenalidomide 
(prescriptions must be filled within 7 days).  The subject may not receive study 
drug until the Investigator has verified that the results of these pregnancy tests are 
negative. 
Male Subjects:   
• Must practice complete abstinence or  agree to use a condom during sexual 
contact with a pregnant female or a female of childbearing potential while 
participating in the study, during dose interruptions and for at least 28 days 
following study drug discontinuation, even if he has undergone a successful 
vasectomy.   
During study participation and for 28 days following discontinuation from the 
study: 


Amendment 4 dated 22 JUN 2021 
 
61
All Subjects: 
• 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.   
• If pregnancy or a positive pregnancy test does occur in a study patient, study drug 
must be immediately discontinued. 
• Pregnancy testing and counseling about pregnancy precautions and the potential 
risks of fetal exposure must be conducted at a minimum of every 28 days and 
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 study drug discontinuation. 
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. 
• Counseling about the requirement for complete abstinence or condom use 
during sexual contact with a pregnant female or a female of childbearing 
potential and the potential risks of fetal exposure to lenalidomide must be 
conducted at a minimum of every 28 days.   
• If pregnancy or a positive pregnancy test does occur in the partner of a male 
study patient during study participation, the investigator must be notified 
immediately. 
Additional precautions 
• Patients should be instructed never to give this medicinal product to another 
person and to return any unused capsules to the study doctor at the end of 
treatment. 


Amendment 4 dated 22 JUN 2021 
 
62
• Female patients should not donate blood during therapy and for at least 28 
days following discontinuation of study drug. 
• Male patients should not donate blood, semen or sperm during therapy or for 
at least 28 days following discontinuation of study drug. 
• Only enough study drug for one cycle of therapy may be dispensed with each 
cycle of therapy.  


Amendment 4 dated 22 JUN 2021 
 
63
APPENDIX IV: Karnofsky Performance Status (KPS) Scale 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


Amendment 4 dated 22 JUN 2021 
 
64
APPENDIX V 
 
WCMC IRB SAE Reporting Forms 
 
http://www.med.cornell.edu/research/for_pol/ins_rev_boa.html 
 


Amendment 4 dated 22 JUN 2021 
 
65
APPENDIX VI: New York State Association Classification of Cardiac Disease 
 
Class 
Functional Capacity 
Objective 
Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain. 
No objective 
evidence of 
cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence 
of minimal 
cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
Objective evidence 
of moderately severe 
cardiovascular 
disease. 
IV 
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart 
failure or the anginal syndrome may be present even at rest.  If 
any physical activity is undertaken, discomfort is increased. 
Objective evidence 
of severe 
cardiovascular 
disease. 
 
 


Amendment 4 dated 22 JUN 2021 
 
66
APPENDIX VII: P450 Substrates and Inhibitors 
 
The following table presents a list of drugs that may interfere with the metabolism of 
clarithromycin.  The drugs that are metabolized through CYP3A4 should be avoided if 
possible. If not possible use with caution.   
 
 
 


Amendment 4 dated 22 JUN 2021 
 
67
APPENDIX VIII: Example Drug Diaries  
Arm: BiRd 
Patient NAME _____________________ 
Cycle #   
REVLIMID (Lenalidomide): Take 25 mg each morning on the dates marked on calendar;          
DECADRON (Dexamethasone): Take ten 4mg pills once weekly on the dates marked on 
calendar; 
BIAXIN (Clarithromycin): Take one 500mg pill a day on the dates marked on calendar. 
ASPIRIN: Take 81mg daily on the dates marked on your calendar;  
BACTRIM (Trimethoprim/Sulfamethoxasole): Take one DS pill daily on the dates marked 
on calendar; 
PRILOSEC (Omeprazole): Take one 20mg pill once a day on the dates marked on calendar. 
Sunday 
Monday 
Tuesday 
Wednesday Thursday 
Friday 
Saturday 
 
Day 1 
mm/dd/yy 
Day 2 
mm/dd/yy 
Day 3 
mm/dd/yy 
Day 4 
mm/dd/yy 
Day 5 
mm/dd/yy 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim 
 ( ) 
Bactrim  
( ) 
Revlimid  
( ) 
Revlimid 
 ( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec 
 ( ) 
Prilosec  
( ) 
 
Decadron 
( ) 
 
 
 
 
Day 6 
mm/dd/yy 
Day 7 
mm/dd/yy 
Day 8 
mm/dd/yy 
Day 9 
mm/dd/yy 
Day 10 
mm/dd/yy 
Day 11 
mm/dd/yy 
Day 12 
mm/dd/yy 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim 
 ( ) 
Revlimid  
( ) 
Revlimid 
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid 
 ( ) 
Revlimid  
( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin 
 ( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec 
 ( ) 
Prilosec  
( ) 
 
 
Decadron 
( ) 
 
 
 
 
Day 13 
mm/dd/yy 
Day 14 
mm/dd/yy 
Day 15 
mm/dd/yy 
Day 16 
mm/dd/yy 
Day 17 
mm/dd/yy 
Day 18 
mm/dd/yy 
Day 19 
mm/dd/yy 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Revlimid  
( ) 
Revlimid 
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 


Amendment 4 dated 22 JUN 2021 
 
68
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec 
 ( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec 
 ( ) 
Prilosec  
( ) 
 
 
Decadron 
( ) 
 
 
 
 
Day 20 
mm/dd/yy 
Day 21 
mm/dd/yy 
Day 22 
mm/dd/yy 
Day 23 
mm/dd/yy 
Day 24 
mm/dd/yy 
Day 25 
mm/dd/yy 
Day 26 
mm/dd/yy 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Revlimid  
( ) 
Revlimid 
( ) 
 
 
 
 
 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Biaxin 
( )( ) 
Aspirin ( ) 
Aspirin ( ) Aspirin ( ) 
Aspirin ( ) 
Aspirin ( ) 
Aspirin ( ) 
Aspirin ( ) 
Prilosec 
 ( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
 
 
Decadron 
( ) 
 
 
 
 
Day 27 
mm/dd/yy 
Day 28* 
mm/dd/yy 
Day 1 
mm/dd/yy 
Day 2 
mm/dd/yy 
Day 3 
mm/dd/yy 
 
 
Bactrim ( ) 
Bactrim 
( ) 
 
 
 
*On Day 28:  See Dr. 
_____________ 
Bring this calendar, your 
empty medication bottles, 
and 24-hour urine 
collection to your 
appointment.  
Biaxin 
( )( ) 
Biaxin 
( )( ) 
 
 
 
Aspirin  
( ) 
Aspirin  
( ) 
 
 
 
Prilosec  
( ) 
Prilosec  
( ) 
 
 
 
 
 
 


Amendment 4 dated 22 JUN 2021 
 
69
Arm: Rd 
Patient NAME ____________________ 
Cycle # 
REVLIMID (Lenalidomide): Take 25 mg each morning on the dates marked on 
calendar;                   
DECADRON (Dexamethasone): Take ten 4mg pills once weekly on the dates 
marked on calendar;  
ASPIRIN: Take 81mg daily on the dates marked on your calendar;   
BACTRIM (Trimethoprim/Sulfamethoxasole): Take one DS pill daily on the dates 
marked on calendar;        
PRILOSEC (Omeprazole): Take one 20mg pill once a day on the dates marked on 
calendar. 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
  Day 1 
mm/dd/yy 
Day 2 
mm/dd/yy 
Day 3 
mm/dd/yy 
Day 4 
mm/dd/yy 
Day 5 
mm/dd/yy 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid 
( ) 
Revlimid 
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Prilosec  
( ) 
Prilosec 
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
 
Decadron 
( ) 
 
 
 
 
Day 6 
mm/dd/yy 
Day 7 
mm/dd/yy 
Day 8 
mm/dd/yy 
Day 9 
mm/dd/yy 
Day 10 
mm/dd/yy 
Day 11 
mm/dd/yy 
Day 12 
mm/dd/yy 
Bactrim  
( ) 
Bactrim 
 ( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Revlimid 
( ) 
Revlimid 
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid 
( ) 
Revlimid 
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin 
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec 
 ( ) 
 
 
Decadron 
( ) 
 
 
 
 
Day 13 
mm/dd/yy 
Day 14 
mm/dd/yy 
Day 15 
mm/dd/yy 
Day 16 
mm/dd/yy 
Day 17 
mm/dd/yy 
Day 18 
mm/dd/yy 
Day 19 
mm/dd/yy 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim 
 ( ) 
Bactrim  
( ) 
Bactrim 
 ( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Revlimid 
( ) 
Revlimid 
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid  
( ) 
Revlimid 
( ) 
Revlimid  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec 
 ( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
 
 
Decadron 
( ) 
 
 
 
 


Amendment 4 dated 22 JUN 2021 
 
70
Day 20 
mm/dd/yy 
Day 21 
mm/dd/yy 
Day 22 
mm/dd/yy 
Day 23 
mm/dd/yy 
Day 24 
mm/dd/yy 
Day 25 
mm/dd/yy 
Day 26 
mm/dd/yy 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Bactrim  
( ) 
Revlimid 
( ) 
Revlimid 
( ) 
 
 
 
 
 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Aspirin  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
Prilosec  
( ) 
 
 
Decadron 
( ) 
 
 
 
 
Day 27 
mm/dd/yy 
Day 28* 
mm/dd/yy 
Day 1 
mm/dd/yy 
Day 2 
mm/dd/yy 
Day 3 
mm/dd/yy 
 
 
Bactrim  
( ) 
Bactrim  
( ) 
 
 
 
*On Day 28:  See Dr. 
_____________ 
Bring this calendar, 
your empty 
medication bottles, 
and 24-hour urine 
collection to your 
appointment.  
 
 
 
 
 
Aspirin  
( ) 
Aspirin  
( ) 
 
 
 
Prilosec  
( ) 
Prilosec  
( ) 
 
 
 
 
 
 
 


Amendment 4 dated 22 JUN 2021 
 
71
APPENDIX IX: Quality of Life 
 
FACIT Fatigue Scale (Version 4) 
 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
HI7 
I feel fatigued
 ..................................................................................................  
0 
1 
2 
3 
4 
HI1
2 
I feel weak all over
 ..................................................................................................  
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”)
 ..................................................................................................  
0 
1 
2 
3 
4 
An2 
I feel tired
 ..................................................................................................  
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired
 ..................................................................................................  
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired
 ..................................................................................................  
0 
1 
2 
3 
4 
An5 
I have energy
 ..................................................................................................  
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities
 ..................................................................................................  
0 
1 
2 
3 
4 
An8 
I need to sleep during the day
 ..................................................................................................  
0 
1 
2 
3 
4 
An1
2 
I am too tired to eat
 ..................................................................................................  
0 
1 
2 
3 
4 
An1
4 
I need help doing my usual activities
 ..................................................................................................  
0 
1 
2 
3 
4 
An1
5 
I am frustrated by being too tired to do the things I want to do
 ..................................................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 


Amendment 4 dated 22 JUN 2021 
 
72
An1
6 
I have to limit my social activity because I am tired
 ..................................................................................................  
0 
1 
2 
3 
4