A Randomized, Phase III Study Comparing Conventional Dose Treatment Using a Combination of Lenalidomide, Bortezomib, and Dexamethasone (RVD) to High-Dose Treatment With Peripheral Stem Cell Transplant in the Initial Management of Myeloma in Patients Up to 65 Years of Age
Phase: PHASE3
Conditions: Multiple Myeloma
Sponsor: Paul Richardson, MD

Title: A Randomized Phase III Study Comparing Conventional Dose Treatment Using a 
Combination of Lenalidomide, Bortezomib and Dexamethasone (RVD) to High-Dose 
Treatment with Peripheral Stem Cell Transplant in the Initial Management of Myeloma in 
Patients up to 65 Years of Age. 
 
NCT Number: NCT01208662 
 
IRB Approval Date: 07/12/2023 

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Agent(s):
Lenalidomide - Celgene Corporation
Bortezomib - Millennium Pharmaceuticals, Inc.and commercially available
Dexamethasone – commercially available 
Melphalan – commercially available 
Cyclophosphamide – commercially available 
Filgrastim – commercially available

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SCHEMA
REGISTRATION
Initial Therapy:
Lenalidomide+bortezomib+dexamethasone (RVD):
1 cycle (21 days)
 
 
RANDOMIZATION 
Stratify according to:
ƒ
ISS stage (stage I, II, or III)
ƒ
Cytogenetics: standard vs. high-risk vs. FISH failures. High-risk is defined as
presence of del(17p), or t(4:14), or t(14;16) using FISH.
Arm A:
Arm B:
ƒ
RVD q 21 days (2 cycles)
ƒ
Collection of peripheral blood 
stem cells (PBSCs) using 
cyclophosphamide and filgrastim 
or G-CSF type Granocyte® or 
equivalent
ƒ
RVD q 21 days (5 cycles)
ƒ
Maintenance Lenalidomide q28 
days (until disesase progression)
ƒ
RVD q 21 days (2 cycles)
 
ƒ
Collection of peripheral blood
stem cells (PBSCs) using 
cyclophosphamide and filgrastim 
or G-CSF type Granocyte® or
equivalent
 
ƒ
Autologous stem cell transplant:
o
Melphalan: Can use original 
formulation or new 
formulation (Evomela)
o
Re-infusion of PBSCs
 
ƒ
RVD q 21 days (2 cycles)
 
ƒ
Maintenance Lenalidomide q28
days (until disease progression)

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:   November 30, 2016
 Abbreviations List 
     
 
 
 
Abbreviation
 
Definition
qC
 
degrees Celsius
PM
 
micromolar
20S
 
20S proteasome subunit
AE
 
adverse event
AIBW
 
adjusted ideal body weight
ALT
 
alanine aminotransferase
ANC
 
absolute neutrophil count
AST
 
aspartate aminotransferase
Bc1-2
 
B-cell lymphoma-2; a gene that inhibits apoptosis
BM
 
Bone marrow
BMT
 
Bone marrow transplant
BSA
 
body surface area
BUN
 
Blood urea nitrogen
CAM
 
cell adhesion molecules
CBC
 
Complete blood count
Cm
 
Centimeter
CR
 
Complete Response
CRF
 
Case report form
CRO
 
Contact research organization
CRP
 
C-reactive protein
CTCAE
 
(NCI) Common Terminology Criteria for Adverse Events
CTEP
 
Cancer Therapy Evaluation Program
CV
 
cardiovascular
DAR
 
Drug accountability record
DLCO
 
Diffuse lung capacity
dL
 
deciliter
DLT
 
Dose Limiting Toxicity
DNA
 
deoxyribonucleic acid
DMC
 
Data Monitoring Committee
DVT
 
Deep vein thrombosis
EBMT
 
European Group for Blood & Marrow Transplant

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:   November 30, 2016
ECG
 
Electrocardiography
ECHO
Echocardiogram
                    EORTC-QLQ
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire
FACT/GOG-
NTX
        Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-      
Neurotoxicity
FDA
Food and Drug Administration
FLC
Free light chain
GCP
Good Clinical Practice
G-CSF
Granulocyte colony stimulating factor
GEP
Gene expression profiling 
GGT
Gamma glutamyltransferase 
GI
Gastrointestinal
GLP
Good Laboratory Practice
HDT
High-dose therapy
HR            
Hazard ratio 
ht
 Height
INB
 I kappa B kinase; cytokine response kinase that activates transcription factor NF-
kappa b at serine 32 and 36
ICAM-1
intercellular adhesion molecule 1
ICH
International Conference on Harmonization
IL-6
Interleukin-6
IND
Investigational New Drug 
IRB
Institutional Review Board 
ISS
International Staging 
System IV
intravenous
INBD
I kappa B alpha-associated protein kinase 
kg
kilogram
Ki
inhibitory constant 
lbs
pounds
LDH
Lactate dehydrogenase
LVEF
Left ventricular ejection fraction 
m2
square meters
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligrams
MM
Multiple myeloma
MR
Minimal response
MRI
Magnetic resonance imaging 

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:   November 30, 2016
MTD
 Maximum tolerated dose 
MUGA
 Multi-gated acquisition scan 
NCI
 National Cancer Institute 
nCR
 near complete response
NF-NB
nuclear factor-NB
Ng                           nanogram 
nM                           nanomole
NYHA
New York Heart Association
OS
Overall survival
p21
p21(ras) farnesyl-protein transferase p27cyclin-dependent kinase inhibitor
p53
tumor suppressor protein with molecular weight of 53 kDa
PBSC
Peripheral blood stem cells
PBSCT
Peripheral blood stem cell transplant
PD
Progressive disease
PE
Pulmonary embolism
PFS
Progression-free survival 
PFT
Pulmonary function test 
PK
pharmacokinetics
PR
Partial response
QACT
Quality Assurance for Clinical Trials
QOL
Quality of life
RR
Response rate
SAE
serious adverse event
SD
Stable disease
SGOT
serum glutamic oxaloacetic transaminase SGPT
 serum glutamic pyruvic 
transaminase 
SPEP
 serum protein electrophoresis

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:   November 30, 2016
Abbreviation
Definition
SUSAR
Suspected unexpected serious adverse event
TTP
Time-to-progression
US
United States
USP
United States Pharmacopeia 
UPEP
Urine protein electrophoresis 
UTI
Urinary tract infection
VCAM-1
vascular cell adhesion molecule 1
VGPR
Very good partial response
WBC
White blood cells
w/w
weight-to-weight ratio
WWDSS
 Worldwide Drug Safety Surveillance 
wt
Weight

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:      November 30, 2016
 
SYNOPSIS
Title
 
A Randomized Phase III study Comparing Conventional Dose
Treatment Using a Combination of Lenalidomide, Bortezomib and 
Dexamethasone (RVD) to High-Dose Treatment with Peripheral Stem 
Cell Transplant in the Initial Management of Myeloma in Patients up 
to 65 Years of Age.
Number of Centers 60
Rationale
 
Treatment Regimen Rationale: For fifteen years, high-dose therapy
(HDT) has been the standard treatment for multiple myeloma (MM) in 
younger patients. In the 1990s, several randomized studies 
demonstrated the superiority of high-dose treatments versus 
conventional chemotherapies in terms of response (Attal et al., 1996; 
Child et al., 2003; Palumbo et al., 2004; Fermand et al., 1998; Blade
et al., 2005), event-free survival (Attal et al., 1996; Child et al., 2003; 
Palumbo et al., 2004; Fermand et al., 1998; Blade et al., 2005) and 
overall survival (OS) (Attal et al., 1996; Child et al., 2003; Palumbo et 
al., 2004). The superiority of HDT over conventional-dose therapy is 
related to obtaining a higher rate of very good partial response
(VGPR) or better, which in turn is correlated with longer PFS, but 
only in some studies with OS (Attal et al., 2007). Indeed, a recent 
meta-analysis by Koreth and colleagues demonstrated PFS and no OS 
advantage (Koreth et al., 2007).
 
For the last 4-5 years, the arrival of novel therapies (thalidomide,
bortezomib and lenalidomide) has revolutionized conventional 
therapeutic regimens. The use of these new therapies has improved 
complete response (CR) and VGPR rates of HDT as well as those of 
conventional-dose therapy, to such a point that these rates have now 
become similar in both groups of treatment. Thus, the arrival of novel 
therapies has brought into question the necessity of HDT as first-line 
therapy in young patients (Attal et al., 2007; Attal et al., 2007).
 
The aim of the protocol is, therefore, to compare the results (in terms of
efficacy, quality of life and cost) of HDT to those of conventional- 
dose treatment, with both treatment arms receiving novel drugs as part 
of induction, consolidation and maintenance.
 
Rationale for the Conventional-Dose Arm (Arm A):
 
Choice of treatment: Since the 1960s, the combination of melphalan +
prednisone (MP) was the standard conventional-dose treatment for
myeloma. Therefore, it was logical to evaluate new drugs in combination
with MP. For the last 2 to 3 years, the combinations MP + thalidomide,
MP  +  bortezomib, or  MP  +  lenalidomide have become or  are  in  the

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:      November 30, 2016
 
process of becoming new standards for the induction treatment of elderly 
patients (Palumbo et al., 2006; Facon et al., 2007; San Miguel et al., 2008; 
Palumbo et al., 2007). Other researchers, seeking to avoid the use of 
alkylating agents in induction treatment, have successfully evaluated 
combinations of dexamethasone and lenalidomide (Rajkumar et al., 2007). 
All of these new strategies have generated promising results, with PR rates 
between 70 and 80%, rates of VGPR between 42 and 50% and durations 
of response of approximately 24 months. However, these results remain 
greatly inferior to the results that are expected for the new high-dose 
strategies with more than 90% PR, including up to 80% VGPR (Attal et 
al., 2007). The only conventional-dose treatment that rivals these high- 
dose results is RVD, developed by the DFCI team, with 100% PR and
74%  VGPR  (Richardson  et  al.,  2007;  Richardson  et  al.,  2008).  It  is 
therefore logical to select RVD for the conventional-dose arm in this 
protocol.
Maintenance  therapy:  Maintenance therapy  used  in  the  conventional- 
dose arm will be identical to that of the high-dose arm. Maintenance with 
lenalidomide (based on the results of the IFM 2005 study) will be used in 
an identical manner in both the high-dose and conventional-dose arms.
Treatment for relapse: To avoid penalizing (in terms of overall survival) 
patients in arm A, who will not receive a transplant in first-line treatment, 
the recommended treatment for relapse will be the use of high-dose 
melphalan with autologous peripheral blood stem cell transplant (PBSCT). A  
study  conducted  by  Fermand  et.  al  demonstrated  that  the  overall 
survival of participants who receive transplant as first-line therapy is 
identical to overall survival of those who receive it as treatment for relapse 
(Fermand et al., 1998). Stem cells will, therefore, be collected from all 
participants after three cycles of RVD and used to support HDT/PBSCT in 
case of relapse for the conventional-dose participants, and after successful 
salvage therapy.
Rationale for HDT Arm (Arm B):
Induction:   The combination   of   dexamethasone, adriamycin   and 
vincristine (VAD regimen) was the standard induction regimen for a long 
time, although rates of response after VAD were mediocre: 75% PR (PR =
50% reduction in monoclonal component), including only 10% VGPR 
(VGPR = at least 90% reduction in monoclonal component) (Harousseau 
et al., 2007). Several randomized studies have recently demonstrated 
that the combination of dexamethasone and one of the new molecules, 
bortezomib (Harousseau et al., 2007) or thalidomide (Macro et al., 2006) 
made it possible to improve pre-transplant response rates. An Italian 
randomized study showed that the combination of dexamethasone, 
bortezomib and  thalidomide  made  it  possible  to  achieve  still  greater

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:      November 30, 2016
 
improvement  in  the results of  induction,  obtaining  93%  PR  with 60%
VGPR (Cavo et al., 2007). Finally, a multi-center study led by DFCI, in
Boston,  MA,  has demonstrated  that  the  combination  of  lenalidomide,
bortezomib and dexamethasone (the so-called RVD regimen) has obtained
100% PR with 74% VGPR, with excellent tolerability (Richardson et al.,
2007; Richardson et al., 2008). This regimen is currently the most promising 
current approach to induction, and will therefore be used in this protocol.
Collection of autologous peripheral blood stem cells: After conventional
induction  using  VAD, mobilization  of  autologous  peripheral blood stem
cells (PBSC) has been performed by G-CSF alone. However, several studies 
that used lenalidomide as induction treatment suggest that mobilization by 
cyclophosphamide and G-CSF is preferable (Kumar et al.,
2007). This combined mobilization will be used in this protocol.
High-dose  therapy: The standard  conditioning  treatment  is high-dose
melphalan  followed  by autologous  peripheral  blood  stem  cell transplant
(PBSCT) ( Moreau e t  a l ., 2 0 0 2 ).   It has recently been r e p o r t e d  t h a t 
combined conditioning using melphalan and bortezomib made it possible to 
improve post-transplant response rates (Roussel et al., 2008). However, this
improvement  was  mainly  found  in  patients  not  receiving  bortezomib as
induction  treatment. Since bortezomib  will  be  used  in  induction  and  in
consolidation in this protocol, transplant conditioning will use melphalan
alone in order to reduce risks of neuropathy in this treatment arm.
Post-transplant
post-transplant
consolidation: Ladetto and colleagues have reported that 
consolidation
using
the
combination
of
bortezomib,
thalidomide and dexamethasone made it possible to convert 22% of VGPR
into full, lasting molecular responses (PCR-) (Ladetto et al., 2007). In the
IFM   2008   pilot study,   the   usefulness   and   safety   of post-transplant
consolidation with  two cycles  of  the  RVD  combination is  being  tested.
Based on the assumption that the results of this pilot study are satisfactory in
terms  of  response  and safety,  two  cycles  of  RVD  has  been  chosen for
consolidation in this protocol.
Post-transplant maintenance therapy: Results from a study by the 

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:      November 30, 2016
 
Intergroupe Francophone du Myélome have demonstrated that post- 
transplant maintenance treatment with thalidomide made it possible to reduce 
tumor mass, prolong duration of response and improve survival (Attal et al., 
2006). This result was recently confirmed by Spencer and colleagues 
(Spencer et al., 2007). However, the neurological toxicity of thalidomide is 
limiting with 68% neuropathy reported in the French study (Attal et al., 
2006). The usefulness of lenalidomide (a thalidomide analogue with 
markedly reduced neurotoxicity) is currently being tested by the IFM  

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:     November 30, 2016
 
with promising results to date (IFM 2005-02 protocol: 614patients,
enrollment completed on August 14, 2008, first interim analysis
on January 4, 2010: PFS superiority of the lenalidomide maintenance arm, 
p<10-6). Based on the assumption that the results of this trial remain 
satisfactory, lenalidomide has been chosen as maintenance therapy in this 
protocol.
Study design
 
 Phase III, multicenter, randomized, open-label study designed to evaluate
the clinical benefit from the drug combination RVD without immediate 
high-dose therapy (HDT) followed by lenalidomide maintenance (Arm A) 
versus RVD plus HDT and PBSCT followed by lenalidomide maintenance 
(Arm B).
Objectives
To achieve the objectives of this study, data from this trial and a parallel 
trial in France will be combined together for analysis. To determine if, in 
the era of novel drugs, HDT is still necessary in the initial management of 
multiple myeloma in younger patients. HDT as compared to conventional
dose treatment would be considered superior if it significantly prolongs
progression-free survival (by at least 9 months).
 
Primary objective: To compare progression-free survival (PFS) between
the Arm A and Arm B.
 
Secondary objectives:
x
To compare the response rates (RR) between the two arms
x
To compare time to progression (TTP) between the two arms
x
To compare the overall survival (OS) between the two arms
x
To compare toxicity between the two arms
x
To define genetic prognostic groups evaluated by gene expression 
profiling (GEP)
x
To examine the best treatment in each GEP-defined prognostic 
group.
x
To compare quality of life (QOL) between the two arms
x
To collect medical resource utilization (MRU) information which 
may be used in economic evaluation models
Determination of
the number of 
patients
To achieve the objectives of this study, data from this trial and a parallel
trial in France  will  be  combined  together  for  analysis.  The  primary 
objective of the study is to determine whether high-dose therapy with 
PBSCT (HDT/PBSCT) plus novel therapy is able to prolong progression- 
free  compared  to  novel  therapy  alone.  The  median  progression-free 
survival in the RVD arm is estimated to be 30 months. The intent-to-treat 
analysis of PFS will be performed using a stratified two-sided log-rank test 
with an overall type I error rate of 5%. The US study has been modified to

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:      November 30, 2016
 
 
allow for maintenance until progression based on recent literature and the
IFM sites will remain at 1 year of maintenance therapy. Therefore, the study 
has been modified to enroll 700 randomized patients from the IFM sites and 720 
randomized patients from the US sites. The US study will have 90% power to 
detect at least a 30% reduction in the hazards. . Interim analysis of PFS will be 
performed at 33% and 69% information with full information defined as 329 
failures. The study will be monitored for early stopping using repeated confidence 
intervals
Study 
duration
x
Planned 3 years of accrual and 3 years of follow-up
x
Inclusion period: Until time of disease progression
x
Follow-up period: Patients will be followed for survival
Study Entry
Criteria
Inclusion Criteria for Registration:
(Laboratory  assessments  must  be  performed  within  21  days  of 
initiation of protocol therapy unless otherwise noted; Bone marrow biopsy, 
skeletal survey, MRI, CT scans, and chest X-ray must be performed within 35 
days of initiation of protocol therapy)
 
-    Patients  diagnosed  with  multiple  myeloma  based  on  International
Myeloma Foundation 2003 Diagnostic Criteria.
According to these criteria, 
the following must be met.
o
Monoclonal plasma cells in the bone marrow   ≥  10%  (or proven  
plasmocytic  infiltration  in  bone  marrow  biopsy) and/or presence 
of a biopsy-proven plasmacytoma (within 35 days)
o
Monoclonal protein (M-protein) present in the serum and/or urine 
(within 21 days).
o
Myeloma-related  organ  dysfunction  (1  or  more)  of  the 
following.
A   variety   of   other   types   of   end-organ 
dysfunctions can occasionally occur and lead to a need for therapy. 
Note: Laboratory assessments used to support the CRAB criteria in 
the IMF 2003 Diagnostic Criteria of MM
are performed at the time of diagnosis.   These assessments are not 
required to be performed within the 21 days of initiation of protocol 
therapy These include:
[C]  Calcium  elevation  in  the  blood,  defined  as serum  
calcium  >  10.5  mg/dl  or  upper  limit  of
                               normal
[R] Renal insufficiency (defined as serum creatinine above 
normal).
[A] Anemia, defined as hemoglobin <10 g/dl or 2 g
                              < normal).
[B] Lytic bone lesions or osteoporosis. If a solitary (biopsy-
proven) plasmacytoma or osteoporosis alone (without   fractures) 
are   the   sole   defining criteria, then  > 30% plasma cells are 
required in the bone marrow or proven plasmocytic  infiltration 
in smoldering or indolent myeloma, but can also include 
symptomatic disease.

    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:      November 30, 2016
This document is confidential. Do not disclose or use except as authorized.
-
Patients must have symptomatic myeloma with myeloma-related organ 
damage as defined above with  laboratory  assessments
-
Patients must have myeloma that is  measurable by  either serum or 
urine evaluation of the monoclonal component or by assay of serum 
free light chains.  Measurable disease is defined as one or more of the 
following: serum M-protein > 1 g/dl (except for patients with IgD or 
IgA myeloma – please see below), urine M-protein > 200 mg/24h, 
and/or serum
FLC    assay:    involved    FLC    level    >    10    mg/dl    
with abnormal serum FLC ratio.  For patients with IgD or IgA 
myeloma, a serum M-protein of greater than or equal to 0.5 g/dl will 
suffice. Seurm free light  chain  patients  not  measurable  by  adequate  
urine  or  serum M protein evaluation may be considered for inclusion.
-
Age  between 18  and 65  years at the time of  signing the informed 
consent document.
-
ECOG performance status <2 (Karnofsky  > 60%, see Appendix III)
-
Negative  HIV  blood  test  within  21  days  of  initiation  of  protocol 
therapy.
HIV-positive   individuals   on   combination   antiretroviral 
therapy are ineligible because of the potential for pharmacokinetic 
interactions with lenalidomide, bortezomib and/or dexamethasone. In 
addition, these individuals are at increased risk of lethal infections 
when treated with marrow-suppressive therapy.
-
All study participants must be registered into the mandatory Revlimid 
REMS® program, and be willing and able to comply with the 
requirements of the REMS® program.
-
Females  of  childbearing  potential*  must  have  a  negative  serum  or 
urine pregnancy test with a sensitivity of at least 50 mlU/ml 10 to 14 
days prior to therapy and repeated again within 24 hours prior to 
prescribing lenalidomide for Cycle 1 (prescriptions must be filled within
7 days as required by Revlimid REMS®) 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.
* A female of childbearing potential is a sexually mature female who: 1) has not 
undergone a hysterectomy (the surgical removal of the uterus) or bilateral 
oophorectomy (the surgical removal of both ovaries) 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 during the preceding 24 consecutive months)
-
Females o f  r e p r o d u c t i v e   potential  must  adhere  to  the  
scheduled pregnancy testing as required in the Revlimid REMS® 
program.
-
Men must agree to use a latex condom during sexual contact with a

    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:      November 30, 2016
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female of childbearing potential even if they have had a successful 
pregnancy precautions and risks of fetal exposure. See Appendix II: 
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods.
-
Ability to  understand  and  willingness  to  sign  a  written  informed
consent document.  Voluntary written consent must be obtained before 
performance of any study-related procedure not part of normal medical 
care, with the understanding that consent may be withdrawn by the 
participant at any time without prejudice to future medical care.
Exclusion Criteria for Registration:
-
Participants  treated  with  any prior systemic  therapy.  Treatment  by 
localized radiotherapy is not an exclusion criterion if an interval of at
least 7 days between the end of radiotherapy and initiation of protocol
therapy is observed.  Intervals of less than 7 days between radiotherapy 
and initiation of protocol therapy will be considered on a case by case 
basis with the lead PI, provided toxicity is not a concern. Similarly, the 
dose of corticosteroids for the treatment of their myeloma received by 
the participant should not exceed the equivalent of 160 mg of 
dexamethasone over a two-week period before initiation of protocol 
therapy.
-
Primary amyloidosis (AL) or myeloma complicated by amylosis.
-
Participants receiving any other investigational agents.
-
Participants with known brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often 
develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events.
-
Poor  tolerability  or  known  allergy  to  any  of  the  study  drugs  or 
compounds  of  similar  chemical  or  biologic  composition  to 
lenalidomide, bortezomib and/or dexamethasone.
-
Platelet count < 50,000/mm3  within 21 days of initiation of protocol 
therapy for patients in whom <50% of bone marrow nucleated cells 
are  plasma  cells;  or  platelet  count  <30,000/mm3   for  patients  in 
whom >50% of bone marrow nucleated cells are plasma cells. 
Transfusion within 7 days of screening  is not allowed to meet platelet 
eligibility criteria.
-
ANC  <  1,000  cells/mm3   within  21  days  of  initiation  of  protocol 
therapy.   Growth factor within 7 days of screening  is not allowed to 
meet ANC eligibility criteria.
-
Hemoglobin < 8 g/dL within 21 days of initiation of protocol therapy.
Transfusion may be used to meet hemoglobin eligibility criteria.
-
Hepatic impairment, defined as bilirubin > 1.5 x institutional upper 
limit of normal (ULN) (Patients with benign hyperbilirubinemia (e.g., 
Gilbert’s syndrome) are eligible) or AST (SGOT), or ALT (SGPT), or 
alkaline  phosphatase  >  2  x  ULN,  within  21  days  of  initiation  of 
protocol therapy.
Renal insufficiency at  the  time  of  screening,  defined  as  serum 

    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:      November 30, 2016
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creatinine >  2.0  mg/dl  or  creatinine clearance <  50  ml/min  (either
actual or calculated), within  7  days of initiation of protocol therapy. 
Creatinine clearance will be the primary eligibility criteria in determining 
renal insufficiency.  The Cockgroft-Gault formula should be used for 
calculating creatinine clearance values, and may be located in Section 
3.2.10.
-
Respiratory compromise, defined as ventilation tests with DLCO <
50%.
-
Participant with clinical signs of heart or coronary failure, or evidence 
of LVEF < 40%.
-
Participant  with  myocardial  infarction  within  6  months  prior  to 
enrollment or have New York Heart Association (NYHA) Class III or 
IV heart failure (See Appendix V), uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, or electrocardiographic evidence 
of acute ischemia or active conduction system abnormalities.  Prior to 
study entry, any ECG abnormality at screening has to be documented 
by the investigator as not medically relevant.
-
Intercurrent  illness  including,  but  not  limited  to  ongoing  or  active 
severe infection, known infection with hepatitis B or C virus, poorly 
controlled diabetes,   severe   uncontrolled   psychiatric   disorder   or 
psychiatric illness/social situations that would limit compliance with 
study requirements.  For patients with a positive hepatitis B antibody 
result, but no signs of active infection, participating sites must contact 
the study PI for approval.
-
Participants with previous history of another malignant condition are 
excluded,  except  for  localized  cancers  that  have  been  adequately 
treated. This includes completely resected basal cell carcinoma or 
squamous cell carcinoma of the skin, in situ malignancy (e.g. DCIS of 
the breast), good risk prostate cancer after curative therapy and/or 
considered appropriate for watchful waiting (e.g. Gleason 6 or less, T2 
or less and PSA< 10) , and stage I cervical cancer. If invasive malignancy 
was experienced 2 or more years ago and confirmed as cured, these 
participants may be considered for the study on case by case basis with 
PI discussion and approval.
-
Female participant who is pregnant or breast-feeding. Pregnant women 
are
excluded    from    this    study    because    lenalidomide    is    an 
immunomodulatory agent with the potential for teratogenic or 
abortifacient effects.   Because there is an unknown but potential risk 
for adverse events in nursing infants secondary to treatment of the mother 
with lenalidomide, breastfeeding should be discontinued if the mother 
is treated with lenalidomide. These potential risks  may also apply to 
other agents used in this study.  Lactating females must agree not to 
breast feed while taking lenalidomide.
-
Inability to comply with an anti-thrombotic treatment regimen (e.g., 
administration of aspirin, enoxaparin, or low molecular weight heparin 
administration (type Innohep® or equivalent)

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-
Peripheral neuropathy • Grade 2 on clinical examination, within 21
days of initiation of protocol therapy.
 
Inclusion and Exclusion Criteria for Randomization
After registration and prior to randomization, participants will receive one 
cycle of RVD.   Participants are not required to meet additional eligibility
or exclusion criteria prior to randomization procedures.
 
Participants must have completed testing for the following randomization
factors:
ƒ
ISS disease stage (stage I, II, or III)
ƒ
Cytogenetics: standard vs. high-risk vs. FISH failures. High-risk is
defined as presence of del(17p), or t(4:14), or t(14;16) using FISH.
ƒ
Country (IFM vs. U.S. center)
Treatment plan
Initial Therapy with 1 cycle of RVD:
x
This cycle will last 21 days
x
Participants will receive 1 cycle of RVD
x
This cycle consists of:
o Lenalidomide: Days 1 to 14
o Bortezomib: Days 1, 4, 8, and 11
o Dexamethasone: Days 1, 2, 4, 5, 8, 9, 11 and 12
x
The following supportive care is required: aspirin, enoxaparin or 
low molecular weight heparin (type Innohep®) or equivalent; 
acyclovir or valaciclovir or equivalent, bisphosphonates (Zometa® 
or equivalent).
x
The following additional medications are strongly recommended: 
sulfamethoxazole and trimethoprim or equivalent; and amoxicillin 
or equivalent.
x
Erythropoietin is allowed
 
Arm A:
 
RVD Therapy: Cycles 2-3
x
Each cycle will last 21 days
x
Participant will receive 2 additional cycles of RVD
x
This cycle consists of:
o Lenalidomide: Days 1 to 14
o Bortezomib: Days 1, 4, 8, and 11
o Dexamethasone: Days 1, 2, 4, 5, 8, 9, 11 and 12
x
The following supportive care is required: aspirin, enoxaparin or 
low molecular weight heparin (type Innohep®) or equivalent; 
acyclovir or valaciclovir or equivalent, bisphosphonates (Zometa® 
or equivalent).
x
The following additional medications are strongly recommended: 
sulfamethoxazole and trimethoprim or equivalent; and amoxicillin 
or equivalent.

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x
Erythropoietin is allowed
PBSC Collection
x
Performed 21 + 7 days after the last dose of lenalidomide in cycle
3 of initial RVD therapy
x
On cyclophosphamide and filgrastim or G-CSF type Granocyte®
or equivalent.
x
• 5 x 106 CD34 cells/kg will be collected.
Consolidation Therapy with RVD: Cycles 4-8
x
Five cycles of RVD will be administered as consolidation therapy
x
Treatment schedule will be identical to that of initial treatment 
except for dexamethasone with reduced dose
x
The following supportive care is required: aspirin, enoxaparin or 
low molecular weight heparin (type Innohep®) or equivalent; 
acyclovir or valaciclovir or equivalent, bisphosphonates (Zometa® 
or equivalent).
x
The following additional medications are strongly recommended: 
sulfamethoxazole and trimethoprim or equivalent; and amoxicillin 
or equivalent.
x
Erythropoietin is allowed
Maintenance therapy
x
Maintenance therapy with lenalidomide will be initiated following 
consolidation therapy.
x
Lenalidomide will be initiated at a low dose for 3 months, after 
which dose escalation may occur if initial dose well tolerated.
x
Maintenance therapy will be continued until disease progression.
x
Bisphosphonates (Zometa ® or equivalent) and erthyropoietin are 
permitted and can be administered according to institutional 
practice.
Recommended treatment of relapse (Please note that no exclusion (wash- 
out) period is applied to this group)
x
Induction will vary according to the initial response and the time of 
relapse/progression – bortezomib-based therapy is recommended.
x
PBSCT conditioned by high-dose melphalan is recommended
x
The following is recommended: melphalan administered over 2 
consecutive days on Day minus 2 and Day minus 1, or as a single 
dose on Day minus 2, according to institutional practice.
Arm B:
RVD Therapy: Cycles 2-3:
x
Each cycle will last 21 days
x
Participant will receive 2 additional cycles of RVD

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x
This cycle consists of:
o Lenalidomide: Days 1 to 14
o Bortezomib: Days 1, 4, 8, and 11
o Dexamethasone: Days 1, 2, 4, 5, 8, 9, 11 and 12
x
The following supportive care is required: aspirin, enoxaparin or 
low molecular weight heparin (type Innohep®) or equivalent; 
acyclovir or valaciclovir or equivalent, bisphosphonates (Zometa® 
or equivalent).
x
The following additional medications are strongly recommended: 
sulfamethoxazole and trimethoprim or equivalent; and amoxicillin 
or equivalent.
x
Erythropoietin is allowed
PBSC Collection
x
Performed 21 + 7 days after the last dose of lenalidomide in cycle
3 of initial RVD therapy
x
On cyclophosphamide and filgrastim or G-CSF type Granocyte®
or equivalent.
x
• 5 x 106 CD34 cells/kg will be collected.
PBSC Transplant
x
Conditioning: melphalan as a divided dose on Day minus 2 and 
Day minus 1, or as a single dose on Day minus 2, according to 
institutional practice if using the original formulation.  If using 
Evomela, recommended on 2consecutive days (Day minus 3 
and Day minus 2), according to institutional practice 
x
Reinfusion of PBSC on Day 0
x
Filgrastim will be administered starting on Day +5 and continuing 
until engraftment, or G-CSF type Neulasta® or equivalent will be 
administered on Day +2 post PBSCT or as per institutional 
practice.
Consolidation Therapy with RVD for 2 cycles: Cycles 4 and 5
x
Two cycles of RVD will be administered as consolidation therapy
x
Treatment schedule will be identical to that of initial treatment 
except for dexamethasone with reduced dose.
x
The following supportive care is required: aspirin, enoxaparin or 
low molecular weight heparin (type Innohep®) or equivalent; 
acyclovir or valaciclovir or equivalent, bisphosphonates (Zometa® 
or equivalent).
x
The following additional medications are strongly recommended: 
sulfamethoxazole and trimethoprim or equivalent; and amoxicillin 
or equivalent.
x
Erythropoietin is allowed

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Maintenance therapy
x
Maintenance therapy with lenalidomide will be initiated 
followingconsolidation therapy.
x
Lenalidomide will be initiated at a low dose for 3 months, after 
which dose escalation may occur if initial dose is well tolerated.
x
Maintenance therapy will be continued until disease progression.
x
Bisphosphonates (Zometa ® or equivalent) and erythropoietin are 
permitted and can be administered according to institutional 
practice.

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TABLE OF CONTENTS
1.
OBJECTIVES ..................................................................................................................................................21
1.1
Study Design .............................................................................................................................................21
1.2
Primary Objectives ...................................................................................................................................21
1.3
Secondary Objectives ...............................................................................................................................21
2.
BACKGROUND ..............................................................................................................................................22
2.1
Study Agents .............................................................................................................................................22
2.2
Study Disease: Multiple Myeloma ............................................................................................................37
2.3
Treatment Regimen Rationale ..................................................................................................................38
2.4
Correlative Studies Background...............................................................................................................42
3.
PARTICIPANT SELECTION........................................................................................................................43
3.1
Inclusion Criteria for Registration ...........................................................................................................43
3.2
Exclusion Criteria for Registration ..........................................................................................................45
3.3
Inclusion and Exclusion Criteria for Randomization ...............................................................................47
3.4
Inclusion of Women, Minorities and Other Underrepresented Populations ............................................47
3.5
Screening Procedures...............................................................................................................................47
4.
REGISTRATION PROCEDURES ................................................................................................................49
4.1
General Registration Guidelines for All Institutions ................................................................................49
4.2
Registration Process for DF/HCC Institutions.........................................................................................50
4.3
Registration Process for Other Participating Institutions ........................................................................51
4.4
General Randomization Guidelines for All Institutions............................................................................52
4.5
Randomization Process for DF/HCC Institutions ....................................................................................52
4.6
Randomization Process for Other Participating Institutions ...................................................................53
5.
TREATMENT PLAN ......................................................................................................................................54
5.1
Pre-treatment Criteria ..............................................................................................................................60
5 .2
Agent Administration ..............................................................................................................................62
5.3
Definition of Dose-Limiting Toxicity .....................................................................................................71
5.4
General Concomitant Medication and Supportive Care Guidelines ........................................................71
5.5
Duration of Therapy/Criteria for early treatment discontinuation ..........................................................73
5.6
Criteria for Removal from Study ..............................................................................................................73

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5.7
Duration of Follow Up .............................................................................................................................74
5.8
Recommended Treatment for Relapse……………………………………………………………………………74
6.
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS....................................75
6.1
Anticipated Toxicities/Adverse Events......................................................................................................75
6.2
Hematologic Toxicity Management ..........................................................................................................83
6.3
Dose Modifications/Delays.......................................................................................................................83
7.
DRUG FORMULATION AND ADMINISTRATION .................................................................................89
 
7.1
Lenalidomide (REVLIMID®) ...................................................................................................................89
 
7.2
Bortezomib (VELCADE®)........................................................................................................................92
 
7.3
Dexamethasone.........................................................................................................................................95
 
7.4
Cyclophosphamide (Cytoxan®)................................................................................................................97
 
7.5
Melphalan.............................................................................................................................99
8.
CORRELATIVE/SPECIAL STUDIES........................................................................................................102
8.1
Proposed Study .......................................................................................................................................102
8.2
Bone Marrow Aspirate Samples .............................................................................................................103
8.3
Peripheral Blood Samples ......................................................................................................................104
9.
STUDY CALENDAR ....................................................................................................................................106
10.
MEASUREMENT OF EFFECT...................................................................................................................111
10.1
Antitumor Effect– Solid Tumors .............................................................................................................111
10.2
Antitumor Effect – Hematologic Tumors ................................................................................................111
10.3
Other Response Parameters ...................................................................................................................116
11.
ADVERSE EVENT REPORTING REQUIREMENTS ........................................................................118
11.1
Definitions ..............................................................................................................................................119
11.2
Adverse Event Recording and Reporting ................................................................................................124
11.3
Reporting Requirements .........................................................................................................................125
11.4
Reporting to the Study Sponsor ..............................................................................................................125
11.5
Reporting to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).....................126
11.6
Reporting to the Food and Drug Administration (FDA) ........................................................................127
11.7
Reporting to the NIH Office of Biotechnology Activities (OBA).............................................................127
11.8
Reporting to the Institutional Biosafety Committee (IBC)......................................................................127
11.9
Reporting to Hospital Risk Management................................................................................................127
11.10
Monitoring of Adverse Events and Period of Observation .....................................................................127
12.
DATA AND SAFETY MONITORING ...................................................................................................128
12.1
Data Reporting .......................................................................................................................................128
12.2
Data Monitoring Committee (DMC) Meetings.......................................................................................129

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12.3
Monitoring ..............................................................................................................................................129
12.4
Audit and Inspection ...............................................................................................................................130
12.5
Drug Accountability ...............................................................................................................................131
13.
REGULATORY CONSIDERATIONS ...................................................................................................131
13.1
Protocol Review and Amendments .........................................................................................................131
13.2
Informed Consent ...................................................................................................................................132
13.3
Ethics and Good Clinical Practice (GCP) .............................................................................................132
13.4
Study Documentation..............................................................................................................................133
13.5
Records Retention...................................................................................................................................133
13.6
Multi-center Guidelines ..........................................................................................................................133
13.7
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA)........133
13.8
Investigator Responsibilities...................................................................................................................134
14.
STATISTICAL CONSIDERATIONS .....................................................................................................134
14.1
Study Objectives/Endpoints and Stratification Factors ..........................................................................134
14.2
Statistical Consideration for the Primary Objective ..............................................................................135
14.3
Analysis of Secondary Endpoints............................................................................................................136
14.4
Toxicity ...................................................................................................................................................137
14.5
QOL Evaluations ....................................................................................................................................137
14.6
Pharmacoeconomics...............................................................................................................................138
14.7
Additional Analysis Information.............................................................................................................138
14.8
Correlative Studies .................................................................................................................................138
14.9
Study Monitoring ....................................................................................................................................138
14.10
Reporting and Exclusions .......................................................................................................................139
15.
PUBLICATION PLAN .............................................................................................................................139
16.
REFERENCES ..........................................................................................................................................139
17.
APPENDICES ...........................................................................................................................................147
Appendix I:  Lenalidomide Information Sheet ......................................................................................................151
Appendix II:  Lenalidomide Risks of Fetal Exposure, Pregnancy testing Guidelines and Acceptable Birth Control
Methods.................................................................................................................................................................153
Appendix III: Performance Status Criteria ..........................................................................................................157
Appendix IV: DuBois Formula for Body Surface Area ........................................................................................158
Appendix V:  The New York Heart Association Classification of Cardiac Disease..............................................159
Appendix VI: Declaration of Helsinki..................................................................................................................160
Appendix VII:  Durie Salmon Stage and International Staging System (ISS) for Multiple Myeloma ...................161
Appendix VIII:  Quality of Life Assessment Tool ..................................................................................................162
Appendix IX: FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 .................................................................167

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Appendix X:  EQ-5D Questionnaire .....................................................................................................................168
Appendix XI: Adjusted Ideal Body Weight (AIBW) Calculation ..........................................................................172
Appendix XII: Corticosteroid EquivalenceTable…………………………………………………………………….…173
Appendix XIII:  Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan ............174

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1.   OBJECTIVES
1.1
Study Design
To achieve the objectives of this study, data from this trial and a parallel trial in France 
will be combined together for analysis.
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the 
clinical benefit from the drug combination lenalidomide, bortezomib and 
dexamethasone (RVD) without immediate high-dose therapy (HDT) and autologous 
peripheral blood stem cell transplant (PBSCT), followed by lenalidomide maintenance 
(Arm A) versus RVD plus HDT and PBSCT, followed by lenalidomide maintenance 
(Arm B).  The aim of the protocol is to determine if, in the era of novel drugs, HDT is 
still necessary in the initial management of multiple myeloma (MM) in younger 
patients. “High-dose” chemotherapy (Arm B) will be considered superior if it 
significantly prolongs progression-free survival as compared to “conventional-dose” 
treatment (Arm A).
1.2
Primary Objectives
To compare progression-free survival (PFS) between Arm A and Arm B
1.3
Secondary Objectives
x
To compare the response rates (RR) between the two arms
x   To compare time to progression (TTP) between the two arms 
x   To compare the overall survival (OS) between the two arms x   
To compare the toxicity between the two arms
x
To define genetic prognostic groups evaluated by gene expression profiling (GEP)
x
To examine the best treatment in each Gene Expression Profile-defined prognostic 
group
x
To compare quality of life (QOL) between the two arms
x
To collect medical resource utilization (MRU) information which may be used in 
economic evaluation models.

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Version Date:      November 30, 2016
 
 
 
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2.
BACKGROUND
2.1 Study Agents
2.1.1  Lenalidomide (REVLIMID®)
Lenalidomide (REVLIMID®) is a proprietary IMiD® compound of Celgene Corporation. 
IMiD® compounds have both immunomodulatory and anti-angiogenic properties which 
could confer antitumor and antimetastatic effects.  Lenalidomide has been demonstrated 
to possess anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha
induced endothelial cell migration, due at least in part to inhibition of Akt phosphorylation 
response to bFGF (Dredge et. al, 2005).  In addition, lenalidomide has a variety of 
immunomodulatory effects. Lenalidomide stimulates T cell proliferation, and the 
production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates IL-
12 production (Corral et. al, 1999).  Upregulation of T cell derived IL-2 production is 
achieved at least in part through increased AP-1 activity (Schafer et. al, 2003).
Although the exact antitumor mechanism of action of lenalidomide is unknown, a 
number of mechanisms are postulated to be responsible for lenalidomide’s activity
against multiple myeloma. Lenalidomide has been shown to increase T cell proliferation, 
which leads to an increase in IL-2 and IFN-gamma secretion. The increased level of
these circulating cytokines augment natural killer cell number and function, and enhance 
natural killer cell activity to yield an increase in multiple myeloma cell lysis (Davies et. 
al, 2001).  In addition, lenalidomide has direct activity against multiple myeloma and 
induces apoptosis or G1 growth arrest in multiple myeloma cell lines and in multiple 
myeloma cells of patients resistant to melphalan, doxorubicin and dexamethasone 
(Hideshima et. al, 2000).
2.1.1.1
Indications
Lenalidomide is indicated for the treatment of patients with transfusion-dependent anemia 
due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion
5q cytogenetic abnormality with or without additional cytogenetic abnormalities. 
Lenalidomide is also approved in combination with dexamethasone for the treatment of 
patients with multiple myeloma that have received at least one prior therapy. All other uses 
are considered investigational.
2.1.1.2
Clinical Pharmacology
Mechanism of Action:
The mechanism of action of lenalidomide remains to be fully characterized.
Lenalidomide possesses immunomodulatory and antiangiogenic properties. Lenalidomide 
inhibited the secretion of pro-inflammatory cytokines and increased the secretion of anti- 
inflammatory cytokines from peripheral blood mononuclear cells. Lenalidomide inhibited 
cell proliferation with varying effectiveness (IC50s) in some but not all cell lines. Of cell

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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.
Pharmacokinetics and Drug Metabolism
Absorption:
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 analyses were performed on 15 multiple myeloma 
patients treated in Phase I studies. Absorption was found to be rapid on both Day 1 and 
Day 28 with time to maximum blood levels ranging from 0.7 to 2.0 hours at all dose 
levels (5mg, 10mg, 25 mg, and 50 mg). No plasma accumulation was observed with 
multiple daily dosing. Plasma lenalidomide declined in a monophasic manner with 
elimination half-life ranging from 2.8 to 6.1 hours on both Day 1 and 28 at all 4 doses. 
Peak and overall plasma concentrations were dose proportional over the dosing range of
5mg to 50mg (Wu et. al, 2004). Exposure (AUC) in MM participants is 57% higher than 
in healthy male volunteers.
2.1.1.3
Pharmacokinetic Parameters
Distribution:
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.
Due to its structural similarities to thalidomide, a known human teratogen, lenalidomide is 
contraindicated in pregnant women and women capable of becoming pregnant. When
there is no alternative, female of childbearing potential may be treated with lenalidomide 
provided adequate precautions are taken to avoid pregnancy. Females must commit either 
to abstain continuously from heterosexual sexual intercourse or to use two methods of 
reliable birth control, including at least one highly effective method (e.g., IUD, hormonal 
contraception, tubal ligation, or partner’s vasectomy) and one additional effective
(barrier) method (e.g., male condom, diaphragm, or cervical cap), beginning at least 28 
days prior to initiating treatment with lenalidomide, during therapy with lenalidomide, 
during therapy delay, and continuing for at least 28 days following discontinuation of

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lenalidomide therapy even if she has amenorrhea. If hormonal or IUD contraception is 
medically contraindicated, two other effective or highly effective methods may be used.
In investigational studies, lenalidomide will be dispensed through a qualified healthcare 
professional (including but not limited to, nurses, pharmacists and physicians). These 
healthcare professionals will be trained by Celgene in requirements specific to counseling 
of participants. Counseling includes verification with the participant that required 
pregnancy testing was performed and results were negative. A Lenalidomide Information 
Sheet (Appendix I) will be supplied with each medication dispense.
2.1.1.4
Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE)
This drug has demonstrated a significantly increased risk of DVT and PE in participants 
with MM who were treated with lenalidomide combination therapy. Participants and 
physicians are advised to be observant for the signs and symptoms of thromboembolism. 
Participants should be instructed to seek medical care if they develop symptoms such as 
shortness of breath, chest pain, or arm or leg swelling. Prophylactic anticoagulation or 
antiplatelet therapy prescribed in conjunction with lenalidomide is required for 
participants enrolled in this current trial.
Complete and updated adverse events are available in the Investigational Drug Brochure 
and the IND Safety Letters.
2.1.1.5
Clinical Experience
A Phase I study in participants with refractory or relapsed MM was conducted to identify 
the maximum tolerated dose (MTD) and to evaluate the safety of lenalidomide given 
orally for up to 4 weeks at 5 mg/day, 10 mg/day, 25 mg/day and 50 mg/day. Secondary 
objectives included evaluation of response to lenalidomide, as well as pharmacokinetics 
and identification of surrogate markers to aid in defining mechanisms of action. 
Participants who tolerated study drug with acceptable toxicity and were without disease 
progression were permitted to continue on therapy beyond 28 days as part of an extension 
phase for over 1 year. Twenty-seven participants were enrolled, of whom 15 had 
undergone prior autologous stem cell transplantation and 16 had received prior 
thalidomide, with a median of 3 prior regimens (range 2-6). All participants had relapsed 
MM and 18 (72%) were refractory to salvage therapy. Two participants were removed 
from study on the first day of treatment due to rapid disease progression, which resulted
in renal dysfunction and rendered them ineligible. The first group of 3 participants were 
treated for 28 d at 5 mg/d without any dose limiting toxicity (DLT). The second cohort of
3 participants commenced therapy at 10 mg/day. In one participant, DLT was 
encountered with grade (G) 2 fever as well as G3 leukopenia and neutropenia, resulting 
in removal from study before day 28. Two participants tolerated drug. Three additional 
participants were treated at 10 mg/day with no attributable toxicity within the first 28
days. In the third cohort of 3 participants at 25mg/day, drug was well tolerated within the 
first 28 days but G3 thrombocytopenia and G3 and G4 neutropenia occurred during the 
second month, resulting in 2 participants being removed from study. In the fourth cohort

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at 50mg/day, the first 3 participants tolerated treatment without DLT in the first 28 days 
and a subsequent 10 participants also tolerated drug without DLT within the first 28 days. 
However, subsequent G3 thrombocytopenia and G3/4 neutropenia in the extension phase 
prompted dose reduction and Granulocyte colony stimulating factor (GCSF) support in
all participants. No significant somnolence, constipation or neuropathy was seen in any 
cohort. Median duration of therapy is currently 4 months [range 2 weeks – 14 months] 
and 11 participants continue on treatment. Maximal protein reductions seen during 
therapy in participants who have received > 28d of treatment are summarized below:
Table 2.1.1 M Protein Reductions in a Phase I Study with Lenalidomide
Dose [mg]
Pts [n]
< 25%
> 25% < 50%
> 50%
Progression
5
3
-
2
1
-
10
5
-
-
1
4
25
3
1
2
-
-
50
13
3
5
4
1
Subtotals
24
4 (17%)
9 (37%)
6 (25%)
5 (21%)
Thus, best responses in protein of > 25% have been seen in 15 of 24 evaluable pts (63%), 
and a <25% reduction has been seen in 4 participants to achieve stable disease or better in
19 of 24 (79%). Pharmacokinetics [days 1-4, and 28] have been completed in 24 
participants and reveal rapid absorption (t max: 1-1.5 h); monophasic elimination (t ½:
3.1-4.2 h), and low to moderate interparticipant variability for AUC (11-52%) and C max 
(3-33%). Furthermore, there was no significant accumulation by day 28. In conclusion, 
these studies suggest Lenalidomide at the dose levels studied has anti-tumor activity, 
continuous pharmacokinetics (PK) with convenient daily oral dosing and acceptable 
toxicity in participants with relapsed and refractory multiple myeloma. (Richardson et al.,
2002).
Given the myelosuppression beyond day 28 seen in all participants at 50 mg/day, this 
dose was considered to be the DLT, and thus the 25 mg/day dose level as a continuous 
daily schedule of administration was considered MTD. Given the activity of the drug 
seen at lower dose levels and the PK characteristics observed, 30 mg/day in divided or
single daily dose was assessed for activity and safety, and to determine whether a divided 
dose schedule is superior. In addition, a 3-week on and one-week off schedule was 
assessed to determine if a cycling schedule would decrease the myelosuppression that
was observed in earlier trials with daily dosing. In this phase II study, 70 participants with 
relapsed and refractory Myeloma were enrolled at several U.S. centers. Richardson et al. 
reported that 26% of participants required dose reduction due to myelosuppression in this 
study. Responses that were observed included 4% of participants with complete responses 
(CR), 17% with partial responses (PR) and 33% with minimal responses (MR). 
Progressive disease (PD) occurred in 15% of participants (Richardson et al., 2002). It was
concluded that daily dosing was better tolerated than twice daily dosing because of a lower 
incidence and severity of myelosuppression.
Data from two phase III trials comparing lenalidomide + dexamethasone to single agent

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dexamethasone in participants with relapsed and/or refractory MM were first presented at 
the 10th International Multiple Myeloma Workshop in Sydney Australia (Weber et al.,
2005; Dimopoulos et al., 2005). Participants who had received 1-3 prior therapies, and 
progressing on their last therapy were randomized to receive lenalidomide, 25 mg/d x 21 
d, placebo d22-28 plus dexamethasone, 40 mg, d 1-4, 9-12, 17-20, q 28d or placebo daily 
x 28 d plus dexamethasone, 40 mg, d 1-4, 9-12, 17-20, q28d. The responses reported are 
summarized in Table 2.1.2 while the incidence of DVT and PE are summarized in Table
2.1.3 (WEBER et al., 2007; Dimopoulos et al., 2007). Anemia, thrombocytopenia, 
neutropenia, fatigue, neuropathy, and constipation were also observed more often in the 
lenalidomide + dexamethasone group compared to the dexamethasone only group, 
however these events were generally manageable.
Table 2.1.2 Response Rates in Phase III Trials of Relapse refractory MM (Celgene
MM-009 and MM-010)
 
Weber et al. 
(NEJM, 2007)
Dimopoulos et al. 
(NEJM, 2007)
 
Lenalidomide
+ Dex (n=177)
Dex Alone
(n=176)
P Value
Lenalidomide
+ Dex (n=176)
Dex Alone
(n=175)
P Value
Overall
Response 
(>PR) Rate 
(%)
 
61%
 
19.9%
<0.001
60.2%
24%
 
<0.001
 
TTP (mo.)
 
11.1
 
4.7
<0.001
11.3
4.7
 
<0.001
 
OS (mo.)
 
29.6
 
20.2
<0.001
Not reached at 
time of 
publication
20.6
 
<0.001
Table 2.1.3 DVT & PE Risks in Phase III Trials of Relapse refractory MM 
(Celgene MM-009 and MM-010)
 
Weber et al.
(NEJM, 2007)
Dimopoulos et al.
(NEJM, 2007)
 
Lenalidomide +
Dex
Dex Alone
Lenalidomide +
Dex
Dex Alone
Deep Vein Thrombosis
(%)
 
11.9
3.4
4.0
 
3.4
Pulmonary Embolism
(%)
 
3.4
0.6
4.5
 
1.1
2.1.2
Bortezomib (VELCADE) for Injection
2.1.2.1
Scientific Background

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Bortezomib (VELCADE®) for Injection is a small molecule proteasome inhibitor 
developed by Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat 
human malignancies. Bortezomib is currently approved by the United States Food and 
Drug Administration (U.S. FDA) and is registered in Europe for the treatment of MM 
patients.
By inhibiting a single molecular target, the proteasome, bortezomib affects multiple 
signaling pathways. The anti-neoplastic effect of bortezomib likely involves several 
distinct mechanisms, including inhibition of cell growth and survival pathways, induction
of apoptosis, and inhibition of expression of genes that control cellular adhesion, migration 
and angiogenesis. Thus, the mechanisms by which bortezomib elicits its antitumor activity 
may vary among tumor types, and the extent to which each affected pathway is critical to 
the inhibition of tumor growth could also differ. Bortezomib has a novel pattern of 
cytotoxicity in National Cancer Institute (NCI) in vitro and in vivo
assays (Adams et al., 1999). In addition, bortezomib has cytotoxic activity in a variety of 
xenograft tumor models, both as a single agent and in combination with chemotherapy 
and radiation (Steiner et al., 2001; Teicher et al., 1999; Cusack et al., 2001; LeBlanc et 
al., 2002; Pink et al., 2002). Notably, bortezomib induces apoptosis in cells that over 
express bcl-2, a genetic trait that confers unregulated growth and resistance to 
conventional chemotherapeutics (McConkey et al., 1999).
Bortezomib is thought to be efficacious in MM via its inhibition of nuclear factor țB 
(NF-țB) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct 
apoptotic effect, and possibly anti-angiogenic and other effects (Hideshima et al., 2001).
2.1.2.2
Nonclinical Pharmacology
Pharmacokinetic (PK) and pharmacodynamic studies were conducted in the rat and 
cynomolgus monkey. Upon intravenous (IV) bolus administration, bortezomib displays a 
rapid distribution phase (t½Į <10 minutes) followed by a longer elimination phase (t½ȕ
5–15 hours). Bortezomib has a large volume of distribution (range 5–50 L/kg). The 
plasma PK profile is well described by a 2-compartment model.
The pharmacodynamic action of bortezomib is well established and can be measured 
through an ex vivo assay (20S proteasome activity) (Lightcap et al., 2000). This assay 
was used to determine the duration of drug effect in lieu of the PK data in the early 
preclinical toxicology studies as well as to set a guide for dose escalation in humans. 
Following dosing with bortezomib in the rat and cynomolgus monkey, proteasome 
inhibition in peripheral blood had a half-life less than 24 hours, with proteasome activity 
returning to pretreatment baseline within 24 hours in monkey and within 48 to 72 hours 
in rat after a single dose of bortezomib. Further, intermittent but high inhibition (>70%) 
of proteasome activity was better tolerated than sustained inhibition. Thus, a twice- 
weekly clinical dosing regimen was chosen in order to allow return of proteasome 
activity towards baseline between dose administrations.
2.1.2.3
Nonclinical Toxicity

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Single-dose IV toxicity studies were conducted with bortezomib in the mouse, rat, dog, 
and monkey to establish the single-dose MTD. The MTDs were 0.25 mg/kg (1.5 mg/m2) 
and 0.067 mg/kg (0.8 mg/m2) in the 2 most sensitive species, rat and monkey, 
respectively.
Repeat-dose multi-cycle toxicity studies of 3 and 6 months in the rat and 9 months in the 
monkey, each with 8-week recovery periods, were conducted to characterize the chronic 
toxicity of bortezomib when administered by the clinical route and regimen of 
administration. The MTD in the 6-month rat study was 0.1 mg/kg (0.6 mg/m2) and the 
key target organs were the gastrointestinal (GI) tract, hematopoietic and lymphoid 
systems. The MTD in the 9-month monkey study was 0.05 mg/kg (0.6 mg/m2) and the 
key target organs were the GI tract, hematopoietic and lymphoid systems, peripheral 
nervous system, and kidney. Full or partial reversibility was observed for each of the 
toxicities described to date. In general, the nature of the toxicity of bortezomib is similar 
across species, and target organs of toxicity in animals have been largely predictive of 
human toxicity. The toxicity of bortezomib in animals is characterized by a steep dose- 
response with mortality seen at dosages above the MTD. The cause of death at acutely 
lethal dosages is considered to be related to indirect cardiovascular (CV) effects of 
hypotension and vascular changes with secondary bradycardia and the cause of death in 
long-term studies has been attributed to GI or hematologic toxicity. The pharmacologic 
effects of bortezomib on the CV system have been extensively characterized and have 
demonstrated that indirect effects on CV function occur only at acutely lethal dosages
and are abrogated by routine supportive care.
Additional detailed information regarding the nonclinical pharmacology and toxicology 
of bortezomib may be found in the Investigator’s Brochure.
2.1.2.4
Clinical Pharmacokinetics and Pharmacodynamics
The clinical pharmacology characterization of bortezomib has been determined from 
phase 1 studies in participants with solid tumors and hematological malignancies, and 
confirmed in phase 2 studies in participants with MM.
Bortezomib demonstrates multi-compartmental PK. Following IV administration of 1 
mg/m2 and 1.3 mg/m2 dose, the mean first-dose maximum observed plasma 
concentrations of bortezomib were 57 and 112 ng/mL, respectively in 11 participants 
with MM and creatinine clearance values >50 mL/min participating in a PK study. In 
subsequent doses, mean maximum observed plasma concentrations ranged from 67 to
106 ng/mL for the 1 mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose.  The mean 
elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours. 
Bortezomib is eliminated more rapidly following the first dose.  Mean Total Body 
Clearances were 102 and 112 L/h following the first dose for doses of 1 mg/m2 and 1.3 
mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses 
of 1 and 1.3 mg/m2, respectively. Clinical experience has shown that the change in 
clearance does not result in overt toxicity from accumulation in this multidose regimen in

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humans.
In participants with advanced malignancies, the maximum pharmacodynamic effect
(inhibition of 20S activity) occurred within 1-hour post dose. At the therapeutic dose of
1.3 mg/m2 in participants with MM, the mean proteasome inhibition at 1-hour post dose 
was approximately 61%.
The time course of proteasome inhibition in participants is characterized by maximum 
inhibition observed within the first hour after administration, followed by partial recovery 
of proteasome activity over the next 6 to 24 hours to within 50% of the pretreatment 
activity. On the Day 1, 4, 8, and 11 schedule, variable (10%–30%) levels of proteasome 
inhibition have been observed at next scheduled dosing. In theory, this advantage allows 
cells to recover proteasome activity for normal cellular housekeeping functions between 
doses.
The relationship between bortezomib plasma concentrations and proteasome inhibition 
can be described by a maximum effect (Emax) model. The Emax curve is initially very 
steep, with small changes in plasma bortezomib concentration over the range of 0.5 to
2ng/mL relating to large increases in the percent inhibition (0–60%). After that, a plateau 
occurs where marginal increases of proteasome inhibition are observed in spite of large 
changes in plasma bortezomib concentrations.
2.1.2.5
Clinical Experience
It is estimated that more than 100,000 participants have been treated with bortezomib, 
including participants treated through Millennium-sponsored clinical trials, Investigator- 
Initiated Studies, the U.S. NCI Cancer Therapy Evaluation Program (CTEP), and with 
commercially available drug. Bortezomib has been commercially available since May 13,
2003.
The overall goal of the Millennium phase 1 program was to determine the MTD and DLT 
of bortezomib in a number of therapeutic settings involving participants with various 
advanced malignancies. In a Phase I trial in participants with refractory hematologic 
malignancies, the MTD for a twice weekly for 4 weeks of a 42 day cycle was 1.04 
mg/m2/dose, with DLTs of thrombocytopenia, hyponatremia, hypokalemia, fatigue, and 
malaise (Orlowski et al., 2002). The toxicity was greatest during the third and fourth 
weeks of therapy. In the 3-week schedule of bortezomib monotherapy (4 doses, given on 
Days 1, 4, 8, and 11 of a 21-day treatment cycle), the DLT occurred at 1.56 mg/m2/dose
(3 participants with Grade 3 diarrhea and 1 with peripheral sensory neuropathy). 
Therefore, the MTD at this schedule was 1.3 mg/m2/dose. In a 35-day treatment cycle
with 4 weekly doses of bortezomib monotherapy, the MTD was 1.6 mg/m2/dose and DLT
included hypotension, tachycardia, diarrhea, and syncope.
In phase 1 clinical studies, anti-tumor activity was reported in participants with NHL, 
MM, Waldenström’s Macroglobulinemia, squamous cell carcinoma of the nasopharynx, 
bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate cancer.

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The safety and efficacy of bortezomib in participants with MM were investigated in two 
phase 2 clinical studies, studies M34100-024 (participants with first relapse) and
M34100-025 (participants with second or greater relapse and refractory to their last prior 
therapy) (Jagganath et al., 2004; Richardson et al., 2002). In M34100-025, 202 heavily
pre-treated participants with refractory multiple myeloma after at least 2 previous 
treatments received bortezomib, 1.3 mg/m2 on Days 1, 4, 8, and 11 of a 21-day treatment 
cycle. The European Group for Blood and Marrow Transplant (EBMT) response criteria, 
as described by Blade (Blade et al., 1998) were utilized to determine disease response. 
CRs were observed in 4% of participants, with an additional 6% of participants meeting
all criteria for CR but having a positive immunofixation test. PR or better was observed 
in 27% of participants, and MR or better was observed in 35%. Seventy percent of 
participants experienced stable disease (SD) or better (Richardson et al., 2005).
The phase 3 study (M34101-039), also referred to as the APEX study, was designed to 
determine whether bortezomib provided benefit (TTP, RR, and survival) to participants 
with relapsed MM relative to treatment with high-dose dexamethasone. The study was 
also designed to determine the safety and tolerability of bortezomib relative to high-dose 
dexamethasone, and whether treatment with bortezomib was associated with superior 
clinical benefit and QOL relative to high-dose dexamethasone.
A total of 669 participants were enrolled and 663 participants received study drug
(bortezomib: 331; dexamethasone: 332). Participants randomized to bortezomib received
1.3 mg/m2 I.V. push twice weekly on days 1, 4, 8, and 11 of a 3-week cycle for up to 
eight treatment cycles as induction therapy, followed by 1.3 mg/m2 bortezomib weekly
on days 1, 8, 15, and 22 of a 5-week cycle for three cycles as maintenance therapy.
Participants randomized to dexamethasone received oral dexamethasone 40 mg once 
daily on days 1 to 4, 9 to 12, and 17 to 20 of a 5-week cycle for up to four treatment 
cycles as induction therapy, followed by dexamethasone 40 mg once daily on days 1 to 4 
followed of a 4-week cycle for five cycles as maintenance therapy. The EBMT response 
criteria, as described by Blade (Blade et al., 1998) were utilized to determine disease 
response. There was a 78% increase in TTP for the bortezomib arm. The responses 
reported are summarized in Table 2.1.4.
Table 2.1.4 Response Rates in a Phase III Trial of Relapsed MM
 
Bortezomib
(n=331)
Dex
(n=332)
P Value
CR+PR
Rate (%)
 
38%
18%
<0.0001
CR+nCR
Rate (%)
 
13%
2%
 
CR
Rate (%)
 
6%
<1%
<0.0001
 
 

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TTP (mo.)
6.2
3.5
<0.0001
In participants who had received only one prior line of treatment (bortezomib: 132; 
dexamethasone: 119), CR + PR was 45% with bortezomib vs. 26% with dexamethasone 
(P=0.0035). With a median 8.3 months of follow-up, overall survival was significantly 
longer (P=0.0013) for participants on the bortezomib arm vs. participants on the 
dexamethasone arm. The probability of survival at one year was 80% for the bortezomib 
arm vs. 66% for the dexamethasone arm, which represented a 41% decreased relative risk 
of death in the first year with bortezomib (P=0.0005).
In participants who had received only one prior line of treatment, the probability of 
survival at one year was 89% for the bortezomib arm vs. 72% for the dexamethasone 
arm, which represented a 61% decreased relative risk of death in the first year with 
bortezomib (P=.0098).
Updated RR and survival data were reported for M34101-039 (Richardson ASH, 2005). 
The updated CR + PR rate was 43% with bortezomib. The CR + nCR rate was 16% with 
bortezomib. With a median 22 months of follow-up, OS was significantly longer for 
participants on the bortezomib arm vs. participants on the dexamethasone arm. The 
median OS was 29.8 months (95% CI: 23.2, not estimable) for the bortezomib arm vs
23.7 months (95% CI: 18.7, 29.1) for the dexamethasone arm (hazard ratio = 0.77, P=
0.0272). The probability of survival at one year was 80% for the bortezomib arm vs.
67% for the dexamethasone arm (P=0.0002).
Studies using bortezomib as monotherapy and in combination with other chemotherapy 
agents are continuing.
2.1.2.6
Potential Risks of Bortezomib
To date, more than 100,000 patients have been treated with bortezomib in both clinical 
trials investigating its use in hematological malignancies and solid tumors, and in patients 
who were treated with commercially available bortezomib.
Prescribing physicians and health care practitioners are referred to their locally approved 
product label for bortezomib regarding Indications and Usage, Contraindications, 
Warnings, and Precautions.
The known anticipated risks of bortezomib therapy are presented below. These risks are 
grouped according to the combined frequency observed in an integrated analysis of AEs
in sponsored clinical studies of single-agent bortezomib dosed at 1.3 mg/m2 twice weekly 
on a 21-day schedule, in patients with multiple myeloma and mantle cell lymphoma.

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
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Table 2.1.5
Known Anticipated Risks of Bortezomib by MedDRA System Organ
Class, Observed Incidence, and Preferred Term
    
S
t
O
Cl
Observed Incidence
Preferred Term
Blood and Lymphatic System Disorders
Most common
Thrombocytopenia*, anaemia* 
Very common
Neutropenia*
Common
Lymphopenia, pancytopenia*, leukopenia*, febrile 
neutropenia
Cardiac Disorders
Common
Tachycardia, atrial fibrillation, palpitations, cardiac 
failure congestive*
Uncommon
Cardiogenic shock*, atrial flutter, cardiac tamponade*r, 
bradycardia, atrioventricular block complete, arrhythmia, 
cardiac arrest*, cardiac failure, arrhythmia, pericardial 
effusion, pericarditis, pericardial diseaser, 
cardiopulmonary failurer 
Ear and Labyrinth Disorders
Uncommon
Deafness, hearing impaired
Eye Disorders
Common
Blurred vision, conjunctivitis, conjunctival haemorrhage
Gastrointestinal Disorders
Most common
 Constipation, diarrhoea*, nausea, vomiting* 
Very common
abdominal pain (excluding oral and throat)
Common
Dyspepsia, pharyngolaryngeal pain, gastroesophageal 
reflux, abdominal distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal haemorrhage*, 
lower gastrointestinal haemorrhage*± rectal 
haemorrhage
Uncommon
Eructation, gastrointestinal pain, tongue ulceration, 
retching, upper gastrointestinal haemorrhage*, 
haematemesis*, oral mucosal petechiae, ileus paralytic*, 
ileus, odynophagia, enteritis, colitis, oesophagitis, 
enterocolitis, diarrhoea haemorrhagic, acute 
pancreatitis*, intestinal obstruction
General Disorders and Administration Site Conditions
Most common
Fatigue, pyrexia
Very common
Chills, oedema peripheral, asthenia
Common
Neuralgia, lethargy, malaise, chest pain, mucosal 
inflammation*
Uncommon
Injection site pain, injection site irritation, injection site 
phlebitis, general physical health deterioration*, 
catheter-related complication
Hepatobiliary Disorders

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:     November 30, 2016
 
 
 
Table 2.1.5
Known Anticipated Risks of Bortezomib by MedDRA System Organ
Class, Observed Incidence, and Preferred Term
    
S
t
O
Cl
Observed Incidence
Preferred Term
Uncommon
Hyperbilirubinaemia, hepatitis*r
Immune System Disorders
Uncommon
Drug hypersensitivity, angioedema
Infections and Infestations
Very common
Upper respiratory tract infection, nasopharyngitis, 
pneumonia*, Herpes zoster* (may cause lesions)
Common
Lower respiratory tract infection*, sinusitis, pharyngitis, 
oral candidiasis, urinary tract infection*, sepsis*, 
bactaeremia*, cellulitis*, Herpes simplex, bronchitis, 
gastroenteritis*, infection
Uncommon
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung infection*, 
infusion site cellulitis, catheter site cellulitis, infusion
site infection, urosepsis*, Aspergillosis*, tinea infection,
Herpes zoster ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpeticr, varicella, empyemar, 
fungal oesophagitisr
Injury, Poisoning, and Procedural Complications
Common
Fall
Uncommon
Subdural haematoma
Investigations
Common
Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, 
blood alkaline phosphatase increased, liver function test 
abnormal, blood creatinine increased*
Uncommon
Gamma-glutamyltransferase (GGT) increased, oxygen 
saturation decreased*, blood albumin decreased, ejection 
fraction decreased*
Metabolism and Nutritional Disorders
Very common
Decreased appetite, anorexia, dehydration* 
Common
Hyperglycaemia, hypoglycaemia, hyponatraemia,
hypokalaemia, hypercalcaemia*
Musculoskeletal and Connective Tissue Disorders
Very common
Bone pain, myalgia, arthralgia, back pain
Common
Muscular weakness 
Uncommon
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon
Tumour lysis syndrome*

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    Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:     November 30, 2016
 
 
 
Table 2.1.5
Known Anticipated Risks of Bortezomib by MedDRA System Organ
Class, Observed Incidence, and Preferred Term
    
S
t
O
Cl
Observed Incidence
Preferred Term
Nervous System Disorders
Most common
Peripheral neuropathy (including all preferred terms 
under the MedDRA High-level term Peripheral 
neuropathy NEC)
Very common
Paresthesia, dizziness excluding vertigo, headache
Common
Polyneuropathy, syncope, dysesthesia, dysgeusia, 
postherpetic neuralgia
Uncommon
Convulsion, loss of consciousness, ageusia, 
encephalopathy, paralysis*,autonomic neuropathy, 
reversible posterior leukoencephalopathy syndromer
Psychiatric Disorders
Very common
Anxiety, insomnia 
Common
Confusional state 
Uncommon
Delirium
Renal and Urinary Disorders
Common
Renal impairment*, renal failure*, haematuria
Uncommon
Micturition disorder
Respiratory, Thoracic, and Mediastinal Disorders
Very common
Cough, dyspnoea
Common
Epistaxis, dyspnoea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary oedema*
Uncommon
Hemoptysis*, acute respiratory distress syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar haemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, pleuritic 
pain
Skin and Subcutaneous Tissue Disorders
Very common
Rash
Common
Rash pruritic, rash erythematous, urticaria, petechiae 
Uncommon
Cutaneous vasculitis, leukocytoclastic vasculitisr 
Vascular Disorders
Common
Hypotension*, orthostatic hypotension
Uncommon
Cerebral haemorrhage*
Source:  VELCADE® (bortezomib) for Injection Investigator’s Brochure Edition 14.
Most common = t 30%, Very common = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%.
*  Fatal outcomes have been reported.
r Indicates a Preferred term not listed in the source table, however the event is deemed medically important 
and so is included.

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   Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
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Table 2.1.6
Reports of Adverse Reactions From
Postmarketing Experience
 
  
System Organ Class
Preferred Term
Blood and lymphatic system disorders
Observed
Incidencea
Disseminated intravascular coagulation
Rare
Cardiac Disorders
Atrioventricular block complete
Rare
Cardiac tamponade
Rare
Ear and labyrinth disorders
Deafness bilateral
Rare
Eye Disorders
Ophthalmic herpes
Rare
Gastrointestinal Disorders
Acute pancreatitis
Rare
Ischemic colitis
Rare
Hepatobiliary disorders
Hepatitis
Uncommon
Liver failure
Unknown
Infections and infestations
Herpes meningoencephalitis
Rare
Septic shock
Rare
Immune System Disorders
Angioedema
Rare
Nervous System Disorders
Autonomic neuropathy
 Rare 
Dysautonomia
 Unknown 
Encephalopathy
Rare
Respiratory, thoracic and mediastinal disorders:
Acute diffuse infiltrative pulmonary diseaseb                         Rare 
Acute respiratory distress syndrome (ARDS)                Rare 
Interstitial pneumonia                                                     Rare 
Lung infiltration                                                             Rare 
Pneumonitis                                                                    Rare 
Pulmonary hypertension                                               Rare

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   Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:      November 30, 2016
 
 
Skin and subcutaneous system disorders
Acute febrile neutrophilic dermatosis
Unknown
Toxic epidermal necrolysis
Unknown
Source:  VELCADE® (bortezomib) for Injection Investigator’s Brochure
Edition 14.
a  Incidence is assigned using the following convention: very common
(t 1/10); common (t 1/100 and    1/10); uncommon (t 1/1000 and
  1/100); rare (t 1/10,000 and    1/1000 ); very rare (   1/10,000, 
including isolated reports).
b  Acute diffuse infiltrative pulmonary disease is a MedDRA Lower 
Level Term which corresponds to a Preferred Term of Interstitial lung 
disease.
Other medical events of interest that are considered not causally related to bortezomib 
include hepatic failure and QT prolongation. Fatal outcomes have been reported.
Females of childbearing potential should avoid becoming pregnant while being treated 
with bortezomib. Genotoxicity testing has shown that bortezomib is negative in the in 
vitro Ames assay and in the in vivo micronucleus assay, but it is a clastogen in the in 
vitro chromosomal aberration assay.
Additional details on the potential risks of bortezomib may be found in the current
Investigator’s Brochure.
2.2
Study Disease: Multiple Myeloma
Multiple myeloma is a malignant proliferation of plasma cells. Accounting for 13% of 
all cases, it is the second most common hematologic malignancy. (Malpas et al., 1998; 
Cohen et al., 1998). Myeloma cells are highly dependent upon the bone marrow 
microenvironment, including the presence of certain cytokines (e.g., IL-6), 
macromolecules in the extracellular matrix, and supportive cells (stromal cells), for their 
growth and survival (Klein et al., 1989; Vidriales and Anderson, 1996; Kawano et al.,
1988). Processes that change the bone marrow microenvironment either retard the 
growth of the tumor or cause myeloma to undergo apoptosis (Anderson et al., 2006).
Patients develop symptoms when the tumor burden is greater than 1011 cells/mm3 (Durie 
and Salmon, 1975). Symptomatic multiple myeloma traditionally requires initiation of 
systemic therapy, which in the past has included melphalan-prednisone (MP) or another 
form of combination chemotherapy (Alexanian and Dimopoulos, 1994; Oken, 1994; 
Oken et al., 1997). Typically, 50% to 60% of patients achieve an objective response to 
these regimens, but less than 5% achieve a true complete remission with conventional 
chemotherapy. The FDA approval of novel agents, such as bortezomib, thalidomide, and 
lenalidomide has greatly enhanced myeloma therapy (Ghobrial et al., 2007). Moreover, 
current studies using multi-drug combinations have further improved results by reducing 
drug resistance (Dimopoulos et al., 2003). Although MM remains incurable, survival

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   Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
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has been extended to ten years and beyond (Richardson et al., 2003; Richardson et al.,
2005; Barlogie et al., 2006; Rajkumar et al., 2006; Weber et al., 2007; Dimopoulos et al.,
2007).
Experience from around the world now suggests that high-dose alkylating agent 
chemotherapy followed by autologous hematopoietic stem cell transplantation can 
achieve high (40%) CR rates and a similar number of partial responses (Schlossman 
and Anderson, 1999).  Synergeic bone marrow transplantation (BMT) has been done 
infrequently, but patients can remain progression-free for long intervals post- 
transplant (Bensinger et al., 1996). Despite an increased survival in most patients and 
long-term survival in a few patients, there is a clear need to improve this intensive 
therapeutic regimen. Unfortunately, relapses occur in the majority of
patients treated with any of these high-dose therapy (HDT) approaches, and there are 
few, if any, cures. Furthermore, despite recent advances, once a relapse occurs after 
single or tandem high-dose therapies and BMT, there are relatively limited therapeutic 
regimens for effective treatment. The bone marrow (BM) reserve has been 
compromised, restricting the use of both chemotherapeutic and novel regimens to 
those without attendant myelosuppression, and whilst outcomes have improved with 
newer agents (please see below), sustained disease stabilization becomes
progressively more difficult to achieve, and patients ultimately succumb to relapsed, 
refractory disease.
2.3
Treatment Regimen Rationale
For fifteen years, HDT has been the standard treatment for MM in younger patients. 
In the 1990s, several randomized studies demonstrated the superiority of high-dose 
treatments versus conventional chemotherapies in terms of response (Attal et al.,
1996; Child et al., 2003; Palumbo et al., 2004; Fermand et al., 1998; Blade et al.,
2005), event-free survival (Attal et al., 1996; Child et al., 2003; Palumbo et al., 2004; 
Fermand et al., 1998; Blade et al., 2005) and overall survival (OS) (Attal et al., 1996; 
Child et al., 2003; Palumbo et al., 2004). The superiority of HDT over conventional- 
dose therapy is related to obtaining a higher rate of very good partial response 
(VGPR) or better, which in turn is correlated with longer PFS, but only in some 
studies OS (Attal et al., 2007). Indeed, a recent meta-analysis by Koreth and 
colleagues demonstrated PFS and no OS advantage (Koreth et al., 2007).
For the last 4-5 years, the arrival of novel therapies (thalidomide, bortezomib and 
lenalidomide) has revolutionized conventional therapeutic regimens. The use of 
these new therapies has improved CR and VGPR rates of HDT as well as those of 
conventional-dose therapy, to such a point that these rates have now become similar 
in both groups of treatment. Thus, the arrival of novel therapies has brought into 
question the necessity of HDT as first-line therapy in young patients (Attal et al.,
2007; Attal et al., 2007).
The aim of the protocol is, therefore, to compare the results (in terms of efficacy, 
quality of life and cost) of HDT to those of conventional-dose treatment, with both

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   Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
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treatment arms receiving novel drugs as part of induction, consolidation and 
maintenance. To achieve the objectives of this study, data from this trial and a 
parallel trial in France will be combined together for analysis.
2.3.1
Rationale for Conventional-Dose Arm (Arm A)
2.3.1.1
Choice of treatment
Since the 1960s, the combination of melphalan + prednisone (MP) was the standard 
conventional-dose treatment for myeloma. Therefore, it was logical to evaluate new 
drugs in combination with MP. For the last 2 to 3 years, the combinations MP + 
thalidomide, MP + bortezomib, or MP + lenalidomide have become or are in the process
of becoming new standards for the induction treatment of elderly patients (Palumbo et al.,
2006; Facon et al., 2007; San Miguel et al., 2008; Palumbo et al., 2007). Other 
researchers, seeking to avoid the use of alkylating agents in induction treatment, have 
successfully evaluated combinations of dexamethasone and lenalidomide (Rajkumar et 
al., 2007). All of these new strategies have generated promising results, with PR rates 
between 70 and 80%, rates of VGPR between 42 and 50% and durations of response of 
approximately 24 months. However, these results remain greatly inferior to the results 
that are expected for the new high-dose strategies with more than 90% PR, including up 
to 80% VGPR (Attal et al., 2007). The only conventional-dose treatment that rivals these 
high-dose results is RVD, developed by the DFCI team, with 100% PR and 74% VGPR
(Richardson et al., 2007; Richardson et al., 2008). It is therefore logical to select RVD for 
the conventional-dose arm in this protocol.
2.3.1.2
Maintenance therapy
Maintenance therapy used in the conventional-dose arm will be identical to that of the 
high-dose arm. Maintenance with lenalidomide (based on the results of the IFM 2005 
study) will be used in an identical manner in both the high-dose and conventional-dose 
arms.
2.3.1.3
Treatment for relapse
To avoid penalizing (in terms of OS) patients in this arm, who will not receive a
transplant in first-line treatment, the recommended treatment for relapse will be the use of 
high-dose melphalan with autologous PBSCT. A study conducted by Fermand et. al 
demonstrated that the OS of participants who receive transplant as first-line therapy is 
identical to OS of those who receive it as treatment for relapse (Fermand et al., 1998). 
Stem cells will, therefore, be collected from all participants after three cycles of RVD and 
used to support HDT/PBSCT in case of relapse for the conventional-dose participants,
and after successful salvage therapy.

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   Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
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2.3.2
Rationale for HDT Arm (Arm B)
2.3.2.1
Induction
The combination of dexamethasone, adriamycin and vincristine (VAD regimen) was the 
standard induction regimen for a long time, although rates of response after VAD were 
mediocre: 75% PR (PR = 50% reduction in monoclonal component), including only 10% 
VGPR (VGPR = at least 90% reduction in monoclonal component) (Harousseau et al.,
2007). Several randomized studies have recently demonstrated that the combination of 
dexamethasone and one of the new molecules, bortezomib (Harousseau et al., 2007) or 
thalidomide (Macro et al., 2006) made it possible to improve pre-transplant response 
rates. An Italian randomized study showed that the combination of dexamethasone, 
bortezomib and thalidomide made it possible to achieve still greater improvement in the 
results of induction, obtaining 93% PR with 60% VGPR (Cavo et al., 2007). Finally, a 
multi-center study led by Dana-Farber Cancer Institute (DFCI), in Boston, MA, has 
demonstrated that the combination of lenalidomide, bortezomib and dexamethasone (the 
so-called RVD regimen) has obtained 100% PR with 74% VGPR, with excellent 
tolerability (Richardson et al., 2007; Richardson et al., 2008). This regimen is currently 
the most promising approach to induction, and will therefore be used in this protocol.
2.3.2.2
Collection of autologous peripheral blood stem cells
After conventional induction using VAD, mobilization of autologous peripheral blood 
stem cells (PBSC) has been performed by G-CSF alone. However, several studies that 
used lenalidomide as induction treatment suggest that mobilization by cyclophosphamide 
and G-CSF is preferable. This combined mobilization will be used in this protocol.
2.3.2.3
High-dose therapy
The standard conditioning treatment is high-dose melphalan followed by autologous 
PBSCT (Moreau et al., 2002). It has recently been reported that combined conditioning 
using melphalan and bortezomib made it possible to improve post-transplant response 
rates (Roussel et al., 2008). However, this improvement was mainly found in patients not 
receiving bortezomib as induction treatment. Since bortezomib will be used in induction 
and in consolidation in this protocol, transplant conditioning will use melphalan alone in 
order to reduce risks of neuropathy in this treatment arm.
2.3.2.4
Post-transplant consolidation
Ladetto  and  colleagues  have  reported  that  post-transplant  consolidation  using  the 
combination of bortezomib, thalidomide and dexamethasone made it possible to convert
22% of VGPR into full, lasting molecular responses (PCR-) (Ladetto et al., 2007). In the 
IFM  2008  pilot study (enrollment completed in December 2009),  the usefulness  and 
safety of post-transplant consolidation with two cycles of the RVD regimen is being 
tested. The first analysis of the consolidation phase of this protocol is planned in October

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   Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
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2010.  Based on the assumption that the results of this pilot study are satisfactory in terms 
of response and safety, two cycles of RVD has been chosen for consolidation in this 
protocol.
2.3.2.5
Post-transplant maintenance therapy
Results from a study by the Intergroupe Francophone du Myelome have demonstrated that 
post-transplant maintenance treatment with thalidomide made it possible to reduce tumor 
mass, prolong duration of response and improve survival (Attal et al., 2006).  This result 
was recently confirmed by Spencer and colleagues (Spencer et al., 2007). However, the 
neurological toxicity of thalidomide is limiting with 68% neuropathy reported in the 
French study (Attal et al., 2006). The usefulness of lenalidomide (a thalidomide analogue 
with markedly reduced neurotoxicity) is currently being tested by the IFM with
promising results to date (IFM 2005-02 protocol: 614 patients, enrollment completed on 
August 14, 2008, superiority of the lenalidomide maintenance arm in terms of PFS 
(p<0.000001) on the first intermediate analysis performed on January 4, 2010).  Based on 
the assumption that the results of this trial remain satisfactory, lenalidomide has been 
chosen as maintenance therapy in this protocol.
2.3.3   Rationale for the type of trial and the primary endpoint
2.3.3.1
Non-inferiority testing
While, in the context of a therapeutic trial, the notion of gradual dose reduction involves 
a non-inferiority test, such a test is impossible to perform in this case, for at least two 
reasons:
a- Sufficient past data is not available to make an estimated projection of overall 
survival for patients receiving these new compounds. Trials using these new 
compounds are recent, and many of them are not yet published. The short-term 
results are promising, but remain uncertain in the long-term. This lack of thorough 
understanding, therefore, makes it impossible to define a non-inferiority range
that would be applicable to the therapeutic regimen to be tested in this current 
trial.
b-  The intermediate endpoint of event-free survival is not an endpoint that can be 
used in a non-inferiority test, because HDT will be offered in those participants 
who progress during maintenance therapy and did not receive it as first-line 
treatment. Fermand et al., in an intervention trial aiming to determine the best
time to use HDT (initial versus relapse) demonstrated that event-free survival was 
very different between the groups (13 months versus 39 months), without, 
however, any difference in OS (HR=1.02, p=0.92)(Fermand et al., 1998).
2.3.3.2
Progression-Free Survival (PFS) as an endpoint
The aim of this protocol is to determine if, in the era of new drugs, HDT (with transplant)
is still necessary in the initial management of myeloma in young patients. Considering 
the toxicity of the transplant, the specificity of the arrangements that it requires, and its

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   Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
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cost, the continued use of transplant as first-line treatment will be considered clinically 
pertinent if it prolongs PFS by at least 9 months as compared to conventional-dose 
treatment. Currently, new protocols using combinations of new drugs at conventional 
doses (melphalan/prednisone/thalidomide (Palumbo et al., 2006; Facon et al., 2007); 
melphalan/prednisone/bortezomib (San Miguel et al., 2008);
dexamethasone/lenalidomide (Rajkumar et al., 2007) yield PFS of around 24 months. The 
RVD combination could improve this result, and a PFS of 30 months may be obtained 
(Richardson et al., 2007; Richardson et al., 2008). The continued use of transplant in
first-line treatment would be warranted if the PFS of the high-dose arm were greater than
39 months. The trial will be considered to be positive if the PFS of the high-dose arm is 
greater by at least 9 months than that of the conventional dose arm.
2.4
Correlative Studies Background
The purpose of this correlative research is to obtain peripheral blood and bone marrow 
samples from patients with multiple myeloma. This correlative research will provide a 
better understanding of the impact of copy number aberrations (CNAs) and their functional 
consequences on MM initiation and progression, as well as novel high value therapeutic 
targets for early intervention and new tools to personalize the strategy of treatment in MM 
patients at risk.
We propose to evaluate whether further stringent CR definition may be able to predict 
superior survival outcome. We will incorporate normalization of serum free light chain, 
molecular CR using ASO-PCR and immunophenotypic CR using multicolor flow 
cytometric immunophenotyping of MM cell in bone marrow to detect minimal residual 
disease.
In addition, we propose to identify genomic alterations to evaluate clinical outcome. We 
will evaluate the role of DNA copy number aberrations (CNAs) by high throughput SNP 
array analysis as well as genome sequencing and gene expression changes by expression 
array on response, and survival outcome. We will investigate mRNA splicing by exon 
array and microRNA profiles in the patients to correlate with clinical endpoints. We will 
investigate both the direct and indirect relationship between CNAs and gene expression 
changes.
Finally, we propose to investigate genomic changes at the time of progression or relapse and 
evaluate mechanisms underlying genomic instability. We will perform genome-wide SNP 
analyses, expression profiling and genome-wide sequencing on paired samples obtained at 
the time of diagnosis and at the time of progression or relapse identify genomic regions with 
amplifications, deletions, and changes in heterozygosity. We will evaluate the mutations in 
light of the known pattern of changes and identify those which may predict different clinical 
outcomes. Based on our data showing that elevated homologous recombination (HR)
activity plays a significant role in ongoing genomic instability in myeloma we will also 
measure HR activity in primary myeloma samples to evaluate if it correlates with 
acquisition of new genomic changes as well as clinical outcome.

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Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
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3.
PARTICIPANT SELECTION
3.1
Inclusion Criteria for Registration
All laboratory assessments should be performed within 21 days of initiation of 
protocol therapyunless otherwise noted.  Bone marrow biopsy, skeletal survey, 
MRI, CT scans, and chest X-ray within 35 days of initiation of protocol therapy are 
permitted to fulfill screening requirements.
3.1.1
Participants must have a diagnosis of MM, according to International Myeloma 
Foundation 2003 Diagnostic Criteria. According to these criteria, the following 
must be met:
ƒ
Monoclonal plasma cells in the bone marrow  ≥10% (or proven 
plasmocytic infiltration in bone marrow biopsy) and/or presence of a 
biopsy-proven plasmacytoma within 35 days of initiation of protocol 
therapy.
ƒ
Monoclonal protein (M-protein) present in the serum and/or urine
ƒ
Myeloma-related organ dysfunction (1 or more) of the following. A 
variety of other types of end-organ dysfunctions can occasionally occur 
and lead to a need for therapy.  Note: Laboratory assessments used to 
support the CRAB criteria in the IMF 2003 Diagnostic Criteria of MM 
are performed at the time of diagnosis.   These assessments are not 
required to be performed within the 21 days of initiation of protocol 
therapy
[C] Calcium elevation in the blood, defined as serum calcium > 10.5 
mg/dl or upper limit of normal
[R] Renal insufficiency (defined as serum creatinine above normal). 
[A] Anemia, defined as hemoglobin <10 g/dl or 2 g < normal
[B] Lytic bone lesions or osteoporosis. If a solitary (biopsy-proven) plasmacytoma or 
osteoporosis alone (without fractures) are the sole defining criteria, then >30% 
plasma cells are required in the bone marrow or proven plasmocytic infiltration in 
bone/bone 
Note: These criteria identify Stage IB (if the creatinine is >2 mg/dl at marrow 
biopsypresentation) and Stages II and III A/B myeloma by Durie-Salmon stage. Stage 

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IA becomes smoldering or indolent myeloma. 
3.1.2
Participants must have documented symptomatic myeloma, with organ damage 
related to myeloma as defined above in section 3.1.1 with laboratory assessments
3.1.3
Participants must have myeloma that is measurable by either serum or urine evaluation 
of the monoclonal component or by assay of serum free light chains. Measurable 
disease is defined as one or more of the following: serum M-protein >
1 g/dl (except patients with IgD or IgA myeloma), urine M-protein > 200 
mg/24 h, and/or serum FLC assay: involved FLC level > 10 mg/dl with 
abnormal serum FLC ratio. For patients with IgD or IgA myeloma, a 
serum M-protein of greater than or equal to 0.5 g/dl will suffice.  Free 
light chain patients not measurable by urine or serum evaluation may be 
considered for inclusion.
3.1.4
Age between 18 and 65 years at the time of signing the informed consent form.
3.1.5
ECOG performance status <2 (Karnofsky >60%, see Appendix III).
3.1.6
Negative HIV blood test within 21 days of study entry. HIV-positive individuals 
on combination antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic (PK) interactions with lenalidomide, bortezomib and/or 
dexamethasone. In addition, these individuals are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.
3.1.7
All study participants must be registered into the mandatory Revlimid REMS® 
program, and be willing and able to comply with the requirements of Revlimid 
REMS®.
3.1.8
Females of childbearing potential* must have a negative serum or urine pregnancy test 
with a sensitivity of at least 50 mIU/mL within 10 – 14 days and again within
24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled 
within 7 days as required by Revlimid REMS®) 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.
* A female of childbearing potential is a sexually mature female who: 1) has not undergone a 
hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of 
both ovaries) 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 
during the preceding 24 consecutive months)
3.1.9
Females of childbearing potential must also agree to ongoing pregnancy testing. 

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3.1.10 Men must agree to use a latex condom during sexual contact with a female of
childbearing potential even if they have had a successful vasectomy. See Appendix II: 
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth
Control Methods.  
3.1.11   Ability to understand and the willingness to sign a written informed consent document. 
Voluntary written informed consent must be obtained before performance of any study-related 
procedure not part of normal medical care, with the understanding that consent may be 
withdrawn by the participant at any time without prejudice to future medical care.
3.2
Exclusion Criteria for Registration
All laboratory assessments should be performed within 21 days of initiation of 
protocol therapy.
3.2.1
Participant treated with any prior systemic therapy for myeloma. Treatment by 
localized radiotherapy is not an exclusion criterion if an interval of at least 7 days 
between the end of radiotherapy and initiation of protocol therapy is observed. 
Intervals of less than 7 days betwen radiotherapy and initiation of protocol 
therapy will be considered on a case by case basis with the lead PI, provided 
toxicity is not a concern. Similarly, the dose of corticosteroids received by the 
participant as part of initial therapy for myeloma should not exceed the equivalent 
of 160 mg of dexamethasone over a two-week period before initiation of protocol 
therapy (see Appendix XII for equivalence table).
3.2.2
Primary amyloidosis (AL) or myeloma complicated by amylosis.
3.2.3
Participants receiving any other investigational agents.
3.2.4
Participants with known brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often 
develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events.
3.2.5
Poor tolerability or known allergy to any of the study drugs or compounds 
of similar chemical or biologic composition to lenalidomide, bortezomib 
and/or dexamethasone.
3.2.6   Participants with platelet level <50,000/mm3, within 21 days of initiation of 
protocol therapy for patients in whom <50% of bone marrow nucleated cells 
are plasma cells; or platelet count <30,000/mm3 for patients in whom >50%

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47
of bone marrow nucleated cells are plasma cells.  Transfusion within 7 days 
of screening is not allowed to meet platelet eligibility criteria.
3.2.7
Participants with an absolute neutrophil count (ANC) <1000/mm3, within 21 
days of initiation of protocol therapy. Growth factor within 7 days of 
screening is not allowed to meet ANC eligibility criteria.
3.2.8
Participants with hemoglobin level < 8 g/dL, within 21 days of initiation of 
protocol therapy. Transfusion may be used to meet hemoglobin eligibility 
criteria.
3.2.9
Hepatic impairment, defined as total bilirubin > 1.5 x institutional ULN 
(Patients with benign hyperbilirubinemia (e.g., Gilbert’s syndrome) are 
eligible.) or AST (SGOT), or ALT (SGPT), or alkaline phosphatase > 2x 
institutional ULN, within 21 days of initiation of protocol therapy.
3.2.10 Renal insufficiency at the time of screening, defined as serum creatinine
>
2.0 mg/dL or creatinine clearance < 50 mL/min (either actual or calculated 
value may be used), within  7 days of initiation of protocol therapy. 
Creatinine clearance will be the primary eligibility criteria in determining renal 
insufficiency. The Cockgroft-Gault formula should be used for calculating 
creatinine clearance values:
(140-age) x Body mass (kg)   x 0.85 (female) or 1.0 (male)
serum creat (mg/dL) x 72
3.2.11 Respiratory compromise, defined as ventilation tests with DLCO < 50%
3.2.12 Participant with clinical signs of heart or coronary failure, or evidence of left 
ventricular ejection fraction (LVEF) < 40%.  Participant with myocardial 
infarction within 6 months prior to enrollment or have New York Heart 
Association (NYHA) Class III or IV heart failure (see Appendix V), 
uncontrolled angina, severe uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia or active conductive system 
abnormalities.  Prior to study entry, any ECG abnormality at screening has
to be documented by the investigator as not medically relevant.
3.2.13 Intercurrent illness including, but not limited to ongoing or active severe
infection, known infection with hepatitis B or C virus, poorly controlled 
diabetes, severe uncontrolled psychiatric disorder or psychiatric illness/social 
situations that would limit compliance with study requirements. For patients 
with a positive hepatitis B antibody result, but no signs of active infection, 
participating sites must contact the study PI for approval.
3.2.14  Participants with previous history of another malignant condition are excluded, 
except for localized cancers that have been adequately treated. This includes

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48
completely resected basal cell carcinoma or squamous cell carcinoma of the 
skin, in situ malignancy (e.g. DCIS of the breast), good risk prostate cancer 
after curative therapy and/or considered appropriate for watchful waiting (e.g. 
Gleason 6 or less, T2 or less and PSA< 10) , and stage I cervical cancer. If 
invasive malignancy was experienced 2 or more years ago and confirmed as 
cured, these participants may be considered for the study on case by case basis 
with PI discussion and approval
3.2.15  Female participants pregnant or breast-feeding. Pregnant women are excluded 
from this study because lenalidomide is an immunomodulatory agent with the 
potential for teratogenic or abortifacient effects. Because there is an unknown 
but potential risk of adverse events in nursing infants secondary to treatment of 
the mother with lenalidomide, breastfeeding should be discontinued if the 
mother is treated with lenalidomide. These potential risks may also apply to 
other agents used in this study. Lactating females must agree not to breast feed 
while taking lenalidomide.
3.2.16 Inability to comply with an anti-throembotic treatment regimen (e.g., 
administration of aspirin, enoxaparin, or low molecular weight heparin 
administration (type Innohep® or equivalent)
3.2.17  Peripheral neuropathy > Grade 2 on clinical examination, within 21 days of 
initiation of protocol therapy.
3.3
Inclusion and Exclusion Criteria for Randomization
After registration and prior to randomization, participants will receive 1 cycle of RVD. 
Participants are not required to meet additional eligibility or exclusion criteria prior to 
randomization procedures.
3.4
Inclusion of Women, Minorities and Other Underrepresented Populations
Women, minorities and members of other underrepresented populations will have equal 
consideration for participation in this trial.  Please note, however, that the prevalence of 
MM is more common among men than women, occurs more frequently with increasing 
age, and develops twice as often among black individuals than among white individuals. 
Inclusion and exclusion criteria are not expected to have a negative effect on recruitment 
or retention of these underrepresented populations.
3.5
Screening Procedures
3.5.1
Registration Screening
The Investigator is responsible for keeping a record of all participants screened for entry 
into the study and subsequently excluded. The reason(s) for exclusion must also be

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recorded. The following screening procedures must be performed within 21 days of 
initiation of protocol therapy. Results of skeletal survey, bone marrow biopsy, chest X-ray, 
MRI, and CT scans within 35 days of initiation of protocol therapy may be used to fulfill 
screening requirements:
o
Participants who are potentially eligible for study participation must sign an 
informed consent form prior to the undertaking of screening procedures for 
this study that are not a part of standard medical care.
o Inclusion and exclusion criteria re-reviewed.
o MM diagnosis will be confirmed and the disease stage at diagnosis 
(according to the criteria of Durie and Salmon, 1975; and the ISS published 
by Greipp et al., 2005 [See Appendix VII]) will be documented.
o Complete medical history will be obtained to include documentation of all 
treatments given for MM and all concomitant medications.
o Baseline Symptom Assessment, including neurotoxicity screening
o Physical examination to include measurement of vital signs, height, weight 
and calculation of body surface area (BSA).
o ECOG performance status will be evaluated (Appendix III)
o Hematology: hemoglobin, hematocrit, white blood cell (WBC) count and 
differential, and platelet count.
o Clinical laboratory tests: Blood chemistry [sodium, potassium, chloride, 
CO2, calcium, magnesium, phosphorous, blood urea nitrogen (BUN), 
creatinine, glucose, albumin, total protein, alkaline phosphatase, total 
bilirubin, AST/SGOT, ALT/SGPT, lactate dehydrogenase (LDH), uric acid, 
TSH], beta 2-microglobulin, C-reactive protein (CRP), B-12 and Folate. 
Albumin should be measured using the nephelometric method when
possible. However, standard institutional methods for measuring albumin are 
also allowed.
o CD4+ and CD8+ lymphocyte count
o HIV, Hepatitis B and Hepatitis C tests
o Urinalysis

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o 12-lead ECG
o LVEF measurement by multiple gate acquisition (MUGA) scan or 
echocardiogram (ECHO)
o Chest X-ray
o Pulmonary function tests (PFTs)
o Serum and urine M component quantification and immunofixation (SPEP, 
UPEP) and 24-hour urine collection for paraprotein measurement
o Assay of serum free light chains
o Serum or urine pregnancy test (sensitivity of at least 50 mIU/mL), for 
females of childbearing potential must be completed. The first test should be 
performed within 10-14 days, and the second test within 24 hours prior to 
initiation of lenalidomide. See Appendix II for more details and for the 
definition of females of childbearing potential used for this trial.
o Skeletal survey for quantification of bone lesions with magnetic resonance 
imaging (MRI) and CT scans as clinically indicated.
o Bone marrow aspiration to be evaluated for morphology and for cytogenetics 
by FISH methods, including marrow karyotype if possible. Bone marrow 
biopsy is also recommended. Results of bone marrow aspirate testing are 
needed in order to perform randomization.
o Bone marrow aspirate and blood collection for correlative studies (See
Section 8 for specimen shipping and handling details):
x
6 mL of bone marrow aspirate will be collected in each of 2 purple 
top tubes (EDTA); 6 mL of blood will be collected in each of 4 
purple top tubes (EDTA); 8.5 mL of blood will be collected in a 
proteomics tube; 10 mL of blood will be collected in a red top tube 
(no additive).
3.5.2
Randomization Screening
There are no additional screening test requirements for randomization. However, results of 
cytogenetics by FISH, and beta-2 microglobulin and albumin from registration screening 
tests are required in order to proceed with randomization because these laboratory results are 
stratification factors in the randomization. The Investigator is responsible for keeping a

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record of the reason(s) that participants do not proceed to randomization. This information 
will be collected in the database.
4.
REGISTRATION PROCEDURES
4.1
General Registration Guidelines for All Institutions
Institutions will register eligible participants with an electronic central registration 
system as well as the DF/HCC Quality Assurance Office for Clinical Trials (QACT) 
central registration system. Registration must occur prior to the initiation of
therapy. Any participant not registered to the protocol before treatment begins will be 
considered ineligible and registration will be denied.
A member of the study team will confirm eligibility criteria and complete the protocol- 
specific eligibility checklist.
Following registration, participants should begin protocol treatment within 72 hours or
as soon a possible. Issues that would cause treatment delays should be discussed with the
Principal Investigator.
4.2
Registration Process for DF/HCC Institutions
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to
5:00 PM Eastern Standard Time. In emergency situations when a participant must begin 
treatment during off-hours or holidays, call the QACT registration line at 617-632-3761 
and follow the instructions for registering participants after hours.
The registration procedures are as follows:
1.
Obtain written informed consent from the participant prior to the performance of any 
study related procedures or assessments.  Once eligibility criteria are confirmed following 
procedures described in Section 3, the patient must first be registered in the eCRF.
2.
Eligible participants will be registered in the eCRF by the participating site. 
Registration must occur prior to the initiation of therapy (RVD Cycle 1, Day 1).
3.
The participating institutions will register eligible participants to this study 24 hours a 
day, 7 days a week, using web-based registration: https:\www.ifm-online.fr/csonline. For 
assistance or questions, the technical support team can be contacted using the link “Contact 
Technical Support”. A user-specific login and password are required to access the website.
4.
Participant study number will be automatically allocated by the online registration 
system based on the following format :

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I    I    I   I  –  I    I    I    I
(3 digits for the site number)  –  (3 digits for the patient number) 
Note: Participant study number will be sequentially allocated for each site.
5.
To be eligible for registration to the study, the participant must meet all 
inclusion and exclusion criteria listed on the eligibility checklist.
6.
Information required for participant registration includes patient information (initials, 
date of birth, sex…), informed consent information, inclusion and exclusion criteria.
Some biological parameters are also required in order to complete registration.
7.
Once all registration information is entered and the web-based system verifies that 
inclusion and exclusion criteria are met, patient registration is confirmed. The site will 
receive an email confirmation with participant study number once the registration process 
is complete. Patients must not begin study treatment prior to receiving email 
confirmation.
8.
To register the participant with the DF/HCC Quality Assurance Office for Clinical 
Trials (QACT) central registration system, complete the protocol-specific eligibility 
checklist using the eligibility assessment documented in the participant’s 
medical/research record. To be eligible for registration to the study, the participant 
must meet each inclusion and exclusion criteria listed on the eligibility checklist.
9.
Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at
617-632-2295.
10.  The QACT Registrar will (a) validate eligibility, and (b) register the participant on 
the study.
11.  The QACT Registrar will send an email confirmation of the registration to the person 
initiating the registration immediately following the registration.
If a participant does not receive protocol therapy following registration, the participant’s 
protocol status must be changed. Notify the QACT Registrar of participant status 
changes as soon as possible.
4.3
Registration Process for Other Participating Institutions
The registration procedures are as follows:
1.    Obtain written informed consent from the participant prior to the performance of any 
study related procedures or assessments.  Once eligibility criteria are confirmed following 
procedures described in Section 3, the patient must be registered in the eCRF.

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If a participant does not receive protocol therapy following registration, the participant’s 
protocol status must be changed. Notify the 10-106 research team of participant status 
changes as soon as possible.
4.4
General Randomization Guidelines for All Institutions
Randomization must occur 2-3 weeks after the initiation of cycle 1 of RVD and prior 
to cycle 2 of RVD.
For those patients who do not continue to randomization, the reason why patient was not 
randomized must be documented and will be collected in the database. Patients who do not 
continue  to  randomization will  be  withdrawn  from  the  study.  These  patients  are  not 
followed for progression or survival.   If a patient is randomized and does not receive 
randomized treatment, they are followed for progression and survival in order to perform 
the intent to treat analysis. The baseline information is also collected on these patients.
4.5  Randomization Process for DF/HCC Institutions
The randomization procedures are as follows:
1.
The participating institution will randomize participants 24 hours a day, 7 days a week, 
using web-based randomization: https:\www.ifm-online.fr/csonline. For assistance or 
questions, the technical support team can be contacted using the link “Contact Technical 
Support”. A user-specific login and password are required to access the website.
2.
Randomization information is entered on the web-based randomization system by
the participating institution. Stratified permuted blocks will be used in the randomization 
using the following stratification factors. Stratification factor information will be 
requested at the time of  randomization, and randomization will be blocked if the 
following data are not entered:
-  ISS Stage I vs. II vs. III. Institutions will provide Beta2- microglobulin level (mg/L) 
and serum albumin level (g/dL) entered from screening visit, and the randomization 
system will compute the ISS stage.
-  Standard vs.  high  risk  vs.  FISH  failures. High-risk  is  defined as  the  presence of 
del(17p), or t(4:14), or t(14;16) using FISH.
-  Country (US)
3.
Once participant randomization data is entered in the eCRF, the randomization 
system will allocate the treatment arm (A or B).  The site will receive an email 
confirmation of treatment arm once the randomization process is complete.
4.
Randomization assignment for must also be entered into the DF/HCC QACT central 
registration system. The QACT registration staff is accessible on Monday through Friday, 
from 8:00 AM to 5:00 PM Eastern Standard Time.

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5.    Enter the randomization assignment on the protocol-specific eligibility checklist.
6.    Fax the eligibility checklist to the QACT at 617-632-2295.
7.    The QACT Registrar will enter the randomization assignment into the QACT
system.
8.
The QACT Registrar will send an email confirmation that the randomization 
assignment has been entered to the person initiating the randomization immediately 
following the randomization.
4.6
Randomization Process for Other  Participating Institutions
The randomization procedures are as follows:
1.    The participating institution will randomize participants 24 hours a day, 7 days a week, 
using web-based randomization: https:\www.ifm-online.fr/csonline.    For assistance or 
questions, the technical support team can be contacted using the link “Contact Technical 
Support”. A user-specific login and password are required to access the website.
2.
Randomization information is entered on the web-based randomization system by the 
participating
institution.
Stratified
permuted
blocks
will
be
used
in
the 
randomization using the following stratification factors.
Stratification factor information 
will be requested at the time of   randomization, and randomization will be blocked if the
following data are not entered:
-
ISS Stage I vs. II vs. III. Institutions will provide Beta2- microglobulin level (mg/L) and 
serum albumin level (g/dL) entered from screening visit, and the randomization system will 
compute the ISS stage.
- Standard vs. high risk vs. FISH failures. High-risk is defined as the presence of del(17p), or 
t(4:14), or t(14;16) using FISH.
-  Country (US)
3. Once participant randomization data is entered in the eCRF, the randomization system will 
allocate  the  treatment  arm  (A  or  B).    The  site  will  receive  an  email  confirmation  of 
treatment arm once the randomization process is complete.
5  TREATMENT PLAN
Expected toxicities and potential risks as well as dose modifications for lenalidomide, 
bortezomib and dexamethasone are described in Section 6 (Expected Toxicities and Dosing 
Delays/Dose Modification). No investigational or commercial agents or therapies other than 
those described below may be administered with the intent to treat the participant’s 
malignancy.

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Initial Therapy: 1 cycle of RVD
Initial Therapy with RVD for 1 Cycle
Agent
Pre-medications;
Precautions
Dose
Route
Schedule
Cycle
Length
Lenalidomide
Anti-thrombotic
therapy (e.g., aspirin, 
enoxaparin or low
molecular weight 
heparin type Innohep®
or equivalent)
25 mg/day
Oral
Days 1-14
for 1 cycle
Bortezomib
 
Doses should be
administered 70-72 
hours apart
1.3 mg/m2
3-5 second IV
injection
Days 1, 4, 8,
and 11 for 1 
cycle (+1
day window)
Dexamethasone
Take with food;
recommended to be 
taken in the morning
20 mg/day
Oral
Days 1, 2, 4,
5, 8, 9, 11 
and 12 for 1
cycle  (+1 
day window).  
Should be 
given day of 
and day after 
Velcade.
 
 
 
 
21 days
(3 weeks)
Arm A Treatment
Arm A:  RVD Cycles 2-3
Agent
Pre-medications;
Precautions
Dose
Route
Schedule
Cycle
Length
Lenalidomide
Anti-thrombotic
therapy (e.g., aspirin, 
enoxaparin or low
molecular weight 
heparin type Innohep®
or equivalent)
25 mg/day
Oral
Days 1-14
for 2 cycles
(+ 7 day 
window is 
allowed
between
cycles
 
 
 
21 days
(3 weeks)
Bortezomib
 
 
 
 
 
Doses should be
administered 70-72 
hours apart
1.3 mg/m2
3-5 second IV
injection
Days 1, 4, 8, 
and 11 for 2 
cycles (+ 7 
day window 
is allowed 
between 
cycles and
+1 day 
window for 
intra-cycle 
visits)
 

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Dexamethasone
Take with food;
recommended to be 
taken in the morning
20 mg/day
Oral
Days 1, 2, 4,
5, 8, 9, 11 
and 12 for 2 
cycles (+ 7
day is
allowed 
between 
cycles and
+1 day 
window for 
intra-cycle 
visits) 
Should be 
given day 
of and day 
after 
Velcade.
Arm A: PBSC Mobilization
Agent
Pre-medications;
Precautions
Dose
Route
Schedule
Cycle
Length
Cyclophosphamide
Per institutional
guidelines; Mesna
3 g/m2
IV
After cycle
3, 21 (+ 7 
days) days 
following 
the final
lenalidomide 
dose
 
 
Single
administrat 
ion
Filgrastim or G-
CSF type
Granocyte® or 
equivalent
Per institutional
guidelines
5 or 10
mcg/kg/day, 
according to
institutional
practice
Subcutaneous
Starting at
least 24
hours and no 
more than 48 
hours after 
cyclophosph 
amide dose 
until PBSC 
collection is 
complete
As needed
for blood 
counts
 
Arm A: Consolidation Therapy with RVD Cycles 4-8
Agent
Pre-medications;
Dose
Route
Schedule
Cycle
 
Precautions
 
 
 
Length
Lenalidomide
Anti-thrombotic
therapy (e.g., aspirin, 
enoxaparin or low 
molecular weight 
heparin type
Innohep®or 
equivalent)
25 mg/day
Oral
Days 1-14
for 5 cycles
(+ 7 day 
window is 
allowed 
between 
cycles)
 
 
 
 
21 days
(3 weeks)

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Bortezomib
 
 
 
 
 
Doses should be
administered 70-72 
hours apart
1.3 mg/m2
3-5 second IV
injection
Days 1, 4, 8,
and 11 for 5 
cycles (+ 7
day window
is allowed 
between 
cycles and
+1 day 
window for 
intra-cycle 
visits)
Dexamethasone
Take with food;
recommended to be 
taken in the morning
10 mg/day
Oral
Days 1, 2, 4,
5, 8, 9, 11 
and 12 for 5 
cycles (+ 7
day window
is allowed 
between 
cycles and
+1 day 
window for 
intra-cycle 
visits).  
Should be 
given day 
of and day 
after 
Velcade.
 
 
 
Arm A: Maintenance Therapy Until Disease Progression  
Agent
Pre-medications;
Dose
Route
Schedule
Cycle
Lenalidomide
Recommended anti- 
thrombotic therapy 
(e.g., aspirin, 
enoxaparin or low 
molecular weight 
heparin type Innohep® 
or equivalent) and as 
clinically indicated
10 mg/day
(months 1-3);
15 mg/day 
(months 4-12, 
if initially well 
tolerated)
Oral
Within 3 
weeks of 
completing 
RVD 
consolidati 
on; Days
1-28 until 
disease 
progressio 
n (+ 14 
day 
window is 
allowed 
between 
cycles)
28 days
(4 weeks)

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Arm B Treatment
Arm B: RVD Cycles 2-3
Agent
Pre-medications;
Precautions
Dose
Route
Schedule
Cycle
Length
Lenalidomide
Anti-thrombotic
therapy (e.g., aspirin, 
enoxaparin or low
molecular weight 
heparin type Innohep®
or equivalent)
25 mg/day
Oral
Days 1-14
for 2 cycles
(+ 7 day 
window is
allowed 
between
cycle)
Bortezomib
 
 
 
 
 
Doses should be
administered 70-72 
hours apart
1.3 mg/m2
3-5 second IV
injection*
Days 1, 4, 8,
and 11 for 2 
cycles (+ 7
day window 
is allowed
between
cycles and
+1 day 
window for 
intra-cycle 
visits)
Dexamethasone
Take with food;
recommended to be
taken in the morning
20 mg/day
Oral
Days 1, 2, 4,
5, 8, 9, 11
and 12 for 2 
cycles (+ 7 
day window 
is allowed 
between 
cycles and
+1 day 
window for 
intra-cycle 
visits). 
Should be 
given day 
of and day 
after 
Velcade.
 
 
 
21 days
(3 weeks)

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Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
Version Date:     November 30, 2016
 
Arm B: PBSC Mobilization
Agent
Pre-medications;
Precautions
Dose
Route
Schedule
Cycle
Length
Cyclophosphamide
Per institutional
guidelines; Mesna
3 g/m2
IV
After cycle
3, 21 (+ 7 
days) days 
following 
the final
lenalidomide 
dose
 
 
Single
administrat 
ion
Filgrastim or G-
CSF type
Granocyte® or 
equivalent
Per institutional
guidelines
5 or 10
mcg/kg/day, 
according to 
institutional
practice
Subcutaneous
Starting at 
least 24
hours and 
not more 
than 48 
hours after
cyclophosph 
amide dose
until PBSC
collection is 
complete
As needed
for blood 
counts
 
Arm B: PBSC Transplant
Agent
Pre-medications;
Precautions
Dose
Route
Schedule
Cycle
Length
Melphalan 
(original 
formulation)
OR
Melphalan 
(Evomela 
formuation)
Per institutional
guidelines
Per institutional 
guidelines
200 mg/m2
(100 mg/m2
/day if 
administered 
over 2 days)
100 mg/ m2 
Per day 
administered 
over 30 minutes 
over 2 days
IV
IV
Day minus 2
and Day 
minus1 or
Day minus 2, 
according to
institutional
practice
Day Minus 3 and 
Day minus 2or 
according to 
institutional 
practice
 
1 or 2 days
2 days
PBSC reinfusion
Acetaminophen,
Diphenhydramine
> 5x106
cells/kg
IV
Day 0
Single
administrat 
ion

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Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
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Filgrastim or G- 
CSF type 
Neulasta® or 
equivalent
Per institutional 
guidelines
Filgrastim: 5 
mcg/kg/day; 
G-CSF type 
Neulasta®: 6 
mg; or 
according to 
institutional 
practice
Subcutaneous
For 
filgrastim: 
Daily, 
starting 
Day+5 until 
engraftment; 
For G-CSF 
type 
Neulasta®: 
on Day +2 
after stem 
cell 
transplant; 
OR as per 
institutional 
practice
As needed 
for blood 
counts
 
Arm B: Consolidation Therapy with RVD for 2 Cycles
Agent
Pre-medications;
Precautions
Dose
Route
Schedule
Cycle
Length
Lenalidomide
Anti-thrombotic
therapy (e.g., aspirin, 
enoxaparin or low
molecular weight 
heparin type Innohep®
or equivalent)
25 mg/day
Oral
Beginning
60-110 days 
after
PBSCT; 
Days 1-14
for 2 cycles
(+ 7 day 
window is 
allowed 
between 
cycles)
Bortezomib
 
 
 
 
 
 
 
Doses should be
administered 70-72 
hours apart
1.3 mg/m2
3-5 second IV
injection*
Beginning
60-110 days 
after 
PBSCT;
Days 1, 4, 8, 
and 11 for 2
cycles (+ 7 
day window
is allowed
between 
cycles and
+1 day 
window for 
intra-cycle
visits)
 
 
 
 
21 days
 
(3 weeks)

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Dexamethasone
Take with food; 
recommended to be 
taken in the morning
10 mg/day
Oral
Beginning
60-110 days 
after 
PBSCT;
Days 1, 2, 4,
5, 8, 9, 11 
and 12 for 2 
cycles (+ 7 
day window 
is allowed 
between 
cycles and
+1 day 
window for 
intra-cycle 
visits).
Should be 
given day 
of and day 
after 
Velcade.
 
Arm B: Maintenance Therapy Until Disease Progression
Agent
Pre-medications;
Precautions
Dose
Route
Schedule
Cycle
Length
Lenalidomide
Recommended anti-
thrombotic therapy 
(e.g., aspirin, 
enoxaparin or low 
molecular weight 
heparin type Innohep® 
or equivalent) and as 
clinically indicated
10 mg/day
(months 1-3);
15 mg/day 
(months 4-12, 
if initially well 
tolerated)
Oral
Within 3
weeks of 
completing 
RVD 
consolidati 
on; Days
1-28 until 
disease 
progressio 
n (+ 14 
day and -7 
day 
window is 
allowed 
between 
28 days
(4 weeks)
*Subcutaneous administration of Bortezomib may be considered in the event of > Grade 1-painful peripheral 
neuropathy; Study PI must approve such change in administration (see Section 6.3.4.3)
5.1 Pre-treatment Criteria
5.1.1
Initiation of New Cycle of RVD Therapy (Day 1)
A new course of treatment may begin on the scheduled Day 1 of a new cycle of 
RVD if the following criteria are met:
ƒ
ANC > 1,000/ mm3 (growth factor support is permitted during cycles 

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of RVD, with the exception of Cycle 1 Day 1; it is allowed on the 
same day as treatment administration) 
ƒ
Platelet count > 50,000/ mm3 (platelet support is permitted during cycles of
RVD; it is allowed on the same day as treatment administration)
* Patients’ local lab results from the previous day may be used to fulfill 
criteria above only if performed within 24 hours from Day 1.
ƒ
Any lenalidomide-related allergic reaction/hypersensitivity or sinus
bradycardia/other cardiac arrhythmia adverse event that may have occurred 
has resolved to < grade 1 severity.
ƒ
Any other lenalidomide or bortezomib-related adverse event that may have
occurred has resolved to < grade 2 severity.
ƒ
Grade 1 with pain or grade 2 peripheral neuropathy requires dose
modification, and grade 2 peripheral neuropathy with pain requires that 
bortezomib be held (See Section 6.3.4.3 for details).
ƒ
Herpes Zoster lesions are dry
If these conditions are not met on Day 1 of a new cycle, the participant will be 
evaluated weekly and a new cycle of therapy will not be initiated until the toxicity has 
resolved as described above.
If lenalidomide is held during lenalidomide maintanence, and the patient comes back the 
following week to be re-evaluated, it is acceptable to only repeat the CBC with diff and 
the history and physical examination at that visit.  However, please repeat the multiple 
myeloma restaging labs if more than 3 weeks has passed during a hold period.
  The maximum amount of time for which a drug may be held due to toxicity is 6 
weeks.  However, treatment delay for more than 3 weeks (for any study treatment) 
will require authorization from the PI.  If drug is held for more than 6 weeks due to 
toxicity, the participant will be removed from study treatment.
If there were dose modifications or delays in the previous cycle, use the following 
guidelines:
ƒ
If lenalidomide was held during the previous cycle and restarted at a reduced
dose level, without interruption for the remainder of the cycle, then the 
reduced dose level will be initiated on Day 1 of the new cycle.
ƒ
If lenalidomide dosing was omitted for the remainder of the previous cycle or
if a new cycle is delayed due to lenalidomide-related toxicity newly 
encountered on the scheduled Day 1, then the new cycle will be started with 
one-level dose reduction.
ƒ
If any two or more doses of bortezomib were held during the cycle (either
consecutively or two or more in one cycle), then the new cycle will be started 
with one level dose reduction.
ƒ
If the new cycle is delayed due to bortezomib-related toxicity newly
encountered on the scheduled Day 1, then the new cycle will be started with 
a one-level dose reduction.
Dose modification guidelines are described in Section 6.3 (Dose Modifications/Delays).

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5.1.2
Intra-cycle RVD Therapy (Days 4, 8 and 11) (+ 1 day)
For intra-cycle dosing on Days 4, 8, and 11 (+ 1 day), the following criteria 
must be met:
ƒ
ANC > 750/mm3 (growth factor support is permitted)
ƒ
Platelet count > 30,000/mm3 (platelet support is permitted)

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* Patients’ local lab results from the previous day may be used to 
fulfill criteria above only if performed within 24 hours of specified 
visit date (Days 4, 8 and 11) (+ 1 day).
Transfusion to support a platelet count of > 50,000/mm3 at investigator 
discretion is permitted.
5.1.3
PBSC Collection and Transplant
Pre-treatment criteria for PBSC collection and PBSC transplant should be 
according to institutional standards.
5.1.4
Initiation of New Cycle of Lenalidomide Maintenance Therapy
A new course of treatment may begin on the scheduled Day 1 of a new cycle if 
the following criteria are met:
ƒ
ANC > 1,000/mm3 (growth factor support is permitted)
ƒ
Platelet count > 50,000/mm3 (platelet support is permitted)
* Patients’ local lab results from the previous day may be used to 
fulfill criteria above only if performed within 24 hours from Day 1.
ƒ
Any lenalidomide-related allergic reaction/hypersensitivity, neuropathy,
or sinus bradycardia/other cardiac arrhythmia adverse event that may 
have occurred has resolved to < grade 1 severity.
ƒ
Any other lenalidomide-related adverse event that may have occurred has
resolved to < grade 2 severity.
If these conditions are not met on Day 1 of a new cycle, the participant will be evaluated 
weekly and a new cycle of therapy will not be initiated until the toxicity has resolved as 
described above. The maximum amount of time for which a drug may be held due to 
toxicity is 6 weeks.  However, treatment delay for more than 3 weeks (for any study 
treatment) will require authorization from the PI.  If drug is held for more than 6 weeks 
due to toxicity, the participant will be removed from study treatment.
Please also refer to section 6.3.4.2 for guidance regarding dosing modification guidelines 
for lenalidomide during maintanence.  
5.2  Agent Administration
5.2.1   Initial Therapy with RVD for 1 Cycle for All Participants
5.2.1.1  Lenalidomide
Lenalidomide (Revlimid®) will be provided to research subjects for the duration 
of their participation in this trial at no charge to them or their insurance providers. 
Lenalidomide will be provided in accordance with the Celgene Corporation’s 

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Revlimid REMS® program. Per standard Revlimid REMS® program 
requirements, all physicians who prescribe lenalidomide for research subjects 
enrolled into this trial, and all research subjects enrolled into this trial, must be

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   Short title: Phase III Study of RVD versus RVD plus auto SCT in newly diagnosed MM participants
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registered in, and must comply with, all requirements of the Revlimid REMS® 
program. Drug will be shipped on a per patient basis by the contract pharmacy to 
the clinic site for IND studies. Only enough lenalidomide for one cycle of 
therapy will be supplied to the patient each cycle.
Participants will only receive treatment with lenalidomide for one cycle. 
Lenalidomide will be given as a single daily oral dose of 25 mg per day on days
1-14 followed by a 7-day rest period. A window of +7 days is allowed between 
RVD treatment cycles. Dose modification guidelines are described in Section 6.3 
(Dose Modifications/Delays).
Lenalidomide capsules should be swallowed whole, and should not be broken, 
chewed or opened. Administration of lenalidomide will be at approximately the 
same time each day. Drug may be taken with or without food.  If a dose is missed 
and less than 12 hours has elapsed since the missed dose, the patient can take the 
dose for that day. If more than 12 hours has elapsed since missing a dose at the 
normal time, the patient should not take the dose, but take the next dose at the 
normal time on the following day. If a dose is missed, it should be taken as soon 
as possible on the same day. If a dose is vomited, the dose should not be made up 
and the participant should continue with the regular schedule of the drug at the 
next dose.  A drug diary will be provided to participants to record oral 
administration of doses.
Participants who take more than the prescribed dose of lenalidomide should be 
instructed to seek emergency medical care if needed and contact study staff 
immediately. Participants experiencing adverse events may need study treatment 
modifications (see Section 6.3).
The following document will be provided to all patients prior to receiving 
lenalidomide therapy:
1)   The Lenalidomide Information Sheet (Appendix I) will be given to each 
patient receiving lenalidomide study therapy. The patient must read this 
document prior to starting lenalidomide study treatment.
2)  The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods document (Appendix II), which provides 
information regarding the risks to the fetus associated with lenalidomide 
exposure, the definition of Female of Childbearing Potential, pregnancy
testing requirements for patients receiving lenalidomide who are females of 
childbearing potential, acceptable birth control methods for both female of 
childbearing potential and male patients receiving lenalidomide in the study, 
and requirements for counseling of all study patients receiving lenalidomide 
about pregnancy precautions and the potential risks of fetal exposure to 
lenalidomide
5.2.1.2  Bortezomib

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Millennium Pharmaceuticals Incorporated will supply bortezomib for the study 
for the first 400 patients enrolled.  Subsequent participants will receive 
bortezumab from the commercial supply.  If the participant receives the drug 
from the commercial supply, this may lead to added costs for the participant or 
the participant’s insurance company.   Bortezomib will be administered at a
dose of 1.3 mg/m2. The appropriate amount of bortezomib will be drawn from 
the injection vial after reconstitution and administered as a 3-5 second IV 
injection/push followed by a standard saline flush or through a running IV line. 
Subcutaneous administration at a concentration of 2.5 mg/mL may be 
considered only in the presence of peripheral neuropathy (see Section 6.3.4.3), 
with approval granted by the Study PI.
Vials are for single use administration. Bortezomib should not be administered 
in participants who have a known allergy to bortezomib, boron or mannitol.
Participants will receive initial treatment with bortezomib for one cycle. 
Participants will receive bortezomib doses on Days 1, 4, 8 and 11 (+1 day 
window) of this cycle followed by a 10-day rest period.  A window of +7 days 
is allowed between RVD treatment cycles. Dose modification guidelines are 
described in Section 6.3 (Dose Modifications/Delays).
Drug will be administered only to eligible participants under the supervision of 
the investigator or identified sub-investigator(s). Participants may be treated
on an out-patient basis, if possible.  The drug will be prepared under the 
supervision of a pharmacist, or appropriately qualified and trained personnel. 
The amount (in mg) of drug to be administered will be determined based on 
BSA.    To calculate BSA, the DuBois formula is the preferred method.  
However, Mosteller is also acceptable. (Appendix IV).   The dose should be 
calculated on Day 1 of the cycle, and should be recalculated at the start of the 
next cycle; the dose administered should remain the same throughout the 
cycle.  If a participant experiences a
notable change in weight (i.e., loss or gain of 5% body weight) within the cycle, 
as determined by an unscheduled weight assessment, then the participant’s dose 
should be recalculated at that time.
At least 72 hours must elapse between bortezomib doses. Dosing at an interval 
of 70 hours may be considered for scheduling, patient convenience or hardship. If 
the patient develops toxicity including neuropathy, this approach, less than 72 
hours between doses, is not recommended.
5.2.1.3  Dexamethasone
Dexamethasone will be obtained by commercial supply in this study.  This may 
lead to added costs for the participant or the participant’s insurance company.
It will be given as a single daily oral dose.  Dexamethasone should be taken at 
approximately the same time each day.  It is recommended that 

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dexamethasone be taken in the morning to reduce insomnia.  Each dose 
should be taken with food.  If a dose of dexamethasone is missed or vomited, 
the participant should continue with the regular schedule of the drug at the 
next dose.  A drug diary will be provided to participants to record oral 
administration of doses.
Participants will receive treatment with dexamethasone for one cycle at 20 mg per 
day. Participants will receive dexamethasone doses on Days 1, 2, 4, 5, 8, 9, 11 
and 12 of this cycle (+ 1 day window), followed by a 9-day rest period.  A 
window of +7 days is allowed between RVD treatment cycles. Dose
modification guidelines are described in Section 6.3 (Dose Modifications/Delays).
5.2.2
Arm A
5.2.2.1   RVD Cycles 2-3
5.2.2.1.1  Lenalidomide
Participants in Arm A will receive treatment with lenalidomide for two additional 
cycles prior to PBSC collection. See Section 5.2.1.1 for details of administration. 
A window of + 7 days is allowed between RVD treatment cycles. Dose 
modification guidelines are described in Section 6.3 (Dose Modifications/Delays). 
Dose modifications will be managed with 5mg capsules.
5.2.2.1.2  Bortezomib
Participants in Arm A will receive treatment with bortezomib for two additional 
cycles prior to PBSC collection. See Section 5.2.1.2 for details of administration. 
A window of + 7 days is allowed between RVD treatment cycles.  An intracycle 
window is allowed of +1 day. Dose modification guidelines are described in 
Section 6.3 (Dose Modifications/Delays).
5.2.2.1.3  Dexamethasone
Participants in Arm A will receive treatment with dexamethasone for two 
additional cycles prior to PBSC collection. See Section 5.2.1.3 for details of 
administration. A window of + 7 days is allowed between RVD treatment 
cycles.  An intracycle window is allowed of +1 day.
Dose modification 
guidelines are described in Section 6.3 (Dose Modifications/Delays).
5.2.2.2   Autologous PBSC Collection 21 days after Cycle 3 of RVD
Following initial therapy with lenalidomide, bortezomib and dexamethasone, 
participants in Arm A will undergo collection of autologous PBSCs. The 

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cyclophosphamide dose will be administered 21 days after the last dose of 
lenalidomide in cycle 3.  A window of + 7 days is allowed for scheduling.
Participants will undergo stem cell mobilization with cyclophosphamide (IV) at a 
dose of 3 g/m2. Filgrastim or G-CSF type Granocyte® or equivalent will be 
administered at a dose of 5 or 10 mcg/kg/day subcutaneously, according to 
institutional practice, starting at least 24 hours and not more than 48 hours after 
cyclophosphamide administration and continuing until the PBSC collection is 
complete. Filgrastim is preferred, but G-CSF type Granocyte® or equivalent is
allowed for those sites who do not use filgrastim. For participants who weigh 
above 120% of their ideal body weight, the adjusted ideal body weight (AIBW)
(See Appendix XI) should be used for cyclophosphamide, filgrastim or G-CSF type 
Granocyte® or equivalent dosing. Beginning ten days after cyclophosphamide or 
start of G-CSF administration, according to institutional practice, participants must 
collect a minimum CD34 count of > 5x106 cells/kg. In case of insufficient 
collection, collection of a minimum CD34 count of > 2x106 cells/kg will be 
allowed.
If a participant is unable to collect a minimum of  > 2x106 cells/kg, it is suggested 
that an additional attempt at mobilization be performed using plerixafor. Plerixafor 
should be administered, in combination with filgrastim or G-CSF type Granocyte®, 
as follows:
x
Filgrastim or G-CSF type Granocyte® 10 mcg/kg/day subcutaneously every 
morning on mobilization days 1 through 5, and thereafter every morning until 
an adequate number of stem cells are collected
x
Plerixafor 0.24 mg/kg/day subcutaneously every evening beginning on 
mobilization day 4 and continuing daily for up to 4 consecutive days until an 
adequate number of stem cell are collected. The plerixafor dose should be 
based on actual weight.
Stem cell collection should be performed 10-11 hours after plerixafor 
administration.
If this additional mobilization attempt fails, a bone marrow sample may be taken 
and used in combination with PBSC.
If no stem cell product is obtained after all above attempts have been made, the 
participant will proceed with consolidation treatment with RVD cycles.
In the event of disease relapse or progression for participants on Arm A, an 
autologous PBSC transplant with high-dose melphalan is recommended, as 
described in Section 5.2.3.3.  Induction will be variable depending on the response 
to the induction treatment and the time of relapse or progression.
5.2.2.3  Consolidation with RVD Cycles 4-8
Following PBSC collection, participants will undergo consolidation therapy with 

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RVD.  In case of grade 2 peripheral neuropathy or grade 1 peripheral neuropathy with 
pain, bortezomib dose reduction is required (See Section 6.3.4.3 for detail). 
In case of grade 2 neuropathy with pain or neuropathy with a grade higher than 2 
during consolidation treatment, hold bortezomib and administer lenalidomide and 
dexamethasone only for the remainder of consolidation.
5.2.2.3.1  Lenalidomide
Participants in Arm A will receive treatment with lenalidomide for five cycles during 
consolidation therapy. See Section 5.2.1.1 for details of administration. A window 
of + 7 days is allowed between RVD treatment cycles.  Dose modification 
guidelines are described in Section 6.3 (Dose Modifications/Delays). Dose 
modifications will be managed with 5mg capsules.
5.2.2.3.2  Bortezomib
Participants in Arm A will receive treatment with bortezomib for five cycles during 
consolidation therapy. See Section 5.2.1.2 for details of administration. A window of
+ 7 days is allowed between RVD treatment cycles.  A window of +1 day is 
allowed for intra cycle visits.  Dose modification guidelines are described in Section
6.3 (Dose Modifications/Delays).
5.2.2.3.3  Dexamethasone
Participants in Arm A will receive treatment with dexamethasone for five cycles 
during consolidation therapy. Participants will receive dexamethasone at 10 mg per 
day on Days 1, 2, 4, 5, 8, 9, 11 and 12, followed by a 9-day rest period. See Section
5.2.1.3 all other details of administration. A window of +1 day is allowed for intra 
cycle visits.  A window of + 7 days is allowed between RVD treatment cycles. 
Dose modification guidelines are described in Section 6.3 (Dose 
Modifications/Delays).
5.2.2.4
Lenalidomide Maintenance Therapy until Disease Progression
Celgene Corporation will supply lenalidomide as 5 mg capsules for oral 
administration. Drug will be shipped to the pharmacy at the study site in individual 
bottles. Lenalidomide investigational supplies are dispensed to the participant in 
individual bottles of capsules. Each bottle will identify the contents as study 
medication and bear the name of Celgene Corporation, quantity contained and 
standard caution statement as follows: Caution: New drug – Limited by Federal law 
to investigational use.  Drug must be dispensed in the original packaging with the
label clearly visible. For appropriate drug accountability, it is recommended that each 
bottle be marked with the institutional protocol number or Celgene tracking number 
(RV-MM-IFM-0444) upon receipt. Additional labels must not cover the Celgene 
label.

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Lenalidomide capsules should be swallowed whole, and should not be broken,
chewed or opened. Administration of lenalidomide will be at approximately the same 
time each day. Drug may be taken with or without food.  If a dose is missed and 
lessthan 12 hours has elapsed since the missed dose, the patient can take the dose for 
that day. If more than 12 hours has elapsed since missing a dose at the normal time, 
the patient should not take the dose, but take the next dose at the normal time on the 
following day. If a dose is vomited, the dose should not be made up and the 
participant should continue with the regular schedule of the drug at the next dose.  A 
drug diary will be provided to participants to record oral administration of doses.
Following completion of consolidation therapy, the participants in Arm A will 
undergo maintenance therapy with lenalidomide until disease progression. 
Participants should continue straight to maintenance therapy and may have up to 3 
weeks following completion of RVD consolidation to begin maintenance. Drug will 
be taken orally at an initial dose of 10 mg/day, continuously for 28 days, of a 28-day 
cycle. A window of + 14 days and -7 days  is allowed between lenalidomide 
treatment cycles. A dose increase to 15 mg/day will be allowed after 3 months at the 
initial dose, if the participant tolerates 10 mg/d without complication. In case of dose 
reduction during the previous cycle, and the cycle was completed without requiring 
further dose modification, then the next cycle will start at the same reduced dose of 
lenalidomide. If lenalidomide dosing was omitted for the remainder of the previous 
cycle or if the new cycle is delayed due to toxicity newly encountered on the 
scheduled Day 1, then the new cycle will be started with a one-level dose reduction 
of lenalidomide. Lenalidomide dose modifications are described in detail in Section 
6.3 (Dose Modifications/Delays). Dose adaptations will be managed with 5 mg 
capsules.
If peripheral neuropathy worsens during maintenance therapy, lenalidomide dose will 
be reduced. If no improvement is seen with dose reduction of lenalidomide, the 
participant will be removed from study.
During maintenance therapy, lenalidomide will be shipped to the pharmacy at the 
study site in individual bottles. Bottles will contain a sufficient number of capsules 
for 1 cycle of dosing. Only enough lenalidomide for 1 cycle may be provided to 
the participant each cycle.
Participants who take more than the prescribed dose of lenalidomide should be 
instructed to seek emergency medical care if needed and contact study staff 
immediately. Participants experiencing adverse events may need study treatment 
modifications (see Section 6.3).
5.2.3
Arm B
5.2.3.1  RVD Cycles 2-3

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5.2.3.1.1  Lenalidomide
Participants in Arm B will receive treatment with lenalidomide for two additional 
cycles prior to PBSC collection. See Section 5.2.1.1 for details of administration. 
Awindow of + 7 days is allowed between RVD treatment cycles. Dose 
modification guidelines are described in Section 6.3 (Dose Modifications/Delays). 
Dose modifications will be managed with 5mg capsules.
5.2.3.1.2  Bortezomib
Participants in Arm B will receive treatment with bortezomib for two additional 
cycles prior to PBSC collection. See Section 5.2.1.2 for details of administration. 
A window of + 7 days is allowed between RVD treatment cycles. A window of
+1 day is allowed for intra cycle visits.
Dose modification guidelines are 
described in Section 6.3 (Dose Modifications/Delays).
5.2.3.1.3  Dexamethasone
Participants in Arm B will receive treatment with dexamethasone for two additional 
cycles prior to PBSC collection. See Section 5.2.1.3 for details of administration. A 
window of + 7 days is allowed between RVD treatment cycles. A window of +1 
day is allowed for intra cycle visits.
Dose modification guidelines are described 
in Section 6.3 (Dose Modifications/Delays).
5.2.3.2   Autologous PBSC Collection 21 days after cycle 3 of RVD
Following initial therapy with lenalidomide, bortezomib and dexamethasone, 
participants in Arm B will undergo collection of autologous PBSCs. This will 
occur 21 days after the last dose of lenalidomide in cycle 3.  A window of + 7 days 
is allowed for scheduling. See Section 5.2.2.2 for further detail of agent 
administration.
If no stem cell product is obtained after all above attempts have been made, the 
participant will proceed with consolidation treatment with RVD for 5 cycles, 
instead of the planned 2 cycles.
5.2.3.3
Autologous PBSC Transplant
Participants in Arm B will undergo conditioning for autologous PBSC transplant with 
melphalan. Melphalan will be administered either as a single dose of 200 mg/m2 IV 
over 30 minutes on day minus 2 OR as a divided dose of 100 mg/m2/day IV over 2 
days on day minus 2 and day minus 1 for a total dose of 200 mg/m2. For participants 
who weigh above 120% of their ideal body weight, the adjusted ideal body weight 
(AIBW) (See Appendix XI) should be used.

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A total of 5x106 cells/kg will be re-infused on day 0.  A minimum of 2x106 cells/kg 
will be allowed in case of insufficient collection. Filgrastim will be administered at a 
dose of 5 mcg/kg/d subcutaneously, starting on day +5 following PBSC transplant. 
For participants who weigh above 120% of their ideal body weight, the adjusted ideal 
body weight (AIBW) (See Appendix XI) should be used.  Filgrastim will continue

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until ANC > 1500/mm3 for 2 days or > 5000/mm3 for one day, or per institutional 
guidelines. Filgrastim is preferred, but G-CSF type Neulasta® or equivalent is allowed 
for those sites who do not use filgrastim. G-CSF type Neulasta® should be 
administered at a dose of 6 mg subcutaneously, on day +2 following PBSC transplant. 
Administration of G-CSF per institutional practice is also permitted.
Supportive care will be administered as per institutional practice.
5.2.3.4
Consolidation with RVD for 2 cycles
Beginning 60-110 days after PBSC reinfusion, participants will undergo
consolidation therapy with RVD.  In case of grade 2 peripheral neuropathy or grade 1 
peripheral neuropathy with pain, bortezomib dose reduction is required (See Section
6.3.4.3 for detail).   In case of grade 2 neuropathy with pain or neuropathy with a 
grade higher than 2 during consolidation treatment, hold bortezomib and administer 
lenalidomide and dexamethasone only for the remainder of consolidation
In discussion with the Principal Investigator and on a case-by-case basis, provisions 
may be made to start at a lower dose of lenalidomide for participants with inadequate 
hematologic parameters at 110 days following PBSC reinfusion.
5.2.3.4.1  Lenalidomide
Participants in Arm B will receive treatment with lenalidomide for two cycles during 
consolidation therapy. See Section 5.2.1.1 for details of administration. A window
of + 7 days is allowed between RVD treatment cycles. Dose modification guidelines
are described in Section 6.3 (Dose Modifications/Delays). Dose adaptations will be 
managed with 5 mg capsules.
5.2.3.4.2  Bortezomib
Participants in Arm B will receive treatment with bortezomib for two cycles during 
consolidation therapy. See Section 5.2.1.2 for details of administration. A window of
+ 7 days is allowed between RVD treatment cycles. A window of +1 day is allowed 
for intra cycle visits.  Dose modification guidelines are described in Section
6.3 (Dose Modifications/Delays).
5.2.3.4.3  Dexamethasone
Participants in Arm B will receive treatment with dexamethasone as a single daily 
oral dose of 10 mg per day for two cycles during consolidation therapy. Participants 
will receive dexamethasone doses on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle, 
followed by a 9-day rest period. A window of + 7 days is allowed between RVD 
treatment cycles. See Section 5.2.1.3 for all other details of administration. A

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window of +1 day is allowed for intra cycle visits.   Dose modification guidelines 
are described in Section 6.3 (Dose Modifications/Delays).
5.2.3.5  Lenalidomide Maintenance Therapy until Disease Progression
Following completion of consolidation therapy, the participants in Arm B will
undergo maintenance therapy with lenalidomide until disease progression. See Section
5.2.2.4 for details of administration. A window of + 14 days and -7 days is allowed 
between lenalidomide treatment cycles.  Lenalidomide dose modifications are 
described in detail in Section 6.3 (Dose Modifications/Delays). Dose adaptations will 
be managed with 5 mg capsules.
If peripheral neuropathy worsens during maintenance therapy, lenalidomide dose will 
be reduced. If no improvement is seen with dose reduction of lenalidomide, the 
participant will be removed from study.
5.3 Definition of Dose-Limiting Toxicity
This section is Not Applicable.
5.4 General Concomitant Medication and Supportive Care Guidelines
5.4.1 Required Concomitant Therapy during cycles of RVD
Lenalidomide increases the risk of thrombotic events in patients who are at high 
risk or with a history of thrombosis, in particular when combined with other drugs 
known to cause thrombosis. When lenalidomide is combined with other agents 
such as steroids (e.g. dexamethasone, prednisone), anthracyclines (Doxil, 
Adriamycin) and erythropoietin the risk of thrombosis is increased.
Thromboprophylaxis is required for all participants during cycles of RVD therapy. 
Participants may receive daily aspirin administration (81 or 325 mg), daily 
enoxaparin (40 mgs), or low molecular weight heparin (type Innohep® 4500 UI 
anti-Xa as needed) or equivalent to decrease the risk of thromboembolic 
complications.
It is recommended that if the platelet count falls below
50,000/mm3, thromboprophylaxis be held to minimize the risk of bleeding and then 
resumed when platelet counts are equal to or above this level.
It is required that participants receive prophylaxis against herpes zoster using oral 
acyclovir (400 mgs twice daily) or valaciclovir (500 mgs twice daily) or equivalent 
antiviral therapy per institutional guidelines and at the discretion of the physician, 
unless the participant has a hypersensitivity to the agents. The dose will be adjusted 
based upon serum creatinine levels according to package insert.

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Concomitant bisphosphonate therapy, according to institutional administration 
guidelines, is also required unless contraindicated.
5.4.2 Recommended Concomitant Therapy during cycles of RVD
It is strongly recommended that participants receive Pneumocystis Pneumonia 
prophylaxis using sulfamethoxazole and trimethoprim (1 tablet three times per 
week) or equivalent therapy and amoxicillin (1 g twice daily) or equivalent 
antibiotic therapy per institutional guidelines and at the discretion of the physician, 
unless the participant has a hypersensitivity to the agents.
It is also recommended that the following vitamins be administered with food as 
supplements to prevent neuropathy at the discretion of the site investigator:
o Multi-B Complex Vitamins, once daily: with B1, B12, B6 at RDA.  B6 
dose should not exceed 100 mg.
o Folic acid 1 mg/daily
o Vitamin E and Vitamin D: Up to 400 IU daily
o Acetyl L-Carnitine: 500 mg twice a day with food AND
Alpha-Lipoic Acid: 500 mg a day with food OR
o
A combination pill of: Alpha lipoic acid 200 mg + Acetyl-L-Carnitine 500 
mg: take ONE twice a day with food.
o
Cocoa butter: (rich in Vitamin E, xanthines and natural serotonins): Apply 
to extremities twice a day with gentle massage. Menthol-based creams can 
also be used for areas of numbness as needed.
Please note that all supplements (except emollient creams) should not be taken on 
days of bortezomib administration.
Other recommended therapy:
o Prophylactic antibiotics, according to individual institution guidelines.
o Mouth care is recommended.
o Erythropoietin is allowed.
o All supportive measures consistent with optimal participant care will be
given throughout the study.
5.4.3  Concomitant Therapy during PBSC Collection and Transplant
During PBSC collection, participants will receive IV bolus of Mesna 600 mg/m2 (or 
dose according to institutional practice) per dose on the day of cyclophosphamide 
administration. Mesna will be administered according to the following schedule or 
per institutional practice: 30 minutes prior to cyclophosphamide and 3, 6, and 9 
hours after cyclophosphamide. A window of + 30 minutes is allowed for 
administration of Mesna doses.  The 9 hour dose may be given orally at double the 
IV dose (1200 mg/m2), and may be self-administered at home. If the 9 hour dose of 
Mesna is missed, it may be taken at a later time that same day. If the 9 hour dose of 
Mesna is vomited, it should not be retaken. A drug diary will be provided to

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participants to record oral administration of the 9 hour dose of Mesna. 
Alternatively, the Mesna dose may be mixed with the cyclophosphamide dose and 
administered IV over a period of 2 hours. For participants who weigh above 120% 
of their ideal body weight, the adjusted ideal body weight (AIBW) should be used 
for dosing.
During PBSC transplant, participants must receive infection prophylaxis, hydration, 
and other supportive care according to standard institutional guidelines. 
Erythropoietin is also allowed.
5.4.4
Concomitant therapy during Lenalidomide Maintenance
Thromboprophylaxis is recommended and as clinically indicated (e.g., if the patient 
has experienced a thrombotic event during the study).
Other allowed therapy includes:
o Concomitant bisphosphonate therapy (Zometa® 4 mg/day monthly or 
equivalent), is permitted and can be administered according to institutional 
practice.
o G-CSF, as needed to support blood counts.
o Erythropoietin
o All supportive measures consistent with optimal participant care will be
given throughout the study.
5.4.5 Other concomitant therapy
Radiotherapy for pain control of existing bone disease should be discussed with the
study PI on a case by case basis.
5.5 Duration of Therapy/Criteria for early treatment discontinuation
Duration of therapy (RVD cycles, stem cell collection and transplant, maintenance) 
will depend on individual response, evidence of disease progression and tolerance. In 
the absence of treatment delays due to adverse events, treatment may continue for a 
total of 8 cycles of RVD therapy followed by 1 year of lenalidomide maintenance
therapy (initial therapy and Arm A) or for a total of 5 cycles of RVD therapy
(including stem cell transplant), followed by 1 year of lenalidomide maintenance
therapy (initial therapy and Arm B), or until one of the following criteria applies:
x
Disease progression,
x
Treatment delay for toxicity for  more than 6 weeks
x
Investigator judgment
x
Pregnancy or suspected pregnancy
x
Unacceptable adverse event(s)/Serious adverse event(s)
x
Participant decision*
x
Participant withdrawal of consent

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x
Non-protocol therapy for multiple myeloma or for other malignancy
x
Death
*Agrees to the use of collected data and to undergo follow-up assessments.
Patients who discontinue the treatment for a reason other than progressive disease (criteria listed 
above) will undergo disease assessments until disease progression.  Once patient has progressed, 
he/she will be followed for survival data only.
5.6    Criteria for Removal from Study
Participants will be removed from study when any of the criteria listed below applies:
x
Participant decision*
x
Participant withdrawal of consent
x
Participant registered but not randomized
x
Death
*Agrees to the use of previously collected data.
The primary reason for study removal and the date the participant was removed must be 
documented in the source documents and in the study-specific case report form (CRF). 
Alternative care options will be discussed with the participant.  There is no exclusion 
(wash-out) period before start of another treatment.
Participants will be informed that they have the right to withdraw from the study at 
any time for any reason, without prejudice to their medical care.
In the event of unusual or life-threatening complications, participating investigators 
must immediately notify the Principal Investigator: Paul Richardson at 
 (telephone) or 
5.7   Duration of FollowUp
Participants will be followed every two months (+/- 3 weeks) during the follow-up period 
after completion of treatment until disease progression or for up to 3 years after the last 
patient has been enrolled. Participants removed from study treatment for unacceptable 
adverse events will be followed for resolution or stabilization of the adverse event. 
Participants removed from study treatment for reasons other than progressive disease 
will be followed until disease progression unless the participant withdraws consent for 
follow-up. Following disease progression, a participant may be followed-up by 
telephone contactfor survival. There is no exclusion (wash-out) period at the end of the 
study before start of another treatment.
5.8 Recommended treatment for relapse
5.8.1
For patients enrolled in Arm A: Induction will be variable depending on the 
response to the initial induction treatment and the time of relapse/progression.

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A  stem  cell  transplant  with  high-dose  melphalan  conditioning  is  recommended.
The total dose of melphalan will depend on the patient’s age at the time of relapse.  The 
following doses are recommended:
” 65 years: 200 mg/m2
> 65 years: 140 mg/m2
5.8.2
For patients enrolled in Arm B:
The relapsed treatment will be variable depending on the response to the initial induction 
treatment and the time of relapse/progression.
6  EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Version 4.0 of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP website 
at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.).
All adverse events experienced by participants will be collected from the time of informed 
consent signature, through the study and until 30 days after completion of therapy, with the 
exception of those participants who withdraw from treatment during RVD cycles, in whom 
adverse events will be collected until 60 days following the last treatment administration. 
Participants continuing to experience toxicity beyond the follow-up periods noted above may 
be contacted for additional assessments until the toxicity has resolved or is deemed 
irreversible.
6.1 Anticipated Toxicities/Adverse Events
A list of the adverse events and potential risks associated with the agents administered 
in this study appear below and will determine whether dose delays and modifications 
will be made or whether the event requires expedited reporting in addition to routine 
reporting.
6.1.1  CAEPRs for CTEP-Supplied Investigational Agent(s) 
This section is not applicable to the study.

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6.1.2
Adverse Event Lists for Lenalidomide
The following is a list of adverse events that are associated with the use of 
lenalidomide.
Events that have occurred in >10% of individuals treated with lenalidomide 
include neutropenia, anemia, thrombocytopenia, fatigue, rash, diarrhea, 
constipation, nausea, loss of appetite, itching, dry skin, muscle cramps, lack or 
loss of strength, dizziness, insomnia, swelling of the extremities, headache, back 
and joint pain, fever, cough, upper respiratory infection, and dyspnea.
Events that have occurred in >1% of individuals treated with lenalidomide include 
risk of DVT, PE, and blood clots that could lead to stroke, heart attack, or organ 
failure, febrile neutropenia, atrial fibrillation, pneumonia or lung infections,
sepsis, dehydration and renal failure.
Events that have occurred in <1% of individuals treated with lenalidomide include 
rare treatment-emergent adverse events of angioedema, serious skin reactions 
including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 
or an allergic skin reaction similar to that seen with thalidomide, tumor lysis 
syndrome (TLS), tumor flare reaction (TFR), and rhabdomyolysis. In addition, 
lenalidomide has been shown to increase the level of digoxin in the blood in some 
patients. Patients will be instructed to inform their doctor if taking digoxin.
There may be an increased risk of second cancers in patients who are on 
lenalidomide maintenance therapy after a bone marrow transplant.
6.1.3
Adverse Event List for Bortezomib

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 Known Anticipated Risks of Bortezomib by MedDRA System Organ Class, Observed
Incidence, and Preferred Term
    
System Organ Class
Observed Incidence
Preferred Term
Blood and Lymphatic System Disorders
Most common
Thrombocytopenia*, anaemia* 
Very common
Neutropenia*
Common
Lymphopenia, pancytopenia*, leukopenia*, febrile 
neutropenia
Cardiac Disorders
Common
Tachycardia, atrial fibrillation, palpitations, cardiac 
failure congestive*
Uncommon
Cardiogenic shock*, atrial flutter, cardiac tamponade*r, 
bradycardia, atrioventricular block complete, arrhythmia, 
cardiac arrest*, cardiac failure, arrhythmia, pericardial 
effusion, pericarditis, pericardial diseaser, 
cardiopulmonary failurer
Ear and Labyrinth Disorders
Uncommon
Deafness, hearing impaired
Eye Disorders
Common
Blurred vision, conjunctivitis, conjunctival haemorrhage
Gastrointestinal Disorders
Most common
 Constipation, diarrhoea*, nausea, vomiting* 
Very common
abdominal pain (excluding oral and throat)
Common
Dyspepsia, pharyngolaryngeal pain, gastroesophageal 
reflux, abdominal distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal haemorrhage*, 
lower gastrointestinal haemorrhage*± rectal 
haemorrhage
Uncommon
Eructation, gastrointestinal pain, tongue ulceration, 
retching, upper gastrointestinal haemorrhage*, 
haematemesis*, oral mucosal petechiae, ileus paralytic*, 
ileus, odynophagia, enteritis, colitis, oesophagitis, 
enterocolitis, diarrhoea haemorrhagic, acute 
pancreatitis*, intestinal obstruction
General Disorders and Administration Site Conditions
Most common
Fatigue, pyrexia
Very common
Chills, oedema peripheral, asthenia
Common
Neuralgia, lethargy, malaise, chest pain, mucosal 
inflammation*
Uncommon
Injection site pain, injection site irritation, injection site 
phlebitis, general physical health deterioration*, 
catheter-related complication
Hepatobiliary Disorders

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 Known Anticipated Risks of Bortezomib by MedDRA System Organ Class, Observed
Incidence, and Preferred Term
    
System Organ Class
Observed Incidence
Preferred Term
Uncommon
Hyperbilirubinaemia, hepatitis*r
Immune System Disorders
Uncommon
Drug hypersensitivity, angioedema
Infections and Infestations
Very common
Upper respiratory tract infection, nasopharyngitis, 
pneumonia*, Herpes zoster* (may cause lesions)
Common
Lower respiratory tract infection*, sinusitis, pharyngitis, 
oral candidiasis, urinary tract infection*, sepsis*, 
bactaeremia*, cellulitis*, Herpes simplex, bronchitis, 
gastroenteritis*, infection
Uncommon
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung infection*, 
infusion site cellulitis, catheter site cellulitis, infusion
site infection, urosepsis*, Aspergillosis*, tinea infection,
Herpes zoster ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpeticr, varicella, empyemar, 
fungal oesophagitisr
Injury, Poisoning, and Procedural Complications
Common
Fall
Uncommon
Subdural haematoma
Investigations
Common
Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, 
blood alkaline phosphatase increased, liver function test 
abnormal, blood creatinine increased*
Uncommon
Gamma-glutamyltransferase (GGT) increased, oxygen 
saturation decreased*, blood albumin decreased, ejection 
fraction decreased*
Metabolism and Nutritional Disorders
Very common
Decreased appetite, anorexia, dehydration* 
Common
Hyperglycaemia, hypoglycaemia, hyponatraemia,
hypokalaemia, hypercalcaemia*
Musculoskeletal and Connective Tissue Disorders
Very common
Bone pain, myalgia, arthralgia, back pain
Common
Muscular weakness 
Uncommon
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon
Tumour lysis syndrome*

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 Known Anticipated Risks of Bortezomib by MedDRA System Organ Class, Observed
Incidence, and Preferred Term
    
System Organ Class
Observed Incidence
Preferred Term
Nervous System Disorders
Most common
Peripheral neuropathy (including all preferred terms 
under the MedDRA High-level term Peripheral 
neuropathy NEC)
Very common
Paresthesia, dizziness excluding vertigo, headache
Common
Polyneuropathy, syncope, dysesthesia, dysgeusia, 
postherpetic neuralgia
Uncommon
Convulsion, loss of consciousness, ageusia, 
encephalopathy, paralysis*,autonomic neuropathy, 
reversible posterior leukoencephalopathy syndromer
Psychiatric Disorders
Very common
Anxiety, insomnia 
Common
Confusional state 
Uncommon
Delirium
Renal and Urinary Disorders
Common
Renal impairment*, renal failure*, haematuria
Uncommon
Micturition disorder
Respiratory, Thoracic, and Mediastinal Disorders
Very common
Cough, dyspnoea
Common
Epistaxis, dyspnoea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary oedema*
Uncommon
Hemoptysis*, acute respiratory distress syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar haemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, pleuritic 
pain
Skin and Subcutaneous Tissue Disorders
Very common
Rash
Common
Rash pruritic, rash erythematous, urticaria, petechiae 
Uncommon
Cutaneous vasculitis, leukocytoclastic vasculitisr 
Vascular Disorders
Common
Hypotension*, orthostatic hypotension
Uncommon
Cerebral haemorrhage*
Source:  VELCADE® (bortezomib) for Injection Investigator’s Brochure Edition 14.
Most common = t 30%, Very common = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%.
*  Fatal outcomes have been reported.
r Indicates a Preferred term not listed in the source table, however the event is deemed medically important 
and so is included.

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Reports of Adverse Reactions From Postmarketing
Experience
 
  
System Organ Class
Preferred Term
Blood and lymphatic system disorders
Observed
Incidencea
Disseminated intravascular coagulation
Rare
Cardiac Disorders
Atrioventricular block complete
Rare
Cardiac tamponade
Rare
Ear and labyrinth disorders
Deafness bilateral
Rare
Eye Disorders
Ophthalmic herpes
Rare
Gastrointestinal Disorders
Acute pancreatitis
Rare
Ischemic colitis
Rare
Hepatobiliary disorders
Hepatitis
Uncommon
Liver failure
Unknown
Infections and infestations
Herpes meningoencephalitis
Rare
Septic shock
Rare
Immune System Disorders
Angioedema
Rare
Nervous System Disorders
Autonomic neuropathy
 Rare 
Dysautonomia
 Unknown 
Encephalopathy
Rare
Respiratory, thoracic and mediastinal disorders:
Acute diffuse infiltrative pulmonary diseaseb                         Rare 
Acute respiratory distress syndrome (ARDS)                Rare 
Interstitial pneumonia                                                     Rare 
Lung infiltration                                                             Rare 
Pneumonitis                                                                    Rare 
Pulmonary hypertension                                               Rare

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Skin and subcutaneous system disorders
Acute febrile neutrophilic dermatosis
Unknown
Toxic epidermal necrolysis
Unknown
Source:  VELCADE® (bortezomib) for Injection Investigator’s Brochure
Edition 15.
a  Incidence is assigned using the following convention: very common
(t 1/10); common (t 1/100 and
1/10); uncommon (t 1/1000 and
1/100); rare (t 1/10,000 and
1/1000 ); very rare (   1/10,000, 
including isolated reports).
b  Acute diffuse infiltrative pulmonary disease is a MedDRA Lower 
Level Term which corresponds to a Preferred Term of Interstitial lung 
disease.
6.1.4
Adverse Event List for Dexamethasone
Events that have occurred in 10-15% of individuals treated with dexamethasone 
include increased appetite, weight gain, sleep disturbance, hypertension, fluid 
retention, ankle swelling, bruising, infection, mood changes, slow wound healing, 
depression, and hyperglycemia, which may lead to fatigue, weight loss, excessive 
thirst and frequent urination.
Events that have occurred in 1-9% of individuals treated with dexamethasone 
include loss of appetite, muscle twitching, increased thirst, frequent urination, 
increased perspiration, diarrhea, nausea, headache, bone thinning, spinal fracture 
or fracture of bones, tachycardia, fungal infections.
Events that have occurred in <1% of individuals treated with dexamethasone 
include blurred vision, personality changes, stomach ulcers with bleeding that 
may cause hematemesis, blood in the stool and abdominal pain.
Other, less frequent, events may include bowel perforation, irritation and bleeding 
of the esophagus, heart failure, allergic reaction that may lead to facial redness, 
shortness of breath, abdominal cramps and hypotension, convulsions, brain 
swelling, dizziness, cataracts, glaucoma and increased blood pressure in the eye, 
development of diabetes, pancreatic inflammation, abdominal swelling, 
hypokalemia, DVT or PE, malaise, swelling and/or redness of skin, allergic skin 
reactions, itching, hirsutism, muscle weakness or loss of muscle mass, rupture of 
tendons, menstrual cycle disturbances, facial puffiness, leading to the appearance 
of a “moon face” hormonal disturbances, and hiccups.
6.1.5
Adverse Event List for Stem Cell Collection
Events that have occurred in individuals undergoing stem cell collection 
include the following: tingling of the lips or fingers, and rarely, nausea, 
vomiting or muscle tightness, due to a sterile anticoagulant used to prevent

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blood from clotting in the collection machine; hypotension, hypertension
or slow pulse; thrombocytopenia or anemia; return of migraine headaches 
(for participants with a history of migraines); serious or life-threatening 
reactions include allergic reactions, infections, seizures, air embolism or 
arrhythmias, but are extremely rare.
In addition, participants receive anticoagulant solution, which contains 
dextrose, during the collection procedure. Participants with a history of 
heart failure or kidney disease may retain some of this fluid causing 
increased weight or swelling of hands or feet, or shortness of breath. 
Participants with diabetes may experience hyperglycemia.
Participants on an Angiotensin Converting Enzyme (ACE) inhibitor 
may experience low blood pressure during the collection procedure, 
and these should not be taken before collection.
6.1.6
Adverse Event List for PBSC Transplant
The following is a list of adverse events that are associated with stem cell 
transplant.
Events that have occurred in >50% of individuals who have undergone stem cell 
transplant include neutropenia, thrombocytopenia, pancytopenia, anemia, fever 
and/or chills, flu-like symptoms, fatigue, loss of appetite and/or weight loss, 
diarrhea, nausea, vomiting, partial hair loss or thinning of hair, and rash or hives.
Events that have occurred in 1-50% of individuals who have undergone stem cell 
transplant include bone pain, inflammation of the throat and tongue, hyponatremia 
that may increase the risk of confusion or seizures, painful or difficult urination, 
bladder irritation, hematuria, abnormal kidney function or kidney damage, and 
abnormal thyroid function.
Events that have occurred in <1% of individuals who have undergone stem cell 
transplant include severe allergic reaction that may lead to tachycardia, wheezing, 
hypotension, sweating, swelling of the throat, facial rash, heart damage, bladder 
damage, lung inflammation or scarring of the lung, abnormal liver function, 
jaundice or liver failure, failure to engraft, life-threatening infection, hemolysis, 
mouth or throat sores, gastrointestinal bleeding, and death.
6.1.7  Study Procedure Risks
In addition to the risks of study drug, needle sticks for blood samples and/or bone 
marrow procedures may cause pain, bruising and rarely, infection at the site where 
blood is drawn.

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6.2 Hematologic Toxicity Management
Neutropenia: may be managed by G-CSF administration. 
Anemia: may be managed by blood transfusion.
Thrombocytopenia: may be managed by platelet or blood transfusion.
6.3 Dose Modifications/Delays
Before each drug dose, the participant will be evaluated for possible toxicities that may 
have occurred after the previous dose(s).  Toxicities are to be assessed according to 
CTEP Version 4.0 of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE). Dose modifications or delays will be done based on the toxicity experienced 
during a cycle of therapy or newly encountered on day 1 of each cycle. The participant 
may continue on therapy if the toxicity can be managed according to the dose 
modification guidelines as outlined below.
Once one of the treatment doses (lenalidomide, bortezomib, or dexamethasone) is 
reduced for toxicity, no re-escalation will be allowed with the exception of 
lenalidomide in case of renal insufficiency during RVD therapy.  Reduction and/or
temporary suspension of one agent and not the others is appropriate if toxicity is related 
primarily to one of the agents.
Drug may be held for no more than 6 weeks due to toxicity. However, treatment delay 
for more than 3 weeks (for any study treatment) will require authorization from the 
PI.  During RVD cycles, if all three concerned treatments are held for more than 6 
weeks, the patient will be withdrawn from the study treatment phase and will be 
followed until disease progression.
During RVD cycles 1-8 (Arm A) and RVD cycles 1-3 (Arm B), if all three drugs are 
held at the same time and two or more consecutive doses of bortezomib are missed, the 
patient may restart the cycle at Day 1 of treatment. Participating sites should contact 
the study PI for approval prior to any RVD cycle restart.
6.3.1  Dose Reduction Steps for Lenalidomide during RVD therapy
Starting dose of 
lenalidomide
1st Dose
Reduction
2nd Dose
Reduction
3rd Dose
Reduction
4th Dose
Reduction
5th Dose
Reduction
25 mg PO qd x
14 days every 21 
days
20 mg PO qd x
14 days every 21 
days
15 mg PO qd x
14 days every 21 
days
10 mg PO qd x
14 days every 21 
days
5 mg PO qd x
14 days every
21 days
Discontinue 
lenalidomide
If there were dose modifications or delays in the previous cycle, use the following 
guidelines:
x
If the cycle was completed without requiring further dose modification, then the 
next cycle will start at the same reduced dose of lenalidomide.

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x
If Lenalidomide was held during the previous cycle and restarted at a reduced 
dose level, without interruption for the remainder of the cycle, then the reduced 
dose level will be initiated on Day 1 of the new cycle.
x
If Lenalidomide dosing was omitted for the remainder of the previous cycle or if a 
new cycle is delayed due to lenalidomide-related toxicity newly encountered on the 
scheduled Day 1, then the new cycle will be started with a one-level dose
reduction.
6.3.2  Dose Reduction Steps for Bortezomib
Starting dose of
bortezomib
1st Dose Reduction
2nd Dose
Reduction
3rd Dose Reduction
1.3 mg/m2 on days
1, 4, 8, and 11
1 mg/m2 on days 1,
4, 8, and 11
0.7 mg/m2 on days
1, 4, 8, and 11
Discontinue
bortezomib
Dose modifications below 0.7 mg/m2 twice weekly (e.g., to once weekly) will require 
prior PI permission and documentation. See Table 6.3.4.3 for separate dose 
modification guidelines for peripheral neuropathy.
If there were dose modifications or delays in the previous cycle, use the following 
guidelines:
x
In case of dose reduction during initial RVD therapy, the participant will receive 
the reduced dose levels (the last level applied during initial therapy
x
If any two or more doses of bortezomib were held during the cycle (either 
consecutively or two or more in one cycle), then the new cycle will be started with 
one level dose reduction.
x
If the new cycle is delayed due to bortezomib-related toxicity newly encountered 
on the scheduled Day 1, then the new cycle will be started with a one-level dose 
reduction.
6.3.3  Dose Reductions Steps for Dexamethasone
Starting dose of
dexamethasone
1st Dose Reduction
2nd Dose Reduction
3rd Dose Reduction
20 mg/d on days 1, 2,
4, 5, 8, 9, 11 and 12
10 mg/d on days 1, 2, 4,
5, 8, 9, 11 and 12
5 mg/d on days 1, 2,
4, 5, 8, 9, 11 and 12
Discontinue
dexamethasone
In case of dose reduction during initial RVD therapy, the participant will receive the 
reduced dose levels (the last level applied during initial therapy).
6.3.4 Dose Modification Guidelines
Each Adverse Event should be attributed to a specific study drug if possible so that 
dose modifications can be made accordingly. Reduction and/or temporary 
suspension of one agent and not the others is appropriate if toxicity is related 
primarily to one of the agents.  Further clarification can be obtained in consultation

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with the PI. If multiple toxicities are noted, the dose adjustment should be made 
according to the most severe toxicity guidelines. Drug may be held for no more than 6 
weeks to allow resolution of toxicity. The same dose modification guidelines will 
apply to maintenance cycles unless otherwise noted.
6.3.4.1  Drug Related Adverse Event Dose Modification Guidelines during RVD therapy
CTCAE Category
AGENTS
Toxicity During a Cycle
 
 
 
 
Lenalidomide
Hold therapy (interrupt). Follow CBC on day 4, 8, 11 (+1 day)
 
Use of G-CSF is allowed and recommended.
 
If neutropenia resolved to < grade 2, resume lenalidomide with
one level dose reduction and continue through the scheduled end 
of the cycle. Otherwise, omit for remainder of cycle and reduce 
the dose of lenalidomide by one dose level at the start of the next 
cycle. Omitted doses are not made up.
 
If thrombocytopenia resolved to < grade 2, resume lenalidomide
with one dose level reduction and continue through the scheduled 
end of the cycle. Otherwise, omit for remainder of cycle and 
reduce the dose of lenalidomide by one dose level at the start of 
the next cycle. Omitted doses are not made up.
 
 
 
 
 
> Grade 3 neutropenia associated with
fever (temperature > 38.5C) or Grade
4 neutropenia 
and/or
Platelet count < 10,000/mm3 or G3
thrombocytopenia with bleeding
 
 
 
 
 
 
Bortezomib
Hold therapy
 
Use of platelet transfusion is allowed.
 
If thrombocytopenia resolved to < grade 2 and neutropenia
resolves to < grade 2 and if the Day 4,8 or 11 (+1 day) dose is 
held, that dose should be omitted and treatment should continue 
with next planned dose (i.e., if Day 8 is skipped, the next dosing 
day is Day 11) resume bortezomib at same dose.
 
If thrombocytopenia resolved to < grade 2 and neutropenia
resolves to < grade 2 and if any 2 or more doses were held due to 
toxicity (either consecutive or two or more in one cycle), then 
reduce the bortezomib dose by one level.
Non-blistering rash
 
Grade 3
Hold (interrupt dose). Follow weekly.
 
If the toxicity resolves to < grade 1, restart lenalidomide with one
level dose reduction and continue through the scheduled end of 
the cycle. Otherwise, omit for remainder of cycle and reduce the 
dose of lenalidomide by one dose level at the start of the next 
cycle. Omitted doses are not made up.
Non-blistering rash
Grade 4
 
 
Lenalidomide
Discontinue lenalidomide study drug for grade 4 toxicity.
Desquamating (blistering) rash-any
Grade or Erythema multiforme > 
Grade 3
 
Lenalidomide
Discontinue lenalidomide study drug.
Sinus bradycardia/ other cardiac
arrythmia Grade 2
 
Lenalidomide
Hold (interrupt) dose.  Follow at least weekly.
If the toxicity resolves to < grade 1 restart at next lower dose

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level.
Sinus bradycardia/ other cardiac
arrythmia Grade > 3
 
Discontinue lenalidomide study drug for grade > 3
Allergic reaction or hypersensitivity
Grade 2-3
Hold (interrupt) dose.  Follow at least weekly.
If toxicity resolves to < grade 1 restart at next lower dose level
Allergic reaction or hypersensitivity
Grade 4
 
Lenalidomide
Discontinue lenalidomide study drug.
Hyperthyroidism or Hypothyroidism
 
Lenalidomide
Omit lenalidomide for remainder of cycle, evaluate etiology, and
initiate appropriate therapy.  Restart lenalidomide at 
investigator’s discretion.  For toxicity attributable to 
lenalidomide, reduce the dose by one dose level.
Peripheral Neuropathy
Bortezomib
See table 6.3.4.3
Neuropathy
Grade 3
 
 
 
 
 
 
 
 
Grade 4
 
 
Lenalidomide
Hold (interrupt) dose.  Follow at least weekly. If the toxicity 
resolves to < grade 1, restart lenalidomide at next lower dose 
level and continue through the scheduled end of the cycle. 
Otherwise, omit for remainder of cycle and reduce the dose of 
lenalidomide by one dose level at the start of the next cycle. 
Omitted doses are not made up.
 
Discontinue lenalidomide.
Herpes Zoster reactivation any grade
Bortezomib
Hold therapy until lesions are dry.  Increase antiviral from
prophylactic to therapeutic dose for 10 days or until lesions are 
healing and dry.
Venous Thrombosis/embolism >
Grade 3
Lenalidomide/
Bortezomib
Hold dose and start anticoagulation; restart at investigator’s
discretion (maintain dose level).
Moderate renal impairment
30ч Creat Clear<50 ml/min
 
Lenalidomide
10mg once daily. The dose may be escalated to 15mg/d after 2
cycles if the patient is tolerating the treatment
Severe renal impairment
Creat Clear<30 ml/min
(not requiring dialysis)
 
15mg every other day. The dose may be escalated to 10mg/d if
the patient is tolerating the treatment.
Severe renal impairment
Creat Clear<30 ml/min
(requiring dialysis)
 
5mg once daily. On dialysis days, the dose should be
administered following dialysis. Alternate etiology for severe 
renal impairment should be evaluated.
Other lenalidomide or bortezomib
related non-hematologic toxicity
Grade > 3
Lenalidomide
Bortezomib
Determine attribution of toxicity and hold appropriate therapy. If
toxicity resolves to < grade 2, resume therapy with one level dose 
reduction.
*Patients with mild hepatic impairment (bilirubin < 1.5 u ULN) do not require a starting 
dose adjustment.  In cases where a patient develops hepatic impairment on study, further 
investigation is needed to determine the cause of their hepatic impairment; in some instances, 
drug discontinuation may be necessary if the Investigator feels a perturbation in liver enzymes 
and/or bilirubin is related to bortezomib.
If a patient is no longer receiving Velcade at day 4 and 11, then the patient does not need to be 
brought in to complete the AE assessments and hematology labs on those days.
6.3.4.2 Dose Modifications for Lenalidomide during Maintenance 
Therapy
CTCAE Category
Toxicity During a Cycle

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Hematologic Dose Modifications
 
Absolute neutrophil count < 500/mm3
If with 15 mg/day, lenalidomide will be held and resumed at a
dose of 10 mg/day when ANC > 500/mm3 and/or platelet count is
> 30,000/mm3
 
and/or
Platelet count < 30,000/mm3
If with 10 mg/day, lenalidomide will be held and resumed at a 
dose of 5 mg/day when ANC > 500/mm3 and/or platelet count is
> 30,000/mm3.
 
If with 5 mg/day, lenalidomide will be held and resumed at a
dose of 5 mg/day for 21 of 28 days when ANC > 500/mm3 and/or 
platelet count is > 30,000/mm3.
 
If with 5 mg/day for 21 of 28 days, lenalidomide will be
discontinued definitively.
Please note that ANC should be >1000 to invitiate a new cycle but 
the dose is not reduced unless ANC <500.  Please also refer to 
section 5.1.4 as well.  
Neurologic Toxicity > Grade 3
If with 15 mg/day, lenalidomide will be held. If toxicity resolves
to < grade 1, lenalidomide may be resumed at a dose of 10 
mg/day.
 
If with 10 mg/day, lenalidomide will be held. If toxicity resolves
to < grade 1, lenalidomide may be resumed at a dose of 5 
mg/day.
 
If with 5 mg/day, lenalidomide will be held. If toxicity resolves to
< grade 1, lenalidomide may be resumed at a dose of 5 mg/day for
21 of 28 days.
 
If with 5 mg/day for 21 of 28 days, lenalidomide will be
discontinued definitively.
Cardiac Toxicity > Grade 2
If with 15 mg/day, lenalidomide will be held. If toxicity resolves
to < grade 1, lenalidomide may be resumed at a dose of 10 
mg/day.
 
If with 10 mg/day, lenalidomide will be held. If toxicity resolves
to < grade 1, lenalidomide may be resumed at a dose of 5 
mg/day.
 
If with 5 mg/day, lenalidomide will be held. If toxicity resolves to
< grade 1, lenalidomide may be resumed at a dose of 5 mg/day for
21 of 28 days.
 
If with 5 mg/day for 21 of 28 days, lenalidomide will be
discontinued definitively.
Renal Failure
30 ml/min ч Creat Clear < 50 ml/min
 
Creat Clear < 30 ml/min
Hold therapy.
If creat clear > 50 ml/min, resume lenalidomide with one level 
dose reduction.
Discontinue lenalidomide study drug.  Alternate etiology for 
severe renal impairment should be evaluated.

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Other Non-Hematologic Toxicity:
Grade 3
 
 
 
Other Non-Hematologic Toxicity:
Grade 4
Hold lenalidomide until toxicity resolves to < grade 2 and contact
study PI.  After consultation with the study PI, drug may be 
resumed at lower dose level, as described above.
 
Discontinue lenalidomide and contact study PI.

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6.3.4.3
Dose modifications for Bortezomib-Related Neuropathic Pain and/or Peripheral
Sensory Neuropathy
The neurotoxicity-directed questionnaire (Appendix IX) is a useful tool for determining 
the presence and intensity of neuropathic pain and/or peripheral neuropathy from the 
participant’s perspective. Neuropathic symptoms are more prominent than abnormalities 
on the clinical examination. After the participant completes the Neurotoxicity-directed 
questionnaire, the questionnaire should be reviewed to assist with the evaluation of the 
onset and intensity of peripheral neuropathy and other neurotoxicities that may possibly 
require intervention or dose modification.
Please also refer to section 5.2.2.3 and section 5.2.23.4 for guidance regarding skipping 
consolidation therapy after mobilization or tranplant.
Recommended Dose Modification for Bortezomib-Related Neuropathic Pain and/or Peripheral Sensory Neuropathy
 
If patient develops 
Grade 1 painful or 
Grade 2 (interfering 
with function but not 
with activities of daily 
living) PN
 
If G1 painful or G2
PN persists despite 
first dose reduction
If patient develops 
Grade 2 painful or 
Grade 3 (interfering 
with activities of daily 
living) PN
If patient develops
Grade 4(sensory
neuropathy which is 
disabling or motor
neuropathy that is life-
threatening or leads to 
paralysis) PN
 
Starting dose of
bortezomib
 
1st Dose Reduction
2nd Dose Reduction
Withhold bortezomib 
until toxicity resolves 
(Grade 1 or less)
 
Discontinue
bortezomib
1.3 mg/m2 on days 1,
4, 8, and 11
1 mg/m2 on days 1, 4,
8, and 11
1.0 mg/m2 once per
week
(Can be IV or SC)
Resume dosing at 0.7
mg/m2 once per week
(Can be IV or SC)
Discontinue
bortezomib 
permanently
Grading based on CTEP Version 4.0 of the NCI Common Terminology Criteria for Adverse Events (CTCAE):
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc htm.
6.3.4.4
Dexamethasone Dose Modifications
Dexamethasone dose modifications
Dyspepsia, gastric or duodenal
ulcer, gastritis Grade 1-2 
(requiring medical management)
Treat with H2 blockers, sucralfate, or omeprazole.  If
symptoms persist despite above measures, decrease 
dexamethasone dose by 1 dose level
> Grade 3 (requiring
hospitalization or surgery)
Hold dexamethasone until symptoms adequately controlled.
Restart and decrease one dose level of current dose along 
with concurrent therapy with H2 blockers, sucralfate, or
omeprazole.  If symptoms persist despite above measures,
discontinue dexamethasone and do not resume.
 
Gastrointestinal
Acute pancreatitis
Discontinue dexamethasone and do not resume.
Cardiovascular
Edema
> Grade 3 (limiting function and 
unresponsive to therapy or 
anasarca)
Diuretics as needed, and decrease dexamethasone dose by 1
dose level; if edema persists despite above measures, 
decrease dose another dose level.  Discontinue
dexamethasone and do not resume if symptoms persist 
despite second reduction.

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Neurology
Confusion or Mood alteration
> Grade 2 (interfering with 
function +/- interfering with 
activities of daily living)
Hold dexamethasone until symptoms resolve. Restart with
one dose level reduction. If symptoms persist despite above 
measures, discontinue dexamethasone and do not resume.
Musculoskeletal
Muscle weakness
> Grade 2 (symptomatic and
Decrease dexamethasone by one dose level. If weakness
persists despite above measures decrease dose by one level.

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interfering with function +/-
interfering with activities of 
daily living
Discontinue dexamethasone and do not resume if symptoms
persist.
Metabolic
Hyperglycemia
> Grade 3 or higher
Treatment with insulin or oral hypoglycemics as needed. If
uncontrolled despite above measures, decrease dose by one 
dose level until levels are satisfactory.
7. DRUG FORMULATION AND ADMINISTRATION
7.1 Lenalidomide (REVLIMID®)
7.1.1 Description
Lenalidomide (REVLIMID®), a thalidomide analogue, is an immunomodulatory agent 
with antiangiogenic 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:
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.
7.1.2  Form
Lenalidomide is 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 
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.
Lenalidomide is available for this study as 5 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.
7.1.3 Storage and Stability

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At the study site, all investigational study drugs will be stored in a locked, safe area to 
prevent unauthorized access. Lenalidomide should be stored according to manufacturer 
instructions reported on labels and storage temperature should not exceed 25ƕC.  Sites 
must contact Celgene in the event of a temperature excursion via email at 
imscdistribution@celgene.com.
7.1.4  Handling
Females of childbearing potential should not handle or administer lenalidomide unless 
they are wearing gloves.
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment.
7.1.5 Availability
Celgene Corporation will supply lenalidomide, as 5 mg and 25 mg capsules for oral 
administration. Lenalidomide is an investigational agent and will be supplied free-of- 
charge. Drug will be shipped to the pharmacy at the study site in individual bottles. 
Bottles will contain a sufficient number of capsules to last for 1 cycle of dosing.
7.1.6  Preparation
Lenalidomide investigational supplies are dispensed to the participants in individual 
bottles of capsules. Each bottle will identify the contents as study medication and bear 
the name of Celgene Corporation, quantity contained and standard caution statement: 
Caution: New drug – Limited by Federal law to investigational use.  Lenalidomide must 
be dispensed in the original packaging with the label clearly visible. For appropriate 
drug accountability, it is recommended that each bottle be marked with the institutional 
protocol number or Celgene tracking number (RV-MM-IFM-0444) upon receipt. 
Additional labels must not cover the Celgene label. Lenalidomide is an oral drug and 
does not require specific preparation details. Only enough lenalidomide for 1 cycle 
may be provided to the participant at the beginning of each cycle.
7.1.7  Administration
During initial therapy, each participant will be given lenalidomide as a single daily 
oral dose on Days 1-14 followed by a 7-day rest period, for 1 cycle.
In Arm A, each participant will be given lenalidomide as a single daily oral dose on 
Days 1-14 followed by a 7-day rest period, for two additional cycles, as initial therapy. 
Following collection of peripheral blood stem cells, participants in Arm A will then be 
given lenalidomide as a single daily oral dose on Days 1-14 followed by a 7-day rest 
period, for five cycles, as consolidation therapy.  After completing consolidation 
therapy, participants in Arm A will receive lenalidomide as a single daily oral dose

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continuously for 28 days of a 28-day cycle, until disease progression.  Participants will 
receive an initial dose of 10 mg/day.  If this dose is well tolerated after three months at
10 mg/day, the participant may be dose escalated to 15 mg/day.
In Arm B, each participant will be given lenalidomide as a single daily oral dose on 
Days 1-14 followed by a 7-day rest period, for two additional cycles, as initial therapy. 
Following collection and reinfusion of peripheral blood stem cells, participants in Arm 
B will then be given lenalidomide as a single daily oral dose on Days 1-14 followed by 
a 7-day rest period, for two cycles, as consolidation therapy.  After completing 
consolidation therapy, participants in Arm B will receive lenalidomide as a single
daily oral dose continuously for 28 days of a 28-day cycle, until disease progression. 
Participants will receive an initial dose of 10 mg/day.  If this dose is well tolerated 
after three months at 10 mg/day, the participant may be dose escalated to 15 mg/day.
A window of + 7 days is allowed between cycles of RVD.
A window of + 14 days and -7 days is allowed between cycles of lenalidomide 
maintenance.
At all times when dispensing lenalidomide protocol therapy, study site personnel will 
review the instructions, printed on the packaging, with participants. Participants will 
be asked to bring any unused drug and empty drug containers to the study site at their 
next scheduled visit.  Study staff will count and record the number of used and unused 
drug at each visit.
7.1.8  Ordering
The investigator or designee will order drug from Celgene Corporation, according to 
the ordering instructions provided by Celgene.
7.1.9  Accountability
The investigator or designee is responsible for taking an inventory of each shipment of 
lenalidomide received, and comparing it with the accompanying accountability form. 
The Investigator, or responsible party designated by the investigator, will verify the 
accuracy of the information on the form, sign and date it, retain a copy in the study file, 
and return a copy to Celgene or its representative. Accurate records will be kept in the 
source documentation of all drug administration (including dispensing and dosing).
7.1.10
Destruction and Return
Celgene will instruct the investigator on the return or destruction of unused lenalidomide. 
If any lenalidomide is lost or damaged, its disposition should be documented in the
source documents. Lenalidomide supplies will be retained at the clinical site pending 
instructions for disposition by Celgene. Participants will be instructed to return all bottles 
(empty bottles or unused capsules).

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If instructed to do so by Celgene, empty bottles and unused supplies of lenalidomide 
should be destroyed according to institutional policies. Destruction will be documented 
in the drug accountability forms.
7.2
Bortezomib (VELCADE®)
7.2.1   Description
Bortezomib for Injection is a small molecule proteasome inhibitor developed by 
Millennium as a novel agent to treat human malignancies. By inhibiting a single 
molecular target, the proteasome, bortezomib affects multiple signaling pathways. The 
anti-neoplastic effect of bortezomib likely involves several distinct mechanisms, 
including inhibition of cell growth and survival pathways, induction of apoptosis, and 
inhibition of expression of genes that control cellular adhesion, migration and 
angiogenesis. Bortezomib is thought to be efficacious in multiple myeloma via its 
inhibition of NF-țB activation, its attenuation of IL-6-mediated cell growth, a direct 
apoptotic effect, and possibly anti-angiogenic and other effects.
7.2.2
Form
Bortezomib for Injection is a sterile lyophilized powder for reconstitution and is 
supplied in sterile, single use vials containing bortezomib and mannitol at a 1:10 ratio. 
For example, vials containing 3.5 mg of bortezomib contain 35 mg of mannitol. 
Bortezomib is manufactured by Millennium Pharmaceuticals Incorporated.
7.2.3
Storage and Stability
At the study site, all investigational study drugs will be stored in a locked, safe area to 
prevent unauthorized access. Vials containing lyophilized bortezomib for Injection 
should be stored according to label requirements. Store at USP Controlled Room 
Temperature which is 25ƕC (77ƕF); excursions permitted from 15 to 30ƕC (59 to 86ƕF). 
U.S. sites are instructed to use the following procedure in the event of a product 
complaint. A product complaint is a verbal, written or electronic expression which 
implies dissatisfaction regarding the identity, strength, purity, quality, or stability of a 
drug product. Individuals who identify a potential product complaint situation should 
immediately contact MedComm Solutions at 1-866-835-2233 and report the event. 
Whenever possible, the associated product should be maintained in accordance with the 
label instructions pending further guidance from a Millennium quality representative.
To date, stability data indicate that the lyophilized drug product is stable for at least 18 
months when stored under the recommended conditions. Stability studies are ongoing, 
and the sponsor will notify the investigator should this information be revised during 
the conduct of the study.
7.2.4
Compatibility

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Each vial of bortezomib for intravenous administration should be reconstituted 
under a laminar flow biological cabinet (hood) within eight hours before dosing with
3.5 mL of normal (0.9%) saline, Sodium Chloride Injection USP, so that the 
reconstituted solution contains bortezomib at a concentration of 1 mg/mL.  Each vial 
of bortezomib for subcutaneous administration should be reconsituted under a 
laminar flow biological cabinet (hood) within eight hours before dosing with 1.4 mL 
(0.9%) saline, Sodium Chloride Injection USP, so that the reconstituted solution 
contains bortezomib at a concentration of 2.5 mg/mL.
7.2.5
Handling
Bortezomib is cytotoxic. As with all cytotoxic drugs, caution is required when preparing 
and handling bortezomib solutions. Cytotoxic drugs should only be handled by staff 
specially trained in the safe handling of such preparations. The use of gloves and other 
appropriate protective clothing is recommended. In case of skin contact, wash the 
affected area immediately and thoroughly with soap and water for at least 15 minutes. If 
product contacts eye, immediately flush eye thoroughly with water for at least 15 
minutes. Always contact a physician after any form of body contact. All materials that 
have been used for preparation should be disposed of according to standard practices. A 
log must be kept of all disposed materials.
7.2.6
Availability
Bortezomib is a  commercially available agent and will be supplied free-of-charge from 
Millennium Pharmaceuticals Incorporated for the first 400 participants enrolled on this 
study. The remaining particpants will receive Bortezomib from the commercial supply.
7.2.7
Preparation
Each vial of bortezomib for intravenous administration should be 
reconstituted in aseptic conditions (e.g., under a laminar flow biological cabinet 
(hood)) within eight hours before dosing with 3.5 mL of normal (0.9%) saline, 
Sodium Chloride Injection USP, so that the reconstituted solution contains 
bortezomib at a concentration of 1 mg/mL.  Prior to reconstitution the vials 
should remain in the cartons to protect them from light.  Dissolution is 
completed in approximately 10 seconds.  The reconstituted solution is clear and 
colorless, with a final pH of 5 to 6.  The reconstituted solution should be 
administered promptly and in no case more than 8 hours after reconstitution.
All materials that have been used for preparation should be disposed of 
according to standard practices.  A log must be kept of all disposed materials.
**Attention** The drug reconstitution for intravenous bortezomib differs
from that of subcutaneous bortezomib, even though the same-sized commercial

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drug vial is used for both modes of administration. Please be sure that you have 
the correct route of administration and correct reconstitution.
Each vial of bortezomib for subcutaneous administration should be 
reconstituted in aseptic conditions (e.g., under a laminar flow biological cabinet 
(hood)) within eight hours before dosing with 1.4 mL (0.9%) saline, Sodium 
Chloride Injection USP, so that the reconstituted solution contains bortezomib
at a concentration of 2.5 mg/mL.  Prior to reconstitution the vials should remain 
in the cartons to protect them from light.  Dissolution is completed in 
approximately 10 seconds.  The reconstituted solution is clear and colorless, 
with a final pH of 5 to 6.  The reconstituted solution should be administered 
promptly and in no case more than 8 hours after reconstitution. All materials 
that have been used for preparation should be disposed of according to standard 
practices. A log must be kept of all disposed materials.
7.2.8
Administration
During initial therapy, each participant will receive bortezomib as a 3-5 second IV push; 
subcutaneous administration may be allowed in the presence of > G1-painful peripheral 
neuropathy or if participants demonstrate poor peripheral veins (SQ administration due 
to poor venous access requires approval from the Study PI). Participants will receive 
bortezomib on days 1, 4, 8, and 11 (+1 day intracycle window), followed by a 10-day rest 
period, for 1 cycle.
In Arm A, each participant will receive bortezomib as a 3-5 second IV push or via 
subcutaneous administration (in presence of > G1-painful peripheral neuropathy) or if 
participants demonstrate poor peripheral veins (SQ administration due to poor venous 
access requires approval from the Study PI).  Participants will receive bortezomib on 
days 1, 4, 8, and 11 (+1 day intracycle window), followed by a 10-day rest period, for
two additional cycles, as initial therapy.  Following collection of peripheral blood stem 
cells, participants in Arm A will then receive bortezomib as a 3-5 second IV push or via 
subcutaneous administration (in presence of > G1-painful peripheral neuropathy or 
compromised venous access- with Study PI approval) on Days 1, 4, 8 and 11 (+1 day 
intracycle window), followed by a 10-day rest period, for 5 cycles, as consolidation 
therapy.
In Arm B, each participant will receive bortezomib as a 3-5 second IV push or via 
subcutaneous administration (in presence of > G1-painful peripheral neuropathy or 
compromised venous access- with Study PI approval) on Days 1, 4, 8, and 11 (+1 day 
intracycle window), followed by a 10-day rest period, for two additional cycles, as 
initial therapy.  Following collection and reinfusion of peripheral blood stem cells, 
participants in Arm B will then receive bortezomib as a 3-5 second IV push or via 
subcutaneous administration (in presence of > G1-painful peripheral neuropathy or 
compromised venous access- with Study PI approval) on Days 1, 4, 8 and 11 (+1 day

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intracycle window), followed by a 10-day rest period, for 2 cycles, as consolidation 
therapy.
For all treatment arms, at least 72 hours must elapse between bortezomib doses.  Dosing 
at an interval of 70 hours may be considered for scheduling, patient convenience or 
hardship. If the patient develops toxicity including neuropathy, this approach, less than
72 hours between doses, is not recommended.
A window of + 7 days is allowed between RVD treatment cycles. A +1 day 
intracycle window is allowed.
Drug will be administered only to eligible participants under the supervision of the 
investigator or identified sub-investigator(s). Participants may be treated on an outpatient 
basis, if possible. The pharmacist will prepare the drug under aseptic condition. The 
amount (in mg) of drug to be administered will be determined based on BSA. BSA is to 
be calculated based on body weight using the DuBois formula (Appendix IV).  The dose 
should be calculated on Day 1 of each cycle; the dose administered should remain the 
same throughout each cycle but should be recalculated at the start of the next cycle. If a 
participant experiences a notable change in weight (eg, loss or gain of 5% body weight) 
within a cycle, as determined by an unscheduled weight assessment, then that
participant’s dose should be recalculated at that time.
The appropriate amount of bortezomib will be drawn from the injection vial and 
administered as an IV push over 3 to 5 seconds followed by a standard saline flush or 
through a running IV line; bortezomib may also be administered subcutaneously (at a 
concentration of 2.5 mg/mL) in presence of > G1-painful peripheral neuropathy or 
compromised venous access (SQ due to poor venous access requires approval from the 
Study PI). Vials are for single use administration.
7.2.9
Ordering
The investigator or designee will order drug supply from Millennium Pharmaceuticals 
for the first 400 participants enrolled globally on this study, according to the ordering 
instructions provided by Millennium. For subsequent participants, the investigator or 
designee will order drug supply from commercial supply.
7.2.10 Accountability
For the drug supplied by Millennium, the investigator or designee must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of 
charge) using the NCI DAR Form or another comparable drug accountability form. (See 
the CTEP home page at http://ctep.cancer.gov for the Procedures for Drug Accountability 
and Storage or to obtain a copy of the DAR.)

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It is not DF/HCC practice to record lot numbers for drugs from the commercial supply, 
so the drug accountability form will not be used for commercial drug.
7.2.11 Destruction and Return
Millennium will instruct the investigator on the destruction of unused study drug.  If any 
study drug is lost or damaged, its disposition should be documented in the source 
documents. Study drug supplies will be retained at the clinical site pending instructions 
for disposition by Millennium.
If instructed to do so by Millennium, unused supplies of bortezomib should be destroyed 
according to institutional policies. Destruction will be documented in the DAR Form.
7.3
Dexamethasone
7.3.1   Description
Dexamethasone is a synthetic adrenocortical steroid. Corticosteroids are naturally- 
occurring chemicals produced by the adrenal glands located above the kidneys. 
Corticosteroids affect the function of many cells within the body and suppress the 
immune system. Corticosteroids also block inflammation and are used in a wide variety 
of inflammatory diseases affecting many organs.
The molecular weight for dexamethasone is 392.47.  It is designated chemically as 9- 
fluoro-11ȕ,17,21-trihydroxy-16Į-methylpregna-1,4-diene-3,20-dione. The empirical 
formula is C22H29FO5 and the structural formula is:
Dexamethasone is stable in air and almost insoluble in water.
7.3.2
Form
Dexamethasone is a white to practically white, odorless, crystalline powder. It is available 
in 2 or 4 mg tablets (commercially) for oral administration. Each tablet contains 
dexamethasone as the active ingredient, and the following inactive ingredients: calcium 
phosphate, lactose, magnesium stearate, and starch. The tablet shell may contain the 
following: D&C Yellow 10, FD&C Yellow 6, and/or FD&C Blue 1.
7.3.3  Storage and Stability

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At the study site, all investigational study drugs will be stored in a locked, safe area to 
prevent unauthorized access.  Dexamethasone should be stored at controlled room 
temperature, 68-77ƕF (20-25ƕC) and not frozen, and according to label requirements.
7.3.4
Handling
Dexamethasone should be handled by trained pharmacy staff.  The use of gloves and 
other appropriate protective clothing is recommended as necessary.
7.3.5
Availability
Dexamethasone supply will be obtained through commercial supply.
7.3.6
Preparation
Dexamethasone is an oral drug, and does not require specific preparation details.
7.3.7
Administration
During initial therapy, each participant will receive dexamethasone as a single oral daily 
dose of 20 mg/d on Days 1, 2, 4, 5, 8, 9, 11 and 12 (+1 day intracycle window),  followed 
by a 9-day rest period, for 1 cycle, as initial therapy.
In Arm A, each participant will receive dexamethasone as a single oral daily dose of 20 
mg/d on Days 1, 2, 4, 5, 8, 9, 11 and 12 (+1 day intracycle window),  followed by a 9-day 
rest period, for two additional cycles, as initial therapy.  Following collection of 
peripheral blood stem cells, participants in Arm A will then receive dexamethasone as a 
single oral daily dose of 10 mg/d on Days 1, 2, 4, 5, 8, 9, 11 and 12 (+1 day intracycle 
window),  followed by a 9-day rest period, for 5 cycles, as consolidation therapy.
In Arm B, each participant will receive dexamethasone as a single oral daily dose of 20 
mg/d on Days 1, 2, 4, 5, 8, 9, 11 and 12 (+1 day intracycle window),  followed by a 9-day 
rest period, for two additional cycles, as initial therapy.  Following collection and 
reinfusion of peripheral blood stem cells, participants in Arm B will then receive 
dexamethasone as a single oral daily dose of 10 mg/d on Days 1, 2, 4, 5, 8, 9, 11 and 12 
(+1 day intracycle window), followed by a 9-day rest period, for 2 cycles, as
consolidation therapy.
A window of + 7 days is allowed between RVD treatment cycles.
7.3.8
Ordering

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The investigator or designee will order drug supply from commercial supply.
7.3.9
Destruction and Return
At the end of the study, unused supplies of dexamethasone should be destroyed and 
documented according to institutional policies.
7.4
Cyclophosphamide (Cytoxan®)
7.4.1   Description
Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen 
mustards. Cyclophosphamide is a white crystalline powder with the molecular formula 
C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. The chemical name for 
cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine
2-oxide monohydrate. Cyclophosphamide is soluble in water, saline, or ethanol and has 
the following structural formula:
An activated form of cyclophosphamide, phosphoramide mustard, alkylates or binds with 
many intracellular molecular structures, including nucleic acids. Its cytotoxic action is 
primarily due to cross-linking of strands of DNA and RNA, as well as to inhibition of 
protein synthesis. Cyclophosphamide is a potent immunosuppressant. It also causes 
marked and persistent inhibition of cholinesterase activity.
Cyclophosphamide is biotransformed principally in the liver to active alkylating 
metabolites by a mixed function microsomal oxidase system. These metabolites interfere 
with the growth of susceptible rapidly proliferating malignant cells. The mechanism of 
action is thought to involve cross-linking of tumor cell DNA.
Cyclophosphamide is well absorbed after oral administration with a bioavailability greater 
than 75%. The unchanged drug has an elimination half-life of 3 to 12 hours. It is 
eliminated primarily in the form of metabolites, but from 5 to 25% of the dose is excreted 
in urine as unchanged drug. Several cytotoxic and noncytotoxic metabolites have been 
identified in urine and in plasma. Concentrations of metabolites reach a maximum in 
plasma 2 to 3 hours after an intravenous dose. Plasma protein binding of unchanged drug 
is low but some metabolites are bound to an extent greater than 60%. It has not been 
demonstrated that any single metabolite is responsible for either the therapeutic or toxic
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effects of cyclophosphamide. Although elevated levels of metabolites of 
cyclophosphamide have been observed in patients with renal failure, increased clinical 
toxicity in such patients has not been demonstrated.
7.4.2
Form
Cyclophosphamide for injection, USP, is a sterile white powder containing 
cyclophosphamide monohydrate. Cyclophosphamide is supplied in vials for single-dose 
use and is available as Intravenous Powder for Solution in the following strengths: 1 g, 2 
g, 500 mg.
7.4.3
Storage and Stability
Reconstituted solutions of lyophilized cyclophosphamide and solutions prepared with 
bacteriostatic water are chemically and physically stable for 24 hours at room 
temperature or for 6 days in the refrigerator. Store vials at or below 77° F (25° C). Do 
not use cyclophosphamide vials if there are signs of discoloration.
7.4.4
Compatibility
The osmolarities of solutions of cyclophosphamide constituted with water and 0.9%
sterile sodium chloride solution are as follows: 5 mL water per 100 mg cyclophosphamide 
(anhydrous) has osmolarity of 74 mOsm/L; 5 mL 0.9% sterile sodium chloride solution 
per 100 mg cyclophosphamide (anhydrous) has osmolarity of 374 mOsm/L.
7.4.5
Handling
Procedures for proper handling and disposal of anticancer drugs should be considered.
To minimize the risk of dermal exposure, always wear impervious gloves when handling 
vials containing cyclophosphamide sterile powder for injection. This includes all handling 
activities in clinical settings, pharmacies, storerooms, and home healthcare settings, 
including during unpacking and inspection, transport within a facility, and dose 
preparation and administration.
7.4.6
Availability
Cyclophosphamide supply will be obtained through commercial supply.
7.4.7
Preparation
Cyclophosphamide must be reconstituted using 0.9% sterile sodium chloride (NS) or 
Sterile Water for Injection (SWFI) as follows: 25 ml NS or SWFI for 500 mg of 
cyclophosphamide, 50 ml NS or SWFI for 1gm cyclophosphamide, 100 ml NS or SWFI 
for 2 gm cyclophosphamide.
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Cyclophosphamide may be prepared for parenteral use by infusion using either of the 
following dilution methods or according to standard institutional practice:
1.   Cyclophosphamide reconstituted with 0.9% sterile sodium chloride may be infused 
following further dilution in the following:
Dextrose Injection, USP (5% dextrose)
Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium 
chloride)
5% Dextrose and Ringer's Injection
Lactated Ringer's Injection, USP
2.   Cyclophosphamide sterile powder may be prepared for parenteral use by infusion by 
adding Sterile Water for Injection, USP. Cyclophosphamide, reconstituted in water, is 
hypotonic and should not be injected directly. Prior to infusion, solutions of 
cyclophosphamide sterile powder reconstituted in Sterile Water for Injection, USP 
must be further diluted in one of the following:
Dextrose Injection, USP (5% dextrose)
Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium 
chloride)
5% Dextrose and Ringer's Injection
Lactated Ringer's Injection, USP
7.4.8  Administration
Participants in Arm A and Arm B will receive cyclophosphamide 21 (+ 7) days following 
the last dose of lenalidomide in cycle 3.  Cyclophosphamide will be administered 
intravenously, at a total dose of 3 g/m2, over a period of 2 hours or per institutional 
practice.
7.4.9
Ordering
The investigator or designee will order drug supply from commercial supply.
7.4.10 Destruction and Return
At the end of the study, unused supplies of cyclophosphamide should be destroyed 
according to institutional policies.
7.5
Melphalan ( new or old 
formulation)
7.5.1   Description
Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or 
L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a 
bifunctional alkylating agent that is active against selected human neoplastic diseases. It

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is known chemically as 4-[bis(2-chloroethyl)amino]-L-phenylalanine. The molecular
formula is C13H18Cl2N2O2 and the molecular weight is 305.20. The structural formula is:
Melphalan is the active L-isomer of the compound and was first synthesized in 1953 by 
Bergel and Stock; the D-isomer, known as medphalan, is less active against certain 
animal tumors, and the dose needed to produce effects on chromosomes is larger than 
that required with the L-isomer. The racemic (DL-) form is known as merphalan or 
sarcolysin.
Melphalan is practically insoluble in water and has a pKa1 of ~2.5.
Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its 
cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, 
probably by binding at the N7 position of guanine. Like other bifunctional alkylating 
agents, it is active against both resting and rapidly dividing tumor cells.
The pharmacokinetics of melphalan after IV administration has been extensively studied 
in adult patients. Following injection, drug plasma concentrations declined rapidly in a 
biexponential manner with distribution phase and terminal elimination phase half-lives of 
approximately 10 and 75 minutes, respectively. Estimates of average total body clearance 
varied among studies, but typical values of approximately 7 to 9 mL/min/kg (250 to 325 
mL/min/m²) were observed. One study has reported that on repeat dosing of 0.5 mg/kg 
every 6 weeks, the clearance of melphalan decreased from 8.1 mL/min/kg after the first 
course, to 5.5 mL/min/kg after the third course, but did not decrease appreciably after the 
third course. Mean (±SD) peak melphalan plasma concentrations in myeloma patients 
given IV melphalan at doses of 10 or 20 mg/m²were 1.2 ± 0.4 and 2.8 ± 1.9 mcg/mL, 
respectively.
The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into 
cerebrospinal fluid (CSF) is low. The extent of melphalan binding to plasma proteins 
ranges from 60% to 90%. Serum albumin is the major binding protein, while Į 1-acid 
glycoprotein appears to account for about 20% of the plasma protein binding. 
Approximately 30% of the drug is (covalently) irreversibly bound to plasma proteins. 
Interactions with immunoglobulins have been found to be negligible.
Melphalan is eliminated from plasma primarily by chemical hydrolysis to 
monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, 
no other melphalan metabolites have been observed in humans. Although the contribution 
of renal elimination to melphalan clearance appears to be low, one study noted an
increase in the occurrence of severe leukopenia in patients with elevated BUN after 10 
weeks of therapy.
7.5.2
Form

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The original formula for Melphalan for Injection is supplied as a sterile, nonpyrogenic, freeze-
dried powder. Each single-use vial contains melphalan hydrochloride equivalent to 50 mg 
melphalan with 20 mg povidone added as an excipient.
The new formulation (Evomela) is supplied in a single carton containing one (1) vial. Each 50 
mg vial contains a white to off-white lyophilized powder in single-dose vial for reconstitution 
(after reconstitution the solution is clear and colorless to light yellow). Each vial contains 50 
mg melphalan free base equivalent to 56 mg melphalan hydrochloride.
7.5.3
Storage and Stability
The orignal formulation of melphalan should be stored at controlled room temperature 15° 
to 30° C (59° to 86° F) and protected from light. A precipitate forms if the reconstituted 
solution is stored at 5° C. Do not refrigerate the reconsituted product.
Store new formulation (Evomela) at room temperature 25°C (77°F). Temperature 
excursions are permitted between 15-30°C (59 86°F). 
7.5.4
Compatibility
Original Melphalan for Injection should be reconstituted using the sterile diluent provided. 
Each vial of sterile diluent contains sodium citrate 0.2 g, propylene glycol 6 mL, ethanol 
(96%) 0.52 mL, and Water for Injection to a total of 10 mL.
 
For the new formulation (Evomela), use normal saline solution (0.9% Sodium Chloride Injection, 
USP) (8.6 mL as directed) to reconstitute Evomela and make a 50 mg/10 mL (5 mg/ mL) nominal 
concentration of melphalan. 
7.5.5
Handling
As with other toxic compounds, caution should be exercised in handling and preparing the 
solution of melphalan. Skin reactions associated with accidental exposure may occur. The use 
of gloves is recommended. If the solution of melphalan contacts the skin or mucosa, 
immediately wash the skin or mucosa thoroughly with soap and water.
Procedures for proper handling and disposal of anticancer drugs should be considered. 
Parenteral drug products should be visually inspected for particulate matter and
discoloration prior to administration whenever solution and container permit. If either
occurs, do not use this product.
Care should be taken to avoid possible extravasation of melphalan and in cases of poor 
peripheral venous access, consideration should be given to use of a central venous line.
7.5.6
Availability

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106
.Either the original formulation or the new formulation can be used depending on local 
availability.  
7.5.7
Preparation
FOR  THE ORGINAL FORMULATION® 
Melphalan for Injection must be reconstituted by rapidly injecting 10 mL of the supplied 
diluent directly into the vial of lyophilized powder using a sterile needle (20-gauge or larger 
needle diameter) and syringe. Immediately shake vial vigorously until a clear solution is 
obtained. This provides a 5-mg/mL solution of melphalan. Rapid addition of the diluent 
followed by immediate vigorous shaking is important for proper dissolution.
Immediately dilute the dose to be administered in 0.9% Sodium Chloride Injection, USP, 
to a concentration not greater than 0.45 mg/mL. Use of standard institutional practice for 
dilution of melphalan is also allowed.
The time between reconstitution/dilution and administration of melphalan should be kept 
to a minimum because reconstituted and diluted solutions of melphalan are unstable.
For the new formulation of Melphalan
Use normal saline solution (0.9% Sodium Chloride Injection, USP) (8.6 mL as directed) 
to reconstitute  Evomela and make a 50 mg/10 mL (5 mg/ mL) nominal concentration of 
melphalan. The normal saline used  to reconstitute each vial should appear to be assisted 
or pulled into the vial by the negative pressure (partial vacuum) present in the vial. 
Discard any vial (and replace with another vial) if there is no vacuum present  when 
reconstituting the vial with normal saline. The reconstituted Evomela drug product is 
stable for 24 hours at refrigerated temperature (5o C) without any  precipitation due to 
the high solubility. The reconstituted Evomela drug product is stable for 1 hour at room 
temperature. Calculate the required volume of Evomela needed for a patient’s dose and 
withdraw that volume from the  vial(s). Add the required volume of Evomela to the 
appropriate volume of 0.9% Sodium Chloride Injection, USP to  a final concentration of 
0.45 mg/mL. The Evomela admixture solution is stable for 4 hours at room temperature 
in addition to the 1 hour  following reconstitution.. Infuse over 30 minutes via an 
injection port or central venous catheter. Evomela may cause local tissue damage should 
extravasation occur. Do not administer by direct injection into a peripheral vein. 
Administer Evomela by injecting slowly into a fast-running IV infusion via a central 
venous access line. Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to  administration, whenever solution and container permit.
7.5.8
Administration
The original formula for melphalan should be administered in carefully adjusted dosage 
by or under the supervision of experienced physicians who are familiar with the drug's 
actions and the possible complications of its use. Melphalan will be administered either 

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as a single dose of 200 mg/m2 i.v. over 30 minutes on day minus 2 OR as a divided dose 
of 100 mg/m2/day i.v. over 2 days on day minus 2 and day minus 1 for a total dose of 
200 mg/m2. For participants who weigh above 120% of their ideal body weight, the 
adjusted ideal body weight (AIBW) should be used (See Appendix XI for AIBW 
calculation).
The recommended dose of the new formulation (Evomela) for conditioning treatment is 
100 mg/m2 /day administered over 30 minutes  by intravenous infusion for 2 
consecutive days (Day -3 and Day -2) prior to autologous stem cell transplantation  
(ASCT, Day 0). For patients who weigh more than 130% of their ideal body weight, 
body surface area should  be calculated based on adjusted ideal body weight.
7.5.9
Ordering
The investigator or designee will order drug supply from commercial supply.
7.5.10 Destruction and Return
At the end of the study, unused supplies of melphalan should be destroyed according 
to institutional policies.
8  CORRELATIVE/SPECIAL STUDIES
8.1
Proposed Study
This trial will provide samples from newly diagnosed and uniformly treated patients to 
comprehensively characterize the MM genome and epigenome, to define molecular 
events driving development and progression of MM, as well as to identify novel 
therapeutic targets, biomarkers, and preventative strategies.
We will attempt to obtain samples on all patients at the following time points: at diagnosis 
(initial therapy), at the time of response determination and at disease relapse. It is 
anticipated that approximately 70% of samples collected will be adequate for gene 
expression profiling (GEP) analysis.

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To evaluate whether further stringent CR definition may be able to predict superior 
survival outcome, we will evaluate normalization of serum free light chain, molecular 
CR using ASO-PCR and immunophenotypic CR using multicolor flow cytometric 
immunophenotyping of MM cell in bone marrow to detect minimal residual disease.
In order to identify genomic alterations and correlate with clinical outcome, the role of 
DNA CNAs by high throughput SNP array analysis as well as genome sequencing and 
gene  expression  changes  by  expression  array  will  be  analyzed  for  response  and 
survival. mRNA splicing by exon array and microRNA profiles in study participants 
will be correlated with clinical endpoints. Both the direct and indirect relationship 
between CNAs and gene expression changes will also be investigated.
To investigate genomic changes at the time of progression or relapse and evaluate 
mechanisms underlying genomic instability, genome-wide SNP analyses, expression 
profiling and genome-wide sequencing on paired samples obtained at the time of 
diagnosis  and  at  the  time  of  progression  or  relapse  will  be  performed  to  identify 
genomic regions with amplifications, deletions, and changes in heterozygosity.   We 
will evaluate the mutations in light of the known pattern of changes and identify those 
which may predict different clinical outcomes.  Based on data showing that elevated 
homologous recombination activity plays a significant role in ongoing genomic instability 
in myeloma HR activity in primary myeloma samples will be measured to correlate with 
acquisition of new genomic changes as well as clinical outcome.
Leftover specimen material from the correlative studies will be stored for future 
unspecified research.
8.2   Bone Marrow Aspirate Samples
Collection of bone marrow aspirate specimens for exploratory analysis will be 
mandatory for this trial. Collections will be obtained at screening, within 42 days of 
PBSCT, prior to lenalidomide maintenance, end of study treatment (post lenalidomide 
maintenance), RVD Cycle 4, Day 1 (Arm B only), at the time of confirmation of 
response (only if previous response assessment was VGPR or better) , at the time of 
disease relapse or progression, and/or when necessary clinical bone marrow aspirate 
samples are obtained. This will not require extra access for participants. Specimens 
will be shipped (via traceable carrier) to and subsequently processed, analyzed, and 
stored at Dana-Farber Cancer Institute.
Additionally, particants have the option to consent for additional collection of bone 
marrow aspirate speciments for exploratory analysis. If a participant agrees to the 
optional samples, these samples will be collected once per year during the maintanence 
portion of the study. The procedure will be done sometime within 3 months before to 3 
months after the anniversary date of the participant’s biopsy which occurred prior to 
lenalidomide maintenance. If a participant is already in the lenalidomide maintenance 
portion of the main study, the biopsies and aspirations will start at the next anniversary

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date from the biopsy prior to lenalidomide maintenance (with a window of 3 months 
before or after the actual date).
These annual biopsies are recommended. In addition to the research samples, the 
results will be used to assess the participant’s disease status and to check for any post 
treatment side effects (such as MDS)
U.S. participating sites are responsible for ordering supplies for collection and shipment 
of bone marrow specimens.
Specimens Required: 2 Purple Top Tubes (EDTA), 6mL each for U.S. sites. 
Specimens must be collected on Mondays, Tuesdays, Wednesdays or Thursdays for 
same-day shipment.
Processing Information: There is no required processing for bone marrow samples at 
each participating site prior to shipment.
Shipping Information for Bone Marrow Aspirate Specimens: 
Label all specimens with the following:
ƒ  Subject Initials
ƒ  Subject study number (will include protocol number)
ƒ  Visit at which sample was drawn (screening, response or relapse/progression)
ƒ  Date sample drawn (mm/dd/yyyy)
ƒ  Time sample drawn (24 hour clock)
Shipping Instructions: Shipments must be sent on the day of collection and cannot 
be batched.
1. An inventory sheet including a complete list of samples shipped (patient number, 
timepoint, study #) must accompany each shipment. Please sign and date the form, and 
retain a copy for site record maintenance.
2. An electronic copy (Word or Excel) of the sample list must also be sent via email. 
The listing must also include a contact name, address and phone number of the person 
who is responsible for the shipment.
3. Please email 
 to notify of an incoming 
shipment.
4. Please ship Monday, Tuesday, Wednesday or Thursday as shipments cannot be 
received on weekends and/or on holidays.
Once drawn, samples may be shipped ambient via overnight air to: 
Dana-Farber Cancer Institute

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Screening evaluations are to be conducted within 21 days prior to initiation of 
protocol therapy with the exception of the myeloma diagnosis. Baseline 
assessments are to be conducted on Cycle 1, Day 1 of initial RVD therapy. If 
screening assessments are performed within 7 days of C1D1, disease assessments 
do not need to be repeated.  All assessments must be performed prior to 
administration of any study medication. Study assessments and medications should 
be administered within + 7 days of the protocol-specified date, unless otherwise 
noted.  See below for detailed scheduled of assessments.

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111
Treatment Days
 
Initial Therapy
(RVD Cycle 1)
Screening
d 21days 
from 
Initiation of 
protocol
therapy21
Baseline
Day 112
Day 4
 
(+  1
day)
 
Day 8
 
(+ 1
day)
 
Day 11
 
(+1 day)
Informed consent
X
Inclusion/Exclusion criteria
X
X
Complete Medical Hx
X
Update
Confirmation Dx and status of disease and prior
Rx
X
Update
 
 
 
Baseline Symptom Assessment
X
X
 
 
Record concurrent therapies/procedures
X
X
X
X
X
Record adverse events
X
X
X
X
Physical examination, ECOG
X
X
 
 
Vital signs
X
X
X
X
X
Ht, Wt, BSA
X
 
 
Directed Neurological exam1
X
X
FACT/GOG NTx questionnaire
X
 
 
QOL Assessment19
X
 
 
Pharmacoeconomic Assessment20
X
 
 
Skeletal survey (CT or MRI as clinically 
indicated)8
X21
X8
 
 
 
Bone Marrow aspiration2
X2
X8,9
12 Lead ECG7
X
X7
 
 
Assessment of cardiac ejection fraction
X21
 
 
Pulmonary function tests
X21
 
 
Chest X-ray
X21
 
 
HIV/Hep B/Hep C
X
 
 
Hematology3
X
X
X
X
X
Serum chemistry 4
X
X4
X4
 
TSH
X
 
 
Beta 2 Microglobulin
X
 
 
B-12, Folate
X
 
 
C-Reactive Protein (CRP)
X
Urinalysis (microscopic analysis, color)
X
Pregnancy test 5
X13
X13
X5,13
 
CD4+ and CD8+ lymphocyte count
X
 
 
Serum and urine M component quantification, 
Immunofixation
X
X9
 
 
 
24hour urine for protein measurement
X
X9
 
 
Serum for FreeLite Testing 6,8
X
X8
 
 
Collection of bone marrow, plasma and serum 
for Correlative Studies11
X
 
 
 
 
Dispense study drug for next cycle15
X15
 
 

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114
 
Treatment Days
Initial Therapy with RVD 
(RVD Cycles 2-3)
At time of 
cyclophosp 
hamide
Within  42d
of PBSCT 
(Day 0)
Inpatient
PBSCT 
Period
Treatment Days
Consolidation Therapy with RVD 
(RVD Cycles 4-5)
Prior to
Len. Main- 
tenance
Len.
Main- 
tenance
End of
Study
Treatment 
and
Follow-up
 
 
 
Arm B
 
Day 112
Day 4 
(+ 1
day)
Day 8 
(+ 1
day)
Day 11 
(+ 1
day)
 
 
 
 
Day 112
Day 4 
(+ 1
day)
Day 8 
(+ 1
day)
Day 11 
(+ 1
day)
 
 
Day 112
 
Record concurrent therapies/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Record adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, ECOG
X
 
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ht, Wt, BSA
X
 
X
X
X
X
X
Directed Neurological exam1
X
X
X
FACT/GOG NTx questionnaire19
X
 
       x
         x 
X
      x
      x
QOL assessment 19
X 19
 
X
X
X19
X19
X20
Pharmacoeconomic assessment20
X20
 
X20
X20
X20
Skeletal survey (CT or MRI as clinically
indicated)8
X8
 
 
 
 
X
 
X8
 
 
 
X
X8
X8
Bone Marrow aspiration2
X8,9
X
X8,9
X
X8,9
X8
12 Lead ECG7
X7
 
X
X7
Assessment of cardiac ejection fraction
 
 
X
 
Pulmonary functions tests
 
 
X
 
Chest X-ray
 
 
X
 
Standard pre-PBSCT assessments (incl  infectious
disease serologies)
 
 
 
 
 
X
 
 
 
 
 
 
 
 
HIV/Hep B/ Hep C
 
 
X
 
PT/PTT
 
 
X
 
Hematology3
X
X
X
X
X
X
Daily
X
X
X
X
X
X3
Serum chemistry, 4
X4
 
X4
X
Daily4
X4
X4
X
X
TSH17
 
 
 
X17
Urinalysis (microscopic analysis, color)
X
Pregnancy test 5
X5,13
 
X5,13
X5,13
X5,13
X5,13
X5,13
X5,13
X5,13
CD4+ and CD8+ lymphocyte count18
X18
 
X18
Serum and urine M component quantification,
Immunofixation
X9
 
 
 
 
X
 
X9
 
 
 
X9
X9
X16
24hour urine for protein measurement
X9
 
X
X9
X9
X9
X16
Serum for FreeLite Testing 6, 8
X8
 
X
X8
X
X
X16
Collection of bone marrow, peripheral blood for
Correlative Studies11
 
 
 
 
 
X22
 
X22
 
 
 
X22
(X) 22
X22
Dispense study drug for next cycle15
X15
 
X15
X15
Perform drug accountability
X
X
X
Follow for Disease progression and survival
 
 
 
X16

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1. To include light touch, pinprick, proprioception, deep tendon reflexes of upper and lower extremities and query for paresthesia and numbness. (neuro consult if indicated)
2. To be evaluated for morphology and cytogenetics by FISH at screening and sample collection for correlative studies.
3. To include WBC, differential, Hgb, Hct and platelet count.  During lenalidomide maintenance, recommended once a week for the first 2 months, once every 2 weeks for the next 2 months, and once 
a month thereafter; must be conducted once per month at miniumum during this period. During follow-up, once every 2 weeks for the first 2 months, then once every month thereafter.
4. To include Na, K, Cl, CO2, Ca, Mg, Phosphorous, BUN, Creatinine, glucose, albumin, total protein, alk phos, total Bili, SGOT/SGPT, LDH, and uric acid at screening, baseline, and Day 1 of 
subsequent cycles.  On day 8, Na, K Cl, CO2 , Mg, BUN and Creatinine only are required.  Serum chemistry labs may be performed more frequently (e.g., on days 4 and 11) if required per 
institutional practice.
5.  Pregnancy tests for females of childbearing potential, defined as a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has not had menses at any time in the preceding 24 consecutive months).
6. For all participants.
7. 12-lead ECG to be done at screening , Cycle 1, Day 1 of RVD, and Day 1 of odd cycles of RVD therapy.
8. To be completed if clinically indicated, at emergence of new symptoms, or at MD discretion. If participants consent to the optional biopsy samples as described in the consent, they will be collected 
yearly during lenolidomide maintanence.
9. M Protein response will be based on objective serum and/or urine M protein changes as measured every cycle. For participants not measured in their urine (such as SPEP or free light chain), 24 
hour urines should be done every 3 months if possible but no lesss than every 6 months. Additional testing (BMBx, skeletal survey, scans) may be required to determine overall responses and confirm 
responses as indicated.  Full response assessment, including skeletal survey and BMBx, will be performed at the end of the study.
10. If routine scheduled visit
11. See Section 8.0 for Correlative studies (bone marrow, plasma and serum) collection and processing instructions.
12. When a study investigator or Nurse Practitioner is unavailable for Day 1 of subsequent cycles, arrangements should be made for the participant to be evaluated by an alternate investigator.  Safety 
labs (CBC and chemistry) will be redrawn on Day 1 and reviewed prior to the administration of drug.
13.  Pregnancy tests must occur  10-14 days before lenalidomide administration and again within 24 hours prior to initiation of lenalidomide.  Females of childbearing potential with regular or no 
menstruation must have a pregnancytest weekly for the first 28 days (including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide.  Females with 
irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 
and Day 28 post the last dose of lenalidomide (see Appendix IV: Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).
15. All participants must be counseled about pregnancy precautions, risks of fetal exposure and other risks.  The counseling must be done at on Day 1 of RVD (or at a minimum of every 28 days) and 
at drug discontinuation.  15.  Only enough lenalidomide for 1 cycle of therapy may be provided to the participant each cycle.
16.  Follow-up assessments will be performed every 2 months during the follow-up period after completion of treatment until disease progression or for up to 3 years after the last patient has been 
enrolled.  These assessments include serum and urine protein electrophoresis, serum and urine immunofixation, immunoglobulins assay, and serum free light chain assay.  Any additional follow-up

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assessments should be performed according to institutional practice.  At these assessments, participants are followed for disease status, survival, long term toxicities and second malignancies. Once a
participant progresses disease assessments are no longer required.
17. TSH will be performed at screening, at investigator’s discretion as clinically indicated and at discontinuation.18.  The CD4+ and CD8+ lymphocyte counts are to be performed on Day 1 of every 
odd cycles of RVD therapy beyond Cycle 1.  In cases where the tests are performed for the anticipated start of a scheduled cycle, which then becomes delayed, these tests do not need to be repeated at 
the delayed start date of that cycle.
19.  Quality of life assessments should be performed at Baseline, RVD Cycle 2, Day 1, prior to cyclophosphamide, RVD Cycle 5, Day 1, RVD Cycle 8, Day 1 (Arm A only), 20 days post PBSCT 
(Arm B only), Cycle 6, Day 1 of lenalidomide maintenance, at the end of study treatment, and at 2 years, and 3 years from the date of baseline assessments. The FACT/GOG NTx questionnaire 
should be performed at Baseline (Cycle 1, Day 1), RVD Cycle 2, Day 1, prior to cyclophosphamide, RVD Cycle 5, Day 1, RVD Cycle 8, Day 1 (Arm A only), 20 days post PBSCT (Arm B only), 
Cycle 6, Day 1 of lenalidomide maintenance, at the end of study treatment, and at 2 years, and 3 years from the date of baseline assessments as well.
20.  EQ-5D questionnaire should be administered at Baseline, RVD Cycle 2, Day 1, prior to cyclophosphamide, RVD Cycle 5, Day 1, RVD Cycle 8, Day 1 (Arm A only), 20 days post PBSCT (Arm
B only), Cycle 6, Day 1 of lenalidomide maintenance, at the end of study treatment, and at 2 years, and 3 years from the date of baseline assessments.
21. Results of bone marrow biopsy, skeletal survey, MRI, CT scans, and chest X-ray within 35 days of initiation of protocol therapy may be used to fulfill screening requirements
22. Bone marrow aspirate and red top peripheral blood tubes will be collected at screening, within 42 days of PBSCT, prior to lenalidomide maintenance, end of study treatment (post lenalidomide 
maintenance), RVD Cycle 4, Day 1 (Arm B only), at the time of confirmation of response (only if previous response is VGPR or better), at the time of disease relapse or progression. Additionally, 
optional samples are collected during lenolidomide maintanence. Yearly biopsies for participants in the maintanance phase are recommended to check disease status and to check for post treatment 
side effects. For the optional samples, they should be collected yearly +/- 3 months from the anniversary date of the biopsy prior to lenalidomide maintance.  For patients already in mainatenance at 
the time of consent, biopsies should start at their next anniversary date (+/- 3 months).
Purple top and proteomics tube collections will be obtained at screening and at the time of disease relapse or 
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10. MEASUREMENT OF EFFECT
In this study, patients must have measurable disease (see Section 10.2.2). The disease 
response will be assessed using criteria based on the International Working Group Uniform 
Response Criteria in Section 10.2.4.1. If the only measurable parameter is serum 
immunoglobulins free light chain (FLC), the participant will be followed by FreeLite™ 
Disease Response Criteria provided in Section 10.2.4.2.
Disease response by the Modified EBMT Response Criteria in Section 10.2.4.3 will also be 
collected on participants as a secondary measure.
The same method of assessment and technique should be used for disease 
measurement at baseline and during follow-up. Disease response should be confirmed 
by two consecutive assessments at a minimum of 6 weeks apart.
10.1 Antitumor Effect– Solid Tumors
This section is not applicable to this study.
10.2 Antitumor Effect – Hematologic Tumors
10.2.1 Definitions
This section is not applicable to this study.
10.2.2 Disease Parameters
Measurable disease. Measurable disease is disease that can be measured either by 
serum or urinary evaluation of the monoclonal component or by serum assay of
FLC and is defined by at least one of the following three measurements.
ƒ
Serum M-protein > 1 g/dl (except patients with IgD or IgA myeloma). For 
patients with IgD or IgA myeloma, a serum M-protein of greater than or 
equal to 0.5 g/dl will suffice.
ƒ
Urine M-protein > 200 mg/24 h
ƒ
Serum FLC assay: Involved FLC level > 10 mg/dl (> 100 mg/l) provided 
serum FLC ratio is abnormal.
10.2.3 Methods for Evaluation of Measurable Disease
All baseline evaluations should be performed on Cycle 1, Day 1 of initial therapy with 
RVD. Response will be assessed by M-protein quantification, protein 
electropheresis and immunofixation from serum and a 24-hour urine collection. A 
serum sample for FreeLiteTM testing will be obtained. In addition, bone marrow

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aspiration and biopsy, as well as skeletal survey will be performed to determine
overall response or confirm response.
he same method of assessment and technique should be used for disease 
measurement at baseline and during follow-up.
10.2.4 Response Criteria
A six-week confirmation measurement for disease response assessments is 
required in this protocol.
10.2.4.1 International Myeloma Working Group Response Criteria
Response criteria for all categories and subcategories of response except CR are 
applicable only to patients who have ‘measurable’ disease, as defined in Section 10.2.2. 
All response categories require two consecutive assessments made at anytime before the 
institution of any new therapy; all categories also require no known evidence of 
progressive or new bone lesions if radiographic studies were performed. Radiographic 
studies are not required to satisfy these response requirements.
Stringent CR: CR as defined below plus normal free light chain ratio and absence of 
clonal cells in bone marrow* by immunohistochemistry or immunofluorescence.**
*Confirmation with repeat bone marrow biopsy is not needed.
**Presence/absence of clonal cells is based upon the k/Ȝ ratio. An abnormal k/l ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for 
analysis. An abnormal ratio reflecting presence of an abnormal clone is k/Ȝ of > 4:1 or  < 1:2.
CR: Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and <5% plasma cells in bone marrow.
*Confirmation with repeat bone marrow biopsy is not needed.
VGPR: Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or  90% or greater reduction in serum M-protein plus urine M-protein 
level <100mg per 24 hours.
PR: > 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by > 90% or 
to < 200mg per 24 hours. If the serum and urine M-protein are unmeasurable, a > 50%
decrease in the difference between involved and uninvolved free light chain levels is required 
in place of the M-protein criteria (definition of measurable disease in Section 10.2.3). If serum 
and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, >
50% reduction in plasma cells is required in place of M-protein, provided baseline bone 
marrow plasma cell percentage was > 30%. In addition to the above listed criteria, if present 
at baseline, a > 50% reduction in the size of soft tissue plasmacytomas is also required.
SD: Not meeting criteria for CR, VGPR, PR or progressive disease. This is not 
recommended as an indicator of response; stability of disease is best described by 
providing the time to progression estimates.
PD: > 25% increase of serum M-protein (which must also be an absolute increase of >
0.5 g/dL) and/or urine M-protein (which must also be an absolute increase of > 200

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mg/24hr). If serum and urine M-protein are unmeasurable, there must be an absolute 
increase of > 10 mg/dL between involved and uninvolved FLC levels. PD is also 
measured by an absolute increase in bone marrow plasma cells > 10%.  In addition to the 
above listed criteria, progression may also be measured by a definite development of new 
bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas or development of hypercalcemia (corrected serum 
calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell 
proliferative disorder.
10.2.4.2   FreeLite™ Disease Response Criteria
Complete Response: For those patients being followed by serum free light chain 
(and NO measurable serum or urine M-spike), which were immunofixation 
negative at enrollment, normalization of serum free light chain ratio.
-  Normalization is defined as the serum free light chain ratio being within the 
normal range. If the serum free light chain ratio is not within the normal range, 
but the individual kappa and lambda light chain values are within normal range, 
this may be considered CR.
Partial Response: If only measurable parameter is serum immunoglobulins free 
light chain (FLC), EITHER of the following changes qualify as partial response:
- A 50% decrease in the difference between involved and uninvolved FLC levels; 
OR
- A 50% decrease in the level of involved FLC AND a 50% decrease (or 
normalization) in the ratio of involved/uninvolved FLC
Progressive Disease: If only measurable parameter is serum immunoglobulins 
free light (FLC), either of the following qualify as progression:
- 50% increase in the difference between involved and uninvolved FLC levels from 
the lowest response level, which must also be an absolute increase of at least
10 mg/dL; OR
- 50% increase in the level of involved FLC AND a 50% increase in the ratio of 
involved/uninvolved FLC from the lowest response level.
10.2.4.3  Modified EBMT Response Criteria

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Response
Criteria for Responsea
Complete response (CR)
Requires all of the following:
 
Disappearance of the original monoclonal protein from the blood and urine on at
least two determinations for a minimum of six weeks by immunofixation studies.
 
<5% plasma cells in the bone marrow on at least two determinations for a
minimum of six weeks. b
 
No increase in the size or number of lytic bone lesions (development of a
compression fracture does not exclude response).c
 
Disappearance of soft tissue plasmacytomas for at least six weeks.
Near Complete Response
(nCR)
Requires the following:
Same as CR, but immunofixation studies continue to show presence of the 
monoclonal protein
Very Good Partial Response
(VGPR)
Requires the following:
> 90% reduction in serum M-protein plus urine M-protein level <100mg per 24 
hours on at least two determinations for a minimum of six weeks.
Partial response (PR)
PR includes participants in whom some, but not all, criteria for CR are fulfilled 
providing the remaining criteria satisfy the requirements for PR.  Required all of 
the following:
 
t50% reduction in the level of serum monoclonal protein for at least two 
determinations six weeks apart.
 
If present, reduction in 24-hour urinary light chain excretion by either t90% or to
<200 mg for at least two determinations six weeks apart.
 
t50% reduction in the size of soft tissue plasmacytomas (by clinical or 
radiographic examination) for at least six weeks.
 
No increase in size or number of lytic bone lesions (development of compression
fracture does not exclude response).c
Minimal response (MR)
MR included participants in whom some, but not all, criteria for PR were 
fulfilled, providing the remaining criteria satisfied the requirements for MR. 
Required all of the following:
 
t25% to d 49% reduction in the level of serum monoclonal protein for at least 
two determinations six weeks apart.
 
If present, a 50 to 89% reduction in 24-hour light chain excretion, which still
exceeds 200 mg/24 h, for at least two determinations six weeks apart.
 
25-49% reduction in the size of plasmacytomas (by clinical or radiographic
examination) for at least six weeks.
 
No increase in size or number of lytic bone lesions (development of compression
fracture does not exclude response).c
No change (NC)
Not meeting the criteria for MR or PD.

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Response
Criteria for Responsea
Progressive disease (PD) 
(for participants not in CR)
Requires one or more of the following:
 
>25% increased in the level of serum monoclonal paraprotein, which must also
be an absolute increase of at least 5 g/L and confirmed on a repeat investigation.
>25% increased in 24-hour urinary light chain excretion, which must also be an 
absolute increase of at least 200 mg/24 h and confirmed on a repeat 
investigation.
>25% increased in plasma cells in a bone marrow aspirate or on trephine biopsy, 
which must also be an absolute increase of at least 10%.
 
Definite increase in the size of existing lytic bone lesions or soft tissue
plasmacytomas.
 
Development of new bone lesions or soft tissue plasmacytomas (not including
compression fracture).
 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8
mmol/L not attributable to any other cause).
Relapse from CR
Required at least one of the following:
 
Reappearance of serum or urinary paraprotein on immunofixation or routine
electrophoresis confirmed by at least one follow-up and excluding oligoclonal 
immune reconstitution.
 t5% plasma cells in the bone marrow aspirate or biopsy.
 
Development of new lytic bone lesions or soft tissue plasmacytomas or definite
increase in the size of residual bone lesions (not including compression fracture).
 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8
mmol/L not attributable to any other cause)e.
a   Based on the criteria reported by Blade et al., 1998.
b   Per Blade et al., 1998, if absence of the monoclonal protein is sustained for 6 weeks it is not necessary to repeat 
the bone marrow except in participants with nonsecretory myeloma where the marrow examination must be 
repeated after an interval of at least 6 weeks to confirm CR.
c   Per Blade et al., 1998, skeletal X-Rays are not required for the definition of response, but if performed there must 
be no evidence of progression of bone disease (no increase in size or number of lytic bone lesions).
d   It is suggested that the reference point for calculating any increase should be the lowest value of the preceding 
confirmed response (MR, PR or CR) or the baseline value if there is no previous confirmed response.
e   Other clinical data may be requested by the IRC, as necessary, to assess the cause of the hypercalcemia.
10.2.5 Duration of Response and Endpoint Definitions
Duration of overall response: The duration of overall response is measured as 
the time from initiation of first response to first documentation of disease 
progression or death. Patients who have not progressed or died are censored at 
the date last known progression-free.
Duration of overall complete response: The duration of overall CR is 
measured as the time from initiation of CR to first documentation of disease
 

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progression or death. Patients who have not progressed or died are censored at 
the date last known progression-free.
Time to progression: Time to progression is defined as the time of 
randomization until progression.  Patients who have died without evidence of 
progression are censored in the TTP analysis at the time of death and patients who 
are alive without progression are censored at the last disease assessment.
Overall survival (OS): OS is defined as the time from randomization to death. 
Alive patients are censored at the date last known alive.
10.2.6 Progression-Free Survival
Progression-Free Survival (PFS): the primary endpoint in this study. PFS is defined 
as the time from randomization to the disease progression or death from any cause. 
Patients who have not progressed or died are censored at the date last known 
progression-free.
10.2.7 Response Review
Central review of disease response assessments is not planned.
10.3  Other Response Parameters
10.3.1 Quality of Life
Quality of Life (QOL) is a secondary endpoint of this study. Measurement of quality of 
life (QOL) has gained widespread acceptance as a means of assessing the effects of 
chronic illness on a patient’s well being. Three QOL instruments will be evaluated in this 
study: The European Organisation for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire - Core (QLQ-C30) (Appendix VIII), the EORTC QLQ- 
MY20 Multiple Myeloma module (Appendix X), and the Functional Assessment of 
Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-NTX) side-effects 
questionnaires (Appendix IX).
The EORTC QLQ-C30 is a cancer-specific, multi-dimensional core QOL instrument that 
incorporates nine multi-item scales including five functional scales (physical, role, 
emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting
and pain) and a global health and quality of life scale. Six single items (dyspnea, 
insomnia, appetite loss, constipation, diarrhea and financial difficulties) are included. 
Response options are a four point Likert scale from “not at all” to “very much” or a seven 
point Likert scale from “very poor” to “excellent.” It is a reliable and valid measure of 
QOL in cancer patients. The EORTC has also developed a module specific for multiple 
myeloma (EORTC QLQ-MY20) to be used in conjunction with the C30 scale. This scale 
is designed to evaluate the effect of the disease and drug therapy in patients with 
myeloma. It provides four scales (disease symptoms, side effects, body image, future
 

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perspective). The instrument consists of a brief questionnaire that has been validated and 
utilized in many countries. The EORTC QLQ-C30 and MY20 together take on average
12 minutes to complete. (Aaronson et. al, 1993; Hjermstad et. Al, 1995; Cocks et. al,
2007).
The questionnaire is designed to be self administered. However, a designated person at 
each site should be responsible for giving the surveys to participants and providing 
materials to assist in survey completion (a clipboard, pen, and envelope to enclose the 
survey in when completed). This person would also be responsible for collecting the 
completed survey, checking for missing items, and answering any questions that arise 
regarding the survey.
The QOL surveys should be administered before the participant sees the physician so that 
the interaction between the participant and physician does not influence the participant’s 
answers to the questionnaire. Ideally, the questionnaire should also be completed before 
the participant is asked about adverse experiences and concurrent illnesses, again so that 
any discussions of health problems do not influence the participant’s answer to the 
questionnaire. It is important that the components of the QOL survey be administered in 
the same order in all study sites.
Participants must have basic fluency in English in order to complete the QOL surveys 
provided. If a participant is not able to speak English, the individual administering the 
questionnaire must determine whether or not the participant has basic fluency in any of 
the languages in which the questionnaire is currently available (mostly European 
languages). Copies of alternative language questionnaires are available from the 
Coordinating Center. If the questionnaire is not currently available in a language in 
which the participant has basic fluency, translation services may be requested. 
Participants who are not able to see or read the questionnaire may have it read to them 
verbatim by study staff and their answers recorded.
If a participant asks the meaning of specific questions, study staff may assist the 
participant by rereading the question for them verbatim. However, the study staff must
not attempt to interpret the question and/or participant responses or provide the participant 
score on the questionnaire. All participants should answer the questions based on what 
they think the questions mean, or the study results may be biased.
After the participant has completed the questionnaire, study staff will check that all of the 
questions have been answered and ask the participant to answer the incomplete item or 
items. If the participant is still unable to complete the question or refuses to answer an 
item or items, accept the questionnaire as incomplete. The physician should not be 
allowed to review the completed questionnaire.
QOL questionnaires will be administered at nine timepoints: baseline, RVD Cycle 2, Day
1, prior to cyclophosphamide administration, RVD Cycle 5 Day 1, RVD Cycle 8 Day 1 
(Arm A only), 20 days post PBSCT (Arm B only), Cycle 6 Day 1 of lenalidomide 
maintenance, at the end of study treatment, and at 2 years and 3 years from baseline.

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QOL domains will be compared between Arm A and Arm B, and include health related 
quality of life, distress, psychological functioning, physical well-being and functional
well-being. Participant answers will be kept confidential and aggregated with information 
from many other participants before analysis.
10.3.2 Pharmaco-economics (Medical Resource Utilization)
Pharmacoeconomics is another secondary endpoint to the trial. Pharmacoeconomics 
assessment will measure the costs of the two treatment arms by comparing markers of 
resource utilization between Arm A and Arm B. During the study, medical resource 
utilization (MRU) data associated with medical encounters related to disease or myeloma 
therapies will be collected for all participants. Specifically, MRU is evaluated based on 
the number of medical care encounters such as hospital admissions and their duration, 
outpatient visits, and diagnostic tests and procedures. The MRU data will be used to 
conduct economic analyses.
MRU data will be collected at the following timepoints: baseline, RVD Cycle 2, Day 1, 
prior to cyclophosphamide administration, RVD Cycle 5 Day 1, RVD Cycle 8 Day 1 
(Arm A only), 20 days post PBSCT (Arm B only), Cycle 6 Day 1 of lenalidomide 
maintenance, at the end of study treatment, and at 2 years and 3 years from baseline. 
Routine MRU elements such as diagnostic tests, blood tests and other related tests, and 
bone scans are collected using the case report forms in this trial.
Data related with hospitalization, reasons for hospitalization, duration of hospitalization, 
and outpatient visits will be collected. It should be noted that outpatient visits for drug 
administration will also be captured.
The EQ-5D will be used to capture participant-reported utilities for use in cost-utility 
analyses in this trial (See Appendix X).  The EQ-5D contains a five item survey with 
three response levels per item measuring mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. It also contains a 0-100 visual analogue scale to 
measure current overall health and 9 optional sociodemographic questions. The EQ-5D 
takes approximately 1 minute to complete (Agency for Healthcare Research and Quality,
2005).
11. ADVERSE EVENT REPORTING REQUIREMENTS
Adverse event collection and reporting is a routine part of every clinical trial. This study 
will use the descriptions and grading scales found in the CTCAE version 4.0 NCI Common 
Terminology Criteria for Adverse Events. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP homepage (http://ctep.info.nih.gov).
Information on all adverse events, whether reported by the participant, directly observed, or 
detected  by  physical  examination,  laboratory  test  or  other  means,  will  be  collected, 
recorded, followed and reported as described in the following sections.

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Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. The investigator should notify the IRB 
and any other applicable regulatory agency of any unanticipated death or adverse event 
occurring after a participant has discontinued or terminated study participation that may 
reasonably be related to the study.
11.1  Definitions
11.1.1 Adverse Event (AE)
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study 
treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study.
An  adverse  event  is  any  change  in  health  occurring  in  a  person  who  is  a 
participant in biomedical research, whether this change is related or not to the 
research or to the product that the research is being conducted on.  This includes 
any newly occurring event or previous condition that has increased in severity or 
frequency since the administration of drug.
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.
11.1.2 Serious adverse event (SAE) and events requiring expeditive reporting
A serious adverse event is an undesirable sign, symptom, or medical condition, 
regardless of causality that:
x
Results in death,
x
Is life-threatening. Life-threatening means that the participant was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form;
x
Requires hospitalization or prolongation of existing hospitalization (i.e., 
the event required at least a 24-hour hospitalization or prolonged a 
hospitalization beyond the expected length of stay). Hospitalization 
admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered SAEs if the 
illness or disease existed before the participant was enrolled in the trial, 
provided that it did not deteriorate in an unexpected manner during the 
trial (e.g., surgery performed earlier than planned);
x
Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions;

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x
Is a congenital abnormality or birth defect;
x
Is an important medical event. An important medical event is an event 
that, when based upon appropriate medical judgment, may jeopardize the 
participant and require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such medical 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, the development of drug dependency or drug 
abuse, or suspected transmission of infectious agents by medicinal 
product.
The following event must also be reported in an expedited manner:
x  Results in pregnancy (see section 11.1.3)
Any adverse event arising after study treatment discontinuation/study termination 
that is possibly related to study treatments/procedures must be reported regardless 
of the delay between event onset and study treatment discontinuation/study 
termination.
Secondary malignancies must be reported as serious adverse events regardless of 
when they occur and regardless of their relationship to the study treatments/ 
procedures.
Events not considered to be serious adverse events are hospitalizations for:
x
Routine treatment or monitoring of the studied indication, not associated 
with  any  deterioration  in  condition,  or  for  elective  procedures  of  a 
condition unrelated to the studied indication or its treatment
x
Elective or pre-planned treatment for a pre-existing condition that did not 
worsen
x
Emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission
x
Respite care
Please note the distinction between seriousness and severity of an AE.  Severity is a 
measure of intensity of an event (mild, moderate, severe).  However, the event itself 
may be of relatively minor medical significance; thus, a severe reaction may not 
necessarily be classified as a serious reaction. This differs from seriousness, which is 
based on patient/event outcome or action criteria described above and are usually 
associated with events that pose a threat to a patient’s life or functioning.  A severe 
adverse event does not necessarily need to be considered serious.  Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations.

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11.1.4 Expectedness
Adverse events can be 'Expected' or 'Unexpected.'
11.1.4.1  Expected adverse event
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the current 
Investigator’s Brochure or is included in the informed consent document 
as a potential risk.  Scheduled hospitalizations for the study treatment, 
participant follow-up and medical conditions related to the progression
of the disease are considered to be expected SAEs.
The investigator must evaluate all abnormal lab results to determine the 
clinical significance. If an abnormal result appears to be clinically 
significant, it must be considered to be an AE.
Refer to Section 6.1 for a listing of expected adverse events associated 
with the study agent(s).
11.1.4.2  Unexpected adverse event
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information
provided in the current Investigator’s Brochure or when it is not included 
in the informed consent document as a potential risk.
11.1.5 Attribution (Causality)
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. It will be assigned by using the WHO causality method 
assessment linked to CTCAE grading system (as follows):
TERM                                                                        DESCRIPTION

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CERTAIN/DEFINITE
A clinical event, including laboratory test abnormality,
occurring in a plausible time relationship to drug 
administration,  and  which  cannot  be  explained  by 
concurrent  disease  or   other  drugs   or   chemicals.  The 
response to withdrawal of the drug (dechallenge) should be 
clinically plausible. The 
event 
must 
be 
definitive 
pharmacologically 
or 
phenomenologically, 
using 
a 
satisfactory rechallenge procedure if necessary. The AE is 
clearly related to the study treatment.
LIKELY/PROBABLE              A  clinical  event,  including  laboratory  test  abnormality, 
with a reasonable time sequence to administration of the 
drug,  unlikely  to  be  attributed  to  concurrent  disease  or 
other drugs or chemicals, and which follows a clinically 
reasonable
response     on     withdrawal     (dechallenge). 
Rechallenge information is not required to fulfil this 
definition. The AE is likely related to the study treatment.
POSSIBLE                        A  clinical  event,  including  laboratory  test  abnormality, 
with a reasonable time sequence to administration of the 
drug, but which could also be explained by concurrent 
disease or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear.   The AE may be 
related to the study treatment.
UNLIKELY                       A  clinical  event,  including  laboratory  test  abnormality, 
with a temporal relationship to drug administration which 
makes a causal relationship improbable, and in which other 
drugs, chemicals or underlying disease provide plausible 
explanations.
The AE is doubtfully related to the study 
treatment.
UNRELATED                   The AE is clearly NOT related to the study treatment
An event will be considered possibly study-related if causality criteria will be
“certain/definite”, “likely/probable”, and “possible”.
The causality criteria “unlikely” and “unrelated” is intended to be used when the 
exclusion of drug causality of a clinical event seems most plausible. It will be used to 
define “not study-related” events.

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An event will also be considered as “concomitant drug-related”, “disease progression- 
related “or “other cause related”.
Causality  will  be  assessed  for  each  investigational  treatment  used  in  the  trial
(bortezomib and lenalidomide)
If a reported SAE is considered an unexpected and suspected serious adverse reaction
(SUSAR), reporting/notification rules described below must be followed.
11.2 Adverse Event Recording and Reporting
Reporting Participating investigators will assess the occurrence of AEs and SAEs at all 
participant evaluation time points during the study.
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study- 
specific case report forms. All AEs must be recorded in the participant’s medical 
record, stating the duration and intensity of the event, action taken by the investigator 
and outcome of the event. The investigator must evaluate the causal relationship 
between the study drug(s) and the adverse event.
The investigator must evaluate all abnormal laboratory results to determine the clinical 
significance.
All AEs detected by the investigator or by the participant must be recorded on the 
appropriate study-specific CRFs, stating the duration and intensity of the event, action 
taken by the investigator and outcome of the event. The investigator must evaluate the 
causal relationship for each AE.
The descriptions and grading scales found in the CTEP Version 4.0 of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE 
reporting. The CTEP Version 4.0 of the CTCAE is identified and located on the CTEP 
website at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Each adverse event will be assessed to determine if it meets the criteria for SAE
reporting. If an SAE occurs, expedited reporting will follow local policies, and 
regulations as appropriate.
Hematologic adverse events will be recorded/reported only if > grade 2 or if an action 
on study drug was required. Grade 3/4 myelosuppression during mobilization and 
transplant is expected and does not require reporting as an SAE.  These events should 
be captured on the adverse event pages of the CRF only.

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11.3 Reporting Requirements
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, 
each participating investigator is required to abide by the reporting requirements set by 
the DF/HCC. The study must be conducted in compliance with FDA regulations, local 
safety reporting requirements, and reporting requirements of the Principal Investigator.
Each investigative site will be responsible to report SAEs that occur at that institution to 
their respective IRB. It is the responsibility of each participating investigator to report 
serious adverse events to the Principal Investigator, the participating site’s IRB, and others 
as described below.
11.4  Reporting to the Study Supporter
11.4.1. Serious Adverse Event Reporting
Serious adverse events (SAE) are defined above.   The investigator must inform 
Celgene and Millennium in writing using an SAE form or MEDWATCH 3500A 
form of any fatal or life threatening SAE within 24 hours but no later than 4 calendar 
days of the sponsor-investigator’s observation or awareness of the event and all 
other serious (non-fatal/non life threatening) events within 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event.  The written report 
must be completed and supplied to Celgene and Millennium by facsimile within 
24 hours but no later than 4 calendar days.  The initial report must be as complete 
as possible and include at minimum the event term, seriousness criteria, intensity of 
the event and the causal relationship between the event and the investigational  
product(s).  Intensity  for  each  SAE,  including  any  lab abnormalities, will be 
determined by using the NCI CTCAE version used at your institution, as a 
guideline, 
whenever 
possible.  
The 
criteria 
are 
available 
online 
at 
http://ctep.cancer.gov/reporting/ctc.html. Information not available at the time of 
the initial report (e.g., an end date for the adverse event or laboratory values received 
after the report) must be documented on a follow-up report.   A final report to 
document resolution of the SAE is required.    The Celgene tracking number 
(RV-MM-IFM-0444) and Millennium tracking number (X05347) and the 
institutional protocol number should be included on SAE reports (or on the fax 
cover letter) sent to Celgene and Millennium.  A copy of the fax transmission 
confirmation of the SAE report to Celgene and Millennium should be attached to 
the  SAE  and  retained with  the  patient records. Celgene and  Millennium may 
request follow-up information on reported SAE’s.
Dana-Farber will be responsible for SAE reporting and management to the FDA, 
Celgene and Millennium and DFCI IRB.
All serious adverse events that occur from the date of informed consent signature, 
during treatment, or within 30 days of the last dose of treatment, with the

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exception of participants who withdraw from treatment during RVD cycles, in 
whom adverse events will be collected until 60 days following the last treatment 
administration, must be reported on a MEDWATCH FDA Form 3500A. This 
includes events meeting the criteria outlined in Section 11.1.2., as well as the 
following:
x
Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at 
least possibly related/associated with the intervention.
x
All Grade 4 (life-threatening or disabling) events unless they are 
expectedAND specifically listed in the protocol as not requiring reporting.
x
All Grade 5 (fatal) events while the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.
Note: If the participant is in long term follow up, report the death at the time of 
continuing review.
Participating investigators must report each serious adverse event, regardless of 
relationship with any study drug or expectedness within 24 hours of learning of 
the occurrence using the MEDWATCH FDA Form 3500A form. In the event that 
the participating investigator does not become aware of the serious adverse event 
immediately (e.g., participant sought treatment elsewhere), the participating 
investigator is to report the event within 24 hours after learning of it and
document the time of his or her first awareness of the adverse event. Report 
serious adverse events by telephone, email or facsimile to:
Dana-Farber Cancer Institute
Paul Richardson, MD
450 Brookline Avenue, LG- 
Boston, MA 02215
Phone: 
Fax: 
Email: 
Email: 
Dana-Farber will inform Celgene and Millennium of any SAE in writing using a 
MEDWATCH FDA Form 3500A within 24 hours of awareness. The Celgene 
tracking number (RV-MM-IFM-0444) and the protocol number should be 
included on SAE reports (or on the fax cover letter).
Information not available at the time of the initial report must be documented on a 
follow-up MEDWATCH Form 3500A.

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11.4.2 IND Action Letters and Safety Reports
The Coordinating Center will distribute IND Action Letters or Safety Reports 
occurring on this trial to all participating institutions for submission to their 
individual IRBs for action as required.
11.4.3  Non-Serious Adverse Event Reporting
Non-serious adverse events will be reported on the adverse event Case Report
Form.
11.5  Reporting to the Institutional Review Board (IRB
Investigative sites within DF/HCC will report all serious adverse events directly to the
DFCI Office for Human Research Studies (OHRS).
Other investigative sites should report serious adverse events to their respective IRB
according to the local IRB policies and procedures in reporting adverse events.
The Principal Investigator will submit SAE reports from outside institutions to the
DFCI Office for Human Research Studies (OHRS) according to DFCI IRB policies and 
procedures in reporting adverse events.
11.6  Reporting to the Food and Drug Administration (FDA)
The Principal Investigator, as holder of the IND, will be responsible for all 
communication with the FDA. The Principal Investigator will report to the FDA, 
regardless of the site of occurrence, any adverse event that is serious, unexpected and 
reasonably related (i.e., possible, probable, definite) to the study treatment.
Unexpected fatal or life-threatening experiences associated with the use of the study 
treatment will be reported to FDA as soon as possible but in no event later than 7 
calendar days after initial receipt of the information.
All other serious unexpected experiences associated with the use of the study treatment 
will be reported to FDA as soon as possible but in no event later than 15 calendar days 
after initial receipt of the information.
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800- 
FDA-0178) using MEDWATCH Form FDA 3500A (Mandatory Reporting Form for 
investigational agents). Forms are available at 
http://www.fda.gov/medwatch/getforms.htm.
An annual safety report containing SAEs, expected SAEs and unexpected SAEs will be 
sent to the FDA and other applicable regulatory authority(ies). Celgene and Millennium

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will receive a copy of the Investigator IND annual report at the time of the 
investigator’s submission to the FDA and/or other regulatory authorities.
11.7 Reporting to the NIH Office of Biotechnology Activities (OBA)
This section is not applicable to this study.
11.8  Reporting to the Institutional Biosafety Committee (IBC)
This section is not applicable to this study.
11.9  Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy.
11.10  Monitoring of Adverse Events and Period of Observation
All adverse events, both serious and non-serious, and deaths that are encountered from 
the date of informed consent signature, throughout the study, and within 30 days of the 
last treatment administration, with the exception of participants who withdraw from 
treatment during RVD cycles, in whom adverse events will be collected until 60 days 
following the last treatment administration, should be followed to their resolution, or 
until the participating investigator assesses them as stable, or the participating 
investigator determines the event to be irreversible, or the participant is lost to follow- 
up.
The presence and resolution of AEs and SAEs (with dates) should be documented on 
the appropriate case report form and recorded in the participant’s medical record to 
facilitate source data verification.
After this period only SAEs considered reasonably study-related by the investigator 
must be reported to the sponsor (for example, delayed SAE) without limitation.
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or
autopsy report).
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the Principal Investigator and their respective IRB of any unanticipated death or 
adverse event occurring after a participant has discontinued or terminated study 
participation that may reasonably be related to the study.

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12  DATA AND SAFETY MONITORING
12.1 Data Reporting
The investigator and/or individual designated by the investigator will be responsible for the 
following study functions: oversee logistics and monitoring of the study, create progress 
reports, verify case report form updating, request additional information and corrections to 
case report form, send correlative samples, SAE reporting to the sponsor and local 
regulatory authorities. This individual will work in accordance with standard operating 
procedures, in cooperation with the project management team and study monitor, as 
delegated by the study sponsor.
12.1.1 Method
Data will be collected via electronic CRF (eCRF) for this study, using an Oracle 
based system. Details for access to this electronic data capture system will be 
provided by the study sponsor.
12.1.2 Data Submission
The schedule for completion of electronic data can be located in the Site Study
Manual.
12.1.3 Database Management and Confidentiality
Data will be entered into an electronic file. The identity of participants participating 
in the study will be made anonymous. Participants will be identified by a unique 
study identifier (study subject number). A participant identification list linking the 
subject number to the participant identifying information will be kept in a secure 
location at each participating study site.
The investigator will take measures to protect the privacy and security of personal 
information for each participant in this trial. No information that could allow 
identification of persons will be communicated to third parties other than those 
legally authorized to have access to this information and who are bound by 
professional confidentiality.
The data will be monitored. Queries will be generated and sent to the participating 
site. Responses to queries will be done directly in the database by the investigators 
and/or individual designated by the investigator. Tracking of changes by the user 
will be performed. A set of work instructions for data validation will be written.
12.2  Data Monitoring Committee (DMC) Meetings

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An independent Data Monitoring Committee (DMC) will be established for this trial. The 
objective of the DMC is to review safety, progress toward completion of study, and interim 
analyses of outcome data as designated in the Data and Safety Monitoring Charter
(DSMC). Adverse events and serious adverse events will be reviewed by the DMC to 
determine the cause of these events and necessary measures will be taken to ensure 
participant safety. The DMC will meet at least once a year to review the trial for data and 
safety issues, and may be scheduled more frequently if needed to review safety (e.g., one 
face-to-face meeting per year with teleconference at other timepoints). Following each 
meeting, the DMC will provide the study team with information concerning findings for 
the trial as a whole related to cumulative toxicities observed and any relevant 
recommendations related to continuing, changing or terminating the trial. The DMC will 
provide a summary of the committee findings to the principal investigator. The principal 
investigator will communicate this information to the IRB as well as participating study 
investigators as necessary.
The DMC members will include physicians with expertise in the field of multiple 
myeloma and statisticians. These DMC members are not affiliated with the participating 
institutions, and are not directly involved with the conceptual design or analysis of the 
trial.
12.3  Monitoring
Involvement in this study as a participating investigator implies acceptance of potential 
audits or inspections, including source data verification, by representatives designated 
by the sponsor. The investigator will grant the monitor or auditor access to the patient’s 
original medical records. The purpose of these audits or inspections is to examine
study-related activities and documents to determine whether these activities were 
conducted and data were recorded, analyzed, and accurately reported in accordance with 
the protocol, institutional policy, Good Clinical Practice (GCP), and any applicable 
regulatory requirements. The patient’s confidentiality will be maintained and will not
be made publicly available to the extent permitted by the applicable laws and
regulations.
Specified data will be monitored for timeliness of submission, completeness, and 
adherence to protocol requirements. Monitoring will begin at the time of participant 
registration and will continue during protocol performance and completion.
A clinical research assistant (CRA) delegated by the sponsor  will regularly visit each 
study center at the time of setup of the trial, one or more times during the trial according 
to the pace of enrollment, and at the end of the trial. The Coordinating Center will be 
responsible for site initiation visits. These visits will be conducted as either an on-site 
visit or via webconference. If investigator meetings are planned they may be considered 
as initiation visits if agreed by the sponsor. Following site initiation, a commercial
CRO will be responsible for on-site monitoring and close-out visits at participating 
sites. The frequency of site monitoring will be dependent on site enrollment, with the 
first visit occurring within two months of first participant enrollment. After the first

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monitoring visit, on-site monitoring will occur approximately once every three months 
or as accrual dictates.
The purpose of these visits is to monitor compliance with the protocol, verify informed 
consent forms, verify compliance with SAE reporting procedures, monitor the tracking of 
study drug (pharmacy visit, storage and accounting of study drug), retrieve regulatory 
documentation, and perform quality control by comparing data from the CRF to the
source documents of the center as per monitoring guidelines requirements. See Appendix
XIII, Section 9.3.1 for further detail on source document verification.
Access to the source documents will be given to the clinical research assistant based on 
the needs of monitoring of the trial and in compliance with GCP. Any visit will be 
subject to a monitoring report via a written description (tracking of visits).
During the course of the study, communication between the Coordinating Center and 
participating sites will occur monthly via teleconference.
12.4
Audit and inspection
In accordance with GCP, the investigators agree to comply with the requirements of the 
sponsor and the Regulatory Authorities with regard to an audit or inspection of the trial.
The audit may be performed at any of the stages of the study, from development of the 
protocol to publication of the results.
Regulatory authorities or the sponsor may request access to all source documents, data 
capture records, and other study documentation for on-site audit or inspection. Direct 
access to these documents must be granted by the investigator, who must provide 
support at all times for these activities.
The investigator will notify DFCI in the event of an audit request and DFCI will 
subsequently notify Celgene and Millennium of such request.
12.5
Drug Accountability
Drug accountability for the drug at all study sites (including all sub-sites) is the 
responsibility of the Principal Investigator. The investigator will ensure that the drug is 
used only in accordance with this protocol and will maintain documentation of 
investigational products inventory, dispensing and destruction.
13.  REGULATORY CONSIDERATIONS
13.1  Protocol Review and Amendments

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This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation.  Millennium and Celgene will be 
notified of all protocol modifications, and will be given opportunity to review and 
provide comment prior to IRB submission. Any changes in study conduct must be 
reported to the IRB and other regulatory authority(ies) in accordance with the 
governing regulations. Changes to the protocol will require written IRB 
approval/favorable opinion prior to implementation, except when the modification is 
needed to eliminate an immediate hazard(s) to participants. The IRB may provide, if 
applicable regulatory authority(ies) permit, expedited review and approval/favorable 
opinion for minor change(s) in ongoing studies that have the approval/favorable 
opinion of the IRB.  The Principal Investigator will disseminate protocol amendment
information to participating investigators. See Appendix XIII, Section 5.0 for details of 
protocol management, including protocol distribution, revisions and closure.
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB and the appropriate regulatory authority(ies). 
Any deviation from the protocol must be fully documented in the source documents.
13.2  Informed Consent
All participants must be provided a consent form describing this study and
providing sufficient information for participants to make an informed decision
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is
involved in any study-related procedure. The consent form must be signed and
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.  The method of 
obtaining and documenting the informed consent and the contents of the consent will 
comply with ICH-GCP and all applicable regulatory requirement(s).
13.3  Ethics and Good Clinical Practice (GCP)
This study is to be conducted according to the following considerations, which 
represent good and sound research practice:
x
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf

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x
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html
x
State laws
x
DF/HCC research policies and procedures 
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit- 
cru/policies-and-procedures/
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB according to the local reporting policy.
13.4  Study Documentation
The investigator must prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the study for each research 
participant. This information enables the study to be fully documented and the study data 
to be subsequently verified.
Original source documents supporting entries in the CRFs include but are not limited to 
hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.
13.5  Records Retention
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.
13.6 Multi-center Guidelines

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This protocol will adhere to the policies and requirements of the Dana- 
Farber/Harvard Cancer Center. The specific responsibilities of the Principal 
Investigator, Coordinating Center, and Participating Institutions are presented in the 
Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(see Appendix XIII).
x
Mechanisms will be in place to ensure quality assurance, protocol compliance, 
and adverse event reporting at each site.
x
Participating institutions will order the agent(s) directly from the supplier. A 
participating site may order the agent(s) only after the initial IRB approval 
for the site has been forwarded to the coordinating center who will forward to 
applicable parties as needed.
13.7
Cooperative  Research  and  Development  Agreement  (CRADA)/Clinical  Trials
Agreement (CTA)
This is not a CTEP-supported study, therefore, this section is not applicable.
13.8   Investigator Responsibilities
The investigator agrees to perform the study in accordance with law no. 2004-806 of 9
August 2004 regarding the public health policy, and with decrees made in application of 
it, with the Declaration of Helsinki and with Good Clinical Practices. All data, all 
documents  and  reports  may  be  subject  to  regulatory  audits  and  inspections,  which 
cannot be opposed based on medical secrecy.
The investigator will inform participants of the objectives and constraints of the study, 
of their rights to refuse to participate in the study or to quit it at any time. When 
information has been given to the potential participant and the investigator has made 
sure that the potential participant has understood the implications of participation in the 
study, the participant’s written consent will be collected by one of the investigators in 
two original copies of the informed consent document. One original copy of the signed 
consent form will be given to the participant and the second original copy will be 
maintained by the investigator in the participant’s study files.
All information collected is confidential. The investigator will take measures to protect 
the privacy and security of personal information for each study in this trial. No 
information that could allow participant identification will be communicated to third 
parties other than those representing the sponsor or regulatory authority, legally 
authorised to have access to this information and bound by professional secrecy.

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14. STATISTICAL CONSIDERATIONS
In the original study, the statistical plan was to compare the two arms stratified by country (IFM,  
US), cytogenetic risk and ISS. The original  protocols for both the IFM and the US  included 
maintenance lenalidomide for one year. Based on the NEJM maintenance paper (CALGB NEJM 
2012) on the benefit of maintenance therapy the US protocol was  revised October 16, 2012 to 
extend maintenance until progression.  The accrual for the US was expanded to include 660 
patients to address the question of conventional dose followed by maintenance until PD versus 
high dose therapy arm followed by maintenance until PD. The accrual for the IFM protocol was 
700 patients to address the question of conventional dose followed by 1-year of maintenance vs. 
high dose therapy arm followed by 1-year of maintenance. 
In February 2016, McCarthy et al presented results from a meta-analysis showing a 50% 
reduction in the hazards for continuous maintenance therapy (EHA February 2016).  With a 
reduction in the failure rate, the time to the full information could be longer than expected in this 
study.  Therefore, to account for this potential reduction in the hazard rates in both arms (the 
hazard ratio remains at 1.43), the sample size is increased to 720 randomized patients; based on 
patient drop out rates from registration to randomization, it is anticipated that 750 patients will 
need to be enrolled in order to reach the 720 randomization figure. With the increase from 660 to 
720 randomized patients, the time to reach full information is 5 months earlier. 
Details on the design changes are summarized below. The sections below include the original 
design (14.2.1), the October 16, 2012 design at the time the US maintenance treatment duration 
was modified  (14.2.2), and the October 2016 change to increase the sample size to account for 
potential reduction in the hazard rates per arm (14.2.3). 
14.1 Study Objectives/Endpoints and Stratification Factors
The primary objective of this randomized phase III study is to compare the progression-free 
survival (PFS) of Arms A (conventional dose arm) and Arm B (high dose therapy arm) in newly 
diagnosed myeloma patients who have completed 1 cycle of RVD. PFS is defined as the time 
from randomization until progression or death from any cause. Patients alive without confirmed 
progression will be censored at the time of the last disease evaluation. Deaths without progression 
are counted as failures even if they occur after the last disease evaluation. Patients are stratified 
by country (US vs. IFM), cytogenetics risk factors (standard, high risk, FISH failures) and ISS 
(Stage I vs. II vs. III). Patients will be randomized equally to the two arms using permuted blocks 
within stratification combinations.
The secondary objectives of the study are to compare the following outcomes between the two 
arms: the response rates (CR, at least VGPR), time to progression, overall survival, toxicity, 
quality of life and pharmaco-economics. The reasons that participants who received 1 cycle of 
therapy did not proceed to the randomization will be collected and reported.  Prognostic groups 
defined by gene expression profiling will be defined in correlative studies. Time to progression 

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(TTP) is defined as the time of randomization until progression. Patients who have died without 
evidence of progression are censored in the TTP analysis and patients who are alive without 
progression are censored at the last disease assessment. Overall survival is defined as the time of 
randomization to death. Patients are censored at the time last known alive.
The planned sample size for the US is 720 randomized patients and for the IFM is 700 
randomized patients. It is anticipated that approximately 1% of the patients will register to the 
study and not proceed to randomization after 1 cycle of therapy.
14.2  Statistical Considerations for the Primary Objective
The primary objective of this protocol is to compare PFS of Arms A (conventional dose arm) and 
B (high dose arm). Protocols using combinations of new drugs at conventional doses using 
melphalan, prednisone and thalidomide (Palumbo et al., 2006; Facon et al., 2007), melphalan, 
prednisone and bortezomib (San Miguel et al., 2008), dexamethasone / lenalidomide (Rajkumar et 
al., 2007) resulted in PFS estimates of between 18- 24 months. The median value of progression-
free survival of participants treated with RVD can thus be estimated at 30 months at the best 
(Richardson et al., 2007). The primary analysis of PFS will be performed using a stratified two-
sided log-rank test with an overall type I error rate of 5%. The primary analysis will be intent to 
treat analysis of all randomized patients. Cases determined to be ineligible after randomization 
will be included in the analysis. PFS in each of the arms will be estimated using the method of 
Kaplan and Meier.
14.2.1 Original design: The IFM and DFCI studies combined have 92% power to detect a 23% 
reduction in the PFS hazard from 0.0231/month on conventional dose arm (Arm A) to 
0.0177/month on high dose therapy arm (Arm B) using a stratified two-sided log-rank test with an 
overall type I error rate of 0.05.  This corresponds to a hazard ratio (hazard of conventional dose 
Arm A/hazard of high dose Arm B) of 1.3.  Full information under the alternative hypothesis is 658 
failures. Assuming median PFS of 30 months on the RVD alone arm (Arm A) and the PFS time 
follows an exponential distribution, this difference corresponds to a 30% increase in median 
survival to 39 months for Arm B. Based on these medians and corresponding failure rates, the 
required number of failures will be observed with 1000 patients enrolled over 36 months with 36 
months of follow-up. Two interim analyses were planned at approximately 33% and 69% 
information. In calendar times these are anticipated to be at approximately 30 months (prior to the 
end of enrollment) and 48 months with the final analyses planned at approximately 72 months. To 
preserve the overall type I error rate, critical values at the interim analysis will be determined using 
the Lan-DeMets error spending rate function corresponding to the O'Brien Fleming boundary. The 
study will also be monitored for early stopping in favor of the null hypothesis using Jennison-
Turnbull repeated confidence interval (RCI) methodology. At each interim analysis, the one-sided 
97.5% repeated confidence upper limit on the hazard ratio will be computed using the critical value 
from the error spending function. If the upper limit lies below the target alternative hazard ratio 
(hazard of the conventional dose /hazard of the high dose) then the DMC may consider stopping 
the trial early in favor of the conventional dose arm.
14.2.2 Design modification for US study change to continuous maintenance therapy 
(October 16, 2012) 

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Reason for design modifications: The original protocols for both studies included maintenance 
lenalidomide for one year. With the recent papers in the NEJM on the benefit of maintenance 
therapy the US protocol will be revised to extend maintenance until progression. The accrual for 
the US will be expanded to include 660 patients to address the question of conventional dose 
followed by maintenance until PD versus high dose therapy arm followed by maintenance until 
PD. The accrual for the IFM protocol will be 700 patients to address the question of conventional 
dose followed by 1-year of maintenance vs. high dose therapy arm followed by 1-year of 
maintenance.
US Study Design Change:  With this amendment, the US study will be designed with 90% power 
to detect a 30% reduction in the PFS hazard from 0.0231/month on conventional dose arm (Arm 
A) with maintenance until PD to 0.0162/month on high dose therapy arm (Arm B) with 
maintenance until PD. (See justification for design change below for further details). A stratified 
two-sided log-rank test will be used with an overall type I error rate of 0.05.  This corresponds to a 
hazard ratio (hazard of conventional dose Arm A/hazard of high dose Arm B) of 1.43.  Full 
information under the alternative hypothesis is 329 failures. Assuming median PFS of 30 months 
on the RVD alone arm (Arm A) and the PFS time follow an exponential distribution, this 
difference corresponds to a 43% increase in median survival to 43 months for Arm B. A power of 
90% was used in this study to adjust for the potential for cross over from the conventional dose 
arm to the high dose therapy arm prior to progression. Based on simulations allowing for constant 
cross over as well as varying patterns of cross over the power is reduced approximately 7-10%  
with up to 15% cross over at 3 years.
It is anticipated that the US accrual will reach 100 randomized patients by 24 months. Based on 
the medians and the corresponding failures rates as well as the extended follow-up among the 
initial 100 patients, the required number of failures will be observed with an additional 560 
patients entered over 30 months with 18 months of follow-up for a total study time of 72 months 
(24 months accrual time for the initial 100 patients, 30 months accrual time for the additional 560 
patients and 18 months of follow-up). Specifically, with 560 patients entered over 30 months 
(monthly accrual rate of 18-19 patients/month) with 18 months of follow-up approximately 261 
events will be observed assuming an exponential distribution with the above specified medians 
and failure rates. Among the initial 100 patients, the minimum follow-up is extended from 36 
months to 48 months and therefore, based on the exponential distribution approximately 68 
failures are expected. Two interim analyses will occur at 33% and 69% information and the final 
analysis at full information. These results will be presented to the data- monitoring committee 
(DMC).  At each DMC meeting toxicity results will be presented and interim analyses if at 
designated information times. To preserve the overall type I error rate, critical values at the 
interim analysis will be determined using the Lan-DeMets error spending rate function 
corresponding to the O'Brien Fleming boundary. The study will also be monitored for early 
stopping in favor of the null hypothesis using Jennison-Turnbull repeated confidence interval 
(RCI) methodology. At each interim analysis, the one-sided 97.5% repeated confidence upper 
limit on the hazard ratio will be computed using the critical value from the error spending 
function.
Study monitoring for slow accrual: Based on concerns about US accrual, consideration will be 
given to closing the US study if the actual accrual rate is less than 80% of the targeted accrual 

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rate of 18-19/month by the fall 2013 DMC Meeting and the impact of the CTN, Alliance and 
other additional sites proves inadequate to meet the amended goals for enrollment.
Justification for the design change: Assuming the median PFS in the conventional dose arm 
(Arm A) remains at 30 months, the change in the reduction percentage in the failure rates/month 
from 23% to 30% is reasonable based on the recent literature which indicates that the median PFS 
from the time of transplant may range from 42-49 months with lenalidomide maintenance 
following autologous transplant. Based on a retrospective evaluation of data at the DFCI a 
median PFS of 45 months was observed from the time of RVD C1 D2 therapy (Luskin, et al, 
ASH 2011).  These estimates were also reported, albeit not directly and with various induction 
strategies, in two studies evaluating maintenance therapy: 1) IFM study NEJM, 2012 which 
reported median PFS 39 months from time of consolidation with DCEP and lenalidomide 
maintenance after various induction therapies (vincristine,dox,dex; VD, other) which is 
approximately 3 months from time of transplant and 10 months from time of diagnosis and 2) the 
CALGB NEJM 2012 which reported median PFS of 46 months from time of  lenalidomide 
maintenance therapy after various induction therapies ( bortezomib, lenalidomide, thalidomide, 
other) which is approximately 3 months from time of transplant. Note the CALGB study counts 
progression and death as an event in the primary endpoint. These numbers could be further 
increased by approximately 6 months to align with the time of randomization on this study (day 1 
of cycle 2 RVD) and would be approximately 47-55 months. However, both of these studies 
excluded patients with progressive disease prior to the time of maintenance/consolidation. These 
patients would be included in this study and therefore, it is anticipated that the median PFS from 
the time of day 1 of cycle 2 RVD would be lower. With these patients included, a median PFS on 
the high dose therapy arm (Arm B) of approximately 43 months is reasonable based on the 
current literature.
The current literature also indicates that the median PFS on the conventional dose arm (Arm A) 
proposed in the original design (30 months) is reasonable. In the US upfront study (Richardson 
et al, 2010, Blood) the median PFS censoring at transplant is approximately 32 months 
extrapolating from the 24 month estimates. The median PFS from the time of induction was 28 
vs. 35 months among the patients <65 years of age who received VAD+ thalidomide vs. 
PAD+bortezomib (Sonneveld, JCO, 2012). Similarly, the median PFS from the time of 
induction was 26 months vs. not reached (3-year estimates of 38 vs. 60%) among the patients 
<65 years of age who received MPR+/- lenalidomide maintenance vs. MEL200 +/- lenalidomide 
maintenance (Palumbo et al, EHA, 2012). However, this included patients who did not receive 
any maintenance therapy and therefore, the median PFS with maintenance can be anticipated to 
be higher than 26 months for MPR. The benefit of maintenance reported on this trial was a 
median PFS of 34 vs. 22 months from time of maintenance therapy for Mel200/MPR patients 
combined.
Impact of the US Study Design Change on the IFM Study : In the original design, the IFM and 
DFCI studies combined have 92% power to detect a 23% reduction in the PFS hazard from 
0.0231/month on conventional dose arm (Arm A) to 0.0177/month on high dose therapy arm (Arm 
B) using a stratified two-sided log-rank test with an overall type I error rate of 0.05.  Full 
information is 658 failures. Current accrual for the IFM protocol has been faster than expected with 
700 randomized patients anticipated to be entered within 24 months. To maintain at least 80% 
power, patients will continue to be followed until 72 months with a minimum follow-up of 48 

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months. This would result in 489 failures under the alternative (83% power).  Two interim analyses 
will occur at 33% and 69% information and the final analysis at full information. To preserve the 
overall type I error rate, critical values at the interim analysis will be determined using the Lan-
DeMets error spending rate function corresponding to the O'Brien Fleming boundary. The study 
will also be monitored for early stopping using Jennison-Turnbull repeated confidence interval 
(RCI) methodology. At each interim analysis, the one-sided 97.5% repeated confidence upper limit 
on the hazard ratio will be computed using the critical value from the error spending function.
Proposed analysis for both the IFM and US Studies: A descriptive analysis will be performed 
to attempt to address a question comparing PFS and OS for maintenance lenalidomide for 1 year 
(700 patients) vs. maintenance lenalidomide until PD (660 patients) overall and by conventional 
dose (350 vs. 330 patients) /high dose therapy arm (350 vs. 330 patients).
14.2.3 Design modification for US study change to increase sample size to 720 patients (12 
October 2016 date)
Reason for design modifications: In February 2016, McCarthy et al presented results  from a 
meta-analysis showing a 50% reduction in the hazards for continuous maintenance therapy (EHA 
February 2016) .  With a reduction in the failure rate, the time to the full information could be 
longer than expected. Therefore, to account for this potential reduction in the hazard rate in both 
arms (the hazard ratio remains at 1.43) and reduce the time to full information by 5 months, the 
sample size is increased to 720 randomized patients.  With 660 and 720 patients the total study 
time with the reduction in hazards is  113 and 118 months, respectively. To derive the number of 
months required to reach full information, the actual accrual patterns through August 2016 and 
projections for the remaining number of patients to reach full accrual are used in the calculations. 
Study Design:  This study is designed with 90% power to detect a 30% reduction in the PFS 
hazard of conventional dose arm (Arm A) with maintenance until PD to high dose therapy arm 
(Arm B) with maintenance until PD. A stratified two-sided log-rank test will be used with an 
overall type I error rate of 0.05.  This corresponds to a hazard ratio (hazard of conventional dose 
Arm A/hazard of high dose Arm B) of 1.43.  Full information under the alternative hypothesis is 
329 failures. A power of 90% was used in this study to adjust for the potential for cross over from 
the conventional dose arm to the high dose therapy arm prior to progression. Based on simulations 
allowing for constant cross over as well as varying patterns of cross over the power is reduced 
approximately 7-10%  with up to 15% cross over at 3 years.
The current accrual patterns are used to determine the time required to reach full information 
with 720 patients randomized.  Table 14.1 lists the actual accrual through August 2016 and the 
projected number of patients in the remaining months to reach 720 patients. Based on the failures 
rates  (λA =0.0231/2= 0.01155, λB =0.0162/2= 0.0081), exponential distribution, and the accrual 
pattern in Table 14.1, the required number of failures  (329) will be observed at 33 months after 
the end of accrual (80 months) for a total study time of 113 months. This is 5 months earlier in 
time than when full information would be observed with 660 patients. 
Two interim analyses will occur at 33% and 69% information and the final analysis at full 
information. These results will be presented to the data- monitoring committee (DMC).  At each 

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DMC meeting toxicity results will be presented and interim analyses if at designated information 
times. To preserve the overall type I error rate, critical values at the interim analysis will be 
determined using the Lan-DeMets error spending rate function corresponding to the O'Brien 
Fleming boundary. The study will also be monitored for early stopping in favor of the null 
hypothesis using Jennison-Turnbull repeated confidence interval (RCI) methodology. At each 
interim analysis, the one-sided 97.5% repeated confidence upper limit on the hazard ratio will be 
computed using the critical value from the error spending function.
Proposed analysis for both the IFM and US Studies: A descriptive analysis will be performed 
to attempt to address a question comparing PFS and OS for maintenance lenalidomide for 1 year 
(700 patients) vs. maintenance lenalidomide until PD (720 patients) overall and by conventional 
dose (350 vs. 360 patients) /high dose therapy arm (350 vs. 360 patients).
Table 14.1. Actual Accrual Per Month from October 2010 through August 2016. 
Numbers for September 2016 to the June 2017 are projected numbers. 
Month
Accrual
Month
Accrual
Month
Accrual
2010-10
1
2013-01
10
2015-04
9
2010-11
1
2013-02
13
2015-05
13
2010-12
3
2013-03
7
2015-06
15
2011-01
0
2013-04
11
2015-07
16
2011-02
3
2013-05
5
2015-08
14
2011-03
4
2013-06
4
2015-09
14
2011-04
1
2013-07
6
2015-10
15
2011-05
2
2013-08
11
2015-11
18
2011-06
2
2013-09
15
2015-12
10
2011-07
3
2013-10
10
2016-01
8
2011-08
7
2013-11
5
2016-02
16
2011-09
4
2013-12
11
2016-03
20
2011-10
6
2014-01
9
2016-04
10
2011-11
4
2014-02
14
2016-05
17
2011-12
2
2014-03
9
2016-06
11
2012-01
3
2014-04
7
2016-07
8
2012-02
6
2014-05
10
2016-08
7
2012-03
4
2014-06
13
2016-09*
10
2012-04
5
2014-07
18
2016-10*
10
2012-05
10
2014-08
14
2016-11*
10
2012-06
4
2014-09
11
2016-12*
10
2012-07
4
2014-10
11
2017-1*
10
2012-08
7
2014-11
14
2017-2*
10
2012-09
8
2014-12
16
2017-3*
10
2012-10
10
2015-01
13
2017-4*
10
2012-11
6
2015-02
13
2017-5*
8
2012-12
4
2015-03
17
*Projected accrual 

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14.3   Analysis of Secondary Endpoints
The secondary objectives of the study are to compare the following outcomes between the 
two arms: the response rates (CR, at least VGPR), time to progression, overall survival, 
toxicity, quality of life and pharmaco-economics. Prognostic groups defined by gene 
expression profiling will be defined in correlative studies. Duration of response is defined 
as the time from beginning of response to progression or death. Time to progression (TTP) 
is defined as the time of randomization until progression. Patients who have died without 
evidence of progression are censored in the TTP analysis and patients who are alive 
without progression are censored at the last disease assessment. Overall survival is defined 
as the time of randomization to death. Patients are censored at the time last known alive.
The proportion of patients with CR, proportion of patients with at least a CR/nCR and the 
proportion of patients with at least a VGPR will be compared rates between the two arms 
using Fisher’s exact test. For response there is at least 80% power to detect differences
of at least 11% in the 2 arms (Fisher’s exact test, two-sided significance level of 0.05).
The median duration of response will be compared using log-rank test.
14.4  Toxicity
The difference in the rate of all grade 3 or higher toxicities will be compared between the 
two groups using Fisher’s exact test. There is at least 80% power to detect differences in 
the 2 arms of at least 10% in more common toxicities (>20%) and differences of at least
5% for rare toxicities (<10%), assuming two-sided Fisher’s exact test, significance level 
of 0.05).
14.5    QOL Evaluations
The QOL will be measured using the The European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core (QLQ-30), the 
MY20 questionnaire, and Functional Assessment of Cancer Therapy/Gynecologic 
Oncology Group-Neurotoxicity (FACT-NTX) side-effects questionnaires. The 
questionnaires will be administered on 9 occasions: baseline (Cycle 1, Day 1), time 
of randomization (Cycle 2, Day 1) , prior to cyclophosphamide administration.RVD 
Cycle 5 Day 1, Cycle 8 Day 1(Arm A only), 20 days post PBSCT (Arm B only)_, 
Maintenance C6D1, End of treatment, and 2 years and 3 years from baseline.  
The QOL domains to be compared between Arm A and Arm B include health 
related quality of life, distress, psychological functioning, physical well-being and 
functional well-being. Differences which can be detected with 80% power between 
the two arms in the change of scores from time of randomization are computed 
using a two-sided t-test with a 0.05/8 significance level assuming 1) standard 
deviations of 4, 8 and 12, 2) correlations of 0.5 and 0.8 between measurements, 3) 
assuming that the number of patients with QOL assessments is 100, 200, 400, and 
700 with equal number of patients per arm. The effect sizes which can be detected 

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for 100, 200, 400, and 700 patients are 0.73,0.51,0.36 and 0.25, respectively. These 
effect sizes translate into the following differences in QOL outcomes using the 
standard deviation of the scores and the correlation of repeated measures. 
Assuming that between 100, 200, 400, and 700 participants complete the 
questionnaires and standard deviation of  4, the differences which can be detected 
with 80% power in the change of the score between the two arms is 3, 2, 1.4, 1.0 
and 0.9, respectively, assuming the correlation is 0.5 and is 1.1, 0.8, 0.6, and 0.4  
assuming the correlation is 0.8.  With a standard deviation of 8, the differences 
which can be detected with 80% power in the change of the score between the two 
arms of 5.8,3.1,2.9 and 2.0, respectively, assuming correlation is 0.5 and 
2.3,1.6,1.2,0.8 assuming the correlation is 0.8, respectively for 100, 200, 400, 700 
participants. With a standard deviation of 16, the differences which can be detected 
with 80% power in the change of the score between the two arms of 8.8, 6.1, 4.3, 
and 3.0, respectively, assuming correlation is 0.5 and 3.5, 2.5, 1.7, 1.2, assuming 
the correlation is 0.8, respectively for 100, 200, 400, 700 participants. Power 
estimates are based on the number of complete cases; and therefore, are 
conservative. In the analysis, multiple imputation methods will be used.
14.6
Pharmacoeconomics
The medical resource utilization will be evaluated in the two arms. Comparisons of 
continuous quantities will be done using the Wilcoxon-rank sum test. With an estimated
150 participants per arm, there is 80% power to detect an effect size of 0.39 using a two- 
sided test with a 0.05 significance level. With an estimated 350 participants per arm, there 
is 80% power to detect an effect size of 0.212 using a two-sided test with a 0.05 
significance level.
14.7  Additional Analysis Information
Statistical analyses for this trial will be performed using the software programs SAS, R, 
Stata9. Patient characteristics will be summarized using proportions for discrete data and 
median  for  continuous  variables  with  comparisons  between  arms  performed  using 
Fisher’s exact test for discrete data and Mann-Whitney rank sum for continuous data. 
Time to event outcomes will be estimated using Kaplan-Meier methods and compared 
between groups using stratified log rank tests. Logistic regression models and Cox 
proportional hazard regression models will be implemented to evaluate the impact of 
baseline information on response and time to event outcomes. Evaluation of factors 
associated with better outcome will include characteristics of the patient and of the 
myeloma, biological and genetic markers. It will be performed using the same statistical 
tests (log rank and Cox model).
14.8  Correlative Studies
Although we will collect samples for all participants, it is expected that adequate 
correlative samples will be available on 70% of the patients. As a result correlative power 

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calculations are based on 700 patients with 350 on each arm. These studies will look for 
early differences for correlative endpoints in terms of outcome (response) and later 
endpoints (PFS and OS).
14.9
Study Monitoring
The study will be monitored by an independent Data Monitoring Committee (DMC). 
The DMC will meet at least once a year and more often if needed (e.g., for safety
review). For each meeting, the study will be reviewed for safety and progress
toward completion. When appropriate, the DMC will also review interim analyses of 
the outcome data.  Copies of the toxicity reports prepared by the DMC meetings will 
be distributed to the Principal Investigator.  The Principal Investigator will then
distribute to sub-investigators.  Any DMC recommendations for changes to the
study will be distributed to the Principal Investigator and then circulated to sub- 
investigators by the Principal Investigator.  Further information is provided in
Section 12.2.
14.10  Reporting and Exclusions
Intent to treat analysis will be used. Therefore, all patients randomized will be 
included in the analysis of the primary endpoint and toxicity.
15.
PUBLICATION PLAN
Data from this trial will be reported once it is released from the DMC for publication. The 
final results of this study will be published in manuscript form in a major peer- reviewed 
journal. The PI will be responsible for submitting the final manuscript for publication.
The final manuscript will be reviewed by all parties involved. Approval will be obtained 
from the primary responsible party before any information can be used or passed on to a 
third party or submitted for publication.
Co-authorship of this manuscript will be determined according to the level of 
participation in the study as measured by accrual from each participating site, thereby 
including individuals who have been most involved in the design, conduct, and analysis 
of the study. Additional individuals may receive acknowledgement in the final 
manuscript for their support of the conduct of the study, as well as their review of the 
manuscript.

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The results will be made public after the DMC has released the data. Detailed 
information on when the interim and final analyses occur are provided in section 14.0.

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APPENDICES 
Appendix I:  Lenalidomide Information Sheet
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES
Please read this Lenalidomide Information Sheet before you start taking study drug and each time 
you get a new supply. This Lenalidomide Information Sheet does not take the place of an informed 
consent to participate in clinical research or talking to your study doctor or healthcare provider 
about your medical condition or your treatment.  
What is the most important information I should know about lenalidomide?
1.
Lenalidomide may cause birth defects (deformed babies) or death of an unborn 
baby. Lenalidomide is similar to the medicine thalidomide. It is known that thalidomide 
causes life-threatening birth defects. Lenalidomide has not been tested in pregnant women 
but may also cause birth defects.  Findings from a monkey study indicate that 
lenalidomide caused birth defects in the offspring of female monkeys who received the 
drug during pregnancy.  
If you are a female who is able to become pregnant:

Do not take study drug if you are pregnant or plan to become pregnant

You must practice complete abstinence or use two reliable, separate forms 
of effective birth control at the same time: 

for 28 days before starting study drug

while taking study drug 

during dose interruptions of study drug 

for 28 days after stopping study drug 

You must have pregnancy testing done at the following times:

within 10 to 14 days and again 24 hours prior to the first dose of 
study drug 

weekly for the first 28 days

every 28 days after the first month or every 14 days if you have 
irregular menstrual periods

if you miss your period or have unusual menstrual bleeding

28 days after the last dose of study drug (14 and 28 days after the 
last dose if menstrual periods are irregular)

Stop taking study drug if you become pregnant during treatment

If you suspect you are pregnant at any time during the study, you 
must stop study drug immediately and immediately inform your 
study doctor.  Your study doctor will report all cases of pregnancy 
to the study sponsor.

Do not breastfeed while taking lenalidomide

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
The study doctor will be able to advise you where to get additional advice on 
contraception. 
If you are a female not of childbearing potential:
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor 
will confirm that you are not able to become pregnant. 
If you are a male:
Lenalidomide is detected in trace quantities in human semen.  The risk to the fetus in 
females of child bearing potential whose male partner is receiving lenalidomide is 
unknown at this time. 

Male patients (including those who have had a vasectomy) must practice complete 
abstinence or must use a condom during sexual contact with a pregnant female or 
a female that can become pregnant:

While you are taking study drug

During dose interruptions of study drug  
   For 28 days after you stop taking study drug  

Male patients should not donate sperm or semen while taking study drug and 
for 28 days after stopping study drug. 

If you suspect that your partner is pregnant any time during the study, you 
must immediately inform your study doctor.  The study doctor will report all 
cases of pregnancy to the study sponsor.  Your partner should call their 
healthcare provider immediately if they get pregnant.
2.   Restrictions in sharing study drug and donating blood:

Do not share study drug with other people.  It must be kept out of the reach 
of children and should never be given to any other person.

Do not give blood while you take study drug and for 28 days after stopping study 
drug 

Do not break, chew, or open study drug capsules.

You will get no more than a 28-day supply of study drug at one time.

Return unused study drug capsules to your study doctor.
Additional information is provided in the informed consent form and you can ask your study doctor 
for more information.
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Appendix II:  Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods
Risks Associated with Pregnancy
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has the effect 
of the lenalidomide on human eggs and sperm.  Lenalidomide is structurally related to thalidomide.  
Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth 
defects.  An embryofetal development study in animals indicates that lenalidomide produced 
malformations in the offspring of female monkeys who received the drug during pregnancy.  The 
teratogenic effect of lenalidomide in humans cannot be ruled out.  Therefore, a risk minimization plan to 
prevent pregnancy must be observed.
All study participants must be registered into the mandatory Revlimid REMS® program, and be willing 
and able to comply with the requirements of Revlimid REMS®.
Criteria for females of childbearing potential (FCBP)
This protocol defines a female of childbearing potential as a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
The investigator must ensure that:

Females of childbearing potential comply with the conditions for pregnancy risk minimization, 
including confirmation that she has an adequate level of understanding

Females NOT of childbearing potential acknowledge that she understands the hazards and 
necessary precautions associated with the use of lenalidomide

Male patients taking lenalidomide acknowledge that he understands that traces of lenalidomide 
have been found in semen, that he understands the potential teratogenic risk if engaged in sexual 
activity with a female of childbearing potential or pregnant female, and that he understands the 
need for the use of a condom even if he has had a vasectomy, if engaged in sexual activity with a 
female of childbearing potential or pregnant female.  
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 intercourse during the 
following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) 
throughout the entire duration of lenalidomide treatment; 3) during dose interruptions; and 4) for at least 
28 days after lenalidomide discontinuation. 
The two methods of reliable contraception must include one highly effective method and one additional 
effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if 
needed. The following are examples of highly effective and additional effective methods of contraception:  
o
Highly effective methods:
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
Intrauterine device (IUD)

Hormonal (birth control pills, injections, implants)

Tubal ligation

Partner’s vasectomy
o
Additional effective methods:

Male condom

Diaphragm

Cervical Cap
Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking 
lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a patient is 
currently using combined oral contraception the patient should switch to one of the effective method listed 
above. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral 
contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with 
dexamethasone.
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection 
at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered 
particularly in patients with neutropenia. 
Pregnancy testing
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be performed for 
females of childbearing potential, including females of childbearing potential who commit to complete 
abstinence, as outlined below.
Before starting lenalidomide
Female Patients:
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to prescribing 
lenalidomide.  The first pregnancy test must be performed within 10-14 days prior to prescribing 
lenalidomide and the second pregnancy test must be performed within 24 hours prior to prescribing 
lenalidomide.  The patient may not receive lenalidomide until the Investigator has verified that the results 
of these pregnancy tests are negative.
Male Patients:
Must agree to practice complete abstinence or agree to use a condom during sexual contact with pregnant 
females or females of childbearing potential throughout the entire duration of lenalidomide treatment, 
during dose interruptions and for at least 28 days following lenalidomide discontinuation, even if he has 
undergone a successful vasectomy.  
During study participation and for 28 days following lenalidomide discontinuation 
Female Patients:

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
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 
28 days of lenalidomide treatment, including dose interruptions and then every 28 days throughout 
the remaining duration of lenalidomide treatment, including dose interruptions, at lenalidomide 
discontinuation, and at Day 28 following lenalidomide discontinuation.  If menstrual cycles are 
irregular, the pregnancy testing must occur weekly for the first 28 days of lenalidomide treatment, 
including dose interruptions, and then every 14 days throughout the remaining duration of 
lenalidomide treatment, including dose interruptions, at lenalidomide discontinuation, and at Day 
14 and Day 28 following lenalidomide discontinuation.  

At each visit, the Investigator must confirm with the FCBP that she is continuing to use two reliable 
methods of birth control at each visit during the time that birth control is required.  

If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide must be 
immediately discontinued.

Pregnancy testing and counseling must be performed if a patient misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment must be temporarily 
discontinued during this evaluation.

Females must agree to abstain from breastfeeding during study participation and for at least 28 days 
after lenalidomide discontinuation.
Male Patients:

Must practice complete abstinence or use a condom during sexual contact with pregnant females 
or females of childbearing potential throughout the entire duration of lenalidomide treatment, 
during dose interruptions and for at least 28 days following lenalidomide discontinuation, even if 
he has undergone a successful vasectomy.  

If pregnancy or a positive pregnancy test does occur in the partner of a male study patient during 
study participation, the investigator must be notified immediately.

Male patients should not donate semen or sperm during therapy or for at least 28 days following 
discontinuation of lenalidomide.
Additional precautions

Patients should be instructed never to give lenalidomide to another person.

Patients should not donate blood during therapy and for at least 28 days following discontinuation 
of lenalidomide.

Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle of therapy. 

Any unused lenalidomide must be returned as instructed through Revlimid REMS® program.

Appendix III:  Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Description
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; some 
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).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
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.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time. Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours.
30
Severely disabled, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
20
Very sick, hospitalization indicated. 
Death not imminent.

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confined to bed or chair.
10
Moribund, fatal processes 
progressing rapidly. 
5
Dead.
0
Dead.
Appendix IV:  DuBois Formula for Body Surface Area 
  The preferred method of calculating BSA is using the DuBois formula that yields the following 
result in meters squared (m2):1
BSA (m²) = Wt (kg)0.425 x Ht (cm)0.725 x 0.007184
1DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight 
be known. Arch Intern Medicine. 1916; 17:863-71.
Although the DuBois BSA formula is preferred, the Mosteller method is also acceptable.
Appendix V:  The New York Heart Association Classification of Cardiac Disease
The following table presents the NYHA classification of cardiac disease:
Class
Functional Capacity
Objective Assessment

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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.
Appendix VI: Declaration of Helsinki
Full detail of the World Medical Association Declaration of Helsinki can be accessed using the 
following link:http://ohsr.od.nih.gov/guidelines/helsinki.html

Appendix VII: Durie Salmon Stage and International Staging System (ISS) for Multiple Myeloma
Stage
Durie Salmon Stage
ISS Stage
I
All of the following:
Hemoglobin value >10 g/dL
Serum calcium value normal or ≤12 mg/dL
Bone x-ray, 0-1 lesion or solitary bone plasmacytoma only
Low M-component production rate — IgG value <5 g/dL; IgA 
value <3 g/Dl; urine light chain M-component on electrophoresis 
<4 g/24 h
Serum B2-microglobulin < 3.5 mg/L  
AND                               
Serum albumin > 3.5 g/dL
II
Neither stage I nor stage III
Serum B2-microglobulin <3.5 mg/L, but serum albumin <3.5 g/dL   
OR
Serum B2-microglobulin 3.5 to <5.5 mg/L, irrespective of serum 
albumin
III
One or more of the following:
Hemoglobin value <8.5 g/dL
Serum calcium value >12 mg/dL
Advanced lytic bone lesions ( > 3 lesions)
High M-component production rate — IgG value >7 g/dL; IgA 
value >5 g/dL — Bence Jones protein >12 g/24 h
Serum B2-microglobulin >5.5 mg/L      

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Adapted from Durie et al. and Greipp et al.

Appendix VIII: Quality of Life Assessment Tool

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Patient Signature: ___________________________________
Date: _____________

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Patient Signature: ___________________________________
Date: _____________

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Appendix IX:  FACT/GOG-Neurotoxicity Questionnaire, Version 4.0
By circling one (1) number per line, please indicate how true each statement has been for you during the 
past 7 days.
ADDITIONAL CONCERNS
Not
at all
A little
bit
Some-
what
Quite
a bit
Very
much
I have numbness or tingling in my hands………
0
1
2
3
4
I have numbness or tingling in my feet…………
0
1
2
3
4
I feel discomfort in my hands………………….
0
1
2
3
4
I feel discomfort in my feet……………………
0
1
2
3
4
I have joint pain or muscle cramps……………
0
1
2
3
4
I feel weak all over……………………………
0
1
2
3
4
I have trouble hearing…………………………
0
1
2
3
4
I get a ringing or buzzing in my ears…………
0
1
2
3
4
I have trouble buttoning buttons………………
0
1
2
3
4
I have trouble feeling the shape of small objects
when they are in my hand………………………
0
1
2
3
4
I have trouble walking…………………………
0
1
2
3
4
Patient Signature: ___________________________________
Date: _____________

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Appendix X:  EQ-5D Questionnaire

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Patient Signature: ___________________________________
Date: _____________

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Appendix XI: Adjusted Ideal Body Weight (AIBW) Calculation
AIBW = Ideal Body Weight + (0.25) x (Actual Body Weight – Ideal Body Weight)
* All weights should be calculated in kilograms
1 inch = 2.54 cm

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Appendix XII: Corticosteroids Equivalence Table
Corticosteroids type
(dose=1mg)
Dexamethasone 
Equivalence Dose (mg)
Hydrocortisone
0.04
Prednisone
0.15
Prednisolone
0.15
Methylprednisolone
0.19
Betamethasone
1.25

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APPENDIX XIII
DFCI Protocol # 10-106
Dana-Farber/Harvard Cancer Center
Multi-Center Data and Safety Monitoring Plan
Table of Contents
1.0
Introduction ……………………………………………………………….........177
1.1  Purpose
1.2  Multi-Center Data and Safety Monitoring Plan Components
2.0     General Roles and Responsibilities …………………………………………...178
 
2.1  Protocol Chair
2.2  Coordinating Center
2.3  Participating Institution
3.0     DF/HCC Quality Assurance Office for Clinical Trials ………………………180
3.1  Organizational Structure

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4.0
Protocol Development …………………………………………………………..180
  4.1   Activation of a Protocol
  4.2   Coordinating Center Support Function
5.0   Protocol Management ……………………………………………………………181
5.1 Protocol Distribution
5.2 Protocol Revisions and Closures
5.3 Informed Consent Requirements
5.4 IRB Documentation
5.5 IRB Re – Approvals
5.6 Participant Confidentiality and Authorization Statement
5.7 Participant Registration and Randomization
5.8 DF/HCC Multi-center Protocol Case Number
5.9 DF/HCC Multi-center Protocol Registration Policy
5.10 Schedule of Data Submission
5.11 Missing and Deficient Data
6.0 Requisitioning Investigational Drug ……………………………………………….190
    
 7.0   Safety Assessments and Toxicity Monitoring …………………………………….190
     
7.1 Serious Adverse Events
7.2 Guidelines for Reporting Serious Adverse Events
7.3 Guidelines for Processing IND Safety Reports
8.0 Protocol Violations and Deviations ………………………………………………… 191
         
8.1 Definitions  

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             8.2 Reporting Procedures
9.0 Quality Assurance …………………………………………………………………….192
        
9.1 Ongoing Monitoring of Protocol Compliance
            9.2 Evaluation of Participating Institution Performance
            9.3 On-Site Auditing
            9.4 Substandard Performance
1.0
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for a DF/HCC Multi-Center research protocol. 
1.1
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center (DF/HCC) 
Multi-center protocol will comply with Federal regulations (21 CFR Part 11); Good Clinical 
Practice (GCP) Guidelines; and  Health Insurance Portability and Accountability Act 
(HIPAA) requirements in accordance with the CTEP Multi-center Guidelines.       
1.2 Multi-Center Data and Safety Monitoring Plan Components
The Multi-Center Data and Safety Monitoring Plan includes the following components:
DF/HCC Multi-center Protocol:  One or more outside institutions collaborating with 

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Dana-Farber/Harvard Cancer Center on a research  protocol where DF/HCC is the Lead 
Institution. Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial 
Affiliates are not viewed as outside sites in this definition.
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center sites (DFCI, MGH, 
BIDMC, CH, BWH) will be the Lead Institution and will be responsible for the 
coordination, development, submission, and approval of a protocol as well as its 
subsequent amendments per the DFCI IRB and applicable regulatory guidelines (CTEP, 
FDA, OBA etc.). 
DF/HCC Contract Principal Investigator:  Investigator located at the Lead Institution 
who will be charged with the responsibility of the administration of the DF/HCC Project. 
This most often will be the Protocol Chair, but occasionally this may be the overall grant 
or contract holder, as applicable.
Protocol Chair:  The Protocol Chair is the Principal Investigator for the DF/HCC 
protocol submitted as the Lead Institution.  For applicable protocols, the Protocol Chair 
will be the single liaison with any regulatory agencies (i.e. CTEP Protocol and 
Information Office (PIO), FDA, OBA etc.). 
Participating Institution:  A participating institution is an institution that desires to 
collaborate with DF/HCC and commits to accruing participants to a DF/HCC protocol.  
The participating institution acknowledges the Protocol Chair as having the ultimate 
authority and responsibility for the overall conduct of the study.   
Coordinating Center: The Lead Institution is the Coordinating Center for the DF/HCC 
Multi-center Protocol. The Coordinating Center will provide the administrative support to 
the Protocol Chair in order that he/she may fulfill the responsibilities outlined in the 
DSMP and as specified in applicable regulatory guidelines (i.e. CTEP Multi-Center 
Guidelines).  In addition to the Lead Institution, the Quality Assurance Office for Clinical 
Trials (QACT) provides support services to assist the Protocol Chair. 
2.0
GENERAL ROLES AND RESPONSIBILITIES
In accordance with the CTEP Multi-center Guidelines, the Protocol Chair (DF/HCC Principal 
Investigator), Coordinating Center (Lead Institution or designee), and the Participating 
Institutions will all agree to the general responsibilities as follows (specific procedures for 
these general responsibilities are detailed in the DSMP):
2.1
Protocol Chair (DF/HCC Principal Investigator)
The Protocol Chair, Paul Richardson, MD will accept responsibility for all aspects of the 
Multi-Center Data and Safety Monitoring Plan to:

Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments.   

Submit the Multi-Center Data and Safety Monitoring Plan as an inclusion to the 

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protocol.

Assure all participating institutions are using the correct version of the protocol.

Monitor progress and overall conduct of the study at all participating institutions. 

Ensure all DFCI IRB, DF/HCC and other applicable (i.e. CTEP, FDA, OBA) 
reporting requirements are met. 

Review data and maintain timely submission of data for study analysis. 

Act as the single liaison with CTEP/PIO Office (CTEP trials) or FDA (sponsor-
investigator IND trials) or OBA (gene therapy trials), as applicable.

Identify participating institutions and obtain accrual commitments.  The title page must 
include the names and contact information for all participating institutions that perform 
the function of recruiting, enrolling, and treating participants for the protocol. The 
Coordinating Center (Lead Institution or designee) must be designated on the title page. 
    2.2   Coordinating Center (Lead Institution)
The Coordinating Center is the DF/HCC Lead Institution’s study team or designee (i.e 
Medical Monitor, Clinical Research Organization). The DF/HCC Lead Institution (Dana-
Farber Cancer Institute) will ensure that all participating sites within the Multi-Center 
Protocol demonstrate their intent and capability of complying with Federal Regulations, 
GCPs and Health Insurance Portability and Accountability Act (HIPAA) requirements.  
To assist the Protocol Chair in meeting his/her responsibilities as required by the DSMP, 
the DF/HCC Lead Institution’s study team or designee will assume the following general 
responsibilities:

Assist in protocol review.

Maintain copies of Institutional Review Board (IRB) approvals from all 
participating institutions.

Maintain CTEP, FDA or OBA correspondence, as applicable.

Maintain updated roster of participants. 

Verify eligibility.

Verify response.

Collect data on protocol specific CRFs.

Prepare all submitted data for review by the Protocol Chair.

Maintain documentation of Serious Adverse Event (SAE) reports submitted 
by Participating Institutions and submit to Protocol Chair for timely review.  

Distribute external Serious Adverse Event safety reports. 

Monitor and audit Participating Institutions either by on-site inspection of 
selected participant records and/or with source documents and research 
records submitted to the Lead Institution. 
   
In addition to the Lead Institution, the DF/HCC Quality Assurance Office for Clinical 
Trials provides the following support services to assist the Protocol Chair:

Provide Central Participant Registration for DF/HCC participants.

Confirm eligibility and consent of DF/HCC participants. 
    2.3   Participating Institution

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The Participating Institution(s) will be identified on the title page for each protocol.   In 
addition, each participating institution will provide to the Lead Institution or designee a 
list of the key personnel assigned to the role for oversight of data management at their site. 
All sites must have office space, office equipment, and internet access that meet HIPAA 
standards.
The general responsibilities for each participating institution are as follows:

Commit to accrual to the Lead Institution’s (DF/HCC) protocol.

Submit protocol and/or amendments to their local IRB.

Update Coordinating Center (Lead Institution or designee) with research staff 
changes on a timely basis.

Submit source documents, research records, and CRFs per protocol specific                              
submission guidelines to the Coordinating Center (Lead Institution or designee). 

Submit Serious Adverse Event reports and pregnancy reports to local IRB and 
directly to the Coordinating Center (Lead Institution or designee).

Submit deviations and violations to local IRB and the Coordinating Center (Lead 
Institution or designee).

For protocols using investigational agents, the participating institution will               
            order their own investigational agents regardless of the supplier (i.e. NCI, 
            pharmaceutical company). 
3.0
DF/HCC QUALITY ASSURANCE OFFICE FOR CLINICAL TRIALS
The DF/HCC QACT is a unit that has been developed to computerize, manage, and monitor 
data for DF/HCC trials.  The DF/HCC QACT is located administratively in the office of the 
Senior Vice President for Clinical Research, at Dana-Farber Cancer Institute.  The QACT 
uses DF/HCC computerized institutional databases for participant registrations and for the 
management of trial data as well as a set of quality assurance programs designed to monitor 
DF/HCC trials.  
3.1
Organizational Structure
The DF/HCC Quality Assurance Office for Clinical Trials administrative structure 
consists of:
DF/HCC Quality Assurance Officer for Clinical Trials: Oversees the functions of the 
DF/HCC QACT.
QACT Assistant Director for Monitoring: Provides direct oversight to the QACT 
Protocol Registrars and Clinical Research Auditors.

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The DF/HCC Protocol Registrars are responsible for the confirmation of each 
participant’s eligibility and consent prior to protocol registration. 
If funded and QACT approved, the DF/HCC Clinical Research Auditors may assist the 
Lead Institution in their auditing responsibilities for multi-center trials. The QACT auditor 
is responsible for systematically evaluating participant safety, protocol compliance, 
institutional SOPs, ICH GCP and Federal regulation compliance, data accuracy and 
investigational drug handling to assure a high standard of quality for DF/HCC trials.
4.0 PROTOCOL DEVELOPMENT  
4.1 Activation of a Protocol
The Protocol Chair is responsible for the coordination, development, and approval of the 
protocol as well as its subsequent amendments, and reporting SAEs, violations and deviations per 
DFCI IRB guidelines and if applicable CTEP Multi-center, FDA or OBA Guidelines.  Further, the 
Protocol Chair will be the single liaison with the CTEP/PIO, the FDA or OBA, as applicable.
To meet these requirements, the Protocol Chair will be responsible for the following minimum 
standards:

Inclusion of the DF/HCC Multi-Center Data and Safety Monitoring Plan in the 
protocol as an appendix.

Identify participating institutions and obtain accrual commitments. The title page 
must include the names and contact information for all participating institutions that 
perform the function of recruiting, enrolling, and treating participants for the 
protocol. The Coordinating Center (Lead Institution or designee) must be designated 
on the title page. 

Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the Protocol Chair.

Ensure that there is only one version of the Protocol and that all Participating 
Institutions use the correct version. 

Oversee the development of data collection forms (case report forms) that are of 
common format for use at all the Participating Institutions. 
4.2 Coordinating Center Support Function

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The DF/HCC Lead Institution’s study staff or designee will provide administrative and clerical 
support to the Protocol Chair for the development and distribution of the protocol. 
The tasks to be performed by the DF/HCC Lead Institution’s study staff or designee include:

Review of the protocol and consent to check for logistics, spelling, and consistency.  
Provide the Protocol Chair a list of queries related to any inconsistencies.

Provide necessary administrative sections, including paragraphs related to 
registration logistics, data management schedules, and multi-center guidelines. 

Maintenance of contact list of all participating institutions in the DF/HCC Multi-
center Protocol and the distribution of updates to the sites as needed. 

Derivation of the study calendar, if applicable.

Assistance in preparation and maintenance of case report forms.

Conduct regular communications with all participating sites (conference call, 
emails, etc).  Conference calls with sites will occur at least monthly and more often 
if needed. 

Maintain documentation of all communications. 
5.0 PROTOCOL MANAGEMENT
The Coordinating Center (Lead Institution of designee) is responsible for assuring that each Participating 
Institution in the DF/HCC Multi-center Protocol has the appropriate assurance on file with the Office of 
Human Research Protection (OHRP).   Additionally, the Lead Institution or designee must maintain copies 
of all IRB approvals, for each participating institution. 
5.1 Protocol Distribution
The final approved protocol and any subsequent amended protocols will be distributed to 
participating centers by the Coordinating Center.   
5.2
Protocol Revisions and Closures
The participating institutions will receive e-mail notification of protocol revisions from the Lead 
Institution or designee.  It is the individual participating institution’s responsibility to notify its IRB 
of these revisions.

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Non life-threatening revisions: Participating institutions will receive email notification of 
protocol revisions regarding non life-threatening events from the Lead Institution or designee. 
Non-life-threatening protocol revisions should be IRB approved and implemented within 90 days 
from receipt of the notification.
Revisions for life-threatening Causes: Participating institutions will receive email notification 
from the Lead Institution or designee concerning protocol revisions required to protect lives with 
follow-up by e-mail.  Life-threatening protocol revisions will be implemented immediately 
followed by IRB request for approval.
Protocol Closures and Temporary Holds: Participating institutions will receive e-mail notification 
of protocol closures and temporary holds, with follow-up by mail from the Lead Institution or 
designee. Closures and holds will be effective immediately.  In addition, the Lead Institution or 
designee will update the Participating institutions on an ongoing basis about protocol accrual 
data so that they will be aware of imminent protocol closures.
5.3 Informed Consent Requirements
The Principal Investigator (PI) at each participating site will identify the physician members of the 
study team who will be obtaining consent and signing the consent form for therapeutic 
protocols. It is DF/HCC policy that Nurses and Fellows cannot obtain consent to greater than 
minimal risk trials. 
5.4 IRB/IEC Documentation
The following must be on file with the DF/HCC Lead Institution or designee prior to participant 
registration:

Approval Letter of the institution's IRB (An Expedited IRB first approval is NOT 
acceptable)

IRB approval for all amendments

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It is the individual in stitution's responsibility to notify its IRB of protocol revisions.  Participating 
institutions will have 90 days from receipt to provide the DF/HCC Lead Institution or designee 
their IRB approval for Major Amendments to a protocol.   
DF/HCC defines a Major Amendment as: A substantive change in the study which may increase 
or decrease the risk to study participants.  Major revisions require full IRB approval.  The 
following criteria are examples of revisions to a protocol that are considered to be major 
amendments:

Change of eligibility (inclusion/exclusion) criteria

Change in design of protocol

Change in statistical section

Change in sample size/accrual (e.g., doubling the sample size)

Change in informed consent

Change of estimated dropout rate

Change of treatment or intervention

Change of device

Change in primary objective evaluation process
5.5 IRB Re-Approval
         
Annual IRB re-approval from the Participating institution is required in order to register 
participants onto a protocol.  There is no grace period for annual re-approvals.
Protocol registrations will not be completed if a re-approval letter is not received by the DF/HCC 
Lead Institution or designee from the Participating Institutions on or before the anniversary of 
the previous approval date.  
5.6 Participant Confidentiality and Authorization Statement
The Health Insurance Portability and Accountability Act of 1996 contains,  as one of its six major 
components, the requirement to create privacy standards for health care information that is 
used or disclosed in the course of treatment, payment or health care operations.  The original 
Privacy Rule, as it has come to be known, was published in December 2000.  The Final Rule was 
published on August 14, 2002, which has modified the privacy rule in significant ways vis-à-vis 
research.

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In order for covered entities to use or disclose protected health information during the course of 
a DF/HCC Multi-Center Protocol the study participant must sign an Authorization.  This 
Authorization may or may not be separate from the Informed Consent.  The DF/HCC Multi-Center 
Protocol, with the approval from the DFCI IRB and if applicable NCI/CTEP, will provide an 
Informed Consent template, which covered entities (DF/HCC Multi-Center Protocol participating 
institutions) must use. 
The DF/HCC Multi-Center Protocol will use all efforts to limit its use of protected health 
information in its trials.  However, because of the nature of these trials, certain protected health 
information must be collected per National Cancer Institute requirements. These are the primary 
reasons why DF/HCC has chosen to use Authorizations, signed by the participant in the trial, 
rather than limited data sets with data use agreements.  
5.7 Participant Registration and Randomization 
5.7.1 Registration Process for DF/HCC Institutions
Registration must occur prior to the initiation of therapy. Any participant not registered to 
the protocol before treatment begins will be considered ineligible and registration will be 
denied. 
A member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist.
 
Following registration, participants may begin protocol treatment. If a participant does not 
receive protocol therapy following registration, the participant’s protocol status must be 
changed. Notify the QACT Registrar of participant status changes as soon as possible.The QACT 
registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM Eastern 
Standard Time. In emergency situations when a participant must begin treatment during off-hours 
or holidays, call the QACT registration line at 617-632-3761 and follow the instructions for 
registering participants after hours.
The registration procedures are as follows:

Obtain written informed consent from the participant prior to the performance of any 
study related procedures or assessments.  Once eligibility criteria are confirmed 
following procedures described in Section 3, the patient must first be registered in the 
eCRF.

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
Eligible participants will be registered in the eCRF by the participating site.  
Registration must occur prior to the initiation of therapy (RVD Cycle 1, Day 1).  

The participating institutions will register eligible participants to this study 24 hours a 
day, 7 days a week, using web-based registration: https:\www.ifm-online.fr/csonline.  
For assistance or questions, the technical support team can be contacted using the link 
“Contact Technical Support”.  A user-specific login and password are required to access 
the website.  

Participant study number will be automatically allocated by the online registration 
system based on the following format : 
I__I__I__I  –  I__I__I__I
(3digits for the site number)   –   (3digits for the patient number)
Note: Participant study number will be sequentially allocated for each site. 

To be eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist.  

Information required for participant registration includes patient information (initials, 
date of birth, sex…), informed consent information, inclusion and exclusion criteria. 
Some biological parameters are also required in order to complete registration.  

Once all registration information is entered and the web-based system verifies that 
inclusion and exclusion criteria are met, patient registration is confirmed. The site will 
receive an email confirmation with participant study number once the registration 
process is complete. Patients must not begin study treatment prior to receiving 
email confirmation.

To register the participant with the DF/HCC Quality Assurance Office for Clinical 
Trials (QACT) central registration system, complete the protocol-specific eligibility 
checklist using the eligibility assessment documented in the participant’s 
medical/research record. To be eligible for registration to the study, the participant 
must meet each inclusion and exclusion criteria listed on the eligibility checklist.

Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 617-
632-2295.

The QACT Registrar will (a) validate eligibility, and (b) register the participant on the 
study.

The QACT Registrar will send an email confirmation of the registration to the person 
initiating the registration immediately following the registration.
If a participant does not receive protocol therapy following registration, the participant’s protocol 
status must be changed. Notify the QACT Registrar of participant status changes as soon as possible.

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5.7.2
Registration Process for Other Participating Institutions
Eligible participants will be registered with a central registration system by the site.  Registration must 
occur prior to the initiation of therapy.  Following registration, participants should begin protocol 
treatment within 72 hours or as soon as possible. 
The registration procedures are as follows:

Obtain written informed consent from the participant prior to the performance of any 
study related procedures or assessments.  Once eligibility criteria are confirmed 
following procedures described in Section 3, the patient must be registered in the eCRF.

Eligible participants will be registered in the eCRF by the participating site.  
Registration must occur prior to the initiation of therapy (RVD Cycle 1, Day 1).  

The participating institutions will register eligible participants to this study 24 hours a 
day, 7 days a week, using web-based registration: https:\www.ifm-online.fr/csonline.  
For assistance or questions, the technical support team can be contacted using the link 
“Contact Technical Support”.  A user-specific login and password are required to access 
the website.  

Participant study number will be automatically allocated by the online registration 
system based on the following format : 
I__I__I__I  –  I__I__I__I
(3digits for the site number)   –   (3digits for the patient number)
Note: Participant study number will be sequentially allocated for each site. 

To be eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist.  

Information required for participant registration includes patient information (initials, 
date of birth, sex…), informed consent information, inclusion and exclusion criteria. 
Some biological parameters are also required in order to complete registration.  

Once all registration information is entered and the web-based system verifies that 
inclusion and exclusion criteria are met, patient registration is confirmed. The site will 
receive an email confirmation with participant study number once the registration 
process is complete.

In addition, the participant must be registered with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. The following 

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-  Standard vs. high risk vs. FISH failures. High-risk is defined as the presence of 
del(17p),  or t(4:14), or t(14;16) using FISH.
-   Country (US) 

Once participant randomization data is entered in the eCRF, the randomization system will 
allocate the treatment arm (A or B).  The site will receive an email confirmation of treatment 
arm once the randomization process is complete. 

Randomization assignment for must also be entered into the DF/HCC QACT central registration 
system.  The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 
5:00 PM Eastern Standard Time. 

Enter the randomization assignment on the protocol-specific eligibility checklist.

Fax the eligibility checklist to the QACT at 617-632-2295.

The QACT Registrar will enter the randomization assignment into the QACT system.
o
The QACT Registrar will send an email confirmation that the randomization 
assignment has been entered to the person initiating the randomization 
immediately following the randomization.
5.7.4
Randomization Process for Other Participating Institutions
Randomization must occur 2-3 weeks after the initiation of cycle 1 of RVD and prior to cycle 2 of 
RVD.
The randomization procedures are as follows:

The participating institution will randomize participants 24 hours a day, 7 days a week, 
using web-based randomization: https:\www.ifm-online.fr/csonline.  For assistance or 
questions, the technical support team can be contacted using the link “Contact Technical 
Support”.  A user-specific login and password are required to access the website.

Randomization information is entered on the web-based randomization system by the 
participating institution. Stratified permuted blocks will be used in the randomization using 
the following stratification factors.  Stratification factor information will be requested at the 
time of  randomization, and randomization will be blocked if the following data are not 
entered:
- ISS Stage I vs. II vs. III. Institutions will provide Beta2- microglobulin level (mg/L) and 
serum albumin level (g/dL) entered from screening visit, and the randomization system 
will compute the ISS stage. 
- Standard vs. high risk vs. FISH failures. High-risk is defined as the presence of del(17p),  
or t(4:14), or t(14;16) using FISH.
- Country (US) 

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
Once participant randomization data is entered in the eCRF, the randomization system will 
allocate the treatment arm (A or B).  The site will receive an email confirmation of treatment 
arm once the randomization process is complete. 

In addition, the participant must be registered with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. The randomization assignment should be 
entered on the protocol-specific eligibility checklist by the research nurse or data manager at the 
participating site, and faxed (617-632-4301) or emailed (ajantha_nithi@dfci.harvard.edu) to the 
DFCI Study Coordinator.      

The DFCI Study Coordinator will randomize the participant on the study with QACT and 
email the research nurse or data manager at the participating site to confirm 
randomization with QACT.
Note: Randomization with the QACT can only be conducted during the business hours of 8am 
– 5pm EST Monday through Friday.
5.8 DF/HCC Multi-center Protocol Case Number
Once eligibility has been established and the participant successfully registered, the participant is 
assigned a protocol case number.  This number is unique to the participant on this trial and must 
be used for eCRF completion and written on all data and QACT correspondence for the 
participant.

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5.9
DF/HCC Multi-center Protocol Registration Policy
    5.9.1  Initiation of Therapy: Participants must be registered with the web-based registration 
system before receiving treatment.  Treatment may not be initiated until the site 
receives an e-mailed copy of the participant’s Registration Confirmation memo from 
the web-based registration system. Therapy must be initiated per protocol 
guidelines.  The Protocol Chair and DFCI IRB must be notified of any exceptions to 
this policy. 
5.9.2 Eligibility Exceptions: The web-based registration system will make no exceptions to 
the eligibility requirements for a protocol.  In addition, the Cancer Therapy 
Evaluation Program (CTEP) specifically prohibits registration of a participant on any 
NCI Sponsored protocol that does not fully and completely meet all eligibility 
requirements.
5.9.3 Verification of Registration, Dose Levels, and Arm Designation: A registration 
confirmation memo for participants registered to this protocol will be emailed to the 
registering institution upon completion of the registration. Treatment may not be 
initiated until the site receives thee-mailed copy of the registration confirmation 
memo. 
5.9.4 Confidentiality: All documents, investigative reports, or information relating to the 
participant are strictly confidential. Any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Lead Institution or 
designee must have the participant’s full name & social security number “blacked 
out” and the assigned protocol case number and protocol number written in (with 
the exception of the signed informed consent document). Participant initials may 
only be included or retained for cross verification of identification.
5.10  Schedule of Data Submission
Electronic case report forms will be used for data collection in this study, and can be accessed 
using the following website: https:\www.ifm-online.fr/csonline.  Completion and submission 
guidelines for these eCRFs can be located in the Study Manual.

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5.11 Missing and Deficient Data
Data submissions are monitored for timeliness and completeness of submission. Participating 
institutions are notified of their data submission delinquencies in accordance with the 
following policies and procedures:
Incomplete or Questionable Data: If study forms are received with missing or questionable 
data, the submitting institution will receive a query from the database.  
6.0 REQUISITIONING INVESTIGATIONAL DRUG
The ordering of investigational agent is generally specified in the protocol. 
Participating sites should order their own agent directly from the supplier regardless of the 
supplier (i.e., NCI or a pharmaceutical company).  
If the agent is commercially available, check with the local Director of Pharmacy and/or 
the Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, 
ensure that the agent can be ordered once the protocol is approved by the local IRB/IEC. 
If the agent is investigational, ensure that the pharmacy will be able to receive and store 
the agent. The local IRB should be kept informed of who will supply the agent (i.e., NCI 
or a pharmaceutical company) so that any regulatory responsibilities can be met in a 
timely fashion. 
7.0 SAFETY ASSESSMENTS AND TOXICITY MONITORING
       
All participants receiving investigational agents will be evaluated for safety.   The safety 
parameters include all laboratory tests and hematological abnormalities, physical examination 
findings, and spontaneous reports of adverse events reported to the investigator by 
participants.  All toxicities encountered during the study will be evaluated according to the NCI 
criteria assigned to the protocol (CTEP Version 4.0) and recorded prior to each course of 
therapy.  Life-threatening toxicities should be reported immediately to the Protocol Chair and 
IRB. 

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Additional safety assessments and toxicity monitoring will be outlined in the protocol.
7.1 Serious Adverse Events
A serious adverse event (SAE) is any adverse drug experience at any dose that results  in any of 
the following outcomes: death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect.  Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions in a participant who has 
never had seizure activity in the past that do not result in inpatient hospitalization, the 
development of drug dependency or abuse; or suspected transmission of an infectious agent by 
a medicinal product.
The CTEP Version 4.0 of the NCI Common Terminology Criteria for Adverse Events (CTCAE) will 
be utilized for AE reporting. The CTEP Version 4.0 of the CTCAE is identified and located on the 
CTEP website at http://ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm .  
7.2 Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Serious Adverse Events (SAEs) will be followed as is 
delineated in the protocol, Section 11.0.
In addition, the Participating Institutions must report the serious adverse events to the Protocol 
Chair and the Coordinating Center (Lead Institution) following the DFCI IRB SAE Reporting 
Requirements. 

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The Lead Institution will maintain documentation of all Adverse Event Reporting and be 
responsible for communicating all SAEs to all Participating sites.
7.3 Guidelines for Processing IND Safety Reports 
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies to 
notify the FDA and all participating investigators of any serious and unexpected adverse 
experiences that are possibly related to the investigational agent. In compliance with these FDA 
regulations, the Protocol Chair is responsible for reviewing all IND Safety Reports and forwarding 
the IND Safety Reports to the Participating Institutions.  The investigators are to file a copy with 
their protocol file and send a copy to their IRB according to their local IRB’s policies and 
procedures.
8.0 PROTOCOL VIOLATIONS AND DEVIATIONS
Neither the FDA nor the ICH GCP guidelines define the terms “protocol violation” or “protocol 
deviation.”  All DF/HCC Protocol Chairs must adhere to those policies set by the DFCI IRB, the 
definitions for protocol violation and deviation as described by the DFCI IRB will be applied for 
reporting purposes for all institutions participating in the DF/HCC Multi-center Protocol. 
8.1 Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol.
Protocol Exception: Any protocol deviation that relates to the eligibility criteria, e.g.,
enrollment of a subject who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol deviation that was not prospectively approved by the 
IRB prior to its initiation or implementation. 
8.2 Reporting Procedures

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The Protocol Chair: is responsible for ensuring that clear documentation is available in the 
medical record to describe all protocol exceptions, deviations and violations. 
The Protocol Chair will also be responsible for ensuring that all protocol violations/deviations 
are promptly reported per DFCI IRB guidelines. 
Participating Institutions: Protocol deviations require prospective approval from DFCI IRB. The 
Participating institution must submit the deviation request to the Protocol Chair or designee, 
who will submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation 
should be submitted to the participating site’s own IRB, per its institutional policy.
A copy of the participating institution’s IRB report and determination will be forwarded to the 
DF/HCC Lead Institution or designee by mail, facsimile, or via e-mail within 10 business days 
after the original submission. 
All protocol violations must be sent to the DF/HCC Lead Institution Protocol Chair or designee 
in a timely manner. 
Coordinating Center:  Upon receipt of the violation/deviation report from the participating 
institution, the DF/HCC Lead Institution or designee will submit the report to the Protocol Chair 
for review. Subsequently, the participating institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will forward all 
violation reports to CTEP via an internal DF/HCC process, as applicable.
9.0 QUALITY ASSURANCE
The quality assurance process for a clinical trial research study requires verification of protocol 
compliance and data accuracy. As the Coordinating Center, the DF/HCC Lead Institution or designee 
with the aid of the QACT provides quality assurance oversight for the DF/HCC Multi-center 
Protocol.

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9.1 Ongoing Monitoring of Protocol Compliance
Monitoring will begin at the time of participant registration and will continue during protocol 
performance and completion.  For this trial, a commercial contract research organization 
(CRO) will perform the ongoing protocol compliance monitoring with the support of the 
Lead Institution or designee, participating institution’s Coordinators, the Principal 
Investigators, and the Protocol Chair.  A Clinical Research Associate (CRA) from the 
commercial CRO will perform on-site monitoring visits to participating sites throughout the 
course of the trial and at study close-out.
9.2 Evaluation of Participating Institution Performance
9.2.1
 ELIGIBILITY CHECKLIST: An eligibility checklist for each participant is completed 
within the web-based registration system prior to registration on protocol.  Eligibility criteria 
and informed consent documentation are verified by the CRA during on-site monitoring.
9.2.5  ACCRUAL OF ELIGIBLE PARTICIPANTS: ANNUAL ACCRUAL RATES FOR ELIGIBLE 
PARTICIPANTS ENROLLED ONTO THERAPEUTIC CLINICAL TRIALS IS CALCULATED FOR 
EACH INSTITUTION. INSTITUTIONS ARE EXPECTED TO MAINTAIN THE MINIMUM ANNUAL 
AVERAGE ACCRUAL AS DEFINED BY THE PROTOCOL GRANT OR CONTRACT. 
9.3 On-Site Auditing
9.3.1 DF/HCC Sponsored Trials

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The participating institutions will be subject to on-site monitoring conducted by a 
commercial contract research organization (CRO).
The Lead Institution or designee will be responsible for site initiation visits.  These visits 
will be conducted as either an on-site visit or via webconference.  If investigator meetings 
are planned, they may be considered as initiation visits if agreed by the sponsor.  
Following site initiation, a commercial CRO will be responsible for on-site monitoring and 
close-out visits at participating sites.  A CRA, delegated by the sponsor, will visit each 
study center one or more times during the trial according to the pace of enrollment, and 
at the end of the trial.  The frequency of site monitoring will be dependent on site 
enrollment, with the first visit occurring within two months of first participant 
enrollment.  After the first monitoring visit, on-site monitoring will occur approximately 
once every three months or as accrual dictates.
  
The purpose of these visits is to monitor compliance with the protocol, verify informed 
consent forms, verify compliance with SAE reporting procedures, monitor the tracking of 
study drug (pharmacy visit, storage and accounting of study drug), retrieve regulatory 
documentation, and perform quality control by comparing data from the CRF to the 
source documents of the center. Source document verification will be performed on 30% 
of the data and will include review of inclusion and exclusion criteria, safety data, and 
data related to study endpoints and disease response. 
During the course of the study, communication with participating sites will occur at least 
monthly via teleconference and more often if needed.  
       9.3.2 Participating Institution
It is the participating institution’s responsibility to notify the DF/HCC Lead 
Institution or designee of all scheduled audit dates (internal or NCI) and re-audit 
dates (if applicable), which involve the DF/HCC Multi-Center Protocol. All 
institutions will forward a copy of final audit and/or re-audit reports and corrective 
action plans (if applicable) to the DF/HCC Lead Institution or designee within 12 
weeks after the audit date. 
The DF/HCC Lead Institution or designee will notify Celgene and Millennium of 
audit requests.

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9.3.3 Coordinating Center (Lead Institution or designee) 
The Protocol Chair will review all DF/HCC Multi-Center Protocol Final Audit 
reports and corrective action plans if applicable. The Lead Institution or designee 
must forward these reports to the DF/HCC QACT per DF/HCC policy for review by 
the DF/HCC Audit Committee. Based upon the audit assessments the DF/HCC 
Audit Committee could accept or conditionally accept the audit rating and final 
report. Conditional approval could require the Protocol Chair to implement 
recommendations or require further follow-up.  For unacceptable audits, the Audit 
Committee would forward the final audit report and corrective action plan to the 
DFCI IRB as applicable.
9.4 Sub-Standard Performance
The Protocol Chair, DFCI IRB and the NCI for CTEP trials, is charged with 
considering the totality of an institution’s performance in considering institutional 
participation in the DF/HCC Multi-Center Protocol.
9.4.1 Corrective Actions: Institutions that fail to meet the performance goals of accrual, 
submission of timely accurate data, and adherence to protocol requirements will be 
recommended for a six- month probation period. Such institutions must respond with 
a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance 
measures. Institutions that fail to demonstrate significant improvement will be 
considered by the Protocol Chair for revocation of participation.