Clinical trial NCT00807599
Conditions: Multiple Myeloma
Keywords: CYCLOPHOSPHAMIDE (CYTOXAN) DEXAMETHASONE G-CSF Lenalidomide MELPHALAN PEG-FILGRASTIM (NEULASTA) 08-121
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2008-12-10; Completion date: 2018-07-01
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the effects, good and bad, of two ways to treat patients with standard-risk symptomatic multiple myeloma. Patients with standard-risk myeloma have myeloma with specific features: levels of 2 blood tests have to be in a specific range and there can be no myeloma tumors found outside of the bones or bone marrow, the areas where myeloma is usually discovered. In past clinical studies, patients with standard-risk myeloma have done well with intensive therapy in the form of stem cell transplant. But multiple myeloma is not curable and, although it may respond to standard treatments including stem cell transplant, myeloma always recurs.

Detailed description:

Arms: arm 1: All patients on this study start with the same treatment, lenalidomide and dexamethasone by mouth. After patients have received 4 cycles of lenalidomide and dexamethasone and are within 2 weeks of completing stem cell collection, they are randomized (like the toss of a coin) to either :

* stem cell transplant right after collection
* continue lenalidomide and dexamethasone, saving stem cell transplant for a later time. arm 2: All patients on this study start with the same treatment, lenalidomide and dexamethasone by mouth. After patients have received 4 cycles of lenalidomide and dexamethasone and are within 2 weeks of completing stem cell collection, they are randomized (like the toss of a coin) to either :

stem cell transplant right after collection

* continue lenalidomide and dexamethasone
* saving stem cell transplant for a later time.
Interventions: intervention 1: Stem cell transplant x 1 or x 2 intervention 2: lenalidomide and dexamethasone
Intervention descriptions: intervention 1: After 4 cycles of Ld, eligible patients will undergo stem cell mobilization and collection with standard-of-care cyclophosphamide and Neupogen (G-CSF) or with plerixafor G-CSF. Mobilization with cyclophosphamide is preferred, but plerixafor is also allowed. Ld will be held for at least 2 weeks prior to stem cell mobilization.

On the SCT arm, patients not achieving VGPR by 3 months after the 1st SCT will undergo a 2nd SCT. All patients, after one or two SCT, will receive maintenance L. intervention 2: Patients will then be randomized to continued Ld or high-dose melphalan with SCT. On the SCT arm patients not achieving VGPR by 3 months after the 1st SCT will undergo a 2nd SCT. All patients after one or two SCT, will receive maintenance L.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
 
 
 
 
A Phase II Clinical Trial for Untreated Patients with 
Multiple Myeloma Eligible for Stem Cell Transplant: Lenalidomide 
(Revlimid®) plus Low-dose Dexamethasone (Ld x 4 cycles) Then Stem 
Cell Collection Followed by Randomization 
to Continued Ld or Stem Cell Transplantation (SCT) 
Plus Maintenance L 
 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
 
Principal 
Investigator/Department: 
Hani Hassoun, MD 
Medicine/Myeloma, Manhattan, 
West Harrison 
 
 
 
Co-Principal 
Investigator(s)/Department: 
Heather Landau, MD 
Medicine/ABMT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. New 
York, NY 10021 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
 
 
 
 
Investigator(s)/Department: 
Elyn Reidel, MS Virginia 
Klimek, MD Lillian 
Reich, MD Alexander 
Lesokhin, MD David 
Chung, MD, PhD 
Nikoletta Lendvai, MD, PhD 
Peter Maslak, MD 
David Straus, MD 
Matthew Matasar, MD 
Paul Hamlin, MD 
Steven Horwitz, MD 
Alison Moskowitz, MD 
Ariela Noy, MD 
M. Lia Palomba, MD 
Carol Portlock, MD 
Anas Younes, MD 
Andrew Zelenetz, MD, PhD 
 
Julie Teruya-Feldstein, MD 
Martin Fleisher, PhD 
Sergio Giralt, MD 
Craig Moskowitz, MD 
Craig Sauter, MD 
Marcel R.M. van den Brink, MD, 
PhD 
Juliet N. Barker, MBBS 
Ann A. Jakubowski, MD, PhD 
Esperanza B. Papadopoulos, MD 
Miguel-Angel Perales, MD 
James W. Young, MD 
Hugo R. Castro-Malaspina, MD 
Parastoo B. Dahi, MD 
Alan M. Hanash, MD, PhD 
Katharine C. Hsu, MD, PhD 
Robert R. Jenq, MD 
Doris M. Ponce, MD 
Roni Tamari, MD 
Brain Shaffer, MD 
Boglarka Gyurkocza, MD 
Michael Scordo, MD 
Oscar Lahoud, MD 
Stefan Berger, MD 
Avni Desai, MD 
John Fiore, MD 
Epidemiology and Biostatistics 
Medicine/Leukemia 
Medicine/Hematology 
Medicine/Myeloma 
Medicine/ABMT 
Medicine/Myeloma 
Medicine/Leukemia 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma, Manhattan, 
West Harrison 
Pathology 
Clinical Laboratories 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
 
 
 
 
Steven Sugarman, MD 
Stuart Lichtman, MD 
Marisa Siebel, MD 
Philip Caron, MD, PhD 
Stephanie Smith-Marrone, MD 
Carolyn Wasserheit-Lieblich, MD 
Nancy Mills, MD 
Michelle Boyar, MD Michael 
Fanucchi, MD Pamela 
Drullinsky, MD Tiffany 
Troso-Sandoval, MD Zoe 
Goldberg, MD 
Arlyn Apollo, MD 
Kenneth Ng, MD 
 
Audrey Hamilton, MD 
Ephraim Casper, MD 
Han Xiao, MD 
Mila Gorsky, MD 
Asma Latif, MD 
Afsheen Iqbal, MD 
Neha Korde, MD 
Abigail Staible, PA 
Ewa Chauvin, MSN, ANP-C 
Megan Scott, NP 
Shani Irby, NP 
Abigail Cohen, NP 
Nicole Lestrange, NP 
Tara Wolff, NP 
Allison Sams, NP 
Ola Landgren, MD, PhD 
Sham Mailankody, MBBS 
 
Eric Smith, MD, PhD 
Malin Hultcrantz, MD 
Michelle Wisniewski, PA 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre, West 
Harrison 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Myeloma 
Medicine/ABMT 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Medicine/Myeloma 
Medicine/Myeloma, Manhattan, 
Commack 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/West Harrison 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
 
 
 
 
 
Consenting 
Professional(s)/Department: 
Hani Hassoun, MD 
 
Heather Landau, MD 
Virginia Klimek, MD 
Lillian Reich, MD 
Alexander Lesokhin, MD 
David Chung, MD, PhD 
Nikoletta Lendvai, MD, PhD 
Peter Maslak, MD 
David Straus, MD 
Matthew Matasar, MD 
Paul Hamlin, MD 
Steven Horwitz, MD 
Alison Moskowitz, MD 
Ariela Noy, MD 
M. Lia Palomba, MD 
Carol Portlock, MD 
Anas Younes, MD 
Andrew Zelenetz, MD, PhD 
 
Sergio Giralt, MD 
Craig Moskowitz, MD 
Craig Sauter, MD 
Marcel R.M. van den Brink, MD, 
PhD 
Juliet N. Barker, MBBS 
Ann A. Jakubowski, MD, PhD 
Esperanza B. Papadopoulos, MD 
Miguel-Angel Perales, MD 
James W. Young, MD 
Hugo R. Castro-Malaspina, MD 
Parastoo B. Dahi, MD 
Alan M. Hanash, MD, PhD 
Katharine C. Hsu, MD, PhD 
Robert R. Jenq, MD 
Doris M. Ponce, MD 
Roni Tamari, MD 
Brain Shaffer, MD 
Boglarka Gyurkocza, MD 
Michael Scordo, MD 
Oscar Lahoud, MD 
Stefan Berger, MD 
Avni Desai, MD 
Medicine/Myeloma, Manhattan, West 
Harrison 
Medicine/ABMT 
Medicine/Leukemia 
Medicine/Hematology 
Medicine/Myeloma 
Medicine/ABMT 
Medicine/Myeloma 
Medicine/Leukemia 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma, Manhattan, West 
Harrison 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/Commack 
Medicine/Commack 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
 
 
 
 
John Fiore, MD 
Steven Sugarman, MD 
Stuart Lichtman, MD 
Marisa Siebel, MD 
Philip Caron, MD, PhD 
Stephanie Smith-Marrone, MD 
Carolyn Wasserheit-Lieblich, MD 
Nancy Mills, MD 
Michelle Boyar, MD Michael 
Fanucchi, MD Pamela 
Drullinsky, MD Tiffany 
Troso-Sandoval, MD Zoe 
Goldberg, MD 
Arlyn Apollo, MD 
Kenneth Ng, MD 
Audrey Hamilton, MD 
Ephraim Casper, MD 
Han Xiao, MD 
Mila Gorsky, MD 
Asma Latif, MD 
Afsheen Iqbal, MD 
Neha Korde, MD 
Ola Landgren, MD, PhD 
Sham Mailankody, MBBS 
Eric Smith, MD, PhD 
Malin Hultcrantz, MD 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre, West Harrison 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/Myeloma, Manhattan, Commack 
Medicine/Myeloma 
Medicine/Myeloma 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
 
 
 
 
 
 
Collaborating Institutions: 
Site’s Role 
 
Raymond L Comenzo, MD (Sub-Investigator) 
Data Collection 
Tufts Medical Center (TMC) 
800 Washington Street 
Boston, MA 02111 
TEL 617-636-6454 
RComenzo@tuftsmedicalcenter.org 
 
Tarun Kewalramani, MD (Sub-Investigator) 
Data Collection 
Lahey Clinic 
41 Mall Road 
Burlington, MA 01805 
TEL 781-744-8400 
tarun.kewalramani@lahey.org 


 
Memorial Sloan Kettering Cancer Center 
IRB Number: 08-121 A(24) Approval 
Date: 13-Feb-2018 
 
 
Table of Contents 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL............................................................... 1 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................ 1 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .......................................................................... 2 
3.0 
BACKGROUND AND RATIONALE ............................................................................... 3 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .................................................. 12 
4.1 
DESIGN .................................................................................................................. 12 
4.2 
INTERVENTION ................................................................................................... 13 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ..................................................................... 15 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ..................................................................... 21 
6.1 
SUBJECT INCLUSION CRITERIA...................................................................... 21 
6.2 
SUBJECT EXCLUSION CRITERIA..................................................................... 22 
7.0 
RECRUITMENT PLAN................................................................................................... 23 
8.0 
PRETREATMENT EVALUATION ................................................................................ 23 
9.0 
TREATMENT/INTERVENTION PLAN ........................................................................ 24 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ........................................ 35 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................... 37 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT............... 47 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................ 50 
14.0 
BIOSTATISTICS ............................................................................................................. 51 
15.0 
RESEARCH PARTICIPANT REGISTRATION PROCEDURES.................................. 52 
15.1   RESEARCH PARTICIPANT REGISTRATION .................................................. 52 
115.2RANDOMIZATION................................................................................................ 52 
16.0 
DATA MANAGEMENT ISSUES .................................................................................. 52 
16.1 
QUALITY ASSURANCE .................................................................................. 53 
16.2 
DATA AND SAFETY MONITORING ............................................................. 54 
16.3 
REGULATORY DOCUMENTATION.............................................................. 54 
17.0 
PROTECTION OF HUMAN SUBJECTS ....................................................................... 55 
17.1 
PRIVACY ........................................................................................................... 56 
17.2 SERIOUS ADVERSE EVENT (SAE) ..................................................................... 56 
17.3 SERIOUS ADVERSE EVENT (SAE) REPORTINGERROR! BOOKMARK NOT 
DEFINED. 
18.0 
INFORMED CONSENT PROCEDURES ....................................................................... 61 
19.0 
REFERENCES ................................................................................................................. 63 
20.0 
APPENDICES .................................................................................................................. 68 
APPENDIX A:  SCHEDULE OF STUDY ASSESSMENTS...................................................... 69 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amended:01-JUN-2016 
 
 
- 0 - 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
1 -
 
 
 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Figure 1. Protocol Schema 
"The need for early ASCT in an era of new drugs is the most important clinical question in 
myeloma today."  Robert A. Kyle and Vincent Rajkumar, Blood 2008; 111:2962 
 
This is a phase II clinical trial for newly diagnosed patients with symptomatic multiple myeloma 
eligible for stem cell transplant (SCT). In this trial we ask whether the regimen of lenalidomide 
and dexamethasone achieves a response profile 2 and 3 years into the disease that is similar to 
the response profile achieved with the more conventional approach of initial therapy followed by 
early high-dose melphalan with stem cell transplant. In this randomized phase II trial, neither 
arm can be considered standard therapy because there is no established standard initial therapy 
for myeloma at this time, nor is there an established role for maintenance therapy with 
lenalidomide. Lenalidomide and low-dose dexamethasone are acceptable, effective and widely 
used initial therapy based on phase II and III trial data but there have been no direct comparisons 
of thalidomide and dexamethasone, bortezomib and dexamethasone, and lenalidomide and 
dexamethasone as initial therapies. Therefore, there is no established standard initial therapy. 
This phase II trial is designed so that results from the two treatment arms will be compared 
directly to each other using a “pick-the-winner” approach. 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
2 -
 
 
 
 
 
Lenalidomide is initially dosed at 25mg/day for 21 of 28 days. Dexamethasone is dosed at 40mg 
weekly. Dexamethasone dosed in this fashion (4 days per cycle) is considered low-dose (d) while 
dexamethasone given in pulses on days 1-4, 9-12 and 17-20 is considered high dose (D). 
Lenalidomide and low-dose dexamethasone (Ld) is the standard dose-schedule based on a recent 
phase III trial and is the dose-schedule we use in this trial. 
 
Newly diagnosed untreated patients with myeloma will receive Ld for 4 cycles and then undergo 
conventional stem cell mobilization with cyclophosphamide and G-CSF (10ug/kg/day) or 
plerixafor and G-CSF and stem cell collection. Mobilization with cyclophosphamide is preferred, 
but plerixafor is also allowed. Then all patients will be stratified into high- and standard-risk 
groups. High-risk patients are those who have baseline high-risk cytogenetics or FISH 
(hypodiploidy, presence of t(4;14) or del 17p) or baseline β2-microglobulin > 3.5.  All other 
patients will be designated as standard-risk. After stratification, patients will be randomized 
either to continue Ld or to undergo standard high-dose melphalan and SCT. 
 
On the Ld arm, patients will resume Ld with prophylactics and dose reductions as indicated. 
 
On the SCT arm, patients will undergo up to 2 SCT. Achievement of at least a 90% reduction in 
myeloma from baseline (very good partial response, VGPR) after the 1st SCT will determine the 
need for a second SCT. Patients who do not achieve a VGPR after the 1st SCT will undergo a 2nd 
SCT. Patients who do not achieve a VGPR after the 2nd SCT will receive lower-dose Ld 
(L=10mg/day on days 1-28 every 28-day cycle, d=20mg flat dose weekly on days 1, 8, 15, and 
22 every 28-day cycle) beginning 3 months after the 2nd SCT. Patients who are high-risk will 
also receive lower-dose Ld after the 1st or 2nd SCT. 
 
All patients will continue on those arms of therapy until progression of disease. 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary objective: 
 
 
To determine the progression free survival (PFS) at 2 years after enrollment in 
untreated patients with multiple myeloma who receive initial therapy with four cycles of Ld, 
undergo stem cell collection and storage, and then are stratified into high- and standard-risk 
groups and randomized either to continue Ld or to undergo SCT with additional Ld for those 
not achieving VGPR or for those having high-risk disease. 
 
Secondary objectives: 
 
 
To assess the CR+VGPR rate at 2 and 3 years 
 
To assess overall myeloma response rates at 2 and 3 years 
 
To assess overall survival 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
3 -
 
 
 
 
 
 
 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
Multiple Myeloma (MM) 
MM is an incurable plasma cell malignancy with over 16,000 new cases and 11,000 deaths 
estimated in the U.S. in 2006.1 It accounts for 10-15% of all hematologic malignancies, with a 
median age at diagnosis of 63 years. Median overall survival remains 4-5 years and long-term 
myeloma-free survivors are rare.  Age and race influence the incidence of MM. MM rarely 
occurs before the age of 40.2 Its incidence increases rapidly with age and is lowest among Asian 
peoples, intermediate among Caucasians in America and Europe, and highest among blacks in 
the USA. The differences in the incidence of MM in different countries appear to be due to 
genetic rather than environmental factors. 
 
The numerous clinical manifestations associated with MM result from bone marrow replacement 
by myeloma plasma cells and the pathologic effects resulting from their overproduction of a 
monoclonal immunoglobulin molecule (“M protein”), which include bone destruction, anemia, 
hypercalcemia, immunodeficiency and renal dysfunction.3 A number of chemotherapeutic 
regimens are employed to treat myeloma. Decades ago prednisone added to oral melphalan 
became the mainstay of therapy (MP) although complete response (CR) was rare (< 5%) and 
median survival did not exceed 3 years.4 The addition of other alkylating agents, anthracyclines 
and vinca alkaloids to MP did not improve survival. Until recently, regimens employed as 
standard initial therapy included VAD and single-agent dexamethasone with response rates that 
ranged from 40-70% with uncommon complete responses.5 
 
Over the past 15 years autologous stem cell transplantation (SCT) has been shown in several 
phase III studies to provide higher CR and survival rates than historical alkylator-based 
therapy.6,7 Although neither achievement of CR nor SCT is a cure, SCT likely adds 1 year to 
survival compared to historical therapy.  For over a decade, the importance of achieving a CR (or 
> VGPR) has been well established with respect to overall survival. In the IFM 90 trial, the 5- 
year overall survival was significantly higher in those with CR or VGPR (72%) 3 months post- 
SCT than in those with PR (39%).6 This point was driven home with the results of the IFM 94 
trial in which patients not achieving at least a VGPR after the first SCT had a survival advantage 
with a second SCT. The CR+VGPR with tandem SCT on IFM 94 was 50%. 
 
Because the new agents available to treat myeloma are so effective, many patients and 
physicians are questioning the role of high-dose melphalan with SCT in the treatment of the 
disease. They question the need for the morbidity and investment of time associated with 1 or 2 
SCT when the response rates with the new agents, lenalidomide and bortezomib in initial 
therapy, for example, are as high as those achieved with historical therapies and high-dose 
melphalan with SCT. In addition to being supported by the improved response rates noted with 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
4 -
 
 
 
 
 
recently approved novel agents, these concerns are supported by several large studies that have 
demonstrated no difference in overall survival with SCT early or late in the course of disease, 
and by retrospective evaluations showing that patients achieving complete responses with 
standard therapy have similar survivals to those achieving complete response (CR) with SCT. 
This trial asks whether continued combination therapy with the new agent lenalidomide and low- 
dose dexamethasone (Ld) is as effective as initial therapy with Ld followed by SCT. In the initial 
phase II trial of lenalidomide and high-dose dexamethasone (LD) investigators at Mayo Clinic 
reported a progression-free survival of about 3 years in myeloma patients of various ISS stages. 
(It is important to note that patients continuing on long-term lenalidomide therapy on that trial 
received low-dose dexamethasone). 
 
Although the median progression-free survival after high-dose melphalan with SCT is 30 
months, two large SCT trials have clearly demonstrated no difference in overall survival between 
patients receiving early or delayed SCT. Therefore, delay of high-dose melphalan will not put 
patients at risk. 
 
Novel agents and response rates 
 
Over the past 5 years the FDA has approved thalidomide, bortezomib and the thalidomide- 
analogue lenalidomide for the treatment of myeloma.8 The effectiveness of these new agents 
combined with dexamethasone and other traditional medications has changed the treatment of 
myeloma. Phase III trials have shown higher response and survival rates with thalidomide 
combined with MP (MPT) versus MP or two cycles of intermediate-dose melphalan (100mg/m2) 
with SCT.9,10 Similarly, thalidomide when combined with pulse dexamethasone (TD) was 
superior to D alone as initial therapy in a transplant-eligible population.11 With thalidomide as 
part of a tandem SCT strategy in a recent large phase II trial, median overall survival was 6.5 
years.12 
 
Phase II trials of bortezomib-based regimens in initial therapy have also shown very high 
complete and overall response rates.13-16 One can now expect complete and near complete 
response rates with initial therapy for myeloma at levels previously attained only with high-dose 
therapy and SCT. The Spanish intergroup (PETHEMA) recently reported results of a phase III 
trial of VMP (bortezomib+MP) versus MP for patients who were not stem cell transplant 
candidates. The CR+VGPR rates were 45% in the VMP and 10% in the MP arm. Both VMP and 
MP contain pulse oral melphalan, a leukemogenic agent; the long-term effects of combining it 
with bortezomib are not known and it is not advisable to use VMP in a young patient who is a 
candidate for SCT because of the risk of leukemia and the deleterious effects of oral melphalan 
on hematopoietic stem cells. Stem cell mobilization and collection are impaired in patients 
receiving more than 200mg of prior oral melphalan. 
 
In a phase II trial of LD in newly diagnosed MM patients, those who received LD as their 
primary therapy and continued on it (with reduction in the dexamethasone dose) until 
progression of disease had a 24% CR and 43% VGPR (CR+VGPR = 67%) best response rate. 
Median time to progression of disease was 32 months.17 At 1 year, the CR+VGPR rate was 56%, 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
5 -
 
 
 
 
 
indicating continued responsiveness in years 2 and 3. There was no difference in response rate 
based on ISS stage.  A phase III ECOG trial comparing lenalidomide with high-dose (LD) versus 
low-dose dexamethasone (Ld) was halted because of significantly better survival in the Ld arm at 
one year (96% vs 88%). Best overall response rates at 1 year were different in the arms, 
however, with CR+VGPR of 52% in the LD versus 42% in the Ld arm. Whether continued use 
of Ld for an additional year increased the CR+VGPR rates is currently unknown. 
 
With these improvements in response, the significance of attaining CR in myeloma and the 
definition of CR have become critical issues in therapy. The latter has undergone several 
iterations over the past 20 years and now is defined as normalization of the marrow, of the serum 
and urine immunofixation studies and of the free light chain levels and ratio also.18 The 
significance of CR has recently been re-examined in a retrospective evaluation of 721 
consecutive patients treated at MD Anderson from 1/87 to 5/06. Patients achieving CR with 
initial therapy, those achieving CR after SCT (with PR or NR to initial therapy) and those 
undergoing SCT in CR from initial therapy all had similar long-term median survivals of 10 to 
14 years as is shown in Figure 2.19 The MD Anderson investigators state that these results 
suggest "that high-dose therapy provided no further benefit after CR had been achieved with 
initial therapy. A randomized trial may be useful to clarify this question." In the light of such 
results and statements, patients, their physicians and myeloma specialists are questioning the role 
of high-dose melphalan and SCT.  Not surprisingly, SCT physicians are responding to these 
concerns. Jean-Luc Harrousseau, a pioneer in MM SCT trials, has written "SCT is being 
challenged again by the introduction of novel agents such as bortezomib, thalidomide, and 
lenalidomide."20 Another pioneer, Bart Barlogie, has written “Although high CR rates may 
translate into extended survival for MEL treatment of patients with good-risk (sic) myeloma, this 
may not hold true following treatment with the newer non-genotoxic agents.”21 
Figure 2. OS with CR after initial therapy or after SCT 
(MD Anderson experience) 
 
 
 
 
 
 
 
 
 
 
 
 
 
A trial conducted at MSKCC (IRB 00-077) contributed to the trend towards better responses 
with initial therapy.22 On that phase II trial, newly diagnosed Durie-Salmon (DS) stage II and III 
myeloma patients received doxorubicin and dexamethasone (AD) followed by thalidomide and 
dexamethasone (TD). (NB: The DS staging system, not the ISS, was used for IRB 00-077.) 
Based on intent-to-treat the overall response rate was 84.4% (38/45) and the CR+VGPR rate 
36% (16/45). The AD/TD schedule was developed after calling attention to the risk of 
thromboembolic complications when thalidomide was simultaneously used with doxorubicin.23 
The rate of thromboembolic complications in the final version of IRB 00-077 was 10%, 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
6 -
 
 
 
 
 
equivalent to the rate with VAD. There were no treatment-related deaths and the incidence of 
neuropathy was nil. 
All patients on the MSKCC clinical trial IRB 00-077 had DS stage II or III myeloma. The DS 
staging system was used for 30 years, despite the fact that newer staging systems were 
developed. The continued use of DS staging was based upon the need to clearly describe and in 
some cases stratify the patients enrolled on clinical studies. The majority of DS stage I patients, 
for example, did not need to be treated at diagnosis and would not be appropriate for aggressive 
initial therapy trials. 
 
The International Staging System (ISS) for myeloma was developed and validated several years 
ago and has been integrated into clinical research here and elsewhere.24 It has supplanted the DS 
staging system and represents a major advance in staging because it does not require inclusion of 
skeletal survey findings, the most inaccurate and confusing component of the DS system, and 
because of its objectivity and ease of application. ISS stage I patients have a serum albumin level 
> 3.5g/dl and β2 microglobulin (B2M) < 3.5mg/dl while ISS stage III patients have B2M > 
5.5mg/dl. ISS stage II patients are neither stage I nor III. 
 
After assessing all of the patients enrolled on all versions of MSKCC clinical trial IRB 00-077 
(n=64) for response and survival by ISS stage, we learned that the response rate to therapy was 
similar in all ISS groups but that ISS stage II and III patients, and patients with extramedullary 
disease (EMD) regardless of stage, had poorer overall survival. ISS stage II and III patients had a 
median survival of 3.5 years while the median survival of ISS stage I patients had not been 
reached with a median follow-up of 4 years. Patients with EMD had a median survival of 1.8 
years. Based on this analysis, we defined ISS stage II or III patients, and those patients with 
EMD, as high risk. Patients with ISS stage I myeloma without EMD were defined as standard 
risk. A subsequent clinical trial at MSKCC (IRB 06-067) was designed for patients with high- 
risk myeloma defined as ISS stage II or III or having EMD. The CR+VGPR rate is 53% in the 
first 27 patients treated. (Landau H, Comenzo RL, unpublished observation). Of note, one 
responder on that trial (not a SCT candidate) relapsed within 6 months of completing therapy on 
06-067 and has responded to 3 cycles of Ld. 
 
Since the phase II clinical trial 06-067 was designed, the cytogenetic data on risk profiles in MM 
have been more cogently assessed. For many years the presence of deletion 13q (del 13q) was 
considered a marker of high-risk MM; we did not find it to be such a marker in patients on 00- 
077 and therefore discounted it and other cytogenetic findings in the design of 06-067. Current 
thinking, however, based on large numbers of patients treated similarly, views hypodiploidy and 
the presence of the t(4;14) or del 17p by FISH, as well as an elevated β2 microglobulin (> 3.5; 
i.e., ISS stage II and III), as markers of high risk.25 A recent retrospective evaluation of over 
1000 cases of myeloma evaluated by FISH supported this view and put the prior significance of 
del 13q in a better perspective.26 Del 13q is easily appreciated on standard karyotype. The 
identification of del 13q on karyotype was a reflection of the proliferative rate of the myeloma 
and of the ease with which that particular abnormality could be visually appreciated with 
traditional metaphase spreads and Giemsa banding. 


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In this trial, then, we use a newer definition of risk: after stem cell collection and prior to 
randomization patients will be stratified into high-risk and standard-risk groups based on the 
criteria of high-risk cytogenetics or FISH (hypodiploidy, t(4;14) or del 17p) or β2 microglobulin 
(B2M) > 3.5. All others will be considered standard risk. The response rates to treatment with Ld 
or with tandem SCT are not different in these groups. A recent study from the University of 
Calgary, Canada, has found that patients with and without t(4;14) responded equally well to 
lenalidomide plus dexamethasone treatment, with little difference between the patient groups in 
either the response rate (CR + PR) or event-free survival.27   However, with conventional 
treatment and SCT, although the response rates are not different in those with t(4;14), the median 
progression-free survival in those patients  after SCT may be as short as 9 months and is 
different than that of patients without the t(4;14).28   We do not know yet whether the use of Ld 
before and after SCT, as we propose, will modify that outcome. Since the fraction of newly 
diagnosed patients with t(4;14) or del 17p is about 20% of patients, and effective therapy (e.g., 
thalidomide, SCT, bortezomib) is available at progression of disease (i.e., removal from study), it 
does not make sense to exclude these patients from this trial. 
 
Stem cell transplant 
 
There have been two large prospective trials in France (IFM 90) and in UK (MRC 9), and one 
large retrospective study of myeloma patients in Nordic countries, showing a survival benefit for 
SCT compared to conventional chemoptherapy.6,7,29 In IFM 90, patients less than 65 years of age 
with DS stage II or III MM were randomized to either SCT after up to 6 cycles of VMCP 
alternating with BCNU, vincristine, Adriamycin and prednisone (BVAP) or to conventional 
chemotherapy with 18 cycles of VMCP alternating with BVAP. The SCT regimen was MEL 140 
mg/m2 and TBI, and recombinant interferon alpha (IFNα) was administered to patients in both 
groups until relapse. By intent-to-treat, SCT patients had a significantly higher response rate than 
those receiving conventional chemotherapy (CR+VGPR 38% versus 14%). At a median follow- 
up of 37 months in the chemotherapy group and 41 months in the SCT group, the latter had 
significantly longer PFS and OS. Multivariate analysis of prognostic factors demonstrated that 
low B2M and treatment-group assignment were significantly related to prolonged EFS and only 
a low B2M was significantly related to prolonged OS. 
 
Recent reports of 2 other trials have cast doubt on the benefit of SCT compared with 
conventional chemotherapy. In a multi-center trial conducted in Spain, patients whose myeloma 
responded to initial chemotherapy were randomized to SCT or continued standard 
chemotherapy.30 The CR rate was significantly higher in the SCT arm (30% vs. 11%) but no 
difference was seen in EFS and OS. However, randomization did not occur at diagnosis, 
introducing a selection bias, and only three-quarters of the patients enrolled were randomized. 
SCT is a useful salvage treatment for patients with primary refractory multiple myeloma; hence, 
those patients would have been excluded by the trial design. In addition, the median PFS was 
higher in the SCT arm (42 months vs. 33 months), a difference that might have achieved 
statistical significance had the size of the patient groups been larger. 


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In a large intergroup trial in the United States, patients under 70 (n=516) received initial therapy 
with VAD and were then randomized to SCT or to vincristine/carmustine/melphalan/ 
cyclophosphamide/prednisolone (VBMCP).31 There was selection bias in this trial also. Of 813 
patients registered and assigned to treatment arms, only 516 were randomized and then only 424 
were treated as planned. There were no differences seen in response rate, PFS and OS between 
the arms. 
 
Simply comparing conventional chemotherapy with SCT is not as salient an issue, however, 
because the results of SCT have improved with the use of melphalan alone at 200mg/m2 (less 
morbidity) and with tandem MEL 200 SCT. Patients not achieving a VGPR after the 1st SCT 
benefit from a 2nd SCT, based on the results of the IFM 94 trial.32   In this randomized trial 1 and 
2 SCT were compared in 399 patients up to 60 years of age.  The 7-year EFS and OS were 
significantly improved in the tandem SCT arm (20% vs. 10% and 42% vs. 21%, respectively). In 
the IFM 94 trial, 75% of patients underwent the 2nd SCT and treatment-related mortality was less 
than 5%. 
 
Because of concerns about the cost and risk of tandem SCT, defining the patients who benefited 
from tandem SCT was important. In the IFM 94 trial, the only factor that distinguished patients 
who benefited from tandem SCT was response to the 1st SCT. Patients with < 90% reduction of 
the M-protein (i.e., those not achieving a VGPR) after the 1st SCT had a longer OS in the tandem 
SCT arm. Patients experiencing CR or VGPR after the 1st SCT had the same OS with or without 
the 2nd SCT. Therefore, in this trial, comparing continued Ld to early SCT, patients randomized 
to SCT will receive a second MEL 200 SCT if their response to the 1st SCT is not at least a 
VGPR with respect to the baseline M-protein studies. 
 
Early versus delayed stem cell transplant 
 
In addition to the important trials described above, there have been two trials examining the 
question of early versus delayed SCT in newly diagnosed patients.33,34 In the first trial, conducted 
at Mayo Clinic in the early 1990's, 118 patients with multiple myeloma had stem cells mobilized 
and collected within 6 months of diagnosis, followed by transplantation only at progression of 
disease.33 Eleven had transplants early due to progressive disease. Overall, with 7 years of 
follow-up at the time of the report, 67 had had SCT, 9 had died of progressive disease before 
SCT, and 42 were alive in plateau phase. Median survival of the group was 58.5 months. 
Predictors of survival were markers of the biology of the myeloma and not treatment-related 
variables: B2MG, bone marrow labeling index (S phase), and hemoglobin level predicted overall 
survival. The investigators concluded "early cryopreservation of blood stem cells followed by 
transplantation at progression is a feasible approach to therapy in patients with myeloma. The 
underlying biology of the disease has a greater impact on survival than the timing of 
transplantation. A prospective randomized trial is required to answer definitively the question of 
the optimal timing of blood cell transplantation." 


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In the mid-1990's Jean-Paul Fermand and his colleagues in the Group ‘‘Myelome Autogreffe’’ 
performed a multi-center prospective randomized trial comparing early and delayed timing of 
autologous SCT for newly diagnosed untreated patients with MM.34 After enrollment, all patients 
received 1 to 2 cycles of intensified CHOP (cyclophosphamide, Adriamycin, vincristine and 
prednisone; the second cycle also included G-CSF) followed by stem cell collection and then 
randomization to early versus late SCT. The early transplantation group (n = 91) received 3 to 4 
cycles of VAMP (V, A and methylprednisolone) followed by autologous SCT with lomustine, 
etoposide, cyclophosphamide, MEL 140 and TBI. Patients in the late transplantation group (n = 
94) received VMCP as induction therapy until a stable plateau phase was reached. Once patients 
showed either disease progression while receiving VMCP, disease resistance (no response or < 
PR after 6 courses of VMCP), or relapsed after responding (n = 81), they then received monthly 
VAMP followed by autologous SCT as rescue therapy. At a median follow-up of 58 months, 
there was no significant difference in OS with an estimated median OS in the early group of 64.6 
and in the late group of 64 months. There was a significant difference in EFS (medians of 39 and 
13 months in the early and late groups respectively). Treatment-related mortality in both groups 
was notable -- 10% and 14% in the early and late groups -- and not surprising given the intensity 
of the regimen. 
 
In this trial, comparing continued Ld to Ld and SCT, the optimal SCT strategy (tandem MEL 
200) will be available to all patients, either on study for those randomized to SCT or off-study at 
progression of disease for those randomized to continued Ld. At the three collaborating centers 
treatment-related mortality in autologous SCT for myeloma is < 1% in all categories of MM 
patients. In the last 3 ASCT trials at MSKCC (IRB # 98-107, 04-024, 05-080) over 100 patients 
have been treated and there has been 1 treatment-related death (on IRB # 98-107) due to 
transfusion-related bacterial sepsis. At TMC, there has been no treatment related death among 
the more than 60 myeloma patients who have received an ASCT in the past 4 years.35 In 
addition, the Ld regimen is likely more effective than the combination chemotherapy regimens 
used on these historical trials and less toxic as well. 
 
Lenalidomide and multiple myeloma 
Lenalidomide (Revlimid®, CC-5013) is a thalidomide analog and a proprietary IMiD® 
compound of Celgene Corporation.  Its anti-neoplastic activity stems from several potential 
mechanisms of action, including direct induction of apoptosis, inhibition of angiogenesis, 
inhibition of pro-survival signals to tumor cells, and stimulation of host anti-tumor immunity.36 
Lenalidomide is FDA-approved for the treatment of low- or intermediate-1-risk myelodysplastic 
syndrome (MDS) with deletion 5q cytogenetic abnormality and transfusion-dependent anemia, 
based on a 64% rate of achieving transfusion-independence (including 33% achieving a 
cytogenetic complete response) in this population of MDS patients in a multi-center phase II 
trial.37 Lenalidomide is also approved in combination with dexamethasone for 
relapsed/refractory multiple myeloma. 


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In pre-clinical studies, lenalidomide has been shown to have direct anti-myeloma activity, 
inducing apoptosis or G1growth arrest in multiple myeloma cell lines and in primary patient 
myeloma cells resistant to melphalan, doxorubicin and dexamethasone.38 A close analog of 
lenalidomide, CC-4047, decreased the binding of myeloma cells to bone marrow stromal cells, 
and decreased the production of pro-myeloma survival factors such as IL-6 and TNF-α within 
the bone marrow environment.39   Thalidomide, lenalidomide, and CC-4047 all increase T cell 
proliferation following T cell receptor-mediated activation, leading to increased IL-2 and IFN-γ 
secretion.40-42   These cytokines in turn can augment natural killer (NK) cell activation and 
strengthen NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against myeloma 
cell lines and primary patient myeloma cells.43,44 
 
In clinical studies, lenalidomide has demonstrated significant activity in both relapsed/refractory 
and untreated multiple myeloma.  Two phase I trials enrolled a total of 44 patients with 
relapsed/refractory myeloma at lenalidomide doses of 5, 10, 25, and 50mg daily.  Grade 3 or 4 
neutropenia and thrombocytopenia occurred in almost all patients in the highest dose cohort after 
28 days of therapy, requiring dose reductions to 25 mg/day, which was determined to be the 
MTD.  One patient had thromboembolism; other toxicities were generally mild and included 
rash, leg cramps, fatigue, and lightheadedness.  Clinical responses were noted in both trials.45,46 
 
A phase II multicenter study randomized 101 relapsed/refractory myeloma patients to 
lenalidomide 15mg BID or 30mg daily for days 1-21 of every 28 days.  Dexamethasone could be 
added for progressive disease (PD) at 4 weeks or stable disease (SD) at 8 weeks.  Thirty-eight 
percent achieved a minimal response (≥25% reduction in paraprotein) or better, including 6% 
CR, and another 47% had stable disease.  An additional 10 of 30 (33%) achieved a PR or better 
after the addition of dexamethasone.  Median time to progression (TTP) was 6 months.  Grade 
≥3 neutropenia and thrombocytopenia were seen in 28% and 18% of patients, respectively, more 
commonly in the BID dosing cohort.47    A larger multicenter study examined the efficacy of 
lenalidomide monotherapy in relapsed/refractory myeloma at 30mg daily for 21 of every 28 
days.  A greater than 50% reduction in paraprotein levels was required for response.  Of 222 
patients enrolled, 53 (25%) achieved a response (PR or CR) and 152 (71%) had SD, with median 
TTP of 6 months.  Neutropenia (40%) and thrombocytopenia (23%) were the most common 
grade 3/4 adverse events in this heavily pretreated population.48 
 
In two double-blind multicenter international phase III clinical trials (MM-009, North 
American, 353 patients; MM-010, Europe, Australia, and Israel, 351 patients), patients with 
relapsed or refractory MM not resistant to dexamethasone (D) were treated with D 40 mg daily 
on days 1-4, 9-12, and 17-20 every 28 days and were randomized to receive either lenalidomide 
(L) 25mg daily orally on days 1-21 every 28 days or placebo.49,50 At a median follow-up from 
randomization of 17.1 months (MM-009) and 16.5 months (MM-010), both studies showed 
significant improvement with LD compared to D in overall response (OR) (MM-009: 61% vs 
20.5%, p<.001; MM-010: 59.1% vs. 24%, p<.001, respectively), time to progression (TTP) 
(MM-009: 11.1 months vs. 4.7 months, p<.001; MM-010: 11.3 months vs. 4.7 months, p<.001, 
respectively), and overall survival (OS) (MM-009: 29.6 months vs. 20.5 months, p<.001; MM- 
010: not estimable vs 20.6 months, p<.001, respectively). In a subgroup analysis on patients with 


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impaired creatinine clearance, no significant difference in response rate, TTP, or OS was 
observed in patients with creatinine clearance above or below 50 ml/min who were treated with 
LD; however, for 16 patients with creatinine clearance <30ml/min, median TTP and OS was 
shorter than for those with creatinine clearance >30ml/min, but still significantly longer than for 
patients treated with D. Lenalidomide in combination with dexamethasone received FDA 
approval in the use of relapsed/refractory multiple myeloma on June 29th, 2006. 
 
LD has also been examined as a first-line therapy for multiple myeloma.  In a phase II study, 
investigators from Mayo clinic treated 34 newly diagnosed myeloma patients with LD on the 
same schedule used in the phase III trials.17 In follow-up presented in 12/07 at the American 
Society of Hematology annual meeting, the data on this trial were up-dated.51 At 1 year, 31 of 34 
(91%) patients had objective responses (≥50% paraprotein reduction), with 6 (18%) CR and 13 
(38%) VGPR (CR+VGPR = 56%).  No patients experienced progression of disease within the 
first 5 months of therapy. Forty-seven percent experienced grade 3/4 non-hematologic toxicity, 
most commonly fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%), and 
rash (6%). Of the 34 patients on the trial, 21 received LD (4 cycles) as their primary therapy and 
continued on Ld to progression of disease. In those patients, best overall responses were 24% CR 
and 43% VGPR (CR+VGPR = 67%) and the median time to progression was 32 months. 
 
On the ECOG phase III trial the one-year survival of 96% with Ld is the highest ever reported 
for an initial therapy trial in multiple myeloma.52 On that trial there was a 9% incidence of 
thromboembolic complications despite prophylaxis with aspirin (325mg).  Ld has now become a 
frequently used initial therapy for myeloma because the toxicity and safety profile is better than 
LD and likely better than that of thalidomide and dexamethasone. In addition, the availability of 
bortezomib as well as SCT give options for second-line therapies should Ld be ineffective. 
 
In this trial we have chosen to use lenalidomide at the starting dose of 25mg QD on days 1-21 
every 28 days, with built-in dose reductions for toxicity, because this is the regimen studied in 
the largest number of patients and is the FDA-approved dose. We also will use low-dose 
dexamethasone based on superior survival in the ECOG phase III trial. In addition, for 
thromboembolic prophylaxis, we will use aspirin for those with no risk factors for 
thromboembolic complications and prescribe prophylactic low-molecular weight heparin 
(LMWH) for those with risk factors (prior deep vein thrombosis or pulmonary embolus > 6 
months prior to enrollment, obesity (body mass index greater than 30), history of vascular 
disease, documented coronary artery disease, pacemaker, or insulin-dependent diabetes). For 
patients whose insurance will not cover LMWH, full-dose Coumadin can be used. Patients who 
experience thromboembolic complications on this trial will be fully anticoagulated and continue 
on therapy. 
 
On this trial then, we are comparing treatment approaches in which the response data indicate 
near parity.  On this trial, at 1-year in the Ld arm, the CR+VGPR rate is likely to be in the 45% 
range. Cyclophosphamide (used for mobilization) may increase the response rate. It is difficult to 
know what the 2-year CR+VGPR rate will be but on the Mayo Clinic phase II trial patients 
continuing to receive Ld showed improved responses as noted above with CR+VGPR of 67% 


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and median time to progression of almost 3 years.  Of note, continuing lenalidomide in 
responding patients until progression of disease is standard practice at this time.53 
 
In the SCT arm the CR+VGPR rates will be in the 50% range but adding maintenance low-dose 
Ld for those failing to achieve VGPR after two SCT and for those with high-risk disease may 
increase those rates. It is important to note that patients experiencing progression of disease in 
either arm of this trial will be able to receive effective second-line therapy with bortezomib- 
based treatment and for those in the Ld arm with SCT. 
 
There is no patient jeopardy attached to being in either arm of this trial. It is also important to 
note that this trial uses a "pick-the-winner" trial design that provides a challenge to Ld to show 
equivalence to SCT. 
 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
Newly diagnosed patients with symptomatic multiple myeloma eligible for SCT will receive Ld 
for 4 cycles and be evaluated for response after every cycle. Patients with progressive disease 
after at least one cycle of treatment, and patients with stable disease after 4 cycles will be 
removed from study. Since the rate of progressive disease on Ld was 0% in the Mayo Clinic 
phase II trial described above, we expect that patients who experience progression of disease 
after 2 or 4 cycles of Ld will be extremely rare. 
 
After completion of 4 cycles of Ld, all patients will then undergo conventional stem cell 
mobilization with cyclophosphamide and G-CSF (10ug/kg/day), or plerixafor and G-CSF, and 
stem cell collection. Mobilization with cyclophosphamide is preferred, but plerixafor is also 
allowed. 
 
After stem cell mobilization and collection, patients will be stratified.  Stratification will be 
based on baseline cytogenetics, FISH and β-2 microglobulin. High-risk patients are those with 
hypodiploidy, t(4;14) or del 17p, or β-2 microglobulin greater than 3.5, while all others will be 
considered standard risk. 
 
Patients will then be randomized to continued Ld or high-dose melphalan with SCT. 
 
On the SCT arm, patients not achieving VGPR by 3 months after the 1st SCT will undergo a 2nd 
SCT. All patients, after one or two SCT, will receive maintenance L as described below. 
On the continued Ld arm (or non-transplant arm), patients will continue Ld as described below. 
Clinical and myeloma status will be evaluated every month during the initial 4 cycles of Ld and 
every 3 months thereafter as described in Section 12 below. Beyond 3 years of treatment, the 
patients will be followed yearly for PFS and OS. At progression of disease patients will come off 


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study and be treated with alternative therapies. Patients on the Ld arm may have high-dose 
melphalan with SCT at progression of disease. 
 
Evaluation of the disease will occur according to the schedule outlined in table 7, section 10. 
 
 
 
4.2 
Intervention 
 
In the initial 4 cycles of therapy, patients will receive oral lenalidomide at the starting dose of 
25mg on days 1-21 every 28 days (one cycle) with dose adjustments for creatinine clearance and 
dose reductions for toxicity as described below. Patients will receive low-dose oral 
dexamethasone at 40mg weekly on days 1, 8, 15 and 22 of each 28-day cycle with dose 
reductions as below for toxicity (the weekly dose could be split over 2 days in the week i.e. 
20mg on days 1, 4, 8, 11, 15, 18, 22, and 25 for better tolerance). 
 
For thromboembolic prophylaxis, patients with no risk factors for thromboembolic complications 
will receive aspirin (325mg or 81mg). Risk factors include prior deep vein thrombosis or 
pulmonary embolus (> 6 months prior to enrollment), obesity, history of vascular disease, 
documented coronary artery disease, pacemaker, or insulin-dependent diabetes. Those with one 
or more risk factors will be prescribed prophylactic low-molecular weight heparin (LMWH). For 
patients whose insurance will not cover LMWH, Coumadin (INR 2-3) can be used. Patients who 
experience thromboembolic complications on this trial will receive Coumadin (INR 2-3) and 
continue on therapy. 
 
Patients will be evaluated by their physician monthly during the first 4 cycles of Ld and patients 
will have response of the myeloma assessed with serum protein electrophoresis (SPEP), serum 
immunofixation (IF) and quantitative immunoglobulins, and serum free light chain assay. 
Patients with non-secretory myeloma will not have bone marrow assessment repeated if they are 
clinically stable.  Patients with progression of disease after at least one cycle of treatment with 
Ld and patients with stable disease after 4 cycles will be removed from study. 
 
After 4 cycles of Ld, eligible patients will undergo stem cell mobilization and collection with 
standard-of-care cyclophosphamide and Neupogen (G-CSF), or with plerixafor and G-CSF. 
Mobilization with cyclophosphamide is preferred, but plerixafor is also allowed. Ld will be held 
for at least 2 weeks prior to stem cell mobilization. 
 
Within 2 weeks after stem cell mobilization and collection has been completed, patients will be 
stratified and randomized by the biostatistician working with the Clinical Trials Office at the 
registration center of MSKCC to either continued Ld or SCT. 
 
For continued Ld, patients will resume Ld at the last dose tolerated during the initial 4 cycles, 
with prophylactics and dose reductions as indicated. Treatment on the continued Ld arm will 
resume at the treating physician’s discretion. Lenalidomide will be continued until progression of 
disease or as tolerated. Low-dose dexamethasone will be continued for 1 year, as tolerated. Dose 


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adjustments will follow guidelines detailed in section 9.2. Patients will be seen every 3 months 
by their physician and their disease will be reassessed for the first 3 years on study. Patients will 
also have a CBC and pregnancy test performed monthly as long as they remain on treatment. 
Beyond 3 years of treatment, the patients will be followed yearly for PFS and OS. 
 
 
 
For SCT, patients are admitted to the hospital. High-dose melphalan is administered in a single 
dose on day -2 or split dose on days -3 and -2, through a central venous catheter. Melphalan 
dose-adjustments are made for age and creatinine clearance. Patients with creatinine clearance > 
51ml/min receive melphalan at 200mg/m2. Patients with creatinine clearance < 51ml/min (to be 
evaluated within 2 weeks of SCT) will receive 140mg/m2.  Patients > 70 years old receive 
140mg/m2 also. Each SCT in a tandem SCT is a clinically discrete event and these rules of dose 
adjustment apply to each SCT. Therefore, it is possible, that patients will get different doses of 
melphalan in tandem SCT. 
 
Patients will receive standard supportive care measures in SCT as previously described except 
that Neulasta (PEG-filgrastim) and not Neupogen is used after SCT on day +1 to aid 
hematopoietic recovery.35,73,74 
 
Post-SCT after discharge patients are followed on a regular basis as per standard of care and as 
deemed necessary by their treating physician.  At 3 months after the first SCT patients will have 
response of the myeloma assessed with serum protein electrophoresis (SPEP), serum 
immunofixation (IF) and quantitative immunoglobulins, serum free light chain assay and bone 
marrow studies. Patients with non-secretory myeloma will have a bone marrow assessment at 3 
months post-SCT. 
 
Patients with less than a VGPR at 3 months post-SCT will undergo a second SCT. At 3 months 
after the 1st or 2nd SCT, all patients will begin maintenance L(L=10mg/day on Days 1-28 of 
every 28 days cycle escalated to 15 mg after 3 cycles, if tolerated). Lenalidomide will be 
continued until progression of disease, as tolerated. Dose adjustments will follow guidelines 
detailed in section 9.2. 
 
For 12 months post-SCT all patients will receive prophylactic acyclovir 400mg PO twice a day 
adjusted for renal function and a daily proton-pump inhibitor. 
 
During the first 3 years on study, patients are seen and evaluated every 3 month by their 
physician and will have response of the myeloma assessed with serum protein electrophoresis 
(SPEP), serum immunofixation (IF) and quantitative immunoglobulins, and serum free light 
chain assay. Patients with non-secretory myeloma will not routinely have bone marrow 
assessment repeated if clinically stable. 
 
Beyond 3 years on study, patients will be seen every once a year with disease assessments at 
those visits for PFS and OS assessment. 


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5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1  Lenalidomide (Revlimid®) 
 
Lenalidomide (L) (REVLIMID®, CC-5013), a thalidomide analogue, is an 
immunomodulatory agent with anti-angiogenic properties.  The chemical name is 3-(4-amino- 
1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical 
structure: 
 
O 
O 
H 
N 
N 
O 
 
 
NH2 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3. 
 
 
 
Formulation 
 
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. 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 in 5 mg, 10 mg, 15 mg and 25 mg capsules for oral administration. 
Each capsule contains lenalidomide as the active ingredient and the following inactive 
ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. 
 
Supporter: Celgene Corporation will provide lenalidomide free of charge through the 
Revlimid REMS® program to enrolled patients. 
 
Mechanism of Action 
 
The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide 
possesses immunomodulatory and antiangiogenic properties.  It inhibits production in the 
bone marrow of cytokines (IL-6, TNF-α, VEGF) important for growth and survival of 
myeloma cells, inhibits COX-2 expression, and decreases tumor angiogenesis.  Lenalidomide 
can directly induce G1 cell cycle arrest and apoptosis in some but not all myeloma cell lines. 
It also stimulates T cell proliferation and cytokine secretion and NK cell cytotoxic activity. 


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Storage 
 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold. 
 
Pharmacokinetics and Drug Metabolism 
 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with 
maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose.  Co- 
administration with food does not alter the extent of absorption (AUC) but does reduce the 
maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of 
lenalidomide is linear. Cmax and AUC increase proportionately with increases in dose. 
Multiple dosing at the recommended dose-regimen does not result in drug accumulation. 
Pharmacokinetic sampling in myelodysplastic syndrome (MDS) patients was not performed. 
In multiple myeloma patients maximum plasma concentrations occurred between 0.5 and 4.0 
hours post-dose both on Days 1 and 28.  AUC and Cmax values increase proportionally with 
dose following single and multiple doses. Exposure (AUC) in multiple myeloma patients is 
57% higher than in healthy male volunteers.  In vitro (14C)-lenalidomide binding to plasma 
proteins is approximately 30%. 
 
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. 
 
Administration 
 
Lenalidomide is an analogue of thalidomide, a known human teratogen that causes severe life- 
threatening human birth defects.  Because of this toxicity, and to limit potential fetal exposure 
to lenalidomide, patients must follow the birth control guidelines outlined in Appendix C.  All 
women of childbearing potential must follow the protocol-dictated timelines for pregnancy 
testing. 
 
Lenalidomide is administered orally.  It may be taken with or without food at approximately 
the same time each day. 
 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through the Revlimid REMS® program.  All physicians who prescribe lenalidomide for 
research subjects enrolled into this trial and all research subjects enrolled into this trial must 
be registered in and must comply with all requirements of the Revlimid REMS® program. 


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Packaging 
Lenalidomide will be shipped directly to patients.   Bottles will contain a sufficient number of 
capsules for one cycle of dosing. 
 
Prescribing Information 
 
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 Revlimid REMS® program. Per 
standard Revlimid REMS® requirements all physicians who prescribe lenalidomide for 
research subjects enrolled into this trial, and all research subjects enrolled into this trial, must 
be registered in and must comply with all requirements of the Revlimid REMS® program. 
Prescriptions must be filled within 14 days, unless the patient is a female of childbearing 
potential, in which case the prescription must be filled within 7 days. Only enough 
lenalidomide for one cycle of therapy will be supplied to the patient each cycle. 
 
 
Accurate records will be kept of all study drug administration, including dispensing and 
dosing, in the source documents. 
 
5.2  Dexamethasone (D) 
 
Formulation: Supplied as 4 mg tablets. 
 
5.3  Cyclophosphamide 
 
General Information 
 
Mechanism of action: Activation by hepatic microsomal enzymes forming 2 major 
intermediates, aldophosphamide and 4-hydroxycylophosphamide, which act as powerful 
alkylating agents and prevent cross linking of DNA strands. 
 
Formulation 
 
Available in both oral and parenteral forms. The parenteral formulation is available as white 
crystals with sodium chloride as an excipient. The 100 mg dose is provided in a 10 mL vial 
and a 500 mg dose in a 30 mL vial. For high dose intravenous therapy there are 1 and 2 gram 
vials which are reconstituted in 50-100 mL of sterile water containing a solution of 20 
mg/mL. 
 
In this protocol, cyclophosphamide is administered at a dose of 3000mg/m2 based on adjusted 
ideal body weight. This is the standard-of-care dose employed for stem cell mobilization at 
MSKCC. 
 
Supplier: Mead Johnson 


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Preparation 
 
The drug may be given by intravenous push or as a slow infusion. Adequate hydration of the 
patient before and 72 hours after high-dose therapy is recommended to reduce the incidence of 
hemorrhagic cystitis. 
 
Storage 
 
Solutions reconstituted as described have 24-hour stability at room temperature. 
 
5.4 Melphalan 
 
General information 
 
Generic name: Melphalan, L-phenylalanine mustard 
Commercial name: Alkeran 
Chemical name: 4-[bis(chloroethyl)-amino]-L-phenylalanine 
Melphalan is an alkylating agent coupled to an amino acid. 
 
Formulation 
 
The drug is supplied in a sterile 50 mg vial, prepared as a lyophilized powder with 20 mg of 
povidone per vial. Ten ml of special diluent is provided for reconstitution. The composition of 
the diluent is sodium citrate (0.20 g), Propylene glycol (6.00 ml), ethanol (95%) (0.5 ml) and 
sterile water. The constituted solution is further diluted with 0.9% sodium chloride injection 
USP to a final concentration of 0.45 mg/ml. 
 
Supplier: Celgene. 
 
ALKERAN for Injection is supplied in a carton containing one single-use 
clear glass vial of freeze-dried melphalan hydrochloride equivalent to 50mg melphalan and 
one 10 ml clear glass vial of sterile diluent. 
 
 
 
 
 
 
Administration 
 
The dose is administered intravenously and IV fluids may be given before and after melphalan 
administration. Furosemide may be given 1 hour after IV melphalan. Intravenous melphalan 
will be used at doses of 140 and 200 mg/m2. It will be administered in a single dose on 1 day. 
 
5.5 Pegfilgrastim (Neulasta(TM)) 


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Pegfilgrastim is the pegylated form of recombinant methionyl human G-CSF (filgrastim). 
Pegfilgrastim is produced by covalently binding a 20-kilodalton (kD) 
monomethoxypolyethylene glycol molecule to the N-terminal methionyl residue of filgrastim. 
 
Formulation 
 
6 MG/0.6 ML SOL. A single fixed dose of 6 milligrams (mg) subcutaneously, given once per 
chemotherapy cycle, is effective and is recommended. 
 
Supplier: Amgen, Inc 
 
Storage 
 
The manufacturer recommends storage of Neulasta(TM) syringes at 2 to 8 degrees C (36 to 46 
degrees F), avoidance of freezing or shaking, and leaving syringes in the carton provided until 
time of use to protect from light (Prod Info Neulasta(TM), 2002). 
 
Contraindications 
 
Prior hypersensitivity to Escherichia coli-derived proteins, filgrastim, or pegfilgrastim. 
 
5.6 Recombinant human granulocyte-colony stimulating factor (NEUPOGEN®, G-CSF) 
 
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by 
recombinant DNA technology. NEUPOGEN® is the Amgen Inc. trademark for Filgrastim, 
recombinant methionyl human granulocyte colony stimulating factor (r-metHuG-CSF). 
NEUPOGEN® is contraindicated in patients with known hypersensitivity to E. coli-derived 
proteins, Filgrastim, or any component of the product. 
 
The only consistently observed clinical toxicity described with Neupogen® is medullary bone 
pain. Other clinical toxicities that have been described include skin rash, and cutaneous 
vasculitis. Since commercial introduction of Neupogen®, there have been rare reports of 
allergic-type reactions. Biochemical abnormalities that may occur include increases in 
alkaline phosphatase, uric acid, and lactate dehydrogenase. 
If required, NEUPOGEN® may be diluted in 5% dextrose. NEUPOGEN® diluted to 
concentrations between 5 and 15 mcg/mL should be protected from adsorption to plastic 
materials by addition of Albumin (Human) to a final concentration of 2 mg/mL. 
 
Do not dilute with saline at any time; product may precipitate. 
 
NEUPOGEN® should be stored in the refrigerator at 2-8 degrees Centigrade (36-46 degrees 
Fahrenheit). Do not freeze. Avoid shaking. Prior to injection, NEUPOGEN® may be allowed 
to reach room temperature for a maximum of 24 hours. Any vial left at room 


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temperature for greater than 24 hours should be discarded. 
 
Commercial NEUPOGEN® is available in 1 mL and 1.6 mL vials at a concentration of 300 
mcg/mL. Discard unused portions. Use only one dose per vial; do not reenter the vial. Do not 
save unused drug for later administration. 
 
5.6  Plerixafor (Mozobil) 
General Information 
Mechanism of Action: Plerixafor is an inhibitor of the CXCR4 chemokine receptor and blocks 
binding of its cognate ligand, stromal cell-derived factor-1α (SDF-1α). SDF-1α and CXCR4 are 
recognized to play a role in the trafficking and homing of human hematopoietic stem cells (HSCs) 
to the marrow compartment. Once in the marrow, stem cell CXCR4 can act to help anchor these 
cells to the marrow matrix, either directly via SDF-1α or through the induction of other adhesion 
molecules. 
 
Formulation 
 
Mozobil (plerixafor injection) is a sterile, preservative-free, clear, colorless to pale yellow, 
isotonic solution for subcutaneous injection. Each mL of the sterile solution contains 20 mg of 
plerixafor. Each single-use vial is filled to deliver 1.2 mL of the sterile solution that contains 24 
mg of plerixafor and 5.9 mg of sodium chloride in Water for Injection adjusted to a pH of 6.0 to 
7.5 with hydrochloric acid and with sodium hydroxide, if required. 
 
Preparation 
 
Vials should be inspected visually for particulate matter and discoloration prior to administration 
and should not be used if there is particulate matter or if the solution is discolored. 
 
The recommended dose of Mozobil is 0.24 mg/kg body weight by subcutaneous (SC) injection. 
Use the patient’s actual body weight to calculate the volume of Mozobil to be administered. Each 
vial delivers 1.2 mL of 20 mg/mL solution, and the volume to be administered to patients should 
be calculated from the following equation: 
0.012 X patient’s actual body weight (in kg) = volume to be administered (in mL) 
 
Recommended Concomitant Medications: Administer daily morning doses of G-CSF 10 
micrograms/kg for 4 days prior to the first evening dose of Mozobil and on each day prior to 
apheresis. 
 
Begin treatment with Mozobil after the patient has received G-CSF once daily for four days. 
Administer Mozobil approximately 11 hours prior to initiation of each apheresis for up to 4 
consecutive days. 
 
Storage 


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Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). 
 
Each vial of Mozobil is intended for single use only. Any unused drug remaining after 
injection must be discarded. 
 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
 Age ≥18 and < 75 
 
 Histologic and serologic findings from MSKCC confirming the diagnosis of multiple 
myeloma.  Standard diagnostic criteria for multiple myeloma will be used, as per the 
revised International Myeloma Working Group diagnostic criteria.79 
 
 Patients must have symptomatic multiple myeloma without advanced organ damage 
(such as multiple fractures or advanced bone disease causing immobilization, renal 
failure, spinal cord compression, or organ compromise due to soft tissue 
plasmacytoma). If immediate therapy with radiation and high-dose steroids (eg, for 
cord compression) or with bortezomib-based therapy (eg, for renal failure) is required, 
the patient is not eligible for this trial. 
 
 Patients may have received 1 cycle of prior therapy with dexamethasone for multiple 
myeloma 
 
 Adequate organ function is required, defined as follows: 
➢ 
ANC ≥ 1,500/μl and platelets≥100,000/μl (unless low ANC and platelets are due 
to multiple myeloma) 
➢ 
Serum bilirubin ≤ 2.0 mg/dl 
➢ 
AST, ALT and alkaline phosphatase < 3 times the upper limit of laboratory 
normal 
➢ 
Adequate renal function as assessed by calculated creatinine using Cockcroft- 
Gault estimation of CrCl (see Appendix H): Subjects must have calculated creatinine 
clearance ≥ 30ml/min by Cockcroft-Gault formula. 
 
 Performance status (ECOG) ≤ 2 (Appendix D). 
 
 Eligible for SCT with LVEF > 50% by MUGA or ECHO, and diffusing capacity > 
50% predicted by pulmonary function testing 
 
 Ability to understand the investigational nature of this study and to give informed 
consent 


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 All  study  participants  must  be  registered  into  the  mandatory  Revlimid  REMS® 
program, and be willing and able to comply with the requirements of the Revlimid 
REMS® program. 
 
 Females  of  childbearing  potential  (FCBP)†   must  have  a  negative  serum  or  urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to and 
again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must 
be filled within 7 days) and must either commit to continued abstinence from 
heterosexual intercourse or begin TWO acceptable methods of birth control, one highly 
effective method and one additional effective method AT THE SAME TIME, at least 
28 days before she starts taking lenalidomide.  FCBP must also agree to ongoing 
pregnancy testing. Men must agree not to father a child and agree to use a latex condom 
during sexual contact with females of child bearing potential even if they have had a 
successful vasectomy.  See Appendix C: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods. 
 
 Able to take aspirin 325mg or 81mg daily as prophylactic anticoagulation (patients 
intolerant to ASA may use Coumadin or low molecular weight heparin). 
 
6.2 
Subject Exclusion Criteria 
 
 Prior treatment for myeloma except for one cycle of dexamethasone 
 
 History of thromboembolic disease within the past 6 months regardless of anti- 
coagulation 
 
 Myocardial infarction within 6 months prior to enrollment, or New York Hospital 
Association (NYHA) Class III or IV heart failure (see APPENDIX F), uncontrolled 
angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of 
acute ischemia or active conduction system abnormalities. 
 
 Pregnant or breast-feeding women are excluded due to the potential teratogenicity of 
lenalidomide. 
 
 Concurrent active malignancy other than non-melanoma skin cancers or carcinoma-in- 
situ of the cervix, or presence of myelodysplastic or myeloproliferative disease. 
Patients with prior malignancies with a disease-free interval of ≥5 years are eligible. 
Patients who have had prior malignancies within the past 5 years but are considered to 
 
 
 
 
† A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy 
or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has 
had menses at any time in the preceding 24 consecutive months). 


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be “cured” with a low likelihood of recurrence may be eligible at the discretion of the 
Principal Investigator. 
 
 Active hepatitis B or C infection 
 
 HIV 1 or 2 positivity 
 
 Any other medical condition or laboratory evaluation that, in the treating physician’s 
or principal investigator's opinion, makes the patient unsuitable to participate in this 
clinical trial 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients seen in the in-patient or out-patient setting who meet eligibility criteria will be 
recruited to this study.  Efforts will be made to ensure that women and minority groups are 
adequately represented in this trial.  All co-investigators agree to follow the treatment protocol 
and to conduct the proposed investigation according to recognized principles of good clinical 
practice. 
 
All participants will be required to sign statements of informed consent and research 
authorization that conform to FDA, IRB and HIPPA guidelines.  All prescribing investigators 
and study participants must also be registered in Revlimid REMS®.  Informed consent will be 
documented by the use of a written consent form approved by the MSKCC IRB. 
 
Previously, a total of 2 patients were recruited and treated at Tufts Medical Center and The 
Lahey clinic. These sites were closed in 2012. 
 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
The following tests must be performed prior to patient enrollment: 
Within 42 days of enrollment: 
 History and physical exam 
 
 Assessment of ECOG performance status.  See Appendix E for ECOG Performance 
Status 
 
 CBC, PT/PTT 
 
 Electrolytes (Na, K, Cl, CO2, Ca), BUN, creatinine, LDH, total bilirubin, AST, ALT, 
alkaline phosphatase, albumin, β2-microglobulin, TSH 
 
 Serum protein electrophoresis (SPEP), serum immunofixation (IF) and quantitative 
immunoglobulins, and serum free light chain assay 


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 24 hour urine collection for total protein, immunofixation (IF), protein electrophoresis, 
and creatinine clearance 
 
 Serum β-HCG (sensitivity of at least 50mIU/ml) for females of childbearing potential 
(must be done within 10-14 days before and again within 24 hours before prescribing 
lenalidomide) 
 
 Hepatitis A, B, C serologies and HIV 1/2 antibody test (unless previously negative 
within the last six months) 
 
 If possible a core biopsy of any suspected site of soft-tissue plasmacytoma with 
specimen sent for cytogenetics and FISH as below 
 
Within 56 days of enrollment: 
 
 Skeletal survey 
 
 Pulmonary function test (including DLCO) 
 
 Bone marrow assessment, defined as: 
 
➢ 
Biopsy to be stained for CD138, CD20 and kappa/ lambda. 
➢ 
Aspirate will be sent for the following tests: 
▪ Routine staining and cell counts. 
▪ 1 to 3 ml of marrow for flow cytometry for myeloma markers, if indicated, 
as per standard procedures of the pathology department. 
▪ 1 to 3 ml of marrow for FISH  analysis / myeloma panel, as per standard 
procedures of the pathology department. 
 
 Echocardiogram or MUGA scan, and electrocardiogram (EKG) 
 
 MRI of the spine or PET/CT 
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1  Administration of therapy 
 
Lenalidomide and Dexamethasone as initial therapy 
 
 Patients with newly diagnosed symptomatic multiple myeloma deemed candidates for 
SCT will be enrolled if they sign the informed consent and are eligible. 
 
 
 Lenalidomide (L) is administered orally at a dose of 25mg daily for days 1-21 of each 28- 
day cycle.  Dexamethasone (d) will begin at 40mg weekly on days 1, 8, 15 and 22 of each 
28-day cycle (the weekly dose could be split over 2 days in the week i.e. 20 mg on days 
1, 4, 8, 11, 15, 18, 22, and 25 for better tolerance). Dose modifications for toxicity will be 
performed as described below 


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 Ld increases the risk of thrombotic events. All patients with no risk factors for 
thromboembolic complications will begin thromboembolic prophylaxis with aspirin 
325mg or 81mg daily at the start of treatment. [Aspirin-intolerant patients should receive 
prophylactic daily low molecular weight heparin (LMWH) or anticoagulation with 
Coumadin (INR 2-3).] Risk factors include prior deep vein thrombosis or pulmonary 
embolus (> 6 months prior to enrollment), obesity (body mass index greater than 30), 
history of vascular disease, documented coronary artery disease, pacemaker, or insulin- 
dependent diabetes. Those with one or more risk factors will be prescribed prophylactic 
low-molecular weight heparin (LMWH). For patients whose insurance will not cover 
LMWH, Coumadin (INR 2-3) can be used. Patients who experience thromboembolic 
complications on this trial will receive Coumadin (INR 2-3) and continue on therapy. 
Concurrent use of recombinant erythropoietin is discouraged due to reports of increased 
thromboembolic events in patients receiving Ld with erythropoietin. For information on 
the risk of venous thromboembolism with combined oral contraception see Appendix B: 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods. 
 Concurrent use of erythropoietin requires full anticoagulation of patients with therapeutic 
doses of LMWH or Coumadin. Anticoagulation should be managed as per MSKCC 
anticoagulation guidelines for platelet counts <50,000/mm3. Anti-microbial prophylaxis is 
not required and is left to the discretion of the treating physician. 
 Prednisone to treat lenalidomide-related rashes is permitted in small doses of no more 
than 10mg per day. 
 Standard supportive care measures may be used at the discretion of the treating physician. 
 
 The lenalidomide starting dose will be based on baseline calculated creatinine clearance 
as follows: 
 
 
Lenalidomide Starting Dose Based on Renal Function at Study Entry 
Baseline Calculated 
Creatinine Clearance 
(by Cockcroft-Gault) 
Starting Lenalidomide Dose 
≥ 60 ml/min 
25mg daily on Days 1 - 21 of each 28-day cycle 
≥ 30 and < 60 ml/min 
10mg daily on Days 1 - 21 of each 28-day cycle 
 
 
 At investigator discretion, patients started with a reduced lenalidomide dose due to 
baseline calculated creatinine clearance ≥ 30ml/min but < 60ml/min, may have their 
lenalidomide dose gradually increased in a step-wise manner at the start of Cycle 2 or at 
the start of subsequent treatment cycles, if they tolerated the prior treatment cycle without 
requiring dose modifications, interruptions or delays due to toxicity.  Lenalidomide dose 
titrations are permitted in 5mg increments on the same dosing schedule (daily on Days 1- 
21 of each 28-day cycle) up to the maximum allowable target dose of 25mg daily on 


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Days 1-21 of each 28-day cycle.  The lenalidomide dose may only be increased at the start 
of a new cycle of therapy, may only be increased once every 28 days (or less frequently), 
and may only be increased if the prior treatment cycle was completed without requiring 
dose modifications, interruptions or delays due to toxicity. 
 
 If a dose of lenalidomide is missed, it should be taken as soon as possible on the same 
day.  If it is missed for the entire day, it should not be made up. 
 
 Patients who take more than the prescribed dose of lenalidomide should be instructed to 
seek emergency medical care if needed and contact study staff immediately. 
 
 Response to Ld as initial therapy will be assessed after every cycle of therapy. Patients 
with progression of disease after at least one cycle, or patients with stable disease after 4 
cycles will be removed from study and offered other therapies including SCT. After 4 
cycles of therapy, patients with a response to Ld will have Ld held for at least 2 weeks 
prior to stem cell mobilization. 
 
 
 
Stem cell mobilization and collection 
 
 All patients will have blood stem cells mobilized according to institutional practices. 
This may include either cyclophosphamide or plerixafor based on AIBW as below and in 
Appendix G) and G-CSF (Neupogen) given at 10ug/kg subcutaneous daily based on 
actual body weight with leukapheresis beginning as per institutional practices. 
Mobilization with cyclophosphamide is preferred, but plerixafor is also allowed. Patients 
will receive prophylaxis antibiotics according to institutional practices. 
 
 Once stem cell collection begins, a target of 10 x 106 CD34+ cells per kg will be sought, 
allowing the collection of adequate stem cells for up to 3 stem cell transplants in a 
patient's lifetime. We will seek a minimal acceptable collection of 4 x 106 CD34+ cells 
per kg, allowing two SCT with the minimum acceptable dose of 2 x 106 CD34+ cells per 
kg per SCT. 
 
 Patients failing to collect the minimum dose may be mobilized as per institutional 
guidelines a second time. Patients who are mobilized twice and have less than 4 million 
stem cells (CD34+ cells) collected per kg will be removed from study. The likelihood of 
this happening is less than 2%. 
 
 Blood stem cells will be cryopreserved according to institutional practices. 
 
 Then all patients will be stratified into high- and standard-risk groups. High-risk patients 
are those who have baseline high-risk cytogenetics or FISH (hypodiploidy, presence of 
t(4;14) or del 17p) or baseline β2-microglobulin > 3.5.  All other patients will be 
designated as standard-risk. After stratification, patients will be randomized either to 
continue Ld or to undergo standard high-dose melphalan and SCT. 


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Continued Lenalidomide and Dexamethasone 
 
 Patients who are randomized to receive continued Ld will be treated as described above, 
but with dexamethasone at 20 mg weekly on days 1, 8, 15, and 22 (the weekly dose could 
be split over 2 days in the week i.e. 10 mg on days 1, 4, 8, 11, 15, 18, 22, and 25 for 
better tolerance). Lenalidomide (L) will remain at a dose of 25mg (or at the last tolerated 
dose) daily for days 1-21 of each 28-day cycle. Lenalidomide will be continued until 
progression of disease, as tolerated. Low-dose dexamethasone will be continued for 1 
year (from the start of initial treatment), as tolerated. Dose adjustments will follow 
guidelines detailed in section 9.2. 
 
 Pregnancy tests must be performed as in Table 7, footnote 4, during the initial 4 cycles of 
Ld, all breaks in therapy including the break between completing the initial 4 cycles of Ld 
through stem cell mobilization and collection, randomization and resumption of Ld. 
 
 Dose reductions of lenalidomide will be made as described below. 
 
Stem cell transplantation 
 
 For SCT, patients are admitted to hospital. 
 
 High-dose melphalan is administered in a single dose on day -2 or a split dose on days -3 
and -2, through a central venous catheter. Melphalan will be administered at a dose of 140 
or 200 mg/m2. Melphalan dose-adjustments are made for age and creatinine clearance. 
Patients > 70 years of age receive 140mg/m2. Patients with creatinine clearance < 
51ml/min (to be evaluated within 2 weeks of SCT) receive 140mg/m2.  Each SCT in a 
tandem SCT is a clinically discrete event and these rules of dose adjustment apply to each 
SCT. Therefore, it is possible that patients will get different doses of melphalan in tandem 
SCT. 
 
 Melphalan will be given based on ideal body weight (IBW- Appendix G) for patients who 
weigh 100-120% of their IBW. For patients who weigh less than 100% of their IBW, 
dosing should be based on actual body weight (ABW). For patients who weigh more than 
120% of their IBW, dosing should be based on the adjusted ideal body weight (AIBW). 
 
 Ideal Body Weight Formulas: 
 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
Females IBW = 45.5 kg + 2.3 kg/inch over 5 feet 
For patients less than 5 feet, subtract 2.3 kg/inch 
 
Adjusted Ideal Body Weight Formula: 
AIBW = IBW + [(0.40) x (Actual BW - IBW)] 


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 Patients will receive standard supportive care measures in SCT as per MSKCC 
institutional practices. 
 
 Post-SCT after discharge patients are followed on a regular basis as per standard of care 
and as deemed necessary by the treating physician through month 3 post-SCT.  This 
applies to all SCT. 
 
 Patients may then be seen and evaluated monthly. 
 
 Patients will be assessed for disease response 3 months after the 1st SCT. 
 
 Patients will receive a 2nd SCT 3 to 6 months after the 1st SCT if the response to the first 
stem cell transplant is less than a VGPR, provided they have fully recovered from the 1st 
SCT. 
 
 
 Recovery from the 1st SCT (i.e., from high-dose melphalan and SCT) is defined by 
achievement of the following clinical criteria: 
➢ 
Mucositis and gastrointestinal symptoms resolved, off hyperalimentation and 
intravenous hydration. 
 
➢ 
Liver and renal function tests within the inclusion criteria for initial autograft. 
 
➢ 
Off antibiotics and Amphotericin B formulations or voriconazole for proven, 
probable or possible infections (defined in accordance with the EORTC/MSG 
criteria).75 Patients who have been treated for an infection but are continuing 
antibiotics, Amphotericin B or voriconazole for prophylaxis are eligible to continue on 
protocol with approval of the Principal Investigator. 
 
➢ 
Completed administration of any radiotherapy. 
 
➢ 
Patients who developed symptoms of cardiac insufficiency after initial enrollment 
will require repeat cardiac testing and must meet the same criteria as for initial study 
entry. 
 
➢ 
Pulmonary function tests must meet initial study entry criteria. 
 
 Patients will be assessed for myeloma response every 3 months beginning 3 months after 
the 2nd SCT for the first 3 years. 
 Beginning 3 months post 1st or 2nd SCT, all patients will receive maintenance L 
(L=10mg/day on Days 1-28 every 28 day cycle, escalated to 15 mg after 3 cycles, if 
tolerated). Lenalidomide will be continued until progression of disease, as tolerated. Dose 
adjustments will follow guidelines detailed in section 9.2. 


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 Beyond 3 years, patients will be observed until progression of disease on a yearly base. 
 
 
 
9.2  Dose Continuation, Modification and Interruption 
 
Patients will be assessed for toxicity at each visit using the NCI CTCAE v3.0 for the grading 
of severity. 
 
 
 
 
 
 
 
 
 
A) Lenalidomide dose reduction steps: 
 
 
 
Table 1: LENALIDOMIDE Dose Reduction Steps 
 
Starting Dose 
25mg daily 
 
Dose Level -1 
20mg daily
 
Dose Level –2 
15mg daily
 
Dose Level –3 
10mg daily
 
Dose Level -4 
5mg daily
 
Dose Level -5 
2.5mg daily
 
Dose Level -6 
2.5 mg every other day
 
B) Dexamethasone dose reduction steps 
 
 
Table 2: Dexamethasone Dose Reduction Steps 
 
Starting Dose 
 
40mg weekly on days 1, 8, 15 and 22 of each 28-day cycle
 
Dose Level -1 
 
20mg weekly on days 1, 8, 15 and 22 of each 28-day cycle
 
Dose Level –2 
 
12mg weekly on days 1, 8, 15 and 22 of each 28-day cycle
 
Dose Level -3 
 
4mg weekly on days 1, 8, 15 and 22 of each 28-day cycle


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Note that for the starting dose level and levels -1and -2, the weekly dexamethasone dose 
could be split over 2 days in the week as detailed in the text and given on days 1, 4, 8, 11, 
15, 18, 22, and 25) 
 
 
 
C) Instruction for initiation of a New Cycle 
 
A new course of treatment may begin on the scheduled Day 1 of a new cycle of initial therapy or 
continued Ld therapy if: 
 The ANC is ≥ 1,000/μL 
 The platelet count is ≥ 50,000/μL 
 Hemoglobin is ≥ 8g/dL 
 
 Any  drug-related  rash,  allergic  reaction/hypersensitivity,  sinus  bradycardia/  other 
cardiac arrhythmia adverse event, dyspepsia, gastritis, gastric or duodenal ulcer or 
confusion or mood alterations that may have occurred has resolved to ≤ grade 1 severity; 
 
 Any other drug-related adverse events that may have occurred have resolved to ≤ grade 
2 severity. 
 
 
A new course of treatment may begin on the scheduled Day 1 of a new cycle of  lenalidomide 
maintenance therapy if: 
 
 The ANC is > 500/μL 
 The platelet count is > 50,000/μL 
 Hemoglobin is > 8g/dL 
 Any drug-related rash, allergic reaction/hypersensitivity, sinus bradycardia/ other cardiac 
arrhythmia adverse event, dyspepsia, gastritis, gastric or duodenal ulcer or confusion or 
mood alterations that may have occurred has resolved to ≤ grade 1 severity; 
 Any other drug-related adverse events that may have occurred have resolved to 
≤ grade 2 severity. 
 
 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly and 
a new cycle of treatment will not be initiated until the toxicity has resolved as described above. 
If the toxicity does not resolve within four weeks, the patient will discontinue the treatment. If 
discontinuation of the treatment occurs before randomization, the patient will be taken off study; 
if after randomization, the patient will remain on study until progression of disease.  If dosing of 
lenalidomide or dexamethasone was halted during the previous cycle and was restarted with a 
one-level dose reduction without requiring an interruption for the remainder of the cycle, then 
that reduced dose level will be initiated on Day 1 of the new cycle. If dosing of lenalidomide or 
dexamethasone was omitted for the remainder of the previous cycle or if the new cycle is 
delayed due to toxicity newly encountered on the scheduled Day 1, then the new cycle will be 
started with dose modifications as described in Section 9.2, Tables 1, 2, 3, 4, 5, and 6. 


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The investigator retains the discretion to delay or hold treatment if safety concerns arise and if 
clinically indicated (e.g. surgical procedure or severe infection). 
 
D) Instructions for dose modifications or interruption during a cycle 
 
See Tables 3, 4, 5, and 6 below for detailed dose modification guidelines. 
 
 
 
Table 3: Dose Modification for Lenalidomide during Initial Therapy or Continued Ld
Therapy 
 
Instructions for Hematologic Toxicities 
 
NCI CTC v3.0 Toxicity 
Grade 
 
Day 2 – 14 of Cycle 
≥ Day 15 of Cycle 
 
Grade 3 neutropenia (ANC 
<1000-500/mm3) associated 
with fever , (temperature ≥ 
38.5oC)  or Grade 4 
neutropenia(<500/mm3) 
 
 
Hold (interrupt dose) 
 
 
Follow CBC weekly 
 
 
If neutropenia has resolved 
to ≤ grade 2 prior to Day 
21, restart at next lower 
dose level and continue the 
cycle 
 
Omit lenalidomide for 
remainder of the cycle 
 
 
G-CSF may be used and the 
dose may be maintained for 
the next cycle at the treating 
physician’s discretion 
 
Thrombocytopenia ≥ Grade 3 
(platelet count < 50,000/mm3) 
 
 
Hold (interrupt dose) 
 
 
Follow CBC weekly 
 
 
If thrombocytopenia 
resolves to ≤ grade 2 prior 
to Day 21, restart at next 
lower dose level and 
continue the cycle 
 
Omit lenalidomide for 
remainder of cycle 
 
Anemia ≥ Grade 3 (Hgb < 
8g/dL 
 
 
Hold (interrupt dose) 
 
 
Follow CBC weekly 
 
 
If anemia resolves to ≤ 
grade 2 prior to Day 21, 
restart at next lower dose 
level and continue the cycle
 
Omit lenalidomide for 
remainder of cycle 
 


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Table 4: Dose Modification for Lenalidomide during Lenalidomide Maintenance 
Therapy 
 
 
 
Instructions for Hematologic Toxicities 
 
NCI CTC v3.0 Toxicity 
Grade 
 
Days 2-28 of Cycle 
 
Grade 3 neutropenia (ANC 
<1000-500/mm3) associated 
with fever , (temperature ≥ 
38.5oC)  or Grade 4 
neutropenia(<500/mm3) 
 
 
Hold (interrupt dose) 
 
 
Follow CBC weekly 
 
 
If neutropenia has resolved to ≤ grade 2 prior to Day 21, restart 
lenalidomide 
 
 
G-CSF may be used and the dose may be maintained for the 
next cycle at the treating physician’s discretion 
 
Thrombocytopenia ≥ Grade 3 
(platelet count < 50,000/mm3) 
 
 
Hold (interrupt dose) 
 
 
Follow CBC weekly 
 
 
If thrombocytopenia resolves to ≤ grade 2 prior to Day 21, 
restart lenalidomide 
 
 
The dose may be maintained for the next cycle at the treating 
physician’s discretion
 
Anemia ≥ Grade 3 (Hgb < 
8g/dL 
 
 
Hold (interrupt dose) 
 
 
Follow CBC weekly 
 
 
If anemia resolves to ≤ grade 2 prior to Day 21, restart 
lenalidomide 
 
 
The dose may be maintained for the next cycle at the treating 
physician’s discretion 
 


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Table 5: Dose Modification for Lenalidomide for Non-Hematologic Toxicities during 
Initial Therapy, Continued Ld Therapy and Lenalidomide Maintenance Therapy 
 
NCI CTC v3.0 Toxicity 
Grade 
 
Day 2 – 14 of Cycle 
≥ Day 15 of Cycle 
 
Non-blistering rash Grade 3 
 
 
Hold (interrupt dose) 
 
 
Follow weekly 
 
 
If the toxicity resolves to ≤ 
grade 1 prior to Day 21, 
restart at next lower dose 
level and continue the cycle
 
Omit lenalidomide for 
remainder of cycle 
 
Non-blistering rash Grade 4 
 
 
Discontinue lenalidomide 
study drug
 
Discontinue lenalidomide 
study drug 
 
Desquamating (blistering) rash 
- any Grade 
 
 
Discontinue lenalidomide 
study drug
 
Discontinue lenalidomide 
study drug 
 
Erythema multiforme ≥ Grade 3 
 
 
Discontinue lenalidomide 
study drug
 
Discontinue lenalidomide 
study drug 
 
Sinus bradycardia/other cardiac 
arrhythmia Grade 2 
 
 
Hold (interrupt) dose 
 
 
Follow at least weekly 
 
 
If toxicity resolves to ≤ 
grade 1 prior to Day 21, 
restart at next lower dose 
level and continue the cycle
 
Omit lenalidomide for 
remainder of cycle 
 
Sinus bradycardia/other cardiac 
arrhythmia ≥ Grade 3 
 
 
Discontinue lenalidomide 
study drug
 
Discontinue lenalidomide 
study drug 
 
Allergic reaction or 
hypersensitivity Grade 2-3 
 
 
Hold (interrupt) dose 
 
 
Follow at least weekly 
 
 
If toxicity resolves to ≤ 
grade 1 prior to Day 21, 
restart at next lower dose 
level and continue the cycle
 
Omit lenalidomide for 
remainder of cycle 
 
Allergic reaction or 
hypersensitivity Grade 4 
 
 
Discontinue lenalidomide 
study drug
 
Discontinue lenalidomide 
study drug 


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Venous thrombosis/embolism ≥ 
Grade 3 
 
 
Hold (interrupt dose) and 
start anticoagulation; restart 
at investigator’s discretion 
(maintain dose level)
 
Omit lenalidomide for 
remainder of cycle 
 
Other non-hematologic toxicity 
assessed as Lenalidomide- 
related ≥ Grade 3 
 
 
Hold (interrupt dose) 
 
 
Follow at least weekly 
 
 
If toxicity resolves to ≤ 
grade 1 prior to Day 21, 
restart at next lower dose 
level and continue the cycle
 
Omit lenalidomide for 
remainder of cycle 
 
Hyperthyroidism or 
hypothyroidism 
 
 
Omit lenalidomide for 
remainder of cycle, 
evaluation etiology, and 
initiate appropriate therapy 
 
 
See Instructions for 
Initiation of a New Cycle 
and reduce the dose of 
lenalidomide by 1 dose 
level 
 
Omit lenalidomide for 
remainder of cycle, 
evaluation etiology, and 
initiate appropriate therapy 
 
 
See Instructions for Initiation 
of a New Cycle and reduce 
the dose of lenalidomide by 1 
dose level 
Table 6: Dose Modification for Dexamethasone 
Dyspepsia 
≥ Grade 3 
 
Hold (interrupt) dexamethasone until ≤ 
grade 1 
 
Reduce dexamethasone by 1 dose 
level and restart 
Gastritis, gastric or duodenal ulcer 
≥ Grade 3 
 
Hold (interrupt) dexamethasone until ≤ 
grade 1 
 
Reduce dexamethasone by 1 dose 
level and restart 
Edema 
≥ Grade 3 
 
Reduce dexamethasone by 1 dose 
level 
Use diuretics, as needed 
Confusion or mood alternations 
≥ Grade 2 
 
Hold (interrupt) dexamethasone until ≤ 
grade 1 
 
Reduce dexamethasone by 1 dose 
level and restart 
Muscle weakness 
≥ Grade 3 
 
Reduce dexamethasone by 1 dose 
level 
 
If symptoms persist, continue to 
reduce dexamethasone by 1 dose level, 
as needed 
Hyperglycemia 
≥ Grade 3 
 
Reduce dexamethasone by 1 dose 
level


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Treat with insulin or oral 
hypoglycemics, as needed 
Acute pancreatitis 
≥ Grade 3 
 
Discontinue dexamethasone and take 
patient off study 
Other non-hematologic toxicity 
assessed as dexamethasone-related 
≥ Grade 3 
 
Hold dexamethasone for remainder of 
cycle 
 
Reduce dexamethasone by 1 dose 
level
 
 
Note that if a dose reduction has occurred for lenalidomide due to toxicity, AND if the 
toxicity has completely resolved to less than grade 1, AND the ANC > 1,000 and the platelet 
count is > 75,0000, dose re-escalation is allowed one step per cycle to a maximum level of 25 
mg during induction or continuous treatment, and 15 mg during maintenance after 
transplantation. 
 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
During the initial 4 cycles of Ld, a patient history, physical exam, Revlimid REMS® 
requirements and toxicity assessments will be performed every month. Complete blood counts 
(CBC) will be performed every two weeks during the first 4 cycles (16 weeks). 
 
For all patients response assessment as described in Section 12 will be performed after every 
cycle of initial Ld therapy and will include a bone marrow biopsy after completion of 4 
cycles, as is shown in Table 7 below. The response of patients who receive SCT will be 
assessed as in Table 7 beginning 3 months after the 1st SCT. Patients not achieving a VGPR 
will undergo a 2nd SCT within 6 months of the 1st SCT and be followed for response as in 
Table 7.  The response of patients who receive tandem SCT will be assessed as in Table 7 
beginning 3 months after the 2nd SCT. 
 
The toxicities of continued Ld and maintenance L will be assessed in both arms. 
 
While on study assessment for adverse events will be done using NCI version 3.0 CTC 
criteria as such events occur and at each monthly follow-up visit. 
 
Patients will be removed from study at the time of progression of disease. The end-of-study 
evaluation will be within 1 month of discontinuation of Ld or of documenting progression of 
disease and will include the assessment as described in Table 7. 
 
All patients will undergo annual assessments of myeloma status as described below in Table 
7. 


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Table 7. Schedule of Study Assessments 
 
Tests and Studies 
Baseline2 
On day 1 of every 
Cycle Before 
Randomization11 
 
 
Every 12 Weeks (+/- 2 
weeks) Once Randomized 
in the first 3 years 
 
 
Annually while 
on study 
And at End of 
 
ASCT10 
Ld only 
Study12 
History and physical exam1 
ECOG PS 
CBC 7 
PT/PTT 
COMP 
TSH 
LDH, B2MG 
SPEP, SIF, Quant Ig, serum 
FLC 
24 hr urine for UPEP, UIF, TP, 
Creatinine clearance 
Pregnancy test3 
Register patient into Revlimid 
REMS® program 
Hepatitis and HIV serologies 
Biopsy of EM disease if 
suspected 
Skeletal survey2a 
MRI spine or PET/CT2a 
Bone marrow assessment2a, 6 
Echocardiogram or MUGA2a 
EKG2a 
PFTs including DLCO2a 
Assess for adverse events and 
review medication diary 5, 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7
X7
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4
X4
X4
X4 
X4 
X 
X 
X 
X 
X 
X 
X 
X13 
X 
X6
X6
X6
X6 
X 
X 
X 
X 
X9
X 
X 
X9 
Prescribe lenalidomide via 
Revlimid REMS® 8 
X 
X 
X8
X8 
1. 
Baseline history and exam must include all prior and current medications, all prior anti- 
cancer therapies, vital signs, height and weight. 
2. 
Within 42 days of enrollment; 
a.   56 days of enrollment 
3. 
Pregnancy tests for females of childbearing potential.  A female of childbearing potential 
(FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 


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consecutive months (i.e., has had menses at any time in the preceding 24 consecutive 
months). 
4. 
Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to 
prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days).  FCBP 
with regular or no menstruation must have a pregnancy test weekly for the first 28 days 
and then every 28 days while on therapy (including breaks in therapy); at discontinuation 
of lenalidomide 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 C: Risks of 
Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods). 
Breaks in therapy include the period after completing the initial 4 cycles of LD through 
stem cell mobilization and collection, randomization and resumption of LD. 
5. 
See APPENDIX B for medication diary 
6. 
See Section 8.0. To be performed at baseline, after first 4 cycles of Ld, 3 months post 
ASCT, annually and at End of Study visit. For transplant patients, the physician may 
forgo the bone marrow biopsy at 12 months from initiation of treatment if the post 
transplant biopsy was performed within 3 months of the annual assessment. For patients 
who have completed 3 years on study bone marrow assessment will be left to MD 
discretion. 
7. 
Complete blood counts (CBC) will be performed every 2 weeks during the first 16 weeks 
and monthly thereafter while on Lenalidomide, with a window of +/- 3 days. 
8. 
Lenalidomide must be prescribed every 4 weeks through and in compliance with the 
Revlimid REMS® program.  Prescriptions must be filled within 7 days.  Consideration 
should be given to prescribing lenalidomide 5 to 7 days in advance of Day 1 of each cycle 
to allow time for required patient and prescriber surveys, and drug shipment to patient. 
Any unused Revlimid® (lenalidomide) should be returned by the patient for disposition in 
accordance with the Revlimid REMS® program. 
9. 
An additional safety assessment will be done approximately 28 days following the last 
dose of lenalidomide. 
10.   Schedule of Assessments to be followed with or without Ld treatment 
11.   These assessments may be done within one week preceding day 1 of every cycle. 
12.   Testing should occur annually +/- 4 weeks;  For patient that have completed 5 years of 
study treatment, annual assessments will be at the MD discretion. 
13.   For patients who have completed 3 years of study treatment Skeletal Survey will be left 
to MD discretion 
 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Toxicity scoring will be done using NCI CTCAE v3.0. 
 
Lenalidomide 


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Thalidomide is teratogenic.  Lenalidomide is a structural analog of thalidomide and it must be 
treated as if it were a known teratogen.  Women of childbearing potential must have a 
negative pregnancy test before and during therapy, and sexually active men and women must 
agree to use adequate contraceptive practices while on study (see Appendix B). 
 
Side-effects include: 
 
Likely 
 
 Fatigue or feeling tired 
 Lack or loss of strength 
 Anemia or a decrease in red blood cells that can cause tiredness (which may require 
transfusion) 
 Thrombocytopenia or a decrease in platelets which can cause you to bruise or bleed easily 
 Leukopenia and neutropenia or a decrease in white blood cells that can make you more 
prone to infections 
 Constipation or difficulty moving your bowels 
 Diarrhea or loose/frequent bowel movements 
 Bone pain 
 Pain in extremity 
 Upper respiratory infection 
 Bronchitis 
 Nasopharyngitis 
 Rhinitis 
 Pneumonia or an infection of the lungs 
 Blurred vision 
 Urinary tract infection 
 Hypokalemia 
 Dysgeusia 
 Hypoesthesia 
 Peripheral neuropathy 
 Tremor 
 Epistaxis or nosebleeds 
 Pharyngitis 
 
 
 
Less Likely 
 Febrile neutropenia 
 Lymphopenia 
 Blood clots 
 Pancytopenia 
 Acute myocardial infarction 


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 Respiratory distress 
 Atrial fibrillation or irregular heartbeat 
 Cardiac failure 
 Cardiac failure congestive 
 Myocardial ischemia 
 Palpitations 
 Tachycardia 
 Chest pain 
 Sepsis or an infection of the blood 
 Bacteremia or presence of bacteria in the blood 
 Dehydration 
 Renal failure (which may require dialysis or may cause swelling) 
 Granulocytopenia 
 Cataracts 
 Abdominal pain 
 Joint pain 
 Back pain 
 Dry mouth 
 Dyspepsia 
 Diabetes mellitus 
 Gastrointestinal motility disorder 
 Toothache 
 Fall 
 Abnormal liver function tests 
 Alanine aminotransferase increased 
 Gamma-glutamyltransferase increased 
 Erysipelas 
 Pyroderma gangrenosum 
 Gastroenteritis 
 Herpes simplex 
 Herpes zoster 
 Influenza 
 Lower respiratory tract infection 
 Sinusitis 
 Hyperglycemia 
 Hyperuricemia 
 Hypocalcemia 
 Hypophosphatemia 
 Hypomagnesemia 
 Hyponatremia 
 Hypothyroidism 
 Iron overload 


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 Muscular weakness 
 Muscle cramps/spasms/pain 
 Cerebrovascular accident 
 Lethargy 
 Paresthesia 
 Nausea 
 Vomiting 
 Chills 
 Weight loss, anorexia 
 Syncope 
 Dizziness 
 Headache 
 Insomnia 
 Pruritus 
 Cough 
 Dyspnea 
 Depression 
 Altered mood 
 Hyperhidrosis 
 Night sweats 
 Hematoma 
 Edema 
 Hypertension 
 Hypotension 
 Peripheral ischemia 
 Thrombosis 
 Peripheral sensory neuropathy 
 
 
The following events have been reported from clinical studies and post-marketing experience: 
 
 Inflammation of the pancreas, which causes increase in pancreatic enzymes (lipase), 
which could result in abdominal pain and discomfort and could require hospitalization 
and intravenous treatment 
 
 Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
 
 Kidney damage which may require dialysis 
 
 Severe skin rash with blisters that can involve the inside of the mouth and other parts of 
the body 
 
 Brain damage which may cause headache, seizure, blindness 


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 Rare treatment-emergent adverse events of angioedema (an allergic skin disease which 
includes small areas of swelling involving the skin and/or the lining of the nose, mouth, 
stomach, and intestines) and serious skin reactions including Stevens-Johnson syndrome 
(SJS) and toxic epidermal necrolysis (TEN).  SJS and TEN are serious allergic skin 
reactions that begin as a rash in one area and later cover more of the body leading to 
separation of the top layer of skin (could be body-wide) which have been reported with 
lenalidomide during commercial use.  These events have the potential to result in death. 
Medical journals have reported patients with allergic skin reaction with thalidomide who 
also developed the same type of reaction with lenalidomide. 
 
 Tumor lysis syndrome (TLS) and tumor flare reaction (TFR) have commonly been 
observed in patients with Chronic Lymphocytic Leukemia (CLL), and uncommonly in 
patients with other lymphomas, who were treated with lenalidomide.  There have been 
rare reports of TLS in patients with Multiple Myeloma (MM) treated with lenalidomide, 
and no reports in patients with Myelodysplastic Syndrome (MDS) treated with 
lenalidomide.  Tumor lysis syndrome is a metabolic complication caused by the break- 
down products of dying cancer cells.  Complications include hyperkalemia (high 
potassium), hyperphosphatemia (high phosphorus), hyperuricemia and hyperuricosuria 
(high uric acid in blood and urine), hypocalcemia (low calcium), and consequent acute 
uric acid nephropathy and acute renal failure (kidney damage).  Tumor lysis syndrome 
can occur with or without treatment of cancer.  Tumor flare reaction is a condition that 
involves any of the following:  increase in size of the cancerous lymph nodes, rash and 
slight fever. 
 
 The rare adverse event of rhabdomyolysis has been seen with lenalidomide treatment. 
This is a serious condition involving destruction of skeletal muscle that can lead to 
kidney damage.  Signs and symptoms include dark, red or cola colored urine, muscle 
tenderness and stiffness, aching (myalgia) or weakness. 
 
 An immune system disorder known as graft versus host disease has been observed in 
subjects who have received lenalidomide in the setting of allo-transplantation. This 
disorder is defined as damage to organs in the body when donor cells attack host organs 
which may cause yellowing of the eyes and skin, itchy dry skin, or muscle weakness. 
 
Hematological Toxicity 
 
Lenalidomide is associated with significant neutropenia (decrease in white blood cells that help 
fight infection) and thrombocytopenia (decrease in platelets that help with blood clotting). You 
will have your blood counts checked frequently when starting treatment with lenalidomide. 
 
Deep Vein Thrombosis and Pulmonary Embolism 
 
Lenalidomide, in combination with dexamethasone, has been associated with an increased 
incidence in thrombotic or thromboembolic events, including DVT, pulmonary embolism, 
thrombosis, and thromboembolism, particularly among patients with MM receiving concomitant 
therapy with an erythropoietic agent and, to a lesser extent, in patients with MDS treated with 
lenalidomide monotherapy. Prophylaxis to reduce the risk of thrombosis should be considered in 


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accordance with study protocols, particularly in patients with additional underlying risk factors, 
such as prior history of a thrombotic event. 
 
Patients with MM taking lenalidomide and dexamethasone, and to lesser extent patients with 
MDS or lymphomas taking lenalidomide monotherapy, as well as patients taking combined oral 
contraceptives or hormone replacement therapy have an increased risk of venous 
thromboembolic events. Physicians should discuss the risk/benefit of contraceptive methods or 
hormonal replacement with their patients. Effective measures to avoid pregnancy must be taken. 
 
Second new cancers 
 
According to researchers, patients with cancer have a higher risk of developing a second new 
cancer when compared to people without cancer.  In clinical studies of newly diagnosed multiple 
myeloma, a higher number of second cancers were reported in patients treated with induction 
therapy (treatment as first step to reducing number of cancer cells) and/or bone marrow 
transplant then lenalidomide for a long period of time compared to patients treated with 
induction therapy and/or bone marrow transplant then placebo (a capsule containing no 
lenalidomide).  Patients should make their doctors aware of their medical history and any 
concerns they may have regarding their own increased risk of other cancers. Cancers such as 
acute myeloid leukemia, B-cell lymphoma, basal cell carcinoma, and squamous cell carcinoma 
of the skin have been seen, as well as tumor flare. 
 
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
 
Reports of progression to acute myeloid leukemia (AML) have been received from MDS studies. 
It is unclear whether lenalidomide indeed increases the risk of AML or if progression merely 
reflects the natural course of the disease.  AML is the rapid multiplication of abnormal cells 
which accumulate in the bone marrow and interfere with the production of normal blood cells. 
AML is a very serious condition which may result in death. 
 
Other Risks 
 
 Patients taking lenalidomide and dexamethasone for multiple myeloma should be careful 
taking drugs that may increase chance of having blood clots (for example drugs to 
increase red blood cell count or hormone replacement therapy). 
 
 Cases of transient (for a short time) liver laboratory abnormalities were reported in 
subjects treated with lenalidomide.  Your doctor will monitor laboratory tests closely and 
recommend treatment interruption until improvement in laboratory results. 
 
 Lenalidomide has been shown to increase the level of digoxin in the blood in some 
patients; please tell your doctor if you are taking digoxin. 
 
Dexamethasone 
 
Side-effects include: 
 
Likely 


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•  Weight gain 
•  Stomach upset or ulcers 
•  Insomnia and mood changes 
•  Fluid retention 
 
 
 
Less likely 
•  Increased blood sugar level 
•  Increased blood pressure 
•  Thinning of the bones 
•  Alterations in hair growth 
•  Decreased muscle mass (myopathy) 
•  Anxiety 
 
Rare but serious 
•  Cataracts 
•  Skin changes 
•  Aseptic necrosis of the hip 
•  Susceptibility to infections 
 
Cyclophosphamide 
 
The maximum dose of cyclophosphamide that can be given without bone marrow 
transplantation is 7 gm/m2 resulting in severe myelosuppression. The pharmacokinetics of 
high dose cyclophosphamide do not differ from that of low doses and there is no evidence that 
enzymes responsible for cyclophosphamide biotransformation and detoxification are 
saturated. 
 
Side-effects include: 
 
Likely 
• A drop in blood counts leading to an increased risk of infection and bleeding 
• Fatigue 
• Hair loss 
• Nausea and vomiting 
• Bleeding from the wall of the bladder 
• Male infertility 
 
Rare but serious 
• Heart inflammation and damage 
• Lung problems 
• Changes in plasma sodium levels 
• Bladder cancer 
• Serious skin reactions 


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• Secondary leukemia 
 
Plerixafor (Mozobil) 
Likely 
• Nausea 
•Vomiting 
•Stomach pain 
•Diarrhea 
•Gas 
•Dizziness 
•Headache 
•Excessive tiredness 
•Difficulty falling asleep or staying asleep 
•Joint pain 
•Pain, redness, hardness, swelling, irritation, itching, bruising, bleeding, numbness, tingling, 
or rash in the place where plerixafor injection was injected 
 
Rare but serious 
•Pain in the left upper part of the stomach or in the shoulder 
•Easy bruising or bleeding 
•Swelling around the eyes 
•Difficulty breathing 
•Hives 
•Fainting 
 
Melphalan 
 
The major systemic toxicity of IV melphalan is bone marrow depression with secondary 
anemia, leukopenia and thrombocytopenia.  This side-effect is exacerbated by prior 
chemotherapy or radiotherapy. 
 
Side-effects include: 
 
Likely 
  Low blood cell counts (bone marrow suppression) that can lead to anemia that requires red 
blood cell transfusions; a decreased number of white blood cells that increases the risk of 
infections and is treated with G-CSF injections and with stem cells; and low platelets that 
increases the risk of bruising and bleeding and is treated with platelet transfusions. 
• Fatigue 
• Nausea, vomiting 
• Hair loss (temporary) 
• Mouth sores 


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• Pain in the mouth requiring pain medicines 
• Pain with swallowing requiring pain medicines 
• Diarrhea and cramping 
 
Less likely 
• Liver damage 
• Allergic reactions (which could make you feel short of breath and/or have a skin rash) 
 
Rare but serious 
• Secondary leukemia 5 to 10 years after exposure 
• Lung damage 
• Blood vessel damage 
• Red blood cell damage due to an immune reaction 
• Death 
Neulasta and Neupogen (G-CSF) 
Side-effects of Neulasta include: 
Likely: 
• Bone pain 
• Exacerbation of preexisting autoimmune disorders 
• Transient and reversible changes in alkaline phosphatase, uric acid and LDH 
• Minor local discomfort associated with subcutaneous injection (temporary) 
Side-effects of Neupogen include: 
Likely 
• Body aches 
• Pain, swelling and redness at the site of injection 
• Bone pain 
• Fever 
• Muscle cramps and pain in your back or legs (relieved by taking Tylenol) 
 
Less likely 
• Inflammation, psoriasis or arthritis may get worse 
 
 
 
Rare but serious 
• Decreased blood pressure and risk of falling 
• Enlargement of the spleen that may lead to rupture 
• Hair thinning 
• Decreased blood platelets which may increase your risk of bruising or bleeding 
• Enlargement of the liver 


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• Allergic reactions 
 
 
 
Stem cell mobilization and collection 
 
Central Venous Catheter 
 
The patients may need to have central venous catheter placed to have stem cells collected. 
Patients with small stature or small arm veins will likely need a catheter placed for stem cell 
collection. A central venous catheter is a flexible sterile tube that will be placed into a large vein 
that runs under your collarbone so that blood can be withdrawn and medications given to you 
more easily and with less discomfort.  This tube is usually placed under local anesthesia.  There 
is a lot of experience with the use of these catheters. 
 
The most common complications are clotting and local infection that sometimes lead to a general 
infection in the blood. Clotting may require the removal of the catheter or treatment of the clot by 
medicines that dissolve blood clots. Infections will be treated with antibiotics and sometimes 
removal of the catheter may be required. There is also a small risk of puncturing the lung at the 
time of the catheter insertion. If this occurs, placement of a temporary chest tube to re-inflate the 
lung may be required and there are no long-term effects once it has resolved. 
 
Side-effects can include: 
 
Likely 
 Clotting 
 Local infection 
 
Less Likely 
 General infection of blood 
 
Rare but serious 
 Puncturing of lung upon catheter insertion 
 
Stem cell mobilization 
 
Patients will have stem cells mobilized. Mobilization with cyclophosphamide is preferred, though 
Mozobil is also allowed. Following chemotherapy for stem cell mobilization, they will receive G-
CSF (filgrastim or pegfilgrastim) as per institutional practices.  Neupogen will help to move the 
stem cells out of the bone marrow into the bloodstream.  Once the number of stem cells in the 
blood stream is high enough, patients will be collected over 2-5 days, while still receiving the 
Neupogen injections. A procedure called leukapheresis will be done to collect the stem cells. 
During this procedure, blood will be collected either through your central venous catheter or 
from a vein in one arm, processed through a machine to remove the white blood cells (stem 
cells), and then the rest of the blood will be returned to the patient through the catheter or a vein 


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in the other arm.  The leukapheresis procedure will last several hours each time.  Patients will be 
asked to sign a separate consent form for the leukapheresis procedure.  Enough stem cells will be 
collected for at least two autologous stem cell transplants. The stem cells will be frozen 
(cryopreserved) until the time when they will be given back to the patient. 
 
Stem cell transplant 
 
A couple of weeks after the stem cells have been collected, patients randomized to stem cell 
transplant will undergo an autologous stem cell transplant using high-dose chemotherapy with 
melphalan given through a central venous catheter.  Since this high-dose treatment destroys the 
normal bone marrow in addition to the myeloma cells, blood stem cells must be given back to the 
patient.  The previously collected stem cells will be thawed and given back to the patient through 
the central venous catheter, similar to a blood transfusion; two days after the patient received the 
melphalan.  On the day after that, the patient will be given Neulasta by injection under the skin. 
Neulasta helps the bone marrow to produce new white blood cells and needs to be given only 
once. After completion of the stem cell transplant, the patient will be followed in the out-patient 
clinic. 
 
At 2 and 4 months after the transplant the response of the patient's myeloma will be evaluated. If 
the patient has not had a greater than 90% reduction in myeloma since the start of treatment, the 
patient will undergo a second stem cell transplant with stem cells already collected. If the patient 
has had a greater than 90% reduction in myeloma, the patient will not have a second stem cell 
transplant. 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Responses will be determined according to the IMWG Response Criteria (that have 
supplanted the older European Group for Blood and Marrow Transplantation (EBMT) 
criteria)76,77 using standard electrophoretic and immunofixation tests of blood and urine for a 
monoclonal protein (M protein), the serum free light chain assay, and the bone marrow 
aspirate and biopsy with immunohistochemical staining.  A Response Review group that 
includes Pathology, Clinical Chemistry, and Hematology will formally score responses. The 
group meets every Tuesday in the early afternoon in Pathology. Research study assistants 
prepare patient data for review and record response decisions. 
 
For all patients, responses will be assessed after every cycle of initial Ld therapy, including a 
bone marrow aspirate and biopsy after the initial 4 cycles. Patients will have response of the 
myeloma assessed with serum protein electrophoresis (SPEP), serum immunofixation (IF) and 
quantitative immunoglobulins, and serum free light chain assay. Patients with non-secretory 
myeloma will have the bone marrow assessment repeated after 4 cycles of initial Ld therapy if 
they have been otherwise clinically stable (i.e., without new lytic lesions, soft-tissue 
plasmacytomas or hypercalcemia). Bone marrow assessment is defined in Section 8.0. 


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For patients randomized to continued Ld, responses will be scored at least every 3 months for 
the first 5 years (and every 6 months beyond 5 years) until progression of disease. For patients 
randomized to SCT, responses will be scored at 3 months after the first and, if performed, 3 
months after the second SCT, including a bone marrow aspirate and biopsy, and then every 3 
months for the first 5 years (and every 6 months beyond 5 years) until progression of disease. 
Testing for response assessment will include serum protein electrophoresis (SPEP), serum 
immunofixation (IF) and quantitative immunoglobulins, and serum free light chain assay. 
Patients with non-secretory myeloma will not have bone marrow studies performed if they 
have been clinically stable as described above. 
 
Annually during the first 5 years after enrollment, and at the time of end-of-study evaluation 
for progression of disease, patients will have response of the myeloma assessed with serum 
protein electrophoresis  (SPEP), serum immunofixation (IF) and quantitative 
immunoglobulins, serum free light chain assay and bone marrow assessment (see table 7 for 
schedule of bone marrow biopsies). Patients in either arm who experience progression of 
disease will undergo end-of-study assessments and will be removed from study to receive 
other therapy in consultation with their physicians. They will continue to be followed for 
overall survival. 
 
Response criteria are as follows for patients with measurable M protein or free light 
chains: Adapted from Durie et al, “International uniform response criteria for multiple myeloma, 
Leukemia 2006; 20:1467-73” [78]. 
 
 Stringent Complete Response (sCR) = CR as defined below plus normal FLC ratio and 
absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. 
 
 Complete Response (CR) = Negative immunofixation on the serum and urine and 
disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. 
 
  Unconfirmed Complete Response (uCR) = All criteria for CR are met, except a bone 
marrow biopsy is not available. 
 
  Near Complete Response (nCR) = Normalization of M-protein as detected by Serum 
Protein Electrophoresis, but M-protein is still detectable by immunofixation. 
 
 Very Good Partial Response (VGPR)  = 90% or greater reduction in serum M- 
component plus urine M-component <100 mg per 24 hours 
 
 Partial Response (PR) = >50% reduction of serum M-protein and reduction in 24-h 
urinary M-protein by >90% or to <200 mg per 24 h. If the serum and urine M-protein are 
unmeasurable, a >50% decrease in the difference between involved and uninvolved FLC 
levels is requires in place of the M-protein criteria. If serum and 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 


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addition to the above listed criteria, if present at baseline, a >50% reduction in the size of soft 
tissue plasmacytomas is also required. 
 
  Stable disease (SD) = Not meeting criteria for sCR, CR, nCR, VGPR, PR, or POD. 
 
  Progressive Disease (PD) = Laboratory/Biochemical Relapse or Progressive Disease: 
Required any one or more of the following: 
o 1) Increase of >25% from lowest response level in: 
▪ a) Serum M-component (the absolute increase must be >0.5 g/dl) and/or 
▪ b) Urine M-component (the absolute increase must be >200 mg/24h 
and/or 
▪ c) The difference between involved and uninvolved FLC levels (only in 
patients without measurable serum and urine M-protein levels). The 
absolute increase must be >10mg/dl and/or 
▪ d) Bone marrow plasma cell percentage (the absolute % must be >10%). 
o 2) Definite development of new bone lesions or soft tissue plasmacytoma or 
definite increase in the size of existing bone lesions or soft tissue plasmacytomas. 
o 3) 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. 
 
 Clinical Relapse (i.e., progressive disease requiring re-treatment or alternate 
treatment) = Clinical relapse or progressive disease requires one or more of: 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB features). It is 
not used in calculation of time to progression or progression-free survival, but is listed here as 
something that can be reported optionally or for use in clinical practice. 
o 1) Development of new soft tissue plasmacytomas or bone lesions. 
o 2) Definite increase in the size of existing plasmacytomas or bone lesions. A 
definite increase is defined as a 50% (and at least 1cm) increase as measured 
serially by the sum of the products of the cross-diameters of the measurable 
lesion. 
o 3) Hypercalcemia (>11.5 mg/dl) [2.65 mmol/l] 
o 4) Decrease in hemoglobin of >2 g/dl [1.25 mmol/l] 
o 5) Rise in serum creatinine by 2 mg/dl or more [177 μmol/l or more] 
 
 
 
Complete response requires confirmation by bone marrow assessment. 
Special considerations in assessing response 
Low-level urinary M proteins may vary from measurement to measurement. For an increase 
in urinary M protein to be considered progression of disease it must be an absolute increase of 
at least 200 mg/day. 


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In quantitative immunoglobulin serum studies, the levels of heavy and light chain are often 
discrepant for technical reasons. If the discrepancy leads to equivocal response values, the 
heavy-chain value will be used since the heavy-chain value is usually a more reliable indicator 
because of its longer half-life and non-renal metabolism. 
 
 
 
In 2% of patients, only the serum free light chain level can be measured as the M protein. In 
these patients, the response criteria are based on changes in the involved free light chain 
levels, and remain statistically the same except that the ratio of kappa-to-lambda in the free 
light chain assay should also be normal in CR. 
 
In 1% of patients, no marker for the M protein exists. In those patients, the response criteria 
are: 
 
  Partial Response (PR) = A reduction of > 50% in marrow plasma cells with no 
progressive disease by skeletal survey or other imaging modality. 
 
  Very good partial response (VGPR) = A reduction of > 90% in marrow plasma cells 
with no progressive disease by skeletal survey or other imaging modality. 
  Complete Response (CR) = Normalization of the bone marrow biopsy, including <5% 
total plasma cells and lack of clonal excess by kappa/lambda staining, with no progressive 
disease by skeletal survey or other imaging modality. 
 
  Stable disease (SD) = An increase in marrow plasma cells by < 25% from baseline or a 
decrease in marrow plasma cells by < 50% from baseline with no progressive disease by 
skeletal survey or other imaging modality. 
 
  Progressive Disease (PD) = An increase in marrow plasma cells of  > 25% from baseline 
after therapy, and/or the occurrence of new hypercalcemia or new lytic lesions by skeletal 
survey or new soft-tissue plasmacytomas. 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Treatment with study drugs is to be discontinued when any of the following occurs: 
  Progressive disease at any point in time during the treatment after at least 1 cycle of Ld 
  Stable disease after 4 initial cycles of Ld 
  Adverse event(s) that, in the judgment of an Investigator, may cause severe or permanent 
harm or which rule out continuation of study drug 
 
  Major violation of the study protocol 
  Withdrawal of consent 
  Patient is lost to follow-up 
  Death 


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  Suspected or confirmed pregnancy 
  If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a 
male study subject during study participation, study drug must be immediately discontinued 
 
Any possible premature discontinuation would be documented adequately with reasons being 
stated, and information would have to be issued according to local requirements (e.g., IRB, 
regulatory authorities, etc.). 
 
 
 
14.0 
BIOSTATISTICS 
 
The protocol has been amended to change the endpoint to 2-year progression free survival (PFS) 
rather than the 2-year response rate. 
 
After initial therapy with 4 cycles of Ld, patients will have stem cells mobilized and collected 
and then will be stratified and randomized as described in Section 15.2 to either SCT or 
continued Ld.  We propose declaring treatment in either arm a success if the 2-year PFS is at 
least 65%.  This 2-year PFS rate was seen in patients receiving induction lenalidomide and 
dexamethasone followed by transplant which is considered the standard of care.  A single stage 
design that differentiates between 2-year PFS rates of 65% and 87% will be used to assess the 
efficacy of the current regimen.  This design has type I and type II error rates both set to 10%. 
A total of 25 patients will be accrued in each arm.  If 20 or more patients are progression free at 
2 years in a treatment arm, then the arm will be considered to have sufficient activity to be of 
interest for further study. In order to reach a number of 50 randomized patients, we estimate that 
approximately 62 patients will need to be enrolled, taking into account patients who do not 
respond or do not tolerate the induction treatment, and who are therefore not randomized. 
 
Results from the two treatment arms will be compared directly to each other using a “pick-the- 
winner” approach.  If both arms are declared desirable by demonstrating at least 20 patients 
progression free by 2 years in their 25 patient cohorts, then the choice of which arm will be 
suitable for further study will be based on the absolute number of responses.  In such a case, if 
the treatment arm with a higher number of responses is also associated with more toxicity, then 
the investigators will weigh both the absolute number of responses and toxicity in selecting 
which arm is suitable for further study.  If the difference in the true response rates of the 
treatment arms is 10% then the chance that the regimen with the higher response rate will be 
picked is over 73%.  If the difference in the true response rates of the treatment arms is 15% then 
the chance that the regimen with the higher response rate will be picked is over 85%. 
 
Progression-free survival from date of randomization will be estimated using the method of 
Kaplan-Meier. Secondary endpoints include CR+VGPR and overall response rates at 2 and 3 
years.  Estimates of the CR+VGPR and overall response rates will be calculated along with 95% 
confidence intervals. 


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15.0 
RESEARCH PARTICIPANT REGISTRATION PROCEDURES 
 
15.1   Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject 
Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
The individual signing the Eligibility Checklist is confirming whether or not the 
participant is eligible to enroll in the study. Study staff are responsible for ensuring that 
all institutional requirements necessary to enroll a participant to the study have been 
completed. See related Clinical Research Policy and Procedure #401 (Protocol 
Participant Registration). 
 
15.2Randomization 
 
Prior to randomization patients will be stratified into high-risk or standard-risk groups 
using the baseline marrow aspirate cytogenetic and FISH findings and the baseline β-2 
microglobulin. The high-risk group includes patients with hypodiploidy by karyotype, 
t(4;14) or del 17p, or  β-2 microglobulin > 3.5. All others are standard risk. 
 
Patients will be randomized to EITHER continued Ld OR SCT within 2 weeks after stem 
cell mobilization and collection are completed using the Clinical Research Database 
(CRDB) by calling the MSKCC PPR registry at 646-735-8000 between the hours of 8:30 
am and 5:30 pm, Monday - Friday.  Randomization will be accomplished by the method 
of random permuted block. 
 
 
16.0 
DATA  MANAGEMENT ISSUES 
 
All patients will be enrolled on protocol at MSKCC. 
 
A Research Study Assistant (RSA) will be assigned to the study at MSKCC.  The responsibilities 
of the RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities of 
the protocol study team. 
 
The data collected for this study will be entered into a secure database (CRDB) by the assigned 
MSKCC RSA.  Source documentation will be available to support the computerized patient 
record. 


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Source Documentation 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should be consistent 
with data entered into CRDB. Relevant source documentation to be maintained throughout the 
study includes: 
o Baseline measures to assess pre–protocol disease status (ex. CT, PSA, bone 
marrow) 
o Treatment records 
o Grade 3-5 toxicities/adverse events not previously submitted with SAE Reports 
o Response designation 
 
16.1 
Quality Assurance 
 
Investigator responsibilities:  Investigator responsibilities are set out in the ICH 
guideline for Good Clinical Practice (GCP) and in the US Code of Federal Regulations. 
 
The Investigator will permit study-related audits by Celgene or its representatives, 
IRB/EC review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct 
access to the facilities where the study took place, to source documents, and to all other 
study documents. 
 
 
The Investigator, or a designated member of the Investigator’s staff, must be available at 
some time during audits to review data and resolve any queries and to allow direct access 
to the subject’s records (e.g., medical records, office charts, hospital charts, and study 
related charts) for source data verification.  The data collection must be completed prior 
to each visit and be made available to the Celgene representative so that the accuracy and 
completeness may be checked. 
 
 
Retention of Records:  All documentation pertaining to the conduct of the study and the 
distribution of the study drug, source documents (original documents, data, and records 
[e.g., hospital records; clinical and office charts; laboratory notes; memoranda; subject’s 
diaries or evaluation checklists; SAE reports, pharmacy dispensing records; recorded data 
from automated instruments; copies or transcriptions certified after verification as being 
accurate copies; microfiches; photographic negatives, microfilm, or magnetic media; x- 
rays; subject files; and records kept at the pharmacy, at the laboratories, and at medico- 
technical departments involved in the clinical study; documents regarding subject 
treatment and study drug accountability; original signed informed consents, etc.]), and all 
IRB correspondence will be retained for at least 2 years after the investigation is 
completed. 
 
16.1.1 Response Review 
 
Since therapeutic efficacy is a stated primary objective, patients’ responses are subject to 
review by MSKCC’s Therapeutic Response Review Committee (TRRC). Radiology, 


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additional lab reports and possibly bone marrow biopsies and/or aspirates will need to be 
obtained for MSKCC TRRC review and confirmation of response assessment. 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001.  The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research.  The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Qualit 
y%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.p 
df 
 
There are several different mechanisms at MSKCC by which clinical trials are monitored for 
data, safety and quality.  There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus there 
are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs.  The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 
 
 
 
16.3 
Regulatory Documentation 
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSKCC Institutional Review Board/Privacy Board (IRB/PB). 
 
16.3.1 Amendments 
Any amendment to this protocol must be agreed to by the MSKCC Principal Investigator and 
reviewed by Celgene Corporation.  Amendments should only be submitted to the IRB after 
consideration of Celgene review.  Each change to the protocol document must be organized 
and approved by the MSKCC IRB/PB. 
 
16.3.2  Additional IRB Correspondence 


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Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant who 
does not meet all the eligibility criteria, pretreatment evaluation, or who requires alteration in 
their study plan. If a deviation from this protocol is proposed for a potential or existing 
participant at MSKCC, approval from the MSKCC IRB/PB is required prior to the action. 
The subject’s medical records will completely describe the deviation from the protocol and 
state the reasons for such deviation. 
 
A protocol violation is anything that occurs with a participant, which deviated from the 
protocol without prior approval from the MSKCC IRB/PB. Protocol violations that are 
identified after they occur should be reported to the MSKCC IRB/PB as soon as possible. 
Protocol violations that are identified after they occur should report to MSKCC IRB/PB as 
soon as possible. 
 
16.3.3 Document maintenance 
 
The MSKCC PI will maintain adequate and accurate records to enable the implementation of 
the protocol to be fully documented and the data to be subsequently verified. 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Participation in this trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to MSKCC’s IRB guidelines. 
 
Patients will be eligible for this trial regardless of gender or racial/ethnic background.  All 
patients must follow the guidelines for pregnancy testing birth control and counseling related 
to the risk of fetal exposure to lenalidomide as outlined in appendix C. 
 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki.  The review of this protocol by the IRB and the 
performance of all aspects of the study, including the methods used for obtaining informed 
consent, must also be in accordance with principles enunciated in the declaration, as well as 
ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of 
Human Subjects and Part 56 Institutional Review Boards. 
 
Potential risks and benefits 
 
The potential risks of this therapy may outweigh the potential benefit in an individual patient. 
The potential risks to patients are related to drug induced adverse effects and are outlined in 
Section 11.0. Appropriate exclusion criteria for patients are listed in Section 6.0: Patient 
Eligibility. Appropriate exclusion of patients with significant organ dysfunction or infection 
will help avoid treatment-related toxicity. Careful monitoring of laboratory parameters and 


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patient symptoms, along with serial assessment for disease recurrence, will be carried out 
routinely in order to minimize the risk of adverse effects during this study. 
 
 
 
Alternatives/Options for treatment 
 
Patients with newly diagnosed standard-risk multiple myeloma have many treatment options. 
Alternative therapy for patients who choose not to enroll on this study include standard 
chemotherapy, autologous or allogeneic stem cell transplant, thalidomide, steroids, 
bortezomib, lenalidomide, some combination of the above, other clinical trials, observation, or 
supportive care. 
 
Costs 
 
Patients will be responsible for all costs related to treatment and complications of treatment, 
including all hospitalizations.  Patients will not be responsible for the cost of lenalidomide. 
 
 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form.  The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form.  A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
 
Celgene affirms the subject’s right to protection against invasion of privacy.  In compliance 
with United States federal regulations, Celgene requires the Investigator to permit their 
representatives and, when necessary, representatives of the FDA or other regulatory 
authorities to review and/or copy any medical records relevant to the study in accordance with 
local laws. 
 
 
 
17.2 Serious Adverse Event (SAE) 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 Death 
 A life-threatening adverse event 
 An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 A congenital anomaly/birth defect 


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 Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. 
Any events that occur after the 30-day period and that are at least possibly related to 
protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of 
Serious Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days 
of the event. The IRB requires a Clinical Research Database (CRDB) SAE report be 
submitted electronically to the SAE Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to  saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to  sae@mskcc.org. 
 
The report should contain the following information: 
 
Fields populated from CRDB: 
 Subject’s initials 
 Medical record number 
 Disease/histology (if applicable) 
 Protocol number and title 
 
Data needing to be entered: 
 The date the adverse event occurred 
 The adverse event 
 The grade of the event 
 Relationship of the adverse event to the treatment (drug, device, or intervention) 
 If the AE was expected 
 The severity of the AE 
 The intervention 
 Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
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58 -
 
 
 
 
 
o Indication if the subject remains on the study 
 If an amendment will need to be made to the protocol and/or consent form 
 If the SAE is an Unanticipated Problem 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office. 
 
17.3 Reporting of SAEs to Study Supporter (Celgene Corporation) 
 
Serious adverse events (SAE) are defined above. The investigator must inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours 
of being aware of that event. The written report must be completed and supplied to Celgene 
by facsimile within 24 hours/1 business day of learning of the event by MSKCC RSA. The 
initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s). Information not available at 
the time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report. The Celgene tracking 
number (RV-MM-PI-0287) and the institutional product number should be included on the 
SAE reports (or on the fax cover letter) sent to Celgene. A copy of the fax transmission 
confirmation of the SAE report to Celgene should be attached to the SAE and retained with 
the patient records. 
 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information: 
 
 
Treatment regimen (dosing frequency, combination therapy) 
 
Protocol description (and number, if assigned) 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics 
 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
The investigator will determine which events are associated with the use of the study drugs. 
For reporting purposes, an AE should be regarded as possibly related to the use of the 
investigational product if the investigator believes: 
 
 
There is a clinically plausible time sequence between onset of the AE and study drug 
administration; and/or 
 
There is a biologically plausible mechanism for the study drug causing or contributing to 
the AE; and 


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IRB Number: 08-121 A(24) 
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The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or 
procedures. 
 
 
 
Follow-up information may be added to a previously submitted report by any of the following 
methods: 
 
 
Adding to the original report and submitting it as follow-up 
 
Adding supplemental summary information and submitting it as follow-up with the 
original form 
 
Summarizing new information and faxing it with a cover letter including subject 
identifiers (i.e. D.O.B. initial, subject number), protocol description and number, if 
assigned, suspect drug, brief adverse event description, and notation that additional or 
follow-up information is being submitted  (The patient identifiers are important so that 
the new information is added to the correct initial report) 
 
17.4 Safety Reports 
 
Reporting SAE to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly associated to 
the drug, and that have not previously been reported in the Investigators brochure, or reference 
safety information document should be reported promptly to the Food and Drug 
Administration (FDA) by telephone or by fax.  Fatal or life threatening SAEs that meet the 
criteria for reporting to the FDA must be reported to the FDA within 7 calendar days after 
awareness of the event.  All other SAEs that meet the criteria for reporting to the FDA must 
be reported to the FDA within 15 calendar days after awareness of the event.  A clear 
description of the suspected reaction should be provided along with an assessment as to 
whether the event is drug or disease related. 
 
Adverse Drug Reaction Reporting 
Toxicity will be scored using CTCAE Version 3.0 for toxicity and adverse event reporting.  A 
copy of the CTCAE Version 3.0 can be downloaded from the CTEP homepage 
(http://ctep.info.nih.gov).  All appropriate treatment areas should have access to a copy of the 
CTCAE Version 3.0.  All adverse clinical experiences, whether observed by the investigator 
or reported by the patient, must be recorded, with details about the duration and intensity of 
each episode, the action taken with respect to the test drug, and the patient’s outcome.  The 
investigator must evaluate each adverse experience for its relationship to the test drug and for 
its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical significance.  If 
any abnormal laboratory result is considered clinically significant, the investigator must 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
 
Pregnancies 


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Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age 
or disease state) of a female subject occurring while the subject is on lenalidomide, or within 
28 days of the subject’s last dose of lenalidomide, are considered immediately reportable 
events. Lenalidomide is to be discontinued immediately. The pregnancy, suspected pregnancy, 
or positive pregnancy test must be reported to Celgene Drug Safety immediately by facsimile 
or email using the Prenancy Initial Report Form. The female subject should be referred to an 
obstetrician-gynecologist, preferable one experienced in reproductive toxicity for further 
evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal 
or abnormal outcome) using the Pregnancy Follow-up Report Form. If the outcome of the 
pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, or 
other appropriate method, within 24 hours of the Investigator’s knowledge of the event using 
the SAE Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form. 
 
In the case of a live “normal” birth, Celgene Drug Safety should be advised as soon as the 
information is available. 
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, the 
male subject taking lenalidomide should notify the Investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately. 
 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ 07922 
Fax: 
(908) 673-9115 
e-mail: 
drugsafety@celgene.com 
 
 
 
Adverse event updates/IND safety reports 
 
Celgene shall notify the Investigator via an IND Safety Report of the following information: 


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IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
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Any AE associated with the use of study drug in this study or in other studies that is 
both serious and unexpected. 
 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
 
The Investigator shall notify his/her IRB promptly of these new serious and unexpected AE(s) 
or significant risks to subjects. 
 
 
 
The Investigator must keep copies of all AE information, including correspondence with 
Celgene and the IRB, on file. 
 
Annual Reports to Celgene 
 
 
This study meets requirements for IND exemption. Annual report must be submitted to 
Celgene for review/approval: 
 
Celgene Corporation 
Attn: Medical Development 
86 Morris Avenue 
Summit, NJ  07901 
Tel: (908) 673-9000 
 
 
All adverse experience reports must include the patient number, age, sex, weight, severity of 
reaction (mild, moderate, severe), relationship to study drug (probably related, unknown 
relationship, definitely not related), date and time of administration of test medications and all 
concomitant medications, and medical treatment provided.   The investigator is responsible 
for evaluating all adverse events to determine whether criteria for “serious” and as defined 
above are present.  The investigator is responsible for reporting adverse events to Celgene as 
described below. 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
 
1.   The nature and objectives, potential risks and benefits of the intended study. 
2.   The length of study and the likely follow-up required. 


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3.   Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4.   The name of the investigator(s) responsible for the protocol. 
5.   The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 
 
 
 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 


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Approval Date: 13-Feb-2018 
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19.0 
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Approval Date: 13-Feb-2018 
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20.0 
APPENDICES 
 
APPENDIX A: 
Schedule of Study Assessments 
APPENDIX B: 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods 
APPENDIX C: 
Diagnostic and Staging Criteria for Multiple Myeloma 
APPENDIX D: 
ECOG Performance Status 
APPENDIX E: 
New York Heart Association Classification Of Cardiac Disease 
APPENDIX F: 
Ideal Body Weight Formulas 
APPENDIX G: 
Abbreviations 
APPENDIX H: 
Appendix is no longer used in the protocol 
APPENDIX I: 
Cockcroft-Gault estimation of CrCl 


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Approval Date: 13-Feb-2018 
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APPENDIX A: SCHEDULE OF STUDY ASSESSMENTS 
 
 
 
Tests and Studies 
Baseline2 
On day 1 of every 
Cycle Before 
Randomization11 
Every 12 Weeks (+/- 2 
weeks) Once Randomized 
in the first 3 years 
Annually 
while on study 
And at End of 
 
ASCT10 
Ld only 
Study12 
History and physical exam1 
ECOG PS 
CBC 7 
PT/PTT 
COMP 
TSH 
LDH, B2MG 
SPEP, SIF, Quant Ig, serum 
FLC 
24 hr urine for UPEP, UIF, TP, 
Creatinine clearance 
Pregnancy test3 
Register patient into Revlimid 
REMS® program 
Hepatitis and HIV serologies 
Biopsy of EM disease if 
suspected 
Skeletal survey2a 
MRI spine or PET/CT2a 
Bone marrow assessment2a, 6 
Echocardiogram or MUGA2a 
EKG2a 
PFTs including DLCO2a 
Assess for adverse events and 
review medication diary 5, 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7
X7
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4
X4
X4
X4 
X4 
X 
X 
X 
X 
X 
X 
X 
X13 
X 
X6
X6
X6
X6 
X 
X 
X 
X 
X9
X 
X 
X9 
Prescribe lenalidomide via 
Revlimid REMS® 8 
X 
X 
X8
X8 
1. 
Baseline history and exam must include all prior and current medications, all prior anti- 
cancer therapies, vital signs, height and weight. 
2. 
Within 42 days of enrollment; For patients who have completed 5 years of study treatment the 
end of study Skeletal Survey is at MD discretion if clinically indicated 
a.   56 days of enrollment 


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Approval Date: 13-Feb-2018 
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3. 
Pregnancy tests for females of childbearing potential.  A female of childbearing potential 
(FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive 
months). 
4. 
Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to 
prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days).  FCBP 
with regular or no menstruation must have a pregnancy test weekly for the first 28 days 
and then every 28 days while on therapy (including breaks in therapy); at discontinuation 
of lenalidomide 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 C: Risks of 
Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods). 
Breaks in therapy include the period after completing the initial 4 cycles of LD through 
stem cell mobilization and collection, randomization and resumption of LD. 
5. 
See APPENDIX B for medication diary 
6. 
See Section 8.0. To be performed at baseline, after first 4 cycles of Ld, 3 months post 
ASCT, annually and at End of Study visit. For transplant patients, the physician may 
forgo the bone marrow biopsy at 12 months from initiation of treatment if the post 
transplant biopsy was performed within 3 months of the annual assessment. For patients 
who have completed 3 years on study bone marrow assessment will be left to MD 
discretion. 
7. 
Complete blood counts (CBC) will be performed every 2 weeks during the first 16 weeks 
and monthly thereafter while on Lenalidomide, with a window of +/- 3 days. 
8. 
Lenalidomide must be prescribed every 4 weeks through and in compliance with the 
Revlimid REMS® program.  Prescriptions must be filled within 7 days.  Consideration 
should be given to prescribing lenalidomide 5 to 7 days in advance of Day 1 of each cycle 
to allow time for required patient and prescriber surveys, and drug shipment to patient. 
Any unused Revlimid® (lenalidomide) should be returned by the patient for disposition in 
accordance with the Revlimid REMS® program. 
9. 
An additional safety assessment will be done approximately 28 days following the last 
dose of lenalidomide. 
10.   Schedule of Assessments to be followed with or without Ld treatment 
11.   These assessments may be done within one week preceding day 1 of every cycle. 
12.   Testing should occur annually +/- 4 weeks; For patient that have completed 5 years of 
study treatment, annual assessments will be at the MD discretion 
13.   For patients who have completed 3 years of study treatment Skeletal Survey will be left 
to MD discretion 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
71 -
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX B: 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 
 
 A male patient taking lenalidomide acknowledges that he understands  that traces of 
lenalidomide have been found in semen, that he understands the potential teratogenic risk 
if engaged in sexual activity with a female of childbearing potential, and that he 
understands the need for the use of a condom even if he has had a vasectomy, if engaged 
in sexual activity with a female of childbearing potential. 
 
Contraception 
 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence from heterosexual 


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IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
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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: 
▪ 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  25 mIU/mL  must  be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below. Patients and physicians must follow pregnancy 
testing requirements as outlined in the Revlimid REMS® program material. 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
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Before starting lenalidomide 
 
Female Patients: 
 
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to 
prescribing lenalidomide.  The first pregnancy test must be performed within 10-14 days prior to 
prescribing lenalidomide and the second pregnancy test must be performed within 24 hours prior 
to prescribing lenalidomide.  The patient may not receive lenalidomide until the Investigator has 
verified that the results of these pregnancy tests are negative. 
 
Male Patients: 
 
Must agree to practice complete abstinence or agree to use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 28 days following lenalidomide 
discontinuation, even if he has undergone a successful vasectomy. 
 
During study participation and for 28 days following lenalidomide discontinuation 
 
Female Patients: 
 
 FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of lenalidomide treatment, including dose interruptions and then every 28 
days throughout the remaining duration of lenalidomide treatment, including dose 
interruptions, at lenalidomide discontinuation, and at Day 28 following lenalidomide 
discontinuation. If menstrual cycles are irregular, the pregnancy testing must occur weekly 
for the first 28 days of lenalidomide treatment, including dose interruptions, and then every 
14 days throughout the remaining duration of lenalidomide treatment, including dose 
interruptions, at lenalidomide discontinuation, and at Day 14 and Day 28 following 
lenalidomide discontinuation. 
 
 At each visit, the Investigator must confirm with the FCBP that she is continuing to use 
two reliable methods of birth control at each visit during the time that birth control is 
required. 
 
 If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide must 
be immediately discontinued. 
 
 Pregnancy testing and counseling must be performed if a patient misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment must be 
temporarily discontinued during this evaluation. 
 
 Females must agree to abstain from breastfeeding during study participation and for at least 
28 days after lenalidomide discontinuation. 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
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Male Patients: 
 
 Must practice complete abstinence or use a condom during sexual contact with pregnant 
females or females of childbearing potential throughout the entire duration of lenalidomide 
treatment, during dose interruptions and for at least 28 days following lenalidomide 
discontinuation, even if he has undergone a successful vasectomy. 
 
 If pregnancy or a positive pregnancy test does occur in the partner of a male study patient 
during study participation, the investigator must be notified immediately. 
 
Additional precautions 
 
 Patients should be instructed never to give lenalidomide to another person. 
 
 Female patients should not donate blood during therapy and for at least 28 days following 
discontinuation of lenalidomide. 
 
 Male patients should not donate blood, semen or sperm during therapy or for at least 28 
days following discontinuation of lenalidomide. 
 
 Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle of 
therapy. 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
75 -
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX C: Diagnostic and Staging Criteria for Multiple Myeloma 
 
 
 
International Staging System (ISS) 
Stage 
Criteria 
I 
β2-microglobulin < 3.5 mg/dL 
 
Serum albumin ≥ 3.5 g/dL 
II 
Neither stage I nor stage II 
III 
β2-microglobulin ≥ 5.5 mg/dL 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
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APPENDIX D: ECOG Performance Status 
 
Grade 
Description 
 
0 
Normal activity, fully active, able to carry on all pre-disease performance 
without restriction 
 
1 
Symptoms, but fully 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) 
 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
 
3 
Capable of only limited self-care, Confined to bed or chair more than 50% of 
waking hours. 
 
4 
Completely disabled.  Cannot carry on any self-care. Totally confined to bed 
or chair. 
5 
Death 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
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APPENDIX E: NEW YORK HEART ASSOCIATION CLASSIFICATION OF 
CARDIAC DISEASE 
The following table presents the NYHA classification of cardiac disease: 
 
 
Class Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 
 
 
 
 
 
 
APPENDIX F:   Ideal Body Weight Formulas 
 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
Females IBW = 45.5 kg + 2.3 kg/inch over 5 feet 
 
For patients less than 5 feet, subtract 2.3 kg/inch 
 
Adjusted Ideal Body Weight Formula: 
AIBW = IBW + [(0.40) x (Actual BW - IBW)] 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
78 -
 
 
 
 
 
 
APPENDIX G 
ABBREVIATIONS 
 
AE 
Adverse event 
AIBW 
Adjusted ideal body weight 
B2M 
Beta-2 microglobulin 
CBC 
Complete blood count 
COMP 
Comprehensive panel (SMA-12) 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXR 
Chest X-ray 
D 
Dexamethasone 
DLCO 
Diffusing Capacity 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
Event-free survival 
EM 
Extramedullary myeloma (soft-tissue disease) 
FISH 
Fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
HCG 
Human chorionic gonadotropin 
IBW 
Ideal body weight 
IL-6 
Interleukin-6 
IRB 
Institutional Review Board ISS
 
International Staging System 
KPS 
Karnofsky Performance Status 
L 
Lenalidomide 
LVEF 
Left Ventricular Ejection Fraction 
MEL 
Melphalan 
MM 
Multiple Myeloma 
MP 
Melphalan and Prednisone MRI
 
Magnetic resonance imaging 
MTD 
Maximum Tolerated Dose 
MUGA 
Multiple Gated Acquisition scan 
NR 
No response 
OS 
Overall Survival 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PFS 
Progression-free Survival 
PFT 
Pulmonary Function Tests 
PLT 
Platelet count 
PR 
Partial response 


Memorial Sloan Kettering Cancer Center
IRB Number: 08-121 A(24) 
Approval Date: 13-Feb-2018 
79 -
 
 
 
 
 
PT/PTT 
Prothrombin time/ Partial thromboplastin time 
SAE 
Serious adverse event 
SCT 
Stem cell transplant 
TBI 
Total body irradiation 
TNF-α 
Tumor necrosis factor alpha 
TSH 
Thyroid-stimulating hormone 
TTP 
Time to progression 
ULN 
Upper limit of the normal range 
VGPR 
Very Good Partial Response 
WBC 
White blood cell count 
 
 
 
 
 
 
Appendix I:  Cockcroft-Gault estimation of CrCl: 
 
 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl): 
(Cockcroft, 1976; Luke 1990) 
 
 
CrCl (mL/min) = 
    (140 –age) x (weight, kg)   
(Males) 
72 x (serum creatinine, mg/dL) 
 
 
CrCl (mL/min) = 
    (140 –age) x (weight, kg)_    x 0.85 
(Females) 
72 x (serum creatinine, mg/dL)