Clinical trial NCT00075829
Conditions: Multiple Myeloma
Keywords: Stage II Multiple Myeloma Stage III Multiple Myeloma Refractory Plasma Cell Neoplasm
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Start date: 2003-12-01; Completion date: 2013-03-01
Enrollment: 710 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study is designed as a Phase III, multi-center trial of tandem autologous transplants versus the strategy of autologous followed by Human Leukocyte Antigen (HLA)-matched sibling non-myeloablative allogeneic transplant. Study subjects will be biologically assigned to the appropriate arm depending on the availability of an HLA-matched sibling. There is a nested randomized phase III trial of observation versus maintenance therapy following the second autologous transplant for patients on the tandem autologous transplant arm.

Detailed description:
Multiple myeloma (MM), characterized by malignant plasma cell proliferation, bone destruction, and immunodeficiency, is a disease with a median age at diagnosis of approximately 65 years. It is responsible for about 1 percent of all cancer-related deaths in Western Countries. Conventional treatments with chemotherapy and radiation therapy are non-curative but improve quality of life and duration of survival. Attempts to cure myeloma through high-dose therapy followed by autografting or allografting have largely failed due to a combination of relapsed disease or transplant related mortality (TRM). High-dose therapy with autologous transplantation is safe and has low TRM (less than 5%), but is associated with a continuing and nearly universal risk of disease progression and relapse. Even so, autologous transplantation is superior to continued conventional chemotherapy. Recent data indicate that tandem autologous transplants are superior to a single procedure. Even with this approach, patients remain at risk of relapse and additional approaches are needed.

DESIGN NARRATIVE:

The overall study design is that of biologic assignment, based on the availability of an HLA-matched sibling, to one of two treatment strategies for MM patients. Patients without an HLA-matched sibling will undergo tandem autologous transplants. Patients with an HLA-matched sibling will undergo an autologous transplant followed by a non-myeloablative allogeneic transplant. In addition, the tandem autologous transplant recipients will be randomized to either observation or one year of maintenance therapy to begin following the second autologous transplant. The large number of MM patients without an HLA-matched sibling enables us to evaluate the role of maintenance therapy following tandem autologous transplants.

Arms: arm 1: One autologous transplant along with a second autologous transplant will be preformed followed by one year of Dexamethasone and Thalidomide maintenance therapy. arm 2: One autologous transplant along with a second autologous transplant will be preformed followed by one year of observation. arm 3: One autologous transplant and one non-myeloablative allogeneic transplant will be preformed and followed by one year of observation.
Interventions: intervention 1: One Autologous Transplant intervention 2: Non-Myeloablative Allogeneic Transplant intervention 3: Second Autologous Transplant intervention 4: Thalidomide intervention 5: Dexamethasone intervention 6: Observation
Intervention descriptions: intervention 1: Melphalan will be administered at a dose of 200 mg/m2. Melphalan will be given in one dose infused on Day -2. Melphalan dose is based on ideal body weight (IBW) for patients who weigh 100-120% of their IBW. All patients will receive an autologous graft with a minimum cell dose of 2.0 x 106 CD34+ cells/kg patient weight. Patients will receive \~5 ug/kg/day of Granulocyte-Colony Stimulating Factor (G-CSF) subcutaneously from Day 5 post-transplant until absolute neutrophil count (ANC) \> 500/mm3 for two days. intervention 2: Upon recovery and at least Day 60 post-autograft, patients with an available 6/6 HLA matched sibling will receive an allograft after non-myeloablative conditioning. Day 0 patients will receive Total Body Irradiation (TBI) 2.0 Gy from a linear accelerator ≤ 20 cGy/min, followed by allogeneic peripheral blood stem cell (PBSC) infusion. Commence cyclosporine (CSA) on Day -3 at 5 mg/kg bid PO for a daily dose of 10 mg/kg/day through Day +84 based on actual body weight. Starting on Day 84, patients in partial or complete response with the absence of graph versus host disease (GVHD) will have CSA tapered so the patient will be off CSA by Day 180. Oral administration of Mycophenolate Mofetil will be at a daily dose of 30 mg/kg/day from the evening of Day 0 until Day 27 post-transplant. intervention 3: Upon recovery from the first autograft, but at least 60 days (preferably between 60-120 days) after the first autograft, patients without an HLA-matched sibling donor will receive a second autograft, also conditioned with melphalan 200 mg/m2. intervention 4: Patients will be initiated on a starting dose of 50 mg/day. The dose will be increased weekly by 50 mg as tolerated to achieve a target dose of 200 mg/day. Patients will be treated for 12 months with thalidomide. intervention 5: Patients will receive dexamethasone at a dose of 40 mg per day during Days 1-4 of each month for 12 months. The first dose of dexamethasone to be given the same day the patient starts thalidomide. intervention 6: One year of observation post-transplants.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
 
A Trial of Tandem Autologous Stem Cell Transplants +/- Post Second 
Autologous Transplant Maintenance Therapy Versus Single 
Autologous Stem Cell Transplant Followed by Matched Sibling Non-
myeloablative Allogeneic Stem Cell Transplant for Patients with 
Multiple Myeloma 
 
 
BMT CTN PROTOCOL 0102 
VERSION 7.0 
 
 
Study Chairpersons 
David Maloney, M.D., Ph.D.1 
Amrita Krishnan, M.D.2 
 
 
Protocol Team 
 
Marian Ewell, Sc.D. 3 
Stephen Forman, M.D. 2 
Sergio Giralt, M.D. 4 
John Klein, Ph.D. 5 
 
Julie Marchick, M.P.H 3 
Marcelo Pasquini, M.D. 5 
Edward Stadtmauer, M.D. 6 
David Vesole, M.D., Ph.D. 5 
 
 
Sponsored by the National Institutes of Health 
National Heart, Lung and Blood Institute 
National Cancer Institute 
 
 
 
1Fred Hutchinson Cancer Research Center 
2City of Hope National Medical Center 
3The EMMES Corporation 
4University of Texas, MD Anderson 
Cancer Center 
5International Blood and Marrow Transplant 
Research, Medical College of Wisconsin 
6University of Pennsylvania Cancer Center 


BMT CLINICAL TRIALS NETWORK 
 
 
Core Study Participants: 
 
Non-Core Study Participants: 
Case Western Reserve University Consortium  
   Oregon Health & Sciences University 
   The Cleveland Clinic Foundation 
   University Hospitals of Cleveland  
   Washington University  
City of Hope National Medical Center, Duarte, CA 
City of Hope Samaritan, Phoenix, AZ 
Dana Farber/Partners Cancer Center 
Duke University Medical Center 
Fred Hutchinson Cancer Research Center  
Memorial Sloan-Kettering Cancer Center 
Stanford Hospital and Clinics 
UCSD/SCRIPPS School of Medicine  
University of Florida College of Medicine 
University of Michigan Medical Center  
University of Minnesota 
University of Nebraska Medical Center 
University of Pennsylvania Cancer Center 
University of Texas, MD Anderson Cancer Center 
 
Baylor College of Medicine, The Methodist Hospital  
   SCT Program 
Baylor Research Institute 
BMT Group of Georgia 
Emory University 
Hackensack University Medical Center 
Indiana BMT at Beech Grove 
Kansas City Blood & Marrow Transplant Program 
Loyola University Medical Center 
Medical College of Wisconsin 
Rocky Mountain Blood and Marrow Transplant Group 
Temple University 
Texas Transplant Institute  
Tufts-New England Medical Center 
Tulane University Hospital 
University of Alabama at Birmingham 
University of Oklahoma Health Sciences Center 
University of Texas Southwestern Medical Center 
University of Wisconsin Hospital & Clinics  
Utah BMT Program 
Vanderbilt University Medical Center 
Virginia Commonwealth University, MCV Hospitals  
 
 
 
SWOG Study Participants: 
DeKalb Medical Center 
Wichita CCOP 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
 Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
 
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PROTOCOL SYNOPSIS – BMT CTN PROTOCOL 0102 
 
A Trial of Tandem Autologous Stem Cell Transplants +/- Post Second Autologous 
Transplant Maintenance Therapy Versus Single Autologous Stem Cell Transplant Followed 
by Matched Sibling Non-myeloablative Allogeneic Stem Cell Transplant for Patients with 
Multiple Myeloma 
 
 
Co-Principal Investigators: 
David Maloney, M.D., Amrita Krishnan, M.D. 
Study Design: 
The study is designed as a Phase III, multi-center trial of tandem 
autologous transplants versus the strategy of autologous followed by 
HLA-matched sibling non-myeloablative allogeneic transplant.  Study 
subjects will be biologically assigned to the appropriate arm depending 
on the availability of an HLA-matched sibling.  There is a nested 
randomized phase III trial of observation versus maintenance therapy 
following the second autologous transplant for patients on the tandem 
autologous transplant arm. 
Primary Objective: 
Post-tandem autologous transplant randomized trial of maintenance 
versus observation: The primary objective is to compare progression-free 
survival at three years between the two arms.  
 
Tandem autologous transplants versus autologous transplant followed by 
HLA-matched sibling non-myeloablative allogeneic transplant: The 
primary objective is to compare progression-free survival at three years 
between the two arms. 
Secondary Objectives: 
Post-tandem autologous transplant randomized trial of maintenance 
versus observation: Secondary objectives are to compare ‘current’ 
myeloma-stable survival, three-year overall survival, and incidence of 
progression. 
Tandem autologous transplants versus autologous transplant followed by 
HLA-matched 
sibling 
non-myeloablative 
allogeneic 
transplant: 
Secondary objectives are to compare ‘current’ myeloma-stable survival, 
three year overall survival, and incidence of progression. 
Tertiary Objectives: 
Post-tandem autologous transplant randomized trial of maintenance 
versus observation: Tertiary objectives include complete remission (CR) 
rate and CR+partial remission (PR) rate at 2 and 12 months after the 
second transplant, time to CR and CR+PR, time to off-study therapy, rate 
of discontinuation of maintenance therapy and duration of maintenance 
therapy, incidence of toxicities Grade  3 according to the CTCAE 
Version 3.0, incidence of infections and quality of life. 
Tandem autologous transplants versus autologous transplant followed by 
HLA-matched sibling non-myeloablative allogeneic transplant: Tertiary 
objectives include CR and CR+PR rates at 2 and 12 months after the 
allograft, time to CR and CR+PR, time to second transplant, time to off-
study therapy, and quality of life. 
Other tertiary outcomes to be evaluated only in the allogeneic transplant 
arm will include incidence of both primary and secondary graft failure 
and incidence and severity of graft-versus-host-disease. 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
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Version 7.0 dated May 15, 2006 
 
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Eligibility Criteria: 
Eligible patients are  70 years of age with Karnofsky scores  70, who 
meet Durie and Salmon criteria for diagnosis of multiple myeloma, who 
have symptomatic MM requiring treatment, who have received at least 
three cycles of systemic therapy and who are within 2-10 months of 
initiation of the initial therapy (this time frame excludes the time for 
mobilization therapy).  Patients must have available an autograft  4.0 x 
106 CD34+ cells/kg patient weight unless it is known prior to enrollment 
that they will receive an allogeneic transplant after their initial 
autologous transplant.  Patients with a consenting, eligible HLA-matched 
sibling must have an autograft  2.0 x 106 CD34+ cells/kg patient 
weight. 
Treatment Description: 
Mobilization therapy will not be specified for the study.  All patients will 
undergo a first autologous peripheral blood stem cell (PBSC) transplant 
with high-dose melphalan (200 mg/m2 IV/day) given on Day –2.  
Melphalan will be given between 2 and 8 weeks after initiation of 
mobilization therapy.   
 
Patients with adequate recovery will receive either a second autologous 
PBSC transplant or a non-myeloablative PBSC allogeneic transplant 
from an HLA-matched sibling.  This post-transplant therapy will be 
initiated at least 60 days (preferably 60-120 days) following the initial 
autologous transplant. 
 
Patients without an HLA-matched sibling donor will be randomized to 
either observation or one year of maintenance therapy with 
dexamethasone and thalidomide to begin following recovery from their 
second autologous PBSC transplant.  This post-transplant therapy will be 
initiated at least 60 days (preferably 60-120 days) following the second 
autologous transplant. 
Quality of Life: 
The FACT-BMT and MOS SF-36 instruments will be used to describe 
the health-related quality of life (HQL) of patients.  A secondary analysis 
will compare the HQL between the two treatment arms.  The self report 
questionnaires will be performed prior to both transplants and post 
second transplant at six months and yearly until three years for English 
and Spanish speaking patients only. 
Accrual Objective: 
Study accrual and analysis is based on the number of standard risk 
multiple myeloma patients with an available HLA-matched sibling 
donor.  A total of 150 standard risk multiple myeloma patients with an 
HLA-matched sibling donor will be accrued.  During this time, it is 
expected that at least 350 standard risk multiple myeloma patients 
without a sibling donor will also be entered on the trial.  In addition, 
high-risk patients with and without HLA-matched siblings will also be 
entered on the trial during the same period. 
Accrual Period: 
The estimated accrual period is three years. 
Study Duration: 
Patients will be followed for at least three years after their second 
transplant. 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
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Version 7.0 dated May 15, 2006 
 
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Outline of Treatment Plan 
 
 
MM meeting eligibility 
criteria including available 
autologous graft of  
 4.0 x 106 CD34+ cells/kg. 
( 2.0 x 106 CD34+ cells/kg 
for auto-allo arm.) 
 
 
 
 
 
High-dose melphalan (200 
mg/m2) + autologous PBSC 
transplant  
( 2x106 CD34+ cells/kg). 
 
 
 
 
 
 
 
Recovered and at least 60 days post-autograft (preferably 
between 60 and 120 days post-autograft). 
 
 
 
 
 
 
Eligible HLA-matched 
sibling donor. 
 
No eligible HLA-matched 
sibling donor. 
 
 
 
 
 
 
Non-myeloablative 
allogeneic PBSC transplant 
(200 cGy TBI, MMF/CSA). 
 
High-dose melphalan (200 
mg/m2) + autologous 
PBSC transplant  
( 2x106 CD34+ cells/kg). 
 
 
 
 
 
 
 
 
 
Observation. 
 
Thalidomide 200 mg/day 
PO for one year.  
Dexamethasone 40 mg/day 
Days 1-4 for 12 months.  
Maintenance to begin at 
least 60 days post second 
autograft (preferably 
between 60 and 120 days). 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
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Version 7.0 dated May 15, 2006 
 
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TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE .............................................................................. 1-1 
1.1 
Background ........................................................................................................................ 1-1 
1.2 
Rationale for Study ............................................................................................................. 1-2 
1.2.1 
High-dose Melphalan as a Treatment for MM ..................................................................... 1-2 
1.2.2 
Tandem Autologous Transplantation ................................................................................... 1-3 
1.2.3 
Allografting in MM............................................................................................................. 1-4 
1.2.4 
Mixed Chimerism ............................................................................................................... 1-6 
1.2.4.1 
Pre-clinical studies .............................................................................................................. 1-6 
1.2.4.2 
Preliminary clinical studies ................................................................................................. 1-6 
1.3 
Post Autologous Transplant Dexamethasone and Thalidomide ............................................ 1-8 
1.4 
Study Approach and Treatment ......................................................................................... 1-10 
2. 
STUDY DESIGN............................................................................................................... 2-1 
2.1 
Study Overview .................................................................................................................. 2-1 
2.2 
Hypothesis and Specific Objectives ..................................................................................... 2-1 
2.2.1 
Hypotheses ......................................................................................................................... 2-1 
2.2.2 
Study Objectives ................................................................................................................. 2-1 
2.2.2.1 
Tandem autologous transplants versus tandem autologous transplants + maintenance therapy 
objectives............................................................................................................................ 2-1 
2.2.2.2 
Tandem autologous transplants versus autologous transplant + non-myeloablative allogeneic 
transplant objectives............................................................................................................ 2-2 
2.3 
Patient Eligibility ................................................................................................................ 2-2 
2.3.1 
Initial Patient Eligibility Criteria ......................................................................................... 2-2 
2.3.2 
Initial Patient Exclusion Criteria.......................................................................................... 2-3 
2.3.3 
Patient Eligibility Criteria for Second Transplant................................................................. 2-4 
2.3.4 
Patient Eligibility Criteria for Tandem Autologous Transplant Patients to Begin Maintenance 
Therapy .............................................................................................................................. 2-4 
2.3.5 
Allograft Donor Eligibility Criteria ..................................................................................... 2-5 
2.3.6 
Allograft Donor Exclusion Criteria...................................................................................... 2-5 
2.3.7 
Timing of Biologic Assignment and Randomization............................................................ 2-5 
2.4 
Study Treatments ................................................................................................................ 2-6 
2.4.1 
Cytoreductive Therapy and First Autologous Stem Cell Transplantation.............................. 2-6 
2.4.1.1 
Allopurinol ......................................................................................................................... 2-7 
2.4.1.2 
Melphalan administration .................................................................................................... 2-7 
2.4.1.3 
Peripheral blood stem cell infusion...................................................................................... 2-8 
2.4.1.4 
G-CSF ................................................................................................................................ 2-8 
2.4.1.5 
Radiation therapy ................................................................................................................ 2-8 
2.4.2 
Second Autologous Transplant for Patients without an HLA-matched Sibling ..................... 2-9 
2.4.3 
One Year of Dexamethasone and Thalidomide Maintenance Therapy or Observation for 
Patients without an HLA-matched Sibling ........................................................................... 2-9 
2.4.3.1 
Thalidomide........................................................................................................................ 2-9 
2.4.3.2 
Dexamethasone ................................................................................................................. 2-10 
2.4.3.3 
Dose Modifications for dexamethasone and thalidomide ................................................... 2-10 
2.4.3.4 
Minimal maintenance doses of thalidomide and dexamethasone ........................................ 2-16 
2.4.4 
Allogeneic Non-myeloablative Transplantation for Patients with an HLA-matched Sibling2-17 
2.4.4.1 
Conditioning regimen ....................................................................................................... 2-17 


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2.4.4.2 
Peri non-myeloablative allogeneic transplant immunosuppression ..................................... 2-18 
2.4.4.3 
Management of post-allotransplant immunosuppression in the setting of disease progression ... 
 ......................................................................................................................................... 2-19 
2.4.4.4 
Management of post-allotransplant immunosuppression in the setting of low or decreasing 
donor peripheral blood t-cell chimerism ............................................................................ 2-19 
2.4.5 
Collection and Infusion of Donor PBSC for Non-myeloablative Transplantation ............... 2-19 
2.4.5.1 
G-CSF administration to donors ........................................................................................ 2-19 
2.4.5.2 
PBSC collection and evaluation ........................................................................................ 2-20 
2.4.5.3 
PBSC infusion .................................................................................................................. 2-20 
2.5 
Supportive Care ................................................................................................................ 2-21 
2.5.1 
Post Autologous Transplantation(s) ................................................................................... 2-21 
2.5.1.1 
Bisphosphonates ............................................................................................................... 2-21 
2.5.1.2 
Prophylaxis against infections ........................................................................................... 2-21 
2.5.1.3 
Growth factors .................................................................................................................. 2-21 
2.5.1.4 
Blood products.................................................................................................................. 2-21 
2.5.1.5 
Immunizations .................................................................................................................. 2-22 
2.5.2 
Post-initiation of Dexamethasone and Thalidomide ........................................................... 2-22 
2.5.2.1 
Coumadin ......................................................................................................................... 2-22 
2.5.3 
Post Non-myeloablative Allogeneic Transplant ................................................................. 2-23 
2.5.3.1 
Bisphosphonates ............................................................................................................... 2-23 
2.5.3.2 
Prophylaxis against infections ........................................................................................... 2-23 
2.5.3.3 
Post-transplant growth factors ........................................................................................... 2-23 
2.5.3.4 
Blood products.................................................................................................................. 2-23 
2.5.3.5 
Post-transplant immunization schedule .............................................................................. 2-24 
2.5.3.6 
Post-transplant donor cellular infusions (DCI) ................................................................... 2-24 
2.6 
Participant Risks ............................................................................................................... 2-24 
2.7 
Therapy Toxicities ............................................................................................................ 2-24 
2.7.1 
Total Body Irradiation (TBI) ............................................................................................. 2-24 
2.7.2 
Mycophenolate Mofetil (MMF) ........................................................................................ 2-25 
2.7.3 
Dexamethasone ................................................................................................................. 2-25 
2.7.4 
Thalidomide...................................................................................................................... 2-25 
2.7.5 
G-CSF .............................................................................................................................. 2-26 
2.7.6 
Cyclosporine ..................................................................................................................... 2-26 
2.7.7 
High-dose Melphalan ........................................................................................................ 2-27 
3. 
STUDY ENDPOINTS AND DEFINITIONS ................................................................... 3-1 
3.1 
Definition of High Risk vs. Standard Risk Myeloma ........................................................... 3-1 
3.1.1 
High Risk Myeloma Patients ............................................................................................... 3-1 
3.1.2 
Standard Risk Myeloma Patients ......................................................................................... 3-1 
3.2 
Definition of Disease Status ................................................................................................ 3-1 
3.3 
Relapse or Progressive Disease (PD) ................................................................................... 3-3 
3.3.1 
Relapse ............................................................................................................................... 3-3 
3.3.2 
Progressive Disease (PD) .................................................................................................... 3-3 
3.4 
Primary Endpoint to be Compared Between Tandem Autologous Transplant Recipients 
Randomized to Maintenance Therapy vs. Observation Following Their Second Transplant . 3-4 
3.4.1 
Three Year Progression Free Survival (PFS) ....................................................................... 3-4 
3.5 
Secondary Endpoints to be Compared Between Tandem Autologous Transplant Recipients 
Randomized to Maintenance Therapy vs. Observation Following Their Second Transplant . 3-4 
3.5.1 
Current Myeloma-Stable Survival ....................................................................................... 3-4 
3.5.2 
Three Year Overall Survival ............................................................................................... 3-4 
3.5.3 
Incidence of Progression ..................................................................................................... 3-4 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
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Version 7.0 dated May 15, 2006 
 
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3.6 
Tertiary Endpoints to be Compared Between Tandem Autologous Transplant Recipients 
Randomized to Maintenance Therapy vs. Observation Following Their Second Transplant . 3-5 
3.6.1 
CR and CR+PR Rates at Two and Twelve Months .............................................................. 3-5 
3.6.2 
Time to CR and CR+PR ...................................................................................................... 3-5 
3.6.3 
Time to Off-study Therapy.................................................................................................. 3-5 
3.6.4 
Quality of Life .................................................................................................................... 3-5 
3.6.5 
Incidence of Toxicities Grade  3 According to the CTCAE Version 3.0 ............................. 3-6 
3.6.6 
Incidence of Infections ........................................................................................................ 3-6 
3.6.7 
Drop Out Rate From Maintenance Therapy ......................................................................... 3-6 
3.6.8 
Duration of Maintenance Therapy ....................................................................................... 3-6 
3.7 
Primary Endpoint to be Compared Between Tandem Autologous Transplant Recipients and 
Tandem Autologous + Non-myeloablative Matched Sibling Allogeneic Transplant Recipients
 ........................................................................................................................................... 3-6 
3.7.1 
Three-Year Progression Free Survival (PFS) ....................................................................... 3-6 
3.8 
Secondary Endpoints to be Compared Between Tandem Autologous Transplant Recipients 
and Tandem Autologous + Non-myeloablative Matched Sibling Allogeneic Transplant....... 3-7 
3.8.1 
Current Myeloma-Stable Survival ....................................................................................... 3-7 
3.8.2 
Three-Year Overall Survival ............................................................................................... 3-7 
3.8.3 
Incidence of Progression ..................................................................................................... 3-7 
3.9 
Tertiary Endpoints to be Compared Between Tandem Autologous Transplant Recipients and 
Tandem Autologous + Non-myeloablative Matched Sibling Allogeneic Transplant ............. 3-7 
3.9.1 
CR and CR+PR Rates at Two and Twelve Months .............................................................. 3-7 
3.9.2 
Time to CR and CR+PR ...................................................................................................... 3-7 
3.9.3 
Time to Second Transplant.................................................................................................. 3-8 
3.9.4 
Time to Off-study Therapy.................................................................................................. 3-8 
3.9.5 
Quality of Life .................................................................................................................... 3-8 
3.10 
Tertiary Endpoints that Only Apply to Allograft Recipients................................................. 3-8 
3.10.1 
Incidence of Primary and Secondary Graft Failure............................................................... 3-9 
3.10.2 
Incidence and Severity of Graft-Versus-Host-Disease (GVHD) ........................................... 3-9 
3.11 
Safety Monitoring Endpoints............................................................................................... 3-9 
3.11.1 
Treatment-related Mortality ................................................................................................ 3-9 
3.11.2 
Regimen-related Toxicity .................................................................................................... 3-9 
4. 
PATIENT ENROLLMENT AND EVALUATION ......................................................... 4-1 
4.1 
Enrollment Procedures ........................................................................................................ 4-1 
4.1.1 
Screening and Eligibility Procedures ................................................................................... 4-1 
4.1.2 
SWOG Patient Registration Procedures ............................................................................... 4-2 
4.2 
Study Monitoring ................................................................................................................ 4-2 
4.2.1 
Follow-up Schedule ............................................................................................................ 4-2 
4.2.2 
Weekly GVHD Monitoring Post Non-myeloablative Allogeneic Transplant ........................ 4-6 
4.2.3 
Adverse Event Reporting .................................................................................................... 4-6 
4.2.4 
Patient Assessments ............................................................................................................ 4-6 
4.2.4.1 
Evaluations prior to the first autologous transplantation ....................................................... 4-7 
4.2.4.2 
Post first autologous transplant ............................................................................................ 4-8 
4.2.4.3 
Evaluations prior to the second transplant (autologous or matched-sibling allogeneic) ......... 4-8 
4.2.4.4 
Post second transplant evaluations....................................................................................... 4-9 
4.2.4.5 
Prior to initiation of dexamethasone + thalidomide for tandem autologous transplant patients 
randomized to maintenance therapy post second autologous transplant .............................. 4-11 
4.2.4.6 
Post initiation of dexamethasone + thalidomide for tandem autologous transplant patients 
randomized to maintenance therapy post second autologous transplant .............................. 4-12 
4.2.5 
Required Observations for Donor ...................................................................................... 4-12 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
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Version 7.0 dated May 15, 2006 
 
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5. 
STATISTICAL CONSIDERATIONS.............................................................................. 5-1 
5.1 
Study Overview .................................................................................................................. 5-1 
5.1.1 
Accrual ............................................................................................................................... 5-1 
5.1.2 
Biologic Assignment and Randomization ............................................................................ 5-2 
5.1.3 
Intention-to-Treat Principle ................................................................................................. 5-2 
5.1.4 
Primary Endpoint ................................................................................................................ 5-3 
5.2 
Statistical Issues Related to Non-randomized Assignment ................................................... 5-3 
5.2.1 
Selection of Patients to Screen for the Study........................................................................ 5-3 
5.2.2 
Compliance with Biological Assignment ............................................................................. 5-3 
5.2.3 
Effects of Clinical Center .................................................................................................... 5-4 
5.2.4 
Effects of Disease Risk Status ............................................................................................. 5-4 
5.2.5 
Effects of Baseline Factors .................................................................................................. 5-5 
5.2.6 
Effects of Time to Recovery from the Auto transplant ......................................................... 5-5 
5.3 
Sample Size and Power Calculations ................................................................................... 5-6 
5.4 
Statistical Stopping Guidelines ............................................................................................ 5-8 
5.4.1 
Statistical Stopping Guideline for Monitoring Accrual of Patients on the Auto-Allo Arm .... 5-9 
5.4.2 
Guidelines for Safety Monitoring ...................................................................................... 5-10 
5.5 
Analysis Plan .................................................................................................................... 5-14 
5.5.1 
Analysis of the Primary Endpoint ...................................................................................... 5-15 
5.5.2 
Analysis of Secondary Endpoints ...................................................................................... 5-15 
5.5.3 
Analysis of Tertiary Endpoints .......................................................................................... 5-16 
5.5.4 
Analyses within Each Treatment Arm ............................................................................... 5-19 
 
 
LIST OF APPENDICES 
 
APPENDIX A 
DURIE AND SALMON CRITERIA FOR THE INITIAL DIAGNOSIS AND 
STAGING OF MULTIPLE MYELOMA 
APPENDIX B  
CONSENT FORMS 
APPENDIX C  
LABORATORY PROCEDURES 
APPENDIX D 
SYSTEM FOR THALIDOMIDE EDUCATION AND PRESCRIBING SAFETY 
(S.T.E.P.S.™) AND DOSAGE AND ADMINISTRATION PROCEDURES 
APPENDIX E  
HUMAN SUBJECTS 
APPENDIX F  
REFERENCES 
 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
 Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
 
1-1
CHAPTER 1 
 
 
1. BACKGROUND AND RATIONALE 
 
1.1 
Background 
 
Multiple myeloma (MM), characterized by malignant plasma cell proliferation, bone destruction 
and immunodeficiency, is a disease with a median age at diagnosis of approximately 65 years.  It 
is responsible for about 1 percent of all cancer-related deaths in Western Countries1.  
Conventional treatments with chemotherapy and radiation therapy are non-curative but improve 
quality of life and duration of survival.  Attempts to cure myeloma through high-dose therapy 
followed by autografting or allografting have largely failed due to a combination of relapsed 
disease or transplant related mortality (TRM).  High-dose therapy with autologous 
transplantation is safe and has low TRM (< 5%), but is associated with a continuing and nearly 
universal risk of disease progression and relapse.  Even so, autologous transplantation is superior 
to continued conventional chemotherapy2.  Recent data discussed below indicate that tandem 
autologous transplants are superior to a single procedure3.  Even with this approach, patients 
remain at risk of relapse and additional approaches are needed. 
 
In contrast, results of allografting and donor lymphocyte infusions (DLI) for relapsed myeloma 
suggest that alloimmune reactions may provide long-term disease control.  Unfortunately, 
conventional approaches to allografting are complicated by 40% TRM4,5.  In the experience at 
Fred Hutchinson Cancer Research Center (FHCRC), Day 100 TRM after conventional 
allografting exceeded 50% in patients  50 years of age6.  The inability of myeloma patients to 
tolerate allografting may relate to an inability of generally elderly and immune suppressed 
patients to tolerate the combined effects of high-dose therapy and allografting in a single 
procedure.  
 
Recent data from a Phase II study using a two-step approach where high-dose melphalan and 
autologous stem cell transplantation was followed by a non-myeloablative allogeneic transplant 
show that donor engraftment can be established with a conditioning regimen of low dose total 
body irradiation (TBI) (200 cGy), cyclosporine (CSA) and mycophenolate mofetil (MMF) 
combined with peripheral blood stem cell (PBSC) allografting.  This study demonstrated that 
allografting can be safely and effectively performed if the high-dose regimen is administered 
separate from the allografting procedure.  In this study, approximately 60% of the patients 
achieved complete remission (CR) with an overall-survival of approximately 85% at one year7.  
One of the objectives of the study was to reduce TRM at three months to < 20%.  This was 
achieved, as only 13% of patients experienced treatment-related mortality. 
 
Another approach to improving autologous transplantation results is the use of post-transplant 
interventions, such as interferon and, more recently, antiangiogenesis agents such as thalidomide.  
Dexamethasone, an effective agent in myeloma, has been combined with thalidomide resulting in 
synergy and no unexpected toxicities8.  Initial results suggest the combination of thalidomide and 
dexamethasone is well tolerated after autologous transplantation9. 
 


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Based on these early encouraging results, the following study is planned.  All patients will 
undergo autologous stem cell transplantation after a conditioning regimen consisting of high-
dose melphalan at a dose of 200 mg/m2.  Starting 60 days or more post-transplant, patients will 
receive either a second autologous transplant or a non-myeloablative allogeneic transplant, based 
on the availability of an HLA-matched sibling donor.  Patients with an HLA-matched sibling 
donor will receive an allograft after conditioning with 200 cGy TBI and then receive post-
transplant immunosuppression with CSA and MMF.  Patients without an eligible HLA-matched 
sibling donor will receive a second autologous transplant after conditioning with melphalan 200 
mg/m2.  Patients who receive tandem autografts will also be randomized to observation or to 
receive post-transplant treatment with thalidomide 200 mg/day for twelve months after their 
second transplant and dexamethasone 40 mg/day on Days 1-4 for 12 months after their second 
transplant.  This approach will provide the proven benefit of high-dose therapy to all patients 
while exploring the long-term benefits/risks of allografting with non-myeloablative conditioning 
and the use of post autologous transplant treatment with dexamethasone and thalidomide.  
 
1.2 
Rationale for Study 
 
1.2.1 High-dose Melphalan as a Treatment for MM 
 
Until a decade ago, the treatment of MM had not significantly improved since the introduction of 
melphalan and prednisone, despite the introduction of several combination chemotherapy 
protocols.  Melphalan-prednisone remained the standard chemotherapy regimen, with response 
rates between 40% to 60%, CR rates of less than 10%, and a median survival of about three 
years10, 11.  Furthermore, none of these therapeutic interventions resulted in cures for patients 
with MM.  Pioneering studies by McElwain et al12, 13 demonstrated that treatment with high 
doses of melphalan could induce responses in refractory myeloma.  The responses were brief and 
were complicated by a high toxic death rate, ranging from 17%-31% in the initial series13, 14.  
Nonetheless, these results stimulated interest in further studies to address the role of high-dose 
therapy in myeloma.  The demonstration by Barlogie et al14, 15 that the toxicity of high-dose 
melphalan could be decreased by autologous bone marrow transplantation and that the addition 
of TBI increased response rates led to wider application of high-dose therapy using autologous 
bone marrow support initially and, more recently, PBSC support.   
 
From the multiple studies reporting the use of melphalan, it is clear that there is a steep dose-
response relationship for this drug in MM.  In a cohort of 47 patients with refractory MM, 
melphalan 100 mg/m2 led to a 46% response rate with 6% CR but with a disease-free survival 
that was shorter than after melphalan 140 mg/m2 or 200 mg/m2, 19.  Doses up to 280 mg/m2 have 
been used in myeloma and other malignancies14, 15, 16.  In a recent Phase I trial involving MM 
patients17, melphalan at a dose of 200 mg/m2 was estimated to be the maximum tolerated dose 
for two cycles administered within 90 days.  
 
With bone marrow or PBSC support following high-dose melphalan, the toxic death rate is now 
less than 3% in most studies18, 19.  At a dose of 200 mg/m2, high response rates in both untreated 
and previously treated patients are reported 16, 20, 20, 21, 22, 23, 24.  
 


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In addition, recent data indicate melphalan 200 mg/m2 is less toxic but equally effective as 
melphalan with TBI25, 26.   
 
1.2.2 Tandem Autologous Transplantation 
 
Recently, Barlogie et al showed the feasibility of tandem autologous PBSC transplants using 
melphalan 200 mg/m2 for the first transplant and melphalan 200 mg/m2 (79 patients) or 
melphalan 140 mg/m2 plus TBI (1,125 cGy) (10 patients) for the second transplant.  Of 123 
patients, 87% completed one autologous transplantation and 76% completed a tandem second 
autologous transplantation by 7.5 and 13 months, respectively, with a median interval between 
autologous transplantations of 4.5 months.  Patients were hospitalized a median of 14 days with 
the first autologous transplantation and only six days with the second.  Cumulative TRM during 
the first 12 months was 4%27.  Barlogie reported 40% CR to tandem transplants and a median 
event-free survival of 49 months, based on an intent to treat analysis in this single center 
experience.  Overall, these results suggest that doses of melphalan of 140 mg/m2 or higher, 
supported by hematopoietic stem cell infusion, provide a high-dose anti-myeloma regimen with 
acceptable toxicity28.   
 
For responding patients, high-dose therapy followed by autologous PBSC rescue has been shown 
to be superior to continued treatment with conventional chemotherapy, leading to the widespread 
use of autologous transplantation for myeloma patients up to and beyond the age of 7029, 30.  
Recently, several studies, including preliminary data from the IFM94 trial, suggest that tandem 
autologous transplants are superior to a single high-dose treatment 3, 31.  In the IFM study, the 
progression free and overall survival curves separated after 3 years with improved disease free 
and overall survival at 6 years post-transplantation for the group that received tandem autologous 
transplants compared to those receiving single transplants.  Overall the median event free 
survival was 31 versus 37 months, 6-year event free survival was 19% versus 28% and 6-year 
overall survival 26% versus 46% for single versus tandem transplants, respectively.  The interim 
results of the “Bologna 96” trial presented at the 2002 ASH meeting further support the above 
findings regarding tandem transplants.  In this randomized trial of single versus tandem 
autologous transplants as part of front line therapy for MM, both remission duration (44 months 
versus 27 months, p=0.005) and median event-free survival (44 months versus 27 months, 
p=0.05) were superior in the tandem autologous transplant arm32.  While the conditioning 
regimens were used in these trials differ, as discussed above, subsequent randomized trials 
comparing melphalan/TBI to melphalan alone have demonstrated that single agent melphalan at 
200 mg/m2 has emerged as the preferred conditioning for autologous transplantation33.  While 
TRM rates observed in these studies are low, patients continued to remain at risk for disease 
relapse and progression, with only a minority of patients remaining disease free at six years. 
 
The cause of relapse following autologous transplantation is either from residual myeloma cells 
left in the patient following conditioning or the re-infusion of myeloma cells with the autologous 
grafts.  CD34+ selection of PBSC and other immune based selection methods have been used to 
decrease myeloma cell contamination of PBSC or bone marrow.  On average, a 2-4 log depletion 
of neoplastic cells from PBSC grafts is reported by different groups34, 35.  Unfortunately, 
randomized studies have not shown that purging the graft improves transplant results or 
decreases the risk of relapse.  Results of a recent randomized trial comparing the use of CD34+ 


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selected versus unselected PBSC in autologous transplantation for patients with MM do not 
show a survival difference to date36.  In addition, more cells must be mobilized and collected 
because of inefficiencies in the cell selection procedure, making the collection procedure more 
difficult.  Lastly, the non-specific removal of other immune cells, including T cells, monocytes, 
macrophages and natural killer cells results in increased immunodeficiency and may lead to 
infections, particularly early CMV reactivation.  In a study at the FHCRC, patients receiving 
CD34+ selected PBSC autografts were found to have increased risk of infections37.  Of three 
MM patients, one died as a result of CMV and polymicrobial pneumonitis at Day 40 post-
transplant.  A second patient developed CMV pneumonitis and required gancyclovir therapy.  
Both of these patients were CMV sero-positive pre-transplant.  A third patient, who was CMV 
sero-negative, developed CMV related infection at approximately three months post-transplant.  
For these reasons, the study described in this protocol will use unmodified PBSC for 
autografting.  
 
1.2.3 Allografting in MM 
 
Although high-dose therapy and autografting result in increased response rates and prolonged 
overall survival29, it is also clear that this approach is seldom curative, since initial responses are 
almost uniformly followed by relapse18, 19.  The inability of autografting to achieve cure for 
patients with MM is emphasized by the update of the IFM 90 trial demonstrating six-year post-
diagnosis event free survival after a single autologous transplant of only 24%38.  Data from the 
IFM94 trial comparing single versus tandem autologous transplants shows a 6-year event free 
survival of 19% in the single transplant arm compared with 28% in patients receiving tandem 
autologous transplants3, 31.  Additional strategies and new approaches are needed.   
 
Despite the potential advantages of graft-versus-tumor immune responses and a tumor free 
source of stem cells, conventional high-dose conditioning with allogeneic bone marrow or PBSC 
transplantation is infrequently used for MM due to a high TRM risk.  When used, it is generally 
limited to younger patients, in contrast to the advanced age profile of MM patients at diagnosis.  
In addition, the poor clinical condition of many patients and the relatively limited availability of 
HLA-compatible donors further limits this approach.  A recent publication analyzing the 
outcomes of patients reported to the European Blood and Marrow Transplant Registry (EBMT) 
suggests that the TRM rate has decreased in recent years due to better control of infection and 
pulmonary toxicity39.  However, even in this group of young patients (median ages ~43-44), 
transplanted a median of 10 months from diagnosis, TRM following conventional allografting 
was 21% at 6 months and 30% overall at two years post-transplant.  Although more toxic, 
allogeneic transplantation appears to be a more potent anti-MM therapy than autologous 
transplantation, with higher CR rates and a longer duration of disease free survival in assessable 
patients2, 40.  Based on reports of a few patients who are disease free 10 and 15 years following 
syngeneic bone marrow transplantation41, 42 and flattening of survival curves at 3-5 years post 
allogeneic transplant, it is likely that some patients are cured by this procedure.  
 
Several observations suggest the existence of graft-versus-myeloma immune activity following 
allogeneic transplantation.  Bjorkstrand demonstrated indirect evidence in a case-matched 
analysis of 189 myeloma patients treated with either autologous transplant or allogeneic 
transplantation.  He found a significantly higher rate of relapse from CR or disease progression 


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from PR in the autologous transplant group compared to patients who underwent allogeneic 
transplantation40.  In addition, the quality of remission appeared greater following allogeneic 
transplantation as molecular remissions were rarely (7%) achieved after autografting (n=15) 
compared to a 50% molecular remission rate seen after allografting (n=14)43.  These data suggest 
that the chemoresistance of myeloma cells might be overcome by immune antitumor effects of 
the allograft. 
 
Alternatively, Bjorkstrand’s data could be explained by the re-infusion of clonogenic tumor cells 
with the autologous graft and the availability of a tumor free graft in patients receiving allografts.  
Gahrton demonstrated some evidence in support of this in a case-matched study of syngeneic, 
autologous and allogeneic transplants for MM44.  While the CR rate in each group was similar, 
the relapse rate in the syngeneic group was similar to that in the allogeneic group, both of which 
were superior to the autologous group.  The lower relapse rate was attributed to either graft 
contamination in the autologous transplant group contributing to relapse or to a graft-versus-MM 
effect in the syngeneic group.  Despite this theoretical advantage of having a tumor-free graft, 
CD34+ selection of autologous grafts that resulted in a median 3.3 log depletion of tumor did not 
result in improvement on disease free or overall survival in MM patients36.  This failure may 
reflect inadequate purging but more likely represents the resistant nature of residual MM in the 
host. 
 
The existence of a graft-versus-myeloma effect has been more directly confirmed by results of 
donor lymphocyte infusion (DLI) in patients who relapsed after failure of conventional 
allografts45, 46, 47.  Salama reported results on 25 patients who received DLI (median dose 1x108 
mononuclear cells/kg) for MM relapsing after an allograft.  Some patients received 
chemotherapy prior to the DLI and some received multiple escalating doses of DLI.  Overall, 7 
of 15 achieved a CR and 3, a partial response (PR).  Lokhorst47 reported on 27 patients receiving 
DLI following partially T cell depleted allotransplants.  The DLI were given a median of 30 
months post-transplant.  Overall, 14 of 27 patients responded with 5 CRs.  Responding patients 
received at least 1x108 mononuclear cells/kg. 
 
However, despite these potential advantages, the high TRM associated with allografting limits its 
widespread use.  The TRM associated with allogeneic bone marrow transplantation for MM 
exceeds that reported after allotransplantation for hematologic malignancies such as acute and 
chronic myeloid leukemias for unclear reasons.  It possibly reflects the high incidence of co-
morbid disease, especially renal failure.  The largest group of myeloma patients treated with 
allogeneic bone marrow transplantation, reported by Gahrton et.al.4, 5, included 162 patients 
treated in 35 different European centers from 1983 to 1993.  Early toxicity was high with an 
approximately 40% mortality within the first six months.  Bensinger et al.48 reported on 80 
patients treated between 1987-1994.  Seventy-one percent of these patients were considered to 
have refractory disease at the time of transplant.  TRM was high, with 42% deaths within the 
first 100 days and a few additional treatment-related deaths later.  These results may be due in 
part to patient selection, since 71% of the patients in the Seattle study were considered refractory 
and had received more than one prior chemotherapy regimen.  As discussed above,39 a recent 
analysis of the EBMT data suggests some improvement in outcome with conventional 
allografting, likely due to better support and favorable patient selection. 
 


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1.2.4 Mixed Chimerism 
 
1.2.4.1 Pre-clinical studies 
 
The approach to be used in this protocol to establish mixed chimerism was based on pre-clinical 
studies performed at FHCRC in a dog model49.  These studies demonstrated that post-transplant 
immunosuppression 
with 
CSA/MMF 
could 
substitute 
for 
pre-transplant 
TBI 
as 
immunosuppression for establishing allografts for MHC-matched littermate donors.  In these 
studies, the administration of CSA for 35 days post-transplant resulted in stable engraftment of 
marrow from seven of seven DLA-identical littermates after conditioning with 450 cGy of TBI50, 
a dose that is myeloablative.  In contrast, without post-grafting CSA, 60% of the dogs rejected 
grafts with this radiation dose.  In subsequent studies49 using bone marrow grafts from DLA-
identical littermates given sub-lethal TBI (200 cGy), post-grafting CSA alone was ineffective for 
establishing donor grafts.  Combination therapy consisting of MMF or methotrexate (MTX) and 
CSA was successful in allowing establishment of stable grafts.  Three of six dogs receiving 
CSA/MTX had transient mixed chimerism between 3 and 11 weeks and three remained stable 
mixed chimeras for up to 130 weeks.  Of 11 dogs receiving CSA/MMF, ten have become long-
term stable mixed chimeras without graft-versus-host-disease (GVHD).  At a lower dose of 100 
cGy of TBI and using post-grafting MMF/CSA, all six dogs rejected bone marrow grafts, but 
two of five PBSC recipients have become stable mixed chimeras.  Conclusions drawn from these 
studies were that CSA/MMF is a potent combination that can control both host-versus-graft and 
graft-versus-host reactions after low dose TBI, thus facilitating engraftment and stable long term 
survival.  PBSC may offer advantages over bone marrow for this purpose.  
 
1.2.4.2 Preliminary clinical studies 
 
Early clinical data in patients treated at the FHCRC hospitals, Stanford University and the 
University of Leipzig have demonstrated the feasibility of translating this novel method of 
transplantation from young dogs to older human patients with a variety of hematopoietic 
malignancies51.  In a series of 45 patients, the non-relapse mortality was 6.7%, and more than 
50% of patients with sustained engraftment had complete remissions of their underlying disease.  
In these trials, patients without prior aggressive chemotherapy were at increased risk of non-fatal 
graft rejection (20% overall), which was subsequently eliminated by the addition of fludarabine 
to the conditioning regimen.  Patients with a preceding autologous transplant had uniform 
engraftment with no graft rejections.  Particularly attractive was the development of a tandem 
approach for patients with myeloma, utilizing a high-dose conditioning regimen with single 
agent melphalan followed by autologous PBSC rescue to cytoreduce the disease.  Following 
resolution of conditioning toxicity (generally 30-90 days) patients received allografts from an 
HLA-identical related donor following non-myeloablative conditioning with 200 cGy TBI.  
Preliminary data from these patients led to the development of a tandem transplant protocol that 
was administered through the Seattle Consortium.  Interim results of that study are summarized 
below. 
 
Sixty-three patients were enrolled on a planned tandem two-step protocol using high-dose 
melphalan and autologous PBSC transplantation followed by non-myeloablative PBSC 
transplantation for treatment of MM at centers in the Seattle Consortium: FHCRC hospitals 


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(n=22), City of Hope (n=19), Stanford University (n=13), University of Toreno (n=3), University 
of Leipzig (n=2), and the University of Colorado (n=1).  Preliminary data from patients with at 
least three months of follow-up following the allograft (as of December 2001) are presented 
below.   
 
The median age was 52 (range 40-71) years.  All 63 patients received the planned autograft and 
60 patients received the non-myeloablative allotransplant.  Three patients died prior to 
allografting, one due to CMV pneumonia (CD34+ selected graft) and two due to disease 
progression following treatment delay because of toxicity.  Approximately 50% of patients 
(29/60) had responding disease at the time of autologous transplantation with seven patients in 
CR and 22 in PR.  All patients receiving allografts had engraftment of donor cells.  Grade II-IV 
acute GVHD occurred in 34/60 patients (40%), but was serious (Grade III/IV) in only four 
patients (6.6%).  Chronic extensive GVHD requiring prolonged immunosuppression occurred in 
26/60 patients (43%).  As of December 21, 2001, seven patients have died of the following 
causes: progressive disease at Day 91 (n=1), GVHD with infection at Days 102, 136, 168 (n=3), 
respiratory failure at Day 104 (n=1), and complications of chronic GVHD at Days 212, 413 
(n=2).  Day 200 TRM was 4/60 (6.6%).  Disease progression has occurred in four patients so far 
(6.6%).  As of December 21, 2001, the CR rate was 50%, PR rate 30%, for an overall response 
rate of 80%.  Responses occurred gradually following allografting with some patients requiring 
one year to achieve CR.  At 12 months, the Kaplan-Meier estimate of survival and progression-
free survival were 85% and 83%, respectively.  Median follow-up is approximately one year, 
with survival up to three years post-allografting in some patients.  Outcome data are available for 
40 patients with >6 months follow-up.   
 
Greater treatment details are available for the first 41 patients treated with this approach with a 
median follow-up of 14 months following the allograft.  Sixty-six percent of the patients had 
Stage III disease.  Forty three percent had relapsed or refractory disease, 40% were in PR and 
15% were in CR at the time of autologous transplantation.  
 
Four patients received CD34+ selected autologous PBSC transplants at FHCRC.  Because a 
higher incidence of CMV infection was observed with CD34+ selected PBSC (including one 
patient dying on Day 31 post autologous CD34+ selected transplant from CMV pneumonia), 
subsequent patients underwent unselected autologous PBSC transplantation.  Non-myeloablative 
allografting was performed at a median 69 days post autologous transplantation, in the outpatient 
setting.  Median donor CD34+ cells were 8.49 x 10 6/kg and donor CD-3 positive cells were 3.53 
x 108/kg.  Median days of hospitalization after allografting were 0 (0-37d).  After allografting, 
the median duration of severe neutropenia (absolute neutrophils count [ANC] < 500) was 0 (0-
19d) and median duration of severe thrombocytopenia (Plt < 20,000) was 0 (0-1d).  ANC nadir 
after allograft was 714 (100-1879); platelet nadir was 94,000 (15,000-192,000) with a median 
RBC transfusion of 0 (0-11) and platelet transfusion of 0 (0-6) units, confirming the non-
myeloablative nature of the 200 cGy TBI conditioning regimen.  All patients engrafted with 
donor cells.  There was no late graft rejection.  
 
Acute GVHD Grade II-IV occurred in 19/40 patients (48%).  Sixteen of forty patients had Grade 
II, one of forty had Grade III and two of forty had Grade IV GVHD.  Chronic GVHD occurred in 
25 (63%) of patients and 18 (45%) had extensive chronic GVHD. 


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Evaluating best disease response, with a median follow-up of 14 months, 24 patients (60%) 
achieved CR, and twelve patients (30%) achieved PR.  Three surviving patients have 
relapsed/progressive disease and have received additional therapy.  
 
One-year survival is 85%.  Six patients have died.  One died from progressive disease at Day 91, 
one from encephalopathy at Day 102, two from Grade IV acute GVHD at Days 136 and 168 and 
two patients from chronic GVHD and infection at Days 212 and 413.  TRM following the 
allograft for this subgroup is 5/40 (13%).  All of these deaths occurred after Day 100 and were 
related to either infection or complications of acute or chronic GVHD.  However, these results 
demonstrate that combining autologous PBSC transplantation with non-myeloablative allogeneic 
transplantation is feasible and safe.  The TRM of 13% for this group with at least one year of 
follow-up is significantly lower than the ~40% TRM generally associated with standard 
allogeneic transplantation or the 21% mortality reported more recently by Gahrton.  Moreover, 
60% of patients achieved CR, which is higher than the CR rate reported with standard autologous 
transplantation.  Lastly, the immunosuppression induced by autologous PBSC transplantation is 
sufficient to allow donor engraftment after a non-myeloablative conditioning regimen with 200 
cGy TBI alone. 
 
1.3 
Post Autologous Transplant Dexamethasone and Thalidomide 
 
Convincing clinical data indicate that high-dose therapy and autologous transplantation produces 
better outcomes than conventional chemotherapy for MM.  In the randomized study by Attal et 
al, the probability of 5-year event-free survival was 28% in patients treated with autologous 
transplant as compared to 10% in those treated with conventional chemotherapy.  As discussed 
earlier, tandem autologous transplants appear to be superior to single autologous transplants in 
the IFM94 trial with 6-year event free survival of 19 versus 28% 3.  New treatments are needed 
to prevent relapse and disease progression. 
 
Strategies to prevent relapse have included various post-transplant maintenance therapies.  Of 
these, interferon is the most extensively studied.  The evidence regarding the role of interferon 
post autologous transplant is conflicting.  A single, relatively small, randomized trial showed a 
non-statistically significant trend to longer progression-free survival with interferon but no 
improvement in overall survival52.  A moderately-sized retrospective EBMT study demonstrated 
a longer median progression-free survival (29 versus 20 months; p=0.006) and longer overall 
survival (78 versus 47 months; p=0.007) in patients receiving post-transplant interferon53.  
Despite these results, interferon is not consistently used post-transplant, largely because of toxic 
side effects.  Other agents used include corticosteroids; in the conventional chemotherapy 
setting, these have impacted survival, but have only recently been explored post-transplant54. 
 
Thalidomide was first introduced in 1953 as a sedative hypnotic, but a large increase in incidence 
of newborns with limb malformations led to its withdrawal in 1960.  The immunosuppressive 
activity of thalidomide was first noted and used in the therapy of lepromatous leprosy55.  Its 
activity in chronic GVHD was reported in 198856.  The exact mechanism of this activity is 
unknown but reports suggest diverse mechanisms including effects on the cell-mediated and 
humoral immunity as well as cytokine modulation57, 58.   


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Folkman and colleagues demonstrated the importance of angiogenesis in tumor development59.  
In a previous study, it was shown that bone marrow angiogenesis was present in patients with 
active MM, but not in patients with monoclonal gammopathy of undetermined significance 
(MGUS)60.  The extent of angiogenesis correlated with the labeling index (LI), an indicator of 
plasma cell proliferation.60, 61.  Therefore, it was proposed that the level of angiogenesis can be 
used as a prognostic indicator for myeloma.  Plasma cells and bone marrow stromal cells in 
myeloma are capable of expressing adhesion molecules and cytokines with angiogenic 
properties61.  The etiology of angiogenesis in myeloma is unknown, and may be related to 
myeloma itself, viral infection, or cytokines such as VEGF.  
 
Thalidomide inhibits angiogenesis in animal models and is active in myeloma with response 
rates of 30% even in patients with advanced and refractory disease62.  Thalidomide also, in pre-
clinical studies, inhibits the production of IL-6 by peripheral blood mononuclear cells63, 64.  Data 
suggest that IL-6 production by marrow stromal cells is important in the pathogenesis of MM64.  
There are reports of possible benefits of thalidomide therapy in MM associated with reduction of 
tumor burden as well as a marked decrease in microvessel density in the bone marrow.  Singhal 
and colleagues reported significant anti-tumor activity of thalidomide in patients with advanced 
and high-risk MM62, 65.  Barlogie and colleagues found combining thalidomide with combination 
chemotherapy produced encouraging results65.  Toxicities of thalidomide therapy include: 
neurologic (somnolence, dizziness, confusion, tremors, loss of co-ordination, tingling, 
numbness), gastrointestinal (constipation, nausea, vomiting, stomatitis), and constitutional 
(weakness, weight loss, fever).  These toxicities are generally moderate with doses of 
thalidomide up to 400 mg/day. 
 
Thalidomide has been used concomitantly with corticosteroids without the occurrence of 
unexpected toxicities and with possible synergistic effects8.  The optimal dose of thalidomide is 
not established, although toxicities are dose-related.  Responses are reported even at 50 mg/day.  
Current trials generally target the maximum tolerated dose up to a daily dose of 200 mg/day9, 66. 
 
High dose chemotherapy with autologous stem cell support is an effective method of inducing 
responses in patients with MM.  Unfortunately, treatment is not curative and most, if not all, 
patients eventually relapse.  Some patients achieve only partial or less than partial responses.  
Therefore, attempts to improve the quality of remission by treating minimal residual disease are 
logical.  It is likely that disease residual after high-dose chemotherapy is resistant to conventional 
chemotherapeutic agents, and use of agents with other mechanisms of action is desirable.  
Thalidomide is such an agent.  Moreover, because of the reported synergism and higher response 
rate (in the range of 40-70%) with combined thalidomide and dexamethasone with acceptable 
toxicity profile in newly diagnosed or relapsed patients with multiple myeloma, this combination 
seems a reasonable maintenance program to be tested in the post autologous transplantation 
setting.  Recently, Alexanian et al reported a 57% response rate using the combination of 
thalidomide and dexamethasone in patients with MM who had PR following an autologous 
peripheral stem cell transplantation.  Approximately 19% converted from PR to CR.  Since 
achievement of CR is considered a prerequisite for prolonged disease free survival, this 
encouraging strategy warrants further study. 
 


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1.4 
Study Approach and Treatment 
 
The introduction of autologous transplantation for MM significantly improved survival for this 
population of patients, yet the potential for further improvement remains by adding additional 
therapy post-autografting.  For those with an HLA-matched sibling, initial results of non-
myeloablative transplants hold promise while for those without, a second autologous transplant 
followed by combinations of effective, tolerable agents such as thalidomide plus dexamethasone 
are worthy of further testing. 
 
Symptomatic patients with Stage II or III MM who have received at least three cycles of 
systemic therapy (with vincristine, adriamycin and dexamethasone [VAD], melphalan plus 
dexamethasone or other similar regimens), who are within 2-10 months of initiation of the initial 
therapy (exclusive of mobilization therapy) and who have an autologous graft of 4x106 CD34+ 
cells/kg patient weight are potentially eligible for the study.  Patients known to have a 
consecutive eligible HLA-matched sibling may have an autograft 2x106 CD34+ cells/kg patient 
weight.  Patients meeting the eligibility criteria will proceed to treatment with high-dose 
melphalan with autologous PBSC support (minimum 2x106 CD34+ cells/kg patient weight).  
Subsequent therapy will be based on biologic assignment to either an allogeneic non-
myeloablative transplant for those patients with an HLA-matched sibling or to a second 
autologous PBSC transplant for those lacking a donor.  Additionally, patients without an HLA-
matched sibling donor will be randomized to either observation or one year of maintenance 
therapy with thalidomide and dexamethasone, the latter to commence following the second 
autologous PBSC transplant. 
 
The second phase of therapy will begin at least 60 days (preferably between 60 and 120 days) 
after the initial autograft, once the patient has recovered sufficiently from the acute toxicity of 
the high-dose melphalan regimen to proceed to the second phase of therapy.  For patients with 
HLA-matched siblings, the conditioning regimen for the allograft will be TBI (200 cGy) 
combined with post-transplant CSA and MMF as an immunosuppressive regimen for achieving 
donor engraftment.  Relatively high levels of CSA are targeted given the low intensity 
conditioning and the need to control host-versus-graft and graft-versus-host reactions. 
 
Patients without an available HLA-matched sibling donor will undergo a second course of high 
dose melphalan (200 mg/m2) followed by autologous PBSC transplant.  These patients will also 
be randomized to either observation or a one-year course of thalidomide 200 mg/day and 
dexamethasone 40 mg/day on Days 1-4 for 12 months following their second autologous PBSC 
transplant. 
 
Two statistical comparisons will be made.  To insure a 5% overall Type I Error, each of the 
comparisons is made at the 2.5% level.  Comparisons are based on comparing three-year 
progression free survival (PFS) of standard risk myeloma patients in an intent to treat analysis.  
The first comparison is of the two tandem autologous transplant (auto-auto) arms, one with and 
one without post-transplant maintenance therapy.  The goal here is to assess whether 
maintenance therapy increases the percent of patients alive and free of disease at three years after 
tandem autologous transplants.  The expected number of available patients without an HLA-
matched sibling allows for this randomized comparison within this group.  The second 


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comparison is between the auto-auto patients and the auto-allo patients.  Here, the patients to be 
included in the auto-auto arm depends on the results of the first test.  If that test shows no 
indication of a difference between the two auto-auto arms, then these two arms will be pooled for 
this comparison.  If the first test shows a significant advantage for one of the auto-auto arms, that 
arm will be used in the comparison against the auto-allo arm. 
 
For this trial, myeloma patients will be grouped into a High Risk or a Standard Risk group.  
Standard Risk is defined as patients with a serum beta 2 microglobulin  4 mg/L and no 
chromosome 13 abnormalities on standard metaphase karyotype analysis.  High Risk patients 
will include those MM patients with a serum beta 2 microglobulin level > 4 mg/L and/or 
chromosome 13 abnormalities on standard metaphase karyotype analysis.  The standard risk 
patients are being analyzed as the primary group as there is a greater potential for imbalance in 
the assignment of high risk patients, in part because of the smaller numbers on study, and their 
outcome may be inferior to the standard risk patients.  At the same time the high risk patients are 
included in the trial; it is important to gather information regarding the role of these therapies in 
this group of patients. 


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Table 1.4 -- Outline of Treatment Plan 
 
 
MM meeting eligibility 
criteria including available 
autologous graft of  
 4.0 x 106 CD34+ cells/kg. 
( 2.0 x 106 CD34+ cells/kg 
for the auto-allo arm.) 
 
 
 
 
 
High-dose melphalan (200 
mg/m2) + autologous PBSC 
transplant 
( 2x106 CD34+ cells/kg). 
 
 
 
 
Recovered and at least 60 days post-autograft (preferably 
between 60 and 120 days post-autograft). 
 
 
 
 
 
 
Eligible HLA-matched sibling 
donor. 
 
No eligible HLA-matched 
sibling donor. 
 
 
 
 
 
 
Non-myeloablative 
allogeneic PBSC transplant 
(200 cGy TBI, MMF/CSA). 
 
High-dose melphalan (200 
mg/m2) + autologous 
PBSC transplant 
( 2x106 CD34+ cells/kg). 
 
 
 
 
 
 
 
 
 
Observation. 
 
Thalidomide 200 
mg/day PO for one 
year.  Dexamethasone 
40 mg/day Days 1-4 
for 12 months. 
Maintenance to begin 
at least 60 days post 
second autograft 
(preferably between 
60 and 120 days). 
 


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CHAPTER 2 
 
 
2. STUDY DESIGN 
 
2.1 
Study Overview 
 
The overall study design is that of biologic assignment, based on the availability of an HLA-
matched sibling, to one of two treatment strategies for MM patients.  Patients without an HLA-
matched sibling will undergo tandem autologous transplants.  Patients with an HLA-matched 
sibling will undergo an autologous transplant followed by a non-myeloablative allogeneic 
transplant.  In addition, the tandem autologous transplant recipients will be randomized to either 
observation or one year of maintenance therapy to begin following the second autologous 
transplant.  The large number of MM patients without an HLA-matched sibling enables us to 
evaluate the role of maintenance therapy following tandem autologous transplants. 
 
2.2 
Hypothesis and Specific Objectives 
 
2.2.1 Hypotheses 
1. Therapy with dexamethasone and thalidomide following tandem autologous transplants 
will improve the response rate and progression free survival compared to observation. 
2. By separating the high-dose therapy temporally from the allogeneic stem cell transplant 
procedure, we can achieve both the benefits of autografting (disease response and 
prolonged survival) and allografting (establishment of full donor chimerism and graft-
versus-myeloma effects).  This approach will lead to less toxicity, reduced TRM, and 
better opportunity to evaluate anti-tumor effects of allografting. 
 
We hypothesize that for patients with an HLA-matched sibling, this strategy will prove superior 
to tandem autografts. 
 
2.2.2 Study Objectives 
 
There are two separate sets of objectives: those that relate to the question of post-tandem 
autologous transplant maintenance therapy for those without an HLA-matched sibling donor and 
those that relate to the comparison of tandem autologous transplants against an autologous 
transplant followed by a non-myeloablative HLA-matched sibling transplant. 
 
2.2.2.1 Tandem autologous transplants versus tandem autologous transplants + maintenance 
therapy objectives 
 
The primary objective of the randomized trial of maintenance therapy versus observation 
following tandem autologous transplants is to compare three-year PFS between the two arms.  
 
Secondary objectives are to compare ‘current’ myeloma-stable survival, three-year overall 
survival and incidence of progression.   


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Tertiary objectives are CR and CR+PR rates at 2 and 12 months after the second transplant, time 
to CR and CR+PR, time to off-study therapy, rate of discontinuation of maintenance therapy, 
duration of maintenance therapy, incidence of toxicities Grade  3 according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 3.0, incidence of infections and 
quality of life. 
 
2.2.2.2 Tandem autologous transplants versus autologous transplant + non-myeloablative 
allogeneic transplant objectives 
 
The primary objective of the trial of tandem autologous transplant versus autologous transplant 
followed by non-myeloablative HLA-matched sibling allogeneic transplant trial is to compare 
three-year PFS between the two arms. 
 
Secondary objectives are to compare ‘current’ myeloma-stable survival, three-year overall 
survival, and incidence of progression.  
 
Tertiary objectives are CR and CR+PR rates at 2 and 12 months after the second transplant, time 
to CR and CR+PR, time to second transplant, time to off-study therapy, and quality of life. 
 
Tertiary objectives for patients who receive an allogeneic transplant are to describe the incidence 
of both primary and secondary graft failure and the incidence and severity of GVHD. 
 
The relative safety of the two arms will be assessed through the collection and analysis of 
adverse events and routine laboratory monitoring. 
 
2.3 
Patient Eligibility 
 
Patients must meet specified eligibility criteria to be registered on the study.  Additional criteria 
must also be met to continue to successive stages of the protocol.  All questions regarding 
eligibility criteria should be directed to the Protocol Coordinator at 301-251-1161. 
 
2.3.1 Initial Patient Eligibility Criteria  
 
Patients fulfilling the following criteria will be eligible for entry into this study: 
1. Patients meeting the Durie and Salmon criteria for initial diagnosis of MM (Appendix A). 
2. Patients with Stage II or III MM (Appendix A) at diagnosis or anytime thereafter. 
3. Patients with symptomatic MM requiring treatment at diagnosis or anytime thereafter. 
4. Patients who are 70 years of age, or younger, at time of first registration. 
5. Patients who have received at least three cycles of initial systemic therapy and are within 
2-10 months of initiation of the initial therapy (this time frame excludes the time for 
mobilization therapy). 


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6. Patients receiving chemotherapy-based mobilization regimens must be able to receive 
high-dose melphalan between 2 and 8 weeks after the initiation of mobilization therapy 
whether delivered at the transplant center or at a referring center. 
7. Patients with adequate organ function as measured by: 
a) Cardiac:  Left ventricular ejection fraction at rest > 40%.  
b) Hepatic:  Bilirubin < 2x the upper limit of normal and ALT and AST < 3x the upper 
limit of normal. 
c) Renal:  Creatinine clearance > 40 ml/min (measured or calculated/estimated).  
d) Pulmonary:  DLCO, FEV1, FVC > 50% of predicted value (corrected for 
hemoglobin), or O2 saturation > 92% of room air. 
8. Patients with an adequate autologous graft defined as a cryopreserved PBSC graft 
containing  4.0 x 106 CD34+ cells/kg patient weight.  If prior to enrollment, it is known 
that a patient will be on the auto-allo arm (i.e., a consenting, eligible HLA-matched 
sibling donor is available), the required autograft must contain at least 2.0 x 106 CD34+ 
cells/kg patient weight.  The graft may not be CD34+ selected or otherwise manipulated 
to remove tumor or other cells.  The graft can be collected at the transplanting institution 
or by a referring center.  For patients without an HLA-matched sibling donor, the 
autograft must be stored so that there are two products each containing at least 2 x 106 
CD34+ cells/kg patient weight. 
 
2.3.2 Initial Patient Exclusion Criteria 
 
Patients with the following will be ineligible for registration onto this study: 
1. Patients that have never advanced beyond Stage I MM since diagnosis (Appendix A) 
2. Patients with non-secretory MM [absence of a monoclonal protein (M protein) in serum 
as measured by electrophoresis and immunofixation and the absence of Bence Jones 
protein in the urine defined by use of conventional electrophoresis and immunofixation 
techniques]. 
3. Patients with plasma cell leukemia. 
4. Karnofsky performance score less than 70%, unless approved by the Medical Monitor or 
one of the Protocol Chairs. 
5. Patients with uncontrolled hypertension. 
6. Patients with uncontrolled bacterial, viral or fungal infections (currently taking 
medication and progression of clinical symptoms). 
7. Patients with prior malignancies except resected basal cell carcinoma or treated cervical 
carcinoma in situ.  Cancer treated with curative intent < 5 years previously will not be 
allowed unless approved by the Medical Monitor or one of the Protocol Chairs.  Cancer 
treated with curative intent > 5 years previously will be allowed. 
8. Female patients who are pregnant (positive -HCG) or breastfeeding. 
9. Patients seropositive for the human immunodeficiency virus (HIV). 


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10. Fertile men or women unwilling to use contraceptive techniques during and for 12 
months following treatment. 
11. Prior allograft or prior autograft. 
12. Patients who have received mid-intensity melphalan (>50 mg IV) as part of prior therapy. 
13. Patients unable or unwilling to provide informed consent. 
14. Prior organ transplant requiring immunosuppressive therapy. 
 
2.3.3 Patient Eligibility Criteria for Second Transplant 
 
In order to be eligible to continue on protocol and receive their second transplant (preferably 
between 60-120 days, but at least 60 days post first transplant), patients must have recovered 
sufficiently from their first transplant.  Conditioning therapy for the second transplant must start 
at least 60 days post first transplant. 
 
Recovery from high-dose melphalan and autografting will be defined by achievement of the 
following clinical criteria: 
1. Mucositis and gastrointestinal symptoms resolved, off hyperalimentation and intravenous 
hydration. 
2. Liver and renal function tests within the inclusion criteria for initial autograft.  
3. Off antibiotics and Amphotericin B formulations or voriconazole for proven, probable or 
possible infections (defined in accordance with the EORTC/MSG criteria67).  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 
Medical Monitor or one of the Protocol Chairs. 
4. Completed administration of any radiotherapy as per Section 2.4.1.5. 
5. 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. 
6. Pulmonary function tests must meet initial study entry criteria.  
 
Fertile men and women must be willing to use contraceptive techniques during and for 12 
months following treatment. 
 
In addition, women of childbearing potential who are pregnant (-HCG positive) or 
breastfeeding will be ineligible to receive their second transplant. 
 
2.3.4 Patient Eligibility Criteria for Tandem Autologous Transplant Patients to Begin 
Maintenance Therapy 
 
Patients without an HLA-matched sibling donor will be randomized to either observation or one 
year of maintenance therapy to begin after their second transplant.  The randomization 
assignment will be revealed when the Post-tandem Autologous Transplant Checklist is 
completed, at least 60 days post second transplant.  Patients without an HLA-matched sibling 


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donor must have recovered sufficiently from their second transplant (preferably between 60-120 
days, but at least 60 days post second transplant) in order to initiate dexamethasone and 
thalidomide maintenance therapy. 
 
Recovery from high-dose melphalan and autografting will be defined by achievement of the 
clinical criteria outlined in Section 2.3.3 above with the exception that patients do not require 
repeat cardiac or pulmonary testing.  
 
In addition, a pregnancy test must be performed 24 hours prior to the initiation of maintenance 
therapy for all women of childbearing potential.  Women are of childbearing potential unless 
they have had a hysterectomy or had no menses or have been post-menopausal for at least 24 
months.  If the patient is pregnant (positive -HCG), they will be ineligible to receive 
maintenance therapy.  Fertile men and women must continue use of contraceptive techniques 
until 4 weeks after completion of maintenance therapy. 
 
2.3.5 Allograft Donor Eligibility Criteria 
1. 6/6 HLA genotypically identical sibling (defined as a match at the serologic ‘split’ level). 
2. Donor must consent to G-CSF administration and to leukapheresis for PBSC allograft.  
3. Donor must have adequate veins for leukapheresis or agree to placement of central 
venous catheter (femoral, subclavian). 
4. Age  75 years at the time patient is initially registered on study. 
 
2.3.6 Allograft Donor Exclusion Criteria 
1.  Identical twin. 
2. Age less than 18 years. 
3. Female patients who are pregnant (positive -HCG) or breastfeeding. 
4. Infection with HIV, viral hepatitis (B or C). 
5.  Known allergy to G-CSF. 
6. Current serious systemic illness. 
7. Uncontrolled bacterial, viral or fungal infection (currently taking medication and 
progression of clinical symptoms). 
8. Donors receiving experimental therapy or investigational agents. 
9. Donors with cancer other than treated basal cell or carcinoma in situ of cervix.  Cancer 
treated with curative intent > 5 years previous will be reviewed on a case-by-case basis 
by the Medical Monitor or one of the Protocol Chairs. 
 
2.3.7 Timing of Biologic Assignment and Randomization 
 
The timing of the biological assignment and randomization depends on the need to identify 
HLA-type and assess HLA-matched siblings for their ability to donate an allograft.  For some 


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patients, this information will be known at the time of consenting for the trial.  For some, the 
complete evaluation of potential sibling donors may be delayed until during or shortly after the 
initial autologous transplant.  This protocol requires that potential sibling donors be HLA-typed 
at the earliest opportunity, and that blood for this purpose be drawn no later than three weeks 
after the initial autologous transplant. 
 
The clinical center will re-register patients once the typing, donor eligibility results and consent 
are available (See Chapter 4.1 Enrollment Procedures).  With this information, the Data 
Coordinating Center will then make the biological assignment.  Patients with an HLA-matched 
sibling who is a consenting eligible donor will be assigned to the auto-allo arm, and those 
without will be assigned to the auto-auto arm.  The auto-auto arm patients will, at the same time, 
be randomized to receive either maintenance therapy with thalidomide and dexamethasone, or 
observation to begin following the second autologous transplant.  The randomization assignment 
will be revealed when the Post-tandem Autologous Transplant Checklist is completed, at least 60 
days post second transplant. 
 
To facilitate an intention-to-treat analysis, all patients will be assigned to one of the three 
treatment arms, even if they are no longer medically eligible for the second transplant or post-
transplant maintenance therapy.  Continued eligibility for the second transplant and for the 
initiation of maintenance therapy will be established at subsequent third and fourth registration 
time points, through the use of eligibility check-lists as outlined in Chapter 4.1 Enrollment 
Procedure. 
 
2.4 
Study Treatments 
 
The immediate pre-transplant evaluation will be carried out according to the operating 
procedures of the participating institutions and should be in keeping with the data reporting 
requirements of this study.  Similarly, special orders and procedures will be those defined by the 
BMT CTN Manual of Procedures (MOP).  All patients enrolled on this protocol will be 
hospitalized in accordance with the procedures for recipients of autologous and non-
myeloablative allogeneic transplants as defined by the treating institution.  All questions 
regarding treatment should be directed to the Protocol Coordinator at 301-251-1161. 
 
2.4.1 Cytoreductive Therapy and First Autologous Stem Cell Transplantation 
 
High-dose melphalan must be given between 2 and 8 weeks after the initiation of mobilization 
therapy whether delivered at the transplant center or at a referring center.  However, if G-CSF is 
employed as mobilization therapy, the transplant center’s institutional guidelines should be 
followed for timing of melphalan dosing and graft collection. 
 
 


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Table 2.4.1 -- High-Dose Melphalan / Autologous SCT 
 
Day 
-2 
-1 
0 
+5 to 
Engraftment 
Melphalan (200 mg/m2 /IV) 
X 
 
 
 
PBSC Infusion 
 
 
X 
 
G-CSF (5 g/kg/day*) SQ or IV 
until ANC > 500 x 2 days 
 
 
 
X 
* G-CSF dosing can be rounded based on patient weight and available G-CSF vial sizes to best 
approximate 5 g/kg/day (e.g. < 70kg use 300 g vial, 70 to 90 kg use 480 g vial and > 90 kg 
use 2 x 300 g vials). 
 
 
2.4.1.1 Allopurinol 
 
Patients may receive 300 mg/day of allopurinol, starting on Day -4 and ending on Day –1 
according to local institutional practice.  
 
2.4.1.2 Melphalan administration 
 
1. Dosage:  
Melphalan will be administered at a dose of 200 mg/m2.  Melphalan will be given in one 
dose infused on Day –2.  Melaphalan dose is based on ideal body weight (IBW) 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 + [(0.25) x (ABW - IBW)] 
2. Administration:  
High-dose melphalan is administered via a central venous catheter following 
reconstitution with the provided sterile diluent.  High-dose melphalan should be 
administered undiluted as a bolus injection or diluted with sodium chloride and infused 
over 15-20 minutes. 
3. Maintenance hydration: 
Hydration to be administered according to local institutional guidelines. 
 


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2.4.1.3 Peripheral blood stem cell infusion 
 
All patients will receive an autologous graft with a minimum cell dose of 2.0 x 106 CD34+ 
cells/kg patient weight.  The graft may not be CD34+ selected or otherwise manipulated to 
remove tumor or other cells.  The autologous graft may be infused on an outpatient basis.  
Patients must comply with all scheduled study visits whether receiving their transplant as an in-
patient or an out-patient.  Cryopreservation and thawing of product will be in keeping with 
FACT standards and local institutional practice.  For autologous transplant, if excess cells were 
collected, all cells up to 5 x 106 CD34+ cells/kg, must be infused.  Giving more than 5 x 106 
CD34+ cells/kg is at the discretion of the center Principal Investigator. 
 
2.4.1.4 G-CSF 
 
Patients will receive ~5 g/kg/day of G-CSF subcutaneously from Day 5 post-transplant until 
ANC > 500/mm3 for two days.  G-CSF dosing can be rounded based on patient weight and 
available G-CSF vial sizes to best approximation of 5 g/kg/day (e.g., < 70 kg use 300 g vial, 
70 to 90 kg use 480 g vial and > 90 kg use 2 x 300 g vials).  If the patient is unable to tolerate 
G-CSF subcutaneously, it may be administered intravenously as per package insert. 
 
2.4.1.5 Radiation therapy 
 
No radiation therapy is permitted concurrent with administration of melphalan.  When blood 
count recovery is adequate (ANC > 1000/mm3, platelets > 80,000/mm3) after autologous 
transplantation, radiation may be administered for the following indications after consultation 
with the Medical Monitor or one of the Protocol Chairs and a radiation oncologist: 
1. Palliation of pain from bone lesions 
2. Prevention of pathologic fractures 
3. Relief of spinal cord compression or nerve root compression  
 
The radiation oncologist will determine dose and duration of radiation to be administered.  
Radiation to the liver or lungs should be avoided. 
 
In addition to blood count recovery, except for emergent indication (e.g. cord compression), 
patients must also be recovered from autologous transplantation with resolution of mucositis, 
resolution of fever, discontinuation of antibiotics and receiving adequate oral hydration and 
nutrition to receive radiation therapy. 
 


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2.4.2 Second Autologous Transplant for Patients without an HLA-matched Sibling 
 
Conditioning for the second transplant will be initiated once the patient has recovered from the 
first transplant.  Recovery from the first autograft will be defined as patients achieving the 
clinical criteria in Section 2.3.3.  Upon recovery from the first autograft, but at least 60 days 
(preferably between 60-120 days) after the first autograft, patients without an HLA-matched 
sibling donor will receive a second autograft, also conditioned with melphalan 200 mg/m2 as 
outlined in Section 2.4.1.1 through 2.4.1.5 and Table 2.4.1.  If indicated, radiation to high-risk 
skeletal lesions may be given pre-transplant as per Section 2.4.1.5.  For autologous transplant, if 
excess cells were collected, all cells up to 5 x 106 CD34+ cells/kg, must be infused.  Giving more 
than 5 x 106 CD34+ cells/kg is at the discretion of the center Principal Investigator. 
 
2.4.3 One Year of Dexamethasone and Thalidomide Maintenance Therapy or Observation for 
Patients without an HLA-matched Sibling 
 
Recovery from high-dose melphalan and autografting will be defined as patients achieving the 
clinical criteria in Section 2.3.3 with the exception that repeat pulmonary function testing and 
assessment of LV ejection fraction are not required. As soon as evaluation of all potential donors 
is complete, all patients without an HLA-matched sibling will be randomized to receive the 
combination of thalidomide and dexamethasone maintenance therapy as outlined below or 
observation.  Maintenance therapy will not begin until recovery from the second autograft.  
Recovery from the second autograft is defined as per Section 2.3.3 with the exception that repeat 
pulmonary function testing is not required. 
 
Table 2.4.3 -- Dexamethasone and Thalidomide Treatment Schedule 
 
 
Months 1-12 
Thalidomide  
200 mg/day PO 
Start 50 mg/day and increase 50 mg/day each 
week as tolerated to target dose of 200 mg/day 
Dexamethasone  
40 mg/day PO 
Days 1-4 of each month 
 
 
2.4.3.1 Thalidomide 
 
Patients will be initiated on a starting dose of 50 mg/day.  The dose will be increased weekly by 
50 mg as tolerated to achieve a target dose of 200 mg/day.  Patients will be treated for 12 months 
with thalidomide.  See Table 2.4.3a for dose modifications for thalidomide based on subject 
toxicity. 
 
Refer to Appendix D for the System for Thalidomide Education and Prescribing Safety 
(S.T.E.P.S.) dosing and administration procedures for thalidomide. 
 
Female patients taking thalidomide must either abstain from all reproductive sexual intercourse 
or use two methods of birth control or at least one highly active method (e.g., intrauterine device 


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[IUD], hormonal [birth control pills, injections or implants], tubal ligation, or partner’s 
vasectomy) and one additional effective method (e.g., latex condom, diaphragm, or cervical cap), 
for at least four weeks before starting thalidomide therapy, during therapy, and for at least four 
weeks after discontinuing thalidomide therapy even when there has been a history of infertility, 
unless due to hysterectomy or because the patient has been post-menopausal or has had no 
menses (that is no menstrual period) for at least 24 consecutive months. 
 
Female patients having any chance of becoming pregnant must have a pregnancy test performed.  
The test should be performed within 24 hours of beginning thalidomide, weekly for the first four 
weeks of treatment, and then every four weeks until 12 months post initiation of maintenance 
therapy if the patient’s periods are regular or every two weeks if they are not. 
 
Male patients must be counseled that thalidomide may be present in their semen.  Men must use 
a latex condom every time they have sexual intercourse with a woman during therapy and for 
four weeks after discontinuing thalidomide, even if they have had a successful vasectomy.  Male 
patients should request that female partners use a second method of birth control in addition to a 
male condom. 
 
2.4.3.2 Dexamethasone  
 
Patients will receive dexamethasone at a dose of 40 mg per day during Days 1-4 of each month 
for 12 months.  The first dose of dexamethasone to be given the same day the patient starts 
thalidomide.  See Table 2.4.3b for dose modifications for dexamethasone based on subject 
toxicity.   
 
2.4.3.3 Dose Modifications for dexamethasone and thalidomide 
 
Treatment modifications are based on toxicity.  All toxicities should be graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. 
 


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Table 2.4.3a  THALIDOMIDE Dose Modification Based on Toxicity 
 
CTCAE Category
Toxicity 
Dosage Change1 
BASED ON INTERVAL TOXICITY 
Dermatology 
Rash Grade 2-3 
Grade 2: 
Macular or papular eruption or erythema with 
pruritus or other associated symptoms or localized 
desquamation or other lesions covering < 50% of 
body surface area. 
Grade 3: 
Severe generalized erythroderma or macular, 
papular or vesicular eruption or desquamation 
covering  50% of body surface area. 
Dose should be held 
until toxicity resolves 
to baseline or  Grade 
1 and then restarted at a 
50% dose reduction1. 
Grade 1: 
Macular or papular 
eruption or erythema 
without associated 
symptoms. 
 
 
Grade 4: 
Stevens-Johnson syndrome and toxic epidermal 
necrolysis, generalized exfoliative, ulcerative or 
bullous dermatitis. 
Discontinue 
thalidomide; no further 
treatment with 
thalidomide. 
Blood/bone 
Marrow 
Neutrophils 
Grade 3: 
ANC  500 - < 1000/mm3. 
Consider G-CSF. 
 
 
Grade 4: 
ANC < 500/mm3. 
 
Dose should be held 
until ANC  500 mm3, 
and then restarted at a 
50% dose reduction1. 
 
Platelets 
Grade 4: 
Platelet count < 25,000 cells/mm3. 
Dose should be held 
until toxicity resolves 
to baseline or  Grade 
2 and then restarted at a 
50% dose reduction. 
Grade 1: 
Platelets  75,000. 
Grade 2: 
Platelets  50,000 -  
< 75,000. 


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CTCAE Category
Toxicity 
Dosage Change1 
BASED ON INTERVAL TOXICITY 
Neurology 
Neuropathy motor 
Grade 2: 
Symptomatic weakness interfering with function, 
but not interfering with activities of daily living. 
Dose should be held 
until toxicity resolves 
to baseline or  Grade 
1 and then restarted at a 
50% dose reduction1, 2. 
Grade 1: 
Asymptomatic, 
weakness on exam/ 
testing. 
 
Grade 3: 
Weakness interfering with activities of daily living 
or bracing or assistance to walk indicated. 
Grade 4: 
Life-threatening or disabling (paralysis). 
Discontinue 
thalidomide 
permanently. 
 
Neuropathy sensory 
Grade 2: 
Sensory alteration or paresthesia (including 
tingling), interfering with function, but not 
interfering with activities of daily living. 
Dose should be held 
until toxicity resolves 
to baseline or  Grade 
1 and then restarted at a 
50% dose reduction1, 2. 
Grade 1: 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia but not 
interfering with 
function. 
 
Grade 3: 
Sensory alteration or paresthesia interfering with 
activities of daily living. 
Grade 4: 
Disabling. 
Discontinue 
thalidomide 
permanently. 


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CTCAE Category
Toxicity 
Dosage Change1 
BASED ON INTERVAL TOXICITY 
Neurology 
continued 
Somnolence/depressed level of consciousness 
 Grade 3: 
Obtundation or stupor or difficult to arouse or 
interfering with activities of daily living. 
 
Dose should be held 
until toxicity resolves 
to baseline or  Grade 
1 and then restarted at a 
50% dose reduction1. 
Grade 1: no description  
Grade 2:  
Somnolence or 
sedation interfering 
with function, but not 
interfering with ADL. 
Grade 4: 
Coma. 
Discontinue 
thalidomide 
permanently. 
Gastrointestinal Constipation  
 Grade 3: 
Symptoms interfering with ADL or obstipation 
with manual extraction indicated. 
Grade 4: 
Obstruction or toxic megacolon. 
Hold until constipation 
 Grade 1, then restart 
with additional 
prophylactic measures 
and/or lower dose1. 
Grade 1: 
Occasional or 
intermittent symptoms; 
occasional use of stool 
softeners, laxatives, 
dietary modification, or 
enema. 
Grade 2: 
Persistent symptoms 
with regular use of 
laxatives or enemas 
indicated. 


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CTCAE Category
Toxicity 
Dosage Change1 
BASED ON INTERVAL TOXICITY 
Constitutional 
Symptoms 
Fatigue 
 Grade 3: 
Severe fatigue interfering with ADL. 
 
Grade 4: 
Disabling. 
Hold until toxicity 
resolves to baseline or 
 Grade 1, then restart 
at 50% dose reduction1. 
Grade 1: 
Mild fatigue over 
baseline. 
Grade 2: 
Moderate or causing 
difficulty performing 
some ADL. 
Other  Grade 
3 Toxicity 
 
Hold until toxicity 
resolves to baseline or 
 Grade 1, then restart 
at 50% dose reduction1. 
 
Notes: 
1If the patient is on 100 mg/day of thalidomide when the toxicity occurs, the dose should be lowered to 
50 mg/day.  The dose may subsequently be increased by 50 mg (1 capsule)/day increments as tolerated 
on a weekly basis up to 200 mg.  Document all dose changes.  Patients who cannot tolerate 50 mg/day 
should discontinue protocol therapy. 
2Thalidomide treatment should be stopped if there is recurrence of dose-limiting peripheral neuropathy 
on the lower dose or failure to resolve to  Grade 1. 
 
 


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Table 2.4.3b  DEXAMETHASONE Dose Modification Based on Toxicity 
 
CTCAE Category
Toxicity 
Dosage Change 
BASED ON INTERVAL TOXICITY 
Gastrointestinal Grade 1-2: 
Requiring medical management. 
Dyspepsia, gastric or duodenal ulcer, gastritis. 
Treat with H2 blockers, 
sucralfate, or 
omeprazole.  If 
symptoms persist 
despite above 
measures, decrease 
dexamethasone dose by 
50% permanently. 
 
 Grade 3: 
Requiring hospitalization or surgery. 
Hold dexamethasone 
until symptoms 
adequately controlled.  
Restart at 50% of 
current dose along with 
concurrent therapy with 
H2 blockers, sucralfate 
or omeprazole.  If 
symptoms persist 
despite above 
measures, discontinue 
dexamethasone and do 
not resume. 
 
Acute pancreatitis. 
Discontinue 
dexamethasone and do 
not resume. 
Cardiovascular 
Edema 
 Grade 3:  
Limiting function and unresponsive to therapy or 
anasarca. 
Diuretics as needed, 
and decrease 
dexamethasone dose by 
25%; if edema persists 
despite above measures 
decrease dose to 50% 
of initial dose; 
discontinue 
dexamethasone and do 
not resume if 
symptoms persist 
despite 50% reduction. 


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CTCAE Category
Toxicity 
Dosage Change 
BASED ON INTERVAL TOXICITY 
Neurology 
Confusion or mood alteration 
 Grade 2: 
Interfering with function but not interfering with 
activities of daily living. 
Hold dexamethasone 
until symptoms 
resolve.  Restart at 50% 
of current dose.  If 
symptoms persist 
despite above 
measures, discontinue 
dexamethasone and do 
not resume. 
Musculoskeletal Muscle weakness 
 Grade 2:  
Symptomatic and interfering with function but not 
interfering with activities of daily living. 
Decrease 
dexamethasone dose by 
25%; if weakness 
persists despite above 
measures decrease dose 
to 50% of initial dose.  
Discontinue 
dexamethasone and do 
not resume if 
symptoms persist 
despite 50% reduction. 
Metabolic 
Hyperglycemia 
 Grade 3 or higher. 
Treatment with insulin 
or oral hypoglycemic 
agents as needed.  If 
uncontrolled despite 
above measures, 
decrease dose by 25% 
decrements until levels 
are satisfactory. 
 
 
2.4.3.4 Minimal maintenance doses of thalidomide and dexamethasone 
 
Whenever possible, for patients requiring dose reductions due to toxicity, an attempt should be 
made to maintain patients on minimal maintenance doses.  Specifically, patients should be 
maintained, if possible, on a minimal dose of thalidomide of 50 mg/day and a minimal dose of 
dexamethasone of 20 mg/day on Days 1-4 of each month. 
 


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2.4.4 Allogeneic Non-myeloablative Transplantation for Patients with an HLA-matched 
Sibling 
 
Upon recovery from their autograft, and at least Day 60 (preferably between 60-120 days) post-
autograft, patients with an available 6/6 HLA matched sibling will receive an allograft after non-
myeloablative conditioning.  Recovery from high-dose melphalan and autograft will be defined 
by achievement of the clinical criteria established in Section 2.3.3.  If indicated, radiation to 
high-risk skeletal lesions may be given pre-transplant as per Section 2.4.1.5.   
 
Pre-transplant conditioning and PBSC infusion may be administered on an outpatient basis.  
Patients must comply with all scheduled study visits whether receiving their transplant as an in-
patient or an outpatient. 
 
 
Table 2.4.4 -- Non-myeloablative Transplant Schedule 
 
 
Day 
 -3 
Day 
 0 
Day 
 +1 
Day 
 +27 
Day 
 +84 
Day 
+114 
Day 
+180 
TBI 200 cGy 
 
X 
 
 
 
 
 
Cyclosporine  
5 mg/kg bid PO * 
Start 
 
 
 
Initiate 
taper 
Off if 
not in  
PR or 
CR and 
no 
GVHD 
on Day 
+84 
Off if 
CR or 
PR and 
no 
GVHD 
on Day 
+84 
Mycophenolate 
Mofetil (MMF)  
15 mg/kg bid PO * 
 
First 
dose 
20:00hrs 
 
Last 
dose 
 
 
 
PBSC Infusion ** 
 
X** 
X*** 
 
 
 
 
* See Section 2.4.4.2 for dose adjustments and for changes if disease progression / relapse. 
** After TBI 
*** If required 
 
 
2.4.4.1 Conditioning regimen 
 
On Day 0, patients will receive TBI 2.0 Gy from a linear accelerator at 20 cGy/min, followed 
by allogeneic PBSC infusion.  It is recommended that TBI be administered between 11:00 a.m. 
and 2:00 p.m. to avoid proximity to CSA/MMF administration. 
 


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2.4.4.2 Peri non-myeloablative allogeneic transplant immunosuppression 
 
Cyclosporine: 
1. Commence CSA on Day –3 at 5 mg/kg bid PO for a daily dose of 10 mg/kg/day (round 
to the nearest 25 mg increment) through Day +84 based on actual body weight.  Starting 
on Day 84, patients in PR or CR and in the absence of GVHD, will have CSA tapered 
such that the patient will be off CSA by Day 180 (approximately 6% decrease every 
seven days).  Patients without at least a PR compared to registration evaluation but 
without disease progression [minimal response (MR), stable disease (SD)] and in the 
absence of GVHD, will have CSA tapered such that the patient will be off CSA by Day 
114. 
2. Dose Adjustments: CSA, whole blood "trough" levels (i.e., just prior to the next dose) 
will be evaluated on Day 0 (the day of transplant) and twice weekly during the first 
week of treatment and adjusted if necessary to maintain blood levels that target 500 
ng/ml (upper end of therapeutic range) during the first month.  Dose reductions should 
only be made if CSA toxicity is present or whole blood levels exceed 600 ng/ml in the 
absence of toxicity.  Further CSA determinations should be performed weekly – until 
CSA is stopped unless high levels are detected (i.e., > 600 ng/ml), or toxicity is 
suspected, in which case more frequent monitoring will be performed as clinically 
indicated.  Dose reductions for high levels without toxicity should be conservative e.g. 
25%, to avoid inadequate immunosuppression.  Patients with severe intolerance of 
cyclosporine, may be placed on FK506 (tacrolimus) after discussion with the Medical 
Monitor or one of the Protocol Chairs. 
After Day 28, the CSA level is to be kept within 200-400 ng/mL, according to local 
institutional practice until the Day 84 taper is initiated. 
3. If there is nausea and vomiting at anytime during CSA treatment, the drug should be 
given intravenously at the appropriate dose. 
4. Drugs that may affect CSA levels are: dexamethasone, phenobarbital (may lower CSA 
levels), steroids, fluconazole, voriconazole, ketoconazole, cimetidine, itraconazole (may 
increase CSA levels).  Patients requiring hemodialysis should have CSA levels 
maintained in the high therapeutic range (400 ng/ml). 
 
Mycophenolate Mofetil: 
1. Oral administration of MMF will be at a daily dose of 30 mg/kg/day (15 mg/kg twice 
daily 8:00 a.m. and 8:00 p.m.) from the evening of Day 0 (i.e. first dose to follow 
allograft infusion).  Doses will be rounded to the nearest 250 mg (capsules are 250 mg).  
MMF dosing is based on ideal body weight (IBW) for patients who weigh 100-120% of 
their IBW, based on actual body weight (ABW) for patients who weigh less than 100% of 
their IBW, and based on adjusted ideal body weight (AIBW) for patients who weigh 
more than 120% of their IBW.  See Section 2.4.1.2 for body weight formulas. 
2. MMF will be given until Day 27 post-transplant and then stopped without tapering.  If 
there is nausea and/or vomiting at any time preventing the oral administration of MMF, 
MMF should be administered intravenously at 15 mg/kg bid. 


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3. Dose Adjustments: If, in the clinical judgment of the investigator, an observed toxicity is 
related to MMF administration, a dose adjustment will be made.  Based on previous 
organ transplant studies, dose adjustments may occur because of hematopoietic or 
gastrointestinal adverse effects.  Dose adjustments will not be made for hematopoietic 
toxicity unless severe neutropenia develops or persists after Day 21 post-transplant (ANC 
< 1000/mm3 for > 5 days).  Any planned dose adjustments for hematologic toxicity must 
be discussed with one of the Protocol Chairs or Medical Monitor.  In the event of 
gastrointestinal toxicity that requires medical intervention including medication for 
control of persistent vomiting or diarrhea and is considered to be due to MMF, a 20% 
dose reduction will be made.  If there is no improvement within 72 hours, MMF will be 
reduced an additional 20%.  For severe gastrointestinal toxicity related to MMF, MMF 
will be stopped.  Patients should be evaluated by both a gastroenterology consultant and 
the site principal investigator to determine the need for dose adjustments.   
 
2.4.4.3 Management of post-allotransplant immunosuppression in the setting of disease 
progression 
 
If the patient progresses  28 days post-non-myeloablative transplant in the absence of GVHD, 
cyclosporine will be tapered off over two weeks to try to induce a graft-versus-myeloma 
reaction. 
 
2.4.4.4 Management of post-allotransplant immunosuppression in the setting of low or 
decreasing donor peripheral blood t-cell chimerism 
 
It is unlikely that donor chimerism will be low following the non-myeloablative allotransplant.  
Should low or decreasing donor peripheral blood T-cell chimerism be documented, no 
adjustments to MMF or CSA dosing are to be made without first discussing the situation with 
one of the Protocol Chairs or the Medical Monitor.  
 
2.4.5 Collection and Infusion of Donor PBSC for Non-myeloablative Transplantation 
 
2.4.5.1 G-CSF administration to donors 
 
All donors will receive G-CSF 16 g/kg/day for five consecutive days from Day -4 to Day 0.  
G-CSF will be administered by daily subcutaneous injections.  The dose of G-CSF may be 
rounded according to body weight and available G-CSF vial sizes to best approximate 16 g/kg.  
If necessary, based on volume, the G-CSF dose can be given in multiple injection sites.  If the 
patient is unable to tolerate G-CSF subcutaneously, it may be administered intravenously as per 
package insert.  These doses will be administered before 10:00 a.m. each day.  The schedule of 
G-CSF administration and PBSC collections can only be ascertained once Day 0 is identified.   
 


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2.4.5.2 PBSC collection and evaluation 
 
Donors will preferably undergo vein to vein collections but may receive an appropriate central 
venous catheter inserted on or before the day of the apheresis.  PBSCs will be collected in the 
afternoon of Day –1 and stored in the refrigerator at 2-8ºC overnight.  A second collection will 
be performed the following afternoon and both collections will be transfused.  Each collection 
will be separately evaluated in the cryobiology laboratory for cellular composition in keeping 
with the BMT CTN MOP for graft characterization. 
 
A minimum dose of 2.0 x 106 CD34+ cells/kg recipient weight will be collected from the donor 
(according to institutional practices) and given.  If  10 x 106 CD34+ cells/kg are collected on 
Day –1, a second collection will not be necessary.  If less than 2.0 x 106 CD34+ cells/kg 
recipient weight are collected with the first two aphereses, a third collection must be performed 
on Day +1.  All cells collected should be infused.  Cryopreservation of donor stem cells may be 
acceptable, but the Medical Monitor or one of the Protocol Chairs must be consulted.   
 
Patients with < 2.0 x 106 CD34+ cells/kg recipient weight available after 3 aphereses will not 
receive an allogeneic transplant on protocol.  Subsequent management of these patients is at the 
discretion of their attending physician.  
 
 
Table 2.4.5 -- Treatment Schedule for Donor 
 
Days 
-4 
-3 
-2 
-1 
0 
1 
G-CSF 16 g/kg SQ or IV 
X 
X 
X 
X 
X 
X** 
PBSC Collection 
 
 
 
X 
X* 
X** 
PBSC Administration 
 
 
 
 
X 
X** 
*  The second PBSC collection can be cancelled only if ≥ 10 x 106 CD34+ cells/kg 
recipient weight are collected with the first apheresis. 
** A third collection is required if < 2.0 x 106 CD34+ cells/kg recipient weight are 
collected with the 2 previous aphereses. 
 
 
2.4.5.3 PBSC infusion 
 
Patients will receive unmodified (other than volume reduction) G-CSF mobilized PBSC from an 
HLA-identical sibling on Day 0 of the treatment regimen.  For patients with and HLA-identical 
sibling donor who requires three aphereses, Day 0 is defined as the day the patient receives the 
product of the first two aphereses.  The PBSC is infused via a central venous catheter using 
standard blood infusion tubing.  If more than 2 x 106 CD34+ cells/kg were collected from the 
donor, all available cells must be infused. 
 


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2.5 
Supportive Care 
 
2.5.1 Post Autologous Transplantation(s) 
 
All supportive care will be given in keeping with BMT CTN MOP and local institutional 
practice. 
 
2.5.1.1 Bisphosphonates 
 
Monthly IV bisphosphonates (either Zometa or Pamidronate according to institutional 
preference) may be initiated (or re-initiated) after the first (or second) autograft according to 
local institutional practice. 
 
2.5.1.2 Prophylaxis against infections  
 
All patients will receive prophylaxis against bacterial, fungal and viral infections during the peri-
transplant period according to the BMT CTN MOP and local institutional practice.  Additional 
specifications/requirements for this study are summarized below.  Infectious prophylaxis will 
include prophylaxis for: 
1. Anti-bacterial:  In keeping with the BMT CTN MOP and local institutional standards. 
2. Pneumocystis carinii:  Prophylaxis will start at the time of engraftment or on Day 30 post 
autologous transplant according to institutional preference.  Prophylaxis should be 
continued until at least six months post autologous transplantation.  
3. Anti-fungal Therapy:  Anti-fungal prophylaxis will be initiated peri-transplant according 
to local institutional practice and will continue until neutrophil recovery post autologous 
transplant. 
4. HSV/VZV prophylaxis will be initiated according to local institutional practice peri-
transplant and continue until six months post autologous transplantation. 
 
2.5.1.3 Growth factors 
 
Patients will receive ~5 g/kg/day of G-CSF subcutaneously from Day 5 post autologous 
transplant until ANC > 500/mm3 for two days.  G-CSF dosing can be rounded based on patient 
weight and available G-CSF vial sizes to best approximate 5 g/kg/day (e.g., < 70 kg use 300 g 
vial, 70 to 90 kg use 480 g vial and > 90 kg use 2 x 300 g vials).  If the patient is unable to 
tolerate G-CSF subcutaneously, it may be administered intravenously as per package insert. 
 
2.5.1.4 Blood products 
 
Transfusion thresholds for blood product support will be in keeping with BMT CTN MOP and 
standard institutional guidelines.  All blood products will be irradiated.  Allogeneic transplant 
candidates who are CMV negative will receive CMV negative or filtered blood products from 
study entry. 
 


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2.5.1.5 Immunizations 
 
Patients should initiate re-immunization programs at one year following the second autologous 
transplant according to local institutional practice and the BMT CTN MOP. 
 
2.5.2 Post-initiation of Dexamethasone and Thalidomide 
 
Continue with supportive care as outlined in Section 2.5.1.  No routine extension of infection 
prophylaxis is planned for patients randomized to maintenance therapy. 
 
Stevens-Johnson syndrome has been reported in a small number of MM patients receiving 
thalidomide, allopurinol and Bactrim.  It is not clear which drugs in the combination were 
responsible for the development of this complication.  Treating physicians should be aware of 
this potential risk and if desired use an alternative to Bactrim for PCP prophylaxis (e.g., dapsone) 
for patients on maintenance thalidomide and dexamethasone until it is discontinued at 12 months 
post initiation of maintenance therapy. 
 
Female patients having any chance of becoming pregnant must have a pregnancy test performed.  
The test should be performed weekly for the first four weeks of treatment, and then every four 
weeks until 12 months post initiation of maintenance therapy if the patient’s periods are regular 
or every two weeks if they are not. 
 
Male patients must use a latex condom every time they have sexual intercourse with a woman 
during therapy and for four weeks after discontinuing thalidomide, even if they have had a 
successful vasectomy.  Male patients should request that female partners use a second method of 
birth control in addition to a male condom. 
 
2.5.2.1 Coumadin 
 
Patients receiving dexamethasone and thalidomide as remission induction therapy for MM have 
an increased risk of developing deep vein thrombosis (DVT).  This risk may be as high as 10%.  
It is unclear whether the risk is the same in patients receiving dexamethasone and thalidomide as 
maintenance therapy after autologous transplantation.  Experience at MD Anderson Cancer 
Center (MDACC) and City of Hope, suggest it is likely lower (personal communication Sergio 
Giralt and Firoozeh Sahebi).  Treating physicians should be aware of this risk and have 
heightened vigilance regarding this possible toxicity in patients randomized to the maintenance 
therapy arm. 
 
Coumadin for DVT prophylaxis may be given according to institutional practice.  Administration 
of coumadin and the incidence of DVT will be monitored by the BMT CTN Data Safety 
Monitoring Board. 
 


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2.5.3 Post Non-myeloablative Allogeneic Transplant  
 
All supportive care will be given in keeping with BMT CTN MOP and local institutional 
practice.   
 
2.5.3.1 Bisphosphonates 
 
Monthly IV bisphosphonates (either Zometa or Pamidronate) may be initiated after the allograft 
according to local institutional preference. 
 
2.5.3.2 Prophylaxis against infections 
 
All patients will receive prophylaxis against bacterial, fungal and viral infections during the peri-
transplant period according to the BMT CTN MOP and local institutional practice.  Additional 
specifications/requirements for this study are summarized below.  Infectious prophylaxis will 
include prophylaxis for:  
1. Anti-bacterial prophylaxis: In keeping with the BMT CTN MOP and local institutional 
standards for allogeneic transplants.  
2. Pneumocystis carinii: Prophylaxis will start at the time of engraftment or on Day 30 post 
allogeneic transplant according to institutional preference.  Prophylaxis should be 
continued until at least six months post allogeneic transplant.  
3. Anti-fungal therapy: Anti-fungal prophylaxis will be initiated peri-transplant according to 
local institutional practice and will continue until at least Day 70 post allogeneic 
transplant.  
4. HSV/VZV: Prophylaxis will be initiated peri-transplant according to local institutional 
practice and will continue until six months post allogeneic transplant. 
5. CMV: Monitoring and preemptive treatment strategy will be in accordance with the BMT 
CTN Technical Committee (Infectious Disease) MOP and local institutional practice. 
 
2.5.3.3 Post-transplant growth factors 
 
Patients will not receive post-transplant growth factors while receiving MMF (Days 0-27 post 
allogeneic transplant).  After Day 27 post allogeneic transplant, G-CSF should be given for 
severe neutropenia (ANC < 500/mm3) as necessary to keep ANC > 1000/mm3. 
 
2.5.3.4 Blood products 
 
See Section 2.5.1.4 for use of blood products. 
 


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2.5.3.5 Post-transplant immunization schedule 
 
Once a patient is off all immunosuppressive therapy or has evidence of T cell function 
(approximately one-year post allogeneic transplant), immunizations may be given in keeping 
with the BMT CTN MOP and local institutional practice. 
 
2.5.3.6 Post-transplant donor cellular infusions (DCI)  
 
DCI may be given to patients for tumor progression but patients receiving DCI will be 
considered a failure for the primary study endpoint of progression free survival.  Prior to 
initiating DCI, the indication must be reviewed with the Medical Monitor or one of the Protocol 
Chairs. 
 
2.6 
Participant Risks 
 
Recipients of transplants incur risks from pre-transplant conditioning and post-transplant 
therapy, which must be weighed against the risk of the disease for which the transplant is 
prescribed.  Major risks following transplantation include: 1) Infection, which can be bacterial, 
viral, parasitic, or fungal.  Often, these infections are life-threatening, particularly when caused 
by viral or fungal agents, and are associated with high mortality in the transplant population;  
2) GVHD, either acute or chronic in nature, may occur following allogeneic transplantation.  The 
degree of GVHD varies from mild cutaneous reactions to extensive widespread and systemic 
involvement of skin, liver, and gastrointestinal tract.  Probably due to a direct association, the 
incidence of fatal infection is greater in patients developing GVHD; 3) Graft Failure can occur 
and is associated with a high-risk of mortality; 4) End Organ Damage of all or any of the major 
organs may occur as a result of reactions to drugs (e.g., melphalan antibiotics, anti-fungal 
medications, MMF, CSA, etc.), and as a result of destructive processes (e.g., infection, GVHD, 
etc.), and may have a fatal outcome; 5) Relapse of MM may occur, especially in patients with 
advanced disease status at time of treatment; 6) Unknown Toxicities may occur in any individual 
patient due to multiple events and cumulative effects which may involve any and all organs, 
including the brain.  Brain damage can result in severe loss of cognitive or neurologic function; 
and, 7) Death. 
 
2.7 
Therapy Toxicities 
 
All toxicities will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 with BMT specific definitions when appropriate. 
 
2.7.1 Total Body Irradiation (TBI) 
 
TBI may cause nausea, vomiting, diarrhea, temporary hair loss, and painful swelling of the 
salivary glands for a few days.  The dose of TBI in this protocol is approximately one-sixth of 
that used in standard transplant protocols.  Therefore, these side effects most likely will be 
milder and severe acute side effects are not expected.  It is also expected that the risk of 
infertility will be lower than standard transplant that uses higher doses of TBI.  The risk of 
secondary malignancies after the low dose TBI is yet to be determined. 
 


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2.7.2 Mycophenolate Mofetil (MMF) 
 
MMF is supplied in 250 mg hard gelatin capsules.  Capsules can be stored at room temperature. 
 
1. Mycophenolate mofetil has not been extensively studied in patients after marrow 
transplantation.  Previous clinical studies in patients after renal allografting suggested that 
the principal adverse reactions associated with the administration of MMF include 
diarrhea, leukopenia, sepsis, vomiting and a higher incidence of certain viral infections 
(CMV, VZV, Herpes Simplex).  Patients will be monitored for the development of these 
complications. 
 
2. Studies in solid organ transplant recipients suggest that MMF may be associated with 
vomiting and diarrhea, decline in hematocrit and white blood cell count, and infection.  In 
the setting of marrow transplantation, several etiologic factors may contribute to 
alterations in GI and hematologic parameters.  MMF has an increased incidence of 
digestive system adverse events, including GI tract ulceration and hemorrhage (3% of 
patients receiving MMF).  Gastrointestinal tract perforations have rarely been observed.  
Most patients in these studies were also on other drugs known to be associated with these 
complications.  Up to 2% of patients receiving MMF for prevention of rejection 
developed severe neutropenia (ANC <500/mm3).  The development of neutropenia may 
be related to MMF itself, concomitant medications, viral infections or some combination 
of these causes.   
 
MMF dose adjustments will be made if clinically indicated if, in the opinion of the 
attending physician, no other cause is thought to be responsible for the abnormality.  
These adjustments should be discussed with the Medical Monitor or one of the Protocol 
Chairs.  Dose adjustments are described in Section 2.4.4.2. 
 
2.7.3 Dexamethasone 
 
Dexamethasone may cause nausea, vomiting, insomnia, agitation, weight gain, fluid retention, 
hypertension, metabolic disturbances (increased glucose, increased potassium, decreased bone 
density), increased risk of infection, gas and heartburn.  Sometimes it may aggravate underlying 
peptic ulcer disease and may cause gastrointestinal bleeding.  Dexamethasone may also cause 
secondary hypertension and hyperglycemia or may aggravate the underlying hypertension and 
diabetes.  All toxicities will be scored according to the modified NCI toxicity criteria.  
 
2.7.4 Thalidomide 
 
1.  Neurologic: Somnolence, dizziness, confusion, tremor, loss of co-ordination, paresthesia 
and numbness.   
2.  Gastrointestinal: Constipation, nausea, vomiting and stomatitis. 
3.  Constitutional: Weakness, weight loss, fever. 
4.  Reproductive: Severe birth defects. 
 


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Thalidomide will be withheld for any Grade 3 toxicity or higher attributable to thalidomide and 
not reversible or easily managed by standard supportive care such as antiemetics, antipyretics 
and intravenous fluids or for any serious medical complication of the transplant to which 
thalidomide is judged to be contributing.  If such toxicity was not considered life-threatening, the 
thalidomide may be resumed at 50% of the original dose.  Escalation of thalidomide dose should 
be considered after one week of therapy on the reduced dose.  Recurrence of similar toxicities at 
Grade 3 or 4 despite dose reduction will be an indication for discontinuation of thalidomide and 
reinstitution will not be permitted.  (See Section 2.4.3.3 for details of dose modification.)   
 
2.7.5 G-CSF 
 
1. Musculoskeletal: In clinical trials, medullary bone pain was the only consistently 
observed adverse event attributed to G-CSF and was reported in approximately 24% of 
patients across all indications.  The bone pain was generally mild to moderate in severity 
and controllable in most patients with non-narcotic analgesia; infrequently, bone pain was 
severe enough to require narcotic analgesia. 
2. Cardiovascular: Rarely fluid retention; transient hypotension; pericardial effusion. 
3. Dermatologic: Local inflammation at the injection site; rarely cutaneous vasculitis. 
4. Other: Transient, mild to moderate elevations of uric acid, LDH, alkaline phosphatase 
and leukocyte alkaline phosphatase when given with cytotoxic drugs. 
5. Rarely, normal donors receiving G-CSF have experienced swelling of their spleen, and 
on occasion, internal bleeding from the spleen or rupture of the spleen.  Bleeding from or 
rupture of the spleen can present as malaise, flank or abdominal pain, or loss of 
consciousness from low blood pressure.  Rupture of the spleen can be very serious and is 
potentially life threatening.  Management of this problem could require blood 
transfusions or surgery. 
 
2.7.6 Cyclosporine 
 
1. Hematologic: Leukopenia, anemia, thrombocytopenia. 
2. Renal: Renal dysfunction.  It is not unusual for serum creatinine and BUN levels to be 
elevated during CSA therapy.  Overt nephrotoxicity early after transplantation is 
characterized by rapidly rising BUN and creatinine.  This form is usually responsive to 
dosage reduction.  Mild nephrotoxicity, generally noted 2-3 months after transplant is 
often responsive to dose reduction.  A form of chronic progressive cyclosporine-
associated nephrotoxicity characterized by serial deterioration in renal function and 
morphologic changes in the kidneys, will often fail to show a reduction in rising serum 
creatinine despite a decrease or discontinuation of cyclosporine. 
3. Gastrointestinal: Gum hyperplasia, oral thrush, diarrhea, nausea, vomiting and abdominal 
discomfort. 
4. Pulmonary: Sinusitis. 
5. Skin: Hirsutism, acne. 


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6. General Nervous System: Tremor, convulsion, headache.  Hypomagnesemia has been 
reported in some, but not all, patients exhibiting convulsions while on cyclosporine 
therapy. 
7. Cardiovascular: Hypertension (usually mild to moderate), cramps. 
8. Other: Flushing, increased low-density lipoproteins.  A few cases of anaphylactoid 
reactions have been reported in patients receiving Sandimmune injection, believed to be 
due to the Cremophor EL used as the vehicle for IV formulation.  Close monitoring of 
patients receiving IV infusion is necessary. 
 
2.7.7 High-dose Melphalan 
 
High-dose melphalan is well tolerated by patients when they are supported with blood 
component transfusions, PBSC transplantation and broad-spectrum antibiotics.  The duration of 
profound bone marrow suppression decreases with the use of PBSC transplantation and colony 
stimulating factors.  Gastrointestinal toxicity, which includes potentially severe stomatitis, 
esophagitis and severe diarrhea, can become the dose-limiting toxicity in these patients.  The 
majority of patients receiving high-dose melphalan will require parental narcotics for mucositis 
related pain, IV hydration and potentially IV alimentation and broad spectrum IV antibiotics.  
Despite moderate to severe symptoms in many patients, recovery is the norm, coincident with 
recovery of granulocytes.  Other toxicities reported include pulmonary fibrosis and interstitial 
pneumonitis, skin hypersensitivity, vasculitis, alopecia, hemolytic anemia, and allergic reaction. 


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CHAPTER 3 
 
 
3. STUDY ENDPOINTS AND DEFINITIONS 
 
3.1 
Definition of High Risk vs. Standard Risk Myeloma 
 
Multiple myeloma patients on the study will be stratified for the purposes of statistical analysis 
into high risk and standard risk groups.  The primary analysis will include only standard risk 
patients.  It is expected that standard risk patients will account for 85% of the patients on the 
study.  Secondary analyses will be conducted on the high risk group. 
 
3.1.1 High Risk Myeloma Patients 
 
High risk myeloma patients on this protocol are defined as having a serum Beta 2 microglobulin 
level > 4 mg/L and /or abnormalities of chromosome 13 on standard metaphase karyotype 
analysis at anytime prior to transplant. 
 
3.1.2 Standard Risk Myeloma Patients 
 
Standard Risk myeloma patients on this protocol have a serum beta 2 microglobulin ≤ 4 mg/L 
and normal cytogenetics by standard metaphase karyotype analysis.  Patients with no karyotype 
analysis or failed analysis are assumed to not have chromosome 13 abnormalities. 
 
3.2 
Definition of Disease Status 
 
Patients at each data collection period are classified into one of the following states.  Until 
progression, all disease classifications are relative to the patient’s pre-transplantation disease 
status. 
 
1. Complete Response (CR) 
 
CR requires all of the following: 
 Absence of the original monoclonal paraprotein in serum and urine by routine 
electrophoresis and by immunofixation maintained for a minimum of six weeks.  The 
presence of new monoclonal bands consistent with oligoclonal immune reconstitution 
does not exclude CR. 
 Less than 5% plasma cells in a bone marrow aspirate and also on trephine bone 
biopsy, if biopsy is performed.   
 No increase in size or number of lytic bone lesions on radiological investigations, if 
performed (development of a compression fracture does not exclude response). 
 Disappearance of soft tissue plasmacytomas. 
 


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Patients in whom some, but not all, the criteria for CR are fulfilled are classified as partial 
response (see below), providing the remaining criteria satisfy the requirements for partial 
response.  This includes patients in whom routine electrophoresis is negative but in whom 
immunofixation has not been performed. 
 
2. Continuing Complete Response (CCR)  
 
CR continuing from CR prior to conditioning. 
 
3. Partial Response (PR) 
 
PR requires the following: 
 Greater than or equal to 50% reduction in the level of the serum monoclonal 
paraprotein, maintained for a minimum of six weeks. 
 
OR 
 Reduction in 24 hour urinary light chain excretion either by greater than or equal to 
90% or to < 200 mg/24 hours, maintained for a minimum of six weeks, in light chain 
disease. 
 Greater than or equal to 50% reduction in the size of soft tissue plasmacytomas (by 
radiography or clinical examination). 
 No increase in size or number of lytic bone lesions on radiological investigations, if 
performed (development of a compression fracture does not exclude response). 
Patients in whom some, but not all, the criteria for PR are fulfilled are classified as 
minimal response (see below), providing the remaining criteria satisfy the requirements 
for minimal response. 
 
4. Minimal Response (MR)  
 
Minimal response requires all of the following: 
 25-49% reduction in the level of the serum monoclonal paraprotein maintained for a 
minimum of six weeks. 
 
OR 
 50-89% reduction in 24 hour urinary light chain excretion, which still exceeds 200 
mg/24 hours, maintained for a minimum of six weeks. 
 25-49% reduction in the size of soft tissue plasmacytomas (by radiography or clinical 
examination). 
 No increase in the size or number of lytic bone lesions on radiological investigations, 
if performed (development of a compression fracture does not exclude response). 
 


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MR also includes patients in whom some, but not all, the criteria for PR are fulfilled, 
provided the remaining criteria satisfy the requirements for MR. 
 
5. Stable Disease (SD)  
 
 Stable values (within 25% above or below value at time response is assessed) 
maintained for at least three months. 
 
3.3 
Relapse or Progressive Disease (PD) 
 
3.3.1 Relapse 
 
Relapse from CR requires one or more of the following: 
 Reappearance of serum or urine paraprotein on immunofixation or routine 
electrophoresis, confirmed by at least one further consecutive investigation within 2-4 
weeks and excluding oligoclonal immune reconstitution. 
 Greater than or equal to 5% plasma cells in a bone marrow aspirate or on trephine bone 
biopsy. 
 Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase 
in the size of residual bone lesions. Development of a compression fracture does not 
exclude continued response and may not indicate progression. 
 Development of hypercalcemia (corrected serum Ca > 11.5 mg/dL or > 2.8 mmol/L) not 
attributable to any other cause. 
 
3.3.2 Progressive Disease (PD)  
 
For patients not in CR, progressive disease requires one or more of the following: 
 > 25% increase in the level of the serum monoclonal paraprotein, which must also be an 
absolute increase of at least 0.5 g/dL and confirmed by at least one repeated investigation. 
 > 25% increase in 24-hour urinary light chain excretion, which must also be an absolute 
increase of at least 200 mg/24 hours and confirmed by at least one repeated investigation.  
 > 25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which 
must also be an absolute increase of at least 10%. 
 Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. 
 Development of new bone lesions or soft tissue plasmacytomas.  
 Development of a compression fracture does not exclude continued response and may not 
indicate progression. 
 Development of hypercalcemia (corrected serum Ca > 11.5 mg/dL or > 2.8 mmol/L) not 
attributable to any other cause. 
 


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3.4 
Primary Endpoint to be Compared Between Tandem Autologous Transplant 
Recipients Randomized to Maintenance Therapy vs. Observation Following Their 
Second Transplant 
 
3.4.1 Three Year Progression Free Survival (PFS) 
 
The primary endpoint to be compared between the two arms is 3-year PFS.   Patients are 
considered a failure for this endpoint if they die or if they progress or relapse.  The time to this 
event is the time from initiation of the first dose of high dose melphalan to relapse/progression, 
death, initiation of non-protocol anti-myeloma therapy, loss to follow-up or the end of the study, 
whichever comes first. 
 
Patients initiating non-protocol anti-myeloma therapy are considered a failure of progression-free 
survival on this protocol. 
 
3.5 
Secondary Endpoints to be Compared Between Tandem Autologous Transplant 
Recipients Randomized to Maintenance Therapy vs. Observation Following Their 
Second Transplant 
 
3.5.1 Current Myeloma-Stable Survival 
 
This function is an estimate of the chance that a patient is alive with stable disease at a given 
point in time.  Patients are said to have stable disease if they are in the state CR, PR, MR, or SD 
relative to their disease state at the most recent prior ascertainment of disease status.  Unlike PFS 
where patients are counted as an event at the time of first progression/relapse, this outcome 
measure takes into account subsequent disease control/response that occurs following the second 
transplant.  A similar approach has been used in analyzing the role of DLI following allogeneic 
transplants for chronic myelogenous leukemia where relapse is expected to be frequent but 
subsequent disease control is also expected after treatment of relapse with DLI68.  A multi-state 
model will estimate this with inputs being the patient’s disease status at each potential 
examination time. 
 
3.5.2 Three Year Overall Survival 
 
The event is death from any cause.  The time to this event is the time from initiation of the first 
dose of high dose melphalan to death, loss to follow-up or the end of the study, whichever comes 
first.  Patients alive at the time of last observation are considered censored. 
 
3.5.3 Incidence of Progression 
 
Patients are considered experiencing an event when they progress.  Deaths without progression 
are considered as a competing risk.  Patients alive with no history of progression are censored at 
time of last follow-up.  Patients initiating non-protocol anti-myeloma therapy are considered to 
have progressed on this protocol. 
 


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3.6 
Tertiary Endpoints to be Compared Between Tandem Autologous Transplant 
Recipients Randomized to Maintenance Therapy vs. Observation Following Their 
Second Transplant 
 
3.6.1 CR and CR+PR Rates at Two and Twelve Months 
 
The numerator for the estimate of the CR rate counts patients who are alive and in CR at two (or 
twelve) months post second autotransplant, and the denominator counts patients who have been 
followed for two (or twelve) months, regardless of survival or remission status.  The numerator 
for the estimate of the CR+PR rate counts patients who are alive and in CR or PR at two (or 
twelve) months.  The proportion of patients in CR and PR will be compared between treatment 
arms using standard techniques for categorical data. 
 
3.6.2 Time to CR and CR+PR 
 
Event is CR (CR or PR).  The time to event is the time to CR (CR or PR).  Patients who die in a 
state other than CR (CR or PR) are considered as failing from a competing risk.  Patients alive 
and not in CR (CR or PR) at the time of last observation are considered as censored for this 
event. 
 
3.6.3 Time to Off-study Therapy 
 
This event is the initiation of anti-myeloma therapy other than those defined by the protocol 
treatment arms.  Patients who die without initiation of an off-study therapy will be considered as 
experiencing a competing risk.  Patients who do not receive an off-study therapy but are alive at 
the end of the study will be considered censored. 
 
3.6.4 Quality of Life 
 
The FACT-BMT69 version 4.0 instrument is comprised of a general core questionnaire, the 
FACT-G, that evaluates the health-related quality of life (HQL) of patients receiving treatment 
for cancer, and a specific module, BMT Concerns, that addresses disease and treatment-related 
questions specific to bone marrow transplant.  The FACT-G consists of four subscales developed 
and normed in cancer patients:  Physical Well-being, Social/Family Well-being, Emotional Well-
being, and Functional Well-being.  Each subscale is positively scored, with higher scores 
indicating better functioning.  The FACT-BMT Total, which is the grand total of all items in the 
FACT-G and BMT modules, will be used as the outcome measure in summarizing the FACT-
BMT data. 
 
The MOS SF-3670, 71 instrument is a general assessment of health quality of life with eight 
components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, 
Vitality, Social Functioning, Role Emotional, and Mental Health Index.  Each domain is 
positively scored, indicating that higher scores are associated with positive outcome.  This scale 
has been widely applied in a variety of outcome studies and is being used in this protocol as a 
generic measure of quality of life.  To facilitate comparison of the results with published norms, 
the Physical Component Summary (PCS) and Mental Component Summary (MCS) will be used 
as the outcome measures in summarizing the SF-36 data. 


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HQL will be compared between the two groups utilizing the FACT-BMT self report, transplant 
specific questionnaire and the generic quality of life tool, the SF-36.  The questionnaires will be 
scored according to standard procedures and the quality of life will be compared at 3 years 
following the initiation of the first autologous transplant.  The self report questionnaires will be 
performed prior to the first and second transplant, and at 6 months, 1, 2 and 3 years post second 
transplant.  Only English and Spanish speaking patients are eligible to participate in the HQL 
component of this trial. 
 
3.6.5 Incidence of Toxicities Grade  3 According to the CTCAE Version 3.0  
 
Grade  3 toxicities will be tabulated for each patient at set intervals over the course of the study.  
The proportion of patients developing toxicity will be compared between treatment arms.  
 
3.6.6 Incidence of Infections 
 
The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for 
each patient.  The proportion of patients in each treatment arm with these infections will be 
compared.  
 
3.6.7 Drop Out Rate From Maintenance Therapy 
 
Compliance with maintenance therapy will be assessed by collecting data from unused pills 
returned to the clinic.  Data on the maximum dose tolerated by the patient will be collected at 
scheduled clinic visits. 
 
3.6.8 Duration of Maintenance Therapy 
 
The duration of maintenance therapy will be established from the date of initiation of therapy to 
the date of permanent discontinuation.  If the medication is withdrawn through a series of dose 
reductions, the date of the last dose upon completion of the taper will be used. 
 
3.7 
Primary Endpoint to be Compared Between Tandem Autologous Transplant 
Recipients and Tandem Autologous + Non-myeloablative Matched Sibling 
Allogeneic Transplant Recipients 
 
3.7.1 Three-Year Progression Free Survival (PFS) 
 
The primary endpoint is three-year PFS.  Patients are considered a failure for this endpoint if 
they die or if they progress or relapse.  The time to this event is the time from initiation of the 
first dose of high dose melphalan to relapse/progression, death, initiation of non-protocol anti-
myeloma therapy, loss to follow-up or the end of the study, whichever comes first. 
 
Patients initiating non-protocol anti-myeloma therapy are considered a failure of progressive-free 
survival on this protocol. 
 


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3.8 
Secondary Endpoints to be Compared Between Tandem Autologous Transplant 
Recipients and Tandem Autologous + Non-myeloablative Matched Sibling 
Allogeneic Transplant 
 
3.8.1 Current Myeloma-Stable Survival 
 
This function is an estimate of the chance that a patient is alive with stable disease at a given 
point in time.  Patients are said to have stable disease if they are in the state CR, PR, MR, or SD 
relative to their disease state at the most recent prior ascertainment of disease status.  Unlike PFS 
where patients are counted as an event at the time of first progression/relapse, this outcome 
measure takes into account subsequent disease control/response that occurs following the second 
transplant (see Section 3.4.1).  
 
3.8.2 Three-Year Overall Survival 
 
The event is death from any cause.  Patients alive at the time of last observation are considered 
censored. 
 
3.8.3 Incidence of Progression 
 
Patients are considered experiencing an event when they progress.  Deaths without progression 
are considered as a competing risk.  Patients alive with no history of progression are censored at 
time of last follow-up. 
 
Patients initiating non-protocol anti-myeloma therapy are considered to have progressed on this 
protocol. 
 
3.9 
Tertiary Endpoints to be Compared Between Tandem Autologous Transplant 
Recipients and Tandem Autologous + Non-myeloablative Matched Sibling 
Allogeneic Transplant 
 
3.9.1 CR and CR+PR Rates at Two and Twelve Months 
 
The numerator for the estimate of the CR rate counts patients who are alive and in CR at two (or 
twelve) months post second transplant, and the denominator counts patients who have been 
followed for two (or twelve) months, regardless of survival or remission status.  The numerator 
for the estimate of the CR+PR rate counts patients who are alive and in CR or PR at two (or 
twelve) months.  The proportion of patients in CR and PR will be compared between treatment 
arms using standard techniques for categorical data.  
 
3.9.2 Time to CR and CR+PR 
 
Event is CR (CR or PR).  The time to event is the time to CR (CR or PR).  Patients who die in a 
state other than CR (CR or PR) are considered as failing from a competing risk.  Patients alive 
and not in CR (CR or PR) at the time of last observation are considered as censored for this 
event. 


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3.9.3 Time to Second Transplant 
 
The event is the initiation of the conditioning regimen for the second transplant (non-
myeloablative allotransplant for patients with donors, second high dose melphalan autologous 
transplant for other patients).  Patients who die without initiation of their second transplant will 
be considered as experiencing a competing risk.  Patients who do not receive an off-study 
transplant but are alive at the end of the study will be considered censored. 
 
3.9.4 Time to Off-study Therapy 
 
This event is the initiation of anti-myeloma therapy other than those defined by the protocol 
arms.  Patients who die without initiation of an off-study therapy will be considered as 
experiencing a competing risk.  Patients who do not receive a second therapy but are alive at the 
end of the study will be considered censored. 
 
3.9.5 Quality of Life 
 
The FACT-BMT69 version 4.0 instrument is comprised of a general core questionnaire, the 
FACT-G, that evaluates the HQL of patients receiving treatment for cancer, and a specific 
module, BMT Concerns, that addresses disease and treatment-related questions specific to bone 
marrow transplant.  The FACT-G consists of four subscales developed and normed in cancer 
patients:  Physical Well-being, Social/Family Well-being, Emotional Well-being, and Functional 
Well-being.  Each subscale is positively scored, with higher scores indicating better functioning.  
The FACT-BMT Total, which is the grand total of all items in the FACT-G and BMT modules, 
will be used as the outcome measure in summarizing the FACT-BMT data. 
 
The MOS SF-3670, 71 instrument is a general assessment of health quality of life with eight 
components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, 
Vitality, Social Functioning, Role Emotional, and Mental Health Index.  Each domain is 
positively scored, indicating that higher scores are associated with positive outcome.  This scale 
has been widely applied in a variety of outcome studies and is being used in this protocol as a 
generic measure of quality of life.  To facilitate comparison of the results with published norms, 
the Physical Component Summary (PCS) and Mental Component Summary (MCS) will be used 
as the outcome measures in summarizing the SF-36 data. 
 
HQL will be compared between the two groups utilizing the FACT-BMT self report, transplant 
specific questionnaire and the generic quality of life tool, the SF-36.  The questionnaires will be 
scored according to standard procedures and the quality of life will be compared at 3 years 
following the initiation of the first autologous transplant.  The self report questionnaires will be 
performed prior to the first and second transplant, and at 6 months, 1, 2 and 3 years post second 
transplant.  Only English and Spanish speaking patients are eligible to participate. 
 
3.10 
Tertiary Endpoints that Only Apply to Allograft Recipients 
 
The following endpoints will be used to describe outcomes associated with only the recipients of 
the HLA-matched sibling allograft.  They will not be compared between the two treatment arms. 


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3.10.1 Incidence of Primary and Secondary Graft Failure 
 
Engraftment is defined as achieving > 5% donor chimerism by Day 56. 
 
Primary graft failure is defined as a donor chimerism < 5% by Day 56 post-transplant.  
Methodology of chimerism is as described in the BMT CTN MOP. 
 
Secondary graft failure is defined by documented engraftment followed by loss of graft as 
defined by donor chimerism < 5% as demonstrated by a chimerism assay. 
 
3.10.2 Incidence and Severity of Graft-Versus-Host-Disease (GVHD)  
 
See the BMT CTN MOP for definitions of acute and chronic GVHD. 
 
3.11 
Safety Monitoring Endpoints 
 
3.11.1 Treatment-related Mortality 
 
There are regimen-specific Treatment-related Mortality (TRM) monitoring plans for each of the 
three treatment arms.  TRM is defined as death occurring in a patient from causes other than 
relapse or progression.  Individuals who relapse or progress are censored for the event of TRM. 
 
3.11.2 Regimen-related Toxicity 
 
There are two regimen-related toxicity monitoring plans for each of the three treatment arms.  
The rates of deep vein thrombosis, sensory neuropathy, renal and hepatic toxicities will be 
monitored.  The occurrence of one of these toxicities is considered an event, even if the condition 
reverses.  Individuals who die are censored for the event of regimen-related toxicity. 
 
1. Deep vein thrombosis, defined as grade III or higher toxicity from the CTCAE Version 
3.0, under the adverse event type thrombosis/ thrombus/embolism. 
 
2. Sensory neuropathy, defined as grade III or higher toxicity from the CTCAE Version 3.0, 
under the adverse event type neuropathy: sensory. 
 
3. Renal toxicity is defined as use of dialysis. 
 
4. Hepatic toxicity, defined as grade III or higher toxicity from the CTCAE Version 3.0, 
under the adverse event type bilirubin (hyperbilirubinemia). 
 
Monitoring will be performed monthly as described in Chapter 5.   


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CHAPTER 4 
 
 
4. PATIENT ENROLLMENT AND EVALUATION 
 
4.1 
Enrollment Procedures 
 
4.1.1 Screening and Eligibility Procedures 
 
Patients will be registered using the Advantage Electronic Data Capture (AdvantageEDCSM) 
system.  Southwest Oncology Group (SWOG) centers should follow instructions in Section 4.1.2 
prior to following the instructions below.  The following procedures should be followed: 
1. An authorized user at the clinical center completes a screening form with demographic 
and primary eligibility screening questions.  The eligibility screening includes a question 
confirming that the patient signed the informed consent form and that they have an 
adequate autologous graft available to them. 
2. If the patient is eligible, a study number is generated.  
3. A visit schedule based on transplant date is available for printing and is referred to as 
‘Segment A Follow-up.’ 
4. The clinical center draws and HLA types blood samples from the patient and sibling(s) as 
soon as possible after initial evaluation to determine the availability of an HLA-matched 
sibling donor.  If possible, this testing will be complete prior to the first autologous 
transplant but it is expected that full donor evaluations will not always be possible to 
complete by this time.  Patient samples for HLA-testing MUST be drawn prior to the first 
autologous transplant and potential donor samples must be drawn no later than three 
weeks after the first autologous transplant.   
5. Either at the time of first registration or as soon as evaluation of all potential donors is 
complete, whichever comes first, an authorized user at the clinical center completes a 
secondary eligibility form indicating whether or not the patient has an HLA-identical 
sibling donor.  This form must be completed for every patient, even if the patient has 
become medically ineligible for a second transplant by the time the donor evaluation is 
complete.  If an HLA-matched sibling is available, the donor and recipient HLA typing 
information is completed on the eligibility form.  If an HLA-matched sibling is not 
available, the Sibling Information Form is required to obtain information pertaining to 
ineligibility of all siblings (non-donors, including those who were HLA typed and those 
who were not typed due to medical reasons).  Patients with a donor are then assigned to 
the auto-allo arm.  Patients without an HLA-matched sibling donor are then randomized 
to either tandem autologous followed by one year of observation or tandem autologous 
followed by one year of maintenance therapy.   
6. After recovery from the 1st autologous transplantation (at least 60 days post first 
transplant), an authorized user at the clinical center completes the Post Autologous 
Transplant Checklist confirming that the patient has recovered and is eligible for either a 
non-myeloablative allogeneic transplant or second autologous transplant.  


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7. If the patient is eligible, the treatment plan is continued.  
8. A visit schedule based on the second transplant date is displayed for printing and is 
referred to as ‘Segment B Follow-up.’ 
9. After recovery from the second autologous transplant (at least 60 days post second 
transplant), an authorized user at the clinical center completes the Post Tandem 
Autologous Checklist for ALL patients biologically assigned to the Tandem Autologous 
± Maintenance Therapy arm.  Completion of the Post-tandem Autologous Checklist will 
ensure comparable baseline data are collected for patients randomized to either one year 
of maintenance therapy with dexamethasone and thalidomide or one year of observation.   
The Post-tandem Autologous Checklist also confirms that the patient has recovered and is 
eligible to begin receiving one year of dexamethasone and thalidomide maintenance 
therapy.  The randomization assignment (one year of observation or one year of 
dexamethasone and thalidomide maintenance therapy) will be revealed after the Post-
tandem Autologous Transplant Checklist is completed. 
10. If the patient is eligible, the visit schedule referred to as ‘Segment B Follow-up’ is 
continued. 
 
4.1.2 SWOG Patient Registration Procedures 
 
Patients from Southwest Oncology Group (SWOG) Member, CCOP and approved Affiliate 
institutions must be registered through the SWOG Data Operations Center in Seattle using the 
SWOG Web Registration System.  Affiliate institutions not approved to register patients directly 
with the Data Operations Center must register through their Member institution.  The Data 
Operation Center will request information from the SWOG Registration Form.  The institution 
must have these documents completed entirely prior to registering the patient in the SWOG Web 
Registration System.  In addition, the Data Operations Center will collect stratification 
information, will request the date informed consent and HIPAA authorization were obtained, and 
will obtain the date of IRB approval for each entry.   
 
 
4.2 
Study Monitoring  
 
4.2.1 Follow-up Schedule 
 
The Follow-up Schedule for scheduled study visits is outlined in Tables 4.2.1a, 4.2.1b and 
4.2.1c.  A detailed description of each of the forms and the procedures required for forms 
completion and submission can be found in the Data Management Handbook. 
 
Follow-up Visits: Follow-up visits are based on segments.  Segment A is defined as the period 
from high-dose melphalan administration until conditioning for the second transplant.  Segment 
B is defined as the period after second transplantation including maintenance therapy (if 
applicable).   
 
 


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Table 4.2.1a -- Follow-up Schedule – Segment A 
 
Study Visit 
Target Day 
(+ 7 Days Post-1st Transplant) 
4 week 
28 days 
100 day1 
100 days 
 
1 If patient has not received second transplant 
 


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Table 4.2.1b -- Follow-up Schedule – Segment B 
Allogeneic Transplant Patients 
 
 
 
Study Visit 
Target Day 
(± 7 Days Prior to Day 100 Post Second Therapy) 
(± 28 Days after Day 100 Post Second Therapy) 
1 week 1, 2 
7 days 
2 week 1, 2 
14 days 
3 week 1, 2 
21 days 
4 week 1, 2 
28 days 
5 week 
35 days 
6 week 
42 days 
7 week 
49 days 
8 week 
56 days 
9 week 
63 days 
10 week 
70 days 
11 week 
77 days 
12 week 
84 days 
13 week 
91 days 
14 week 
98 days 
120 day (4 months) 
120 days 
6 month 
180 days 
9 months 
270 days 
12 month 
365 days 
18 month 
540 days 
24 month 
730 days 
30 month 
900 days 
36 month 
1,095 days 
 
1 Chemistry panel required twice per week. 
2 Refer to Section 4.2.4.4 for frequency of follow-up for CBC. 


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Table 4.2.1c -- Follow-up Schedule -- Segment B 
Tandem Autologous Transplant Patients 
 
 
 
Study Visit 
Target Day 
(± 7 Days Prior to Day 100 Post Second Therapy) 
(± 28 Days after Day 100 Post Second Therapy) 
1 week 1, 2 
7 days 
2 week 1, 2 
14 days 
3 week 1, 2 
21 days 
4 week 1, 2 
28 days 
8 week 
56 days 
Day 60 
60 days 
9 week 3 
63 days 
10 week 3 
70 days 
11 week 3 
77 days 
12 week 
84 days 
Day 100 
100 days 
16 week 3 
112 days 
20 week 3 
140 days 
24 week 3 
168 days 
6 month 
180 days 
28 week 3 
196 days 
32 week 3 
224 days 
36 week 3 
252 days 
9 months 
270 days 
40 week 3 
280 days 
44 week 3 
308 days 
48 week 3 
336 days 
52 week 3 
364 days 
12 month 
365 days 
56 week 3 
392 days 
18 month 
540 days 
24 month 
730 days 
30 month 
900 days 
36 month 
1,095 days 
 
1 Chemistry panel required twice per week. 
2 Refer to Section 4.2.4.4 for frequency of follow-up for CBC. 
3 For patients taking dexamethasone/thalidomide maintenance therapy. 


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Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are 
detailed in the Data Management Handbook.  Forms that are not entered into the web-based data 
entry system within the specified time will be considered delinquent.  A missing form will 
continue to be requested either until the form is entered into the web based data entry system and 
integrated into the DCC's master database, or until an exception is granted and entered into the 
Missing Form Exception File, as detailed in the Data Management Handbook. 
 
Reporting Patient Deaths: Recipient Death Information must be entered into the web-based 
data entry system within 24 hours of knowledge of the patient’s death.  If the cause of death is 
unknown at that time, it need not be recorded at that time.  However, once the cause of death is 
determined, the form must be updated in the web-based data entry system. 
 
IBMTR Data Reporting:  All transplant centers will be required to pre-register patients with 
the IBMTR for all transplants performed at their center whether or not they enroll in a BMT 
CTN Protocol.  In addition, the transplant center must complete the IBMTR TED Day 100 
Report Form (including the Core, Graft and Disease Inserts) and IBMTR TED Follow-up Form 
(including the Core and Disease Inserts) yearly for all patients enrolled in BMT CTN protocols.  
IBMTR forms will be submitted directly to the IBMTR at the times specified on the Forms 
Submission Schedule. 
 
4.2.2 Weekly GVHD Monitoring Post Non-myeloablative Allogeneic Transplant 
 
GVHD should be monitored in accordance with BMT CTN guidelines as specified in the Manual 
of Procedures.  Patients should be assessed weekly until Day 100 post-transplant for GVHD.  
After Day 100, patients will be assessed at each study visit for the presence of GVHD. 
 
4.2.3 Adverse Event Reporting 
 
Unexpected, grade 3-5 adverse events (AE) will be reported through an expedited AE reporting 
system.  Unexpected, grade 4-5 AEs must be reported within 24 hours of knowledge of the 
event.  Unexpected, grade 3 AEs must be reported within three business days of knowledge of 
the event.  Expected AEs will be reported using NCI’s Common Terminology Criteria for 
Adverse Events (CTCAE) Version 3.0 at regular intervals as defined on the Form Submission 
Schedule. 
 
4.2.4 Patient Assessments 
 
Tables 4.2.5 and 4.2.5a summarize patient clinical assessments over the course of the study.  All 
assessments prior to and after both transplants are considered standard of care. 
 


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4.2.4.1 Evaluations prior to the first autologous transplantation 
The following observations must be determined ≤ 12 weeks prior to initiation of high-dose 
melphalan either before or after initiation of mobilization therapy depending on transplant 
center standard of practice.  If these tests are done prior to mobilization therapy and there is 
clinical suspicion of cardiac or pulmonary toxicity following mobilization therapy, these tests 
must be repeated prior to the initiation of high-dose melphalan.   
1. EKG. 
2. LV ejection fraction by MUGA, echocardiogram or MRI according to local institutional 
practice. 
3. DLCO, FEV1 and FVC (or O2 saturation). 
 
Infectious disease testing, including CMV titer, hepatitis panel (HepA Ab, HepB SAb, HepB 
SAg, HepB Core Ab, HepC Ab), herpes simplex titre, syphilis, HIV and HTLV1 antibody, 
should be determined in accordance with FACT guidelines (i.e., 30 days prior to the initiation 
of mobilization therapy).  If there is clinical suspicion of new infection, tests must be repeated 
prior to the initiation of high-dose melphalan. 
 
The following observations are to be determined  8 weeks prior to the initiation of high-dose 
melphalan either before or after initiation of mobilization therapy depending on transplant 
center standard of practice.   
1. History, physical examination, height and weight. 
2. CBC with differential and platelet count, creatinine clearance, creatinine, bilirubin, 
alkaline phosphatase, ALT, sodium, magnesium, potassium, chloride and CO2. 
3. Baseline Disease Evaluation 
a) Skeletal survey to include cranium, axial skeleton and proximal long bones. 
b) Unilateral bone marrow biopsy and aspirates to pathology, aspirate to cytogenetics for 
standard metaphase karyotype analysis. 
4. Laboratory Disease Evaluation 
a) Quantitative serum immunoglobulin levels. 
b) Serum protein electrophoresis (SPEP).  
c) 24 hour urine collection to determine creatinine clearance and protein excretion, urine 
protein electrophoresis (UPEP).  Creatinine clearance may be calculated. 
d) Immunofixation of serum protein and urine protein regardless of SPEP and UPEP 
results. 
e) Serum beta 2 microglobulin (B2M serum). 
5. One vial (10cc) of nucleated cells and one vial (10cc) serum from patient’s peripheral 
blood for future testing. 
6. Flow cytometry analysis of autologous graft per the Graft Characterization section of the 
BMT CTN MOP.  


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The following observations should be determined  4 weeks prior to the initiation of high-dose 
melphalan before or after mobilization depending on transplant center standard of care. 
 
1. Pregnancy test (for women of childbearing potential).  Women are of childbearing 
potential unless they have had a hysterectomy or had no menses or have been post-
menopausal for at least 24 months. 
2. Health quality of life assessment (for English and Spanish speaking patients only). 
 
The Karnofsky performance score should be determined  2 weeks prior to the initiation of 
high-dose melphalan. 
 
Samples for HLA typing should be drawn from the patient and sibling(s) and typed as soon as 
possible after initial evaluation to determine the availability of an HLA-matched sibling donor.  
If possible, this testing should be complete prior to the first autologous transplant but it is 
expected that it will not always be possible to complete full donor evaluations by this time.  
Patient samples for HLA-testing MUST be drawn prior to the first autologous transplant and 
potential donor samples must be drawn no later than three weeks after the first autologous 
transplant.  Testing MUST be complete prior to the second transplant.  HLA Class I typing can 
be done by serologic or DNA methods.  HLA Class II typing must be done using DNA 
methodology. 
 
4.2.4.2 Post first autologous transplant 
 
A toxicity assessment will be done at four weeks post first autologous transplant. 
 
4.2.4.3 Evaluations prior to the second transplant (autologous or matched-sibling allogeneic) 
 
The following observations will be done  4 weeks prior to initiation of conditioning for the 
second transplant (auto or allo).  Observation 10 is required for the allogeneic arm only. 
1. History, physical examination, height and weight. 
2. Pregnancy test (for women of childbearing potential).  Women are of childbearing 
potential unless they have had a hysterectomy or had no menses or have been post-
menopausal for at least 24 months. 
3. Karnofsky performance score. 
4. CBC with differential, platelet count, creatinine clearance, creatinine, bilirubin, alkaline 
phosphatase, ALT, sodium, magnesium, potassium, chloride and CO2. 
5. Chest X-ray. 
6. LV ejection fraction (if clinically significant cardiac symptoms/signs develop after the 
first autologous transplant). 
7. DLCO, FEV1 and FVC (or O2 saturation). 


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8. Laboratory Disease Evaluation 
a) Quantitative serum immunoglobulin levels. 
b) Serum protein electrophoresis (SPEP).  
c) 24 hour urine collection to determine creatinine clearance and protein excretion, urine 
protein electrophoresis (UPEP).  
d) Immunofixation of serum protein and urine protein regardless of SPEP and UPEP 
results. 
e) Serum beta 2 microglobulin (B2M serum). 
9. Unilateral bone marrow biopsy and aspirates to pathology only to confirm complete 
responses based on clinical and laboratory data.  Bone marrow aspirate to cytogenetics 
only if previously documented abnormal cytogenetics. 
10. Heparinized peripheral blood samples (10cc) from all patients on the allogeneic arm for 
chimerism assays. 
11. Flow cytometry analysis of allogeneic graft per the Graft Characterization section of the 
BMT CTN MOP. 
12. One vial (10cc) of nucleated cells and one vial (10cc) serum from patient’s peripheral 
blood for future testing. 
13. Health quality of life assessment (for English and Spanish speaking patients only). 
 
4.2.4.4 Post second transplant evaluations 
 
Post second autologous transplant for tandem autologous transplant group:  
1. CBC twice per week until Day 28 (or four weeks), then at 8 weeks, 12 weeks, 6 months, 
one year, and then yearly until three years post-transplant. 
2. Comprehensive chemistry panel defined as CBC with differential and platelet count, 
creatinine, bilirubin, alkaline phosphatase, ALT, magnesium, sodium, potassium, 
chloride, CO2 twice a week until Day 28 (or four weeks) and then at 8 weeks, 12 weeks, 
6 months, one year and then yearly until three years post-transplant. 
3. Toxicity assessments at 4, 8, 12 weeks, 6 months, one year, and every 6 months until 
three years post-transplant. 
4. One vial (10cc) of nucleated cells and one vial (10cc) serum from patient’s peripheral 
blood for future testing at 8 weeks, 6 months, 9 months, one year and then every 6 
months post-transplant. 
5. Obtain the following laboratory data at 8 weeks*, 6 months, 9 months, one year and 
every 6 months until three years post-transplant. 
a) Quantitative serum immunoglobulin levels. 
b) Serum protein electrophoresis (SPEP).  
c) 24-hour urine collection to determine protein excretion, urine protein electrophoresis 
(UPEP).  


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d) Immunofixation of serum protein and urine protein regardless of SPEP and UPEP 
results. 
e) Serum beta 2 microglobulin (B2M serum). 
*For tandem autologous patients, this evaluation may be replaced by the disease 
assessment required just prior to initiation of maintenance therapy.  If the initiation of 
maintenance therapy is predicted to be delayed beyond three months post second 
transplant, a disease assessment at eight weeks must be carried out. 
6. Skeletal survey will be repeated at 6 months and one year post second transplant and then 
yearly until three years post-transplant. 
7. Bone marrow aspirate and biopsy to pathology to confirm complete responses based on 
clinical and laboratory data.  At 8 weeks and 6 months, a bone marrow aspirate is sent to 
cytogenetics only if there has been previously documented abnormal cytogenetics.  All 
patients are to have samples sent for cytogenetics at one year and then yearly until three 
years post-transplant for standard metaphase karyotype analysis.  Bone marrow biopsy 
should be repeated at any time point to confirm relapsed MM. 
8. Health quality of life assessment at 6 months, 1 year and then yearly until three years 
post-transplant (for English and Spanish speaking patients only). 
 
Post non-myeloablative transplantation: 
1. History and physical exam to assess GVHD weekly until Day 100 post-transplant, then at 
4 months, 6 months, one year and then yearly until three years post-transplant.  GVHD 
evaluation and grading to be in keeping with BMT CTN MOP. 
2. CBC at least twice a week from Day 0 until ANC > 500 for 2 days after nadir reached.  
Thereafter CBC twice per week until Day 28 (or 4 weeks), then at 8 weeks, 12 weeks, 6 
months, one year and then yearly until three years post-transplant. 
3. Comprehensive chemistry panel defined as CBC with differential and platelet count, 
creatinine, bilirubin, alkaline phosphatase, ALT, magnesium, sodium, potassium, 
chloride, CO2 twice a week until Day 28 (or four weeks) and then at 8 weeks, 12 weeks, 
6 months, one year and then yearly until three years post-transplant. 
4. Heparinized peripheral blood (10cc) for quantitation of chimerism on Weeks 4, 8, and 12, 
6 months and one year post-transplant. 
5. One vial (10cc) of nucleated cells and one vial (10cc) serum from patient’s peripheral 
blood for future testing at 8 weeks, 6 months, 9 months, one year and then every 6 
months until three years after post-transplant. 
6. Toxicity assessments at 4, 8, 12 weeks, 6 months, one year and every 6 months until three 
years post-transplant. 
7. Obtain the following laboratory data at 8 weeks, 6 months, 9 months, one year and every 
6 months until three years post-transplant.  
a) Quantitative serum immunoglobulin levels. 
b) Serum protein electrophoresis (SPEP).  


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c) 24-hour urine collection to determine protein excretion, urine protein electrophoresis 
(UPEP).  
d) Immunofixation of serum protein and urine protein must be done regardless of SPEP 
and UPEP results. 
e) Serum beta 2 microglobulin (B2M serum). 
8. Skeletal survey will be repeated at 6 months and one year post-allograft and then yearly 
until three years post-transplant. 
9. Bone marrow aspirate and biopsy for pathology to confirm complete responses based on 
clinical and laboratory data.  At 8 weeks and 6 months, a bone marrow aspirate is sent to 
cytogenetics only if previously documented abnormal cytogenetics.  All patients must 
send a bone marrow aspirate to cytogenetics at one year, and then yearly until three years 
post-transplant for standard metaphase karyotype analysis.  Bone marrow biopsy should 
be repeated at any time point to confirm relapsed / progressive MM. 
10. Health quality of life assessment at 6 months, one year and then yearly until three years 
post-transplant (for English and Spanish speaking patients only). 
 
4.2.4.5 Prior to initiation of dexamethasone + thalidomide for tandem autologous transplant 
patients randomized to maintenance therapy post second autologous transplant 
 
The following observations will be done 2 weeks prior to initiation of dexamethasone + 
thalidomide maintenance therapy.  Observation 2 is required 24 hours prior to the initiation of 
thalidomide. 
1. History, physical examination, height and weight. 
2. Pregnancy test (for women of childbearing potential) within 24 hours prior to initiation of 
thalidomide.  Women are of childbearing potential unless they have had a hysterectomy 
or had no menses or have been post-menopausal for at least 24 months. 
3. Karnofsky performance score. 
4. CBC with differential, platelet count, creatinine clearance, creatinine, bilirubin, alkaline 
phosphatase, ALT, sodium, magnesium, potassium, chloride and CO2. 
5. Bone marrow aspirate and biopsy for pathology to confirm complete responses based on 
clinical and laboratory data.  Bone marrow aspirate for cytogenetics only if previously 
documented abnormal cytogenetics. 
6. Laboratory Disease Evaluation 
a) Quantitative serum immunoglobulin levels. 
b) Serum protein electrophoresis (SPEP).  
c) 24-hour urine collection to determine creatinine clearance and protein excretion, urine 
protein electrophoresis (UPEP).  
d) Immunofixation of serum protein and urine protein regardless of SPEP and UPEP 
results. 


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e) Serum beta 2 microglobulin (B2M serum). 
 
4.2.4.6 Post initiation of dexamethasone + thalidomide for tandem autologous transplant 
patients randomized to maintenance therapy post second autologous transplant 
 
The post second transplant evaluation outlined in Section 4.2.4.4 for the tandem autologous 
transplant group should be continued.  In addition, a pregnancy test (for women of childbearing 
potential) is required weekly for the first four weeks of maintenance therapy, and then every four 
weeks until 12 months post initiation of maintenance therapy if the patient’s periods are regular 
or every two weeks if they are not.  Women are of childbearing potential unless they have had a 
hysterectomy or had no menses or have been post-menopausal for at least 24 months. 
 
Refer to Appendix D for the System for Thalidomide Education and Prescribing Safety 
(S.T.E.P.S.TM) dosing and administration procedure for thalidomide. 
 
4.2.5 Required Observations for Donor 
 
Routine pre-allografting work-up in keeping with FACT guidelines, BMT CTN MOP and 
institutional standard practice of care.  Work-up to include the following: 
1. HLA typing of heparinized peripheral blood sample to determine if eligible HLA-
matched donor.  If possible, testing should be complete prior to the first autologous 
transplant.  All potential donor samples must be drawn no later than 3 weeks post first 
autologous transplant. 
2. History, physical examination, height and weight. 
3. Pregnancy test (for women of childbearing potential).  Women are of childbearing 
potential unless they have had a hysterectomy or had no menses or have been post-
menopausal for at least 24 months. 
4. Lab tests: CBC with differential and platelet counts, creatinine clearance, creatinine, 
bilirubin, alkaline phosphatase, ALT, magnesium, sodium, potassium, chloride, CO2, 
hepatitis panel (HepA Ab, HepB SAb, HepB SAg, HepB Core Ab, HepC Ab), CMV titer, 
herpes simplex, syphilis, HIV and HTLV I serologies and ABO Rh blood typing.  If 
donor has antibodies against red cell antigens of the recipient, the titers will be 
determined.  CBC will be checked prior to and after leukapheresis collection, and 
thereafter if clinically indicated. 
5. Heparinized peripheral blood sample (20 cc) for chimerism assays. 
6. Five cryovials, each containing 2-5 x 106 nucleated cells from allograft blood stem cells 
to be obtained for the central repository per the Graft Characterization section of the 
BMT CTN MOP. 
7. Evaluation of toxicities experienced post initiation of G-CSF. 
 
Donors must be contacted by phone approximately 30 days post initiation of G-CSF for a 
toxicity evaluation. 


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Table 4.2.5 -- Pre-autologous Transplant, Pre-second Intervention and Donor 
Evaluations 
 
Required Studies / Testing 
Prior to 1st 
Auto 
Transplant 
4 Weeks 
Post-1st 
Autologous 
Transplant 
Pre Second 
Transplant 
(Auto or 
Allo) 1 
Prior to Initiation 
of Maintenance 
Therapy  
Donor 
History, Physical Examination, Height and 
Weight 
X 
 
X 
X 
X 
Pregnancy Test2 
X 
 
X 
X 
X 
Karnofsky Performance Score 
X 
 
X 
X 
 
CBC with Differential, PLT, Creatinine 
Clearance3, Creatinine, Bilirubin, Alkaline 
Phosphatase, ALT, Sodium, Magnesium, 
Potassium, Chloride and CO2 
X 
 
X 
X 
X  4, 5 
CMV Titer, Hepatitis Panel (A, B, C) Herpes 
Simplex, Syphilis 
X 
 
 
 
X 
HIV/HTLV1 Antibody 
X 
 
 
 
X 
Chest X-ray 
 
 
X 
 
 
EKG 
X 
 
 
 
 
LV Ejection Fraction  
X 
 
X 6 
 
 
DLCO/FEV1/FVC 
X 
 
X 
 
 
Toxicity Assessment 
 
X 
 
 
X12 
Skeletal Survey 
X 
 
 
 
 
Bone Marrow Aspirate and Biopsy to 
Pathology; Bone Marrow Aspirate to 
Cytogenetics 
X 
 
X 7, 8 
X 7, 8 
 
HLA Typing 
X 
 
 
 
X 
Serum Immunoglobulin Levels 
X 
 
X 
X 
 
SPEP and Immunofixation 
X 
 
X 
X 
 
24 Hr Urine for UPEP and Immunofixation 
X 
 
X 
X 
 
B2M Serum 
X 
 
X 
X 
 
Chimerism Studies 
 
 
X 9 
 
X 
Nucleated Cells 10 
 
 
 
 
X 
Nucleated Cells and Serum 11 
X 
 
X 
 
 
Health Quality of Life 
X 
 
X 
 
 
Flow Cytometry Analyzing Graft 
X 
 
X 9 
 
 
1 To be performed within 4 weeks of intervention. 
2 For women of childbearing potential. 
3 Only required prior to the first autologous transplant and prior to the second autologous or allogeneic transplant. 
4 Including ABO Rh blood typing.  If donor has antibodies against red cell antigens of the recipient, the titers will be determined. 
5 CBC will be checked prior to and after leukapheresis collection, and thereafter if clinically indicated. 
6 If clinically significant cardiac symptoms/signs develop post-autograft. 
7 Bone marrow aspirate to cytogenetics only if previously documented abnormal cytogenetics. 
8 Unilateral bone marrow biopsy & aspirates to pathology only to confirm complete responses based on clinical & laboratory data. 
9 For the allogeneic arm only. 
10 Five vials, each containing 2-5 x 106 nucleated cells from the allograft, cryopreserved for central repository. 
11 One vial (10cc) of nucleated cells and one vial (10cc) of serum from patient’s peripheral blood for future testing. 
12 On Days 5 and 30 (via telephone) post-initiation of G-CSF. 


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Table 4.2.5.a – Post Second Transplant Evaluations 
Study Assessments/ 
Weeks Post Second Therapy 
Months Post Second Therapy 
Testing 
1 
2 
3 
4 
5 
6 
7 
88 
9 
10 
11 
12 
13 
14 
4 
6 
9 
12 
18 
24 
30 
36 
GVHD Assessments1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Pregnancy Test2 
 
 
 
 
 
 
 
See Section 4.2.4.6 
 
 
 
 
CBC3  
See Section 4.2.4.4  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Chemistry Panel4 
2 x per week7 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Chimerism1 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Toxicity 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Skeletal Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Nucleated Cells and 
Serum9 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
BM Aspirate & Biopsy 
to Pathology, BM 
Aspirate to Cytogenetics5 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Serum Immunoglobulin 
Levels 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
SPEP and 
Immunofixation6 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
24 Hour Urine for UPEP, 
Protein Excretion and 
Immunofixation6 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
B2M Serum 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Health Quality of Life 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
1 For allogeneic transplant arm only. 
2 For women of childbearing potential. 
3 Will be reported on case report form only on Day 28 to document engraftment for allogeneic arm only. 
4 Chemistry panel: differential and platelet count, creatinine, bilirubin, alkaline phosphatase, ALT, magnesium, sodium, potassium, chloride, and CO2 
5 Bone marrow (BM) aspirate and biopsy to pathology to confirm complete responses based on clinical and laboratory data.  Bone marrow aspirate to cytogenetics only if 
previously documented abnormal cytogenetics for week 8 and 6 month assessment.  All patients must send a bone marrow aspirate to cytogenetics yearly post second 
transplant.  Bone marrow biopsy should be repeated at anytime point to confirm relapse/progressive MM. 
6 Regardless of results of SPEP and UPEP. 
7 Will not be reported on case report form. 
8 For tandem autologous patients only: This evaluation, except for the toxicity assessment, may be replaced by the disease assessment required just prior to initiation of 
maintenance therapy (see Table 4.2.5).  If the initiation of maintenance therapy is predicted to be delayed beyond 3 months post second transplant, a disease assessment at 
8 weeks must be carried out. 
9 One vial (10cc) of nucleated cells and one vial (10cc) of serum from patient’s peripheral blood for future testing. 


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CHAPTER 5 
 
 
5. STATISTICAL CONSIDERATIONS 
 
5.1 
Study Overview 
 
The overall study design is that of biologic assignment, based on the availability of an HLA-
matched sibling, to one of two treatment strategies for MM patients.  Patients without an HLA-
matched sibling will undergo tandem autologous transplants (auto-auto).  Patients with an HLA-
matched sibling will undergo an autologous transplant followed by a non-myeloablative 
allogeneic transplant (auto-allo).  In addition, the auto-auto patients will be randomized to either 
observation or one year of maintenance therapy to begin following their second autologous 
transplant.  The large number of available patients without an HLA-matched sibling enables us 
to evaluate the role of maintenance therapy following tandem autologous transplants. 
 
Two primary statistical comparisons will be made.  To insure a 5% overall Type I Error each of 
the comparisons is made at the 2.5% level.  Comparisons are based on comparing three-year PFS 
in an intent to treat analysis. 
 
The first comparison is of the two auto-auto arms.  The goal here is to assess whether 
maintenance therapy increases the percent of patients alive without disease progression three 
years after tandem autologous transplants.  
 
The second comparison is between the auto-auto patients and the auto-allo patients.  Here the 
auto-auto arm depends on the results of the first test.  If that test shows no indication of a 
difference between the two auto-auto arms, then these two arms will be pooled for this 
comparison.  If the first test shows a significant advantage for one of the auto-auto arms, that arm 
will be used in this comparison.  The goal here is to assess whether a graft-versus-myeloma 
effect associated with the auto-allo strategy results in a better outcome for patients with MM. 
 
5.1.1 Accrual 
 
Accrual will remain open until, at a minimum, 150 standard risk patients are assigned to the 
auto-allo arm.  It is estimated that three years of accrual will be necessary to enroll the targeted 
sample size.  Assuming that patients with HLA-matched sibling donors comprise between 20-
30% of eligible patients, approximately 350-600 standard risk patients will likely be accrued to 
the auto-auto arm during the time it takes to accrue the target number of auto-allo patients. 
 
Both Core and non-Core centers will participate.  However, only centers that anticipate 
enrollment of at least 20 standard risk patients may participate in the trial.  This requirement is 
necessary to ensure that all participating centers will enroll at least two patients on the auto-allo 
treatment arm. 
 
A center that performs only autologous transplants may participate, provided that all patients 
who are eligible for the auto-allo arm are referred to the same transplant center for their non-


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myeloablative allogeneic transplant.  The allogeneic transplant center will serve as the center of 
record for the purposes of monitoring and analyzing accrual or other study data.  This provision 
will permit fuller participation of the Southwest Oncology Group (SWOG), which is essential to 
reach the accrual goal. 
 
5.1.2 Biologic Assignment and Randomization 
 
To prevent bias in determining whether donors are eligible or not for donation, and resultant bias 
in the biological assignment, all available siblings will be HLA-typed and all HLA-matched 
siblings will be assessed for donation whenever feasible.  If a patient is deemed unsuitable to be 
a donor, the reasoning will be reviewed with the Protocol Chair or the Protocol Officer.  Patients 
with an HLA-matched sibling who is a suitable donor are biologically assigned to the auto-allo 
arm of the study.  Those patients without a suitable HLA-matched sibling donor are assigned to 
the auto-auto arm.  In order to facilitate an intent-to-treat analysis, the biological assignment will 
take place even if the patient becomes medically ineligible for the second transplant, or must be 
transplanted on a different treatment arm than their biological assignment would indicate. 
 
The timing of the biological assignment and randomization depends on the need to identify, 
HLA-type, and assess HLA-matched siblings for their ability to donate an allograft.  For most 
patients, this information will be known at the time of consenting for the trial.  For some, the 
complete evaluation of potential sibling donors may be delayed until during or shortly after the 
initial autologous transplant.  This protocol requires that potential sibling donors be HLA-typed 
at the earliest opportunity, and that blood for this purpose be drawn no later than three weeks 
after the initial autologous transplant. 
  
The clinical center will re-register patients once the typing and donor eligibility results are 
available.  At this time, the Coordinating Center will make a biological assignment.  Patients 
with an HLA-matched sibling who is an eligible donor will be assigned to the auto-allo arm, and 
those without will be assigned to the auto-auto arm, and further randomized to receive either 
maintenance therapy with thalidomide and dexamethasone, or observation.  To facilitate an 
intention-to-treat analysis, all patients will be assigned to one of the three treatment arms, even if 
they are no longer medically eligible for the second transplant or post-transplant maintenance 
therapy.   
 
At a third registration time point, after recovery from the first autologous transplant, the clinical 
center will complete a third eligibility questionnaire confirming that the patient has recovered 
and is eligible for either the non-myeloablative allogeneic transplant, or the second autologous 
transplant, depending on the biological assignment received at the second registration.  At a 
fourth registration time point, the clinical center will complete a final eligibility questionnaire for 
auto-auto patients, confirming that the patient meets criteria for receipt of thalidomide and 
dexamethasone.   
 
5.1.3 Intention-to-Treat Principle 
 
In the primary analysis of three-year progression-free survival, patients will be classified 
according to their original assignment to one of the three treatment arms, even if they are later 


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found to be medically ineligible to receive a second transplant or thalidomide/dexamethasone 
maintenance therapy, in accordance with the intent-to-treat principle.  Some tertiary analyses 
such as the assessment of Health Quality of Life, GVHD or the assessment of compliance and 
duration of maintenance therapy, may be conducted on an as-treated rather than intention-to-treat 
basis. 
 
5.1.4 Primary Endpoint 
 
The primary endpoint for the study is three-year progression-free survival. 
 
5.2 
Statistical Issues Related to Non-randomized Assignment 
 
It is not feasible to randomly assign patients to tandem autologous transplants versus an 
autologous followed by an allogeneic transplant.  A randomized study would entail enrolling 
only patients potentially eligible for the allogeneic transplant.  Based on the experience of 
transplant physicians and population studies, patients with HLA-matched sibling donors 
comprise only 20-30% of the patient population.  Restricting enrollment to such patients would 
make it impossible to meet the accrual goals for the study in a timely fashion. 
 
There are many possible sources of heterogeneity in a multi-center clinical trial.  In a large 
randomized trial, chance ensures balance of both known and unknown risk factors across 
treatment arms.  A non-randomized study is vulnerable to differential assignment of higher risk 
patients to one or the other treatment arm.  Potential sources of heterogeneity include: (1) 
selection of patients to screen for the study; (2) degree of compliance with biological allocation; 
(3) differences in clinical care practices at participating institutions; (4) baseline disease risk 
status; (5) baseline factors such as donor/recipient age, donor/recipient gender, and recipient 
performance status; and (6) time to recovery from auto transplant.  The data analytic plan for 
each of these is discussed briefly. 
 
5.2.1 Selection of Patients to Screen for the Study 
 
Each clinical center is required to register consecutive transplant recipients with the International 
Bone Marrow Transplant Registry (IBMTR).  Data are collected on all transplanted patients, 
irrespective of whether they are enrolled in a BMT CTN trial.  These data will be used to 
determine if the proportion of allograft recipients, demographic composition, performance status, 
and disease risk of patients screened and entered in the study are representative of the population 
of transplant patients treated at that center who were potentially eligible for entry in the study 
based on disease, disease stage and duration, age and performance score reported on IBMTR 
registration forms.  Comparison of registered and enrolled patients will be performed every four 
months. 
 
5.2.2 Compliance with Biological Assignment 
 
The procedures for the biological assignment of patients are described in detail in Section 5.1 
above.  The DCC will query the transplant center for additional data as needed to validate the 
biological assignment, and to ensure that the patient is correctly classified in the final intent-to-


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treat analysis.  For example, if the patient did not receive an allograft, the DCC will follow-up on 
all siblings who were not typed to determine if any were eligible donors.  If an HLA-matched 
sibling is deemed unsuitable to be a donor, the reasoning will be reviewed with the Protocol 
Chair or the Protocol Officer. 
 
The DCC will monitor each clinical Center’s compliance with the biological assignment 
procedures.  It is anticipated that the rates of donor refusal for the allograft transplant will be 
roughly comparable across institutions, and that the treating physician will refuse to perform the 
allograft transplant in fewer than 5% of cases based on toxicity of the initial autograft.  Refusal 
rates will be monitored closely over the course of the study. 
 
5.2.3 Effects of Clinical Center 
 
In a multi-center trial, center effects are particularly important given the large number of 
treatment decisions that are left to the centers.  It is important to avoid a study design that 
confounds center and treatment effects.  In a large randomized trial, chance ensures that the ratio 
of patients assigned to each treatment arm does not vary greatly across clinical centers, and these 
ratios can be fixed by design using center-specific or stratified randomization.  In this biological 
assignment study, center effects are accounted for by using stratification in the analysis of the 
primary endpoint. 
 
Since the primary analysis is stratified by clinical center, it is crucial to ensure that each clinical 
center enrolls patients in both treatment arms.  At least two individuals are required to estimate 
variability within a stratum, so, at a minimum, each center must enroll two patients in each 
treatment arm.  A clinical center that fails to meet this goal will comprise an empty stratum that 
does not contribute to the final test statistic.  
 
A two-step process will be used to ensure that this does not occur.  First, only centers that expect 
to enroll at least 20 standard risk patients will participate.  If a center enrolls at least 20 standard 
risk patients, chance should result in the assignment of at least two standard risk patients to the 
allograft treatment arm.  The second provision employs a statistical stopping guideline for 
accrual.  These procedures are further described in Section 5.4.  
 
At the close of enrollment, it is still possible that despite these precautions, one or more centers 
will have fewer than two standard risk patients on the allograft arm.  All of the sites will be 
ranked in terms of the number of standard risk allograft subjects enrolled, and the smallest sites 
will be pooled together until this criterion is met.  The rationale behind the pooling procedure is 
that the size of a center, i.e., the number of transplants it performs is more predictive of outcome 
than other factors, such as geographic region. 
 
5.2.4 Effects of Disease Risk Status 
 
It is anticipated that approximately 15% of all presenting patients will be high-risk, as predicted 
by bone marrow cytogenetic results showing abnormalities of chromosome 13 by standard 
metaphase analysis, or a 2 microglobulin level > 4.0 mg/L.  Differential assignment of high-
risk patients to one or other of the treatment arms could bias subsequent treatment comparisons.  


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Because so few patients are categorized as high-risk, and the anticipated differences in outcome 
associated with risk are great, it is anticipated that post-hoc modeling will not suffice to adjust 
for this risk  
 
Separate analyses of data from standard risk and high-risk patients will be performed to avoid 
biased treatment comparisons if the allocation of high-risk patients is not balanced across 
treatment arms.  The analysis in standard risk patients will be considered primary, and there is 
adequate statistical power for this primary comparison.  The analysis in high-risk patients will be 
exploratory, and will aid in designing future studies.  Center effects will be accounted for in the 
primary analysis by stratifying on clinical center. 
 
5.2.5 Effects of Baseline Factors 
 
A post-hoc analysis will be performed assessing the comparability of patients allocated to each 
treatment arm with respect to baseline Karnofsky performance status, age and 2 microglobulin 
levels.  It is anticipated that these factors will be highly prognostic, and that their effects may not 
be completely captured in a single low/high-risk status indicator.  Specifically, although high-
risk patients are defined as those having a 2 microglobulin level above 4 mg/L, there may be 
additional prognostic value for different 2 microglobulin levels below 4 mg/L. 
 
Other baseline demographic factors such as donor age and gender were considered, and rejected, 
as candidates for post-hoc adjustment.  Donor age is highly correlated with recipient age when 
HLA-identical siblings are serving as donors.  The range of ages in the study population is not 
anticipated to be wide enough to lead to imbalances between the treatment arms.  Recipient-
donor gender mismatch is not anticipated to be a strong predictor of outcome in the allograft 
transplant setting, and thus does not warrant adjustment. 
 
Performance status will be compared using a chi-squared test, while age and 2 microglobulin 
levels will be compared using a Wilcoxon test.  If statistically significant (p < 10) differences in 
the treatment arms are found with respect to either of these baseline prognostic factors, a 
secondary analysis of the primary endpoint will be performed adjusting for these covariates in a 
Cox proportional hazards model. 
 
5.2.6 Effects of Time to Recovery from the Auto transplant 
 
Based on data from the Seattle Consortium, it is anticipated that fewer than 5% of patients 
allocated to the auto-allo arm will be unable to receive an allograft because of toxicity from the 
auto transplant.  As described previously, these patients will be analyzed as if they received the 
allograft, according to the intent-to-treat principle. 
 
The course of the initial auto transplant is a risk factor for the outcome of the subsequent 
allogeneic transplant.  The time to recovery from the initial auto transplant contributes to the 
time to initiation of the second intervention, which will be compared between treatment arms 
using a log-rank test.  Details of the analysis, including definitions of the event of interest, the 


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competing risks and censoring events are described in Section 5.5.2, Analysis of Secondary 
Endpoints.  
 
5.3 
Sample Size and Power Calculations 
 
The study sample size is specified in terms of the target number of standard risk patients with an 
HLA matched sibling donor.  Accrual will remain open until, at a minimum, 150 standard risk 
patients are assigned to the auto-allo arm.  During the accrual period, enrollment will be open to 
all eligible patients, including high-risk patients and those without HLA-matched sibling donors.  
The exact composition of the study population will depend on the series of eligible patients 
presenting at each clinic.  During the accrual period we anticipate enrollment of 150 standard 
risk patients on the auto-allo arm and between 350-600 patients on the auto-auto arms.   
 
Power depends on the number of standard risk patients with an eligible HLA-matched sibling 
donor, and the proportion of the total population of eligible patients who have such a donor.  
There is debate on the value of this proportion, and power calculations were based on a range of 
values from .20 to .30.  The value of .2 is in line with estimates based on census data on family 
sizes in the 1960s.  The value of .3 is reported in the literature but may be high given that this is 
an older population and some siblings may be medically ineligible to act as donors. 
 
Table 5.3 provides estimates of the probability of making various decisions under different 
likelihoods that a patient has a donor and on different combinations of 3-year PFS.  The table is 
based on 10,000 simulated samples.  The baseline estimate of a 45% 3-year PFS in the worst 
case is based on data from the French IFM-94 randomized trial of single versus tandem 
autologous stem cell transplants for MM.  This estimate is supported by data from the ABMTR 
database.  The 3-year PFS following APBSCT for MM in patients > 18 years of age is 42% ± 
5%.  The 3-year PFS was not different in patients <60 years (44 ± 6%) and those > 60 years 
(35% ± 10%).  From the table we see that the proposed design has approximately 80% power of 
detecting a difference of 15% in PFS between the auto and allo arms or between the two auto 
arms.  It has approximately the correct type I error rate as well. 
 


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Table 5.3 -- Simulated Probabilities of Making Primary Decision 
 
Prob 
Of 
HLA-
Sib 
PFS 
Auto 
Arm 
1 
PFS 
Auto 
Arm 
1 
PFS 
Allo 
Arm 
1 
Prob 
Accept 
Both 
H0 
Prob. 
Reject 
Auto 
Accept 
Auto-
Allo 
Prob. 
Accept 
Auto 
Reject 
Auto-
Allo 
Prob 
Reject 
Both 
H0 
Power 
of 
Auto-
Auto 
Test 
Power 
of 
Auto-
Allo 
Test 
0.20 
0.45 
0.45 
0.45 
95.28 
2.18 
2.35 
0.19 
2.37 
2.54 
0.20 
0.45 
0.45 
0.60 
14.39 
1.57 
83.06 
0.98 
2.55 
84.04 
0.20 
0.45 
0.45 
0.65 
1.26 
0.57 
96.24 
1.93 
2.50 
98.17 
0.20 
0.45 
0.55 
0.65 
5.91 
39.89 
35.97 
18.23 
58.12 
54.20 
0.20 
0.45 
0.55 
0.70 
0.61 
15.51 
41.36 
42.52 
58.03 
83.88 
0.20 
0.45 
0.60 
0.60 
5.68 
89.94 
2.37 
2.01 
91.95 
4.38 
0.20 
0.45 
0.50 
0.60 
25.66 
12.75 
58.54 
3.05 
15.80 
61.59 
0.20 
0.45 
0.50 
0.65 
4.41 
6.59 
79.81 
9.19 
15.78 
89.00 
0.25 
0.45 
0.45 
0.45 
94.71 
2.43 
2.56 
0.30 
2.73 
2.86 
0.25 
0.45 
0.45 
0.60 
16.30 
1.81 
81.26 
0.63 
2.44 
81.89 
0.25 
0.45 
0.45 
0.65 
1.86 
0.70 
95.66 
1.78 
2.48 
97.44 
0.25 
0.45 
0.55 
0.65 
8.88 
35.77 
45.71 
9.64 
45.41 
55.35 
0.25 
0.45 
0.55 
0.70 
1.03 
16.41 
54.41 
28.15 
44.56 
82.56 
0.25 
0.45 
0.60 
0.60 
12.84 
80.90 
4.35 
1.91 
82.81 
6.26 
0.25 
0.45 
0.50 
0.60 
29.62 
10.84 
58.26 
1.28 
12.12 
59.54 
0.25 
0.45 
0.50 
0.65 
5.75 
6.43 
82.51 
5.31 
11.74 
87.82 
0.30 
0.45 
0.50 
0.65 
7.64 
6.62 
82.27 
3.47 
10.09 
85.74 
0.30 
0.45 
0.45 
0.45 
94.89 
2.34 
2.52 
0.25 
2.59 
2.77 
0.30 
0.45 
0.45 
0.60 
19.00 
1.81 
78.68 
0.51 
2.32 
79.19 
0.30 
0.45 
0.45 
0.65 
2.80 
1.36 
94.36 
1.48 
2.84 
95.84 
0.30 
0.45 
0.55 
0.65 
12.35 
30.73 
51.59 
5.33 
36.06 
56.92 
0.30 
0.45 
0.55 
0.7 
1.48 
17.05 
62.71 
18.76 
35.81 
81.47 
0.30 
0.45 
0.60 
0.6 
21.55 
69.76 
6.96 
1.73 
71.49 
8.69 
0.30 
0.45 
0.50 
0.6 
33.77 
9.26 
56.21 
0.76 
10.02 
56.97 
 
 


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5.4 
Statistical Stopping Guidelines 
 
There are several statistical stopping guidelines employed in this study.  These guidelines are 
designed to assist an independent Data and Safety Monitoring Board (DSMB) in overseeing the 
study.  The DSMB may also request additional interim analyses and develop other criteria for 
determining when to intervene in the enrollment or treatment of patients in the study.   
 
Monitoring of key safety endpoints will be conducted monthly, and if rates significantly exceed 
pre-set thresholds, the NHLBI will be notified in order that the DSMB can be advised.  Policies 
and composition of the DSMB are described in the BMT CTN’s Manual of Procedures. 
 
The first center-specific stopping guideline monitors accrual of standard risk patients at each 
clinical center and is designed to guard against a clinical site enrolling fewer than two patients on 
the auto-allo arm.  Enrollment is temporarily suspended at centers where the stopping guideline 
is invoked while the DCC evaluates screening and referral practices.   
 
A second set of stopping guidelines monitor the incidence of TRM.  After the first auto 
transplant, which all subject receive, three-month TRM will be monitored in a single study-wide 
cohort.  After the second transplant, six-month TRM will be monitored separately by intent-to-
treat assignment to the auto-allo or two auto-auto arms.  A fifth TRM stopping rule will consider 
nine-month TRM (pooled over all treatment arms and both transplants) in the cohort of patients 
65 years of age. 
 
Monitoring for TRM associated with the first transplant will commence with the initiation of 
conditioning for the first transplant and will continue until the initiation of conditioning for the 
second transplant, or if a second transplant is not performed, until six months post first 
transplant.  Monitoring for TRM associated with the second transplant will commence with 
initiation of conditioning for the second transplant and extend for six months post second 
transplant.  Monitoring for TRM in the cohort of patients 65 years of age will commence with 
initiation of conditioning for the first transplant, and extend for six months post second 
transplant, or if a second transplant is not performed, until six months post first transplant.  
 
A third set of stopping guidelines monitor the incidence of regimen-related toxicities.  DVT and 
sensory neuropathy have been reported with the dexamethasone/thalidomide regimen, but will be 
monitored in both auto-auto arms to provide a randomized internal control group.  Cyclosporine 
associated renal and hepatic toxicity will be monitored in the auto-allo arm. 
 
Monitoring for the specific toxicities will commence with the initiation of conditioning for the 
second transplant.  Monitoring for DVT and sensory neuropathy will extend for 12 months 
following the second autologous transplant.  Monitoring for renal and hepatic toxicity will 
extend for 12 months following the allogeneic non-myeloablative transplant. 
 
The null hypotheses for sequential monitoring are that the true rate of six-month TRM is less 
than 5% after auto transplant and less than 20% after allo transplant, that the true rate of nine-
month TRM is less than 20% in subjects 65 years of age or older, and that the 12-month 
incidence of each post second transplant regimen-related toxicity is less than 10%.  If any of the 


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observed incidence rates are substantially in excess of these targets, the null hypothesis will be 
rejected, and the NHLBI will be notified.  These guidelines are provided as an “early warning” 
system.  Suspension of enrollment is not automatic, but at the discretion of the NHLBI upon 
recommendation of the DSMB, which will have the opportunity to request and review additional 
analyses. 
 
There are no planned interim analyses for efficacy in this study, because the anticipated accrual 
period is three years, and the primary endpoint is three-year disease-free survival.  However, if 
accrual is much slower than anticipated, the Data and Safety Monitoring Board will be consulted, 
and consideration will be given to interim analyses for efficacy in the fourth or fifth year of the 
study, using either group sequential methods or stochastic curtailment to conserve type I error. 
 
5.4.1 Statistical Stopping Guideline for Monitoring Accrual of Patients on the Auto-Allo Arm 
 
To guard against a clinical site enrolling fewer than two patients on the auto-allo arm, accrual of 
standard risk patients at each clinical center will be monitored.  Monitoring begins with the 11th 
patient, and is then conducted continuously as each subsequent patient is enrolled.  Table 5.4.1 
shows the criteria that would trigger a Data Coordinating Center (DCC) review of screening and 
referral practices for an individual center.  Note that only standard risk patients are tallied. 
 
Table 5.4.1 -- DCC Screening and Referral Practices Review 
 
          Total Enrolled  
Assigned to Allograft 
 
 
 
 
 
  0 – 11 
 
No review 
12 – 17 
 
Review if 0 patients assigned to the allograft arm 
18 – 23 
 
Review if 1 or fewer patients assigned to the allograft arm 
24 – 29 
 
Review if 2 or fewer patients assigned to the allograft arm 
30 – 35 
 
Review if 3 or fewer patients assigned to the allograft arm 
36 – 41 
 
Review if 4 or fewer patients assigned to the allograft arm 
42 – 47 
 
Review if 5 or fewer patients assigned to the allograft arm 
48 – 53 
 
Review if 6 or fewer patients assigned to the allograft arm 
 
 
If any of the criteria in Table 5.4.1 are met, enrollment at the site is suspended while the DCC 
conducts a review.  However, this monitoring scheme is designed to provide minimal 
impediments to accrual.  If the true proportion of patients with HLA-matched sibling donors is 
0.25, the probability that the DCC would review screening and referral practices at any given 
clinical center is only .055 if the center enrolls 20 patients, and 0.10 if the center enrolls 50 
patients.   
 
The monitoring scheme is based on the lower boundary of a truncated level 0.10 sequential 
probability ratio test (SPRT).  This SPRT requires 50 patients to achieve 90% power to reject the 
null hypothesis of an allograft proportion of 0.25 versus the alternative of 0.10.  After 20 patients 
are enrolled, power is only 48%.  However, the goal of monitoring is merely to prevent sparse 
strata, not to definitively test this hypothesis.   
 


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5.4.2 Guidelines for Safety Monitoring 
 
Transplant Related Mortality (TRM) 
 
The rate of TRM will be monitored monthly until enrollment to the applicable cohort is closed.  
Each month, the null hypothesis that six month post second transplant TRM is less than or equal 
to 20% after allo transplantation or 5% after auto transplantation will be tested against the 
alternative that it is greater.  For the purpose of the stopping rule, TRM is defined as death 
without relapse or progression, and subjects who relapse or progress are censored.  An extension 
of the SPRT will be used.  A description of this sequential testing procedure is provided below. 
 
The SPRT can be represented graphically.  At each monthly interim analysis, the total time on 
study is plotted against the total number of observed deaths.  The continuation region of the 
SPRT is defined by two parallel lines.  Only the lower boundary will be used for monitoring each 
treatment arm to protect against poor six month post second transplant non-relapse survival.  If 
the graph falls below the lower boundary, the SPRT rejects the null hypothesis, and concludes 
that there are more deaths than predicted by the observed time on study.  Otherwise, the SPRT 
continues until enrollment to the treatment arm reaches the target goal.  
 
This procedure assumes an exponential distribution for the time until failure during the first six 
months following the second transplant, but censors follow-up time after six months.  Only 
deaths without relapse or progression that occur on or before the patient has been followed for 
six months post-initiation of the second transplant are counted.  Total time for monitoring the 
TRM is from initiation of the second transplant to death, relapse or progression, or to six months, 
whichever comes first, summed for all individuals on study. 
 
There are five stopping guidelines for TRM: one for TRM associated with the first transplant in 
the entire study population, three treatment-specific guidelines for TRM associated with the 
second transplant, and a guideline for TRM associated with either transplant in the age group 65 
years.  These stopping guidelines were all developed from an SPRT contrasting 20% versus 30% 
six-month TRM for TRM after allotransplant, and 5% versus 10% for six-month TRM after 
autotransplant.  The parameters of the SPRT were adjusted so that the probability of stopping 
would be approximately 1%, 10%, and 90% if six-month TRM were 15%, 20%, and 30%, 
respectively after allotransplant, or 2.5%, 5% and 10.0% after autotransplant. 
 
The usual measures of performance of an SPRT are the error probabilities  and  of rejecting 
H0 when  = 0 and of accepting H1 when  = 1, respectively, and the expected sample size 
E(N|i).  The actual operating characteristics of the truncated test, shown in Table 5.4.2a, were 
determined in a simulation study.  The simulation assumed exponential time to failure after the 
first transplant, and uniform accrual of 600 patients over a three-year time period, of whom 42 
patients (7% of 600) were over age 65.  Assuming 5% of patients never receive a second 
transplant, 142 patients were assigned to the allograft arm, and 214 patients were assigned to 
each of the two autograft arms.  
 


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Table 5.4.2a   
Operating Characteristics of Sequential Testing Procedure for 
Transplant-related Mortality from a Simulation Study with 100,000 Replications 
 
Operating Characteristics for TRM for 1st Auto Tx, N = 600 
True 3 Month Mortality 
2.5% 
5% 
7.5% 
10% 
Probability Reject Null 
0.003 
0.10 
0.71 
0.99 
Mean Month Stopped 
36.9 
34.0 
19.5 
8.5 
Mean # Deaths in 3 Mo. 
14.6 
26.8 
22.2 
11.4 
Mean # Patients Enrolled 
598 
551 
320 
141 
Operating Characteristics for TRM for 2nd Allo Tx, N = 142 
True 6 Month Mortality 
15% 
20% 
25% 
30% 
Probability Reject Null 
 0.01 
 0.12 
0.47 
0.85 
Mean Month Stopped 
36.7 
34.8 
28,7 
20.5 
Mean # Deaths in 6 Mo. 
18.3 
22.9 
22.8 
17.8 
Mean # Patients Enrolled 
 133.1 
 125.5 
101.8 
69.6 
Operating Characteristics for TRM for 2nd Auto Tx, N = 214 
True 6 Month Mortality 
2.5% 
5% 
7.5% 
10% 
Probability Reject Null 
0.005 
0.11 
0.50 
0.86 
Mean Month Stopped 
36.9 
34.8 
 27.9 
19.9 
Mean # Deaths in 6 Mo. 
4.6 
8.6 
9.8 
8.4 
Mean # Patients Enrolled 
201.6 
189.2 
148.4 
101.1 
Operating Characteristics for TRM for 1st and 2nd Auto Tx for Age 65, N = 42 
True 9 Month Mortality 
15% 
20% 
25% 
30% 
Probability Reject Null 
0.02 
0.09 
0.27 
0.53 
Mean Month Stopped 
36.7 
35.5 
 32.9 
28.8 
Mean # Deaths in 9 Mo. 
5.9 
7.6 
8.8 
9.1 
Mean # Patients Enrolled 
41.6 
40.4 
37.6 
33.2 
 
TRM associated with the first transplant is monitored in all subjects (N = 600), from the 
initiation of conditioning for the first transplant, until the initiation of conditioning for the second 
transplant, or if a second transplant is not performed, until six months post first transplant.  The 
SPRT rejects the null hypothesis in favor of the alternative 99% of the time when the true six-
month TRM is 10%, 10% of the time when the true six-month TRM is 5%, and less than 1% of 
the time when the true rate is 2.5%.  This corresponds to a type I error rate of = 0.10 and a type 
II error rate of = 0.01.  When the true six-month TRM rate is 10%, on average, the DSMB will 
be consulted 8.5 months after opening, when 11.4 deaths have been observed in 141 patients. 
 
After the second transplant, six-month TRM will be monitored separately by intent-to-treat 
assignment to the auto-allo or two auto-auto arms.  The calculation of power for the SPRT 
assumes that 5% of subjects will not receive a second transplant, and results presented for the 
SPRT are conditional on receipt of a second transplant. 
 
After the allotransplant, the procedure rejects the null hypothesis in favor of the alternative 12% 
of the time when the true six-month TRM is 20%, and 85% of the time when the true rate is 




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the second transplant.  (Refer to Section 5.4.2 Transplant Related Mortality for a discussion of 
the statistical methodology used.)  The parameters of the SPRT were adjusted so that the 
probability of stopping would be approximately 1%, 10%, and 95% at cumulative incidence of 
5%, 10%, and 20%, respectively. 
 
The usual measures of performance of an SPRT are the error probabilities  and  of rejecting 
H0 when  = 0 and of accepting H1 when  = 1, respectively, and the expected sample size 
E(N|i).  The actual operating characteristics of the truncated test, shown in Table 5.4.2b, were 
determined in a simulation study.   
 
The simulation assumed exponential time to failure after the first transplant, and uniform accrual 
of 600 patients over a three-year time period, of whom 150 patients were assigned to the 
allograft arm, and 225 patients were assigned to each of the two autograft arms.  The initiation of 
conditioning for the second transplant was assumed to occur uniformly between 60 to 120 days 
after the initial autotransplant, with monitoring of toxicities extending for up to twelve months 
post second transplant in the auto-allo arm and each of the auto-auto arms. 
 
 


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Table 5.4.2b 
Operating Characteristics of Sequential Testing Procedure 
Regimen-related Toxicity > 10% 
from a Simulation Study with 100,000 Replications 
 
Operating Characteristics for Auto-Allo Arm, N = 150 
True 1 Year Incidence 
5% 
10% 
15% 
20% 
Probability Reject Null 
0.00 
0.10 
0.54 
0.91 
Mean Month Stopped 
36.9 
35.1 
27.8 
19.4 
Mean # Events in 1 Year 
5.8 
10.9 
12.0 
9.2 
Mean # Patients with Second 
Transplant 
141.4 
133.9 
103.7 
68.7 
Operating Characteristics for Auto-Auto Arm, N = 225 
True 1 Year Incidence 
5% 
10% 
15% 
20% 
Probability Reject Null 
0.00 
0.10 
0.61 
0.97 
Mean Month Stopped 
36.9 
34.9 
25.7 
16.5 
Mean # Events in 1 Year 
8.8 
16.3 
16.2 
10.3 
Mean # Patients with Second 
Transplant 
212.2 
199.4 
142.4 
84.5 
 
In the auto-allo arm, the procedure rejects the null hypothesis in favor of the alternative 10% of 
the time when the true twelve-month event rate is 10%, and 91% of the time when the true rate is 
20%.  This corresponds to a type I error rate of  = 0.10 and a type II error rate of  = 0.09.  
When the twelve-month event rate is 20%, on average, the DSMB will be consulted 19.4 months 
after opening, when 9.2 events have been observed in 68.7 patients in the twelve months 
following their second transplant. 
 
In each of the auto-auto arms, the procedure rejects the null hypothesis in favor of the alternative 
10% of the time when the true one-year event rate is 10%, and 97% of the time when the true 
rate is 20%.  This corresponds to a type I error rate of  = 0.10 and a type II error rate of  
 = 0.03.  When the true one-year event rate is 20%, on average, the DSMB will be consulted 
16.5 months after opening, when 10.3 events have been observed in 84.5 patients in the year 
following their second transplant. 
 
5.5 
Analysis Plan 
 
All analyses are based on an intent-to-treat.  In such an analysis, patients are considered as being 
in the auto-allo arm at the time of their initial autologous transplant if they have an HLA-
matched sibling donor whether or not the allogeneic transplant takes place.  Likewise, patients 
without an HLA-matched sibling donor randomized to maintenance therapy following their 
second autologous transplant are analyzed with this group whether or not they actually receive 
their second autologous transplant or maintenance therapy. 
 


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5.5.1 Analysis of the Primary Endpoint 
 
The primary outcome of the trial is myeloma progression-free survival at three years following 
the initial autologous transplant.  The primary null hypotheses of the study are: 1) that there is no 
difference in 3-year progression free survival between the two auto-auto arms; and, 2) that there 
is no difference between in 3-year progression free survival between the “best” auto-auto arm(s) 
and the auto-allo arm.  The best auto-auto arm is either a pooled arm or the better of the two 
auto-auto arms depending on the results of the comparison of the auto-auto arms (maintenance 
therapy versus no maintenance therapy).  The alternative hypotheses are: 1) PFS differs with use 
of maintenance therapy after tandem autologous transplantation; and, 2) PFS differs between 
auto-auto and auto-allo tandem transplant strategies.    
 
In the final analysis, the endpoint of 3-year PFS will be estimated using the Kaplan-Meier 
product limit estimator, and compared between treatment arms using the modified Mantel-
Haenszel test statistic stratified on clinical center 72.  The 2.5% significance level will be used to 
ensure that the chance of incorrectly deciding that one of the treatment plans is different from the 
other when there is no difference between the treatments is at most 5%.  Standard confidence 
intervals will be computed for the measure.  In the event that there are no significant differences 
between the arms, a post-hoc power analysis will be performed.   
 
The primary analysis of myeloma progression-free survival at three years following the initial 
autologous transplant is described above.  A secondary analysis of the primary endpoint will also 
be conducted.  This secondary analysis complements the primary analysis, by permitting the 
clinical investigators to examine all pairwise comparisons of treatment arms, in a way that 
controls type I error.  A two degree of freedom level .05 stratified weighted log-rank test will be 
performed comparing the three treatment arms.  If any differences are found using the omnibus 
test, all pair-wise comparisons will be examined.  It is not anticipated that there will be any 
differences in the results obtained from the primary and secondary analysis.  However, if there 
are discrepancies, the primary analysis will be given precedence in report and publications. 
 
5.5.2 Analysis of Secondary Endpoints 
 
A number of secondary outcomes will be examined to compare the patient’s disease status over 
time between treatment arms. 
 
Current Myeloma-Stable Survival: 
Patients on either arm may progress and then be salvaged by more aggressive therapy, such as 
DLI on the allogeneic arm or dexamethasone and thalidomide on the auto-auto-maintenance arm.  
The “current myeloma-stable survival” distribution is an estimate of the likelihood that a patient 
will be alive with stable disease at any given point in time. 
 
These survival curves will be compared between the two arms of the study across all time points 
using a technique found in Klein et. al73.  
 
We will also estimate for each arm the probability a patient is alive with stable disease at 2, 6, 9, 
12, 18, 24, 30 and 36 months.  In the analysis at K months, the numerator for this estimate counts 


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patients alive with at least stable disease, and the denominator counts all patients followed to K 
months, regardless of survival status.  These probabilities will be compared using standard tests 
for binomial proportions. 
 
Overall Survival: 
The event is death from any cause.  Patients alive at the time of the last observation are 
considered censored.  Overall survival will be compared between treatment arms using a log-
rank test, and the survival curves will be estimated using the Kaplan Meier Estimator. 
 
Time to Progression: 
The event is progression.  Death without progression is considered a competing risk.  Patients 
alive with no history of progression are considered as censored observations.  Time to p will be 
compared between treatment arms using a log-rank test, and the cumulative incidence curves will 
be estimated.  
 
5.5.3 Analysis of Tertiary Endpoints 
 
CR and CR+PR Proportion at Two and Twelve Months: 
The numerator for the estimate of the CR rate counts patients who are alive and in CR at two (or 
twelve) months post first auto transplant, and the denominator counts patients who have been 
followed for two (or twelve) months, regardless of survival or remission status.  The numerator 
for the estimate of the CR+PR rate counts patients who are alive and in CR or PR at two (or 
twelve) months.  The proportion of patients in CR and PR will be compared between treatment 
arms using standard techniques for categorical data. 
 
Time to CR and CR+PR: 
The event is CR (CR or PR).  The time to event is the time to CR (CR or PR).  Patients who die 
in a state other than CR (CR or PR) are considered as failing from a competing risk.  Patients 
alive and not in CR (CR or PR) at the time of last observation are considered as censored for this 
event.  Time to CR (CR or PR) will be compared between treatment arms using a log-rank test, 
and the cumulative incidence curves will be estimated. 
 
Time to Off-study Therapy: 
The event is the initiation of any anti-myeloma therapy other than that defined by the protocol 
treatment arms.  Patients who die without initiation of an off-study therapy will be considered as 
experiencing a competing risk.  Patients who do not receive an off-study therapy but are alive at 
the end of the study will be considered censored.  Time to off-study therapy will be compared 
between treatment arms using a log-rank test, and the cumulative incidence curves will be 
estimated. 
 
Health Quality of Life: 
 
Overview 
The goal of the Health Quality of Life (HQL) component of this trial is to describe the HQL of 
study participants and to determine if the there are differences in quality of life among recipients 
of the different treatment strategies in this protocol.  All patients registered to the clinical trial are 


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potentially eligible for the study, and consent for participation will be obtained as part of consent 
for the clinical trial.  Patients who cannot communicate in English or Spanish, can not complete 
HQL questionnaires due to cognitive, linguistic or emotional difficulties, will be excluded from 
the study.  We anticipate that 90% of registered patients will be eligible, and that compliance will 
be roughly 80% among surviving patients, based on experiences with The Unrelated Donor 
Marrow Transplantation Trial [TCD Trial] (formerly the T Cell Depletion Trial) and other 
studies of HQL conducted for the NHLBI in bone marrow transplant recipients.   
 
Instruments, Administration and Scoring Methods 
In order to minimize response burden and increase the chance of complete response, the 
selection of instruments has been limited to the FACT-BMT74 and the SF-3670, 71.  The FACT-
BMT is comprised of a general core questionnaire, the FACT-G, evaluates the Quality of Life 
(QOL) of patients receiving treatment for cancer, and a specific module, BMT Concerns, that 
addresses disease and treatment-related questions specific to bone marrow transplant.  The MOS 
SF-36 is a general assessment of health quality of life that has been widely applied in a variety of 
outcome studies and is being used in this trial as a generic measure of QOL.   
 
HQL will be assessed through a self-administered questionnaire distributed to patients at clinic 
visits.  The assessments will be conducted at baseline prior to the initiation of the conditioning 
regimen for the first transplant, again within two weeks prior to the initiation of the second 
transplant, and at yearly intervals from baseline.  The protocol permits administration within a 2 
week window before the target date for the first two interviews, and within a +/- 2 week window 
centered on the target date for the subsequent yearly interviews.  The HQL instruments will be 
scored according to standard methods for these tools.  Specifically, the FACT-BMT will be 
scored using software provided in the FACIT Manual Version 4.074, and the MOS SF-36 will be 
scored using software provided in the SF-36 Health Survey Manual and Interpretation Guide70 
and the SF-36 Physical and Mental Health Summary Scales:  A User’s Manual71.    
 
Analysis and Interpretation of Results 
While descriptive analyses will consider all HQL outcomes, following the lead of David Cella in 
the analysis of ECOG Study 559275, the primary HQL endpoint for hypothesis testing will be the 
Trial Outcome Index (TOI).  The FACT-BMT TOI is derived by adding the scores on the 
Physical Well-Being and Functional Well-Being subscales of the FACT-BMT, to the BMT 
symptoms module score.  At two years post-transplant, it is anticipated that the TOI, which 
contains relevant questions about physical functioning and BMT symptoms, will be most 
sensitive to long term differences in HQL attributable to differences in treatment strategy. 
 
The initial analysis of the questionnaire data will focus on describing and reporting the HQL of 
study participants, through tables, graphs, and summary statistics characterizing the HQL scores 
over time in each treatment arm.  Differences in QOL between the two auto-auto strategies and 
between the auto-auto and auto-allo strategies will be assessed in several ways.  First, the 
marginal QOL scores given that the patient is alive will be compared at the specific time points 
described above using simple T-tests.  Second, the Integrated Quality Adjusted Survival76 will be 
compared.  This latter approach aggregates QOL over the entire period of observation, and 
accounts for potential differences in survival rates.  If an examination of patterns of missing data 
indicates that there is substantial informative censoring due to causes other than death, 


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techniques for joint modeling of survival and longitudinal data developed by Schluchter77, and 
extended by Ibrahim et. al78, will be considered. 
 
Statistical Power and Sample Size Considerations 
The trial is not designed to be powered for a primary endpoint of detecting differences in QOL 
between the different treatment strategies.  The HQL analysis in the study will be primarily 
descriptive.  We can, however, estimate the power of the study to detect differences between the 
groups based on expected survival and prior HQL studies.  The TCD Trial observed a baseline 
mean FACT-BMT TOI score of 67.2, with a standard deviation of 13.8 units, and a mean SF-36 
Physical Component Score of 41.6, with a standard deviation of 10.2 units.  These data are 
consistent with published norms for the FACT-BMT in transplant recipients, and the SF-36 in 
cancer patients, respectively 70, 74. 
 
Formal hypothesis testing for the FACT-TOI endpoint will proceed according to the plan 
described previously for the PFS endpoint.  The null hypotheses of the HQL study are: 1) that 
there is no difference in 3-year FACT-TOI between the two auto-auto arms; and, 2) that there is 
no difference in the 3-year FACT-TOI between the "best" auto-auto arm(s) and the auto-allo 
arm.  The best auto-auto arm is either a pooled arm or the better of the two auto-auto arms 
depending on the results of the comparison of the auto-auto arms (maintenance versus no 
maintenance).  The alternative hypotheses are that the treatments have different long term HQL 
as measured by the FACT-TOI. 
 
To illustrate the statistical power available, consider a comparison of the FACT-TOI at the three-
year time point between the tandem autograft patients randomized to observation and 
maintenance.  Assuming 150 auto-allo patients, and 450 auto-auto patients, 90% of whom will 
be eligible for HQL study, a 45% survival rate at 3 years, and an 80% response rate, 
approximately 146 auto-auto patients will complete the third year interview.  The estimated 
sample size of 73 per arm is sufficient to detect, with statistical power of 80%, a difference in the 
FACT-TOI score of 7.1 units, and a difference in the SF-36 PCS score of 5.3 units, using a two-
sided level .025 test.   
 
Incidence of Toxicities Grade 3 According to the CTCAE Version 3.0 
For both arms, toxicities that occur over the course of time will be tabulated. 
 
Grade  3 toxicities will be tabulated for each patient at set intervals over the course of the study.  
The proportion of patients developing toxicity will be compared between treatment arms. 
 
Incidence of Infections 
The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for 
each patient according to criteria in the BMT CTN Manual of Operations. The proportion of 
patients developing infections will be compared between treatment arms. 
 


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5.5.4 Analyses within Each Treatment Arm 
 
A number of outcomes are specific to only one of the study arms.  Between treatment arm 
comparisons will not be performed, but descriptive statistics will be computed. 
 
Drop Out Rate and Duration of Maintenance Therapy 
For patients in the tandem autologous transplant arm randomized to receive maintenance therapy 
after the second autograft, the proportion of patients complying with the maintenance therapy at 
2, 6, 9,and 12 months, and the duration of maintenance therapy will be estimated. 
 
Incidence of Primary and Secondary Graft Failure 
Engraftment is defined as reaching 5% donor chimerism.  Median time to engraftment will be 
estimated from the cumulative incidence of engraftment, treating death as a competing risk.  
 
The rate of Primary Graft Failure will be estimated as the number of patients who have failed to 
engraft by Day 56 post-allograft transplant, divided by the total number of patients who receive 
an allograft transplant.   
 
The rate of Secondary Graft Failure will be estimated as the number of patients who engraft (at 
any time prior to one year), and subsequently lose chimerism (< 5%) in the first year post-
engraftment, divided by the total number of patients who engraft in the first year. 
 
Incidence and Severity of Graft-versus-Host Disease 
GVHD will be graded according to criteria in the BMT CTN MOP.  The cumulative incidence 
curves for acute and chronic GVHD will be estimated treating death as a competing risk. 
 


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A-1 
 
APPENDIX A 
 
DURIE AND SALMON CRITERIA FOR THE INITIAL DIAGNOSIS AND 
STAGING OF MULTIPLE MYELOMA 
 
 
 
INITIAL DIAGNOSIS 
 
 Major criteria: 
i)  Plasmacytoma on tissue biopsy. 
ii)  Bone marrow plasmacytosis with > 30% plasma cells. 
iii) Monoclonal globulin spike on serum electrophoresis exceeding 3.5 g/dL for IgG peaks or 
2.0 g/dL for IgA peaks, > 1.0 g/24h of kappa or lambda light chain excretion on urine 
electrophoresis in the absence of amyloidosis. 
 
 
 Minor criteria 
a) Bone marrow plasmacytosis with 10% to 30% plasma cells. 
b) Monoclonal globulin spike present, but less than the levels defined above. 
c)  Lytic bone lesions. 
d)  Normal IgM < 50 mg/dL, IgA < 100 mg/dL, or IgG < 600 mg/dL. 
 
 
 Diagnosis will be confirmed when any of the following features are documented in 
symptomatic patients with clearly progressive disease.  The diagnosis of myeloma requires a 
minimum of one major + one minor criterion or three minor criteria that must include a + b: 
a)  i + b, i + c, i + d (i + a not sufficient). 
b)  ii + b, ii + c, ii + d. 
c)  iii + a, iii + c, iii + d.  
d)  a + b + c, a + b + d. 
 
 


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STAGING 
 
The Durie and Salmon classification uses three multiple myeloma stages. 
 
Stage I 
All of the following: 
 Hemoglobin greater than 10 g/dL 
 Serum calcium less than 12 mg/dL 
 Normal bone structure or solitary plasmacytoma on radiographs 
 Low M component 
 IgG less than 5 g/dL 
 IgA less than 3 g/dL 
 Urine light chains less than 4 g/24 hr 
 
 
Stage II 
Fitting neither Stage I nor Stage III 
 
 
Stage III 
One or more of the following: 
 Hemoglobin less than 8.5 g/dL 
 Serum calcium greater than 12 mg/dL 
 Advanced lytic bone lesions 
 Hyper M component 
 IgG greater than 7 g/dL 
 IgA greater than 5 g/dL 
 Urinary light-chain excretion greater than 12 g/24 hr 
 
 
Subclassification 
A: serum creatinine less than 2.0 mg/dL 
B: serum creatinine equal to or greater than 2.0 mg/dL 
 
 
 
 


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B-1 
 
APPENDIX B 
 
CONSENT FORMS 
 
 
 
PATIENT INFORMED CONSENT 
 
 
DONOR INFORMED CONSENT 


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Patient Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 1 of 30 
Patient Initials ________ 
 
Informed Consent to Participate in Research 
 
 
 
 
 
 
 
 
 
 
You are being asked to take part in a large research study.  About 800 patients will take part in 
this study at many centers around the country.  Your participation in this study is expected to last 
approximately 3 and a half years. 
 
This consent form tells you about the study.  The Principal Investigator (the person in charge of 
this research) or a co-worker of the Principal Investigator will also describe this study to you and 
answer all of your questions.  Furthermore, throughout your treatment your care will be 
discussed with you and questions answered as needed.  Before you decide whether or not to take 
part, read the information below and ask questions about anything you do not understand.  
Taking part in this study is entirely your choice. 
 
1. 
Name of the Subject (“Study Subject”) 
 
2. 
Title of Research Study 
 
A Trial of Tandem Autologous Stem Cell Transplants +/- Post Second Autologous Transplant 
Maintenance Therapy Versus Single Autologous Stem Cell Transplant Followed by HLA-
Matched Sibling Non-Myeloablative Allogeneic Stem Cell Transplant for Patients with Multiple 
Myeloma 
 
3a. 
Principal Investigator Contact Information 
 
Insert name, affiliation and contact information.  
 
3b. 
Contact information for emergencies after hours or on weekends or holidays 
 
Call (###) ###-####, the in-patient Bone Marrow Transplant Unit.  Ask to speak to the Charge 
Nurse. 
 


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IRB # 
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Patient Initials ________ 
 
4. 
Sponsor and Source of Funding or Other Material Support 
 
The sponsor of this study, The National Institutes of Health (NIH), is providing financial support 
for the coordination of this study through the Blood and Marrow Transplantation Clinical Trials 
Network (BMT CTN).   
 
5. 
What is the purpose of this study? 
 
You are being asked to take part in this research study because you have multiple myeloma 
(MM), a cancer of the bone marrow.  The study described in this consent form is designed to test 
different treatment strategies for patients with multiple myeloma.  Multiple myeloma is 
considered incurable with chemotherapy (drugs that kill cancer) given at usual doses.  This 
standard chemotherapy sometimes produces remission (absence of disease) in some individuals, 
but the disease recurs in all patients.  Past studies have shown that high-dose chemotherapy can 
improve the survival of myeloma patients.  However, this intensive therapy damages the special 
cells in the bone marrow called blood stem cells.  Blood stem cells are cells found in the bone 
marrow and blood stream that produce all of the body’s blood cells.  Without healthy blood stem 
cells, a person cannot produce white blood cells (which fight infection), red blood cells (which 
transport oxygen to cells) or platelets (which help blood clot).  Blood stem cells can be collected 
before chemotherapy to be returned intravenously (through a vein) after high-dose chemotherapy 
is given.  This procedure is called autologous stem cell transplantation (SCT).  Autologous 
transplantation is accepted standard therapy for patients with multiple myeloma.  Although high-
dose chemotherapy with autologous SCT has significantly improved the survival of myeloma 
patients, it does not cure them and the potential to further improve treatment remains.  One 
approach has been to kill myeloma cells left after the first autologous SCT with another course of 
high dose therapy and a second autologous SCT.  Studies have shown that receiving two 
autologous transplants a few months apart (tandem autologous SCT) improves survival for 
patients with multiple myeloma.  Unfortunately, this approach still does not cure myeloma.  It is 
not known if additional drugs given after tandem autologous SCTs will further improve survival 
of patients with multiple myeloma.  This study will test whether additional treatment after two 
autologous transplants (standard care) will further improve the disease control and survival of 
patients with multiple myeloma.  This will be tested by randomizing patients without a sibling 
donor to receive additional treatment for one year or no further treatment after their second 
autologous transplant.  Randomizing means assigning to a treatment by chance, like the flip of a 
coin. 
 
Another type of transplant is an allogeneic stem cell transplant where the patient receives high 
doses of chemotherapy, with or without radiation, followed by an infusion of blood stem cells 
donated by a sibling (brother or sister) who has the same tissue type (genetically matched).  As 
with an autologous SCT, the blood stem cells would rescue your bone marrow from the toxic 
effects of chemotherapy and radiation.  However, because the stem cells come from a healthy 
donor, these blood stem cells also replace your immune system with the donor’s immune system.  
This new immune system also helps fight your myeloma.  This effect of an allogeneic SCT is 
called a graft-versus-tumor effect.  Unfortunately, the traditional type of allogeneic SCT that 


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IRB # 
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Patient Initials ________ 
 
uses high doses of chemotherapy and radiation can have many serious side effects and a high-
risk of treatment-related death, particularly in patients with multiple myeloma.  
 
The inability of many myeloma patients to tolerate a traditional allogeneic SCT may relate to 
combining the toxic effects of high-dose therapy and the immune effects of the allogeneic SCT 
in a single procedure.  Recent studies have shown that a less toxic type of allogeneic SCT, called 
a non-myeloablative SCT (also sometimes called a mini transplant or reduced intensity 
transplant), when done following recovery from an autologous SCT, can more safely be carried 
out and still control MM.  In this study, a patient who has a matched sibling donor will receive 
an autologous SCT followed by a non-myeloablative transplant once he or she has recovered 
from the autologous SCT. 
 
The purpose of this study is to look at two different treatment approaches that involve stem cell 
transplants to improve the outcome of patients with multiple myeloma and to compare them with 
a common current approach, tandem autologous SCT.  The two new approaches being studied 
are: 1) the use of additional drugs after tandem autologous SCT; and, 2) the use of a non-
myeloablative allogeneic SCT after a single autologous SCT.  Patients who don’t have a matched 
sibling who can donate blood stem cells will undergo tandem autologous SCT.  They will also be 
randomized (assigned by chance, like the flip of a coin) to receive additional therapy (a 
combination of two medications given by mouth called dexamethasone and thalidomide) or 
observation (disease will be watched with no more treatment) after recovery from the second 
autologous SCT. 
 
Patients with a matched sibling donor who can donate stem cells will undergo a single 
autologous SCT and upon recovery will receive a non-myeloablative SCT from their sibling after 
first receiving low dose radiation therapy.  
 
The two main purposes of this study are to determine: 
1. For MM patients without a matched sibling donor, whether additional therapy after 
tandem autologous SCTs improves disease control and survival. 
2. For MM patients with a matched sibling donor, whether tandem autologous transplants 
(with or without additional therapy) or a single autologous transplant followed by a non-
myeloablative SCT from their matched sibling improves disease control and survival. 
 
The study may find that patients who have different treatments for MM have similar results. 
 
6. 
What will be done if you take part in this research study? 
 
If you decide to take part in this study and have signed the informed consent, you and your 
matched sibling, if you have one, will be evaluated to make sure it is safe for you to participate in 
the study.  Before starting treatment in this study, your doctor will check your general health.   
 
 


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IRB # 
_____________________________________________________________________________________________ 
 
 
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You will have the following tests and evaluations to find out if you can participate: 
 
 Medical history and physical examination, including height and weight. 
 Blood tests (approximately 4 – 5 tablespoons)  
 Urine tests 
 Electrocardiogram (ECG or EKG), a picture of the electrical action of the heart) 
 Echocardiogram (a picture of the heart in motion made using ultrasound or sound waves) 
or MUGA scan (a picture of your heart after a small amount of radioactive material is 
injected into the bloodstream through a vein) to evaluate your heart function 
 Pulmonary Function Test (PFT), which is a breathing test that tells how your lungs are 
working, measures the amount of air taken into your lungs and exhaled as you breath) 
 Bone marrow biopsies and aspirates.  A bone marrow aspiration is a procedure in which 
an area of the hipbone is numbed, and a small sample of bone marrow is withdrawn. A 
bone marrow biopsy is similar to a bone marrow aspiration, except a sample of bone is 
removed through the needle. 
 If you are a woman able to have children, a serum pregnancy test will also be performed.  
If you are pregnant, you will not be able to take part in this study. 
 
Some additional x-rays will be done to evaluate your disease.  These tests will help your doctor 
determine the amount of disease you have at the start of treatment and to follow the status of 
your disease throughout your treatment. 
 
This study is divided into two phases and is explained in detail below.  All patients will undergo 
the Phase I treatment portion of this study, using high-dose melphalan followed by an autologous 
SCT.  Under the Phase II treatment portion of this study, if you have a matched sibling donor, 
you will receive a non-myeloablative allogeneic SCT using your sibling’s stem cells (referred to 
as Treatment Arm A).  If you do not have a matched sibling who can serve as your donor, you 
will receive a second autologous SCT (referred to as Treatment Arm B) using the same high-
dose melphalan chemotherapy as described in this consent under Phase I.  Patients in Treatment 
Arm B will be randomized (like the tossing of a coin) to receive or not receive two additional 
medications (dexamethasone and thalidomide) given by mouth following their second 
autologous SCT.  Your doctor will tell you which Treatment Arm you will be treated on and, if 
treated on Arm B, whether or not you are to receive the additional drug therapy. 
 
One of the objectives of this study is to evaluate how the treatment affects the quality of the 
patient’s life and whether there is a difference between the two treatment arms.  Therefore, all 
English and Spanish speaking patients will be asked to complete questionnaires asking about 
their quality of life before the first and second transplant, and at 6 months, 1, 2 and 3 years after 
the second transplant.  It will take you approximately half an hour to complete the 
questionnaires. 


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Outline of Treatment Plan 
 
 
MM meeting eligibility 
criteria including available 
autologous graft.  
 
 
 
 
 
PHASE 1 
 
 
High-dose melphalan  
autologous PBSC transplant.  
 
 
 
 
 
PHASE 2 
 
Recovered at least 60 days after autologous SCT 
(preferably between 60 and 120 days after SCT). 
 
 
 
 
ARM A 
ARM B 
Eligible matched sibling 
donor. 
 
No eligible matched sibling 
donor. 
 
 
 
 
 
 
Non-myeloablative transplant.   
High-dose melphalan + 
autologous SCT.  
 
 
 
 
 
 
 
 
 
 
Observation. 
 
Thalidomide 200 
mg/day for one year.  
Dexamethasone 40 
mg/day Days 1-4 of 
each month for 12 
months. Drugs to 
begin at least 60 days 
following second 
autologous SCT 
(preferably between 
60 and 120 days). 
 


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Phase I Treatment (All Study Participants) 
 
Central Venous Catheter:  You will need to have central venous catheter (CVC) placed to 
participate in the study.  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.  Complications include 
blood clots and infection.  Clotting may require removal of the catheter or treatment of the clot 
by instilling a medicine that dissolves blood clots into the line.  If you develop an infection you 
will require treatment with antibiotics and your catheter may need to be replaced.  Other 
uncommon side effects may include swelling of the face and arm and/or lung collapse.  If the 
lung collapses, it may be necessary to place a tube between the ribs to allow the lung to re-
expand. 
 
Mobilization and Leukapheresis: You will receive chemotherapy to release your blood stem 
cells from your bone marrow into your circulating blood (mobilization) so that they can be 
collected.  Your doctor will explain the side effects, benefits and type of the chemotherapy you 
will receive to mobilize your blood stem cells.  Following chemotherapy for stem cell 
mobilization, you will receive a bone marrow stimulating medication called granulocyte-colony 
stimulating factor (G-CSF) by injection under your skin daily for approximately 10 days.  G-CSF 
will help to move your stem cells out of the bone marrow into the bloodstream.  You or someone 
who agrees to be responsible may be taught how to give you the G-CSF, so you can receive it at 
home.  Once the number of stem cells in your blood stream is high enough, they will be collected 
over 2-5 days, while you are still receiving the G-CSF injections. A procedure called 
Leukapheresis will be done to collect your stem cells.  During this procedure, your 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 you through your catheter or a vein in the other arm.  The leukapheresis 
procedure will last approximately several hours each time.  You will be asked to sign a 
separate consent form for the leukapheresis procedure.  Enough stem cells will be collected 
from you for two autologous SCTs in case you do not have a matched sibling donor to donate 
stem cells.  Your stem cells will be frozen (cryopreserved) until the time when they will be given 
back to you. 
 
Autologous Stem Cell Transplant: A couple of weeks after your stem cells have been collected, 
you will undergo an autologous SCT using high-dose chemotherapy with a drug called 
melphalan given over 15 to 20 minutes through your central venous line.  Since this high-dose 
treatment destroys the normal bone marrow in addition to the myeloma cells, your blood stem 
cells (blood cells able to repopulate the bone marrow) must be given back to you.  Your 
previously collected stem cells will be unfrozen and given back to you through your central 
venous catheter, similar to a blood transfusion, two days after you received the melphalan.  
Starting on the fifth day after you received your stem cells, you will be given the drug G-CSF, 
subcutaneously (under the skin).  The G-CSF helps to stimulate the bone marrow to produce 
cells and will continue until your white blood count returns to normal.   


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Table -- High-Dose Melphalan / Autologous SCT 
 
Day 
-2 
-1 
0 
+5 to 
Engraftment 
Melphalan (200 mg/m2 /IV) 
X 
 
 
 
Stem cell infusion 
 
 
X 
 
G-CSF (5 g/kg/day) SQ or IV 
until white cells recover 
 
 
 
X 
 
 
After your stem cells have been reinfused, it will take about two weeks before adequate numbers 
of blood cells are made.  During this time you may not be making any blood cells and therefore 
may require several red blood cell and platelet transfusions.  Because your immune system is 
very weak, you may develop serious infections.  You will be watched closely and receive 
antibiotics at the earliest sign of infection.  During the time that your blood counts will be low, you 
may have mouth sores and feel very tired.  You will receive medications to lessen these symptoms 
as much as possible.  You will probably have a poor appetite during this time and may need to be 
given feedings through the central venous catheter.  You may also receive pain medications as 
needed to minimize and control discomfort and pain.  Once you begin to make new blood cells, the 
risk of serious infections will gradually be reduced.  You should gradually come to the point where 
you will no longer require red cell and platelet transfusions.  You should gradually regain your 
appetite.  Although it is possible that the entire process may be done in the outpatient setting, it is 
also possible that a hospital stay of approximately 3 to 4 weeks will be necessary.   
 
After completion of the transplant process, you will be followed in the outpatient clinic facility at 
least weekly, or as clinically indicated, until you are ready for your second SCT. 
 
Phase II Treatment 
 
Approximately 60 to 120 days after your autologous SCT, you will receive one of two therapies.  
If one of your siblings is a match and is able and willing to serve as your stem cell donor, you 
will receive a non-myeloablative SCT using your sibling’s stem cells (referred to as Treatment 
Arm A).  If you do not have a matched sibling who can donate stem cells, you will receive a 
second autologous SCT using the same high-dose melphalan chemotherapy (referred to as 
Treatment Arm B).   
 


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Treatment Arm A (allogeneic NMSCT) 
 
Table – Allogeneic Non-myeloablative Stem Cell Transplant Schedule 
 
 
Day 
 -3 
Day 
 0 
Day 
 +1 
Day 
 +27 
Day 
 +84 
Day 
+114 
Day 
+180 
TBI 200 cGy 
 
X 
 
 
 
 
 
Cyclosporine  
twice a day 
Start 
 
 
 
Initiate 
taper 
Off if 
not in 
PR* or 
CR* and 
no 
GVHD 
on Day 
+84 
Off if 
CR or 
PR and 
no 
GVHD 
on Day 
+84 
Mycophenolate 
Mofetil (MMF) 
twice a day 
 
First 
dose 
20:00hrs 
 
Last 
dose 
 
 
 
Stem cell infusion  
 
X 
X 
 
 
 
 
* CR complete remission: PR partial remission. 
 
If you have a matched sibling donor who is able and willing to donate stem cells for your 
transplant, he or she will have stem cells collected from his/her bloodstream by leukapheresis 
after treatment for several days with G-CSF.  In most cases, the leukapheresis of the donor is 
done using the veins in the arms.  Occasionally, if the donor’s veins are not large enough, a 
central vein catheter may be required. 
 
Your treatment will start three days before you are to receive your sibling’s stem cells.  You will 
begin taking an anti-rejection drug called cyclosporine, by mouth, twice daily for three days.  On 
the fourth day you will receive a low dose of total body irradiation (TBI).  The purpose of TBI is 
to allow your body to accept the donor cells without rejecting them.  After the TBI is completed, 
your sibling’s stem cells will be given to you through your central venous catheter.  This is called a 
non-myeloablative allogeneic transplant (mini-transplant or reduced intensity transplant). 
 
After the allogeneic non-myeloablative SCT you will continue to receive cyclosporine (CSA) 
and will start taking another medication, mycophenolate mofetil (MMF). The evening of your 
transplant, you will receive one dose of mycophenolate mofetil (MMF) by mouth.  Starting the day 
after your transplant, you will be given MMF twice a day for a total of 27 days.  MMF and CSA 
are given to prevent your body from rejecting your sibling’s stem cells and to help decrease the 
risk of developing a complication called graft-versus-host-disease (GVHD).  GVHD is a 
condition where your donor’s immune cells attack your skin, liver, intestines and potentially 
other organs.  Most patients transplanted with stem cells from a matched donor develop only a 
mild or moderate case of GVHD.  However, some patients develop very severe GVHD, which 
can be fatal. 
 


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Because the chance of developing GVHD can persist many months after an allogeneic NMSCT, 
you will continue to receive cyclosporine for 84 days after your transplant.  After 84 days, the 
cyclosporine dose will be gradually reduced based on how your disease has responded to the 
allogeneic NMSCT and whether you have developed GVHD.  If there is no evidence that your 
multiple myeloma is worse and you do not have active GVHD, CSA will be stopped 
approximately 6 months after your non-myeloablative transplant.  Patients with active GVHD 
may require CSA or other drugs that control GVHD for a longer period of time, as long as they 
have active GVHD.  While you are taking CSA, blood tests to monitor the amount of CSA in your 
blood will be done at least weekly for the first several months and your dose of CSA will be 
adjusted if necessary to maintain the proper level in your blood.  
 
Blood tests will be performed frequently to evaluate your response to treatment and possible side 
effects of treatment.  If necessary, platelet and red cell transfusions will be given to maintain 
adequate levels and antibiotics will be given to treat or prevent infection.  You may also require 
intravenous nutritional support and pain medications during or after transplantation.  You will be 
monitored closely for any signs and symptoms of GVHD. 
 
The medications cyclosporine and mycophenolate mofetil, although approved for sale by the 
Food and Drug Administration (FDA) and used commonly in stem cell transplantation, are not 
specifically approved by the FDA for use in stem cell transplantation.  However, studies have 
shown that CSA and MMF have been successful in preventing and controlling GVHD. 
 
Discharge and Follow up 
 
After completion of your allogeneic non-myeloablative SCT, you will visit the outpatient clinic 
facility at least weekly for the first 2 to 3 months and then at least monthly until 6 months after 
your allogeneic non-myeloablative SCT.  If you were referred from another doctor in order to 
undergo this procedure, you may return to the care of the referring doctor approximately six 
months after your allogeneic non-myeloablative SCT.  You will need to return to the 
____________________(medical facility performing transplant) at least every 6 months until 3 
years after your allogeneic non-myeloablative SCT for evaluations.  Most patients regain their 
strength and are able to return to their previous level of activity approximately 6 months after their 
allogeneic non-myeloablative SCT.  However, each patient is different and your recovery may take 
longer or may even be a shorter period of time.  Your ability to fight off infections may be 
weakened for at least one year or longer after the transplant and it may take you longer to recover 
from an infection or cold.  Therefore, you will need to be careful and call your doctor if you have 
any symptoms of an infection or cold (e.g. fever, chills, cough, shortness of breath, sore throat or 
just not feeling well) during the first several months after transplant.  If you are not sure, you may 
contact your doctor anytime and let him/her know how you are feeling and they will advise you on 
what to do.  You should also call your doctor if you experience a skin rash, diarrhea, nausea, 
vomiting, jaundice (yellow skin), dry mouth, dry eyes, weight loss or difficulty breathing.  These 
symptoms could be due to GVHD and require further evaluation. 
 


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Treatment Arm B (Second Autologous SCT) 
 
If you do not have a matched sibling that can donate stem cells, you will have a second 
autologous SCT using the same procedure that is described under Phase I.  You also will be 
randomized (like the tossing of a coin) between observation and receiving maintenance therapy 
(two anti-myeloma medications - dexamethasone and thalidomide) to begin once you recover 
from your second autologous transplant.  The reason for this randomization is to determine 
whether or not receiving additional therapy will improve the outcome after tandem autologous 
SCT.  Results from two recent studies show that thalidomide may slow the rate of relapse after 
autologous transplantation.  These studies show that time to worsening disease may be longer in 
patients who get thalidomide.  In these studies, thalidomide did not prolong survival, and did 
increase the number of side effects.  The dose and timing of of thalidomide was different in these 
reported studies than in this study.  We do not know if it is better to wait until a relapse occurs to 
use this drug.  We also do not know whether thalidomide will significantly affect quality of life.  
 
If you were randomized to receive maintenance therapy with dexamethasone and thalidomide, 
you will receive these two drugs beginning at least 60 days after your second autologous SCT.  
You will receive 40 mg of the drug dexamethasone for four days a month (once a day by mouth), 
for a total of 12 months.  The drug thalidomide will be given every day for 12 months.  You will 
start thalidomide 50 mg a day by mouth and the dose will be increased each week if you are 
tolerating it, until you reach a maximum dose of 200 mg per day.  
 
 
Table  -- Dexamethasone and Thalidomide Treatment Schedule 
 
 
Months 1-12 
Thalidomide  
200 mg/day PO 
Start 50 mg/day and increase 50 mg/day each week 
as tolerated to target dose of 200 mg/day 
Dexamethasone 
40 mg/day PO 
Days 1-4 of each month 
 
 
You will be seen in the clinic at least weekly, or as clinically indicated, for the first several 
months, regardless of whether you were randomized to observation or maintenance therapy with 
dexamethasone and thalidomide.  After three months you will be seen at least every month until 
6 months after transplant and then you will be seen at least every 6 months until three years.  If 
necessary, you may require more frequent follow-up. 
 
Additional assessments:  If you are a female patient that has any chance of becoming pregnant, you 
must have a serum pregnancy test performed.  The test will be performed within 24 hours of 
starting thalidomide, weekly for the first four weeks of taking thalidomide, and then every four 
weeks if your periods are regular or every two weeks if they are not, until you have finished taking 
thalidomide (12 months). 
 


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7. 
Will You Provide Blood Samples for Research? 
 
Research Blood Samples 
Genetic material is any sample of tissue, blood, fluid, etc. obtained from you during the study.  
With your permission, 20 samples of your blood (2 teaspoons for each sample) will be collected 
during the course of the study and stored to be used solely for research purposes.  The samples will 
be stored for future studies that will look at responses to treatment based on factors not yet known.  
These factors may relate to characteristics of your MM or to how your body tolerated the study 
treatments.  Usually these blood samples can be drawn from you at the time of routine blood 
collections.  Your confidentiality will be maintained because no identifying markers (name, etc.) 
will remain with the sample.   
 
All BMT CTN research samples will be paired with the respective donor or recipient sample and 
given unique bar code designations that cannot be linked back to the donor or the recipient.  All 
research samples will become property of the NHLBI after conclusion of the BMT CTN Protocol 
#0102 study.  An NHLBI Biologic Specimen Repository Utilization Committee will advise 
NHLBI on requests for samples to perform research with these anonymous samples.  If an 
Investigator request for these samples is approved by the committee, the NHLBI may provide a 
panel of the specimens requested using unique code numbers.  Laboratory test results, clinical 
information, etc., associated with the coded samples are provided to the Investigator only after 
completion of the main protocol.  Samples sent to researchers cannot be linked with any 
remaining sample at the repository.  
 
If you agree to allow your blood to be kept for research, you are free to change your mind at any 
time.  We ask that you contact [Principal Investigator] in writing and let him/her know you are 
withdrawing your permission for your blood to be used for research.  His/her mailing address is 
on the first page of this form.   
 
You are free not to take part in this additional future research.  There will be absolutely no 
change in your care as a result of your refusal to give these additional samples.  Please 
indicate your choice below:  
 I agree to provide blood for future research. 
 I do not agree to provide blood for future research. 
 
 
_________________________________________________ 
_______________________ 
Signature 
 
 
 
 
 
 
 
 
Date 
 


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8. 
What are the possible discomforts and risks? 
 
The treatment used in this study may cause all, some, or none of the side effects listed below.  
Also, there is always the chance of unexpected new side effects. 
 
ALL PATIENTS 
 
Central Venous Catheter: There has been considerable experience with the use of central venous 
catheters.  The most common complications are clotting and local infection which sometimes lead 
to a generalized infection in the blood.  Clotting may require the removal of the catheter or 
treatment of the clot by a fibrinolytic agent (medicines that dissolve blood clots).  Infections will be 
treated with antibiotics, and sometimes, removal of the catheter may be required.  Occasionally, 
there has been skin redness at the catheter exit site, which may require treatment with an antibiotic.  
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 reinflate the lung may be required and there are no long-
term effects once it has resolved. 
 
G-CSF: G-CSF may cause local pain and burning at the injection site and some patients 
experience pain in their bone when treated with this drug.  The bone pain is generally mild to 
moderate in severity and controllable in most patients with oral medication. The growth factor 
may cause your white count to become very high, which could affect your blood flow.  Your 
white blood cell count will be measured, and if it becomes too high, the dose of the growth factor 
will be reduced or stopped.  Less common possible side effects include headaches, body aches, 
upset stomach, skin rash, fatigue and trouble sleeping.  Local inflammation and rarely an 
infection at the G-CSF injection site may also occur. 
 
Leukapheresis: If you have a central venous catheter, this procedure will be done through the 
catheter and not through a vein.  If done through a vein, the needle insertion used for the 
Leukapheresis procedure may cause local bruising and infection in the vein or on the skin around 
the vein.  The bruising resolves on it own and has no additional risks.  The infection in the vein 
or of the skin around the vein would be treated with antibiotics.   
 
Your blood will be thinned with citrate during the Leukapheresis procedure.  Citrate decreases 
the calcium in the blood sometimes causing temporary numbness or tingling of the fingertips or 
around the mouth.  Should you experience any numbness, you must tell the nurse operating the 
machine.  You will be given a dose of calcium to reverse this side effect, before the problem 
becomes severe.  Other possible side effects of the collection procedure include lightheadedness, 
nausea or more rarely, fainting due to temporary lowering of the blood pressure.  Stopping the 
procedure and giving additional intravenous fluids can correct this.  Occasionally, the filtering 
process also removes platelets (the cells that help the blood to clot).  If your platelet count falls 
low enough to place you in danger of bleeding, any further collection will be postponed until a 
replacement transfusion is given.   
 


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AUTOLOGOUS STEM CELL TRANSPLANT 
 
Melphalan:  The most common side effect in patients who have received melphalan has been 
nausea and vomiting (mild to moderate), loss of appetite (mild), diarrhea and skin rash.  Your 
doctor will prescribe drugs to prevent and lessen these side effects should they occur.  Melphalan 
will irritate your skin if it leaks outside of the vein while being given.  Let your doctor or nurse 
know if you feel any burning, stinging or pain while you are receiving this drug.  Notify your 
doctor right away if the area around the injection becomes red or swollen after you receive the 
drug.  Side effects that occur several days or a week later include low blood count, mouth sores, 
temporary hair loss, fatigue and poor appetite.  You may need blood and platelet transfusions 
while your counts are low and/or antibiotics to fight infections.  Mouth sores which sometimes 
extend into the throat or esophagus can be painful, and some patients may require 7 to 10 days of 
morphine or a similar medication to control the discomfort.  Mouth sores can also make eating 
difficult.  If this occurs, patients will receive their nutrition intravenously until the problem 
resolves.  In rare instances, melphalan can cause lung damage or a secondary cancer (a cancer 
caused by prior cancer treatment).  Secondary cancers are often very difficult to treat and can be 
fatal.  
 
Infusion of Autologous Stem Cells: The stem cell infusion is given similar to a blood 
transfusion. It is given through your central venous catheter.  You will be given pre-medications 
just prior to the infusion to decrease the risk of a reaction.  There is a very slight risk of infection 
due to contamination of the stem cell products during their storage or drawing.  Some patients 
react to the preservative called DMSO, which is used in the freezing process of your stem cells.  
You may notice a garlic taste or smell from the DMSO.  Common, less serious reactions for 
patients receiving an autologous SCT include mild wheezing, mild shortness of breath, back or 
chest pain or lightheadedness. In rare instances, a severe allergic reaction called anaphylaxis can 
occur leading to a drop in blood pressure or extreme difficulty in breathing.  You will be 
monitored very closely during the infusion and afterwards to look for these reactions and given 
medications and/or intravenous fluids to correct these side effects.  These complications are 
reversible with treatment.  
 
Risk of Infection and Other Complications of Low Blood Counts: After any of the therapies in 
this study, but before the stem cells have begun to make new blood cells, your ability to fight 
infections will be very low.  During that time you will be very susceptible to serious infections 
and will need to take extra precautions to limit your exposure to infectious agents.  Bacteria, 
fungi and viruses that can easily be destroyed by a healthy person’s immune system can cause a 
serious, and sometimes fatal infection in patients with low white blood cell counts.  You will be 
given medications to prevent infections and to treat them if you develop one as determined by 
your doctor.  
 
After transplantation you may not be able to make red blood cells or platelets for approximately 
two to three weeks until the stem cells start growing in your bone marrow.  If your red blood cell 
count is very low, you may have severe fatigue or shortness of breath.  If your platelet count is 
low, there is a small chance of serious bleeding.  Therefore, you may need red blood cell and 
platelet transfusions. 


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The risk of dying from the complications of an autologous transplant is less than 5%.  This 
means that for every hundred patients who have an autologous transplant for multiple myeloma, 
up to 5 of them may die from complications of the treatment.  It is not possible to know before 
your transplant if you will die from complications of treatment. 
 
NON-MYELOABLATIVE ALLOGENEIC STEM CELL TRANSPLANT (Allogeneic 
NMSCT) 
 
Total Body Irradiation (TBI): The immediate effects of irradiation may include nausea, vomiting, 
diarrhea, loss of appetite, painful swelling of the salivary gland under the jaw for a few days, and 
temporary hair loss.  TBI may lower your blood counts.  The dose of TBI used in this protocol is 
approximately one-sixth of that used in conventional transplant protocols, and severe side effects 
are not expected and have not been seen in other patients receiving this dose of TBI.  TBI has been 
associated with causing sterility; however, it is expected that the risk of infertility will be lower 
than the risk after transplants that use higher doses of TBI.  Although TBI can theoretically cause 
abnormalities in children born to transplant survivors, the incidence of genetic abnormalities has 
not been reported to be greater than the general population.  However, this is a potential risk and 
birth control should be used for at least one year after transplant to minimize risks of conceiving.  
In addition, there may be a small increased risk of you developing other cancers in the future as a 
consequence of having received chemotherapy and TBI.  Cancers that are caused by treatment with 
chemotherapy or radiation are often fatal. 
 
Infusion of Allogeneic Stem Cells: The infusion of your donor’s stem cells into you is generally 
well tolerated.  There is a very slight risk of infection due to contamination of the stem cell 
products.  There is a slight risk that the stem cells will not grow after they are infused.  If this 
occurs, you would be expected to recover your blood counts with your own blood cells, if they 
were relatively normal prior to this treatment.  There is a very small chance that if your donor’s 
cells do not grow, your blood counts would not recover.  If this were to happen, you could die from 
this problem. 
 
Risk of Infection and Other Complications of Low Blood Counts: It is possible but not likely 
that you will develop low blood counts after your allogeneic stem cell transplant.  However, even 
if your blood counts are normal your ability to fight infections is decreased after allogeneic 
transplant.  Therefore, you will be very susceptible to serious infections for a period of time after 
your transplant and will need to take extra precautions to limit your exposure to infectious 
agents.  You will be given medications to prevent infections and to treat them if one develops.  
 
After transplantation you may not be able to make red blood cells or platelets for a few weeks 
and may need red blood cell and platelet transfusions. 
 
The risk of dying from the complications of an allogeneic transplant as described in this consent 
are estimated to be less than 20%.  This means that for every hundred patients who undergo a 
non-myeloablative allogeneic transplant for multiple myeloma, up to 20 of them may die from 


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complications of the treatment.  It is not possible to know before your transplant whether you 
will die from complications of treatment. 
 
Mycophenolate Mofetil (MMF): MMF is a recently approved drug used for suppressing the 
immune system and has not been extensively used in stem cell transplantation.  Preliminary 
studies indicate that this drug is reasonably well tolerated in the transplant setting.  There are a 
small number of patients who have received transplants and had reversible decreases in their red 
cell or white cell count while receiving MMF.  Your blood counts will be monitored closely and 
if significant decrease is noted, lowering your dose or stopping your MMF may be indicated.  
Other uncommon side effects include nausea, vomiting, diarrhea, and abdominal discomfort.  
Occasional cases of gastrointestinal bleeding have also been reported in transplant patients.  
Your MMF dose may also be decreased if you have severe gastrointestinal (gut) side effects.  
 
Cyclosporine: The immediate effects of this drug may include nausea or vomiting when given 
orally.  Other possible side effects include developing high blood pressure (hypertension), shaking 
of the hands (tremor), increased facial hair growth, headache, and an effect on mental function.  
These effects are generally reversible upon decreasing the dose of the drug.  An occasional patient 
has had a seizure but it is unclear whether cyclosporine, other drugs, or a combination of drugs was 
responsible.  Some patients given intravenous cyclosporine for the treatment of GVHD have 
experienced a painful sensation in the hands or feet or both.  The pain went away after the GVHD 
improved or when the cyclosporine was switched from the intravenous to the oral form. 
 
The dose of cyclosporine may need to be reduced or possibly withheld if routine blood tests show a 
change in kidney function.  This effect on the kidneys seems to increase when other drugs, which 
might cause kidney problems, are given at the same time, especially certain antibiotics.  
Occasionally, the kidney damage is severe enough to require the use of an artificial kidney 
machine (hemodialysis).  During treatment, cyclosporine blood levels will be monitored 
periodically to determine if there are increased risks of side effects that warrant adjusting the dose. 
 
Graft-Versus-Host-Disease: Graft-versus-host-disease (GVHD) is a known complication of 
allogeneic stem cell transplantation.  This is a process where the donor’s stem cells cause 
inflammation of your skin, liver, gastrointestinal system and/or other organs.  About 50% of 
patients who have undergone a non-myeloablative allogeneic stem cell transplant have 
developed GVHD.  Your risk of developing GVHD is thought to be about the same.  
Cyclosporine and mycophenolate mofetil will be given to you in this study to minimize the risk 
of developing GVHD.   
 
GVHD is called acute GVHD when it starts during the first one hundred days after your 
transplant.  It can cause a skin rash, inflammation of the liver and nausea, vomiting and/or 
diarrhea.  Graft-versus-host-disease starting later on, more than 100 days after your transplant, is 
called chronic GVHD.  It may cause mouth sores, diarrhea, inflammation of the liver, weight 
loss, joint pain, dry eyes, dry mouth, skin thickness and joint problems, and, rarely, lung damage.  
You may develop acute, chronic or both.  If you develop GVHD, several medications to control 
the severity of GVHD are available and are usually successful in getting rid of or controlling the 
symptoms.  Your doctor will discuss with you the different types of treatment available to treat 


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GVHD.  Both acute GVHD and chronic GVHD are usually mild to moderate in severity.  
However, severe GVHD or complications of its treatment can be fatal. 
 
LOW RISK PATIENTS 
 
Multiple myeloma does not behave the same in all patients.  There are lab tests that can, in 
general, identify patients who have a better survival after autologous transplantation than other 
MM patients.  These lab tests include a blood test called beta-2 microglobulin and a standard 
bone marrow test called cytogenetics or chromosome study.  As a group, patients with normal 
cytogenetics in the bone marrow and a low beta 2 microglobulin level in their blood have a better 
outcome than other MM patients after autologous SCT.  On average this low risk group of 
patients have a survival of greater than 7 years following either single or tandem autologous 
SCT.  These patients, however, are not cured of their MM and eventually they will succumb to 
their disease.  It is possible that for this low risk group of patients, there is a greater risk of 
complications and dying from the allogeneic non-myeloablative SCT in the first few years after 
the transplant than if they had tandem autologous SCT.  It is possible though that in the long-
term, the benefit of a graft versus myeloma effect may result in a better outcome for the patients 
who received allogeneic non-myeloablative SCT.  For low risk patients, this short term risk must 
be considered when considering participating in the study. 
 
MAINTENANCE THERAPY (ARM B OF PHASE II) 
 
Dexamethasone: This medication may temporarily increase blood pressure and blood sugar 
levels.  Some patients require medication to control their blood sugar.  Steroid medications have 
also been known to cause insomnia (difficulty sleeping), personality changes and depression.  
Dexamethasone may also cause nausea, vomiting, increased appetite, stretch marks, weight gain, 
fluid retention, gas and heartburn.  These symptoms usually go away once the medication is 
stopped.  Gas and heartburn can be treated with medications.  Call your doctor if you experience 
these symptoms.  Dexamethasone can also cause thinning and weakening of the bones. 
 
Thalidomide: Thalidomide may very likely cause sleepiness, decreased alertness, constipation, 
increased appetite, weight gain, loss of sex drive, nausea, skin rash, dry skin, numbness and 
tingling of the hands and/or feet, dry mouth and temporary hair loss.  Less likely side effects of 
thalidomide include slowing of the heart, depression, swelling of the face, hands, or feet, 
irregular menstrual periods, and milky like fluid leaking from the nipples.  Your thalidomide 
dose will be adjusted to try and minimize these symptoms. 
 
Reproductive Risks: Thalidomide causes severe birth defects in unborn babies if females who 
are pregnant take the drug.  The risk of thalidomide causing damage to the embryo is up to 50% 
for females taking thalidomide during the “sensitive period” which is estimated to range from 
35-50 days after the last menstrual period.  It is not known whether thalidomide may cause birth 
defects in unborn babies if it is taken after the “sensitive” period.  A single dose of thalidomide, 
however, may cause birth defects. 
 


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Birth defects observed in babies exposed to thalidomide during pregnancy include absent or 
abnormal legs and arms; spinal cord defects; cleft lip or palate; absent or abnormal external ear; 
heart, kidney and genital abnormalities; and, abnormal formation of the digestive system, 
including blockage of necessary openings.  An association between thalidomide and autism has 
also been proposed. 
 
Because of the severity of these abnormalities, it is extremely important that pregnancies 
do not occur while you are taking thalidomide. 
 
You should discuss with your doctor what the best methods of birth control are for you.  
Remember, however, than no method of birth control besides complete abstinence provides 
100% protection from pregnancy. 
 
If you are a female patient taking thalidomide, you must either abstain from all reproductive 
sexual intercourse or use two methods of birth control or at least one highly active method (e.g., 
intrauterine device [IUD], hormonal [birth control pills, injections or implants], tubal ligation, or 
partner’s vasectomy) and one additional effective method (e.g., latex condom, diaphragm, or 
cervical cap), for at least four weeks before starting thalidomide therapy, during therapy, and for 
at least four weeks after discontinuing thalidomide therapy even when there has been a history of 
infertility, unless due to hysterectomy or because you have been post-menopausal or have had no 
menses (that is no menstrual period) for at least 24 continuous months. 
 
If you are a female patient and have any chance of becoming pregnant, you must have a serum 
pregnancy test performed.  The test will be performed within 24 hours of beginning thalidomide, 
weekly for the first four weeks of treatment, and then every four weeks if the patient’s periods 
are regular or every two weeks if they are not, until you have finished taking thalidomide (12 
months). 
 
If you are a male patient, you will be counseled that thalidomide may be present in your semen.  
You must use a latex condom every time you have sexual intercourse with a woman during 
therapy and for four weeks after discontinuing thalidomide, even if you have had a successful 
vasectomy.  You should request that female partners use a second method of birth control in 
addition to using a male condom. 
 
You must be willing and able to participate in the FDA mandated System for Thalidomide 
Educational Prescribing and Safety (S.T.E.P.S.™) if you are to receive thalidomide.  Hence, you 
will be asked to sign a separate mandatory consent form (as part of the S.T.E.P.S.™ system).  
Also, all doctors and pharmacists will be registered to prescribe or dispense thalidomide. 
 


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ALL PATIENTS 
 
Blood Drawing: The risks of drawing blood from a vein include discomfort at the site of 
puncture (where the needle is placed in the vein); possible bruising and swelling around the 
puncture site; rarely, an infection; and uncommonly, faintness from the procedure.  If you have a 
central line or catheter, these risks will not apply to you and the risks of the central line were 
explained to you at the time you had the line or catheter placed.  Occasionally even if you have a 
central catheter, you may require blood draws from a vein requiring a needle stick. 
 
Bone Marrow Aspiration and Biopsy: A bone marrow aspiration is a procedure in which an area 
of the hip (buttock area) is numbed with local anesthetic, and a small sample of bone marrow is 
withdrawn.  A bone marrow biopsy is similar to a bone marrow aspiration, except a sample of 
bone is removed through the needle.  When the local anesthesia is given, you may initially feel a 
burning sensation in your skin and bone surface for several seconds.  During the actual procedure 
itself, you may temporarily feel pressure and/or pain of varying degrees.  If necessary, you may 
ask your physician for additional local anesthesia or a medication to ease your stress.  You also 
may experience bleeding, and/or bruising after the procedure is completed and you may 
experience soreness in the area for a few days afterwards.  Rarely an infection can develop. 
 
Bone marrow aspirates and biopsies will be used to check how your disease is responding to the 
study treatments. 
 
Unexpected Organ Damage and Other Side Effects:  Although your major organs function 
well, it is possible that unexpected heart, lung, kidney, or liver damage may occur as a result of 
this therapy, which are rarely life-threatening and usually reversible with treatment.  You will be 
informed if problems arise and the measures being taken to help you.  Rarely, multi-organ failure 
(such as lung and kidney failure) may occur, which is often fatal despite intensive medical 
management.  Other unpredictable side effects can occur and will be explained to you and treated 
by your physicians should unforeseeable problems arise.   
 
Late Effects: These may include gland problems resulting in poor growth and sterility.  There 
may be poor function of the thyroid gland, requiring thyroid hormone supplementation.  There is 
also a risk of second cancers as a result of the chemotherapy and/or underlying disease.  The risk 
of developing and dying from a secondary cancer is far less than the risk of dying from your 
disease without treatment.  The long-term effects upon heart, lung, and brain are unknown. 
 
Risk to the Unborn: The treatments in this study have not been proven to be safe at any stage of 
pregnancy.  Therefore, if you are pregnant or nursing, you are not eligible for this study.  Women 
who have the potential of becoming pregnant must use some effective method of birth control.  
Effective birth control would be defined as the following: 1) refraining from all acts of vaginal 
intercourse (ABSTINENCE); 2) consistent use of birth control pills; 3) injectable birth control 
methods (Depo-Provera, Norplant); 4) tubal sterilization or male partner who has undergone a 
vasectomy; 5) placement of an IUD (intrauterine device); and, 6) use, with every act of 
intercourse, of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam. 
 


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Sterility and Future Childbearing Potential for Men and Women: Chemotherapy and /or 
irradiation may affect fertility.  Male patients may become sterile (unable to produce sperm).  
Female patients may find that their menstrual cycle becomes irregular or stops permanently.  
However, this DOES NOT MEAN THAT YOU CANNOT BECOME PREGNANT, and you 
must use some effective method of birth control.  Damage to reproductive tissue may result in 
birth defects or permanent inability to father a child or become pregnant.  You should discuss 
these risks and options in detail with your doctor before entering this study. 
 
Other Information: 
 
There may be some unknown or unanticipated discomforts or risks associated with this treatment 
in addition to those specified above, but every precaution will be taken to assure your personal 
safety and to minimize discomforts. 
 
Throughout the study, the researchers will tell you of new information that might affect your 
decision to remain in the study. 
 
If you wish to discuss the information above or any other discomforts you may experience, you 
may ask questions now or call your doctor _______________________, the Principal 
Investigator or contact person listed on the front page of this form. 
 
9a. 
What are the possible benefits to you for taking part in this study? 
 
Although this study cannot be guaranteed to be of benefit to you, it is hoped that your taking part 
may lead to the improvement or disappearance of your myeloma and prolongation of your life.  
However, no benefit is guaranteed. 
 
9b. 
What are the possible benefits to others? 
 
A possible advantage of this study is that benefit to others may result from the knowledge gained 
from your participation in this research study.  
 
10. 
If you choose to take part in this study, will it cost you anything? 
 
You are responsible for the costs of treatment for your disease on this protocol.  Your insurance 
provider may not cover all or part of these costs.  You are not required to pay for tests or 
research samples that are being performed or collected only for research purposes.  You or your 
family will have to pay installments based on your verified ability to pay.  If you have concerns 
or questions regarding coverage or potential charges, you should contact (contact person’s name) 
at (###) ###-####, or the Principal Investigator of the study, to review the situation. 
 
11. 
Will you receive payment for taking part in this research study? 
 
No. 
 


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12. 
What if you are injured because of the study? 
 
You agreed to take the risks listed above.  If you experience an injury that is directly caused by 
this study, only the professional medical care you receive at the [participating clinical facility] 
will be provided without charge.  Hospital expenses will be paid by you or your insurance 
provider.  No other compensation is offered.  By signing this form you have not waived any of 
your legal rights.  If you have any questions about injuries, you may call [insert name] at (###) 
###-####. 
 
13. 
What other options or treatments are available if you do not want to be in this 
study? 
 
Participation in this study is entirely voluntary.  You are free to refuse to be in the study, and 
your refusal will not affect current or future health care you receive at this institution.  You and 
your doctor will discuss any other treatment options available to you. 
 
Current therapies for multiple myeloma include: 
 Chemotherapy using single or combinations of drugs 
 Single autologoustransplants with or without additional drugs to prevent relapse after 
transplantation 
 Double autologous transplants with or without additional drugs to prevent relapse after 
transplantation 
 Allogeneic transplantation using a related or unrelated donor 
 
You may also be eligible to receive other investigational treatment or you may decide not to 
receive any treatment.  Your doctor will discuss these and other possible treatment approaches 
with you. 
 
14a. 
How can you withdraw from this research study? 
 
If you agree to be in this study, you are free to change your mind.  At any time you may 
withdraw your consent to be in this study and for us to use your data.  If you withdraw from the 
study, you will continue to have access to health care at [participating clinical facility].  If you 
decide to withdraw, we ask that you tell the [Principal Investigator] in writing; his/her mailing 
address is on the first page of this form.  If you do withdraw your consent, there will be no 
penalty and you will not lose any benefits to which you are otherwise entitled. 
 
Due to the nature of your illness and the study treatments, it is important to continue to receive 
medical follow-up even if you withdraw from the research study.  If you have any questions 
about your rights as a study subject, you may call the Institutional Review Board (IRB) office at 
(###) ###-####. 
 


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14b. 
If you withdraw, can information about you still be used and/or collected? 
 
If you withdraw from the study, we ask that you agree that we can continue using all information 
about you that has already been collected as part of the study prior to your withdrawal, and to 
continue to allow your doctor to tell us about your progress until 12 months after your transplant.  
You may, of course, say no. 
 
14c. 
Can the Principal Investigator withdraw you from this research study? 
 
You can be taken off the study (with or without your consent) for any of the following reasons: 
 You do not qualify to be in the study because you do not meet the study requirements.   
 You need a medical treatment not allowed in this study. 
 The investigator decides that continuing in the study would be harmful to you. 
 The study treatments have a bad effect on you. 
 You become pregnant as the study treatment could be harmful to the fetus. 
 You are unable to keep appointments or take study drugs as directed. 
 Other study-specific reasons; for example, if the study treatment you are taking has been 
found to be unsafe. 
 The study is cancelled by the Food and Drug Administration (FDA) or the National 
Institutes of Health (NIH). 
 Your myeloma returns. 
 
15. 
How will your privacy and the confidentiality of your research records be 
protected? 
 
Study records that have your name will be kept private as required by law.  You will not be 
identified by name in the central study records.  Your records will be given a unique code 
number.  The key to the code will be kept in a locked file in the offices of the Coordinating 
Center for the study.  Authorized persons from the [participating clinical facility], the hospital or 
clinic (if any) involved in this research, and the Institutional Review Board have the legal right to 
review your research records and will protect their confidentiality to the extent permitted by law.  
This research study is sponsored by and conducted with funds from the National Institutes of 
Health; therefore, the sponsor, the sponsor’s agent, the Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN), the investigators conducting this study, Southwest Oncology 
Group, and the FDA also have the legal right to review your research records.  Otherwise, your 
research records will not be shown to anyone without your consent unless required by law or a 
court order. 
 
If the results of this research are published or presented at scientific meetings, your name will not 
be disclosed. 
 


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16. 
Expiration date for retention of records 
 
The study results will stay in your research record at [insert Institution] for at least six years or 
until after the study is completed, whichever is longer.  At that time either the research 
information not already in your medical record will be destroyed or your name and other 
identifying information will be removed from such study results.  Research information in your 
medical record will be kept indefinitely. 
 
17. 
How will the researcher(s) benefit from your being in this study? 
 
In general, presenting research results helps the career of a scientist.  Therefore, the Principal 
Investigator may benefit if the results of this study are presented at scientific meetings or in 
scientific journals.  In addition, the sponsor is providing funds to the Principal Investigator to 
facilitate the conduct of this study. 
 
18. 
HIPAA1 authorization to use and disclose individual health information for 
research purposes 
 
a. Purpose:  As a research participant, I authorize the Principal Investigator and the 
researcher’s staff to use and disclose my individual health information for the purpose of 
conducting the research study entitled A Trial of Tandem Autologous Stem Cell 
Transplants +/- Post Second Autologous Transplant Maintenance Therapy Versus Single 
Autologous Stem Cell Transplant Followed by Matched Sibling Non-myeloablative 
Allogeneic Stem Cell Transplant for Patients with Multiple Myeloma. 
b. Individual Health Information to be Used or Disclosed: My individual health information 
that may be used or disclosed to conduct this research includes: demographic information 
(e.g., age, date of birth, sex, weight), medical history (e.g., diagnosis, complications with 
prior treatment), physical examination findings, and laboratory test results obtained at the 
time of work-up and after transplantation (e.g., bone marrow tests, blood tests, biopsy 
results). 
c. Parties Who May Disclose My Individual Health Information:  The researcher and the 
researcher’s staff may obtain my individual health information from (list hospitals, 
clinics or providers from which health care information can be requested). 
 
 
 
d. Parties Who May Receive or Use My Individual Health Information:  The individual 
health information disclosed by parties listed in item “c.” above and information 
                                                   
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of 
health information. 


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disclosed by me during the course of the research may be received and used by the 
following parties: 
­ Principal Investigator and the researcher’s staff 
­ Dr. David Maloney, Study Chairperson and staff/laboratories at Fred Hutchinson 
Cancer Research Center 
­ Dr. Amrita Krishnan, Study Chairperson and staff/laboratories at City of Hope 
National Medical Center 
­ National Heart, Lung and Blood Institute (NHLBI) and National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH), study sponsors 
­ Blood and Marrow Transplant Clinical Trials Network (BMT CTN), data 
coordinating center 
­ Southwest Oncology Group (SWOG), clinical trials cooperative group 
­ U.S. government agencies that are responsible for overseeing research such as the 
Food and Drug Administration (FDA) and the Office of Human Research Protections 
(OHRP) 
­ U.S. government agencies that are responsible for overseeing public health concerns 
such as the Centers for Disease Control (CDC) and federal, state and local health 
departments 
­ Celgene (the manufacturer of thalidomide) and the S.T.E.P.S.™ Survey Coordinating 
Center (Slone Epidemiology Unit of Boston University School of Public Health) 
e. Right to Refuse to sign this Authorization:  I do not have the sign this Authorization.  If I 
decide not to sign the Authorization, I will not be allowed to participate in this study or 
receive any research-related treatment that is provided through the study.  However, my 
decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits. 
f. Right to Revoke:  I can change my mind and withdraw this authorization at any time by 
sending a written notice to the Principal Investigator to inform the researcher of my 
decision.  If I withdraw this authorization, the researcher may only use and disclose the 
protected health information already collected for this research study.  No further health 
information about me will be collected by or disclosed to the researcher for this study. 
g. Potential for Re-disclosure: My individual health information disclosed under this 
authorization may be subject to re-disclosure outside the research study and no longer 
protected.  Examples include potential disclosures for law enforcement purposes, 
mandated reporting or abuse or neglect, judicial proceedings, health oversight activities 
and public health measures. 
h. This authorization does not have an expiration date. 
 


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19. 
Further Information 
 
If you have further questions concerning this project at any time, you are free to ask them of Dr. 
___________, who will be available to answer them.  His/her telephone number is located on the 
first page of the consent. 
 
20. 
Consent Instructions 
 
To voluntarily become a participant in this research study I must confirm the following and sign 
below.  
* I have read all of the information in the Informed Consent and I have had time to think about 
it. 
* All of my questions have been answered to my satisfaction.  If I did not understand any of the 
words or parts of this study, I asked the study doctor or the research staff to explain what I did 
not understand.   
* I voluntarily agree to be part of this research study and to follow the study procedures as 
directed.  I agree to keep the research staff informed of my current contact information. 
* I have been informed that I may discontinue my participation in this study at any time. 
* Signing this consent form is not a waiver of my legal rights. 
* I have received a signed copy of this Informed Consent to keep for my reference.  
 
 
 
 
 
 
 
 
 
 
 
Subject Name (please print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Signature or Legal Representative (relationship) 
 
 
Date & Time 
 
 
 
 
 
 
 
 
 
 
        
Name of Individual Conducting Informed Consent Discussion  
(please print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Individual Conducting Informed Consent Discussion  
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Witness (where Applicable) 
 
 
 
 
Date 
 


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I have fully explained the research study to the subject and answered all of the subjects 
questions. 
 
 
 
 
 
 
 
 
 
 
 
Name of Principal Investigator or Authorized Representative  
(please print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator or Authorized 
 
 
 
Date 
Representative 


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THALOMID™ (thalidomide) Informed Consent Forms 
 
Important Information and Warnings for ADULT MALES 
WARNING: SEVERE, LIFE THREATENING HUMAN BIRTH DEFECTS.  
IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN 
BABY.  THALIDOMIDE SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO COULD BECOME 
PREGNANT WHILE TAKING THE DRUG. EVEN A SINGLE DOSE [1 CAPSULE (50, 100 OR 200 MG)] TAKEN BY A PREGNANT 
WOMAN CAN CAUSE SEVERE BIRTH DEFECTS.  
CONSENT FOR MEN: 
INIT: _______ 
1.  
I understand that severe birth defects can occur with the use of THALOMID 
(thalidomide).  I have been warned by my doctor that any unborn baby will almost 
certainly have severe birth defects or can even die if a woman is pregnant or becomes 
pregnant while taking THALOMID (thalidomide). 
INIT: _______ 
2. 
1 have been told by my doctor that I must NEVER have unprotected sexual contact with 
a woman who can become pregnant.  Because THALOMID (thalidomide) is present in 
semen, my doctor has explained that I must either completely abstain from sexual contact 
with women who are pregnant or able to become pregnant, or I must use a latex condom 
EVERY TIME I engage in any sexual contact with women who are pregnant or may 
become pregnant while taking THALOMID (thalidomide) -- and for 4 weeks after I 
stop taking the drug, even if I have had a successful vasectomy. 
INIT: _______ 
3. 
I know that I must inform my doctor if I have had unprotected sexual contact with a 
woman who can become pregnant; or if I think, FOR ANY REASON, that my sexual 
partner may be pregnant.  If my doctor is not available, I can call Celgene Drug Safety at 
1-888-423-5436 or 1-888-668-2528 for information on emergency contraception. 
INIT: _______ 
4. 
I understand that THALOMID (thalidomide) will be prescribed ONLY for me.  I must 
not share it with ANYONE, even someone who has similar symptoms to mine.  It must 
be kept out of the reach of children and should NEVER be given to women who are able 
to have children. 
INIT: _______ 
5.  
I agree any unused drug will be returned to Celgene by calling 1-888-423-5436.  
Shipping costs will be paid by Celgene. 
INIT: _______ 
6. 
I have read the THALOMID (thalidomide) patient brochure and/or viewed the 
videotape, "Important Information for Men and Women Taking THALOMID 
(thalidomide)."  I understand the contents, including other possible side effects from 
THALOMID (thalidomide).  I know that I cannot donate blood or semen while taking 
THALOMID™ (thalidomide). 
INIT: _______ 
7.  
I understand that I must participate in a telephone survey and patient registry while I am 
on THALOMID (thalidomide). 
INIT: _______ 
8. 
My doctor has answered any questions I have asked. 
INIT: _______ 
9. 
I understand that I might be asked to participate in an additional voluntary survey by mail 
or telephone to evaluate this S.T.E.P.S program.  My agreement or disagreement will 
not interfere with my ability to receive THALOMID (thalidomide). 
INIT: _______ 
10.  I acknowledge I may be contacted by a Celgene representative in regards to following the 
rules of the S.T.E.P.S.  program. 
 
AUTHORIZATION: 
This information has been read aloud to me in the language of my choice.  I understand that if I do not follow all of 
my doctor's instructions, I will not be able to receive THALOMID (thalidomide).  I now authorize my doctor to 
begin my treatment with THALOMID (thalidomide). 
 
______________________________________________________________   ______________________________ 
Patient Name (please print)                                Social Security No. (only last six digits required)    Date of birth (mm/dd/yyyy)         Patient, Parent/Guardian Signature            Date (mm/dd/yyyy) 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Patient Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 27 of 30 
Patient Initials ________ 
 
I have fully explained to the patient the nature, purpose, and risks of the treatment described above, especially the 
risks to women of childbearing potential.  I have asked the patient if he has any questions regarding his treatment 
with THALOMID (thalidomide) and have answered those questions to the best of my ability.  I will comply with 
all of my obligations and responsibilities as a prescriber registered under the S.T.E.P.S. restricted distribution 
program. 
 
____________________________________________________   ________________________________________ 
Physician Name (please print)                                                                     DEA No.                                               Physician Signature                                                                     Date (mm/dd/yyyy) 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Patient Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 28 of 30 
Patient Initials ________ 
 
THALOMID™ (thalidomide) Informed Consent Forms 
 
Important Information and Warnings for ADULT FEMALES OF CHILDBEARING POTENTIAL 
WARNING: SEVERE, LIFE THREATENING HUMAN BIRTH DEFECTS.  
IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN 
BABY.  THALIDOMIDE SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO COULD BECOME 
PREGNANT WHILE TAKING THE DRUG.  EVEN A SINGLE DOSE [1 CAPSULE (50, 100 OR 200 MG)] TAKEN BY A 
PREGNANT WOMAN CAN CAUSE SEVERE BIRTH DEFECTS.  
CONSENT FOR FEMALES OF CHILDBEARING POTENTIAL: 
INIT: _______ 
1.  
I understand that severe birth defects can occur with the use of THALOMID 
(thalidomide).  I have been warned by my doctor that my unborn baby will almost 
certainly have severe birth defects or can even die if I am pregnant or become pregnant 
while taking THALOMID (thalidomide). 
INIT: _______ 
2.  
I understand that I must not take THALOMID (thalidomide) if I am pregnant, breast-
feeding a baby, or able to get pregnant and not using the required two methods of birth 
control. 
INIT: _______ 
3.  
If I am having sexual relations with a man, and I am less that 50 years of age, and/or 
menses stopped due to treatment of my disease, I understand that it I am able to become 
pregnant.  I must use at least one highly effective method and one additional effective 
method of birth control (contraception) AT THE SAME TIME: 
 
At least one highly effective method 
­ IUD 
­ Hormonal 
(birth 
control 
pills, 
injections, patch, implants) 
­ Tubal ligation (tubes tied) 
­ Partner's vasectomy 
AND 
One additional effective method 
­ Latex condom 
­ Diaphragm 
­ Cervical cap 
 
These birth control methods must be used for at least 4 weeks before starting 
THALOMID (thalidomide) therapy, all during THALOMID (thalidomide) therapy, 
and for at least 4 weeks after THALOMID (thalidomide) therapy has stopped.  I must 
use these methods unless I completely abstain from heterosexual sexual contact.  If a 
hormonal (birth control pills, injections, patch or implants) or IUD method is not 
medically possible for me, I may use another highly effective method or two barrier 
methods AT THE SAME TIME. 
INIT: _______ 
4. 
I know that I must have a pregnancy test done by my doctor within 24 hours prior to 
starting THALOMID (thalidomide) therapy, even if I have not had my menses due to 
treatment of my disease, then every week during the first 4 weeks of THALOMID 
(thalidomide) therapy.  I will then have a pregnancy test every 4 weeks if I have regular 
and/or no menstrual cycles, or every 2 weeks if my cycles are irregular while I am taking 
THALOMID (thalidomide). 
INIT: _______ 
5. 
I know that I must immediately stop taking THALOMID (thalidomide) and inform my 
doctor if I become pregnant while taking the drug; if I miss my menstrual period, or 
experience unusual menstrual bleeding; stop using birth control; or think, FOR ANY 
REASON, that I may be pregnant.  If my doctor is not available, I can call Celgene Drug 
Safety at 1-888-423-5436 or 1-888-668-2528 for information on emergency 
contraception. 
INIT: _______ 
6. 
I am not now pregnant, nor will I try to become pregnant for at least 4 weeks after I have 
completely finished taking THALOMID (thalidomide). 
INIT: _______ 
7. 
I understand that THALOMID (thalidomide) will be prescribed ONLY for me.  I must 
not share it with ANYONE, even someone who has similar symptoms to mine.  It must 
be kept out of the reach of children and should NEVER be given to women who are able 
to have children. 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Patient Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 29 of 30 
Patient Initials ________ 
 
INIT: _______ 
8.  
I agree any unused drug will be returned to Celgene by calling 1-888-423-5436.  
Shipping costs will be paid by Celgene. 
INIT: _______ 
9. 
I have read the THALOMID (thalidomide) patient brochure and/or viewed the 
videotape, "Important Information for Men and Women Taking THALOMID 
(thalidomide)."  I understand the contents, including other possible side effects from 
THALOMID (thalidomide).  I know that I cannot donate blood while taking 
THALOMID™ (thalidomide). 
INIT: _______ 
10.  I understand that I must participate in a telephone survey and patient registry while I am 
on THALOMID (thalidomide). 
INIT: _______ 
11. My doctor has answered any questions I have asked. 
INIT: _______ 
12. I understand that I might be asked to participate in an additional voluntary survey by mail 
or telephone to evaluate this S.T.E.P.S program.  My agreement or disagreement will 
not interfere with my ability to receive THALOMID (thalidomide). 
INIT: _______ 
13.  I acknowledge I may be contacted by a Celgene representative in regards to following the 
rules with the S.T.E.P.S program. 
 
AUTHORIZATION: 
This information has been read aloud to me in the language of my choice.  I understand that if I do not follow all of 
my doctor's instructions, I will not be able to receive THALOMID (thalidomide).  I now authorize my doctor to 
begin my treatment with THALOMID (thalidomide). 
 
______________________________________________________________   ______________________________ 
Patient Name (please print)                                Social Security No. (only last six digits required)    Date of birth (mm/dd/yyyy)         Patient, Parent/Guardian Signature            Date (mm/dd/yyyy) 
 
I have fully explained to the patient the nature, purpose, and risks of the treatment described above, especially the 
risks to women of childbearing potential.  I have asked the patient if he has any questions regarding his treatment 
with THALOMID (thalidomide) and have answered those questions to the best of my ability.  I will comply with 
all of my obligations and responsibilities as a prescriber registered under the S.T.E.P.S. restricted distribution 
program. 
 
____________________________________________________   ________________________________________ 
Physician Name (please print)                                                                     DEA No.                                               Physician Signature                                                                     Date (mm/dd/yyyy) 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Patient Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 30 of 30 
Patient Initials ________ 
 
THALOMID™ (thalidomide) Informed Consent Forms 
 
Important Information and Warnings for ADULT FEMALES NOT OF CHILDBEARING POTENTIAL 
WARNING: SEVERE, LIFE THREATENING HUMAN BIRTH DEFECTS.  
IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN 
BABY.  THALIDOMIDE SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO COULD BECOME 
PREGNANT WHILE TAKING THE DRUG.  EVEN A SINGLE DOSE [1 CAPSULE (50, 100 OR 200 MG)] TAKEN BY A 
PREGNANT WOMAN CAN CAUSE SEVERE BIRTH DEFECTS.  
CONSENT FOR FEMALES NOT OF CHILDBEARING POTENTIAL: 
INIT: _______ 
1.  
I understand that severe birth defects can occur with the use of THALOMID 
(thalidomide).  I have been warned by my doctor that my unborn baby will almost 
certainly have severe birth defects or can even die if a woman is pregnant or becomes 
pregnant while taking THALOMID (thalidomide). 
INIT: _______ 
2. 
I certify that I am not now pregnant, nor am I of childbearing potential as I have been in a 
natural menopause for at least 24 months (been through the changes of life); or I had my 
uterus/womb completely removed (hysterectomy). 
INIT: _______ 
3. 
I understand that THALOMID (thalidomide) will be prescribed ONLY for me.  I must 
not share it with ANYONE, even someone who has similar symptoms to mine.  It must 
be kept out of the reach of children and should NEVER be given to women who are able 
to have children. 
INIT: _______ 
4.  
I agree any unused drug will be returned to Celgene by calling 1-888-423-5436.  
Shipping costs will be paid by Celgene. 
INIT: _______ 
5. 
I have read the THALOMID (thalidomide) patient brochure and/or viewed the 
videotape, "Important Information for Men and Women Taking THALOMID 
(thalidomide)."  I understand the contents, including other possible side effects from 
THALOMID (thalidomide).  I know that I cannot donate blood while taking 
THALOMID™ (thalidomide). 
INIT: _______ 
6.  
I understand that I must participate in a telephone survey and patient registry while I am 
on THALOMID (thalidomide). 
INIT: _______ 
7. 
My doctor has answered any questions I have asked. 
INIT: _______ 
8. 
I understand that I might be asked to participate in an additional voluntary survey by mail 
or telephone to evaluate this S.T.E.P.S program.  My agreement or disagreement will 
not interfere with my ability to receive THALOMID (thalidomide). 
INIT: _______ 
9.  
I acknowledge I may be contacted by a Celgene representative in regards to following the 
rules with the S.T.E.P.S program. 
 
AUTHORIZATION: 
This information has been read aloud to me in the language of my choice.  I understand that if I do not follow all of 
my doctor's instructions, I will not be able to receive THALOMID (thalidomide).  I now authorize my doctor to 
begin my treatment with THALOMID (thalidomide). 
 
______________________________________________________________   ______________________________ 
Patient Name (please print)                                Social Security No. (only last six digits required)    Date of birth (mm/dd/yyyy)         Patient, Parent/Guardian Signature            Date (mm/dd/yyyy) 
 
I have fully explained to the patient the nature, purpose, and risks of the treatment described above, especially the 
risks to women of childbearing potential.  I have asked the patient if he has any questions regarding his treatment 
with THALOMID (thalidomide) and have answered those questions to the best of my ability.  I will comply with 
all of my obligations and responsibilities as a prescriber registered under the S.T.E.P.S. restricted distribution 
program. 
 
____________________________________________________   ________________________________________ 
Physician Name (please print)                                                                     DEA No.                                               Physician Signature                                                                     Date (mm/dd/yyyy) 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 1 of 13  
 
 
Donor Initials _______  
Donor Informed Consent to Participate in Research 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is a consent form for a research study.  This clinical trial is a research study to determine 
better treatment for patients with Multiple Myeloma (MM).   
 
We invite you to join this study because: 
 Your brother or sister has multiple myeloma (mm) 
 Your blood stem cells are a match for your brother or sister 
 Their disease may be treated by a blood stem cell transplant, and 
 They want to join the MM research study 
 
It is very important for you to know your choices before you decide to join a research study. 
 
Your sibling who has multiple myeloma may be helped by a blood stem cell transplant (SCT).  
Stem cells are cells found in the bone marrow and blood stream that rebuild your blood, bone 
marrow and the immune system.   
 
This study uses two sources of blood stem cells for transplant:  autologous and allogeneic. 
 An autologous transplant uses blood stem cells collected from the patient  
 An allogeneic transplant uses blood stem cells collected from a brother or sister who 
are a tissue match with the patient. 
 
Doctors currently use both sources of blood stem cells for transplants.  At present autologous 
transplants are considered standard therapy for multiple myeloma.  Allogeneic transplants as 
planned in this study are considered investigational. Information from this study will help 
doctors understand the best treatment choices for MM.   
 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 2 of 13  
 
 
Donor Initials _______  
We determined that you are a tissue-match to your sibling by testing your blood.  We tested to 
see if your antigens matched your sibling’s antigens.  Since all of these antigens matched, your 
sibling is a tissue-match with you.   
 
This consent describes the collection of stem cells from your blood to transplant into your 
sibling.  The donation process for stem cells is not experimental.  The treatment for your sibling 
is part of a research clinical trial. 
 
Patients will first have a transplant using their own cells.  A few months after they have 
recovered from their first transplant, patients with a matched sibling donor will receive blood 
stem cells from their matched sibling.  Patients who do not have a matched sibling donor will 
have a second autologous transplant. 
 
This consent form outlines the process, potential risks and benefits of donating your stem cells 
for transplantation into your sibling. 
 
 
1. 
Name of the Donor 
 
 
 
2. 
Title of the Research Study 
 
A Trial of Tandem Autologous Stem Cell Transplants +/- Post Second Autologous Transplant 
Maintenance Therapy Versus Single Autologous Stem Cell Transplant Followed by HLA-
Matched Sibling Non-Myeloablative Allogeneic Stem Cell Transplant for Patients with Multiple 
Myeloma 
 
3a. 
Principal Investigator Contact Information 
 
Insert name, affiliation, and contact information 
 
3b. 
Contact information for emergencies after hours or on weekends or holidays 
 
Call (###) ### - ####, the in-patient Bone Marrow Transplant Unit.  Ask to speak to the Charge 
Nurse. 
 
4. 
Sponsor and Source of Funding 
 
The National Institutes of Health (or NIH), provides financial support for this study through the 
Blood and Marrow Transplantation Clinical Trials Network (BMT CTN).   
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 3 of 13  
 
 
Donor Initials _______  
5. 
What will be done if you take part in this research study? 
 
You will undergo a brief medical evaluation and a series of blood tests to prepare for the possible 
stem cell donation.  The following tests and procedures will be done: 
 
 Medical history, physical examination 
 Blood tests 
 Urine tests 
 If you are a woman able to have children, a blood test to check for pregnancy will be 
done.  If you are pregnant, you cannot take part in this study. 
 Other tests, such as a chest x-ray or electrocardiogram (ECG or EKG, a picture of the 
electrical action of the heart) will be done if your physician feels it is necessary. 
 
If your medical evaluation shows any problems or concerns, you will be told about them.  This 
will be kept private and not shared with your sibling unless you agree. 
 
Procedures: 
 
Only a small quantity of stem cells is normally present in the blood.  A drug called G-CSF 
(granulocyte-colony stimulating factor) can increase the number of these stem cells in the blood.  
This drug allows enough stem cells to be collected from you for transplantation into your sibling. 
 
If the medical exam and blood tests confirm that you are a suitable donor, you will receive 
injections of G-CSF into the skin (like an insulin injection) once a day for 5 days to stimulate the 
release of your stem cells into your blood.  You must come to the donor center or clinic each day 
for the G-CSF injections unless these can be arranged at home. 
 
On the fourth and fifth day of G-CSF injections (and possibly the sixth day) you will go to the 
donor center to have stem cells collected by a machine called a blood cell separator.  The 
procedure of collecting stem cells is called apheresis.  Each apheresis procedure takes about 4 to 
6 hours.  The procedure of collecting stem cells involves removing blood from a vein in one arm, 
passing the blood through the machine where stem cells are collected, and the rest of your blood 
cells and plasma (the liquid portion of your blood) are returned to you through a vein in your 
other arm.  This procedure will involve placing a needle in each of your arms, collecting the cells 
over approximately four to six hours during which time you will be required to lie relatively still.  
If the veins in your arms are not large enough for the needles, you will need to have a temporary 
central venous catheter placed to collect your stem cells.  A central venous catheter is a sterile 
flexible tube that will be placed into a large vein under local anesthesia.  Your physician will 
explain this procedure to you in more detail and you will be required to sign a separate consent 
form for this procedure. 
 
Sometimes, not enough stem cells are obtained with two aphereses.  If this occurs, you will need 
to undergo a third apheresis procedure to try to collect enough stem cells. 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 4 of 13  
 
 
Donor Initials _______  
 
This process will not deplete your blood and bone marrow of stem cells.  Healthy people have 
sufficient stem cells following the collection (aphereses) to produce a normal level of blood cells 
and the body will replace the lost stem cells with new ones. 
 
You will be weighed and have blood tests (1-2 teaspoons) including a complete blood count 
before each collection.  We repeat the complete blood count after each apheresis procedure.   
 
The following table summarizes the schedule and procedures you undergo when donating stem 
cells. 
 
 
DONATION SCHEDULE 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
 
 
G-CSF (16 
g/kg/SQ) 
injection 
 
 
 
 
 
 
 
 
 
 
 
You may  
need to do  
another day 
 
 
 
 
 
Weight 
measured and 
blood tests 
done 
 
 
 
 
You may  
need to do 
another day 
 
 
 
 
 
(Apheresis) 
Blood stem 
cell collection 
 
 
 
 
You may  
need to do 
another day 
 
 
 
 
 
Blood cells 
counted 
 
 
 
 
You may  
need to do 
another day 
 
 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 5 of 13  
 
 
Donor Initials _______  
6. 
How long will I be in the study? 
 
You will be in the study for up to several months from the time you sign the consent until 
approximately one month after stem cell collection.  The actual process of taking G-CSF and 
then collecting your stem cells though takes less than a week.  You will be contacted by phone 
approximately 30 days after initiation of G-CSF.  You will be asked to answer questions about 
your health since your stem cells were collected. 
 
7. 
Will you provide blood samples for research? 
 
Research Blood Samples 
Genetic material is any sample of tissue, blood, fluid, etc. obtained from you during the study.  
With your permission, 3-5 teaspoons from your blood stem cell collection will be collected and 
stored to be used solely for research purposes.  The samples will be stored for future studies that will 
look at responses to treatment based on factors not yet known.  Your confidentiality will be 
maintained because no identifying markers (name, etc.) will remain with the sample.    
 
All BMT CTN research samples will be paired with the respective donor or recipient sample and 
given unique bar code designations that cannot be linked back to the donor or the recipient.  All 
research samples will become property of the NHLBI after conclusion of the BMT CTN Protocol 
#0102 study.  An NHLBI Biologic Specimen Repository Utilization Committee will advise 
NHLBI on requests for samples to perform research with these anonymous samples.  If an 
Investigator’s request for these samples is approved by the committee, the NHLBI may provide a 
panel of the specimens requested using unique code numbers.  Laboratory test results, clinical 
information, etc., associated with the coded samples are provided to the Investigator only after 
completion of the main protocol.  Samples sent to researchers cannot be linked with any 
remaining sample at the repository. 
 
If you agree to allow your blood stem cells to be kept for research, you are free to change your mind 
at any time.  We ask that you contact {Principal Investigator} in writing and let him know you are 
withdrawing your permission for your blood to be used for research.  His mailing address is on the 
first page of this form.   
 
You are free not to take part in this additional future research.  There will be absolutely no 
change in your care as a result of your refusal to give these additional samples.  Refusal to 
participate does not affect your sibling’s care.  Please indicate your choice below:  
 
 I agree to provide blood stem cells for future research. 
 I do not agree to provide blood stem cells for future research. 
 
 
____________________________________                                        _______________________ 
Signature                                                                                                  Date 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 6 of 13  
 
 
Donor Initials _______  
8. 
What are the possible discomforts and risks? 
 
There may be side effects from taking G-CSF and donating stem cells.  The G-CSF and 
apheresis may cause some, all or none of the side effects listed below.  You should discuss these 
with your doctor. In addition, there is always the chance of new, unexpected or previously 
unknown side effects.  Other drugs will be given to make side effects less serious and less 
uncomfortable.  Many side effects go away shortly after the G-CSF and apheresis is stopped, but 
in some cases side effects can be serious, long-lasting, permanent or life threatening.  Death is 
very rare, but possible.   
 
Your physician and the apheresis nurse will check you closely to see if any of these side effects 
are occurring and routine blood tests will be done to monitor the effects of treatment. 
 
Risks and side effects include: 
 
G-CSF: Less than ½ teaspoon (2 ml) G-CSF will be injected under your skin each day.  Injection 
of G-CSF under the skin could cause some local pain or burning sensation at the injection site.  
Most people experience varying levels of pain in their bones when treated with this drug.  The 
pain is usually relieved with acetaminophen (Tylenol) or ibuprofen (Motrin, Advil).  
Aspirin or aspirin containing drugs must not be taken during G-CSF administration and for two 
weeks after your last apheresis collection procedure without physician approval.  Other, less 
frequently reported side effects of G-CSF include skin rash, headaches, muscle aches, nausea, 
vomiting, muscle cramps and trouble sleeping.  These symptoms usually go away within a few 
days after stopping the drug.  Other rare potential side effects include signs of allergy such as a 
rapid heart rate, dizziness, shortness of breath, itching or rash.  Temporary changes in laboratory 
values that monitor liver and bone changes can also occur.  These return to normal after stopping 
the drug.  Rarely, normal donors receiving G-CSF have experienced swelling of their spleen and 
on occasion, internal bleeding from rupture of the spleen.  Symptoms of this side effect are pain 
in the upper left-side just below the rib cage, general fatigue and weakness, or loss of 
consciousness from low blood pressure.  Rupture of the spleen can be very serious and is 
potentially life threatening.  Management of this problem could require blood transfusions or 
surgery.  G-CSF could cause your white count to be very high which will be monitored when 
your white blood cell count is measured.  If it becomes too high, the dose of G-CSF will be 
reduced.  Other, unanticipated side effects may occur which have not been reported before.  If 
you have any unusual symptoms, you should report them immediately.  
 
Long-term (beyond one year) safety data on G-CSF administered to normal, healthy people is 
limited, but so far has not identified any late problems for donors.  Possible interactions of  
G-CSF with other drugs have not been fully evaluated; therefore, it is important that you report 
all drugs, both prescription and non-prescription to the donor center.  There is a theoretical 
possibility that G-CSF can accelerate the growth of tumors or cancers, although currently there is 
no evidence of this effect, and therefore the possibility cannot be excluded.   
 
Apheresis (collection of stem cells from the blood stream): If possible, apheresis will be done 
through your veins.  The needle insertion used for the apheresis procedure may cause local 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 7 of 13  
 
 
Donor Initials _______  
bruising and infection in the vein or on the skin around the vein.  The bruising resolves on its 
own and has no additional risks.  An infection would be treated with antibiotics.   
 
To prevent clotting, your blood will be thinned with citrate (an anticoagulant) during the 
apheresis procedure.  Citrate decreases the calcium in the blood sometimes causing temporary 
numbness or tingling of the fingertips or around the mouth.  Should you experience any 
numbness, you must tell the nurse operating the machine.  If not corrected by replacing calcium, 
this complication could progress to severe muscle cramps while your calcium is low.  Other 
possible side effects of the collection procedure include lightheadedness, nausea or more rarely, 
fainting due to temporary lowering of the blood pressure.  Stopping the procedure and giving 
intravenous fluids can correct this.  Occasionally, the filtering process also removes platelets (the 
cells that help the blood to clot).  If your platelet count falls low enough to place you in danger of 
bleeding (less than 30,000 ml), any further collection will be postponed until a replacement 
transfusion is given.   
 
You will also lose some platelets with the stem cells.  If your platelet count drops low enough to 
place you in danger of bleeding any further collections will be delayed until your platelet count 
increases. 
 
Central Venous Catheter: If your arm veins are too small to allow apheresis, you will require a 
central venous catheter to donate cells.  A central venous catheter is a flexible sterile tube that 
will be placed into a large vein so that blood can be withdrawn more easily and with less 
discomfort.  This tube is placed under local anesthesia.  There is considerable experience with 
the use of central venous catheters.  Complications include blood clots and infection.  Clotting 
may necessitate removal of the catheter or treatment of the clot by injecting a medicine 
(streptokinase or urokinase) that dissolves blood clots.  If you develop an infection you will 
require treatment with antibiotics and your catheter may need to be replaced.  Other uncommon 
side effects may include swelling of the face and arm and/or lung collapse.  If the lung collapses, 
it may be necessary to place a tube between the ribs to allow the lung to re-expand.  There are no 
long-term effects once it has resolved. 
 
Venipuncture: Drawing blood from a vein is painful (like a pin-prick) and may be associated 
with bleeding into the skin (bruising).  Very rarely it may result in an infection.   
 
Risks to the Unborn: Since the G-CSF and apheresis used in this study can affect an unborn 
baby, you should not become pregnant or father a baby while on this study.  Since it is also not 
known how apheresis affects breast milk, you should not nurse your baby while on this study. 
 
You can not be pregnant and be in this study 
 
9a. 
What are the possible benefits to you for taking part in this study? 
 
There is no direct medical benefit to you for taking part in this study.  
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 8 of 13  
 
 
Donor Initials _______  
9b. 
What are the possible benefits to others? 
 
The possible benefit to your sibling may be improvement in the control of their multiple 
myeloma and possibly prolonged survival.  We hope the information learned from this study will 
benefit other patients with multiple myeloma in the future. 
 
10. 
If you choose to take part in this study, will it cost you anything? 
 
There is no financial benefit to you by participating in this treatment protocol.  Usually, the 
insurance policy of the stem cell recipient will cover the cost of the donor evaluation and stem 
cell collection.  The transplant coordinator will help you identify insurance coverage before you 
incur charges for your evaluation and donation.  If you have concerns or questions regarding 
coverage or potential charges, you should contact (contact person’s name) at (###) ### - #### to 
review the situation. 
 
11. 
Will you receive compensation for taking part in this research study? 
 
No. 
 
12. 
What if you are injured because of the study? 
 
You agree to take the risks listed above.  If you experience an injury that is directly caused by 
this study, only the professional medical care you receive at the [participating clinical facility] 
will be provided without charge.  Hospital expenses will be paid by you or your insurance 
provider.  No other compensation is offered.  By signing this form, you have not waived any of 
your legal rights.  If you have any questions about injuries, you should contact [insert name] at 
(###) ###-####. 
 
13. 
What other options or treatments are available if you do not want to be in this study? 
 
Participation in this study is entirely voluntary.  You are free to refuse to be in the study and your 
refusal will not influence current or future health care you receive at this institution.   
 
Instead of being in this study, your sibling may have these options: 
 
 Treatment with other drugs or combination of drugs. 
 Autologous or allogeneic stem cell transplant. 
 No therapy at this time, with care to help them feel more comfortable. 
 
Your sibling may receive these treatments at this or other centers even if you or they choose not to 
take part in this study. 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 9 of 13  
 
 
Donor Initials _______  
14a. 
How can you withdraw from this research study? 
 
You may stop participating at any time.  However, if you decide to stop participating in the 
study, we encourage you to talk to the study doctor first.  Your sibling will have chemotherapy 
and receive an autologous stem cell transplant approximately 60 to 120 days before your stem 
cells are needed.  Leaving the study early may affect your sibling’s treatment. 
 
If you decide to withdraw, we ask that you notify [Principal Investigator] in writing; his/her mailing 
address is on the first page of this form.   
 
If you have any questions regarding your rights as a donor, you may call the Institutional Review 
Board (IRB) office at (###) ###-####. 
 
14b. 
If you withdraw, can information about you still be used and/or collected? 
 
If you withdraw from the study, we will ask your permission to continue using all information 
about you that has already been collected as part of the study prior to your withdrawal.   
 
14c. 
Can the Principal Investigator withdraw you from this research study? 
 
Your doctor may decide to take your sibling off this study if their condition becomes worse, side 
effects of their treatment are severe or life threatening, or the treatment is no longer in their best 
interest.  If your sibling leaves the study there will be no need for you to donate stem cells. 
 
Your doctor may also decide to take you off this study if the G-CSF or apheresis causes severe, 
unmanageable or life threatening side effects in you. 
 
15. 
How will your privacy and the confidentiality of your research records be protected? 
 
Study records that identify you will be kept confidential as required by law.  You will not be 
identified by name in the study records.  Your records will be assigned a unique code number.  The 
key to the code will be kept in a locked file in the Data and Coordinating Center.  Authorized 
persons from [Clinical Center Name], the hospital or clinic (if any) involved in this research, and the 
Institutional Review Board have the legal right to review your research records and will protect the 
confidentiality of them to the extent permitted by law.  This research study is sponsored and 
conducted under the authority of the National Institutes of Health; therefore, the sponsor and the 
sponsor’s agent also have the legal right to review your research records.  Otherwise, your research 
records will not be released without your consent unless required by law or a court order. 
 
If the results of this research are published or presented at scientific meetings, your identity will not 
be disclosed. 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 10 of 13  
 
 
Donor Initials _______  
16. 
Expiration Date for Retention of Records 
 
The study results will be retained in your research record for at least six years or until after the study 
is completed, whichever is longer.  At that time either the research information not already in your 
medical record will be destroyed or your name and other identifying information will be removed 
from such study results.  Research information in your medical record will be kept indefinitely. 
 
17. 
How will the researcher(s) benefit from your being in this study? 
 
In general, presenting research results helps the career of a scientist.  Therefore, the Principal 
Investigator may benefit if the results of this study are presented at scientific meetings or in 
scientific journals.  In addition, the sponsor is providing funds to the Principal Investigator to 
facilitate the conduct of this study. 
 
18. 
HIPAA1 authorization to use and disclose individual health information for 
research purposes 
 
a. Purpose:  As a research participant, I authorize the Principal Investigator and the 
researcher’s staff to use and disclose my individual health information for the purpose of 
conducting the research study entitled A Trial of Tandem Autologous Stem Cell 
Transplants +/- Post Second Autologous Transplant Maintenance Therapy Versus Single 
Autologous Stem Cell Transplant Followed by Matched Sibling Non-myeloablative 
Allogeneic Stem Cell Transplant for Patients with Multiple Myeloma. 
b. Individual Health Information to be Used or Disclosed: My individual health information 
that may be used or disclosed to conduct this research includes: demographic information 
(e.g., age, date of birth, sex, weight), medical history (e.g., diagnosis, complications with 
prior treatment) and physical examination findings. 
c. Parties Who May Disclose My Individual Health Information:  The researcher and the 
researcher’s staff may obtain my individual health information from (list hospitals, 
clinics or providers from which health care information can be requested). 
 
 
 
d. Parties Who May Receive or Use My Individual Health Information:  The individual 
health information disclosed by parties listed in item “c.” above and information 
disclosed by me during the course of the research may be received and used by the 
following parties: 
­ Principal Investigator and the researcher’s staff 
                                                   
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of 
health information. 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 11 of 13  
 
 
Donor Initials _______  
­ Dr. David Maloney, Study Chairperson and staff/laboratories at Fred Hutchinson 
Cancer Research Center 
­ Dr. Amrita Krishnan, Study Chairperson and staff/laboratories at City of Hope 
National Medical Center 
­ National Heart, Lung and Blood Institute (NHLBI) and National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH), study sponsors 
­ Blood and Marrow Transplant Clinical Trials Network (BMT CTN), data 
coordinating center 
­ Southwest Oncology Group (SWOG), clinical trials cooperative group 
­ U.S. government agencies that are responsible for overseeing research such as the 
Food and Drug Administration (FDA) and the Office of Human Research Protections 
(OHRP) 
­ U.S. government agencies that are responsible for overseeing public health concerns 
such as the Centers for Disease Control (CDC) and federal, state and local health 
departments 
e. Right to Refuse to sign this Authorization:  I do not have the sign this Authorization.  If I 
decide not to sign the Authorization, I will not be allowed to participate in this study or 
receive any research-related treatment that is provided through the study.  However, my 
decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits. 
f. Right to Revoke:  I can change my mind and withdraw this authorization at any time by 
sending a written notice to the Principal Investigator to inform the researcher of my 
decision.  If I withdraw this authorization, the researcher may only use and disclose the 
protected health information already collected for this research study.  No further health 
information about me will be collected by or disclosed to the researcher for this study. 
g. Potential for Re-disclosure: My individual health information disclosed under this 
authorization may be subject to re-disclosure outside the research study and no longer 
protected.  Examples include potential disclosures for law enforcement purposes, 
mandated reporting or abuse or neglect, judicial proceedings, health oversight activities 
and public health measures. 
h. This authorization does not have an expiration date. 
 
 
19. 
Further Information 
 
If you have further questions concerning this project at any time, you are free to ask them of 
Dr._______________, who will be available to answer them.  His/her telephone number is located 
on the first page of this consent. 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 12 of 13  
 
 
Donor Initials _______  
20. 
Consent Instructions 
 
To voluntarily become a participant in this research study I must confirm the following and sign 
below.  
 
*I have read all of the information in the Informed Consent and I have had time to think about it. 
 
*All of my questions have been answered to my satisfaction.  If I did not understand any of the 
words or parts or this study, I asked the study doctor or the research staff to explain what I did 
not understand.   
 
*I voluntarily agree to be part of this research study and to follow the study procedures as 
directed.  I agree to keep the research staff informed of my current contact information. 
 
*I have been informed that I may discontinue my participation in this study at any time. 
 
*Signing this consent form is not a waiver of my legal rights. 
 
*I have received a signed copy of this Informed Consent to keep for my reference.  
 
 
 
 
 
 
 
 
 
 
 
Subject Name (please print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Signature or Legal Representative (relationship) 
 
 
Date & Time 
 
 
 
 
 
 
 
 
 
 
        
Name of Individual Conducting Informed Consent Discussion  
(please print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Individual Conducting Informed Consent Discussion  
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Witness (where Applicable) 
 
 
 
 
Date 
 
 
 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
Donor Consent 
 
IRB # 
_____________________________________________________________________________________________ 
 
 
Page 13 of 13  
 
 
Donor Initials _______  
I have fully explained the research study to the subject and answered all of the subjects 
questions. 
 
 
 
 
 
 
 
 
 
 
 
Name of Principal Investigator or Authorized Representative  
(please print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator or Authorized 
 
 
 
Date 
Representative 
 
 
 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
 Version 7.0 dated May 15, 2006 
 
C-1 
 
APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
1. HLA TYPING 
 
HLA typing will be performed for all patients and sibling(s) as soon as possible after initial 
evaluation to determine the availability of an HLA-matched sibling donor.  If possible, this 
testing will be complete prior to the first autologous transplant but it is expected that full donor 
evaluations will not always be possible to complete by this time.  Patient samples for HLA-
testing MUST be drawn prior to the first autologous transplant and potential donor samples must 
be drawn no later than three weeks after the first autologous transplant. 
 
HLA typing of heparinized peripheral blood can be done by either serologic or DNA methods for 
HLA-A, -B.  DNA methods must be utilized for DRB1.  
 
The specimens for HLA typing will be:  
a) Donor – 5 ml peripheral blood sample(s) from sibling/family member, and  
b) Patient – 5 ml peripheral blood sample from the recipient. 
 
 
2. CHIMERISM – Autologous/Allogeneic Transplant Patients Only 
 
A heparinized peripheral blood sample from patient and donor is required for chimerism studies 
2 weeks pre-allogeneic transplant to subsequently determine the host or donor origin of ANC 
recovery.  All pre-transplant samples will be stored for future evaluation of post-transplant 
chimerism. 
 
A 10 ml heparinized peripheral blood sample must also be obtained from the patient at weeks 4, 
8, and 12, then at 6 months and one year post allogeneic transplant.  
 
 
3. PATHOLOGY/CYTOGENETICS STUDIES 
 
Unilateral bone marrow biopsies and aspirates are required for pathology analysis and aspirates 
are required for cytogenetic analysis prior to the first transplant (baseline) and yearly following 
the second transplant.  Other bone marrow assessments as summarized in the schedule of 
evaluations (Chapter 4) do not require the inclusion of bone marrow pathology/cytogenetics 
unless the original diagnostic marrow or the baseline marrow documented abnormal 
pathology/cytogenetics. 
 
Cytogenetic studies by standard metaphase karyotype analysis will be conducted per institutional 
guidelines. 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
 Version 7.0 dated May 15, 2006 
 
C-2 
 
 
4. FLOW CYTOMETRY 
 
According to the BMT CTN Graft Evaluation MOP, the hematopoietic stem cell content of the 
product (graft) should be determined using CD45-FITC and CD34-PE staining to identify stem 
cells within the WBC component of the product. 
 
Allogeneic donor products will also be analyzed to determine the B, T and NK cell content using 
CD3, CD4, CD8, CD19 and CD56 expression as detected by flow cytometry.  Autologous grafts 
require CD34 enumeration at a minimum. 
 
Flow cytometry will be done in keeping with the BMT CTN MOP and local institutional 
practice, and will be performed prior to infusion of the graft. 
 
 
5. RESEARCH SPECIMENS 
 
All BMT CTN research samples will be paired with the respective donor or recipient sample and 
given unique bar code designations that cannot be linked back to the donor or the recipient.  All 
research samples will become property of the NHLBI after conclusion of the BMT CTN Protocol 
#0102 study.  An NHLBI Biologic Specimen Repository Utilization Committee will advise 
NHLBI on requests for samples to perform research with these anonymous samples.  If an 
Investigator’s request for these samples is approved by the committee, the NHLBI may provide a 
panel of the specimens requested using unique code numbers.  Laboratory test results, clinical 
information, etc., associated with the coded samples are provided to the Investigator only after 
completion of the main protocol.  Samples sent to researchers cannot be linked with any 
remaining sample at the repository. 
 
For Donors Only: 
Five vials, each containing 2-5 x 106 nucleated cells (~1ml per cryovial) from the donor blood 
stem cells must be obtained prior to the allogeneic transplant.  Transplant Centers should follow 
controlled-rate freezing SOPs for cryopreserving research samples as for product storage.  
Samples will be shipped annually to the NHLBI Repository in compliance with the shipping 
procedures specified in the BMT CTN MOP and the BMT CTN 0102 Laboratory Sample 
Information Guide.   
 
Christine DeMasco 
NHLBI Repository 
SeraCare BioServices 
217 Perry Parkway 
Gaithersburg, MD  20877 
Phone: 
(301) 208-8100, x196 
Fax: 
(301) 208-8829 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
Multiple Myeloma Protocol – 0102 
 Version 7.0 dated May 15, 2006 
 
C-3 
 
For Patients Only:  Peripheral blood samples (one 10ml serum sample and one 10ml nucleated 
cell sample) will be collected for future testing at the time of disease staging and shipped 
quarterly to the Repository in compliance with the shipping procedures specified in the BMT 
CTN MOP. 
 
Peripheral blood samples will be collected prior to the first autologous transplant and prior to the 
second transplant (auto or allo), and at 8 weeks, 6 months, 9 months and every 6 months until 3 
years after the second transplant.  
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
 
 
 
 
 
 
   Multiple Myeloma Protocol – 0102 
 Version 7.0 dated May 15, 2006 
 
C-4 
 
SCHEDULE OF LABORATORY EVALUATIONS 
 
 
Type of Sample 
Type of Storage 
Dates Samples Obtained 
Shipping Specifications 
Test 
Location 
HLA Typing 
5 ml peripheral blood 
or according to 
institutional practice 
Store according to 
institutional 
practice 
Prior to the 1st autologous transplant 
N/A 
Transplant 
Center 
Chimerism 
10 ml heparinized 
peripheral blood or 
according to 
institutional practice 
Store according to 
institutional 
practice 
≤ 2 weeks prior to the allogeneic transplant 
for patient and donor.  Weeks 4, 8 and 12, 
6 months and one year post allogeneic 
transplant for patient 
N/A 
Transplant 
Center 
Cytogenetic Studies 
Volume of bone 
marrow aspirate 
determined according 
to institutional practice 
Store according to 
institutional 
practice 
Prior to the 1st autologous transplant and 
yearly following the second transplant.  
Bone marrow aspirates must be done prior 
to the second transplant, prior to initiation 
of maintenance therapy (if applicable) and 
at 8 weeks and 6 months post second 
transplant only if previously documented 
abnormal cytogenetics. 
N/A 
Transplant 
Center 
Flow Cytometry 
Volume of graft 
determined according 
to institutional practice 
Store according to 
institutional 
practice 
Prior to 1st autologous transplant and prior 
to allo transplant . 
N/A 
Transplant 
Center 
Donor Research 
Specimen Nucleated 
Cells 
5 vials each containing 
2 – 5 x 106 nucleated 
cells collected from 
allograft (1mL 
cryovial) 
Follow controlled-
rate freezing SOPs 
for crypreserving 
research samples 
as for product 
storage at -150° 
Prior to allogeneic transplant 
(at time of donation) 
Liquid nitrogen shipment 
annually to Repository in 
compliance with shipping 
procedures specified in the 
BMT CTN MOP 
TBD 
Patient Research 
Specimen Disease 
Assessments (Serum) 
10 ml peripheral blood 
Let sample sit for 
30 minutes. 
Centrifuge for 10 
minutes.  Remove 
serum, alioquot 
into cryovials and 
freeze at -70° 
Prior to first autologous transplant, prior to 
second transplant (auto or allo) and at 8 
weeks, 6 months, 9 months, 12 months and 
then every 6 months until 3 years post 
second transplant 
Frozen shipment quarterly 
to Repository in 
compliance with shipping 
procedures specified in the 
BMT CTN MOP 
TBD 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
 
 
 
 
 
 
   Multiple Myeloma Protocol – 0102 
 Version 7.0 dated May 15, 2006 
 
C-5 
 
 
Type of Sample 
Type of Storage 
Dates Samples Obtained 
Shipping Specifications 
Test 
Location 
Patient Research 
Specimen Disease 
Assessments 
(Nucleated Cells) 
10 ml peripheral blood 
Obtain white 
blood cell pellet 
(by ficoll) and 
freeze in cryovial 
at -70°  
Prior to first autologous transplant, prior to 
second transplant (auto or allo) and at 8 
weeks, 6 months, 9 months, 12 months and 
then every 6 months until 3 years post 
second transplant 
Frozen shipment quarterly 
to Repository in 
compliance with shipping 
procedures specified in the 
BMT CTN MOP 
TBD 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
 
      Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
 
D-1 
 
APPENDIX D 
 
SYSTEM FOR THALIDOMIDE EDUCATION AND PRESCRIBING SAFETY 
(S.T.E.P.S.™) AND DOSAGE AND  
ADMINISTRATION PROCEDURES 
 
 
 
 
This appendix is an excerpt (pages 27-39) of the S.T.E.P.S.™ document found at 
 
http://www.celgene.com/images/pdf/$FILE/Balancing.pdf 
 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
 
      Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
 
D-2 
 
 
 
System for 
   Thalidomide 
     Education and 
       Prescribing 
         Safety 
 
 
 
 
THALOMID
TM 
(thalidomide) 
 
 
 
Balancing the Benefits 
and the Risks 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
 
      Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
 
D-3 
 
 
DOSAGE AND ADMINISTRATION 
THALOMID™ (THALIDOMIDE) MUST ONLY BE ADMINISTERED IN COMPLIANCE WITH ALL OF THE 
TERMS OUTLINED IN THE S.T.E.P.S.™ PROGRAM.THALOMID™ (THALIDOMIDE) MAY ONLY BE PRESCRIBED 
BY PRESCRIBERS REGISTERED WITH THE S.T.E.P.S.™ PROGRAM AND MAY ONLY BE DISPENSED BY 
PHARMACISTS REGISTERED WITH THE S.T.E.P.S.™ PROGRAM. 
Drug prescribing to women of childbearing potential should be contingent upon initial and continued confirmed 
negative results of pregnancy testing. 
 
 
Acute ENL Reaction 
For an acute episode of cutaneous ENL, THALOMID™ (thalidomide) dosing should be initiated at 100 to 300 mg/d, 
administered once daily with water, preferably at bedtime and at least 1 hour after the evening meal.1 Patients weighing 
less than 50 kg should be started at the low end of the dose range. 
 
 
Severe ENL Reaction 
In patients with a severe cutaneous ENL reaction or in those who have previously required higher doses to control 
the reaction, THALOMID™ (thalidomide) may be initiated at higher doses, up to 400 mg/d.1 THALOMID™ 
(thalidomide) should be administered once daily at bedtime or in divided doses with water, and should be taken at 
least 1 hour after meals.
1
 In patients with moderate to severe neuritis associated with a severe ENL reaction, 
corticosteroids may be initiated concomitantly with THALOMID™ (thalidomide).1 Corticosteroid usage can be 
tapered and discontinued when the neuritis has ameliorated.
 1
 
 
THALOMID™ (thalidomide) should be usually continued until signs and symptoms of active reaction have sub- 
sided, usually at least 2 weeks.
1
 The daily THALOMID™ (thalidomide) dose can then be tapered in 50-mg decree 
ments every 2 to 4 weeks.1 Patients who have a documented history of requiring prolonged maintenance treatment 
to prevent the recurrence of cutaneous ENL or who experience a flare during tapering should be maintained on the 
minimum dose necessary to control the reaction.
 1 
 Tapering of THALOMID™ (thalidomide) and discontinuation of 
the drug should be attempted every 3 to 6 months in 50-mg decrements every 2 to 4 weeks.
 1
 
 
 
 
 
27 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
 
      Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
 
D-4 
 
 
 
Summary of Dosage and Administration for Cutaneous ENL 
 
For an episode of cutaneous ENL,THALOMID™ (thalidomide) 100 to 300 mg/d should be administered 
once daily and continued until signs and symptoms have subsided, usually at least 2 weeks. 
 
For severe reactions, THALOMID™ (thalidomide) doses as high as 400 mg/d may be needed. 
 
After signs and symptoms have subsided, the daily THALOMID™ (thalidomide) dose should be tapered in 
50-mg decrements every 2 to 4 weeks. Patients with a documented history of requiring prolonged maintenance 
treatment to prevent ENL recurrence or who experience a flare during tapering should be maintained 
on the minimum dose necessary to control the reaction. In these patients, a THALOMID™ (thalidomide) 
tapered withdrawal should be attempted every 3 to 6 months. 
 
In patients with moderate to severe neuritis associated with a severe ENL reaction, corticosteroids should be 
started concomitantly with THALOMID™ (thalidomide). Steroid usage can be tapered and discontinued 
when the neuritis has ameliorated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
 
      Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
 
D-5 
 
 
SYSTEM FOR THALIDOMIDE EDUCATION AND PRESCRIBING SAFETY (S.T.E.P.S.™) 
 
Description 
 
The System for Thalidomide Education and Prescribing Safety, S.T.E.P.S.™, is a multicomponent system designed to 
help ensure that fetal exposure to THALOMID™ (thalidomide) does not occur. The system also creates awareness 
of other potential side effects that can occur during therapy with THALOMID™ (thalidomide). S.T.E.P.S.™ requires 
that all prescribers and pharmacies register to prescribe or dispense THALOMID™ (thalidomide) and all patients 
complete an informed consent process and participate in a mandatory and confidential surveillance registry. 
 
Program Process 
 
Prescriber Registration Process 
 
All prescribers interested in treating patients with THALOMID™ (thalidomide) must register in the THALOMID™ 
(thalidomide) Prescriber Registry via a Prescriber Registration Card that is located in every S.T.E.P.S.™ folder.1 
Prescribers must complete, sign, and return the 
Prescriber Registration Card; by doing so, prescribers 
agree to prescribe THALOMID™ (thalidomide) in 
accordance with all the terms listed on the card. 
Prescribers must wait for registration confirmation 
prior to prescribing THALOMID™ (thalidomide). 
All materials that are necessary to comply with 
S.T.E.P.S.™ program requirements are contained in 
the S.T.E.P.S.™ folder (Figure 3).The contents of ONE 
FOLDER should be used with ONE PATIENT, and 
kept with the patient’s medical record.  Additional 
S.T.E.P.S.™ folders can be obtained from a Celgene 
Immunology Specialist or by calling 1-888-4-CELGENE. The S.T.E.P.S.™ folder contains the following information 
and materials to help ensure that fetal exposure to THALOMID™ (thalidomide) does not occur: 
 
 
 
 
 
29 
Figure 3. S.T.E.P.S.™ materials for prescribers and patients. 
 
 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
 
      Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
 
D-6 
 
• Prescriber Registration Card: All prescribers must register. 
• Thalidomide Victims Association of Canada letter: A cautionary message to the prescriber and patient from 
thalidomide victims. 
• Information for Men and Women Taking THALOMID™ (thalidomide): This brochure should be used for 
patient counseling regarding the teratogenic risks as well as other side effects and precautions associated 
with THALOMID™ (thalidomide) therapy.  A video presentation of this information will be provided to the 
prescriber’s office upon registration. 
• Your Contraceptive Choices: This brochure is provided to assist in counseling patients on choosing two 
appropriate contraceptive methods. 
• Emergency Contraception: This brochure should be used to assist patients in the event they have unprotected 
heterosexual sexual intercourse while taking THALOMID™ (thalidomide). 
• Patient Referral Form: A form that must be used if another health-care professional is chosen to provide 
contraceptive counseling for the patient. 
• Patient Quiz: The quiz is provided to verify patient understanding of the risks and requirements of therapy. 
• Consent Form (Figure 4): This informed consent document must be understood and signed before any 
patient can receive THALOMID™ (thalidomide). 
• Thalidomide Survey Forms: These mandatory and confidential enrollment and follow-up surveys must be 
completed by the patient and prescriber.  Men must participate, as well as women, because fetal exposure to 
THALOMID™ (thalidomide) could occur as a result of the presence of the drug in semen or through sharing 
the medication. Included are forms for patients aged 18 or older. Forms for patients under 18 years of age 
are available by calling 1-888-4-CELGENE. 
 
Important Information for Men and Women Taking THALOMID™ (thalidomide), the Consent Form, Patient Quiz, 
and Survey Forms are available in 14 languages and can be obtained through a Celgene Immunology Specialist or 
by calling 1-888-4-CELGENE. 
 
S.T.E.P.S.™ program requirements differ for male and female patients. Both male and female patients 
must receive: 
• Information regarding the general guidelines for taking THALOMID™ (thalidomide). 
 
 
 
 
 
 
 
30 


BMT CLINICAL TRIALS NETWORK 
 
 
 
 
 
      Multiple Myeloma Protocol – 0102 
Version 7.0 dated May 15, 2006 
 
D-7 
 
Figure 4. THALOMID™ (thalidomide) informed consent form. 
 
Important Information and Warnings for All Patients Taking THALOMID™ (thalidomide) 
WARNING: SERIOUS HUMAN BIRTH DEFECTS  
IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. THALIDOMIDE 
SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO COULD BECOME PREGNANT WHILE TAKING THE DRUG. EVEN A SINGLE 
DOSE [I CAPSULE (50 mg)] TAKEN BY A PREGNANT WOMAN CAN CAUSE SEVERE BIRTH DEFECTS.  
CONSENT FOR WOMEN: 
INIT: _______ 
1.  
I understand that I must not take THALOMID™ (thalidomide) if I am pregnant, breast-feeding a baby, or able to get pregnant and not using the required two 
methods of birth control. 
INIT: _______ 
2.  
I understand that severe birth defects can occur with the use of THALOMID™ (thalidomide).  I have been warned by my doctor that my unborn baby will almost 
certainly have serious birth defects or maybe even die if I am pregnant or become pregnant while taking THALOMID™ (thalidomide). 
INIT: _______ 
3.  
I understand that it I am able to become pregnant, I must use at least one highly effective method and one additional effective method of birth control contraception 
AT THE SAME TIME: 
 
At least one highly effective method 
­ 
IUD 
­ 
Hormonal (birth control pills, injections, or implants) 
­ 
Tubal ligation 
­ 
Partner's vasectomy 
AND 
One additional effective method 
­ 
Latex condom 
­ 
Diaphragm 
­ 
Cervical cap 
 
These birth control methods must be used for at least 4 weeks before starting THALOMID™ (thalidomide) therapy, all during THALOMID™ (thalidomide) 
therapy, and for at least 4 weeks after THALOMID™ (thalidomide) therapy has stopped.  I must use these methods even if I am infertile, unless I have had a 
hysterectomy or because I have been postmenopausal for at least 24 months (been through the changes of life).  The only exception is if I completely avoid 
heterosexual sexual intercourse. If a hormonal (birth control pills, injections, or implants) or IUD method is riot medically possible for me, I may use another highly 
effective method or two barrier methods AT THE SAME TIME. 
INIT: _______ 
4.  
I know that I must have a pregnancy test done by my doctor within) the 24 hours prior to starting THALOMID™ (thalidomide) therapy, then every week during the 
first 4 weeks of THALOMID™ (thalidomide) therapy. I will then have a pregnancy test every 4 weeks if I have regular menstrual cycles, or every 2 weeks if my 
cycles are irregular while I am taking THALOMID™ (thalidomide). 
INIT: _______ 
5.  
I know that I must immediately stop taking THALOMID™ (thalidomide) and inform my doctor if I become pregnant while taking the drug; if I miss my menstrual 
period, or experience unusual menstrual bleeding; stop using birth control; or think, FOR ANY REASON, that I may be pregnant.  If my doctor is not available, I 
can call (XXX)-XXX-XXXX for information on emergency contraception. 
INIT: _______ 
6.  
1 am not now pregnant, nor will I try to become pregnant for at least 4 weeks after I have completely finished taking THALOMID™ thalidomide). 
INIT: _______ 
7.  
I understand that THALOMID™ (thalidomide) will be prescribed ONLY for me.  I must NOT share it with ANYONE, even someone who has symptoms similar to 
mine.  It must be kept out of the reach of children and should never be given to women who are able to have children. 
INIT: _______ 
8.  
I have read the THALOMID™ (thalidomide) patient brochure and/or viewed the videotape, "Important Information for Men and Women Taking THALOMID™ 
(thalidomide)."  I understand the contents, including other possible health problems from THALOMID (thalidomide), so-called "side effects. "  I know that I cannot 
donate blood while taking THALOMID™ (thalidomide). 
INIT: _______ 
9. 
My doctor has answered any questions I have asked. 
INIT: _______ 
10. 
I understand that I must participate in a survey and patient registry while I am on THALOMID™ (thalidomide), which will require completing additional forms. 
CONSENT FOR MEN: 
INIT: _______ 
1. 
I understand that I must not take THALOMID™ (thalidomide) if I cannot avoid unprotected sex with a woman, even if I have had a successful 
vasectomy. 
INIT: _______ 
2. 
I understand that severe birth defects or death to an unborn baby have occurred when women took thalidomide during pregnancy. 
INIT: _______ 
3. 
1 have been told by my doctor that I must NEVER have unprotected sex with a woman because it is hot known if the drug is present in semen or 
sperm.  My doctor has explained that I must either completely avoid heterosexual sexual intercourse or I must use a latex condom EVERY TIME I 
have sexual intercourse with a female partner while I am taking THALOMID™ (thalidomide) and for 4 weeks after I stop taking the drug, even if I 
have had a successful vasectomy. 
INIT: _______ 
4. 
I also know that I must inform my doctor if I have had unprotected sex with a woman or if I think, FOR ANY REASON, that my sexual partner may 
be pregnant.  If my doctor is not available, I can call (XXX) XXX-XXXX for information on emergency contraception. 
INIT: _______ 
5. 
I understand that THALOMID™ (thalidomide) will be prescribed ONLY for me.  I must NOT share it with ANYONE, even someone who has 
symptoms similar to mine.  It must be kept out of the reach of children and should never be given to women who are able to have children. 
INIT: _______ 
6. 
I have read the THALOMID™ (thalidomide) patient brochure and/or viewed the videotape, "Important Information for Men and Women Taking 
THALOMID™ (thalidomide)."  I understand the contents, including other possible health problems from THALOMID™ (thalidomide), so-called 
"side effects."  I know that I cannot donate blood or semen while taking THALOMID™ (thalidomide). 
INIT: _______ 
7. 
My doctor has answered any questions I have asked. 
INIT: _______ 
8.  
I understand that I must participate in a survey and patient registry while I am on THALOMID™ (thalidomide), which will require completing 
additional forms. 
AUTHORIZATION: 
This information has been read aloud to me in the language of my choice.  I understand that if I do not follow all of my doctor's instructions, I will not be able to receive THALOMID™ 
(thalidomide).  I now authorize my doctor to begin my treatment with THALOMID™ (thalidomide). 
 
______________________________________________________________   ______________________________ 
Patient Name (please print)                                Social Security No. (only last six digits required)    Date of birth (mm/dd/yyyy)         Patient, Parent/Guardian Signature            Date (mm/dd/yyyy) 
 
I have fully explained to the patient the nature, purpose, and risks of the treatment described above, especially the risks to women of childbearing potential. I have asked the patient if 
she/he has any questions regarding her/his treatment with THALOMID™ (thalidomide) and have answered those questions to the best of my ability. I will ensure that the appropriate 
components of the patient consent form are completed. In addition, I will comply with all of my obligations and responsibilities as a prescriber registered under the S.T.E.P.S. restricted 
distribution program. 
 
____________________________________________________   ________________________________________ 
Physician Name (please print)                                                                     DEA No.                                               Physician Signature                                                                     Date (mm/dd/yyyy) 
 
 
 
 
 
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• Comprehensive counseling on the risk of birth defects, other side effects, and important precautions associated 
with THALOMID™ (thalidomide) therapy as outlined in the brochure entitled Important Information for 
Men and Women Taking THALOMID™ (thalidomide) and in the informed consent form. 
• Mandatory contraception and emergency contraception counseling. 
In addition, female patients also must receive: 
• Specific contraceptive counseling on the TWO methods of birth control they must use before, during, and 
after therapy. 
• Pregnancy testing. 
 
Pharmacy Registration Process 
All retail and hospital pharmacies must be registered to dispense THALOMID™ (thalidomide). A registration card 
(Figure 5) outlining the terms for dispensing must be signed by the head pharmacist or director of pharmacy and 
returned to Celgene Corporation.  When the registration information is received, the pharmacy’s eligibility to 
dispense THALOMID™ (thalidomide) will be activated. Pharmacies must agree to: 
• Refuse prescriptions written more than 7 days prior to presentation. 
• Collect and retain on file a signed informed consent form with an initial prescription for THALOMID™ 
(thalidomide).Telephone prescriptions are not permitted. 
• Register THALOMID™ (thalidomide) patients via facsimile or phone. 
• Dispense blister packs intact. 
• Dispense a maximum prescription of a 4-week (28-day) supply of THALOMID™ (thalidomide) therapy 
with no automatic refills. 
• Dispense subsequent prescriptions only if fewer than 7 days of therapy remain on the previous prescription. 
• Verify patient registry and record subsequent prescriptions via on-line transmission or phone. 
• Educate all staff pharmacists about the dispensing procedures for THALOMID™ (thalidomide). 
• Accept unused THALOMID™ (thalidomide) returned by patients. 
 
Failure to comply with all requirements of the S.T.E.P.S.™ program may result in the pharmacy’s not being 
permitted to dispense THALOMID™ (thalidomide). 
 
 
 
 
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Figure 5. Pharmacy registration card. 
 
System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) 
Pharmacy Registration 
All retail and hospital pharmacies must be registered to dispense THALOMID™ (thalidomide). Please review 
the steps that must be followed with every patient and return this card to Celgene Corporation. Registration 
must be signed by the Head Pharmacist or Director of Pharmacy. 
Before dispensing THALOMID™ (thalidomide), I accept responsibility to: 
■ Refuse prescriptions written more than 7 days prior to presentation 
■ Collect and file a signed informed consent form with initial prescriptions (telephone prescriptions are not permitted) 
■ Register patients via fax or phone 
■ Dispense blister packs intact 
■ Dispense a maximum of a 4-week (28-day) supply of THALOMID™ (thalidomide) therapy, with no automatic refills 
■ Dispense subsequent prescriptions only if fewer than 7 days of therapy remain on the previous prescription 
■ Verify patient registration and record subsequent prescriptions via on-line transmission or phone 
■ Educate all staff pharmacists about the dispensing procedure for THALOMID™ (thalidomide) 
■ Accept unused THALOMID™ (thalidomide) returned by patient 
I understand that if I fail to comply with all requirements of the S.T.E.P.S. program, my pharmacy may 
not be permitted to dispense THALOMID™ (thalidomide). 
 
Pharmacist Name _________________________________ Title_____________________________________ 
Signature ______________________________ Pharmacy Name ____________________________________ 
Address ___________________________________________________________________________________ 
City_________________________________________________ State _________ Zip____________________ 
Phone________________________________________ Fax_________________________________________ 
Pharmacy No.________________ NABP No. _______________ Preferred wholesaler____________________ 
©1998 Celgene Corporation   
 
 
Printed in the U.S.A.  
 
 
7/98  
 
 
CG071 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Prescribing Procedures for THALOMID™ (thalidomide) 
Initial Visit 
When considering THALOMID™ (thalidomide) therapy for a patient, the prescriber must do the following: 
• Establish appropriateness of THALOMID™ (thalidomide) therapy versus therapeutic alternatives: 
— THALOMID™ (thalidomide) is indicated for the acute treatment of the cutaneous manifestations of 
moderate to severe ENL.THALOMID™ (thalidomide) is not indicated as monotherapy for such ENL 
treatment in the presence of moderate to severe neuritis.  THALOMID™ (thalidomide) also is indicated 
as maintenance therapy for prevention and suppression of the cutaneous manifestations of 
ENL recurrence. 
• Provide comprehensive counseling on the risks and benefits of THALOMID™ (thalidomide) therapy: 
— Patients must be counseled on the risk of birth defects, other side effects, and important precautions 
associated with THALOMID™ (thalidomide) therapy. 
— Men must be instructed to use a latex condom every time they have sexual intercourse with a woman, 
even if they have undergone a successful vasectomy. 
— Utilize the patient education materials provided. 
• Determine if patient has childbearing potential: 
— If patient has undergone a hysterectomy, been postmenopausal, or had no menses for at least 24 
months, continue with the instructions provided in the INITIATING THALOMID™ (thalidomide) 
THERAPY section. 
— If patient is sexually mature and does not meet the above criteria, provide contraceptive 
counseling, including counseling on emergency contraception. 
• Female patients must thoroughly understand the need for two forms of contraception to be used AT THE 
SAME TIME, beginning 4 weeks before therapy, throughout therapy, and for 4 weeks after stopping therapy 
with THALOMID™ (thalidomide). 
• Contraceptive methods must include one highly effective method (eg, IUD, hormonal [birth control pills, 
injections, or implants], tubal ligation, or partner’s vasectomy) and one additional effective method (eg, latex 
condom, diaphragm, or cervical cap). 
 
 
 
 
 
 
 
 
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• If IUD or hormonal contraception is medically contraindicated, another highly effective method or two barrier 
methods must be used AT THE SAME TIME. 
• Utilize the patient education materials provided. 
— Prescribers may refer patients to another health-care professional for contraceptive 
counseling using the Patient Referral Form. 
• Continue selected birth control options for 4 weeks prior to initiating THALOMID™ (thalidomide). 
 
Initiating THALOMID™ (thalidomide) Therapy 
 
The following steps must be completed prior to initiating THALOMID™ (thalidomide) therapy1: 
• Repeat patient counseling. 
• Perform pregnancy test (female patients), even if continuous abstinence is the chosen method of 
birth control. 
— Test must satisfy a sensitivity of least 50 mIU/mL. 
— Test must be performed on female patients of childbearing potential, with negative results 
in written form, within the 24 hours prior to initiating THALOMID™ (thalidomide) therapy. 
— Women of childbearing potential also must receive a pregnancy test every week for the first 4 weeks, 
then every 4 weeks thereafter if their menstrual cycles are regular. 
— If the menstrual cycle is irregular, female patients must receive a pregnancy test every 2 weeks thereafter. 
— Pregnancy testing and counseling should be performed if a patient misses her period or if there is any 
abnormality in menstrual bleeding. 
— If pregnancy does occur during treatment, the drug must be immediately discontinued. Any 
suspected fetal exposure to THALOMID™ (thalidomide) must be reported immediately to the FDA 
via the MedWATCH number at 1-800-FDA-1088 and also to Celgene Corporation. The patient should 
be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation 
and counseling. 
 
 
 
 
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•Administer the THALOMID™ (thalidomide) patient quiz. 
— Gauge patient understanding of the requirements for taking the drug. 
— If the patient cannot answer all of the questions correctly, review the material that he or 
she does not understand. 
— Readminister patient quiz.  Repeat until the patient satisfactorily understands all risks and correctly 
answers all questions or reconsider the appropriateness of THALOMID™ (thalidomide) therapy. 
• Complete the informed consent form. 
— The consent form must be read to the patient and/or parent/legal guardian in the language of his or 
her choice. Each statement must be initialed by the patient and/or parent/legal guardian to indicate 
understanding, and the form must be completed and signed by the prescriber and patient and/or 
parent/legal guardian. 
— If the patient is under 18 years of age, his or her parent or legal guardian must read this material, 
sign the form, and agree to ensure compliance. 
— Retain “Prescriber” copy with patient record. 
— Mail “Survey Coordinators” copy (via self-mailing format). 
— Instruct patient to retain “Patient” copy and to present “Pharmacist” copy with prescription 
to pharmacist. 
• Complete the mandatory and confidential survey enrollment form. 
— Instruct patients to complete the confidential section, seal the survey, and return it to you. 
— Complete prescriber section and return survey in the envelope provided to the Slone Epidemiology 
Unit of Boston University School of Public Health. 
— Men must complete the survey, as well as women, because failure to use a latex condom during 
sexual intercourse with a woman or drug-sharing could result in fetal exposure to thalidomide. 
• Provide prescription. 
— Prescriptions cannot be issued by telephone. 
— Prescribe no more than 4 weeks (28 days) of therapy, with no automatic refills. 
— Inform patients that all prescriptions must be filled within 7 days. 
— It is recommended that female patients initially receive no more than a 1-week supply for each of the 
first 4 weeks to coincide with weekly pregnancy testing requirements. 
 
 
 
 
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Female Patient Monitoring During First 4 Weeks of Therapy 
 
During the first 4 weeks of therapy, the following must be performed: 
• Repeat patient counseling. 
• Perform pregnancy tests every week for the first 4 weeks of therapy. 
— It is recommended that the tests be performed within the 24 hours before providing subsequent prescriptions. 
— Pregnancy tests must be performed even if continuous abstinence is the chosen method of birth control. 
• If pregnancy test is negative, provide prescription for a 1-week supply of THALOMID™ (thalidomide). 
 
Subsequent Patient Visits 
On subsequent patient visits (after the first 4-week period) the following must be conducted1: 
• Repeat patient counseling. 
• Perform pregnancy test (female patients) every 4 weeks if patient’s menstrual cycles are regular, 
every 2 weeks if cycles are irregular. 
— It is recommended that the tests be performed within the 24 hours before providing subsequent prescriptions. 
— Pregnancy tests must be performed even if continuous abstinence is the chosen method of birth control. 
• If pregnancy test is negative or if the patient is male, provide prescription for no more than a 4-week 
(28-day) supply of THALOMID™ (thalidomide) therapy. 
• Complete the follow-up survey form. 
— Forms are included in the S.T.E.P.S.™ folder. 
— Female patients must complete the form every month.  Men must complete the follow-up survey at 
each visit or at least every 3 months. 
 
 
 
 
 
 
 
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Filling a THALOMID™ (thalidomide) Prescription 
 
The patient must present the pharmacy copy of the completed consent form along with the initial prescription to 
the pharmacist.  The pharmacist must then: 
• Ensure that the prescription was written within 7 days of presentation. 
• Collect and retain the pharmacy copy of the signed informed consent form. 
• Complete a patient registration form and enroll the patient in the S.T.E.P.S.™ Patient Registry by telephone 
or facsimile. 
• Dispense blister packs intact. 
• Dispense no more than a 4-week (28-day) supply of THALOMID™ (thalidomide), with no automatic refills. 
 
When subsequent prescriptions are presented to the pharmacy, the pharmacist must: 
• Ensure that the prescription was written within 7 days of presentation. 
• Verify patient registration and record subsequent prescriptions in the THALOMID™ (thalidomide) Patient 
Registry via on-line transmission or telephone. 
• Ensure that fewer than 7 days remain on the previous prescription. 
• Dispense blister packs intact. 
• Dispense no more than a 28-day supply of THALOMID™ (thalidomide). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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HOW SUPPLIED AND DISPENSED 
 
THALOMID™ (thalidomide) is supplied in 50-mg white, opaque, hard gelatin capsules imprinted with 
“Celgene” and a “DO NOT GET PREGNANT” logo.
1
  Boxes contain six blister packages containing 14 capsules 
each (84 capsules total).
1 
 
THALOMID™ (thalidomide) should be dispensed in no more than a 1-month supply and only on presentation of a 
new prescription written within the previous 7 days.
 1
  Informed consent and compliance with the mandatory 
patient registry and survey are required for both men and women prior to dispensing.
 1 
 THALOMID™ (thalidomide) 
prescribing to women of childbearing potential should be contingent upon initial and continued confirmed 
negative results of pregnancy testing.
 1 
 Prescriptions cannot be telephoned to the pharmacy. 
 
THALOMID™ (thalidomide) must not be repackaged.
 1
  Packages of THALOMID™ (thalidomide) should be stored 
at 59 F to 86 F (15 C to 30 C) and protected from light.
 1
 
 
Further information about THALOMID™ (thalidomide) and S.T.E.P.S.™ can be obtained by calling Celgene 
Corporation at 1-888-4-CELGENE. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_______________________ 
1 Manson JM. 1986. Teratogenicity. Cassarett and Doull's Toxicology: The Basic Science of Poisons. Third Edition.  Pages 195-
220. New York: MacMillan Publishing Co. 
 
 
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E-1 
 
APPENDIX E 
 
HUMAN SUBJECTS 
 
 
1. Subject Consent 
 
A conference will be held with the patient, donor and family to discuss this study and alternative 
treatments available for the treatment of the underlying disease.  The conference will be 
conducted by the principle investigator or other designated physician.  All potential risks 
associated with the use of high-dose melphalan, TBI, and immunosuppressive drugs should be 
discussed as objectively as possible.  It should be explained that patients offered this protocol 
have advanced MM with life expectancy of no more than several years with conventional 
treatments.  Furthermore, it should be explained that the patient would be likely to benefit in 
terms of disease control and prolongation of survival from an autologous transplant alone, but 
would likely relapse from the disease.  In addition, the risk of conventional allogeneic transplant 
for MM should be described.  
 
The procedure for collecting peripheral blood mononuclear cells and toxicities of G-CSF will be 
explained to the donor.  The donor should be counseled as to the risks of treatment with G-CSF 
and be informed that leukapheresis at several time points will be necessary.  Informed consent 
from the donor and patient will be obtained using a form approved the Institutional Review 
Board of the institution enrolling the patient. 
 
2. Confidentiality 
 
Confidentiality will be maintained by individual names being masked and assigned a patient 
identifier code.  The code relaying the patient’s identity with the ID code will be kept separately 
at the center.  The ID code will be transmitted to the network. 
 
3. Participation of Women and Minorities and Other Populations 
 
Women and ethnic minorities and other populations will be included in this study.  Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities 
expected from data reported to the IBMTR and from published data on incidence of MM in these 
groups.  Centers will be notified if their rates differ significantly from those expected and asked 
to develop appropriate recruitment strategies. 
 


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F-1 
APPENDIX F 
 
REFERENCES 
 
 
                                                                                                                                                                    
1 Riedel DA, Pottern LM.  The epidemiology of multiple myeloma.  Hematol Oncol Clin North 
Am 6: 225-247, 1992. 
2 Bensinger WI, Buckner CD, Anasetti C, Clift R, Storb R, Barnett T, Chauncey T, Shulman H, 
Appelbaum FR.  Allogeneic marrow transplantation for multiple myeloma: An analysis of risk 
factors on outcome.  Blood 88: 2787-2793, 1996. 
3 Attal M, Harousseau J, Falcon T, Guihot F, Doyen C, Fuzibet J, Monconduit M, Hullen C, 
Caillot D, Bouabdallah R, Villat L, Sotto J, Grosbios B, Bataille R.  Double Autologous 
Transplantation Improves Survival of Multiple Myeloma Patients: Final Analysis of a 
Prospective Randomization Study of the ‘Intergroupe Francophone du Myelome’ (IFM 94).  
Blood 100: Number 11, 2002 (Abstract 7). 
4 Gahrton G, Tura S, Ljungman P, Belanger B, Brandt L, Cavo M, Facon T, Granena A, 
Gratwohl A, Löwenberg B, Nikoskelainen J, Reiffers J, Samson D, Selby P, Verdonck L, Volin 
L, for the European Group for Bone Marrow Transplantation.  Allogeneic bone marrow 
transplantation in multiple myeloma.  N Engl J Med 325: 1267-1273, 1991. 
5 Gahrton G, Tura S, Ljungman P, Blade J, Brandt L, Cavo M, Facon T, Gratwohl A, Hagenbeek 
A, Jacobs P, De Laurenzi A, Van Lint M, Michallet M, Nikoskelainen J, Reiffers J, Samson D, 
Verdonck L, De Witte T, Volin L.  Prognostic factors in allogeneic bone marrow transplantation 
for multiple myeloma.  J Clin Oncol 13, No 6: 1312-1322, 1995. 
6 Personal communications from Dr. David Maloney. 
7 Maloney DG, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Molina, AJ, Besinger W, 
McSweeney PA, Storer BE, Niederwieser D, Chauncey T, Appelbaum FR, Blume KG, Forman 
SJ, Strob R.  Combining an Allogeneic Graft-vs-Myeloma Effect with High-dose Autologous 
Stem Cell Rescue in the Treatment of Multiple Myeloma.  Presentation at the American Society 
of Hematology 43rd Annual Meeting and Exposition, Blood 98: Part 1 of 2, #1822, 2001. 
(Abstract) 
8 Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R.  Thalidomide with Dexamethasone 
for Resistant Multiple Myeloma.  Blood 96 (11): 167a, 2000. 
9 Alexanian R, Weber D, Giralt S, Delasalle K.  Consolidation therapy of multiple myeloma with 
thalidomide-dexamethasone after intensive chemotherapy.  Annals of Oncology 13: 1116-1119, 
2002. 
10 Boccadoro M, Marmont F, Tribalto M, Avvisati G, Andriani A, Barbui T, Cantonetti M, 
Carotenuto M, Comotti B, Dammacco F, Frieri R, Gallamini A, Gallone G, Giovangrossi P, 
Grignani F, Lauta VM, Liberati M, Musto P, Neretto G, Petrucci MT, Resegotti L, Pileri A, 
Mandelli F.  Multiple myeloma: VMCP/BAP alternating combination chemotherapy is not 
superior to melphalan and prednisone even in high-risk patients.  J Clin Oncol 9: 444-448, 1991. 


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11 Gregory WM, Richards MA, Malpas JS.  Combination chemotherapy versus melphalan and 
prednisolone in the treatment of multiple myeloma: an overview of published trails.  J Clin 
Oncol Vol. 10: 334-342, 1992. 
12 McElwain TJ, Powles RL.  High-dose intravenous melphalan for plasma cell leukaemia and 
myeloma.  Lancet i: 822-824, 1983. 
13 Selby P, McElwain TJ, Nandi AC, Perren TJ, Powles RL, Tillyer CR, Osborne RJ, Slevin ML.  
Multiple myeloma treated with high dose intravenous melphalan.  Br J Hematol 66: 55-62, 1987. 
14 Barlogie B, Hall R, Zander A, Dicke K, Alexanian R.  High-dose melphalan with autologous 
bone marrow transplantation for multiple myeloma.  Blood 67: 1298-1301, 1986. 
15 Barlogie B, Alexanian R, Dicke KA, Zagars G, Spitzer G, Jagannath S, Horwitz L.  High-dose 
chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma.  
Blood 70: 869-872, 1987. 
16 Reece D, Vesole D, Flomenberg N, Badros A, Filicki J, Herzig R, Howard D, Johnson V, 
Meisenberg B, Rapoport A, Xun C, Philips G.  Intensive Therapy with High-dose Melphalan 
(MEL) 280mg/m2 Plus Amifostine Cytoprotection and ASCT as Part of Initial Therapy in 
Patients with Multiple Myeloma.  Blood, 100: Number 11, 2002 (Abstract #1672). 
17 Weaver CH, Zhen B, Schwartzberg LS, Leff R, Magee M, Geier L, Deaton K, Lewkow L, 
Buckner CD.  Phase I-II evaluation of rapid sequence tandem high-dose melphalan with 
peripheral blood stem cell support in patients with multiple myeloma.  Bone Marrow Transplant 
22: 245-251, 1998. 
18 Barlogie B, Jagannath S, Vesole D, Tricot G.  Autologous and allogeneic transplants for 
multiple myeloma.  Semin Hematol 32: 31-44, 1995. 
19 Cavo M, Benni M, Gozzetti A, Tura S.  The role of haematopoietic stem cell-supported 
myeloablative therapy for the management of multiple myeloma.  Baillieres Clin Haematol 8: 
795-813, 1995. 
20 Cunningham D, Paz-Ares L, Gore ME, Malpas J, Hickish T, Nicolson M, Meldrum M, Viner 
C, Milan S, Selby PJ.  High-dose melphalan for multiple myeloma: long-term follow-up data.  J 
Clin Oncol 12: 764-768,1994. 
21 Gore ME, Viner C, Meldrum M, Bell J, Milan S, Zuiable A, Slevin M, Selby PJ, Clark PI, 
Millar B, Maitland JA, Judson IR, Tillyer C, Malpas JS, McElwain TJ.  Intensive treatment of 
multiple myeloma and criteria for complete remission.  Lancet ii: 879-882, 1989. 
22 Harousseau J-L, Attal M, Divine M, Marit G, Leblond V, Stoppa A-M, Bourhis J-H, Caillot D, 
Boasson M, Abgrall J-F, Facon T, Linassier C, Cahn J-Y, Lamy T, Troussard X, Gratecos N, 
Pignon B, Auzanneau G, Sugita K.  Autologous stem cell transplantation after first remission 
induction treatment in multiple myeloma: A report of the French registry on autologous 
transplantation in multiple myeloma.  Blood 85: 3077-3085, 1995. 
23 Jagannath S, Vesole DH, Glenn L, Crowley J, Barlogie B.  Low-risk intensive therapy for 
multiple myeloma with combined autologous bone marrow and blood stem cell support.  Blood 
80: 1666-1672, 1992. 


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24 Vesole DH, Tricot G, Jagannath S, Desikan KR, Siegel D, Bracy D, Miller L, Cheson B, 
Crowley J, Barlogie B.  Autotransplants in multiple myeloma: what have we learned?  Blood 88: 
838-847, 1996. 
25 Barlogie B, Jagannath S, Naucke S, Mattox S, Bracy D, Crowley J, Tricot G, Alexanian R.  
Long-term follow-up after high-dose therapy for high-risk multiple myeloma.  Bone Marrow 
Transplant 21: 1101-1107, 1998. 
26 Goldschmidt H, Hegenbart U, Hohaus S, Benner A, Wannenmacher M, Haas R, Ho AD.  
High-dose melphalan (HD-MEL) plus total body irradiation (TBI) induces higher non-
hematological toxicity without improving remission status, event free – (EFS) – and overall 
survival (OS) compared to HD-MEL alone in patients with multiple myeloma (MM).  Blood  92 
(Suppl 1): 129a, 1998.(Abstract) 
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37 Personal communication with L. Holmberg. 
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