A Phase II Study of Maintenance Treatment With Sequential Bortezomib, Thalidomide and Dexamethasone Following Autologous Peripheral Blood Stem Cell Transplant in Patients With Multiple Myeloma
Phase: PHASE2
Conditions: Multiple Myeloma and Plasma Cell Neoplasm, Neurotoxicity
Sponsor: City of Hope Medical Center

IRB # 06143 
05/27/14 
V10 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
DIVISION OF HEMATOLOGY       
TITLE:  
A PHASE II STUDY OF MAINTENANCE TREATMENT WITH SEQUENTIAL BORTEZOMIB, 
THALIDOMIDE AND DEXAMETHASONE FOLLOWING AUTOLOGOUS PERIPHERAL BLOOD STEM 
CELL TRANSPLANT IN PATIENTS WITH MULTIPLE MYELOMA 
CITY OF HOPE PROTOCOL NUMBER/VERSION: 
IRB # 06143 
VERSION: 10 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
Initial Review         
  Protocol Dated 08-22-2007      
  Version: 00 
Initial Approval     
  Protocol Dated 09-11-2007      
  Version: 00 
Amendment 01  
    Protocol Dated 12-13-2007      
  Version: 01 
Amendment 02  
    Title Page Dated 02/26/2008   
   Version: 02 
Amendment 03  
    Protocol Dated 04-09-08    
  Version: 03 
Amendment 04  
    Protocol Dated 09-02-08    
  Version: 04 
Amendment 05  
    Protocol Dated 01-07-09    
  Version: 05 
    Amendment 06 
Protocol Dated 01-28-10   
     Version: 06 
    Amendment 07 
Protocol Dated 06-08-10   
     Version: 07 
    Amendment 08 
Protocol Dated 10-22-10   
     Version: 08 
    Amendment 09 
Title Page Dated 01-15-13 
     Version 09 
    Amendment 10 
Title Page Dated 05-27-14 
     Version 10 
DISEASE SITE: 
Bone Marrow 
STAGE (If applicable): 
I - III 
 
MODALITY(IES): 
TYPE (e.g., Pilot, Phase I):
Phase II  
PRINCIPAL INVESTIGATOR: 
Firoozeh Sahebi, M.D. 
COLLABORATING INVESTIGATOR(S): 
George Somlo, M.D. 
Stephen Forman, M.D. 
PARTICIPATING CLINICIANS:  
Ravi Bhatia, M.D. 
Ji-Lian Cai, M.D. 
Len Farol, M.D.  
Chatchada Karanes, M.D. 
Amrita Krishnan, M.D. 
Auayporn Nademanee, M.D. 
Ryotaro Nakamura, M.D.  
Margaret R. O’Donnell, M.D.
Pablo Parker, M.D.
Leslie Popplewell, M.D. 
David Senitzer, Ph.D. 
Eileen Smith, M.D. 
David Snyder, M.D. 
Ricardo Spielberger, M.D. 
Anthony Stein, M.D.  
Samer Khaled, M.D. 
Robert Chen, M.D. 
Tanya Siddiqi, M.D. 
Myo Htut, M.D.  
Department of Medical Oncology: 
Warren Chow, M.D. 
Department of Biostatistics: 
Paul Frankel, Ph.D. 
Department of Cytogenetics: 
Joyce Collins, M.D. 
Department of Transfusion Medicine: 
Sean Wang, M.D. 

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Pablo Parker, M.D.                                    David Snyder, M.D.                       Chatchada Karanes,M.D. 
Maria Delioukina, M.D.                            Ravi Bhatia, M.D.  
Robert Chen, M.D. 
Myo Htut, M.D.                                         Tanya Siddiqi, M.D. 
Samer Khaled, M.D. 
Department of Medical Oncology: 
Warren Chow, M.D. 
 
Department of Biostatistics: 
Paul Frankel, Ph.D. 
 
Department of Cytogenetics: 
Joyce Collins, M.D. 
 
Department of Transfusion Medicine: 
Shirong Wang, M.D. 

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PROTOCOL SUMMARY 
TITLE:  
 
A PHASE 11 STUDY OF MAINTENANCE TREATMENT WITH SEQUENTIAL 
BORTEZOMIB, THALIDOMIDE AND DEXAMETHASONE FOLLOWING 
AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANT IN PATIENTS 
WITH MULTIPLE MYELOMA 
OBJECTIVES:
 
The primary objectives of this study are: 
x
To assess the feasibility and toxicities of maintenance therapy with sequential bortezomib, 
thalidomide, and dexamethasone following high dose melphalan and autologous peripheral 
blood stem cell transplant in patients with multiple myeloma. 
 
x
To assess whether administration of maintenance therapy with sequential bortezomib, 
thalidomide, and dexamethasone can improve progression-free survival following 
autologous peripheral stem cell transplant. 
 
The secondary objectives of this study are : 
x
To assess whether administration of maintenance therapy with sequential bortezomib, 
thalidomide, and dexamethasone can increase complete remission (CR) rate and duration of 
response following autologous peripheral stem cell transplant. 
 
x
To assess the impact of maintenance therapy with sequential bortezomib, thalidomide, 
dexamethasone on overall survival following autologous peripheral stem cell transplant. 
 
x
To evaluate the influence of chromosome abnormalities on outcome by performing 
cytogenetics, and fluorescence in situ hybridization (FISH) studies on baseline and post 
transplant bone marrow specimens.        
 
PATIENT POPULATION: 
 
1.  Stage II - III MM 
2.  Progressive Stage I MM 
3.  Patients with Peripheral Neuropathy no greater than grade I 
4.  No evidence of resistance to bortezomib and thalidomide prior to transplant 

NUMBER OF PATIENTS: 
 
A total of 45 patients will be accrued. 
 
STUDY DESIGN AND METHODOLOGY: 
 
AUTOLOGOUS   
 
     A minimum of 4 x 10 6 CD 34 + cell/kg 
PERIPHERAL STEM CELL                            is obtained  
PROCURMENT 
 
 
 
TRANSPLANT                                       
 
DAY –2 
Melphalan 100 mg/m2 IV 
 
DAY –1 
Melphalan 100 mg/m2 IV 
 
DAY  0 
Reinfusion of collected stem cells 
(mimimum cell dose of 2x106 CD 34 + cell/kg)   
DAY  +5 
Start Filgrastim 5mcg/kg, Daily, IV 
 
MAINTENANCE 
Within a minimum of 4–8 weeks after autologous peripheral stem cell transplantation bortezomib 
will be administered as maintenance treatment at 1.3 mg/m2 once a week for three weeks followed 
by one-week rest for a maximum of 6 months.  Additionally, patients will receive dexamethasone 
at 40 mg/day D 1-4 of every month. Dexamethasone will be given for a total of 12 months. Two 
weeks after completion of bortezomib maintenance therapy patients will be started on thalidomide 
at 50 mg per day and thalidomide dose will be escalated to target dose of 200 mg per day till 
disease progression. 
 
 
 
 
 
    
     
     
 
Bortezomib 
     
 
Dexamethasone                                                                          x 12 months 
    
 
 
 
 
 
Thalidomide                               till disease progression 
 
Within 4 – 8 weeks of 
Transplant 
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6 Months  
      
 
 
 
 
 
                                                     
 
 
 
 

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STATISTICAL PROCEDURES: 
Sample Size  
The objectives of this Pilot study are to evaluate the feasibility and toxicities of maintenance 
therapy, complete response rate, duration of response, 3-year progression-free and overall survival 
rates.  
 
The maintenance therapy is considered feasible if more than 70% of the subjects are able to 
receive a minimum of 4 months of bortezomib therapy (patients able to receive bortezomib but on 
a reduced dose per protocol would not be considered “unable to tolerate”).  The maintenance 
therapy is considered not feasible if less than 50% of the subjects are able to tolerate bortezomib 
therapy.  With the early stopping rules, and more than 25/45 tolerating considered a success, this 
study has 85% power to determine feasibility with a type  I error of 10% and an 84% chance of 
early stopping if not feasible (based on 5000 simulations). A second feasibility marker regarding 
thalidomide will be also be assessed, but is not the basis of the sample-size and no related interim 
stopping rules are formalized for that component of the maintenance therapy.  
 
To evaluate for feasibility during the study while preventing excess patients from receiving the 
therapy if it is clearly not feasible, we will enforce the following:  
 
Early Stopping Rules 
Inability to continue to receive bortezomib for a minimum of 4 months per protocol dose 
modification guidelines will constitute intolerance.    The study will hold accrual, if the following 
numbers of patients able to tolerate bortezomib are observed (patients accrued will continue 
therapy per protocol): 
 
Patients with 4  
                     Stop if the Number Able to 
Months Follow-up 
                     Tolerate Bortezomib is: 
              5 
                                             0 
              15 
                                             <=8 
              25 
                                             <=13 
              35 
                                             <=19 
 
In order to accommodate the fact that several patients may be undergoing maintenance therapy 
when the stopping rule is activated, the following rule is to be followed: If after a hold on study 
accrual, the percent of patients unable to tolerate maintenance therapy remains above 50%, the 
study will not re-open. If the percent of patients unable to tolerate drops below 50%, accrual may 
re-start if the stopping condition was at 25 patients or less (if stopped at 35 patients with 4 months 
of follow-up, with <=19 able to tolerate, there will be no restart).  
 
The regimen, if feasible, will also be evaluated for its potential to improve three-year progression-
free survival. Historical data suggest approximately 52% of the patients are expected to be 
progression-free at 3 years after autologous stem cell transplant followed by maintenance 
thalidomide (Attal et al., Blood Nov 2006; 108 (10), P3289-3294). With 45 patients, there is 81% 
power to detect an improvement to a 66% 3-year progression-free survival with the proposed 

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maintenance therapy with a one-sided type I error of 10%. This assumes an accrual time of 24 
months, and a minimum follow-up of 36 months. The critical value for 3-year PFS rate is 60%, 
which, if observed, would suggest that the proposed therapy is a promising new maintenance 
therapy. This calculation is based on a constant hazard model, and on a parametric exponential 
estimate. 
 
Criteria for Feasibility 
If the study accrues to the full 45 patients, the trial will be considered a success on the primary 
endpoint of feasibility if 26 or more patients tolerated treatment.  If the estimated feasibility rate in 
the study group is equal to 70% then the 95% confidence interval would range from 57% to 83%.  
 
Analytic Plan 
The primary endpoint of feasibility will be estimated as a proportion along with the 95% 
confidence interval for the binomial.  If our accrual goal is met with no premature termination due 
to significant toxicity, a secondary goal of assessing response, progression-free survival (PFS), and 
overall survival (OS) will be carried out.  Survival estimates will be made using the product-limit 
method of Kaplan and Meier, with 95% confidence limits calculated using the logit transformation.   
It is hoped that PFS and OS will be further improved with the use of the proposed maintenance 
therapy.  If the patient discontinues maintenance therapy due to adverse events or personal choice, 
patient will be taken off protocol. 

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TABLE OF CONTENTS 
1.0 
SCHEMA 
2.0  
OBJECTIVES 
3.0  
BACKGROUND AND RATIONALE 
4.0  
THERAPEUTIC AGENTS 
5.0 
PATIENT ELIGIBILITY 
6.0
TREATMENT PLAN 
7.0
SUPPORTIVE CARE POST TRANSPLANT 
8.0 
EVALUATION AND TOXICITIES 
9.0 
STUDY PARAMETERS 
10.0 
EVALUATION AND RESPONSE 
11.0 
REPORTING DATA 
12.0 
STATISTICAL CONSIDIRATIONS 
13.0 
MINORITIES AND WOMEN STATEMENT 
14.0
ETHICAL AND REGULATORY CONSIDERATIONS 
15.0
DATA AND SAFETY MONITORING  
16.0
DEFINITIONS AND PROCEDURES FOR AE AND SAE REPORTING 
17.0 
ADMINISTRATIVE REQUIREMENTS 
18.0 
BIBLIOGRAPHY 
19.0 
APPENDIX

 
1.0 SCHEMA 
 
 
 
AUTOLOGOUS
 
 
A minimum of 4 x 10 6 CD 34 + cell/kg 
PERIPHERAL STEM CELL 
 
is obtained 
PROCURMENT
 
 
 
 
TRANSPLANT
 
DAY –2 
 Melphalan 100 mg/m2 IV 
 
DAY -1            Melphalan 100 mg/m2 IV 
 
DAY  0  
 Reinfusion of collected stem cells  
                        (minimum cell dose of 2x106 CD 34 +  cell/kg) 
    
DAY  +5           Start Filgrastim 5mcg/kg, Daily, IV 
 
 
MAINTENANCE
Within a minimum of 4 – 8 weeks after autologous peripheral stem cell transplantation bortezomib 
will be administered as maintenance treatment at 1.3 mg/m2 once a week for three weeks followed 
by one-week rest for a total duration of 6 months.  Additionally, patients will receive 
dexamethasone at 40mg/day D 1-4 of every month.  Dexamethasone will be given for a total of 12 
months. Two weeks after completion of bortezomib maintenance therapy patients will be started 
on thalidomide at 50mg per day.  The dose will be escalated at 50mg per week to a target dose of 
200mg per day.  Dose reduction to a minimum dose of 50 mg every other day is allowed for 
thalidomide related toxicities.  Thalidomide will be continued till disease progression.
 
 
 
 
    
     
 
Bortezomib 
     
     
 
Dexamethasone                                                                         x 12 months                       
    
 
 
 
 
             Thalidomide                               till disease progression 
6 Months  
 
Within 4 – 8 weeks of 
Transplant 
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2.0 
OBJECTIVES
 
 
 
2.1.1
PRIMARY OBJECTIVES 
-
To assess the feasibility and toxicities of maintenance therapy with 
sequential bortezomib, thalidomide, and dexamethasone following high 
dose melphalan and autologous peripheral blood stem cell transplant in 
patients with multiple myeloma. 
-
To assess whether administration of sequential bortezomib, thalidomide, 
and dexamethasone can improve progression-free survival
 
2.1.2
SECONDARY OBJECTIVE    
 
-
To assess whether administration of sequential bortezomib, thalidomide, 
and dexamethasone can increase complete remission (CR) rate and 
duration of response in patients with multiple myeloma.   
 
-
To assess the impact of maintenance therapy with sequential 
bortezomib, thalidomide, dexamethasone following transplant on overall 
survival. 
 
-
To evaluate the influence of cytogenetic abnormalities including but not 
limited to chromosome 13 deletion, 14 q32 abnormality, t (4;14), 
chromosome 1 q21 amplification and chromosome 17 deletion on 
outcome by performing conventional cytogenetic study and fluorescence 
in situ hybridization (FISH) studies on baseline and post transplanted 
bone marrow specimens.        
.
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
The incidence of multiple myeloma (MM) has been on the rise accounting for 
approximately 10% of all hematological malignancies and 1% of all cancer-related 
death in Western countries.  Five in 100,000 Americans suffer from MM; the entire 
spectrum of plasma cell dyscrasias affects an even greater percentage of the 
population.  These diseases include benign gammopathy, macroglobulinemia, and 
solitary plasmacytoma and, within the category of MM, smoldering and indolent 
forms as well as immunoblastic lymphoma and plasma cell leukemia1.  Adverse 
prognostic factors such as high plasma cell labeling index, elevated beta-2 
microglobulin and C-reactive protein, the presence of specific chromosomal 
abnormalities, plasmablastic morphology and abnormal renal function, poor 
performance status at diagnosis and elevated serum levels of interleukin-6 are of 
grave clinical significance.2-4 Chemotherapy with melphalan and prednisone, a 

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combination of alkylating agents, or vincristine, doxorubicin is effective in 50-70% 
of patients with newly diagnosed MM; however, less than 10% of patients will 
achieve complete remission5,6.  Unfortunately, the effects of chemotherapy are 
usually short lasting. The median survival of patients with MM is 30-36 months.  
The lack of long-term effectiveness is due to either primary, or acquired resistance.  
Attempts to improve overall response and response duration have been focusing on 
overcoming drug resistance due to over expression of the MDR-1 gene product7, or 
utilizing myeloablative therapy followed by autologous or allogeneic peripheral 
blood progenitor cell rescue (PBPC).8
 
3.2 
High-dose chemo-/radiotherapy in the treatment of MM. 
 
Single agent high-dose melphalan therapy results in response rates of > 80% with 
complete response rates of > 30% as described in earlier studies without the use of 
stem cell support. In a recent update, 1/3 of the patients from the original cohort 
treated with high-dose melphalan were reported to be alive at 9 years9, 10. Thousands 
of patients with multiple myeloma have received dose-intense bone marrow 
ablative therapy followed by autologous bone marrow, or peripheral stem cell 
rescue, worldwide8, 11, 16 A prospective randomized study (IFM90) comparing high-
dose consolidation therapy and stem cell rescue following induction therapy to 
conventional chemotherapy alone, reported higher complete response rates (22% 
versus 5%) and improved progression-free and overall survivals with transplant 
(projected 5 year event-free and overall survivals 28% and 52% versus 10% and 
12%).  17 Comparison of early vs. late (at the time of progression) autologous 
transplants favor early high-dose therapy resulting in prolonged progression-free 
survival and quality of life while in response.18 Tandem cycle high-dose 
chemo/radiotherapy in the setting of a total therapy in the largest series by a single 
institution suggested additional benefit associated with the second transplant in a 
series of 231 patients, independent of the presence of unfavorable cytogenetics and 
elevated beta 2 microglobulin; with a median follow-up of 4.2 years among 
surviving patients actuarial 5-year event-free and overall survivals were 42% and 
58%, respectively.19  A recent prospective randomized study by the French group 
(IFM 94) reported  seven year event-free and overall survival of 20% and 40% 
respectively with tandem autologous transplant twice the rate obtained with single 
transplant, suggesting a benefit in favor of tandem autologous transplant.20 
However, the benefit was observed only in patients who did not have a very good 
partial response (VGPR) within three months after first autologous transplant.  
Furthermore a recent randomized study by an Italian group reported only PFS 
advantage with no difference in OS with tandem autologous stem cell transplant as 
compared to single autologous transplant. 42   Overall the benefit from tandem 
autologous transplant remains marginal and majority of the patients still experience 
recurrent disease. 
 
Allogeneic bone marrow transplantation has been associated with a disappointing 
median overall survival of 13 months in a registry review by the European Group 

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for Blood and Bone Marrow Transplantation, with approximately 40% early, 
treatment-related mortality, caused by regimen-related toxicities, infections, and 
acute or chronic graft versus host disease.16  More recent data suggest diminished 
early mortality rates possibly due to incorporation of PBPC reinfusions in addition 
to ongoing assessment of the role of the so called mini transplants.21 
Currently early utilization of myeloablative therapy is recommended with 
autologous stem cell transplantation in order to consolidate complete or partial 
response to conventional treatment.  In addition, even patients with previously 
untreated or refractory disease may respond to high-dose therapy, with the 
possibility of long-term disease control.8 
 
3.3      Chromosomal abnormalities as prognostic indicators in MM 
Cytogenetic abnormalities can be detected in significant numbers of MM cases; the 
presence of 11q, -13 and deletion 13q, t (4;14) have been associated with worse 
survival.19  Frequent abnormalities observed in MM include t(4;14) (p16;q32), 
t(11;14) (q13;q32), t(8;14) (q24;32), t(14;18) (q32;q21), t (14;16) (q32; q23), 13q14 
(Rb loss), chromosome 17 deletion, and others. 22One of these translocations, 
t(4;14) may lead to dysregulations of two separate oncogenes providing one of 
many potential targets for specific interventions in the future.  More recently high 
amplification of chromosome 1q21 has been linked to worse outcome following 
transplant.23  Global gene expression profiling on highly purified malignant plasma 
cells from 351 newly diagnosed patients with multiple myeloma treated with 
autologous stem cell transplantation revealed a statistically significant over 
representation of chromosome 1 gene in a group of 70 genes whose expression was 
linked to poor outcome.  In particular, over expression of CKS1B, which maps to an 
amplicon at 1 q21 in myeloma and regulates proteolysis of the cyclin dependent 
kinase inhibitor P27kip1 was significantly over expressed in patients with poor 
prognosis. 24  
 
3.4       Maintenance therapy after autologous stem cell transplant in MM 
 
Despite prolongation of disease free survival and overall survival with autologous 
stem cell transplant majority of the patients experience relapse within a few years of 
transplant.  Maintenance therapy might prolong response and survival by inhibiting 
proliferation and inducing apoptosis of malignant cells that have not been 
eliminated by chemotherapy.  The use of maintenance therapy post autologous stem 
cell transplant was initially studied using alfa-interferon.  This approach was shown 
to exert anti-myeloma activity but was associated with significant toxicities and no 
statistical difference in overall survival in a randomized study. 25 
 
A phase II study conducted at COH investigated the role of maintenance 
thalidomide after single autologous stem cell transplant.  A total of 29 patients were 
enrolled. With a median follow up of 27.7 months, estimated 2 year overall survival 
was 83% and progression free survival was 49%.  At 6 months 45% of patients 

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achieved CR or near CR, suggestive of additional benefits from maintenance 
thalidomide.26 In this study patients with chromosome 13 abnormality had a PFS of 
only 16% despite maintenance thalidomide.  A randomized study (IFM9902) 
reported improvement in event free survival with maintenance thalidomide post 
tandem autologous stem cell transplant with a 3 year post randomization probability 
of EFS of 52% as compared to 36% in the observation arm and 37% in the 
pamidronate arm.  They also reported an overall survival advantage in favor of 
maintenance thalidomide with 4-year post diagnosis probability of survival of 87% 
versus 77% in the observation arm and 74% in the pamidonate arm. 27  In this study 
the benefit from maintenance thalidomide was seen in patients who had no 
chromosome 13 abnormality suggesting that the negative impact of chromosome 13 
abnormality cannot be overcome by maintenance thalidomide alone.  A study by the 
Arkansas group also reported an increase in CR rate and 5 - year EFS with the 
addition of thalidomide to tandem autologous transplant plan throughout (Total 
Therapy II) with no difference in OS. 37   They reported shorter survival from 
relapse in patients who received thalidomide.  This shorter post relapse survival was 
traced to high amplification of chromosome 1q21, which was more often present on 
the thalidomide arm.  It must be noted that the shorter post relapse survival may be 
related to the fact that relapse occurred later on maintenance thalidomide, as OS 
was similar in the two treatment arms in Total Therapy II.  Furthermore French 
(IFM9902) study reported a similar post relapse survival in the 3 treatment groups.  
27  Another randomized study by an Australian group compared thalidomide as 
maintenance therapy following single autologous stem cell transplant in 
combination with prednisone to prednisone alone.  In this study thalidomide was 
continued for 12 months post transplant and prednisone was continued till disease 
progression.  The thalidomide maintenance arm demonstrated superior PFS 
(P=0.0003) and OS (P=0.02) compared to prednisone arm supporting the use of 
maintenance thalidomide post autologous stem cell transplant. 43
 
Based on these results, further studies investigating the potential role of newer anti-
myeloma agents such as bortezomib, in combination with dexamethasone and 
thalidomide as maintenance therapy following autologous stem cell transplantation 
are warranted especially in patients with adverse prognostic features.  Furthermore, 
the results of recent studies with bortezomib indicate that response rate, EFS and 
OS are all independent of chromosomal abnormalities such as chromosome 13 
deletion in patients with relapsed or refractory multiple myeloma supporting the 
addition of bortezomib to thalidomide as maintenance therapy in the high risk 
patients. 39
 
 
4.0 THERAPEUTIC AGENTS 
4.1.1 Bortezomib 
 

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-Mechanism of action:  Bortezomib is a first-in-class inhibitor of proteasome 
activity that effectively interrupts the degradation of proteins involved in cell cycle 
regulation and apoptosis.  By inhibiting a single molecular target, the proteasome, 
bortezomib affects multiple signaling pathways.  The anti-neoplastic effect of 
bortezomib likely involves several distinct mechanisms, including inhibition of cell 
growth and survival pathways, induction of apoptosis, and inhibition of expression 
of genes that control cellular adhesion, migration and angiogenesis.  Thus, the 
mechanisms by which bortezomib elicits its antitumor activity may vary among 
tumor types, and the extent to which each affected pathway is critical to the 
inhibition of tumor growth could also differ.  Bortezomib has a novel pattern of 
cytotoxicity in National Cancer Institute (NCI) in vitro and in vivo assays (Adams 
et al., 1999).  In addition, bortezomib has cytotoxic activity in a variety of xenograft 
tumor models, both as a single agent and in combination with chemotherapy and 
radiation (Steiner et al., 2001; Teicher et al., 1999; Cusack et al., 2001; LeBlanc et 
al., 2002; Pink et al., 2002).  Notably, bortezomib induces apoptosis in cells that 
over express bcl-2, a genetic trait that confers unregulated growth and resistance to 
conventional chemotherapeutics (McConkey et al., 1999).  Bortezomib is thought to 
be efficacious in multiple myeloma via its inhibition of nuclear factor NB (NF-NB) 
activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct 
apoptotic effect, and possibly anti-angiogenic and other effects (Hideshima et al., 
2001).   
-Clinical Pharmacokinetics and Pharmacodynamics:  The clinical pharmacology 
characterization of bortezomib has been determined from phase 1 studies in subjects 
with solid tumors and hematological malignancies, and confirmed in phase 2 
studies in subjects with multiple myeloma. 
Bortezomib demonstrates multi-compartmental pharmacokinetics. Following 
intravenous administration of 1.0 mg/m2 and 1.3 mg/m2 dose, the mean first-dose 
maximum observed plasma concentrations of bortezomib were 57 and 112 ng/mL, 
respectively in 11 patients with multiple myeloma and creatinine clearance values 
>50 mL/min participating in a pharmacokinetics study.  In subsequent doses, mean 
maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1.0 
mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose.  The mean elimination 
half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours.  
Bortezomib is eliminated more rapidly following the first dose.  Mean Total Body 
Clearances were 102 and 112 L/h following the first dose for doses of 1.0 mg/m2 
and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent 
doses for doses of 1.0 and 1.3 mg/m2, respectively.  Clinical experience has shown 
that the change in clearance does not result in overt toxicity from accumulation in 
this multidose regimen in humans.  In subjects with advanced malignancies, the 
maximum pharmacodynamic effect (inhibition of 20S activity) occurred within 1-
hour post dose.  At the therapeutic dose of 1.3 mg/m2 in subjects with multiple 
myeloma, the mean proteasome inhibition at 1-hour post dose was approximately 
61%.  The time course of proteasome inhibition in subjects is characterized by 
maximum inhibition observed within the first hour after administration, followed by 
partial recovery of proteasome activity over the next 6 to 24 hours to within 50% of 

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the pretreatment activity.  On the Day 1, 4, 8, and 11 schedule, variable (10%–30%) 
levels of proteasome inhibition have been observed at next scheduled dosing.  In 
theory, this advantage allows cells to recover proteasome activity for normal 
cellular housekeeping functions between doses.  The relationship between 
bortezomib plasma concentrations and proteasome inhibition can be described by a 
maximum effect (Emax) model.  The Emax curve is initially very steep, with small 
changes in plasma bortezomib concentration over the range of 0.5 to 2.0 ng/mL 
relating to large increases in the percent inhibition (0–60%).  After that, a plateau 
occurs where marginal increases of proteasome inhibition are observed in spite of 
large changes in plasma bortezomib concentrations.  .  In a Phase I trial in patients 
with refractory hematologic malignancies, the MTD for a twice weekly for 4 weeks 
of a 42 day cycle was 1.04 mg/m2/dose, with DLTs of thrombocytopenia, 
hyponatremia, hypokalemia, fatigue, and malaise (Orlowski et al., 2002).  The 
toxicity was greatest during the third and fourth weeks of therapy. In the 3-week 
schedule of VELCADE monotherapy (4 doses, given on Days 1, 4, 8, and 11 of a 
21-day treatment cycle), the DLT occurred at 1.56 mg/m2/dose (3 subjects with 
Grade 3 diarrhea and 1 with peripheral sensory neuropathy).  Therefore, the MTD at 
this schedule was 1.3 mg/m2/dose.  In a 35-day treatment cycle with 4 weekly doses 
of VELCADE monotherapy, the MTD was 1.6 mg/m2/dose and DLT included 
hypotension, tachycardia, diarrhea, and syncope.  In phase 1 clinical studies, anti-
tumor activity was reported in subjects with NHL, multiple myeloma, 
Waldenström’s Macroglobulinemia, squamous cell carcinoma of the nasopharynx, 
bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate cancer. 
Bortezomib has demonstrated no irreversible adverse effect on hematopoietic stem  
cells.28   
-Clinical Experiences:  Several studies have reported encouraging results using  
bortezomib alone or in combination with dexamethasone in both relapsed/refractory  
multiple myeloma and  previously untreated disease.   The SUMMIT STUDY (The  
study of uncontrolled MM managed with proteasome inhibitor therapy) was a  
prospective open-label phase II study in 202 patients with relapsed/refractory  
multiple myelomas.29 The median number of previous treatment was 6 with 64% of  
patients having had stem cell transplant and 83% were previously treated with  
thalidomide.  The overall response rate of 35% with complete or near complete 
 response rates of 10%, partial response rate of 18% and minimal response rate of  
7%.  The most commonly reported adverse events were GI (such as nausea,  
diarrhea, and vomiting), fatigue, transient thromocytopnia (40%) and peripheral  
neuropathy (31%).  A phase III randomized study, APEX TRIAL (The Assessment  
of Proteasome Inhibition of Extending Remission) compared bortezomib with high  
dose dexamethasone in 669 patients with relapsed or refractory multiple myeloma  
with one to three previous treatments.30 In this study bortezomib was administered  
at 1.3mg/m2 on day 1, 4, 8, and 11 for eight five-week cycles, followed by weekly  
treatment on days 1, 8, 15, and 22 for three  five-week cycles. The dexamethasone  
arm of the trial was stopped after a preplanned interim analysis revealed significant  
clinical benefits in survival and time to disease progression for patients receiving  
bortezomib.  Significant activity in previously untreated patients with  

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multiple myeloma treated with bortezomib has also been reported.  A phase II  
study of bortezomib alone and in combination with dexamethasone in 32 previously  
untreated patients reported an overall response rate of 88% with CR + nCR rate of  
20%.  The most common adverse events were sensory neuropathy (31%),  
constipation (28%), myalgia (13%), and neutropenia (13%).31  Another phase II  
study of bortezomib in high risk newly diagnosed multiple myeloma was conducted  
by the Eastern Cooperative Oncology Group (E2A02).  High risk patients were  
defined B2 – microglobulin levels of > 5.5mg/L, ch13q deletion or plasma cell  
labeling index > 1.  Patients received induction treatment with bortezomib  
1.3mg/m2  on day 1, 4, 8, and 11 every 21 days for 8 cycles.  After induction,  
patients were scheduled to receive bortezomib 1.3mg/m2 every other week  
indefinitely.  Alternatively, eligible patients could undergo PBSC mobilization after  
4 cycles.  In patients with progressive disease during maintenance treatment, the  
induction was repeated.  A total of 44 patients were enrolled.  Preliminary data were  
presented in 19 patients, 13 patients (68.4%) achieved a partial response.  One of 2  
evaluable patients with deletion 13q, 6 of 8 evaluable patients with LI > 1 and 11 of  
15 evaluable patients with B2 - microglobulin >  5.5 mg/L achieved a partial  
response (38). 
 
Potential Risks of Bortezomib 
 
More than 55,000 people have been exposed to Bortezomib (Velcade).  
Known Anticipated Risks of VELCADE by MedDRA System Organ Class, Observed 
Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Blood and Lymphatic System Disorders 
Most common 
Thrombocytopenia that may increase the risk of 
bleeding*, anemia* 
Very common  
Neutropenia* 
Common  
Lymphopenia, pancytopenia*, leukopenia* 
Uncommon 
Febrile neutropenia 
Cardiac Disorders 
Common  
Arrhythmias including tachycardia, atrial fibrillation, 
and palpitations; acute development or exacerbation of 
cardiac failure, including congestive heart failure*; 
pulmonary edema* 
Uncommon 
Cardiogenic shock*, new onset of decreased left 
ventricular fraction*, atrial flutter, cardiac tamponade*, 
bradycardia, atrioventricular block (complete) 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impairment 
Eye Disorders 
Common  
Blurred vision, conjunctival infection and irritation 

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Known Anticipated Risks of VELCADE by MedDRA System Organ Class, Observed 
Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Uncommon 
Conjunctival hemorrhage 
Gastrointestinal Disorders 
Most common 
Constipation, diarrhea*, nausea, vomiting* 
Very common  
Gastrointestinal and abdominal pain, excluding oral and 
throat 
Common  
Dyspepsia, pharyngolaryngeal pain, gastroesophageal 
reflux, abdominal distension, stomatitis and mouth 
ulceration, dysphagia, gastrointestinal hemorrhage 
(upper and lower gastrointestinal tract)*, rectal 
hemorrhage (includes hemorrhagic diarrhea) 
Uncommon 
Eructation, tongue ulceration, retching, upper 
gastrointestinal hemorrhage*, hematemesis*, oral 
mucosal petechiae, ileus paralytic*, odynophagia, 
enteritis, colitis, oesphagitis, fungal oesphagitis, 
enterocolitis, acute pancreatitis* 
General Disorders and Administration Site Conditions 
Most common 
Asthenic conditions, including weakness, fatigue, 
lethargy, and malaise; pyrexia 
Very common  
Rigors, edema of the lower limbs 
Common  
Neuralgia, chest pain, mucosal inflammation* 
Uncommon 
Injection site pain and irritation, injection site phlebitis, 
general physical health deterioration*, injection site 
cellulitis, catheter site cellulitis, injection site infection 
Hepatobiliary Disorders 
Common  
Abnormal liver function tests 
Uncommon 
Hyperbilirubinemia, hepatitis* 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 
Infections and Infestations 
Very common  
Upper respiratory tract infection, nasopharyngitis, lower 
respiratory tract and lung infections*, pneumonia*, 
Herpes zoster* 
Common  
Herpes zoster disseminated,*, postherpetic neuralgia, 
sinusitis, pharyngitis, oral candidiasis, urinary tract 
infection*, catheter-related infection*, sepsis and 
bacteremia*, cellulitis and other skin infections*, Herpes 
simplex 
Uncommon 
Bronchitis, gastroenteritis*, septic shock*, urosepsis*, 
aspergillosis*, tinea infections, Herpes zoster 
ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic 
Injury, Poisoning, and Procedural Complications  
Common  
Catheter-related complication 
Investigations 
Common  
Increased ALT, increased AST, increased alkaline 
phosphatase 

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Known Anticipated Risks of VELCADE by MedDRA System Organ Class, Observed 
Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Uncommon 
Increased GGT, oxygen saturation decreased*, blood 
albumin decreased 
Metabolism and Nutritional Disorders 
Most common 
Decreased appetite and anorexia, which may result in 
dehydration and/or weight loss 
Very common  
Dehydration* 
Common  
Hyperglycemia, hypoglycemia, hyponatremia, 
hypokalemia, hypercalcemia* 
Musculoskeletal and Connective Tissue Disorders 
Very common  
Bone pain, pain in limb, myalgia, arthralgia 
Nervous System Disorders 
Most common 
Peripheral neuropathy (including all preferred terms 
under the MedDRA high-level term peripheral 
neuropathy NEC) 
Very common  
Paresthesia and dysesthesia; dizziness, excluding 
vertigo; headache 
 
Common  
Polyneuropathy, syncope, dysgeusia 
Uncommon 
Convulsions, loss of consciousness, ageusia, 
encephalopathy, paralysis*, reversible posterior 
leucoencephalopathy syndrome 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon 
Tumor lysis syndrome* 
Psychiatric Disorders 
Very common 
Anxiety  
Common 
Confusion  
Renal and Urinary Disorders 
Common 
Renal impairment, including renal failure and increased 
serum creatinine*; hematuria 
Uncommon 
Difficulty in micturition 
Respiratory, Thoracic, and Mediastinal Disorders 
Very common 
Cough, dyspnea  
Common 
Epistaxis, exertional dyspnea, pleural effusion*, 
rhinorrhea, hypoxia* 
Uncommon 
Hemoptysis*, acute respiratory distress*, respiratory 
failure*, pneumonitis*, lung infiltrates, pulmonary 
alveolar hemorrhage*, interstitial lung disease*, 
pulmonary hypertension* 
Skin and Subcutaneous Tissue Disorders 
Very common 
Skin rash, which can be pruritic, erythematous, and can 
include evidence of leukocytoclastic vasculitis 
Common 
Urticaria 
Uncommon 
Leukocytoclastic vasculitis 
Vascular Disorders 
Very common 
Hypotension* 
Common 
Orthostatic/postural hypotension, petechiae 

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Known Anticipated Risks of VELCADE by MedDRA System Organ Class, Observed 
Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Uncommon 
Cerebral hemorrhage* 
Source:  VELCADE Investigator’s Brochure, Edition 10 
ALT = alanine transaminase; AST = aspartate transaminase; GGT = gamma glutamyl transferase  
Most common = t 30%, Very common = 10% to 29%, Common=1% to 9%, Uncommon= < 1%,  
* Fatal outcomes have been reported 
Other medical events of interest that are considered not causally related to VELCADE include hepatic failure and QT 
prolongation.  Fatal outcomes have been reported. 
Women of childbearing potential should avoid becoming pregnant while being treated with 
VELCADE.  Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames 
assay and in the in vivo micronucleus assay, but it is a clastogen in the in vitro chromosomal 
aberration assay. 
 
Additional details on the potential risks of Velcade may be found in the Investigator’s Brochure. 
 
Preparation, Handling, and Storage of Bortezomib (Velcade) 
Vials containing lyophilized VELCADE for Injection should be stored according to 
the label requirements.  For the United States, store at USP Controlled Room 
Temperature which is 25ºC (77ºF); excursions permitted from 15 to 30ºC (59 to 
86ºF).  For Europe, do not store above 30ºC (86ºF).  To date, stability data indicate 
that the lyophilized drug product is stable for at least 18 months when stored under 
the recommended conditions. Stability studies are ongoing, and Millennium 
Pharmaceuticals, Inc. will notify the investigator should this information be revised 
during the conduct of the study.  VELCADE is cytotoxic.  As with all cytotoxic 
drugs, caution is required when preparing and handling VELCADE solutions.  
Cytotoxic drugs should only be handled by staff specially trained in the safe 
handling of such preparations. The use of gloves and other appropriate protective 
clothing is recommended.  In case of skin contact, wash the affected area 
immediately and thoroughly with soap and water for at least 15 minutes.  If product 
contacts eye, immediately flush eye thoroughly with water for at least 15 minutes.  
Always contact a physician after any form of body contact. All materials that have 
been used for preparation should be disposed of according to standard practices. A 
log must be kept of all disposed materials. 
Drug is available in sterile, single use vials containing 3.5 mg of VELCADE.  Each 
vial of VELCADE for Injection should be reconstituted under a laminar flow 
biological cabinet (hood) within eight hours before dosing with 3.5 mL of normal 
(0.9%) saline, Sodium Chloride Injection USP, so that the reconstituted solution 
contains VELCADE at a concentration of 1 mg/mL.  Prior to reconstitution the 
vials should remain in the cartons to protect them from light.  Dissolution is 

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completed in approximately 10 seconds.  The reconstituted solution is clear and 
colorless, with a final pH of 5 to 6.  Reconstituted VELCADE should be 
administered promptly and in no case more than 8 hours after reconstitution.  All 
materials that have been used for preparation should be disposed of according to 
standard practices.  A log must be kept of all disposed materials. 
 
  
 
 
 
4.1.2   Thalidomide 
 
Mechanism of action of thalidomide is not fully understood.  In multiple myeloma, 
thalidomide has been shown to block different pathways for disease progression. In 
addition to anti-angiogenic properties, thalidomide also possesses 
immunomodulatory and anti-inflammatory properties. Thalidomide reduces 
production of vascular endothelial growth factor (VEGF) and interleukin6 (IL-6), a 
growth factor for proliferation of myeloma cells, by bone marrow stromal cells. 40 
This drug can modulate the expression of cell surface adhesion molecules like TNF-
alpha, ICAM- 1 and VCAM 1. Thalidomide also generates apoptotic signals 
through activating capspase-8 mediated cell death, promoting c-jun terminal kinase 
(JNK) which leads to increased permeability of mitochondrial pores, and increasing 
production of pro-apoptotic proteins such as cytochrome C and second 
mitochondrial-derived activator of caspase (Smac).  In addition, thalidomide 
modulates host immune response by augmenting the activity of natural killer (NK) 
cells through increased production of IL-2 from activated T-cells. 41
 
Teratogenecity is the most serious side effect of thalidomide. S.T.E.P.S (System for 
Thalidomide and Prescribing Safety) program has been designed to minimize the 
chance of fetal exposure to thalidomide. Under this program, women of 
childbearing age are monitored for pregnancy, and both male and female patients 
are instructed to abstain from sexual intercourse or to use highly effective 
contraceptive methods. 
 
The incidence of toxicities with thalidomide usually correlates with the dose of the 
drug. Patients usually tolerate doses of 200 mg/day or less well and experience 
more side effects with higher doses. Incidence of certain toxicities such as 
constipation and sedation decreases with time, whereas incidence of peripheral 
neuropathy and hypothyroidism increases in frequency. Somnolence (~75%), 
constipation (~85%), xerostomia (~10%), tremors (~35%), skin rash (~45%), and 
neutropenia (15-25%) are the most common side effects of thalidomide. Severe 
incidence of somnolence (~5-10%), constipation (~5%), and peripheral neuropathy 
(~3-5%) has been reported in less than 10% of patients. Less common side effects 
of thalidomide include: bradycardia (~25%), peripheral edema (~15%), anasarca 
(~3%), ataxia (~15%), hearing loss (~3%), Steven- Johnson syndrome (<3%), and 
headaches (~10%). Although rare, seizures, confusion, impotence, elevation of liver 
enzymes, hypothyroidism, menstrual irregularities, hyperglycemia, and 
hypoglycemia have also been reported. Peripheral neuropathy can occur in about 

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80% of patients, with grade 3-4 neuropathy occurring in about 3-5% of all patients. 
This side effect usually occurs after 6 months of therapy. Deep venous thrombosis 
(DVT) and pulmonary embolism (PE) are serious side effects occurring in ~ 1-3% 
of patients receiving single-agent thalidomide. The incidence of thrombosis can 
climb to 15-25% when thalidomide is added to standard chemotherapy. Use of 
prophylactic low-molecular weight heparin, warfarin, and aspirin for all patients 
receiving thalidomide is being studied.  Currently they are recommended during 
induction treatment with combination of thalidomide and dexamethasone when 
tumor burden is high.  The incidence of DVT during maintenance therapy with 
thalidomide post autologous stem cell transplant has not been reported to be high 27 
and role of DVT prophylaxis in this setting remains to be determined.  Therefore no 
anticoagulation therapy will be used during maintenance therapy in this study. 
 
 
How supplied: Oral capsule: 50, 100, and 200 mg 
5.0 
PATIENTS ELIGIBILITY 
 
5.0a 
INCLUSION CRITERIA  
 
5.1a 
Multiple Myeloma patients with symptomatic disease, stage II or III at diagnosis or 
progressive stage I requiring chemotherapy and/or radiation therapy (by Salmon-
Durie classification), who are not eligible for tandem transplant study using TMI; 
(protocol 04064) because of previous radiation or eligibility criteria.  
Documentation of disease staging by both Salmon-Durie classification and 
International Staging System (ISS) is required.  
 
5.2a 
Patients with non-secretory myeloma should have measurable serum free–light 
chain protein by the Free-lite test or measurable disease such as a soft tissue 
myeloma. 
 
5.3a 
A minimum of 4 x 106 of CD 34 Positive cell/kg has been harvested. 
 
5.4a 
Patients must be < 70 years old at the time of enrollment. 
 
5.5a 
A KPS of t 70 % is required unless the KPS is impaired due to bone disease.    
 
5.6a 
No contraindication to the collection of a minimum of 4 x 106 CD34+ cells/kg by  
apheresis. 
 
5.7a 
All patients must have signed a voluntary, informed consent in accordance with 
institutional and federal guidelines. 
 

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5.8a 
Adequate hepatic function as demonstrated by bilirubin, < 1.5 mg/dl, and SGOT 
and SGPT < 2.5 x upper limits of normal. 
 
5.9a 
Acceptable renal function as demonstrated by measured creatinine clearance of t 
40cc/min. 
 
5.10a Absolute neutrophil count of > 1000/ȝl, platelet count of > 100,000/ȝl. 
 
5.11a Cardiac ejection fraction > 45% by MUGA scan  and/or by echocardiogram. 
 
5.12a Adequate pulmonary function as demonstrated by DLCO > 50% of predicted lower 
limit.  
 
5.13a HIV antibody tests negative. 
 
5.14a No other medical, or psychosocial problems which in the opinion of the primary  
physician or principal investigator would place the patient at unacceptably high risk 
from this treatment regimen. 
 
 
5.0b 
EXCLUSION CRITERIA 
5.1b 
Presence of peripheral neuropathy t grade II.  
 
 
            5.2b 
Patients with evidence of disease progression (with > 25% increase in M protein) on 
bortezomib and or thalidomide therapy prior to transplant. 
5.2c 
Pregnant or nursing women, as well as women of child bearing age, who are 
unwilling to use a dual method of contraception and men who are unwilling to use 
condom. 
 
5.2d 
Patients with history of hypersensitivity to bortezomib, boron or mannitol. 
 
6.0 
TREATMENT PLAN 
 
 
6.1 
Pre-treatment Evaluation to be done within 6 weeks of enrollment.  If  PSC 
collection is prolonged beyond 3 days, an additional 7-10 days will be allowed for the pre-
treatment evaluations. 
 
6.1.1 History and physical examination. 
 
6.1.2 Radiographic evaluation: Bone survey, MRI of the involved area as 
indicated clinically.   
 
6.1.3 Chest X-ray. 

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                                                        6.1.4 Pulmonary function tests 
 
6.1.5 MUGA scan or echocardiogram. 
 
                        6.1.6 CBC, differential count, platelet count, renal and liver function tests, 
electrolyte, blood sugar, ca, and uric acid (should be done within 4 weeks of 
enrollment).                       
 
 
 
6.1.7 Urine analysis (should be done within 4 weeks of enrollment). 
 
                                                        6.1.8 24 urine collection for total protein, protein electrophoresis, immuno  
electrophoresis, and creatinine clearance.  Creatinine clearance will be 
repeated after transplant prior to start of bortezomib. 
 
                                          6.1.9 Hepatitis panel, HIV antibody, HSV and CMV antibody. 
                        6.1.10  Unilateral bone marrow biopsy and aspirate and biopsy for morphology, 
cytogenetics and FISH.   
 
6.1.11 Serum protein electrophoresis, quantitative serum immunoglobulins,          
serum immunofixation electrophoresis, and free light chain assay (FLC). 
 
6.1.12 Beta-2 Microglobulin level and albumin level for International Staging 
            System (ISS) documentation. 
 
6.1.13 Serum pregnancy test for women of childbearing potential (should be done 
within 4 weeks of enrollment and repeated every 4 wks while on 
maintenance therapy). 
 
                        6.1.14 HLA, ABO and Rh typing.  These tests may be done prior to autologous 
PSCT. 
 
6.1.15 Double lumen Hickman catheter will be placed prior to stem cell harvest. 
(CBC, Comprehensive metabolic panel, pregnancy test for patients in child 
bearing age should be done immediately prior to start of melphalan). 
 
6.2 
Patient Registration 
 
After all pre-treatment evaluations have been performed and autologous PSC at a 
minimum dose of 4 x 106 CD34 + cell /kg has been harvested and separated into 2 
bags with a minimum of 2 x 106 CD34 + cell /kg per bags.   Eligibility requirements 
must be reviewed by a member of the department of Biostatistics and the principal 
investigator.  Patients will be registered to the trial after completion of stem cell 
collection and signing the informed consent form.  
 
 

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6.3 
High-Dose Chemotherapy 
 
6.3.1 Melphalan 
 
6.3.1.1   DAY –3, -2 and -1  
Admission (patients will be admitted on day -3 per COH standard 
practice),  history and physical, Comprehensive Metabolic Panel 18, 
Mg, CBC, differential and PLT count.  Review of required 
laboratory, screening and radiographic data.  
 
Prophylactic IV, or p.o. fluconazole at 400 mg daily will be given to 
patients on D +1, after melphalan started. 
 
Intravenous hydration per standard bone marrow transplant 
procedure is initiated on admission. After 4 hours of hydration on 
day –2 and –1 melphalan 100 mg/m2   will be infused in <  30 
minutes.  Hydration is continued for at least 24 hours after the last 
dose of melphalan.   
 
Appropriate intravenous antiemetics will be given. 
Melphalan should be dosed based on ideal body weight for patients 
who weigh 100 – 120% of their ideal body weight.  For patient who 
weigh less than 100% of their ideal body weight, dosing is based on 
actual bodyweight.  For patients who weigh above 120% of their 
ideal body weight, the adjusted ideal body weight (AIBW) should be 
used: 
AIBW = Ideal Body Weight + [(0.25) x (Actual BW – Ideal BW)] 
 
  
 
6.3.1.2  DAY  0 
 
 
A minimum cell dose of 2 x 106 CD-34 + cell/kg of previously 
collected peripheral blood stem cells will be reinfused.  The 
remainder of cryo-preserved autologous peripheral blood stem cells 
could be stored at the discretion of the treating physician for possible 
future use in the event of disease progression for a second 
autologous PSCT.  Patients will be taken off study at the time of 
disease progression. 
 
 
6.3.1.3  Day +5 
 
 
Filgrastim 5 ȝg/kg daily, IV, or SQ will be started.  Continue with 
Filgrastim until ANC > 1000/ is achieved per COH standard practice or 
per physician’s discretion.  

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6.3.3
Maintenance Therapy 
 
  
Patients will be started on maintenance therapy approximately within 4 – 8 
weeks after transplant. Patients should have at least a WBC > 3.0 and or 
ANC > 1000, platelet count > 100,000 and no peripheral neuropathy > grade 
II, within 14 days before bortezomib.  Creatinine clearance is repeated prior 
to start of bortezomib and should be > 20 ml/min.  
 
 
           6.3.3a Bortezomib:  will be administered IV bolus at 1.3 mg/m2 once a week for 3 
weeks (days 1, 8, & 15) followed by 1 week rest.  The Bortezomib cycle 
should be repeated every 28 days +/- 4 days for patient schedule flexibility.   
Bortezomib will be started within 4-8 weeks after transplant and continued 
for 6 cycles after transplant.  Patients should have WBC > 3000, ANC > 
1000, and platelets > 100, 000 on day 1 of each cycle. 
 
           6.3.3b Dexamethasone:  will be started at 40 mg daily D1-4 of every month for 
approximately a total duration of 12 months. 
 
           6.3.3c   Thalidomide:  Two weeks after completion of bortezomib patient will be 
started on thalidomide at 50mg per day.  The dose will be escalated by 50mg 
per week if tolerated to a target dose of 200mg/day till disease progression.  
Dose reduction to a minimum of 50 mg every other day allowed for 
thalidomide related toxicities. 
 
6.4 
Dose Adjustments – Only 2 dose reductions are allowed.  Patients who require dose 
reductions below 0.7 mg/m2 will be taken off study. 
 
Dose Level 
Bortezomib Dose 
1 
1.3 mg/m2
-1 
1 mg/m2
-2 
0.7 mg/m2
 
6.4.1 Bortezomib:  For grade t II peripheral neuropathy bortezomib will be held.  
It may be resumed at the next lower dose level if peripheral neuropathy 
resolved or decreased to < grade I.  For persistent peripheral neuropathy 
grade t II with no improvement after 12 weeks bortezomib is discontinued 
permanently.   
 
For grade III hematologic toxicities bortezomib will be held for up to 4 
weeks until the patient has WBC > 3.0, ANC > 1000 and PLT > 100,000 
before bortezomib is restarted at the next lower dose level.  If a patient 
experiences grade II hematologic toxicities, bortezomib is held until the day 
1 parameters are met.  Bortezomib should be restarted at the same dose, 
unless a dose-reduction is approved by the PI, but NOT dose reduces when 

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treatment parameters are met.  If treatment is delayed by more than 4 weeks 
due to allow for recovery of hematologic toxicity, the patient will be taken 
off study.  Dose interruption or discontinuation is not required for 
lymphopenia of any grade. 
 
For days 8 and 15, patients must have WBC > 2000, ANC > 1000, and 
platelets >50,000. 
 
For any other grade t III toxicity bortezomib will be held until toxicity is 
resolved or is grade < I.  The dose then will be reduced to next lower level 
from 1.3mg/m2 to 1mg/m2 and from 1mg/m2 to 0.7mg/ m2.  Dose 
interruption or discontinuation is not required for lymphopenia of any grade. 
 
6.4.2
Dexamethasone:  for any grade III or more toxicity dexamethasone will be 
held.  Dose can be reduced by 50% to 20mg D1-4 for the subsequent cycles. 
 
6.4.3
Thalidomide:  For any grade t III toxicities thalidomide will be held until 
the toxicity is resolved.  Dose will be reduced by 50% to a minimum of 
50mg every other day.  Dose may be later on escalated to the target dose of 
200mg per day at the discretion of the treating physician.  If bortezomib is 
discontinued prior to completion of 6 months, patients can start thalidomide 
earlier, at least 2 weeks after the last dose of bortezomib.  Patients must not 
have peripheral neuropathy > grade II, before the start of thalidomide. 
 
6.4.4
Patients unable to tolerate lowest dose of bortezomib, dexamethasone, and 
thalidomide need to stop the treatment with that agent permanently.  
 
 
7.0
SUPPORTIVE CARE POST TRANSPLANT 
Prophylactic IV, or p.o. fluconazole at 400 mg daily will be given to patients on D +1, after 
melphalan started. 
Patients will be supported through IV hydration and TPN, red cell and platelet transfusions as 
needed. CBC, PLT and SMA7, SMA 12, and Mg and weekly chest x-ray (as needed) as well as 
the necessary fever workup will be done.  Patients can be followed in the outpatient unit unless 
they develop neutropenic fever, uncontrollable diarrhea or other problems requiring inpatient 
care.  Inpatient care will be provided in rooms equipped with HEPA filter and they will be in 
protective isolation.  All blood products will be filtered and radiated.   
Patients should receive prophylaxis against PCP and varicella – zoster according to City of 
Hope standard practice.  Patients will also receive bisphosphonate therapy as clinically 
indicated, once a month.  Bisphosphonate therapy will be continued till CR is achieved.  It 
can be discontinued in patients who remain in CR per COH guidelines.   

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DVT prophylaxis:  No DVT prophylaxis is recommended during Velcade phase of 
maintenance study.  However, during Thalidomide phase of the study, prophylactic aspirin 
or low molecular weight heparin or warfarin are suggested only in patients with a past 
medical history of DVT on Thalidomide or at high risk of developing DVT/PE unless 
contraindicated.   High risk will be defined as history of DVT/PE in the past, significant 
family history of DVT/PE, smoking history, use of oral contraceptives, and concurrent use 
of epoetin.   
 
            8.0      EVALUATION AND TOXICITIES 
 
Physical evaluation, laboratory and radiographic evaluation will be performed as outlined 
in the treatment regimen.  When evaluating toxicity, the National Cancer Institute Common 
Toxicity Criteria (NCI CTC), version 3.0 will be used.            
 
Table 8.a.    
Management of Patients with Bortezomib (VELCADE) Related Neuropathic Pain 
and/or Peripheral Sensory or Motor Neuropathy 
Recommended Dose Modification for VELCADE related Neuropathic Pain and/or Peripheral Sensory or Motor 
Neuropathy  
Severity of Peripheral Neuropathy  
Signs and Symptoms  
Modification of Dose and Regimen  
Grade 1 (paresthesias, weakness and/or loss of reflexes) 
without pain or loss of function  
No action  
Grade 2 (interfering with  
function but not with activities of daily living)  
Withhold VELCADE therapy until toxicity resolves.  
When toxicity resolves or if < gr I reinitiate with a reduced 
dose of VELCADE at the next dose level. 
Grade 2 with pain or Grade 3 (interfering with  
activities of daily living)  
Withhold VELCADE therapy until toxicity resolves.  
When toxicity resolves or if < gr I reinitiate with a reduced 
dose of VELCADE at the next dose level 
Grade 4 (Sensory neuropathy which is disabling or motor 
neuropathy that is life threatening or leads to paralysis)  
Discontinue VELCADE  
Grading based on NCI Common Terminology Criteria CTCAE v3.0    
NCI Common Terminology Criteria website - http://ctep.info.nih.gov/reporting/ctc.html  
ADL = activities of daily living 
The neurotoxicity-directed questionnaire (see FACT/GOG- Neurotoxicity Questionnaire, Version 
4, Appendix 18.1) is a useful tool for determining the presence and intensity of neuropathic pain 
and/or peripheral neuropathy from the patient’s perspective.  Neuropathic symptoms are more 
prominent than abnormalities on the clinical examination.  After the patient completes the 
neurotoxicity-directed questionnaire, the questionnaire should be reviewed to assist with the 
evaluation of the onset and intensity of peripheral neuropathy and other neurotoxicities that may 
possibly require intervention or dose modification. 
 

                                                                           27 
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9.0 
 STUDY PARAMETERS   
 
 
 
 
                
 
 
 
 
Within 6 Wks 
Prior to 
enrollment## 
 
Melphalan 
PBSCT 
  
Post PBSCT 
Prior to Start 
of 
Bortezomib 
 
Bortezomib 
Maintenance 
Therapy  
Day 1, 8, & 15 
(Q28 days +/- 
4 days) 
 
Q 1 mo** 
Post PBSCT 
±  2 weeks 
for the first 
year 
 
Q 3 mos** 
Post 
PBSCT 
±  2 weeks 
for the first 
year 
 
Post 
PBSCT 
after  6 
cycles 
of 
bortezo
mib 
 
 
Q yr+ 
Post 
PBSCT 
±  2 weeks 
2 – 4 years 
 
 
History and Physical 
 
 
X 
 
 
X 
 X 
 
 
 
 
X 
 
     X 
 
       X 
 
CBC, DIFF, PLT/SMA7 
 
X 
 
X 
 
X 
 
X# 
 
 
X 
 
X 
 
X 
 
Renal, liver function 
tests, 
 
X 
 
X 
 
X 
  
 
 
X 
 
X 
 
X 
 
Ca, uric acid 
 
X 
 
 
  
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
  
 
 
 
 
 
 
 
 
Chest X-ray 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bone x-rays, MRI (if 
indicated), 
 
X 
 
 
 
 
 
 
 
 
X  
 
X 
 
SPEP, QIG, IEP, Beta-
2 Microglobulin, serum 
FLC 
 
X 
 
 
 
 X 
 
 
 
X 
 
X 
 
X 
 
24 hr urine for PEP, IEP, 
total protein, creatinine 
clearance* 
 
X 
 
 
 
         X 
 
 
 
 
 
X 
 
X 
 
MUGA Scan/ or echo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PFT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AB, RH, HLA Typing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BM, ASP, BX, for flow 
cytometry, morphology, 
cytogenetics,  
 
X 
 
 
 
X 
  
 
 
 
 
X 
 
X 
 
Serum B-HCG** 
 
X 
 
X 
 
X 
 
X** 
 
X 
 
 
 
 
 
X 
 
HIV, Hepatitis Panel to 
include A,B,C; Herpes 
and CMV Titer 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-GOG 
Neurotoxicity 
Questionnaire to be 
completed*** 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
*creatinine clearance is obtained at enrollment and prior to start of bortezomib. 
**B-HCG is repeated in women of childbearing age prior to start of melphalan and then monthly as long as 
receiving maintenance therapy. 

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***FACT- GOG Neurotoxicity questionnaire will be completed at baseline (within 6 wks prior to 
enrollment) and at 2 months post transplant and once a month after that for the first year.  For the second 
year the questionnaire will be completed every 3 months as long as on thalidomide for the duration of the 
study. 
# 
CBC, PLT, and Diff only. 
## 
An additional 7-10 days will be allowed if PSC collection is prolonged beyond 3 days. 
+  
SPEP, QIg, IEP and Serum FLC are repeated every 3-4 months in years 2-4. 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
Response is evaluated based on a new International myeloma working group uniform 
esponse criteria.
r 
36   
Table 1 
International Myeloma Working Group uniform response criteria:  CR and 
other response categories 
Response subcategory 
 
 
Response criteriaa
sCR 
 
 
 
 
CR as defined below plus 
 
 
 
 
 
Normal FLC ratio and 
 
 
 
 
 
Absence of clonal cells in bone marrowb by immunohistochemistry or 
 
 
 
 
 
immunofluorescencec 
 
CR 
 
 
 
 
Negative immunofixation on the serum and urine and 
 
 
 
 
 
Disapperance of any soft tissue plasmacytomas and 
 
 
 
 
 
< 5% plasma cells in bone marrowb 
 
VGPR  
 
 
 
Serum and urine M-protein detectable by immunofixation but not on 
Electrophoresis or 90% or greater reduction in serum M-protein plus 
urine M-protein level < 100mg per 24 h 
 
PR 
 
 
 
 
> 50% reduction of serum M-protein and reduction in 24-h urinary  
 
 
 
 
 
M-protein by > 90% or to < 200mg per 24 h 
If the serum and urine M-protein are unmeasurable,d a > 50% decrease in 
the difference between involved and uninvolved FLC levels is required in 
place of the M-protein criteria 
If serum and urine M-protein are unmeasurable, and serum free light 
assay is also unmeasurable, > 50% reduction in plasma cells is required in 
place of M-protein, provided baseline bone marrow plasma cell 
percentage was > 30% 
In addition to the above listed criteria, if present at baseline, a . 50% 
reduction in the size of soft tissue plasmacytomas is also required 
 
SD (not recommended for use as an 
Not meeting criteria for CR, VGPR, PR or progressive disease 
Indicator of response; stability of disease 
is best described by providing the time to 
p rogression estimates) 
Abbreviations: CR. complete response: FLC, free light chain; PR, partial response; SD, stable disease;sCR, stringent 
complete response; VGPR, very good partial response. 

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aAll response categories require two consecutive assessments made at anytime before the institution of any new 
therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies were 
performed.  Radiographic studies are not required to satisfy these response requirements. 
bConfirmation with repeat bone marrow biopsy not needed. 
CPresence/absence of clonal cells is based upon the NeO ratio by immunohistochemistry and/or immunofluorescence 
requires a minimum of 100 plasma cells for analysis.  An abnormal ratio reflecting presence of an abnormal clone is 
NeO of > 4:1 or < 1:2. 
dRefer to table 4 for definitions of measurable disease. 
 
 
 
Table 2
 International Myeloma Working Group uniform response criteria: disease 
progression and relapse 
Relapse subcategory 
 
 
Relapse criteria 
  
Progressive diseasea 
 
 
Progression Disease: requires any one or more of the following: 
To be used for calculation of time of  
progression and progression-free 
 
Increase of  > 25% from baseline in 
survival end points for all patients   
Serum M-component and/or (the absolute increase must be > 0.5 g/dl)b
including those in those in CR (includes  
Urine M-component and/or (the absolute increase must be > 200 mg/24 h 
primary progression disease and disease  
Only in patients without measurable serum and urine M-protein levels: 
progression on or off therapy) 
 
the difference between involved anduninvolved FLC levels. The absolute  
increase must be >l0mg/dl. 
Bone marrow plasma cell percentage: the absolute % must be > 10%C
Definite development of new bone lesions or soft tissue plasmacytomas 
or definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dl or 
2.65 mmol/1) that can be attributed solely to the plasma cell proliferative 
disorder 
 
Clinical relapsea  
 
 
Clinical relapse requires one or more of: 
Direct indicators of increasing disease and/or end organ dysfunction 
(CRAB features)b It is not used in calculation of time to progression or 
progression-free survival but is listed here as something that can be 
reported optionally or for use in clinical practice 
1. Development of new soft tissue plasmacytomas or bone lesions 
2. Definite increase in the size of existing plasmacytomas or bone lesions. 
A definite increase is defined as a 50% (and at least 1 cm) increase as 
measured serially by the sum of the products of the cross-diameters of the 
measurable lesion 
3. Hypercalcemia (>11.Smg/dI) [2.65 mmol/l] 
4. Decrease in hemoglobin of > 2 g/dl [1.25 mmol/1] (see Table 3 for 
further details) 
5. Rise in serum creatinine by 2mg/dl or more [177 Pmol/l or more) 
 
Relapse from CRa (To be used only if  
 Any one or more of the following: 
The end point studied is DFS)d 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis  
Development of > 5% plasma cells in the bone marrowc
Appearance of any other sign of progression (i.e., new plasmacytoma, 
lytic bone lesion, or hypercalcemia see below) 
 

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Abbreviations: CR. complete response: DFS, disease-free survival. 
aAll relapse categories require two consecutive assessments made at anytime before classification as relapse or disease 
progression and/or the institution of any new therapy. 
bFor progressive disease, serum M-component increases of > 1 gm/dl are sufficient to define relapse if starting M-
component is > 5g/dl. 
CRelapse from CR has the 5% cutoff versus 10% for other categories of relapse. 
dFor purposes of calculating time to progression and progression-free survival, CR patients should also be evaluated 
using criteria listed above for progressive disease. 
 
11.0 
REPORTING DATA 
 
11.1 
All primary data will be maintained by the Department of Biostatistics, City of Hope  
National Medical Center. This includes on study flow sheets, consent forms and off-study  
forms. 
 
11.2
Removal of patients from protocol therapy: If at any time the constraints of this protocol 
are detrimental to the patient’s health, the patient experience disease progression and /or 
the patient no longer wishes to continue protocol therapy, protocol therapy shall be 
discontinued and patient to be removed from the study.  In this event: 
 
x
Document the reason(s) for discontinuation of therapy. 
x
Follow the patient for survival, progression, and relapse, per study parameters. 
 
                           12.0 
STATISTICAL CONSIDERATIONS 
 
12.1
Sample Size  
The objectives of this Phase II study are to evaluate the feasibility and toxicities of 
maintenance therapy, complete response rate, duration of response, 3-year 
progression-free and overall survival rates.  
 
The maintenance therapy is considered feasible if more than 70% of the subjects are 
able to receive a minimum of 4 months of bortezomib therapy (patients able to 
receive bortezomib but on a reduced dose per protocol would not be considered 
“unable to tolerate”).  The maintenance therapy is considered not feasible if less 
than 50% of the subjects are able to tolerate bortezomib therapy.  With the early 
stopping rules, and more than 25/45 tolerating considered a success, this study has 
85% power to determine feasibility with a type I error of 10% and an 84% chance 
of early stopping if not feasible (based on 5000 simulations). A second feasibility 
marker regarding thalidomide will be also be assessed, but is not the basis of the 
sample-size and no related interim stopping rules are formalized for that component 
of the maintenance therapy.  
 
To evaluate for feasibility during the study while preventing excess patients from 
receiving the therapy if it is clearly not feasible, we will enforce the following:  
 

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12.2
Early Stopping Rules 
 
Inability to continue to receive bortezomib for a minimum of 4 months per protocol 
dose modification guidelines will constitute intolerance.  The study will hold 
accrual, if the following numbers of patients able to tolerate bortezomib are 
observed (patients accrued will continue therapy per protocol): 
 
 
 
 
 
Patients with 4  
                                  Stop if the Number Able to 
 
 
Months Follow-up 
                       
Tolerate Bortezomib is: 
               
 
5 
                                               
0 
               
 
15 
                                               
<=8 
               
 
25 
                                              
<=13 
               
 
35 
                                               
<=19 
In order to accommodate the fact that several patients may be undergoing 
maintenance therapy when the stopping rule is activated, the following rule is to be 
followed: If after a hold on study accrual, the percent of patients unable to tolerate 
maintenance therapy remains above 50%, the study will not re-open. If the percent 
of patients unable to tolerate drops below 50%, accrual may re-start if the stopping 
condition was at 25 patients or less (if stopped at 35 patients with 4 months of 
followup, with <=19 able to tolerate, there will be no restart).  
 
The regimen, if feasible, will also be evaluated for its potential to improve three-
year progression-free survival. Historical data suggest approximately 52% of the 
patients are expected to be progression-free at 3 years after autologous stem cell 
transplant followed by maintenance thalidomide (Attal et al., Blood Nov 2006; 108 
(10), P3289-3294). With 45 patients, there is 81% power to detect an improvement 
to a 66% 3-year progression-free survival with the proposed maintenance therapy 
with a one-sided type I error of 10%. This assumes an accrual time of 24 months, 
and a minimum follow-up of 36 months. The critical value for 3-year PFS rate is 
60%, which, if observed, would suggest that the proposed therapy is a promising 
new maintenance therapy. This calculation is based on a constant hazard model, and 
on a parametric exponential estimate. 
 
12.3 
Criteria for Feasibility 
 
If the study accrues to the full 45 patients, the trial will be considered a success on 
the primary endpoint of feasibility if 26 or more patients tolerated treatment.  If the 
estimated feasibility rate in the study group is equal to 70% then the 95% 
confidence interval would range from 57% to 83%.  
 
12.4 
Analytic Plan 
 

                                                                           32 
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The primary endpoint of feasibility will be estimated as a proportion along with the 
95% confidence interval for the binomial.  If our accrual goal is met with no 
premature termination due to significant toxicity, a secondary goal of assessing 
response, progression-free survival (PFS), and overall survival (OS) will be carried 
out.  Survival estimates will be made using the product-limit method of Kaplan and 
Meier, with 95% confidence limits calculated using the logit transformation.   It is 
hoped that PFS and OS will be further improved with the use of the proposed 
maintenance therapy.  If the patient discontinues maintenance therapy due to 
disease progression or personal choice, patient will be taken off protocol. Patients 
who discontinue maintenance treatment due to toxicities will remain on the study 
and will be followed for the study endpoints including disease response, PFS and 
overall survival. We will summarize the duration and the dose of boretzomib 
therapy and the duration and the dose of sequential thalidomide therapy.
 
 
12.5
Toxicity Grading 
 
When evaluating toxicities of maintenance therapy The National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0 will 
be used to grade adverse events as well as to assign perceived attribution of these 
events to the study treatment regimen.  By these criteria, toxicity is defined as an 
adverse event considered to possibly, probably or definitely related to treatment. 
 
                            
                  13.0 
GENDER AND ETHNICITY STATEMENT 
 
The City of Hope has a plan in place to increase minority recruitment to our studies in 
compliance with the National Institute of Health policy for recruitment of women and 
minorities. 
 
The table below shows the distribution by sex and race of the patients accrued to 
therapeutic clinical studies at City of Hope for the past five years.  Our goal is to maintain 
our high accrual of women while continuing to increase the accrual of minority subjects. 
 
 
 
Accrual Goal by Sex and Ethnicity  
 
 
 
 
 
By Sex 
 
By Ethnicity 
 
Site 
 
Accrual 
Goal 
 
Female 
 
Male 
 
White 
 
Hispanic 
 
Black 
 
Asian/ 
Other 
 
Unknown 
 
Multiple 
Myeloma 
 
45 
 
 
21 
(47%) 
 
24 
(53%) 
 
24 
(53%) 
 
9 
(20%) 
 
10 
(22%) 
 
2 
(4%) 
 
0 
(1%) 
 
14.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 

                                                                           33 
Protocol # 06143 
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This study is to be approved by the Institutional Review Board of the City of Hope.  All 
patients will have signed an informed consent for participation in research activities, and 
will have been given a copy of the Experimental Subject's Bill of Rights. 
 
When results of this study are reported in medical journals or at meetings, identification of 
those taking part will be withheld.  Medical records of patients will be maintained in 
strictest confidence, according to current legal requirements.  However, they will be made 
available for review, as required by the Food and Drug Administration (FDA) or to other 
authorized users such as the National Cancer Institute (NCI) under the guidelines 
established by the Federal Privacy Act. 
 
15.0 DATA AND SAFETY MONITORING 
 
A) Definition of Risk Level 
 
This is a Risk Level 3 study, as defined in the “Guidance, Policy and 
Procedures for Data and Safety Monitoring for In-House Trials at City 
of Hope”, http://www.infosci.coh.org/ocrqa/forms/guidance.doc 
because it is a phase II clinical trial where the risks are at least 
balanced by the potential benefit to subjects and the importance of the 
knowledge that may result. 
 
B) Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) consisting of the PI, Collaborating Investigator, 
CRA, protocol nurse, and statistician is responsible for monitoring the data and safety of this 
study, including implementation of any stopping rules for safety and efficacy.  
Data and safety will be reported to the COH DSMB.  Protocol specific data collection will 
include toxicities > grade 3 based on NCI CTCAE, version 3.0.  Reporting of data and safety 
to the DSMB will occur after the first 5 patients were enrolled and then after every 10 
patients enrolled using the PMT report. 
16.0      DEFINITIONS 
 
A. Adverse Event Definition:  
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the 
treatment.  An adverse event can be any unfavorable and unintended sign (eg, including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
drug, whether or not it is considered to be drug related.  This includes any newly occurring 
event or previous condition that has increased in severity or frequency since the 
administration of drug. 

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B. Serious Adverse Event Definition 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that: 
x
Results in death. 
x
Is life-threatening.  Life-threatening means that the patient was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
x
Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered AEs if the illness or disease 
existed before the patient was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (eg, surgery performed earlier than planned). 
x
Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a persons’ ability to conduct normal life functions. 
x
Is a congenital anomaly/birth defect. 
x
Is an important medical event.  An important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in 
the definitions for SAEs.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.   
Clarification should be made between the terms “serious” and “severe” since they ARE 
NOT synonymous.  The term “severe” is often used to describe the intensity (severity) of a 
specific event (as in mild, moderate, or severe myocardial infarction); the event itself, 
however, may be of relatively minor medical significance (such as a severe headache).  
This is NOT the same as “serious,” which is based on patient/event outcome or action 
criteria described above and are usually associated with events that pose a threat to a 
patient’s life or functioning.  A severe adverse event does not necessarily need to be 
considered serious.  For example, persistent nausea of several hours duration may be 
considered severe nausea but not an SAE.  On the other hand, a stroke resulting in only a 
minor degree of disability may be considered mild, but would be defined as an SAE based 
on the above noted criteria.  Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
C. Procedures for AE and SAE Reporting 
Investigator-sponsor must report all serious adverse event (SAE) regardless of relationship 
with any study drug or expectedness to the COH DSMB and IRB and Millennium as soon 
as possible, but no later than 5 calendar days of the investigator-sponsor’s observation or 
awareness of the event.  All sub-investigators must report all SAEs to the investigator-

                                                                           35 
Protocol # 06143 
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sponsor so that the investigator-sponsor can meet his/her foregoing reporting obligations to 
Millennium.  
SAE Reporting to COH:  Adverse events must be reported to the 
COH DSMB and IRB according to definitions and guidelines at 
http://www.infosci.coh.org/ocrqa/forms/guidance.doc and 
http://resadmin.coh.org/doc/irb3810.doc, which are defined below.  
AEs will be monitored by the PMT.  Less than serious adverse events 
will be reported only at the time of protocol continuation reports. 
Investigator-sponsor must also provide Millennium with a copy of all communications 
related to the Study or Drug with the applicable regulatory authority, including, but not 
limited to, telephone conversation logs, as soon as possible but no later than 5 calendar 
days of that communication.  
Millennium’s Product Safety Department will send to the investigator-sponsor a monthly 
listing of the SAE reports received for SAE verification.  Investigator-sponsor will be 
responsible for forwarding such reports to any sub-investigator(s) and providing any 
follow-up safety information requested by Millennium. 
SAE Reporting to Millennium, Contact Information (North America Reporting) 
Millennium Product Safety 
Fax: (617) 551-3746 
Telephone: (617) 551-2972 
E-mail: productsafety@mpi.com
 
 
For both serious and non-serious adverse events, the investigator or sub-investigator must 
determine both the intensity of the event and the relationship of the event to drug administration.
 
Relationship to drug administration will be determined by the investigator or sub-investigator 
responding yes or no to the question: Is there a reasonable possibility that the adverse event is 
associated with the drug? 
Intensity for each adverse event, including any lab abnormality, will be determined by using the 
NCI CTCAE, version 3.0, as a guideline, wherever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html.  
17.0 
ADMINISTRATIVE REQUIREMENTS 
17.1    Good Clinical Practice 
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
drug as described in the protocol and Investigator’s Brochure.  Essential clinical documents 
will be maintained to demonstrate the validity of the study and the integrity of the data 

                                                                           36 
Protocol # 06143 
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collected.  Master files should be established at the beginning of the study, maintained for 
the duration of the study and retained according to the appropriate regulations.   
17.2    Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki (see section 8.5).  The IRB/IEC will review all appropriate study 
documentation in order to safeguard the rights, safety and well-being of the patients.  The 
study will only be conducted at sites where IRB/IEC approval has been obtained.  The 
protocol, Investigator’s Brochure, informed consent, advertisements (if applicable), written 
information given to the patients (including diary cards), safety updates, annual progress 
reports, and any revisions to these documents will be provided to the IRB/IEC by the 
investigator.  Millennium requests that informed consent documents be reviewed by 
Millennium or designee prior to IRB/IEC submission.   
17.3    Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative prior to study participation.  
The method of obtaining and documenting the informed consent and the contents of the 
consent will comply with ICH-GCP and all applicable regulatory requirement(s). 
17.4    Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, 
tudy reports and communications will identify the patient by initials and the assigned 
patient number.  The investigator will grant monitor(s) and auditor(s) from Millennium or 
its designees and regulatory authority(ies) access to the patient’s original medical records 
for verification of data gathered on the data capture records and to audit the data collection 
process.  The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
17.5   Protocol Compliance 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies).  
Changes to the protocol will require approval from Millennium and written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is 
needed to eliminate an immediate hazard(s) to patients.  The IRB/IEC may provide, if 
applicable regulatory authority(ies) permit, expedited review and approval/favorable 
opinion for minor change(s) in ongoing studies that have the approval /favorable opinion of 
the IRB/IEC.  The investigator will submit all protocol modifications to Millennium and 
the regulatory authority(ies) in accordance with the governing regulations.  
Any departures from the protocol must be fully documented in the source documents.   
17.6    On-site Audits 
Regulatory authorities, the IEC/IRB and/or Millennium’s clinical quality assurance group 
may request access to all source documents, data capture records, and other study 
documentation for on-site audit or inspection.  Direct access to these documents must be 
guaranteed by the investigator, who must provide support at all times for these activities. 

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17.7     Drug Accountability 
Accountability for the drug at all study sites is the responsibility of the principal 
investigator.  The investigator will ensure that the drug is used only in accordance with this 
protocol.  Drug accountability records indicating the drug’s delivery date to the site (if 
applicable), inventory at the site (if applicable), use by each patient, and return to 
Millennium or disposal of the drug (if applicable and if approved by Millennium) will be 
maintained by the clinical site.  Accountability records will include dates, quantities, lot 
numbers, expiration dates (if applicable), and patient numbers.   
 
All material containing VELCADE will be treated and disposed of as hazardous waste in 
accordance with governing regulations. 
17.8     Premature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator or 
Millennium, there is sufficient reasonable cause.  Written notification documenting the 
reason for study termination will be provided to the investigator or Millennium by the 
terminating party.  Circumstances that may warrant termination include, but are not limited 
to: 
x
Determination of unexpected, significant, or unacceptable risk to patients 
x
Failure to enter patients at an acceptable rate 
x
Insufficient adherence to protocol requirements 
x
Insufficient complete and/or evaluable data 
x
Plans to modify, suspend or discontinue the development of the drug 
should the study be closed prematurely, all study materials must be returned to Millennium. 
17.9     Record Retention 
The investigator will maintain all study records according to ICH-GCP and applicable  
regulatory requirement(s).   
18.0    BIBLIOGRAPHY 
 
1. Riedel DA.  In:  Epidemiology and biology of multiple myeloma.  GI Obrams and 
M Potter (eds.), Springer-Verlag, New York, 1991, pp. 13-16 
 
2. Kyle RA.  Epidemiology and biology of multiple myeloma.  GI Obrams and M 
Potter (eds.), Springer-Verlag, New York, 1991, pp. 75-81 
 
3. Barlogie B, Smallwood L, Smith T, Alexanian R.  High serum levels of lactic 
dehydrogenase identify a high-grade lymphoma-like myeloma.  Annals Int Med 
110:521-25, 1989 
 
4. Barlogie B, Epstein J, Selvanayagam P, Alexanian R.  Plasma cell myeloma -New 
biological insights and advances in therapy.  Blood 73:865-79, 1989 
 

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5. Boccadoro M, Marmont F, Tribalto M, et al.  Multiple myeloma:  Alternating 
combination chemotherapy (VCMP/VBAP) is not superior to melphalan and 
prednisone (MP) even in high risk patients.  J Clin Oncol 9:444-448, 1991 
 
6. Barlogie B, Smith L, Alexanian R.  Effective treatment of advanced multiple 
myeloma refractory to alkylating agents.  N Engl J Med 310:1353-1356, 1984. 
 
7. Sonneveld P, Durie BGM, Lokhorst HM, et al.  Modulation of multidrug-resistant 
multiple myeloma by cyclosporin.  Lancet 340:255-59, 1992. 
 
8. Barlogie B., Thomas ED, Blume GG and Forman SJ. , Hematopoietic cell 
transplantation for multiple myeloma in Hematopoietic Cell Transplantation, 
Boston, Blackwell Scientific Publishers, 1998:1003-1013 
 
9. Cunningham D, Paz-Ares L, Gore ME, et al.  High-dose melphalan for multiple 
myeloma:  Long-term follow-up data.  J Clin Oncol 12:764-768, 1994 
10. Cunningham D, Paz-Ares L, Milan S, et al.  High-dose melphalan and autologous 
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