Conditions: Multiple Myeloma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 47
Healthy volunteers: no

Brief summary:
This phase III randomized trial compares three different peripheral stem cell mobilization regimens for patients with multiple myeloma who have received primary induction therapy or other therapies. Up to 180 patients will be enrolled. Patients eligible for treatment will be randomized to one of the three following mobilization regimens:

Arm A = VELCADE, CYCLOPHOSPHAMIDE, \& G-CSF Arm B = VELCADE \& G-CSF Arm C = CYCLOPHOSPHAMIDE \& G-CSF Arm D = PLERIXAFOR \& G-CSF Arm E = PLERIXAFOR, VELCADE, \& G-CSF

Detailed description:
PRIMARY STUDY OBJECTIVES

• To compare the efficacy of the following peripheral stem cell mobilization regimens for MM: i. High dose cyclophosphamide, VELCADE, and G-CSF ii. VELCADE and G-CSF iii. High dose cyclophosphamide and G-CSF

SECONDARY STUDY OBJECTIVES

• To evaluate biomarkers as surrogate markers of mobilization in each arm To evaluate changes in tumor mass as defined by standard response parameters. To evaluate the safety of each of the arms.

This phase III randomized trial compares three different peripheral stem cell mobilization regimens for patients with multiple myeloma who have received primary induction therapy

Primary Endpoints

a) Percentage of patients able to collect \>6 x 106 CD34+ cells/kg in \< 2 collections.

Secondary Endpoints

1. Engrafting: Neutrophil recovery (ANC \>0.5 of \<12 days), Plt recovery (\>20K untransfused \<20 days)) after mel 200 based transplant.
2. Toxicities

Arms:
arm 1: VELCADE at 1.3 mg/m2 IVP on days 1, 4, 8 and 11 in combination with high-dose cyclophosphamide at 2.0 g/m2 on day 4. G-CSF is given for ten (+/- two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day. Pheresis will commence once ANC of 1.5 is reached. arm 2: VELCADE at 1.3 mg/m2 IVP on days 1, 4, 8 and 11. G-CSF is given for ten (+/- two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day. Day 12 start pheresis collection arm 3: High-dose cyclophosphamide at 2.0 g/m2 on day 1. G-CSF is given for ten (+/- two) consecutive days starting on day 2 at a dose of 10 micrograms/kg/day. Pheresis will commence once ANC of 1.5 is reached. arm 4: G-CSF is given for ten (+/- two) consecutive days starting on day 1 at a dose of 10 micrograms/kg/day. Plerixafor is given on day 4, approximately 11 hours prior to stem cell collection attempt on Day 5. Both G-CSF and plerixafor are continued daily until collection is complete. Pheresis will commence for everyone on Day 5 regardless of ANC status. arm 5: Bortezomib at 1.3 mg/m2 IVP on days 1, 4, 8 and 11. G-CSF is given for ten (+/- wo) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day.

Plerixafor is given on day 12, approximately 11 hours prior to stem cell collection attempt and is continued daily until collection is complete. Pheresis will commence for everyone on Day 13 regardless of ANC status.

Interventions: intervention 1: bortezomib (Velcade) intervention 2: cyclophosphamide intervention 3: G-CSF intervention 4: Plerixafor
Intervention descriptions: intervention 1: 1.3 mg/m2 IVP on days 1, 4, 8 and 11 intervention 2: 2.0 g/m2 (day 4 for Arm A and day 1 for Arm C) intervention 3: given for ten (+/- two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day (start on day 2 for Arm C and start on Day 1 for Arm D) intervention 4: plerixafor is given on day 4, approximately 11 hours prior to stem cell collection attempt on Day 5, plerixafor daily until stem cell collection is complete (Arm D), start on Day 12, approximately 11 hours prior to stem cell collection attempt and plerixafor daily until collection if complete (Arm E)

Protocol document:
Prot_SAP_000.pdf: 
 
Amendment #6.1, Version: October 26, 2015 
IRB Number: 1005011049 
 
 
  
 
 
TITLE: A Prospective Randomized Trial Comparing Three Different Peripheral Stem 
Cell Mobilization Regimens in Patients with Symptomatic Multiple Myeloma or 
Lymphoma 
Principal Investigator (Cornell): 
 
Ruben Niesvizky, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator (Emory): 
     Jonathan Kaufman, MD 
 
 
 
 
 
      
 
 
 
 
 
      
 
 
 
 
 
      
 
 
 
 
 
 
      
      
 
 
 
Principal Investigator (New York University Cancer Institute):  
 
 
 
 
 
Amitabha Mazumder, MD 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator (Memorial Sloan-Kettering Cancer Center): 
 
 
 
 
 
      Heather Landau, MD 
 
 
 
 
 
      
 
 
 
 
 
      
 
 
 
 
 
      
 
 
 
 
 
      
 
 
 


 
Principal Investigator (Columbia Presbyterian Medical Center): 
 
 
 
 
 
      Jordan Schecter, MD 
 
 
 
 
 
*VELCADE is the exclusive trademark of Millennium Pharmaceuticals, Inc., registered in the 
United States and internationally. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amendment History: 
Original Protocol Date: July 8, 2010 
Amendment #1:             December 20, 2010 
Amendment #2:             March 28, 2011 
Amendment #3 :            March 12, 2012 
Amendment #4 :            February 15, 2013 
Amendment #5 :            May 31, 2014 
Amendment #6 :            July 22, 2015 
Amendment #6.1 :         October 26, 2015 
 
 


 
Amendment #6.1, Version: October 26, 2015 
IRB Number: 1005011049 
 
 
 
TREATMENT SCHEMA 
 
 
 
ARM A 
ARM B* 
ARM C** 
*Effective January 16, 2013, Arm B is closed to further accrual.  
**Effective July 9, 2015, Arm C is closed to further accrual.  
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Bortezomib  
1.3 mg/m2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
2.0 g/m2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G-CSF 
10 mcg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Bortezomib 
1.3 mg/m2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G-CSF 
10 mcg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Cyclophosphamide 
2.0 g/m2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G-CSF 
10 mcg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOBILIZATION REGIMEN: Bortezomib, CYCLOPHOSPHAMIDE, G-CSF 
MOBILIZATION REGIMEN 2: Bortezomib & G-CSF 
MOBILIZATION REGIMEN 3: CYCLOPHOSPHAMIDE & G-CSF 
Start apheresis – Day 15 (or when wbc > 50K/μl, whichever occurs first) 


 
 
ARM D 
Start apheresis – Day 5; continue G-CSF and plerixafor daily until stem cell harvest is complete.  
ARM E 
Start apheresis – Day 13; continue G-CSF and plerixafor daily until stem cell harvest is 
complete.  
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Plerixafor  
0.24 mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G-CSF 
10 mcg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Bortezomib  
1.3 mg/m2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plerixafor          
0.24 mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G-CSF 
10 mcg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MOBILIZATION REGIMEN 4: Plerixafor & G-CSF 
MOBILIZATION REGIMEN 5: Bortezomib, Plerixafor, G-CSF 


i
TABLE OF CONTENTS 
Page 
SCHEMA ........................................................................................................................................ i 
 
1. OBJECTIVES ..........................................................................................................................1 
1.1 
Objectives ......................................................................................................................1 
1.2 
Study E ndpoints .............................................................................................................1 
 
2. BACKGROUND ......................................................................................................................2 
2.1 
Disease ...........................................................................................................................2 
2.2 
Prognosis of Myeloma ...................................................................................................2 
2.3 
Rationale ........................................................................................................................2 
2.4 
Working Hypothesis…………………………………………………………………..4 
2.5 
Preliminary Findings……………………………………………………………….....4 
2.6 
Conclusions…………………………………………………………………………...5 
 
3. INVESTIGATIONAL AGENTS……………………………………………………………6 
3.1 
Bortezomib ....................................................................................................................6 
3.2 
High-dose C yclophosphamide .....................................................................................10 
3.3 
G-CSF (NEUPOGEN)……………………………………………………………….10 
3.4 
Plerixafor .....................................................................................................................10 
 
4. PATIENT SELECTION .......................................................................................................11 
4.1 
Inclusion Criteria  ........................................................................................................11 
4.2 
Exclusion Criteria ........................................................................................................12 
 
5. REGISTRATION PROCEDURES ......................................................................................13 
5.1  
Central Patient Registration .........................................................................................13 
 
6. TREATMENT PLAN ............................................................................................................13 
6.1 
Study Design ...............................................................................................................13 
6.2 
Stopping Rules……………………………………………………………………….14 
6.3 
Risks…………………………………………………………………………………15 
6.4 
General Concomitant Medication and Supportive Care Guidelines ...........................15 
 
6.5       Duration of Therapy and Criteria for Removal from Study.........................................16 
6.6       Duration of Follow Up .................................................................................................17 
 
7. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................17 
 
8. ADVERSE EVENTREPORTING REQUIREMENTS ......................................................19 
8.1  
Study Agent / Method Risks ........................................................................................19 
8.2  
Adverse Event Characteristics .....................................................................................25 
8.3  
Adverse Event Recording ............................................................................................25 
8.4  
Adverse Event Reporting .............................................................................................25 
 


ii
 
 
9. PHARMACEUTICAL INFORMATION ............................................................................28 
9.1 
Clinical P harmacology .................................................................................................28 
9.2 
Bortezomib Supply and Dosage...................................................................................29 
9.3 
G-CSF 30 
9.4 
High-dose Cyclophosphamide .....................................................................................31 
9.5 
Plefixafor…. .…...........................................................................................................33 
10. STUDY EVALUATIONS ......................................................................................................33 
 10.1 
Schedule of Events .......................................................................................................35 
10.2 
Evaluation of Response ................................................................................................35 
10.3 
Post Study Follow Up ..................................................................................................36 
 
10.4 
Procedure for early removal from study ......................................................................36
 
11. MEASUREMENT OF EFFECT ..........................................................................................37 
11.1 
Disease Response ........................................................................................................37 
11.2 
Duration of Response ..................................................................................................37 
 
12. DATA REPORTING / REGULATORY CONSIDERATIONS ........................................37 
 
12.1  Data Collection………………………………………………………………………37 
 
12.2 
Regulatory Considerations ...........................................................................................38 
 
12.3 
Data Monitoring Committee ……………………………………………………..….38 
 
13. STATISTICAL CONSIDERATIONS .................................................................................38 
13.1 
Study Design / Endpoints.............................................................................................38 
13.2 
Sample Size / Accrual rate ...........................................................................................39 
13.3 
Analysis of Secondary Endpoints ................................................................................39 
13.4     Randomization…………………………………………….…………………………39 
 
14. PROTOCOL AMMENDMENTS AND DEVIATIONS .....................................................40 
 
15. REGULATORY CONSIDERATIONS ...............................................................................40 
15.1 
Institutional Review Board/Ethics Committee Approval ............................................40 
15.2 
Informed Consent P rocedures ......................................................................................41 
15.3 
Protecting Privacy and Confidentiality ........................................................................41 
15.4 
Study Records Requirements .......................................................................................41 
15.5 
Protection of Human Rights .........................................................................................42 
15.6 
Premature Discontinuation of Study ............................................................................42 
15.7 
Benefits of the Protocol ...............................................................................................42 
15.8 
Risks in Relation to Anticipated Benefit .....................................................................42 
15.9 
Alternative Treatments.................................................................................................42 
15.10 Incentives ....................................................................................................................43 
15.11 Costs          ....................................................................................................................43 
 
16. ADMINISTRATIVE REQUIREMENTS…………………………..……………………..43 
 
16.1    On-Site Audits ……………………………………………….………………...…….43  
 
16.2    Drug Accountability………………………………………………………………….43 


iii
 
 
REFERENCES .............................................................................................................................44 
APPENDICES 
APPENDIX A 
Performance Status Criteria ...............................................................................................47
APPENDIX B 
WCMC SAE Reporting Forms ..........................................................................................48 
 
APPENDIX C 
International Uniform Multiple Myeloma Response Criteria ............................................49 
      APPENDIX D 
            Body Surface Area and Creatinine Clearance Calculations……………………………..50 
      APPENDIX E 
            FACT/GOG-Neurotoxicity Questionnaire, Version 4.0…………………………………51 
     APPENDIX F 
            New York Heart Association Classification of Cardiac Disease……………………..….52 
 
     APPENDIX G 
International Myeloma Working Group Diagnostic Criteria………………………….....53 
 
     APPENDIX H 
            Common Terminology Criteria for Adverse Events…………………………….…….…55 
 


 
 
 
 
1. OBJECTIVES 
1.1. 
Study Objectives  
 
 
 
PRIMARY STUDY OBJECTIVES 
 To compare the efficacy of the following peripheral stem cell mobilization regimens 
for Multiple Myeloma (MM):  
A. High dose cyclophosphamide, Bortezomib, and G-CSF 
B. Bortezomib and G-CSF 
C. High dose cyclophosphamide and G-CSF  
D. Plerixafor and G-CSF 
E. Bortezomib, plerixafor, and G-CSF 
SECONDARY STUDY OBJECTIVES 
 To evaluate biomarkers as surrogate markers of mobilization in each arm. 
 To evaluate changes in tumor mass as defined by standard response parameters. 
 To evaluate the safety of each of the arms. 
 
EXPLORATORY OBJECTIVE 
 To attempt to establish the predictive value and correlation of Hematopoietic 
Progenitor Cells (HPC) and Absolute Neutrophil Count (ANC) in each arm. This 
objective is only applicable to Weill Cornell Medical College as sub-sites will not 
participate in the correlative studies. 
 
This is a phase III, randomized trial comparing three different peripheral stem cell mobilization 
regimens for patients with multiple myeloma who have received primary induction therapy. 
Effective January 16, 2013, Arm B is closed to further accrual due to futility.  Effective July 9, 
2015, Arm C is closed to further accrual due to futility.  
 
1.2 
Study Endpoints 
 
PRIMARY STUDY ENDPOINTS 
 
 Percentage of patients able to collect >6 x 106 CD34+ cells/kg in < 2 collections. 
SECONDARDY STUDY ENDPOINTS 
 Engrafting: Neutrophil recovery (ANC >0.5 in <20 days), Platelet recovery (>20K 
untransfused <20 days) after melphalan 200 based transplant.  
 Toxicities 


2
2.  BACKGROUND 
 
2.1  
Disease 
Multiple Myeloma (MM) is a neoplastic disorder of unknown etiology characterized by an 
abnormal accumulation and proliferation of monoclonal plasma cells producing excess quantities 
of a single immunoglobulin protein isotype (M-protein). It is estimated that 14,000 new cases of 
myeloma are diagnosed in the US each year1 accounting for approximately 1% of all cancers, 
and 10-15% of all hematological malignancies2. The disease is twice as common in blacks as 
whites3. MM usually occurs in older individuals with a median age of 69 years old. 
Lymphoma, neoplasm originating from lymphoid tissue, has many different subtypes 
corresponding to the complexity of the human immune system. Prognosis and growth rate vary 
widely, but all lymphomas are characterized by exquisite sensitivity to chemotherapy. High dose 
chemotherapy with stem cell support is standard of care for patients with recurrent lymphoma 
and, depending on the subtype and chemotherapy sensitivity, can result in cure or in prolonged 
remission. 
 
2.2 
Prognosis of myeloma 
 
The overall median survival for patients with MM is 36 months, with stage I, II, and III patients 
surviving a median of >60, 41, and 23 months respectively4.  Several prognostic factors have 
been identified.  An elevated serum level of beta-2 microglobulin (ß2M), a component of the 
class I HLA molecule, is a powerful prognostic indicator of shortened survival5.  ß2M is excreted 
by the kidney and renal insufficiency will increase serum levels of ß2M. The plasma cell labeling 
index (PCLI) identifies the percentage of proliferating plasma cells in S-phase of the cell cycle 
and is a powerful independent predictor of progression and survival6. An elevated serum lactate 
dehydrogenase (LDH) predicts an aggressive course with lymphoma-like features7. 
Translocations such as t(4,14) and t(14,16) confer poor prognosis8. Investigators have found that 
achieving a complete remission early in the disease may be important in predicting long-term 
survival9,10.  Indeed, Kyle et al suggested that an objective response to standard therapy is by far 
the most important feature of long-term survivors11. Major controlled trials have confirmed this 
seminal observation even in the context on high-dose chemotherapy12. Based on those 
observations, the goal of achieving an early CR should allow patients to sustain long-term 
survival and perhaps lead to a cure. 
 
2.3  
Rationale 
 
2.3.1 Treatment: Stem Cell Transplant and Mobilization 
 
Though more targeted and effective therapies have been evolving over the last 10 years, multiple 
myeloma (MM) remains incurable13,14. For newly diagnosed patients, treatment with high dose 
chemotherapy and stem cell transplantation (PBSCT) has extended median survival from 3 to 5-
7 years and has thus emerged as the standard of care. Most groups agree that for PBSCT 
candidates, those patients who are young enough and fit enough to endure the rigorous therapy, 
initial therapy is based on a two-phase treatment approach. Typically this consists of induction 


3
therapy and consolidation therapy with high-dose melphalan and subsequent PBSC rescue. When 
this two-phase model was pioneered, most transplant candidates received dexamethasone (Dex) 
based regimens. 15 However, PBSC harvests are not always successful and still are associated 
with significant morbidity16. Typical regimens for stem cell collection in MM include G-CSF 
alone or in combination with high dose cyclophosphamide. Though a “successful” harvest 
usually describes a CD34+ yield of 2-5 x 106 cells/kg, the newer evidence for the efficacy of 
double autologous transplant would necessitate CD34+ collections closer to 10 million cells. 
Thus there is both room and need to optimize the transplant process, specifically in terms of 
PBSC mobilization and collection. For transplant candidates, initial therapies must be tailored 
with the transplant end goal in mind, as it seems that they will affect the success and robustness 
of stem cell harvest and subsequent re-infusion.  Induction regimens, therefore, cannot include 
stem cell toxic drugs such as alkylators like nitrosureas and melphalan, which are known to 
hinder the success of PBSC harvests17. Most recently, the newest immunomodulatory drug, 
lenalidomide, has come under scrutiny as well. Lenalidomide treated patients suffer of poor 
mobilization and their collection is substantially reduced18. We and others have noted that the 
addition of cyclophosphamide to GCSF will overcome the inhibitory effect of lenalidomide. 19 
The routine use of cyclophosphamide however is often complicated by neutropenia and sepsis 
requiring hospitalizations, hence, delaying the transplant and causing significant increase in 
morbimortality and costs.  
 
Recently a new molecule, plerixafor (Mozobil™, Genzyme Corp.) a CXCR4 inhibitor has been 
FDA approved for use in combination with granulocyte-colony stimulating factor (G-CSF) to 
mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent 
autologous transplantation in patients with non-Hodgkin lymphoma (NHL) and MM who fail 
prior mobilization attempts or who are at high risk of failure.  
The efficacy and safety of plerixafor in combination with G-CSF in NHL and MM were 
evaluated in two placebo-controlled studies. Patients were randomized to receive either 
plerixafor 0.24 mg/kg or placebo each evening prior to apheresis. All patients received G-CSF 10 
micrograms/kg daily for four days prior to the first dose of plerixafor or placebo and prior to 
apheresis. Results from 302 patients with MM were analyzed. 
In the MM study, only 72 percent of patients who were mobilized with plerixafor and G-CSF 
collected ≥ 6 X 106 CD34+ cells/kg from the peripheral blood in two or fewer apheresis sessions 
compared with 34 percent of patients who were mobilized with placebo and G-CSF (p <0.001). ). 
Of note only about 54% of pts reached target CD34+ collection after 1 pheresis, 78% after 2 
pheresis sessions, 87% after 3 and 4 pheresis sessions, suggesting a plateau effect) 20. 
 
Safety data for plerixafor in combination with G-CSF were obtained from 983 patients enrolled 
in 16 clinical studies (593 patients enrolled in randomized Studies 1 and 2 plus 410 patients 
enrolled in 14 additional non-randomized studies). Patients were primarily treated with plerixafor 
at daily doses of 0.24 mg/kg SC. Median exposure to plerixafor was two days (range one to 
seven days). 
The most common adverse reactions (≥ 10 percent) reported in patients who received plerixafor 
in conjunction with G-CSF that were more frequent than in patients who received placebo were 
diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness and vomiting. 


4
Prescribing physicians and patients should be aware of the potential for tumor cell mobilization 
in leukemia patients, increased circulating leukocytes and decreased platelet counts, splenic 
enlargement, and fetal harm when administered to pregnant women. Plerixafor has a 
cumbersome dosing schedule:    GCSF is given for 4 days prior to the first dose of plerixafor 
then on each morning of apheresis. Plerixafor is administered in the evening starting on day 5. 
Plerixafor should be given approx.  11 hours prior to the initiation of apheresis for up to 4 
consecutive days. Dose modifications are required for renal impairment. Pts with a Cr CL < 50 
ml/min should have their plerixafor dose reduced by 1/3 to 0.16mg/kg not to exceed 27mg/day21.  
2.3.2 Treatment: Response and Outcomes  
A substantial body of data suggests that patients fare better if meaningful responses are achieved 
during therapy. Such evidence makes a case for the use of agents known to achieve an effective 
cell kill during stem cell mobilization and harvest, even if patients have just been subjected to a 
substantial amount of anti-myeloma therapy. Recent studies, such as the French IFM 94 and U.S 
TT1,2,3 trials suggest that a double rather than single autologous transplant correlates with 
longer progression free and overall survival. In consideration of some of these newer 
developments, the importance of a robust PBSC collection has become increasingly evident22.23  
 
2.4 
Working Hypothesis  
 
Given the known in vitro and in vivo synergy between alkylating agents and proteasome 
inhibitors, we sought to optimize the potential for concurrent cytoreduction by adding 
bortezomib to a standard cyclophosphamide mobilization regimen. This pilot study, included 22 
evaluable patients, whose prior therapy consisted of six cycles of chemotherapy were mobilized. 
Patients received IV push bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 in combination with 
high-dose cyclophosphamide at 3 g/m2 on day 8. G-CSF was given for 10 consecutive days 
starting on day 9.  
2.5 
Preliminary Findings (See Table Below)  
 
The number of CD34+ cells collected far exceeded the study goal of 10x106 cells/kg, a collection 
result typical of standard mobilizations using cyclophosphamide and/or G-CSF alone. Twenty-
two (100%) patients had more than adequate collections in a single day. Median CD34+ 
collection was 21x106 cells/kg in 1-5 collection days (range of 9.3-294.2 x 106). Mobilization 
with this regimen was not only robust but the mobilization window was highly predictable, 
eliminating the need for guess work in collection timing; furthermore, the amount of collection 
days was limited to only one day in the great majority of patients, thus suggesting that this 
regimen will allow efficient planning of pheresis sessions and will reduce the number of pheresis 
needed, ultimately reducing costs.  Noteworthy is that all patients who began mobilization with 
less than a CR continued to respond positively to treatment, including one transition from nCR to 
CR and one from SD to PR. No patients progressed or moved to lower response categories. This 
suggests that this is the only regimen which contributes to tumor mass reduction, thus, improving 
ultimately outcomes. So far 20 patients were able to high dose melphalan supported by 
autologous stem cell transplantation post protocol mobilization. All showed typical and adequate 


5
engraftment after CD34+ infusions. The median number of days to ANC recovery was 11 days 
(range 10-17). Platelet recovery median 18 days (range 13-24) 24.  
 
Patient 
Days 
Required 
for 
Collection 
Days to 
collection 
CD34+ Stem 
Cells 
(million/kg) 
Stem Cells 
Infused 
(x10^6/kg) 
Viability 
Day of 
neutrophil 
engraftment 
Day of 
platelet 
engraftment 
1 
1 
18 
21.2 
5.778 
85% 
14 
20 
2 
1 
18 
47.4 
13.22 
80% 
11 
13 
3 
1 
19 
22 
9.87 
60% 
13 
22 
4 
1 
18 
17.9 
9.03 
90% 
10 
15 
5 
4 
19 
40.6 
5.44 
97% 
11 
21 
6 
1 
18 
19.9 
9.24 
94% 
10 
16 
7 
3 
19 
294.157 
17.73 
91% 
10 
17 
8 
2 
17 
13.8 
6.32 
80% 
13 
24 
9 
5 
18 
9.25 
4.25,   2.74 
80%,   
94% 
11 
18 
10 
2 
17 
21.4 
9.05 
93% 
16 
21 
11 
1 
24 
50.033 
no 
transplant 
no 
transplant 
 
 
12 
2 
19 
66.149 
12.83 
85% 
11 
11 
13 
1 
18 
30.377 
7.38 
93% 
11 
11 
14 
2 
16 
43.637 
10.02 
92% 
12 
15 
15 
1 
19 
50.984 
12.72 
87% 
13 
11 
16 
1 
17 
15.584 
5.31 
93% 
11 
13 
17 
1 
17 
6.794 
6.66 
92% 
12 
13 
18 
1 
17 
31.668 
9.2 
95% 
11 
20 
19 
1 
17 
7.769 
7.397 
92% 
10 
11 
20 
1 
16 
43.89 
11.06 
98% 
10 
21 
21 
1 
18 
23.22 
no 
transplant 
no 
transplant 
 
 
22 
1 
17 
13.996 
3.47 
90% 
16 
16 
Early data from work in mouse models indicates that bortezomib may have a mobilization effect 
through effects on SDF-1 where as CXCR4 is the target for plerixafor.  Data in mouse models 
shows the combination of G-CSF + Bortezomib is significantly better than either agent alone in 
terms of increasing the white blood count (WBC), colony-forming unit – 
granulocyte/macrophage (CFU-GM), and colony-forming unit – erythroid (CFU-E). The 
combination appears to be additive26 . We can therefore conclude that the use of bortezomib for 
mobilization may offer a less cumbersome, safer and effective regimen.  
 
2.6 
Conclusions  
 
Bortezomib in addition to high-dose cyclophosphamide (Cytoxan) followed by G-CSF is a 
novel, well-tolerated and efficacious combination for stem cell mobilization in patients with 
multiple myeloma (MM). This regimen not only yields a high number of stem cells within a 
short collection time, but also provides the potential for further cytoreduction. Of particular 


6
importance is that this regimen overcomes any inhibitory effect of lenalidomide, which is the 
most common induction regimen in MM. Our objectives, therefore, are to critically test this new 
mobilization regimen against standard of care (Cyclophosphamide and G-CSF) and a control 
group of Bortezomib and G-CSF in a prospective, randomized fashion. This trial is of particular 
interest given the following issues:  
 
1) Consistency in number of collections required and predictability of the timing in stem 
cell collection when bortezomib is used.  
2) Potential benefit on engraftment and co-morbidities when a higher than average number 
of stem cell are infused  
3) Advantage of mega-mobilization in order to adequately cryopreserve for future use (in 
the relapse setting)  
4) Potential benefit in lenalidomide treated patients and high risk patients  
5) New biological insights in stem cell biology  
6) If this trial shows that bortezomib/GCSF is as good as cyclophosphamide/GCSF could 
potentially eliminate chemotherapy as mobilizing agent.  (Less toxicity in terms of 
myelosupression, renal/kidneys etc.)  
7) Not all patients with MM successfully collect with plerixafor and G-CSF alone.  This 
trial may show that adding bortezomib to plerixafor and G-CSF increases the chances of 
a successful collection.  
 
Bortezomib, a recently approved 26S proteasome inhibitor, appears to be effective even in 
patients with poor prognostic features for transplant such as del 13q14 and has been shown to be 
non-stem cell toxic. Our objective is to achieve maximum response before transplant as well as a 
successful mobilization and harvest of PBSCs, which we defined as at least 10 x 106 CD34+ 
cells/kg in under 2 leukapheresis procedures. 
 
Bortezomib also has activity in lymphoma and its use in stem cell mobilization may also be 
useful in this disorder. 
 
Use of Peripheral Blood CD34 counts as a measure of stem cell mobilization and collection. 
The yield of a stem cell collection is determined by the peripheral blood CD34, the volume of 
collection and   to a lesser degree by a  number of other factors such as the instrument utilized for 
collection, the hematocrit, WBC and even serum albumin (see for example Hosing 2013, Ford 
1998, Hollingsworth 1999). The peripheral blood CD34 on the first day of collection is the best 
measure of “mobilizing” efficiency and is widely utilized (Hosing 2013) and will be the primary 
outcome measure for this study. 
 
3. INVESTIGATIONAL AGENTS 
 
3.1      VELCADE® (bortezomib) for Injection 
3.1.1 Scientific Background 
VELCADE® (bortezomib) for Injection is a small molecule proteasome inhibitor developed by 
Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies.  


7
Bortezomib is currently approved by the United States Food and Drug Administration (US FDA) 
and it is registered in Europe for the treatment of multiple myeloma patients who have received 
at least one prior therapy. 
  
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 
B (NF-B) 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). 
3.1.2     Nonclinical Pharmacology 
Pharmacokinetic (PK) and pharmacodynamic studies were conducted in the rat and cynomolgus 
monkey.  Upon intravenous (IV) bolus administration, bortezomib displays a rapid distribution 
phase (t½ <10 minutes) followed by a longer elimination phase (t½ 5–15 hours).  Bortezomib 
has a large volume of distribution (range 5–50 L/kg).  The plasma PK profile is well described 
by a 2-compartment model. 
The pharmacodynamic action of bortezomib is well established and can be measured through an 
ex vivo assay (20S proteasome activity) (Lightcap et al., 2000).  This assay was used to 
determine the duration of drug effect in lieu of the PK data in the early preclinical toxicology 
studies as well as to set a guide for dose escalation in humans.  Following dosing with 
bortezomib in the rat and cynomolgus monkey, proteasome inhibition in peripheral blood had a 
half-life less than 24 hours, with proteasome activity returning to pretreatment baseline within 24 
hours in monkey and within 48 to 72 hours in rat after a single dose of bortezomib.  Further, 
intermittent but high inhibition (>70%) of proteasome activity was better tolerated than sustained 
inhibition.  Thus, a twice-weekly clinical dosing regimen was chosen in order to allow return of 
proteasome activity towards baseline between dose administrations. 
3.1.3 Nonclinical Toxicity 
Single-dose IV toxicity studies were conducted with bortezomib in the mouse, rat, dog, and 
monkey to establish the single-dose maximum tolerated dose (MTD).  The MTDs were 0.25 


8
mg/kg (1.5 mg/m2) and 0.067 mg/kg (0.8 mg/m2) in the 2 most sensitive species, rat and 
monkey, respectively. 
 
Repeat-dose multi-cycle toxicity studies of 3 and 6 months in the rat and 9 months in the 
monkey, each with 8-week recovery periods, were conducted to characterize the chronic toxicity 
of bortezomib when administered by the clinical route and regimen of administration.  The MTD 
in the 6-month rat study was 0.10 mg/kg (0.6 mg/m2) and the key target organs were the 
gastrointestinal (GI) tract, hematopoietic and lymphoid systems.  The MTD in the 9-month 
monkey study was 0.05 mg/kg (0.6 mg/m2) and the key target organs were the GI tract, 
hematopoietic and lymphoid systems, peripheral nervous system, and kidney.  Full or partial 
reversibility was observed for each of the toxicities described to date.   
 
In general, the nature of the toxicity of bortezomib is similar across species, and target organs of 
toxicity in animals have been largely predictive of human toxicity.  The toxicity of bortezomib in 
animals is characterized by a steep dose-response with mortality seen at dosages above the MTD.  
The cause of death at acutely lethal dosages is considered to be related to indirect cardiovascular 
(CV) effects of hypotension and vascular changes with secondary bradycardia and the cause of 
death in long-term studies has been attributed to GI or hematologic toxicity.  The pharmacologic 
effects of bortezomib on the CV system have been extensively characterized and have 
demonstrated that indirect effects on CV function occur only at acutely lethal dosages and are 
abrogated by routine supportive care. 
 
Additional detailed information regarding the nonclinical pharmacology and toxicology of 
bortezomib may be found in the Investigator’s Brochure. 
 
3.1.4 Clinical Experience  
It is estimated that more than 100,000 patients have been treated with bortezomib, including 
patients treated through Millennium-sponsored clinical trials, Investigator-Initiated Studies, the 
US NCI Cancer Therapy Evaluation Program (CTEP), and with commercially available drug.  
Bortezomib has been commercially available since 13 May 2003. 
 
The overall goal of the Millennium phase 1 program was to determine the MTD and dose-
limiting toxicity (DLT) of bortezomib in a number of therapeutic settings involving subjects with 
various advanced malignancies.  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 bortezomib monotherapy (4 doses, given on Days 1, 4, 8, and 11 of a 21-day 
treatment cycle), the DLT occurred at 1.56 mg/m2/dose (3 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 bortezomib monotherapy, the MTD was 1.6 
mg/m2/dose and DLT included hypotension, tachycardia, diarrhea, and syncope.   
In phase 1 clinical studies, anti-tumor activity was reported in 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. 


9
The safety and efficacy of bortezomib in subjects with multiple myeloma were investigated in 
two phase 2 clinical studies, studies M34100-024 (subjects with first relapse) (Jagannath et al, 
2004) and M34100-025 (subjects with second or greater relapse and refractory to their last prior 
therapy) (Richardson et al, 2003).  In M34100-025, 202 heavily pre-treated subjects with 
refractory multiple myeloma after at least 2 previous treatments received bortezomib, 1.3 mg/m2 
on Days 1, 4, 8, and 11 of a 21-day treatment cycle. The European Group for Blood and Marrow 
Transplant (EBMT) response criteria, as described by Blade, (Blade et al., 1998) were utilized to 
determine disease response.  CRs were observed in 4% of subjects, with an additional 6% of 
patients meeting all criteria for CR but having a positive immunofixation test.  PR or better was 
observed in 27% of subjects, and the overall response rate (CR, PR and minor response [MR] 
combined) was 35%.  Seventy percent of subjects experienced stable disease or better.   
 
The phase 3 study (M34101-039) (Richardson et al, 2005), also referred to as the APEX study, 
was designed to determine whether bortezomib provided benefit (time to progression [TTP], 
response rate, and survival) to patients with relapsed or refractory MM relative to treatment with 
high-dose dexamethasone.  The study was also designed to determine the safety and tolerability 
of bortezomib relative to high-dose dexamethasone, and whether treatment with bortezomib was 
associated with superior clinical benefit and quality of life relative to high-dose dexamethasone. 
A total of 669 patients were enrolled and 663 patients received study drug (bortezomib: 331; 
dexamethasone: 332).  Patients randomized to bortezomib received 1.3 mg/m2 I.V. push twice 
weekly on days 1, 4, 8, and 11 of a 3-week cycle for up to eight treatment cycles as induction 
therapy, followed by 1.3 mg/m2 bortezomib weekly on days 1, 8, 15, and 22 of a 5-week cycle 
for three cycles as maintenance therapy. Patients randomized to dexamethasone received oral 
dexamethasone 40 mg once daily on days 1 to 4, 9 to 12, and 17 to 20 of a 5-week cycle for up to 
four treatment cycles as induction therapy, followed by dexamethasone 40 mg once daily on 
days 1 to 4 followed of a 4-week cycle for five cycles as maintenance therapy. The European 
Group for Blood and Marrow Transplant (EBMT) response criteria, as described by Blade 
(Blade et al., 1998) were utilized to determine disease response.  There was a 78% increase in 
TTP for the bortezomib arm. Median TTP was 6.2 months for the bortezomib arm and 3.5 
months for the dexamethasone arm (P<.0001). CR (complete response) + PR (partial response) 
was 38% with bortezomib vs. 18% with dexamethasone (P.0001). CR was 6% with bortezomib 
vs. 1% with dexamethasone (P<.0001). The CR + nCR rate was13% with bortezomib vs. 2% 
with dexamethasone. In patients who had received only one prior line of treatment (bortezomib: 
132; dexamethasone: 119), CR + PR was 45% with bortezomib vs. 26% with dexamethasone 
(P=.0035). With a median 8.3 months of follow-up, overall survival was significantly longer 
(P=.0013) for patients on the bortezomib arm vs. patients on the dexamethasone arm. The 
probability of survival at one year was 80% for the bortezomib arm vs. 66% for the 
dexamethasone arm, which represented a 41% decreased relative risk of death in the first year 
with bortezomib (P=.0005). In patients who had received only one prior line of treatment, the 
probability of survival at one year was 89% for the bortezomib arm vs. 72% for the 
dexamethasone arm, which represented a 61% decreased relative risk of death in the first year 
with bortezomib (P=.0098). Updated response rates and survival data were reported for M34101-
039 (Richardson ASH, 2005). The updated CR (complete response) + PR (partial response) rate 
was 43% with bortezomib. The CR + nCR rate was 16% with bortezomib. With a median 22 
months of follow-up, overall survival was significantly longer for patients on the bortezomib arm 


10
vs. patients on the dexamethasone arm. The median overall survival was 29.8 months (95% CI: 
23.2, not estimable) for the bortezomib arm vs. 23.7 months (95% CI: 18.7, 29.1) for the 
dexamethasone arm (hazard ratio = 0.77, P= 0.0272). The probability of survival at one year was 
80% for the bortezomib arm vs. 67% for the dexamethasone arm (P=0.0002).    
 
Studies using bortezomib as monotherapy and in combination with other chemotherapy agents 
are continuing.   
 
3.2 
High-dose Cyclophosphamide (CYTOXAN) 
3.2.1 Scientific Background 
  
Cyclophosphamide is an alkylating agent that prevents cell division primarily by cross-linking 
DNA strands. The cell continues to synthesize other cell constituents (RNA and protein), an 
imbalance occurs and the cell dies. Cyclophosphamide is considered cell cycle phase non-
specific. Cyclophosphamide is bio-transformed principally in the liver to active alkylating 
metabolites that cross-link to tumor-cell DNA. 
 
3.3         G-CSF (NEUPOGEN) 
 
3.3.1  Scientific Background  
 
NEUPOGEN is the trademark name for G-CSF also known as Filgrastim, a human granulocyte 
colony-stimulating factor. It is a 175 amino acid protein manufactured by recombinant DNA 
technology. NEUPOGEN is produced by Escherichia coli (E. coli) bacteria into which has been 
inserted the human granulocyte colony-stimulating factor gene.  
 
Colony stimulating factors are glycoproteins which act on hematopoietic cells by binding to 
specific cell surface receptors and stimulating proliferation, differentiation commitment, and 
some end-cell functional activation. NEUPOGEN regulates the production of neutrophils from 
the bone marrow. NEUPOGEN® is indicated for the mobilization of hematopoietic progenitor 
cells into the peripheral blood for collection by leukapheresis. Mobilization allows for the 
collection of increased numbers of progenitor cells capable of engraftment compared with 
collection by leukapheresis without mobilization or bone marrow harvest. After myeloablative 
chemotherapy‚ the transplantation of an increased number of progenitor cells can lead to more 
rapid engraftment‚ which may result in a decreased need for supportive care. 
NEUPOGEN® is a sterile‚ clear‚ colorless‚ preservative-free liquid for parenteral administration 
containing Filgrastim at a specific activity of 1.0 ± 0.6 x 108 U/mg (as measured by a cell 
mitogenesis assay).  The product is available in single use vials and prefilled syringes. 25 
 
3.4         Plerixafor 
 
Plerixafor (Mozobil), a hematopoietic stem cel1 mobilizer, is indicated in combination with 
grulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the 
peripheral blood for collection and subsequent autologous transplantation in patients with non-
Hodgkin's lymphoma and multiple myeloma.  Plerixafor acts by inhibiting the interaction 


11
between SDF-1 (stem cell derived factor 1) and CXCR4 (chemokine receptor type 4) which 
abrogates the main force binding CD34 cells to the bone marrow stroma.  Plerixafor has been 
shown to enhance stem cell harvest yield when used in combination with G-CSF as opposed to 
G-CSF alone in patients with non-Hodgkin lymphoma and multiple myeloma.11 
4.  PATIENT SELECTION 
4.1 
Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to be eligible to participate in this 
study: 
 Subject has voluntarily agreed to participate by giving written informed consent 
before performance of any study-related procedure not part of normal medical care, 
with the understanding that consent may be withdrawn by the subject at any time 
without prejudice to future medical care. Informed Consent must be obtained prior to 
mobilization. 
 Subject has a confirmed diagnosis of multiple myeloma as specified by the 
International Myeloma Working Group criteria, detailed in Appendix G or subject has 
a diagnosis of lymphoma and is in need of stem cell transplant. 
 Subject is    18 years of age at the time of signing the informed consent form. 
 Subject has a Karnofsky performance status above 60%. 
 Subjects must have measurable monoclonal protein, free light chains, and/or M-spike 
in blood or urine and/or measurable disease by imaging techniques such as MRI and 
PET scan. 
 Female subject is either post-menopausal for at least 1 year before screening visit, is 
surgically sterilized or if they are of childbearing potential, agree to practice 2 
effective methods of contraception from the time of signing the informed consent 
form through 30 days after the last dose of bortezomib, or agree to completely abstain 
from heterosexual intercourse.  
 Male subject, even if surgically sterilized (i.e., status post vasectomy) must agree to 1 
of the following:  practice effective barrier contraception during the entire study 
treatment period and through a minimum of 30 days after the last dose of study drug, 
or completely abstain from heterosexual intercourse. 
 Subject has a life expectancy of > 12 weeks.  
 Subject must meet the following laboratory parameters within 14 days before 
enrollment: 
o 
Absolute neutrophil count (ANC) ≥1500 cells/mm3 (≥1000 for patients with 
bone marrow biopsy displaying >50% involvement by myeloma). In study 
centers that have the equipment capability, ANC > 1.0 will not be the 
benchmark to start stem cell collection. A minimum requirement of ≥ 20 x 106 
CD34+ cells/ml will be required to start stem cell collection. 
o 
Platelets count ≥ 50,000/mm3 (≥ 30,000 for patients with bone marrow 
biopsy displaying >50% involvement by myeloma)  


12
o 
Hemoglobin > 9.0 g/dL 
o 
Serum SGOT/AST <3.0 x upper limits of normal (ULN) 
o 
Serum SGPT/ALT <3.0 x upper limits of normal (ULN) 
o 
Serum creatinine < 2.5 mg/dL or creatinine clearance > 40ml/min  
o 
Serum total bilirubin  < 1.5 x ULN  
 Subject must have a MUGA scan or echo with LVEF >50% within 6 months of 
enrollment.  
4.2     Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not eligible to participate in this 
study. 
 Subject has a history of allergic reactions to compounds containing boron, mannitol, 
or VELCADE 
 Subject has a prior history of other malignancies (except for basal cell or squamous 
cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless disease 
free for  5 years. 
 Subject has a NYHA Class III or IV heart disease and/or a history of active unstable 
angina, congestive heart disease, severe uncontrolled cardiac arrhythmia, 
electrocardiographic evidence of acute ischemia, active conduction system 
abnormalities or myocardial infarction within 6 months prior to enrollment. Prior to 
study entry, any ECG abnormality at Screening has to be documented by the 
investigator as not medically relevant. 
 Female subjects who are pregnant or breastfeeding. Women of childbearing potential 
and men must agree to use adequate contraception prior to study entry and for the 
duration of study participation.  Confirmation that the subject is not pregnant must be 
established by a negative serum -human chorionic gonadotropin (-hCG) pregnancy 
test result obtained during screening.  Pregnancy testing is not required for post-
menopausal or surgically sterilized women. 
 Subject has a known HIV or hepatitis A, B, or C positivity---ONLY IF ACTIVE 
 Subject has active viral or bacterial infections or any coexisting medical problem that 
would significantly increase the risks of this treatment program. 
 Subject has concurrent, uncontrolled medical condition, laboratory abnormality, or 
psychiatric illness which could place him/her at unacceptable risk, including, but not 
limited to, uncontrolled hypertension, uncontrolled diabetes, active uncontrolled 
infection, and/or acute chronic liver disease (i.e., hepatitis, cirrhosis). 
 Subject has Grade 2 peripheral neuropathy. 
 Subject has participated in clinical trials with other investigational agents not 
included in this trial, within 14 days of the start of this trial and throughout the 
duration of participation in this trial. 
 Subject has been diagnosed or treated for another malignancy within 3 years of 
enrollment, with the exception of complete resection of basal cell carcinoma or 
squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate 
cancer after curative therapy. 


13
 Subject has received radiation therapy within 3 weeks before randomization. 
Enrollment of subjects who require concurrent radiotherapy (which must be localized 
in its field size) should be deferred until the radiotherapy is completed and 3 weeks 
have elapsed since the last date of therapy. 
 Subject has had prior mobilization or stem cell transplant. 
 
5. REGISTRATION PROCEDURES 
 
5.1     Central Patient Registration 
 
Patients will be centrally randomized and registered with the Weill Cornell Medical 
College (WCMC), Division of Hematology and Medical Oncology, Joint Clinical Trials 
Office.  To register a patient, email the following documents to Christina Persaud at 
cpp2005@med.cornell.edu. You may also fax the documents to the Clinical Trials Office 
at 646-962-1610: 
 WCMC Patient Enrollment Form 
 First and last page of the fully executed informed consent form, plus additional pages 
if checkboxes are required. 
 Fully executed HIPAA research authorization form 
 Eligibility checklist signed and dated by investigator and research nurse 
 Documentation of any eligibility waivers requested  
 For inpatients, signed consent documentation template 
 
Central registration information is reviewed and entered into the HemOnc centralized research 
database.  For patients enrolled at Weill Cornell Medical College, documentation of patient 
registration will be faxed to the Investigational Pharmacy to allow for release of study agent. All 
participating sub-sites will notify their pharmacy for release of study drug as per institutional 
guidelines.  
 
6. TREATMENT PLAN 
 
6.1      Study Design  
 
This phase III, randomized trial compares three different peripheral stem cell mobilization 
regimens for patients with multiple myeloma who have received primary induction therapy rev 
or other therapies. Up to 198 patients will be enrolled. Effective January 16, 2013, Arm B is 
closed to further enrollment due to futility. Effective July 9, 2015, Arm C is closed to further 
enrollment due to futility. Patients eligible for treatment will be randomized to one of the 
following mobilization regimens:  
 
A. Arm A: 
 
Bortezomib at 1.3 mg/m2 IVP on days 1, 4, 8 and 11 in combination with high-dose 
cyclophosphamide at 2.0 g/m2 on day 8. G-CSF is given for ten (+/- two) consecutive 
days starting on day 9 at a dose of 10 micrograms/kg/day. Pheresis will commence 
once absolute neutrophil count (ANC) of 1.0 is reached*. 


14
B. Arm B: This Arm is closed to further accrual. 
 
Bortezomib at 1.3 mg/m2 IVP on days 1, 4, 8 and 11. G-CSF is started on day 9 at a 
dose of 10 micrograms/kg/day. Pheresis collection is started on Day 15 or whenever 
the total white blood cell count is > 50,000 / μl, whichever occurs first*. G-CSF is 
continued until pheresis goal has been met.  
 
C. Arm C: This Arm is closed to further accrual. 
High-dose cyclophosphamide at 2.0 g/m2 on day 1. G-CSF is given for ten (+/- two) 
consecutive days starting on day 2 at a dose of 10 micrograms/kg/day. Pheresis will 
commence once ANC of 1.0 is reached*. 
 
      D.   Arm D:  
G-CSF is given for ten (+/- two) consecutive days starting on day 1 at a dose of 
10 micrograms/kg/day. Plerixafor is given on day 4, approximately 11 hours prior 
to stem cell collection attempt on Day 5.  Both G-CSF and plerixafor are 
continued daily until collection is complete. Pheresis will commence for everyone 
on Day 5 regardless of ANC status. 
 
D. Arm E: 
 
Bortezomib at 1.3 mg/m2 IVP on days 1, 4, 8 and 11. G-CSF is given for ten (+/- 
two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day. 
Plerixafor is given on day 12, approximately 11 hours prior to stem cell collection 
attempt and is continued daily until collection is complete. Pheresis will 
commence for everyone on Day 13 regardless of ANC status.  
 
The decision to collect is at the discretion of the primary physician/ Principal Investigator.  
 
* In study centers that have the equipment capability, ANC > 1.0 will not be the benchmark to 
start collection. Instead, peripheral blood CD34+ cells/ ml will be determined by flow cytometry 
on a subject’s blood sample on each morning of proposed collection and will be the primary 
determinant of whether stem cell collection is attempted for the day.  A minimum requirement of 
≥ 20 x 106 CD34+ cells/ml will be required to start stem cell collection.  If the subject fails to 
reach this benchmark, stem cell collection for the day will be aborted for futility and the patient 
will return the next day for reevaluation.  If the subject fails to achieve an adequate peripheral 
blood CD34+ cell count after 14 days of G-CSF on Arms A and C, or 10 days of G-CSF on Arm 
B, D and E, the collection attempt will be deemed a failure and the patient will be taken off 
study. HPC analysis will not be used to determine eligibility to start stem cell collection. In study 
centers without ready access to flow cytometry analysis of CD34+ cell content of peripheral 
blood, ANC will be the sole marker to start stem cell collection. 
 
6.2 Stopping Rules 
 
Stopping rules will be implemented once 10 patients are accrued in each arm and the rule will 
not allow more than 4 failures in the 10 accrued patients per arm.  Failure is defined as:  If > 40% 


15
of patients fail to collect the target CD34+ cells in two or less collections in any arm, then the 
arm will be terminated. 
Due to futility, Arm B is closed to further accrual effective January 16, 2013. Arm C is closed to 
further accrual effective July 9, 2015. For arms A and C, three out of four subjects randomized to 
mobilize sufficiently. Accrual will continue on Arms A and D and E as planned. 
 
After 10 patients are evaluated in each arm we are going to attempt to establish the predictive 
value and correlation of HPC and ANC in each arm.  We will later use that data to better define 
the optimal time for commencing leukapheresis. 
 
6.3  Risks of Insufficient Stem Cell Collection 
 
The risk of insufficient stem cell collection is a risk associated with any mobilization program.  
Usually a patient who fails to mobilize with one strategy will succeed at a second attempt by 
adding a medication called Mozobil (plerixafor). Failure to mobilize stem cells successfully will 
preclude the performance of an autologous stem cell transplant.  In this protocol, patients who 
fail any of the three mobilization arms will be offered standard of care mobilization plerixafor.  
 
6.4 Concomitant Treatment 
 
6.4.1 Required Concurrent Therapy 
 
Investigators should consider using antiviral prophylaxis in subjects being treated with 
bortezomib. 
 
Mesna may be given at the discretion of the study doctor as per institutional guidelines.  
 
The following medications/supportive therapies are required during study participation, as 
applicable: 
 Antiviral agent 
 
6.4.2 Prohibited Concurrent Therapy 
 Participation in clinical trials with other investigational agents, not included in this trial, 
within 14 days of the start of this trial and throughout the duration of this trial. 
Treatment Compliance 
 
All drug will be administered to eligible patients under the supervision of the investigator or 
identified sub-investigator(s).  The pharmacist will maintain records of drug receipt (if 
applicable), drug preparation, and dispensing, including the applicable lot numbers, patients’ 
height, body weight, and body surface area (see Appendix D), and total drug administered in 
milliliters and milligrams.  Any discrepancy between the calculated dose and dose administered 
and the reason for the discrepancy must be recorded in the source documents. 


16
Precautions and Restrictions 
It is not known what effects bortezomib has on human pregnancy or development of the embryo 
or fetus.  Therefore, female patients participating in this study should avoid becoming pregnant, 
and male patients should avoid impregnating a female partner.  Nonsterilized female patients of 
reproductive age and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below. 
Female patients must meet 1 of the following: 
 Postmenopausal for at least 1 year before the screening visit, or 
 Surgically sterile, or 
 If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing the informed consent form through 30 days after 
the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse. 
It is strongly recommended that at least 1 of these 2 methods be highly effective (see examples 
below). 
Highly effective methods 
Other effective methods (barrier methods) 
Intra-uterine devices (IUD) 
Latex condom 
Hormonal contraceptives (birth control 
pills/oral contraceptives, injectable 
contraceptives, contraceptive patches, or 
contraceptive implants) 
Diaphragm with spermicide 
Cervical cap 
Sponge 
If one of the highly effective methods cannot be used, using 2 effective methods at the 
same time is recommended.  
Male patients, even if surgically sterilized (i.e., status post vasectomy) must agree to 1 of the 
following: 
 Practice effective barrier contraception during the entire study treatment period and 
through a minimum of 30 days after the last dose of study drug, or completely abstain 
from heterosexual intercourse. 
6.5 Duration of Therapy and Criteria for Removal from Study 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The investigator also has the right to withdraw, 
and in some cases is required to withdraw, patients from the study for any of the following 
reasons: 
 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Occurrence of unacceptable adverse event(s), 
 
Suspected or confirmed pregnancy, 


17
 The patient achieves a stable plateau and is eligible to proceed to high dose 
chemotherapy and stem cell transplantation, 
 The development of any co-morbid condition or excessive toxicity that would make 
further participation in the protocol unsafe, 
 
Protocol violations, 
 
Non-compliance, 
 
Administrative reasons, 
 
Failure to return for follow-up, 
 
Patient decides to withdraw from the study, or 
 General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
At the time of study withdrawal or completion of the study, all study procedures outlined for the 
End of Treatment visit must be completed.  The primary reason for a patient’s withdrawal from 
the study is to be recorded in the source documents. 
 
The duration of the study includes a 21-day treatment schedule, an end of study visit, and a 
specified period time for survival follow up.    
 
6.6   Duration of Follow Up 
 
Patients who do not withdraw consent will be followed for survival after removal from study or 
until death, whichever occurs first.  Patients removed from study for unacceptable adverse events 
will be followed for life, unless they withdraw consent. 
 
7. DOSING DELAYS/DOSE MODIFICATIONS 
 
Patients will be evaluated for toxicity throughout treatment.  Doses of study medications will be 
held for neuropathy toxicity Grade  2 with pain.  
 
Dose escalation will not be allowed in any patient, and there must be at least 72 hours between 
each dose of bortezomib.   
 
Before each drug dose, the patient will be evaluated for possible toxicities that may have 
occurred after the previous dose(s).  Toxicities are to be assessed according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0.  
 
All previously established or new toxicities observed any time, with the exception of neuropathic 
pain and peripheral sensory neuropathy, are to be managed as follows: 
 If the patient experiences febrile neutropenia, a Grade 4 hematologic toxicity (including a 
platelet count <25  109/L) or any Grade 3 non-hematologic toxicity considered by the 
investigator to be related to bortezomib, then drug is to be held. 
 For hematologic toxicities, bortezomib is to be held for up to 2 weeks until the patient has 
a hemoglobin value of > 9.0 g/dL , platelet value of ≥ 50,000/mm3 (≥ 30,000 for patients 
with bone marrow biopsy displaying >50% involvement by myeloma), and neutrophil 


18
value of ≥1500 cells/mm3 (≥1000 for patients with bone marrow biopsy displaying >50% 
involvement by myeloma) 
 For non-hematologic toxicities, bortezomib is to be held for up to 2 weeks until the 
toxicity returns to Grade 1 or better. 
 
No dose modifications or reductions will be made. Subjects are anticipated to receive four doses 
in each respective arm. If the four doses are interrupted at any point, no further attempts to re-
dose will be made.  
 
Patients who experience bortezomib-related neuropathic pain and/or peripheral sensory 
neuropathy are to be managed as presented in Table 7.1 Management of Patients with 
bortezomib Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy. Once the 
dose is reduced for peripheral neuropathy, the dose may not be re-escalated. 
Table 7-1   Management of Patients with VELCADE Related Neuropathic Pain and/or Peripheral Sensory or Motor 
Neuropathy 
Recommended Dose Modification for bortezomib related Neuropathic Pain and/or Peripheral Sensory or Motor 
Neuropathy  
Severity of Peripheral Motor Neuropathy  
Signs and Symptoms  
Modification of Dose and Regimen  
Grade 1: Asymptomatic; clinical or diagnostic observations 
only; intervention not indicated  
No action  
Grade 1 with pain or Grade 2: Moderate Symptoms; limiting 
instrumental activities of daily life (ADL)  
Reduce bortezomib to 1.0 mg/m2 
Grade 2 with pain or Grade 3: Severe Symptoms; limiting 
self-care ADL; assistive device indicated 
Withhold* VELCADE therapy until  
toxicity resolves. When toxicity resolves reinitiate with  
a reduced dose of VELCADE at 0.7mg.m2 and change  
treatment schedule to once per week.*  
Grade 4 : Life-threatening consequences; urgent intervention 
indicated  
Discontinue bortezomib 
Severity of Peripheral Sensory Neuropathy 
Signs and Symptoms 
Modification of Dose and Regimen 
Grade 1: Asymptomatic; loss of deep tendon reflexes or 
paresthesia 
No action 
Grade 1 with pain or Grade 2: Moderate symptoms; limiting 
instrumental ADL 
Reduce bortezomib to 1.0 mg/m2 
Grade 2 with pain or Grade 3: Severe symptoms; limiting 
self-care ADL 
Withhold* bortezomib therapy until toxicity resolves. When 
toxicity resolves, reinitiate with a reduced dose of bortezomib 
at 0.7 mg/m2 and change treatment schedule to once per week*
Grade 4: Life-threatening consequences; urgent intervention 
indicated 
Discontinue bortezomib 
Grading based on NCI Common Terminology Criteria CTCAE v4.0   
NCI Common Terminology Criteria website - http://ctep.info.nih.gov/reporting/ctc.html 
ADL = activities of daily living 
*Key: 
Reduce by one dose level: 
bortezomib dose reduction from 1.3 to 1.0, or 1.0 to 0.7 mg/m2/dose.  
Reduce by two dose levels: 
bortezomib dose reduction from 1.3 or 1.0 to 0.7 mg/m2/dose. 
Hold:   
 
 
Interrupt bortezomib for up to 2 weeks until the toxicity returns to Grade 1 or better. 
Schedule change: Schedule change from bortezomib twice per week (Days 1, 4, 8 and 11 on a Q3W cycle)       to once 


19
per week (Days 1, 8, 15, and 22 on a Q5W cycle).  If the treatment schedule is already once weekly, then it should 
remain once weekly. 
Patients with mild hepatic impairment (bilirubin < 1.5  ULN) do not require a starting dose 
adjustment.  Please note that patients with bilirubin levels ≥ 1.5  ULN are excluded from 
enrollment in this protocol.  If a patient develops moderate or severe hepatic impairment with 
bilirubin ≥ Grade 2 (> 1.5 -3.0 X ULN) while on study, the investigator should hold bortezomib 
until the toxicity returns to < Grade 2. Restarting bortezomib at the next lower dose level could 
be considered at the Investigator’s discretion and following exclusion of bortezomib-induced 
liver impairment and careful consideration of liver disease due to other causes, such as, but not 
limited to, active infection and multiple myeloma-related liver disease. 
 
The neurotoxicity-directed questionnaire (see Appendix E) 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. 
 
8.  ADVERSE EVENT REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug under investigation.  Safety will be monitored by evaluation of adverse events 
reported by patients or observed by investigators or research staff, as well as by other 
investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc. 
  
8.1 Study Agents / Method Risks 
 
8.1.1 Bortezomib 
 
To date, more than 100,000 patients have been treated with bortezomib in both clinical trials 
investigating its use in hematological malignancies and solid tumors, and in patients who were 
treated with commercially available bortezomib. 
 
Prescribing physicians and health care practitioners are referred to their locally approved product 
label for bortezomib regarding Indications and Usage, Contraindications, Warnings, and 
Precautions. 
 
The known anticipated risks of bortezomib therapy are presented in Table 8-1 Known 
Anticipated Risks of bortezomib and Table 8-2 Reports of Adverse Reactions from Post-
marketing Experiences. These risks are grouped according to the combined frequency observed 
in an integrated analysis of AEs in sponsored clinical studies of single-agent bortezomib dosed at 
1.3 mg/m2 twice weekly on a 21-day schedule, in patients with multiple myeloma and mantle 
cell lymphoma. 


20
Table 8-1   Known Anticipated Risks of bortezomib by MedDRA System Organ Class, Observed Incidence, and 
Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Blood and Lymphatic System Disorders 
Most common 
Thrombocytopenia*, anemia* 
Very common  
Neutropenia* 
Common  
Lymphopenia, pancytopenia*, leukopenia*, febrile 
neutropenia 
Cardiac Disorders 
Common  
Tachycardia, atrial fibrillation, palpitations, cardiac 
failure congestive* 
Uncommon 
Cardiogenic shock*, atrial flutter, cardiac tamponade*, 
bradycardia, atrioventricular block complete, arrhythmia, 
cardiac arrest, cardiac failure, arrhythmia, pericardial 
effusion, pericarditis, pericardial disease, 
cardiopulmonary failure 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impaired 
Eye Disorders 
Common  
Blurred vision, conjunctivitis, conjunctival hemorrhage  
Gastrointestinal Disorders 
Most common 
Constipation, diarrhea*, nausea, vomiting* 
Very common  
abdominal pain (excluding oral and throat) 
Common  
Dyspepsia, pharyngolaryngeal pain, gastroesophageal 
reflux, abdominal distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal hemorrhage*, 
lower gastrointestinal hemorrhage*± rectal hemorrhage 
Uncommon 
Eructation, gastrointestinal pain, tongue ulceration, 
retching, upper gastrointestinal hemorrhage*, 
hematemesis*, oral mucosal petechiae, ileus paralytic*, 
ileus, odynophagia, enteritis, colitis, esophagitis, 
enterocolitis, diarrhea hemorrhagic, acute pancreatitis*, 
intestinal obstruction 
General Disorders and Administration Site Conditions 
Most common 
Fatigue, pyrexia 
Very common  
Chills, edema peripheral, asthenia 
Common  
Neuralgia, lethargy, malaise, chest pain, mucosal 
inflammation* 
Uncommon 
Injection site pain, injection site irritation, injection site 
phlebitis, general physical health deterioration*, 
catheter-related complication 
Hepatobiliary Disorders 
Uncommon 
Hyperbilirubinemia, hepatitis* 


21
Table 8-1   Known Anticipated Risks of bortezomib by MedDRA System Organ Class, Observed Incidence, and 
Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 
Infections and Infestations 
Very common  
Upper respiratory tract infection, nasopharyngitis, 
pneumonia*, Herpes zoster* 
Common  
Lower respiratory tract infection*, sinusitis, pharyngitis, 
oral candidiasis, urinary tract infection*, sepsis, 
bacteremia*, cellulitis, Herpes simplex, bronchitis, 
gastroenteritis*, infection 
Uncommon 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung infection, 
infusion site cellulitis, catheter site cellulitis, infusion 
site infection, urosepsis*, Aspergillosis*, tinea infection, 
Herpes zoster ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic, varicella, empyema, 
fungal esophagitis 
Injury, Poisoning, and Procedural Complications  
Common 
Fall 
Uncommon 
Subdural hematoma 
Investigations 
Common  
Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, 
blood alkaline phosphatase increased, liver function test 
abnormal, blood creatinine increased* 
Uncommon 
Gamma-glutamyltransferase (GGT) increased, oxygen 
saturation decreased*, blood albumin decreased, ejection 
fraction decreased* 
Metabolism and Nutritional Disorders 
Very common  
Decreased appetite, anorexia, dehydration* 
Common  
Hyperglycemia, hypoglycemia, hyponatremia, 
hypokalemia, hypercalcemia* 
Musculoskeletal and Connective Tissue Disorders 
Very common  
Bone pain, myalgia, arthralgia, back pain 
Common 
Muscular weakness 
Uncommon 
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon 
Tumor lysis syndrome* 


22
Table 8-1   Known Anticipated Risks of bortezomib by MedDRA System Organ Class, Observed Incidence, and 
Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Nervous System Disorders 
Most common 
Peripheral neuropathy (including all preferred terms 
under the MedDRA High-level term Peripheral 
neuropathy NEC) 
Very common  
Paresthesia, dizziness excluding vertigo, headache 
Common  
Polyneuropathy, syncope, dysesthesia, dysgeusia, post 
herpetic neuralgia 
Uncommon 
Convulsion, loss of consciousness, ageusia, 
encephalopathy, paralysis*,autonomic neuropathy, 
posterior reversible encephalopathy syndrome 
Psychiatric Disorders 
Very common 
Anxiety, insomnia  
Common 
Confusional state  
Uncommon 
Delirium 
Renal and Urinary Disorders 
Common 
Renal impairment*, renal failure*, hematuria 
Uncommon 
Micturition disorder 
Respiratory, Thoracic, and Mediastinal Disorders 
Very common 
Cough, dyspnea  
Common 
Epistaxis, dyspnea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary edema 
Uncommon 
Hemoptysis*, acute respiratory distress syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar hemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, pleuritic 
pain 
Skin and Subcutaneous Tissue Disorders 
Very common 
Rash 
Common 
Rash pruritic, rash erythematous, urticaria, petechiae 
Uncommon 
Cutaneous vasculitis, leukocytoclastic vasculitis  
Vascular Disorders 
Common 
Hypotension*, orthostatic hypotension 
Uncommon 
Cerebral hemorrhage* 
Source:  VELCADE® Investigator’s Brochure Edition 16. 
Most common =  30%, Very common = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%. 
* Fatal outcomes have been reported. 
 Indicates a Preferred term not listed in the source table, however the event is deemed medically important 
and so is included. 
Prior to MedDRA version 14.0, posterior reversible encephalopathy syndrome (PRES) was termed 
‘reversible posterior leukoencephalopathy syndrome (RPLS)’. 


23
Table 8-1   Known Anticipated Risks of bortezomib by MedDRA System Organ Class, Observed Incidence, and 
Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Table 8-2   Reports of Adverse Reactions From Postmarketing Experience 
System Organ Class 
 
Preferred Term 
Observed 
Incidencea 
Blood and lymphatic system disorders 
 
 
Disseminated intravascular coagulation  
Rare 
Cardiac Disorders 
 
 
Atrioventricular block complete 
Rare 
 
Cardiac tamponade 
Rare 
Ear and labyrinth disorders 
 
 
Deafness bilateral 
Rare 
Eye Disorders 
 
 
Ophthalmic herpes 
              Optic neuropathy 
              Blindness 
 
Rare 
Rare 
Rare 
Gastrointestinal Disorders 
 
 
Acute pancreatitis  
Rare 
 
Ischemic colitis 
Rare 
Hepatobiliary disorders 
 
 
Hepatitis 
Uncommon 
 
Liver failure 
Unknown 
Infections and infestations 
 
 
Herpes meningoencephalitis 
Rare 
 
Septic shock 
              Progressive multifocal leukoencephalopathy 
Rare 
Very rare 
Immune System Disorders 
 
 
Angioedema 
Rare 
Nervous System Disorders 
 
 
Autonomic neuropathy 
Rare 
 
Dysautonomia 
Unknown 
 
Encephalopathy 
Rare 
Respiratory, thoracic and mediastinal disorders: 
 
 
Acute diffuse infiltrative pulmonary diseaseb  
Rare 
 
Acute respiratory distress syndrome (ARDS) 
Rare 
 
Interstitial pneumonia 
Rare 


24
Table 8-1   Known Anticipated Risks of bortezomib by MedDRA System Organ Class, Observed Incidence, and 
Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
 
Lung infiltration 
Rare 
 
Pneumonitis 
Rare 
 
Pulmonary hypertension 
Rare 
Skin and subcutaneous system disorders 
 
 
Acute febrile neutrophilic dermatosis 
Unknown 
 
Toxic epidermal necrolysis 
Unknown 
Source:  VELCADE® Investigator’s Brochure Edition 16. 
a Incidence is assigned using the following convention:  very common 
( 1/10); common ( 1/100 and  1/10); uncommon ( 1/1000 and 
 1/100); rare ( 1/10,000 and  1/1000 ); very rare ( 1/10,000, 
including isolated reports). 
b Acute diffuse infiltrative pulmonary disease is a MedDRA Lower 
Level Term which corresponds to a Preferred Term of Interstitial lung 
disease. 
Other medical events of interest that are considered not causally related to bortezomib include 
hepatic failure and QT prolongation.  Fatal outcomes have been reported. 
 
Women of childbearing potential should avoid becoming pregnant while being treated with 
bortezomib.  Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames 
assay and in the in vivo micronucleus assay, but it is a clastogen in the in vitro chromosomal 
aberration assay. 
 
Additional details on the potential risks of bortezomib may be found in the current Investigator’s 
Brochure. 
8.1.2 High-dose Cyclophosphamide (CYTOXAN) 
 
Possible serious side effects associated with cyclophosphamide include malignancy, sterility, 
hemorrhagic cystitis, congestive heart failure, immunosuppression, anaphylaxis, leukopenia, 
thrombocytopenia and cardiomyopathy. 
 
Possible common side effects associated with cyclophosphamide include alopecia, nausea, 
vomiting, cystitis, anorexia, diarrhea, rash, headache, dizziness, darkened skin, darkened nails and 
stomatitis. 
 
8.1.3 G-CSF (NEUPOGEN) 
 
Possible serious side effects associated with G-CSF include splenic rupture, Adult Respiratory 
Distress Syndrome (ARDS), anaphylaxis and thrombocytopenia. 


25
Possible common side effects associated with G-CSF include bone pain, musculoskeletal pain, 
splenomegaly, injection site reactions, elevated alkaline phosphatase, elevated lactate 
dehydrogenase (LDH), hyperuricemia, nausea, abdominal pain, flank pain, headache, 
thrombocytopenia, anemia, hypotension, and leukocytosis.3 
8.1.4    Plerixafor (Mozobil) 
Possible side effects associated with plerixafor include diarrhea, nausea, and local injection site 
reaction (observed in over 10% of patients). Other problems with digestion and general 
symptoms like dizziness, headache, and muscular pain were found in more than 1% of patients. 
Allergies occur in less than 1% of cases. Most adverse effects in clinical trials were mild and 
transient 
8.2  
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
Attribution of the AE: 
o Definite – The AE is clearly related to the study treatment. 
o Probable – The AE is likely related to the study treatment. 
o Possible – The AE may be related to the study treatment. 
o Unlikely – The AE is doubtfully related to the study treatment. 
o Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
8.3     Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific adverse event (AE) log.  The AE log 
will be maintained by the research staff and kept in the patient’s research chart.  Adverse events 
will be entered into the RedCap database. Additional information about RedCap can be found in 
Section 12.1.1.  
 
8.4       Serious Adverse Event (SAE) Reporting 
 
8.4.1 Definition of SAE 
 
SERIOUS ADVERSE EVENTS include death, life threatening adverse experiences, 
hospitalization or prolongation of hospitalization, disability or incapacitation, overdose, 
congenital anomalies, suspected or positive pregnancy, and any other serious events that 
may jeopardize the subject or require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. 
 
8.4.2 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy.  The 


26
IRB requires immediate reporting of all unexpected and study-related (definite or probable) 
adverse events.  The following procedure will be followed for reporting SAE to the IRB: 
 
 Complete the SAE Cover Sheet (See Appendix B) 
 If the event is unexpected AND definitely or probably related to the study, complete the 
IRB Unexpected, Study-related Adverse Events, Incidents, and Information Reporting 
Form.  This form should be submitted within 24 hours of investigator notification of the 
event. 
 If the event is expected OR possibly or unrelated to the study, only the SAE Cover Sheet 
must be completed.  These events will be reported to the IRB at the time of continuing 
renewal on the Adverse Event & IND Safety Reporting Cumulative Table. 
 
Forms may also be downloaded from the IRB website at: 
http://www.med.cornell.edu/research/for_pol/ins_rev_boa.html 
8.4.3
Reporting of SAE to Millennium 
Adverse events (AEs) may be spontaneously reported by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures.  AEs which are serious must be reported to Millennium. 
Pharmacovigilance (or designee) from first dose of bortezomib up to and including 30 days after 
administration of the last dose of bortezomib.  When possible, signs and symptoms indicating a 
common underlying pathology should be noted as one comprehensive event.  Any SAE that 
occurs at any time after completion of bortezomib treatment or after the designated follow-up 
period that the investigator-sponsor and/or sub-investigator considers to be related to any study 
drug must be reported to the Millennium Pharmacovigilance (or designee).  Planned hospital 
admissions or surgical procedures for an illness or disease that existed before the patient was 
enrolled in the trial are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (e.g., surgery was performed earlier or later than planned).  
All SAEs should be monitored until they are resolved or are clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness(es). 
This is an investigator-initiated study.  The principal investigator, Dr. Ruben Niesvizky, (who 
may also sometimes be referred to as the investigator-sponsor), is conducting the study and 
acting as the sponsor. Therefore, the legal/ethical obligations of the principal investigator include 
both those of a sponsor and those of an investigator. 
 
Investigator-sponsor must report all serious adverse events (SAE) regardless of relationship with 
any study drug or expectedness to Millennium Pharmacovigilance (or designee) as soon as 
possible, but no later than 5 calendar days of the investigator-sponsor’s observation or awareness 
of the event.  In the event that this is a multisite study, the investigator-sponsor is responsible to 
ensure that the SAE reports are sent to Millennium Pharmacovigilance (or designee) from all 
sites participating in the study.  Sub-investigators must report all SAEs to the investigator-
sponsor so that the investigator-sponsor can meet his/her foregoing reporting obligations to 
Millennium Pharmacovigilance, unless otherwise agreed between the investigator-sponsor and 
sub-investigator(s).  Millennium Pharmacovigilance (or designee) may request follow-up 


27
information to a reported SAE, which the investigator-sponsor will be responsible for providing 
to Millennium Pharmacovigilance (or designee). 
The SAE report must include event term(s), serious criteria, and the investigator-sponsor’s or 
sub-investigator’s determination of both the intensity of the event(s) and the relationship of the 
event(s) to study drug administration. 
Intensity for each SAE, including any lab abnormality, will be determined by using the NCI 
CTCAE, version used at your institution, as a guideline, whenever possible.  The criteria are 
available online at http://ctep.cancer.gov/reporting/ctc.html.  
Relationship to all study drugs for each SAE will be determined by the investigator-sponsor or 
sub-investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)?  
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 will send to the investigator-sponsor a quarterly 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 
 
Millennium Pharmacovigilance 
SAE and Pregnancy Reporting Contact Information:  
North America 
PPD, Inc. 
Safety and Medical Management, US 
 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and must permanently discontinue study drug(s).  
All pregnancies and suspected pregnancies must be reported to Millennium Pharmacovigilance 
(or designee; see Section 8.4.3 for contact information) immediately.  The pregnancy must be 
followed for the final pregnancy outcome (i.e., delivery, still birth, miscarriage) and Millennium 
Pharmacovigilance will request this information from the investigator-sponsor. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to Millennium Pharmacovigilance (or designee) immediately 
(see Section 8.4.3 for contact information).  Every effort should be made to follow the pregnancy 
for the final pregnancy outcome.  
 


28
8.4.4     Adverse event updates and IND safety reports 
Millennium shall notify the Investigator via an IND Safety Report of the following information: 
 Any AE associated with the use of study drug in this study or in other studies that is both 
serious and unexpected. 
 Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
The Investigator shall notify his/her IRB promptly of these new serious and unexpected AE(s) or 
significant risks to subjects. The Investigator must keep copies of all AE information, including 
correspondence with Millennium and the IRB, on file. 
  
 
9. PHARMACEUTICAL INFORMATION 
 
 
9.1  
Clinical Pharmacology 
 
9.1.1 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 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. 


29
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. 
 
9.2 
Bortezomib Supply and Dosage 
 
Drug is available in sterile, single use vials containing 3.5 mg of bortezomib.  Each vial of 
bortezomib 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 bortezomib at a concentration of 
1 mg/mL.  Prior to reconstitution the vials should remain in the cartons to protect them from 
light.  Dissolution is completed in approximately 10 seconds.  The reconstituted solution is clear 
and colorless, with a final pH of 5 to 6.  Reconstituted bortezomib 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. 
 
9.2.1 Bortezomib Administration 
 
Drug will be administered only to eligible patients under the supervision of the investigator or 
identified sub-investigator(s).  Patients may be treated on an out-patient basis, if possible.   
The pharmacist will prepare the drug under aseptic conditions.  The amount (in mg) of drug to be 
administered will be determined based on body surface area.  Body surface area is to be 
calculated based on body weight using a standard nomogram (see Appendix E).  The dose should 
be calculated on Day 1 of each cycle; the dose administered should remain the same throughout 
each cycle but should be recalculated at the start of the next cycle.  If a patient experiences a 
notable change in weight (e.g., loss or gain of 8 lbs or 3.6 kg) within a cycle, as determined by 
an unscheduled weight assessment, then the patient’s dose should be recalculated at that time 
based on clinical judgment. 
 
The appropriate amount of bortezomib will be drawn from the injection vial and administered as 
an intravenous (IV) push over 3 to 5 seconds followed by a standard saline flush or through a 
running IV line.  Vials are for single use administration. The initial dose of bortezomib 
administered will be 1.3 mg/m2.  The dose may be modified.  Please refer to section 6.0.  
 
There must be at least 72 hours between each dose of bortezomib.       
 
9.2.2 Bortezomib Storage and Special Handling Instructions  
 
Bortezomib for Injection is a sterile lyophilized powder for reconstitution and is supplied in vials 
containing bortezomib and mannitol at a 1:10 ratio.  For example, vials containing 3.5 mg of 
bortezomib contain 35 mg of mannitol.   
 


30
Vials containing lyophilized bortezomib 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. 
Bortezomib is cytotoxic.  As with all cytotoxic drugs, caution is required when preparing and 
handling bortezomib solutions.  Cytotoxic drugs should only be handled by staff specially trained 
in the safe handling of such preparations. The use of gloves and other appropriate protective 
clothing is recommended.  In case of skin contact, wash the affected area immediately and 
thoroughly with soap and water for at least 15 minutes.  If product contacts eye, immediately 
flush eye thoroughly with water for at least 15 minutes.  Always contact a physician after any 
form of body contact. All materials that have been used for preparation should be disposed of 
according to standard practices. A log must be kept of all disposed materials. 
 
Bortezomib Return 
 
For commercially-labeled bortezomib for IND-exempt studies, please contact Millennium to 
arrange for study drug return procedures.  Any unused or expired bortezomib must be returned to 
Millennium.  Drug return activity must be documented in the drug accountability log. 
 
Millennium Study Drug Product Complaints 
 
A product complaint is a verbal, written, or electronic expression which implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact MedComm Solutions 
(see the following contact information below) and report the event.  Whenever possible, the 
associated product should be maintained in accordance with the label instructions pending 
further guidance from a Millennium quality representative. 
 
For Product Complaints, call MedComm Solutions at 
 
 
9.2.3 Bortezomib Blinding, Packaging and Labeling 
 
Bortezomib will be supplied in vials as open-label stock.  Both the box label and vial label 
will fulfill all requirements specified by governing regulations. 
 
 
 
 
 
 


31
9.3 
G-CSF, or Neupogen (filgrastim): 
 
9.3.1 Description 
 
Filgrastim is a human granulocyte colony stimulating factor (G-CSF), produced by recombinant 
DNA technology.  NEUPOGEN is the Amgen Inc. trademark for filgrastim, recombinant 
methionyl human granulocyte colony stimulating factor (rmetHu G-CSF). Other names:   
 
 G-CSF  
 Granulocyte Colony Stimulating Factor  
 Neupogen  
 recombinant methionyl human granulocyte - colony stimulating factor; r - methHuG –
CSF 
 
9.3.2 Contraindications 
 
NEUPOGEN is contraindicated in patients with known hypersensitivity to E. coli - derived 
proteins, filgrastim, or any component of the product. 
9.3.3
Dilution/Storage 
If required, NEUPOGEN may be diluted in 5% dextrose.  NEUPOGEN  diluted to 
concentrations between 5 and 15 mcg/ml should be protected from adsorption to plastic materials 
by addition of albumin (Human) to a final concentration of 2mg/ml.  Do not dilute with saline at 
any time; product may precipitate. 
 
NEUPOGEN should be stored in the refrigerator at 2-8 degrees Centigrade (36-46 degrees 
Fahrenheit).  Do not freeze.  Avoid shaking.  Prior to injection, NEUPOGEN may be allowed to 
reach room temperature for a maximum of 24 hours.  Any vial left at room temperature for 
greater than 24 hours should be discarded. 
 
9.3.4 How Supplied 
 
Commercial NEUPOGEN is available in 1ml and 1.6ml vials at a concentration of 300mcg/ml 
and 480mcg/ml. Discard unused portions. Use only one dose per vial; do not reenter the vial.  Do 
not save unused drug for later administration. 
 
9.3.5 Toxicity  
  
The only consistently observed clinical toxicity described with NEUPOGEN is medullary bone 
pain. Other clinical adverse events that have been described include skin rash, and cutaneous 
vasculitis.  Since commercial introduction of NEUPOGEN, there have been rare reports of 
allergic-type reactions.  Biochemical abnormalities that may occur include increases in alkaline 
phosphatase, uric acid, and lactate dehydrogenase." 


32
9.4 
High-dose Cyclophosphamide (Cytoxan) 
Commonly used brand name(s): Cytoxan; Neosar; Procytox. 
  
Cyclophosphamide is classed as an alkylating agent of the nitrogen mustard type. An activated 
form of cyclophosphamide, phosphoramide mustard, alkylates or binds with many intracellular 
molecular structures, including nucleic acids. Its cytotoxic action is primarily due to cross-
linking of strands of DNA and RNA, as well as to inhibition of protein synthesis. 
 
9.4.1 Other actions/effects 
 
Cyclophosphamide is a potent immunosuppressant. It also causes marked and persistent 
inhibition of cholinesterase activity 
 
 
9.4.2 Absorption 
 
Well absorbed after oral administration (bioavailability greater than 75%) 
 
9.4.3 Distribution 
 
Crosses blood-brain barrier to limited extent. 
9.4.5 Protein binding 
 
Very low (some active metabolites greater than 60%) 
 
9.4.6 Biotransformation 
 
Hepatic (including initial activation and subsequent degradation 
 
9.4.7 Half-life 
 
Unchanged drug 3 to 12 hours 
 
9.4.8 Time to peak concentration 
 
Plasma Metabolites: 2 to 3 hours after intravenous administration 
 
9.4.9 Elimination 
 
Renal, 5 to 25% unchanged 
In dialysis Cyclophosphamide is dialyzable 
 
9.4.10 Side/adverse effects 
 
Signs of potential side effects, especially, amenorrhea, leukopenia, infection, cardiotoxicity, 


33
SIADH, hemorrhagic cystitis, hyperuricemia, uric acid nephropathy, nonhemorrhagic cystitis, 
nephrotoxicity, pneumonitis, interstitial pulmonary fibrosis, anemia, thrombocytopenia, 
anaphylactic reaction, hemorrhagic colitis, hepatitis, hyperglycemia, redness or swelling or pain 
at site of injection, and stomatitis 
 
Physician or nurse can help in dealing with side effects 
 
Possibility of hair loss; normal hair growth should return after treatment has ended; new hair 
may be slightly different in color or texture 
 
9.5 Plerixafor (Mozobil) 
 
Plerixafor is a macrocyclic compound and a bicyclam derivative.  It is a strong base; all eight 
nitrogen atoms accept protons readily. The two macrocyclic rings form chelate complexes with 
bivalent metal ions, especially zinc, copper and nickel, as well as cobalt and rhodium. The 
biologically active form of plerixafor is its zinc complex. 
 
9.5.1    Pharmacokinetics 
Following subcutaneous injection, plerixafor is absorbed quickly and peak concentrations are 
reached after 30 to 60 minutes. Up to 58% are bound to plasma proteins, the rest mostly resides 
in extravascular compartments. The drug is not metabolized in significant amounts; no 
interaction with the cytochrome P450 enzymes or P-glycoproteins has been found. Plasma half-
life is 3 to 5 hours. Plerixafor is excreted via the kidneys, with 70% of the drug being excreted 
within 24 hours. 
 
9.5.2     Pharmacodynamics 
In the form of its zinc complex, plerixafor acts as an antagonist (or perhaps more accurately a 
partial agonist) of the alpha chemokine receptor CXCR4 and an allosteric agonist of 
CXCR7.[10] The CXCR4 alpha-chemokine receptor and one of its ligands, SDF-1, are important 
in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell 
quiescence. The in vivo effect of plerixafor with regard to ubiquitin, the alternative endogenous 
ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization 
of hematopoietic stem cells from the bone marrow to the bloodstream as peripheral blood stem 
cells. 
 
 
 
 
 
 
 
 
 
 
 
 


34
10. STUDY EVALUATIONS 
Table 4: Study Calendar 
Schedule of Assessments for Arms A, B, and E  
 
Screening11 
Day 1 
Day 4 
Day 8 
 
 
 
Day 11 
Day 21 
On days of 
Stem Cell 
collection 
End of 
Treatment10 
Complete Medical History 
X 
 
 
 
 
 
 
 
X 
Physical Exam, KPS 
X 
 
 
 
 
 
 
 
X 
Neuropathy Assessment 
X 
X X 
X 
 
X 
 
 
X 
Vital Signs 
X 
X X 
X 
 
X 
 
 
X 
Weight and Height 
X 
 
 
 
 
 
 
 
X 
EKG 
X 
 
 
 
 
 
 
 
X 
CBC w. Diff and Platelets 
X9 
X 
X 
X 4, 6 
 
X 
 
 
X 
Complete Metabolic Profile1 
X9 
 
 
 
 
 
 
 
X 
SPEP, IF, Quantitative IGs 
X 
 
 
 
 
 
 
 
X 
24-Hr U for UTP, UPEP, UIF 
X 
 
 
 
 
 
 
 
X 
Serum Free Light Chains 
X 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
X 
Serum Pregnancy Test (WCBP)2 
X 
 
 
 
 
 
 
 
 
Bone Marrow Biopsy & Aspirate 
X 
 
 
 
 
 
 
 
X3 
MUGA or Echo 
X 
 
 
 
 
 
X5 
 
 
VELCADE Dispensing 
 
X 
X 
X 
 
X  
 
 
 
Cyclophosphamide Dispensing 
 
 
X4 
 
 
 
 
 
CD 34 analysis 8 
X 
X X
X 
 
X 
X 
X6 
 
Correlative Studies 7 
X 
X X 
X 
 
X 
X 
X6 
 
Concomitant Medications 
 
CONTINUOUS  
Toxicity Assessment 
 
CONTINUOUS 
1 
Includes sodium, potassium, chloride, CO2, calcium, magnesium, phosphorus, blood urea nitrogen (BUN), creatinine, 
glucose, albumin, total protein, alkaline phosphate, total bilirubin, SGOT/AST, SGPT/ALT, lactate dehydrogenase (LDH), 
uric acid 
2 
Within 7 days of start of treatment (Day 1) 
3 
To confirm complete response or when clinically indicated 
4 
Only for patients randomized to Arm A 
5 
Screening MUGA to be performed within 6 months prior to treatment then repeated when clinically indicated 
6 
+/- 2 days  
7 
Patients undergo hematopoietic colony-forming assays, flow cytometry and viability testing for mobilized CD34+ cells, 
and plasma chemokine levels (SDF-1 and KitL). DNA/RNA will be extracted for genomics.  Correlative studies will only be 
performed at WCMC and for subjects enrolled at WCMC only. Approved for 6 patients in Arm A and 6 patients in Arm B. 
8  
In study centers that have the equipment capability, ANC > 1.0 will not be the benchmark to start collection. Instead, 
peripheral blood CD34+ cells/ ml will be determined by flow cytometry on a subject’s blood sample on each morning of 
proposed collection.  A minimum requirement of ≥ 20 x 106 CD34+ cells/ml will be required to start stem cell collection.  If 
the subject fails to reach this benchmark, stem cell collection for the day will be aborted for futility and the patient will 
return the next day for reevaluation.  If the subject fails to achieve an adequate peripheral blood CD34+ cell count after 14 
days of G-CSF on Arms A and C, or 10 days of G-CSF on Arm B, the collection attempt will be deemed a failure and the 
patient will be taken off study. HPC analysis will not be used to determine eligibility to start stem cell collection. In study 
centers without ready access to flow cytometry analysis of CD34+ cell content of peripheral blood, ANC will be the sole 
marker to start stem cell collection.  
9 
To be performed within 14 days of enrollment 
10   All subjects will undergo an End of Treatment visit. End of Treatment visits are to be performed within 3 days of study 
withdrawal or Day 21 
11   Screening procedures will be performed within 28 days of enrollment, unless otherwise indicated 
 
 


35
Schedule of Assessments for Arms C and D 
 
1
Includes sodium, potassium, chloride, CO2, calcium, magnesium, phosphorus, blood urea nitrogen (BUN), 
creatinine, glucose, albumin, total protein, alkaline phosphate, total bilirubin, SGOT/AST, SGPT/ALT, 
lactate dehydrogenase (LDH), uric acid 
2 
Within 7 days of treatment 
3 
Patients undergo hematopoietic colony-forming assays, flow cytometry and viability testing for mobilized 
CD34+ cells, and plasma chemokine levels (SDF-1 and KitL). DNA/RNA will be extracted for genomics. 
Correlative studies will only be performed at WCMC and for subjects enrolled at WCMC only. Approved 
for 6 patients in Arm C. 
4 
In study centers that have the equipment capability, ANC > 1.0 will not be the benchmark to start 
collection. Instead, peripheral blood CD34+ cells/ ml will be determined by flow cytometry on a subject’s 
blood sample on each morning of proposed collection.  A minimum requirement of ≥ 20 x 106 CD34+ 
cells/ml will be required to start stem cell collection.  If the subject fails to reach this benchmark, stem cell 
collection for the day will be aborted for futility and the patient will return the next day for reevaluation.  If 
the subject fails to achieve an adequate peripheral blood CD34+ cell count after 14 days of G-CSF on Arms 
A and C, or 10 days of G-CSF on Arm B, the collection attempt will be deemed a failure and the patient 
will be taken off study. HPC analysis will not be used to determine eligibility to start stem cell collection. 
In study centers without ready access to flow cytometry analysis of CD34+ cell content of peripheral blood, 
ANC will be the sole marker to start stem cell collection. This is being done for subjects enrolled at 
WCMC only. 
5 
To be performed within 14 days of enrollment. 
6 
To confirm complete response or when clinically indicated 
7 
All subjects will undergo an End of Treatment visit. End of Treatment visits are to be performed within 3 
days of study withdrawal or Day 21 
8 
Screening procedures will be performed within 28 days of enrollment, unless otherwise indicated 
9 
+/- 2 days 
 
Screening8 
 
Day 1 
 
 
Day 8 
 
 
On days of Stem 
Cell collection 
End of Treatment7 
Complete Medical History 
X 
 
 
 
X 
Physical Exam, KPS 
X 
 
 
 
X 
Vital Signs 
X 
X 
 
 
X 
Neuropathy Assessment 
X 
 
 
 
X 
Weight and Height 
X 
X 
 
 
 
EKG 
X 
 
 
 
X 
CBC w. Diff and Platelets 
X5 
X 
X9 
 
X 
Complete Metabolic Profile1 
X5 
X 
 
 
 
SPEP, IF, Quantitative IGs 
X 
 
 
 
X 
Serum Free Light Chains 
X 
 
 
 
X 
24-Hr Urine collection for UTP, 
UPEP, UIF 
X 
 
 
 
X 
Urinalysis 
X 
 
 
 
X 
Serum Pregnancy Test (WCBP)2 
X 
 
 
 
 
Bone Marrow Biopsy & 
Aspirate 
X 
 
 
 
X6 
MUGA or echo 
X 
 
 
 
 
Cyclophosphamide Dispensing 
 
X 
 
 
 
CD 34 analysis  4 
X 
 
 
X9 
 
Correlative Studies 3 
 
 
 
X9 
 
Concomitant Medications 
CONTINUOUS 
Toxicity Assessment 
CONTINUOUS 


36
10.1 
Correlative Studies  
Correlative studies will be done on select patients enrolled at Weill Cornell Medical College 
only.  
Daily CD34 quantification (When possible, excluding weekends):  
Arm A: starting day 9  
Arm B: starting day 9 (approved for 10 patients only) 
Arm C: starting day 5 
Arm D: starting day 4 
Arm E: starting day 12 
 
Selected patients will undergo hematopoietic colony-forming assays, flow cytometry and 
viability testing for mobilized CD34+ cells, and plasma chemokine levels (SDF-1 and KitL). 
DNA/RNA will be extracted for genomics.  
10.2.  Evaluation of Response 
10.2.1 Efficacy Evaluations 
 Percentage of patients able to collect >6 x 106 CD34+ cells/kg in < 2 collections. 
 Engrafting: Neutrophil recovery (ANC >0.5 of <20 days), Platelet recovery (>20K 
untransfused <20 days) after mel 200 based transplant.  
 Toxicities 
10.2.2 Tumor Response 
Hematological parameters and paraprotein levels will be monitored at screening and end of 
treatment. Formal response evaluations will be performed between 2-6 weeks after stem cell 
collection. This evaluation will be according to the International Uniform Response Criteria for 
Multiple Myeloma (EBMT criteria) presented in Appendix C. For quantitative immunoglobulins, 
and M-protein in serum and 24-hour urine, the investigator will use results provided by the New 
York- Presbyterian Hospital Laboratories. Serum free light chain data will be used for 
exploratory analysis only. 
 
Myeloma Protein Measurements in Serum and Urine: 
Blood samples for quantitation of immunoglobulins and M-protein by serum protein 
electrophoresis (SPEP), and a 24-hour urine sample for quantitation of M-protein by urine 
electrophoresis (UPEP) are to be collected from all subjects during the Screening Phase and at 
the End of Treatment Visit. If the assessment of progressive disease is based on one of these 
tests, then confirmation is required. 
 
Blood and 24-hour urine samples for M-protein measurement (including immunofixation at 
screening and after complete response [CR]) will be analyzed by the NewYork-Presbyterian 
Hospital Laboratories.  
 
Bone Marrow Examination: 
Bone Marrow aspiration and biopsy are to be performed for all subjects during the Screening 


37
Phase, and for any subject who achieves a CR. Repeat collection and evaluation of bone marrow 
is not required to confirm CR if the monoclonal antibody remains undetectable in a second assay 
6 weeks after the initial observation of a CR. 
 
Our response criteria will follow the modified version of EBMT and International Uniform 
Response Criteria (IURC).  Therefore, no scans are required.   
 
10.3 
Post study follow-up 
 
All attempts will be made to follow patients until progression or death.  Subjects who have been 
discontinued from study will still be followed in a clinic setting to the fullest extent possible on a 
monthly to bi-monthly basis.  Those who choose not to resume regular clinic follow-up will be 
contacted every 6 months by telephone or electronically to collect post study information.  The 
post-study collection information will consist of telephone interview between the clinical 
investigator and the discontinued patient.  The information requested will be current disease 
status, current treatment use, and physical status of the patient.  
 
10.4 
Procedure for early removal from study 
 
Any possible premature discontinuation would be documented adequately with reasons being 
stated, and information would have to be issued according to local requirements (e.g., IRB, 
regulatory authorities, etc.). 
 
The responsible Clinical Investigator and/or Millennium have the right to discontinue this study 
at any time for reasonable medical or administrative reasons in any single center.  Possible 
reasons for termination of the study could be but are not limited to: 
 Unsatisfactory enrollment with respect to quantity or quality. 
 Inaccurate or incomplete data collection. 
 Falsification of records. 
 Failure to adhere to the study protocol. 
11. MEASUREMENT OF EFFECT 
11.1  Disease Response 
 
Disease response category (e.g. partial response, very good partial response, complete response, 
stringent complete response) will be as defined by the International Uniform Response Criteria 
for Multiple Myeloma (Appendix C). 
 
11.2  Duration of Response  
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for complete response or partial response (whichever is first 
recorded) until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded since the 
treatment started). 


38
12.  DATA REPORTING / REGULATORY CONSIDERATIONS 
12.1     Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, and 
efficacy data for all enrolled patients.  
12.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software system that is 
fully supported by the Weill Cornell Medical College Clinical and Translational Science Center 
(CTSC).  It is a tool for the creation of customized, secure data management systems that include 
Web-based data-entry forms, reporting tools, and a full array of security features including user 
and group based privileges, authentication using institution LDAP system, with a full audit trail 
of data manipulation and export procedures.  REDCap is maintained on CTSC-owned servers 
that are backed up nightly and support encrypted (SSL-based) connections.  Nationally, the 
software is developed, enhanced and supported through a multi-institutional consortium led by 
the Vanderbilt University CTSA. REDCap will be used by all participating sites for data 
collection for this study. 
 
12.2     Regulatory Considerations 
All protocol amendments and consent form modifications will be made by the Principal 
Investigator.  Millennium will have the opportunity to review and approve the changes prior to 
submission of these changes to the local IRB and distribution to participating sites. 
12.3     Data Safety Monitoring Board 
 
The Data Safety Monitoring Board (DSMB) at Weill Cornell Medical College will be composed 
of medical and statistical independent reviewers and will meet to review the efficacy and safety 
data and determine a risk/benefit analysis in this subject population.  The purpose of the DSMB 
is to advise on serious safety considerations, lack of efficacy and any other considerations within 
the charge to the Committee.  The DSMB may request additional meetings or safety reports as 
deemed necessary upon discussion with Millennium and its representatives.  The Principal 
Investigator, Dr. Ruben Niesvizky, will be the safety contact for all DSMB related analysis 
outcomes. 
 
Dr. Niesvizky’s office is located at: 
 
 
 
The phone number to Dr. Niesvizky’s office is: 
  
The DSMB may stop the study following review of results from each interim analysis.  The first 
interim analysis will examine only safety information from the first ten patients accrued to each 
arm.  Safety will be evaluated by CTC criteria.  Any grade 5 toxicity that is due to 
treatment will be considered unacceptable, and the study arm will be terminated.  The 


39
second interim, conducted when the database is more mature (60 patients enrolled – 20 patients 
in each arm A, D and E), will examine both safety and efficacy, including toxicity data, 
protocol adherence, and protocol deviations.  Appropriate efficacy and safety data summaries 
will be provided to the DSMB after each interim analysis. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
13.1.1 Primary Endpoints 
 
 
The primary endpoint in all five treatment arms is the percentage of patients who are able to 
achieve greater than 6 x 106 CD34+ stems cells/kg harvested (defined as effectiveness).  Ninety-
five percent confidence intervals will be estimated for the effectiveness proportions in all three 
treatment arms via binomial proportions.  As well, 95% confidence intervals for the differences 
in effectiveness proportions between the three treatment arms will be estimated via binomial 
proportions.  The chi-square test will be used to compare the effectiveness proportion between 
the three groups and pair-wise group comparisons will be performed with adjustment for 
multiple comparisons (Scheffe).  Multivariate logistic regression will be used to compare the 
effectiveness proportions between pairs of treatment arms, controlling for demographic and 
prognostic factors that may not have been successfully balanced after randomization. 
 
13.2 
Sample Size/Accrual Rate 
 
With the closures of the CTX-GCSF (standard of care) arm and the Bortezomib-GCSF arm, 
approximately 66 patients each in the CTX-Bortezomib-GCSF arm (Arm A), Plerixafor-GCSF 
arm (Arm D), and Plerixafor-Bortezomib-GCSF arm (Arm E), will allow for the detection of 1) a 
≥18% absolute difference between the percentage of patients in arm A vs. E who are able to 
achieve greater than 6 x 106 CD34+ stems cells/kg harvested (defined as effectiveness), and 2) a 
≥28% absolute difference between the percentage of patients in arm D vs. E who are able to 
achieve greater than 6 x 106 CD34+ stems cells/kg harvested (defined as effectiveness), with 
90% and 95% power, respectively, and a two-sided alpha level of 5%.  This calculation assumes 
an effectiveness proportion of 70% in the Plerixafor-GCSF arm, 80% in the CTX-Bortezomib-
GCSF arm, and 98% in the Plerixafor-Bortezomib-GCSF arm.  
 
For the comparison of the CTX-Bortezomib-GCSF arm (Arm A) and the Plerixafor-GCSF arm 
(Arm D), with 66 patients per arm, an observed ≥10% absolute difference between the 
percentage of patients in each arm who experience effectiveness will only be considered 
exploratory (i.e., hypothesis-generating) and not formally powered. 
 
The above sample size/power calculation has been adjusted for the possibility of early stopping 
as discussed in section 6.2 (i.e., stopping rules will be implemented once 10 patients are accrued 
in each arm and the rule will not allow more than 4 failures in the 10 accrued patients per arm).  
The overall alpha level (type I error rate) has been modified to account for the possibility of early 
stopping of an arm after the accrual of 10 patients per arm.  The final analysis comparing the 
efficacy proportions between the treatment arms (A vs. E and D vs. E) will use an adjusted 


40
significance level that accounts for the possibility of early stopping. 
13.3 
Analysis of Secondary Endpoints 
Secondary endpoints include 1) the mean and median number of stem cells collected for the 
patients in each treatment arm, 2) measures of tumor mass change (as defined by standard 
response parameters), 3) the prevalence of biomarkers as surrogate markers of mobilization, 4) 
patient safety, and 5) patient toxicity.  The ANOVA test (or nonparametric Kruskal-Wallis test, 
as appropriate) will be performed for comparing the mean (or median) number of stem cells 
collected in each treatment arm.  The chi-square test (or Fisher’s exact test, as appropriate) will 
be used to compare tumor mass change response proportions (i.e., CR, PR, SD, etc.) between the 
three treatment arms and to compare the prevalence of specific biomarkers between the three 
treatment arms. 
The frequency of subjects experiencing toxicities will be tabulated.  Toxicities will be assessed 
and graded according to CTCAE v. 4.0 terminology.  Exact 95% confidence intervals around the 
toxicity proportions will be calculated to assess the precision of the obtained estimates. 
13.4     Randomization 
Stratified and blocked randomization will be performed at all participating sites.  Randomization 
will be stratified by participating institution.  A series of randomized blocks of 6 will be 
generated for each participating institution, using a 1:1:1 allocation ratio (for accrual into arms 
A, D, and E going forward).  This will provide assurance that after six patients are enrolled at 
any participating site, there will be two patients assigned to each of the three treatment arms.  
After the closing of arms B and C, and the addition of arms D and E, randomization will still 
commence in a 1:1:1 allocation ratio.  Since some accrual has already occurred on arm A, 
however, it will finish accrual before arms D and E.  After arm A completes accrual, the 
randomization scheme will be adjusted to provide a 1:1 allocation into the remaining arms D and 
E.  A block size of 6 will still be utilized, but after six patients are enrolled at any participating 
site, there will be three patients assigned to arm D and 3 patients assigned to arm E.  This will 
ensure that we have 66 patients in each of the three treatment arms at study completion 
(assuming none of the current arms are subject to early closure). 
 
14.  PROTOCOL AMENDMENTS AND DEVIATIONS 
 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies).   
 
All protocol amendments and consent form modifications will be made by the Principal 
Investigator.  Changes to the protocol will require approval from Millennium and written IRB 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to patients.  The investigator will submit all protocol 
modifications to Millennium and the regulatory authority(ies) in accordance with the governing 
regulations. 
 


41
Written verification of IRB approval will be obtained before any amendment, which affects 
subject safety or efficacy, is implemented.  Amendments that are administrative in nature do not 
require IRB approval but will be submitted to the IRB for information purposes. 
The IRB may provide, if applicable regulatory authority(ies) permit, expedited review and 
approval/favorable opinion for minor change(s) in ongoing studies that have the approval 
/favorable opinion of the IRB.  
 
Any departures from the protocol must be fully documented in the source documents. 
 
15.  REGULATORY CONSIDERATIONS 
15.1 
Institutional Review Board Approval 
 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki.  The review of this protocol by the IRB and the 
performance of all aspects of the study, including the methods used for obtaining informed 
consent, must also be in accordance with principles enunciated in the declaration, as well as ICH 
Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human 
Subjects and Part 56 Institutional Review Boards. The investigator will be 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 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.   
The Investigator will be responsible for preparing documents for submission to the relevant IRB 
and obtaining written approval for this study.  The approval will be obtained prior to the 
initiation of the study. 
The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number. 
 
All protocol amendments will be reviewed by Millennium prior to submission and approval by 
the Institutional Review Board (IRB) before they can be implemented. The investigator is also 
responsible for notifying the IRB of any serious deviations from the protocol, or anything else 
that may involve added risk to subjects. 
The IRB 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 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 by the 
investigator.  Millennium requests that informed consent documents be reviewed by Millennium 
or designee prior to IRB submission.   


42
15.2 
Informed Consent Procedures 
The Investigator must obtain written informed consent from a subject or his/her guardian or legal 
representative prior to study participation as per GCP’s as set forth in the CFR and ICH 
guidelines. 
 
Documentation that informed consent occurred prior to the subject’s entry into the study and the 
informed consent process should be recorded in the subject’s source documents.  The original 
consent form, signed and dated by the subject and by the person consenting the subject prior to 
the subject’s entry into the study, must be maintained in the Investigator’s study files.   At the 
pre-admission consultation, patients will be fully informed as to the purposes and potential risks 
and benefits involved in this study. Patients will have ample opportunity to ask questions before 
consenting. Legal guardians will sign informed consent for legally incompetent patients in 
accordance with hospital policy. 
15.3 
Protecting Privacy and Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, study 
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. 
15.4 
Study records requirements 
 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the study drug, that is copies of CRFs and source documents 
(original documents, data, and records [e.g., hospital records; clinical and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; pharmacy dispensing 
records; recorded data from automated instruments; copies or transcriptions certified after 
verification as being accurate copies; microfiches; photographic negatives, microfilm, or 
magnetic media; x-rays; subject files; and records kept at the pharmacy, at the laboratories, and 
at medico-technical departments involved in the clinical study; documents regarding subject 
treatment and study drug accountability; original signed informed consents, etc.]) be retained by 
the Investigator for as long as needed to comply with ICH-GCP and applicable regulatory 
requirement(s) (generally 2 years after discontinuing clinical development or after the last 
marketing approval).  The Investigator agrees to adhere to the document/records retention 
procedures by signing the protocol.  
15.5 
Protection of Human Rights 
 
Participation in this trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to Weill Cornell Medical College IRB guidelines.  
Patients will be eligible for this trial regardless of gender or racial/ethnic background.   


43
15.6 
Premature Discontinuation of Study 
The responsible local clinical Investigator as well as Millennium have the right to discontinue 
this study at any time for reasonable medical or administrative reasons in any single center. 
Written notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party. Possible reasons for termination of the study 
could be but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to patients 
 Unsatisfactory enrollment with respect to quantity or quality. 
 Inaccurate or incomplete data collection. 
 Falsification of records. 
 Failure to adhere to the study protocol. 
 Serious adverse events, intolerability of drug regimen, or sudden/unexpected death in any 
of the early trial (up to three patients) participants, as outline in section 9.2. 
 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. 
15.7 
Benefits of the Protocol 
 
The potential benefit of this study is the discovery of a superior mobilization regimen for MM 
patients.  Knowledge will be acquired about this treatment program, its tolerability, and the 
effectiveness of the combination of VELCADE, high-dose cyclophosphamide (CYTOXAN) and 
G-CSF in mobilizing peripheral stem cells in patients with multiple myeloma.  
15.8 
Risks in Relation to Anticipated Benefit 
 
The risks associated with participation in this trial are commensurate with the expected risks of 
other potential therapies and are reasonable given the potential benefit to patients with multiple 
myeloma. 
15.9 
Alternative Treatments 
Patients who refuse to participate in the study or decided to withdrawal from the study will be 
given the option to choose standard chemotherapy, other investigation studies, supportive care, 
or no anti-cancer treatment at all.  Some patients treated with standard chemotherapy do benefit.  
While the results of this therapy have been encouraging, long-term remissions are rare, no 
patients are cured and none of the drugs used in these standard treatments are free of side effects.  
We believe that this novel regimen will improve response rates and duration of remission. 
15.10 Incentives 
 
No incentives will be offered to patients/subjects for participation in the study.  Participation is 
voluntary. 


44
15.11 Costs 
Patients and/or their medical insurance coverage will be responsible for paying for their 
hospitalization, doctor visits, diagnostic tests, chemotherapy drugs, and other medicines used in 
their care directly. These costs are expected to be equivalent to those of standard treatment. 
Bortezomib will be provided to research subjects by Millennium Pharmaceuticals, Inc. for the 
duration of their participation in this trial at no charge to the subject or their insurance providers. 
G-CSF and high dose cyclophosphamide (Cytoxan) will be obtained through normal commercial 
channels.  
16.  ADMINISTRATIVE REQUIREMENTS 
16.1     On-Site Audits 
Regulatory authorities, the IRB and/or Millennium 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. 
16.2     Drug Accountability 
Accountability for the drug at all study sites (including sub-sites, if applicable) is the 
responsibility of the investigator-sponsor. The investigator-sponsor 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 will be maintained by the site and/or sub-sites.  Accountability records 
will include dates, quantities, lot numbers, expiration dates (if applicable), and patient numbers.   
 
Any unused or expired commercially labeled bortezomib must be returned to Millennium.  
Bortezomib destruction at any study site is not allowed for commercially labeled product that is 
associated with this Investigator Initiated Study. 
 
All material containing bortezomib will be treated and disposed of as hazardous waste in 
accordance with governing regulations. 
 
 
 
 
 
 
 
 
 
 
 
 


45
REFERENCES 
1 Munshi NC, Tricot G, Barlogie B: Plasma cell neoplasms, in De Vita VT, Hellman S, 
Rosenberg SA (ed): Cancer : Principles & Practice on Oncology, 6th edition, Philadelphia, 
PA. Lippincott Williams & Wilkins, 2001, pp 2465-2499. 
 
2 Wingo PA, Tong T, Bolden S.  Cancer Statistics: 1995. CA Cancer J Clin 1995, 45:8-30. 
3 Michaeli J, Durie BGM. Plasma cell disorders. Textbook of internal medicine. 2nd edition. 
Philadelphia: JB Lippincott, 1991: 1087-1096. 
 
4
Riedel DA and  Pottern LM.  The epidemiology of multiple myeloma.  
Hematology/Oncology Clinics of North America 1992, 6:225 
5 BG Durie, D Stock-Novack, SE Salmon, P Finley, J Beckord, J Crowley, and CA Coltman. 
Prognostic value of pretreatment serum beta 2 microglobulin in myeloma: a Southwest 
Oncology Group Study. Blood 1990 75: 823-830. 
 
6 Greipp PR. Pronosis in myeloma. Mayo Clin Proc. 1994 Sep; 69(9): 895-902.  
 
7 Dimopoulos MA, Barlogie B, Smith TL, Alexanian R. High serum lactate dehydrogenase 
level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern 
Med. 1991 Dec 15; 115(12): 931-5.  
 
8 Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI, Reece D, Chun K, Keith Stewart A. The 
t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem 
cell transplant. Br J Haematol. 2004 Apr;125(1):64-8. 
 
9 Niesvizky R, Siegel D, Glassman J, Straus D, Fine J, Lyons L, Michaeli J. Impact of early 
response to sequential high-dose chemotherapy on outcome of patients with advanced 
myeloma and poor prognostic features. Leuk Lymphoma. 2002 Mar;43(3):607-12.  
 
10 Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, 
Lentzsch S, Munshi N, Niesvizky R, San Miguel J, Ludwig H, Bergsagel L, Blade J, Lonial 
S, Anderson KC, Tosi P, Sonneveld P, Sezer O, Vesole D, Cavo M, Einsele H, Richardson 
PG, Durie BG, Rajkumar SV; Mobilization in myeloma revisited: IMWG consensus 
perspectives on stem cell collection following initial therapy with thalidomide-, 
lenalidomide-, or bortezomib-containing regimens.International Myeloma Working Group. 
Blood. 2009 Aug 27;114(9):1729-35. Epub 2009 Jun 26. 
  
11 Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, Kumar S, 
Munshi NC, Dispenzieri A, Kyle R, Merlini G, San Miguel J, Ludwig H, Hajek R, Jagannath 
S, Blade J, Lonial S, Dimopoulos MA, Einsele H, Barlogie B, Anderson KC, Gertz M, Attal 
M, Tosi P, Sonneveld P, Boccadoro M, Morgan G, Sezer O, Mateos MV, Cavo M, Joshua D, 
Turesson I, Chen W, Shimizu K, Powles R, Richardson PG, Niesvizky R, Rajkumar SV, 


46
Durie BG;  International myeloma working group (IMWG) consensus statement and 
guidelines regarding the current status of stem cell collection and high-dose therapy for 
multiple myeloma and the role of plerixafor (AMD 3100). IMWG. Leukemia. 2009 
Oct;23(10):1904-12. Epub 2009 Jun 25. 
 
12 Giralt S, Vesole DH, Somlo G, Krishnan A, Stadtmauer E, Mccarthy P, Pasquini MC; 
Tandem vs single autologous hematopoietic cell transplantation for the treatment of multiple 
myeloma: a systematic review and meta-analysis. Blood and Marrow Transplant Clinical 
Trials Network Multiple Myeloma Working Group. J Natl Cancer Inst. 2009 Jul 
1;101(13):964; author reply 966-7. Epub 2009 Jun 17. N 
 
13 Niesvizky R, Siegel D, Michaeli J: Biology and treatment of multiple myeloma. Blood 
Reviews 7:24-33, 1993  
14  Mark T, Niesvizky R, Coleman M. Novel agents in myeloma: an exciting saga. Cancer. 
2008 Nov 24;115(2):236-242. 
 
15 Niesvizky R, Glassman J, Straus D, Fine J, Siegel D and Michaeli J: Vincristine, 
Doxorubicin, and Dexamethasone (VAD) Followed by Sequential High-Dose 
Cyclophosphamide (CTX) is Effective in Rapidly Reducing Tumor Mass in Patients with 
Advanced Myeloma and Poor Prognostic Features. Leukemia and Lymphoma, 43(3), 607-
612, 2002. 
 
16 Niesvizky R, Choy CG, Fine J, Glassman J, Reich L, Straus D, Zhu A, Michaeli J: Impact of 
initial response on disease progression following tandem peripheral blood stem cell 
transplants in patients with poor prognosis multiple myeloma. ASH December, 1998. 
Abstract # 2728. 
 
17 Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, 
Lentzsch S, Munshi N, Niesvizky R, San Miguel J, Ludwig H, Bergsagel L, Blade J, Lonial 
S, Anderson KC, Tosi P, Sonneveld P, Sezer O, Vesole D, Cavo M, Einsele H, Richardson 
PG, Durie BG, Rajkumar SV. Mobilization in myeloma revisited: IMWG consensus 
perspectives on stem cell collection following initial therapy with thalidomide, lenalidomide 
or bortezomib- containing regimens. Blood. 2009 Jun 26. 
 
18 Mazumder A , Kaufman J, Niesvizky R , Lonial S , Vesole D.H., Jagannath S. Effect of 
lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated 
multiple myeloma patients. Leukemia. 2008 Jun;22(6):1280-1 
 
19 Tomer Mark, Jessica Stern, Jessica Furst, April LaRow, Roger N Pearse, John Harpel, 
Tsiporah Shore, Michael Schuster, John P Leonard, Paul J Christos, Morton Coleman, Ruben 
Niesvizky. Cyclophosphamide Overcomes the Suppressive Effect of Lenalidomide Therapy 
On Stem Cell Collection In Preparation for Autologous Stem Cell Transplantation for 
Multiple Myeloma.  Biology of Blood and Marrow Transplantation, 2008 Jul;14(7):795-8. 


47
20 DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, Maziarz RT, 
Hosing C, Früehauf S, Horwitz M, Cooper D, Bridger G, Calandra G; 3102 Investigators. 
Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for 
autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009 Jun 
4;113(23):5720-6. Epub 2009 Apr 10. 
 
21 Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, Kumar S, 
Munshi NC, Dispenzieri A, Kyle R, Merlini G, San Miguel J, Ludwig H, Hajek R, Jagannath 
S, Blade J, Lonial S, Dimopoulos MA, Einsele H, Barlogie B, Anderson KC, Gertz M, Attal 
M, Tosi P, Sonneveld P, Boccadoro M, Morgan G, Sezer O, Mateos MV, Cavo M, Joshua D, 
Turesson I, Chen W, Shimizu K, Powles R, Richardson PG, Niesvizky R, Rajkumar SV, 
Durie BG. International myeloma working group (IMWG) consensus statement and 
guidelines regarding the current status of stem cell collection and high-dose therapy for 
multiple myeloma and the role of plerixafor (AMD 3100). Leukemia. 2009 Jun 25.  
 
22 Paul G. Richardson, Ruben Niesvizky, Kenneth C. Anderson, Joan Bladé. When You Look 
Matters: The Effect of Assessment Schedule on Progression-Free Survival. J Natl Cancer 
Inst. 2008 Mar 5;100(5):373. Epub 2008 Feb 26  
23 Ruben Niesvizky, Paul G. Richardson, S. Vincent Rajkumar, Pieter Sonneveld, Michael W. 
Schuster, Morton Coleman, David Irwin, Edward A. Stadtmauer, Thierry Facon, Jean-Luc 
Harousseau, Dina Ben-Yehuda, Sagar Lonial, Hartmut Goldschmidt, Donna Reece, Jesús F. 
San Miguel, Mario Boccadoro, Jamie D. Cavenagh, William S. Dalton, Anthony L. Boral, 
Dixie-Lee Esseltine, Rachel Neuwirth, Kenneth C. Anderson, Joan Bladé. The relationship 
between quality of response to bortezomib and clinical benefit in the international, 
randomized, phase 3 APEX trial in relapsed multiple myeloma Br J Haematol. 2008 
Sep;143(1):46-53. Epub 2008 Jul 3 
24 Tomer Mark,1 Megan C. Manco,1 Maureen Lane,1 Maureen Ward,1 Donna Skerrett,2 Scott 
Ely,2 Michael W. Schuster,1 Tsiporah B. Shore,1 Roger N. Pearse,1 Faiza Zafar,1 Selina 
Chen-Kiang,2 Morton Coleman,1 Ruben Niesvizky1 “The Effect of Bortezomib, 
Cyclophosphamide, and Filgrastim on Complete Remission Rates and CD34+ Stem Cell 
Collections in Multiple Myeloma” 
 
25 Neupogen ® (Filgrastim) Prescribing Information. Available at 
http://www.neupogen.com/pi. html#description.  
26  Gazitt, Y. et al. Personal communication. 


48
APPENDIX A: Performance Status Criteria 
 
ECOG Performance Status Scale 
 
 
Karnofsky1 Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
Source:Mor V, Laliberte L, Morris JN, Wiemann M.  The Karnofsky Performance Status Scale:  an examination of 
its reliability and validity in a research setting.  Cancer 1984;53:2002-2007. 
Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the palliative treatment 
of cancer. Cancer1948; 1(4):634-656. 
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM, ed. 
Evaluation of Chemotherapeutic Agents. New York: Columbia University Press, 1949, I9 1-205. 
 
 
 
 
 
 


49
APPENDIX B: WCMC IRB SAE Reporting Forms 
http://www.med.cornell.edu/research/for_pol/ins_rev_boa.html 


50
APPENDIX C: International Uniform Response Criteria for Multiple Myeloma  
Stringent Complete Response (sCR) requires all of the following: 
 
All of the criteria of complete response  
 
Normal serum free light chain ratio 
 
Absence of monoclonal cells on bone marrow aspirate by immunohistochemistry or immunofluorescence 
Complete Response (CR) requires all of the following: 
 
Absence of the original monoclonal protein in serum and urine by inmmunofixation. The presence of oligoclononal bands consistent with 
oligoclonal immune reconstitution does not exclude CR. 
 
≤5% plasma in a bone marrow aspirate and also on trephine bone biopsy, if biopsy is performed. If absence of monoclonal protein is sustained 
for 6 weeks it is not necessary to repeat the bone marrow, except in patients with non-secretory myeloma where the marrow examination must 
be repeated after an interval of at least 6 weeks to confirm CR. 
 
No increase in size or number of lytic bone lesions (development of a compression fracture does not exclude response) 
 
Disappearance of soft tissue plasmacytoma. 
Very Good Partial Response (VGPR) requires all of the following: 
 
Negative serum and urine protein electrophoeresis with persistence of monoclonal protein detectable on immunofixation OR 
 
≤90% reduction in serum monoclonal protein level with urine monoclonal protein level < 100mg in 24 hour collection.  
Partial Response (PR) requires all of the following: 
 
50% reduction in the level of the serum monoclonal paraprotein. 
 
Reduction in 24h urinary light chain excretion either by 90% or to <200mg. 
 
For patents with  light chain only disease, then a 50% reduction in the difference between the involved and uninvolved free light chain level 
may be substituted for the M-protein measurement.  
 
For patients with non-secretory myeloma only, 50% reduction in plasma cells in a bone marrow aspirate and on trephine bone biopsy, if biopsy 
is performed. 
 
50% reduction in the size of soft tissue plasmacytomas (by radiography or clinical examination). 
 
No increase if size or number of lytic bone lesion (development of a compression fracture does not exclude response) 
Stable Disease (SD) requires the following: 
 
Not meeting the criteria stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response 
(PR) 
Plateau: 
 
Stable values (within 25% above or below value at the time response is addressed) 
Patients in which no significant change (<50% decrease or <25% increase from baseline) in the production rate of the monoclonal serum protein or 
Bence-Jones protein excretion and no new lytic lesions and/or plasmacytomas are detected. 
Relapse from CR requires at least one of the following: 
 
Reappearance of serum or urinary paraprotein on immunofixation or routine electrophoresis, confirmed by at least one further investigation and 
excluding oligoclonal immune reconstitution. 
 
≥5% plasma in a bone marrow aspirate or trephine bone biopsy. 
 
Development of new lytic lesions of soft tissue plasmacytomas or definite increase in the size of residual bone lesions (development of a 
compression fracture does not exclude continued response and may not indicate progression). 
 
Development of hypercalcemia (corrected serum calcium >11.5mg/dl or 2.8 mmol/l) not attributable to any other cause. 
Progressive disease (PD) for patients not in CR requires one or more of the following: 
 
>25 increase in the level of the serum monoclonal paraprotein, which must also be an absolute increase of at least 5g/L and confirmed by at 
least one repeated investigation. 
 
>25 increase in the 24h urinary light chain excretion, which must also be an absolute increase of at least 200mg/24h and confirmed by at least 
one repeated investigation. 
 
>25% increase in plasma cells in a bone marrow aspirate and on trephine bone biopsy, which must also be an absolute increase of at least 10%. 
 
Definite increase in the size of 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 calcium >11.5mg/dl or 2.8 mmol/l) not attributable to any other cause. 


51
APPENDIX D: Body Surface Area and Creatinine Clearance Calculations 
Body surface area (BSA) should be calculated using a standard nomogram that yields the 
following results in meters squared (m2): 
BSA = 
3131
)
(
)
(
lbs
Wt
inches
Ht

 
or 
BSA = 
3600
)
(
)
(
kg
Wt
cm
Ht

 
 
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as follows: 
 
CrCl (ml/min) =  (140-age) (actual wt in kg)               
 
 
 
   72 x serum creatinine (mg/dl) 
For females use 85% of calculated CrCl value. 
Note: In markedly obese patients, the Cockroft-Gault formula will tend to overestimate the 
creatinine clearance. (Adipose tissue tends to contribute little creatinine requiring renal 
clearance.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 


52
                                                                                                                                                             
APPENDIX E: FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 
FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 
By circling one (1) number per line, please indicate how true each statement has been for you 
during the past 7 days. 
ADDITIONAL CONCERNS 
Not 
at all
A little
bit
Some- 
what 
Quite 
a bit 
Very 
much
I have numbness or tingling in my hands………
0
1
2 
3 
4
I have numbness or tingling in my feet…………
0
1
2 
3 
4
I feel discomfort in my hands………………….
0
1
2 
3 
4
I feel discomfort in my feet……………………
0
1
2 
3 
4
I have joint pain or muscle cramps……………
0
1
2 
3 
4
I feel weak all over……………………………
0
1
2 
3 
4
I have trouble hearing…………………………
0
1
2 
3 
4
I get a ringing or buzzing in my ears…………
0
1
2 
3 
4
I have trouble buttoning buttons………………
0
1
2 
3 
4
I have trouble feeling the shape of small objects 
when they are in my hand………………………
0
1
2 
3 
4
I have trouble walking…………………………
0
1
2 
3 
4
________________________________ 
Sources:  Cella DF, Tulsky DS, Gray G, Sarafian B, Lloyd S, Linn E, et al.  The functional assessment of 
cancer therapy (FACT) scale:  development and validation of the general measure.  J Clin Oncol 
1993;11(3):570-79. 


53
                                                                                                                                                             
APPENDIX F: New York Heart Association Classification of Cardiac Disease 
 
The following table presents the NYHA classification of cardiac disease: 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
_______________________________ 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & 
Co; 1994:253-256 
 


54
                                                                                                                                                             
APPENDIX G: International Myeloma Working Group Diagnostic Criteria 
Diagnosis   
Diagnostic Criteria: All Three Required 
Symptomatic multiple myelomaa
 
Monoclonal plasma cells in the bone marrow >/=10% 
and/or presence of a biopsy-proven plasmacytoma 
 
Monoclonal protein present in the serum and/or urineb 
 
Myeloma-related organ dysfunction (>/=1)c  
[C] Calcium elevation in the blood (serum 
calcium >10.5 mg/l or upper limit of normal 
[R] Renal insufficiency (serum creatinine >2mg 
per 100 ml) 
[A] Anemia (hemoglobin <10 g per 100 ml or 2 
g <normal) 
[B] Lytic bone lesions or osteoporosisd 
Monoclonal gammopathy of 
undetermined significance 
(MGUS) 
 
Serum monoclonal protein lowe 
 
Monoclonal bone marrow plasma cells <10% 
 
No evidence of end-organ damage attributable to the 
clonal plasma cell disorder: 
 
Normal serum calcium, hemoglobin level and serum 
creatinine 
 
No bone lesions on full skeletal X-ray survey and/or 
other imaging if performed 
 
No clinical or laboratory features of amyloidosis or light 
chain deposition disease 
Smoldering or indolent myelomaf 
 
Monoclonal protein present in the serum 3 g per 100 ml 
or higher or 
 
Monoclonal plasma cells 10% or greater present in the 
bone marrow and/or a tissue biopsy 
 
No evidence of end-organ damage attributable to the 
clonal plasma cell disorder: 
 
Normal serum calcium, haemoglobin level and serum 
creatinine 
 
No bone lesions on full skeletal X-ray survey and/or 
other imaging if performed 
 
No clinical or laboratory features of amyloidosis or light 
chain deposition disease 
Solitary plasmacytoma of bone  
 
Biopsy-proven plasmacytoma of bone in a single site 
only. X-rays and magnetic resonance imaging and/or 
 
FDG PET imaging (if performed) must be negative 
outside the primary site.  


55
                                                                                                                                                             
 
The primary lesion may be associated with a low serum 
and/or urine M-component 
 
The bone marrow contains no monoclonal plasma cells 
 
No other myeloma-related organ dysfunction 
Adapted with permission from Kyle and Rajkumar, Criteria for diagnosis, staging, risk stratification and response assessment of 
multiple myeloma..Leukemia 2009; 23: 3–9. 
aThese criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA becomes 
smoldering or indolent myeloma. 
bIf no monoclonal protein is detected (non-secretory disease), then >/= 30% monoclonal bone marrow plasma cells 
and/or a biopsy-proven plasmacytoma required. 
cA variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy. Such 
dysfunction is sufficient to support classification as myeloma if proven to be myeloma related. 
dIf a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) is the sole defining criteria, 
then >/= 30% plasma cells are required in the bone marrow. 
eLow is defined as serum M protein <3.0 g per 100 ml. 
fThese criteria identify Stage IA myeloma by Durie/Salmon stage. 
Source: International Myeloma Foundation. IMWG Criteria for the Diagnosis of Myeloma and Guidelines for the 
Diagnostic Work-Up of Myeloma. 2010. 14 Mar 2011 <http://myeloma.org/ArticlePage.action?articleId=2970> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX H: Common Terminology Criteria for Adverse Events 
http://ctep.cancer.gov/reporting/ctc.html