Conditions: Multiple Myeloma
Keywords: Multiple Myeloma Transplant
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 54
Healthy volunteers: no

Brief summary:
The hypothesis for this study is that the regimen consisting of fludarabine, melphalan and bortezomib improves the progression free survival and the response rate compared to historical controls of fludarabine and melphalan alone.

Detailed description:
Multiple myeloma is the second most prevalent blood cancer (10%) after non-hodgkin's lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset.

The historical control 2-year progression-free survival (PFS) is assumed to be 35%. The proposed therapy of fludarabine, melphalan and bortezomib is expected to improve the PFS by 20%.

Arms:
arm 1: None

Interventions: intervention 1: Fludarabine monophosphate, melphalan, Bortezomib
Intervention descriptions: intervention 1: * Fludarabine will be administered at a dose of 30/mg/m2 IV daily for 4 days starting on transplant day -5.
* Melphalan will be administered at a dose of 140 mg/m2 on transplant day-2
* Bortezomib will be administered by rapid IV push at a dose of 1.6mg/m2 on days-4 and -1. The bortezomib should be given at least 20 hours after the melphalan.

Protocol document:
Prot_SAP_000.pdf: 
Protocol, Amendment 5, 08Nov2019 
Page 1 of 41 
Protocol Number:  Pro00001261 
A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplantation for 
Multiple Myeloma Using a Conditioning Regimen of Fludarabine, Melphalan, 
and Bortezomib 
 
Protocol Version: 
 
 
Date of Protocol: 
Original, v.1  
 
 
 10Feb2010 
Amendment 1  
 
 
 20Jul2011 
Amendment 2  
 
 
 27Dec2012 
Amendment 3  
 
 
 29May2013 
Amendment 4  
 
 
 09Feb2016 
Amendment 5                                      08Nov2019 
 
 
BLOOD AND MARROW TRANSPLANTATION PROGRAM 
HACKENSACK UNIVERSITY MEDICAL CENTER 
 
 
Principle Investigator: 
Michele Donato, M.D.  (551) 996-5900 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol, Amendment 5, 08Nov2019 
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VELCADE is the exclusive trademark of Millenium Pharmaceuticals, Inc., registered in theUnited States 
and internationally 
TABLE OF CONTENTS 
1 
INTRODUCTION AND STUDY RATIONALE ............................................................. 7 
1.1 
Overview of the Disease ........................................................................................ 7 
1.2 
Clinical Studies of High-Dose Therapy of Multiple Myeloma ............................. 7 
1.3 
Autologous hematopoietic stem cell transplantation for multiple myeloma ......... 7 
1.4 
Allogeneic stem cell transplatation for multiple myeloma .................................... 8 
1.5 
Transplant regimen intensity .................................................................................. 8 
1.6 
Fludarabine-melphalan conditioning regimen for multiple myelmoma ................ 9 
1.7 
Bortezomib ............................................................................................................. 9 
1.8 
Bortezomib in allogeneic transplantation ............................................................ 11 
2 
STUDY RATIONALE .................................................................................................... 12 
2.1 
Primary Objective ................................................................................................ 12 
2.2 
Secondary Objectives........................................................................................... 12 
3 
INVESTIGATIONAL PLAN .......................................................................................... 13 
3.1 
Overall Design and Plan of the Study .................................................................. 13 
3.2 
Patient Inclusion and Exclusion Criteria .............................................................. 13 
3.3 
Donor Inclusion and Exclusion Criteria .............................................................. 14 
3.4 
Patient Evaluation ................................................................................................ 15 
3.5 
Donor Evaluation ................................................................................................. 16 
3.6 
HSC Product Evaluation ...................................................................................... 16 
3.7 
Post-Transplant Evaluation .................................................................................. 16 
3.8 
Post transplant re-staging of disease .................................................................... 17 
3.9 
Study Medications ............................................................................................... 20 
3.10 
Outline of Treatment Plan .................................................................................... 20 
3.11 
Conditioning Regimen ......................................................................................... 21 
3.12 
Stem cell infusion ................................................................................................ 21 
3.13 
Graft versus host disease (GVHD) prophylaxis................................................... 21 
3.14 
Supportive care after transplant ........................................................................... 21 
3.15 
Post-transplant cytokine administration ............................................................... 21 
3.16 
GvHD Management ............................................................................................. 21 
4 
ADVERSE EVENTS ....................................................................................................... 22 
4.1 
Definitions............................................................................................................ 22 
4.2 
Procedures for AE and SAE Reporting ............................................................... 23 
4.3 
Assessment of Toxicity (Appendix B) ................................................................. 23 
4.4 
Assessment of Causality ...................................................................................... 24 
4.5 
Follow-up of Advesre Experiences ...................................................................... 24 
5 
Statistical Evaluation ....................................................................................................... 25 
5.1 
Endpoints ............................................................................................................. 25 
5.2 
Descriptive analysis ............................................................................................. 25 
5.3 
Accrual, Registration and Follow-up ................................................................... 26 


Protocol, Amendment 5, 08Nov2019 
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5.4 
Sample Size and Power Calculations ................................................................... 26 
5.5 
Efficacy analysis .................................................................................................. 26 
5.6 
Statistical Hypothesis ........................................................................................... 27 
5.7 
Primary endpoint .................................................................................................. 27 
5.8 
Secondary endpoints ............................................................................................ 27 
5.9 
Safety analysis ..................................................................................................... 28 
5.10 
Monitoring Compliance ....................................................................................... 29 
5.11 
Data Management and Analysis .......................................................................... 29 
6 
ADMINISTRATIVE REQUIREMENTS ....................................................................... 31 
6.1 
Good Clinical Practice ......................................................................................... 31 
6.2 
Ethical Considerations ......................................................................................... 31 
6.3 
Patient Information and Informed Consent.......................................................... 31 
6.4 
Donor Information and Informed Consent .......................................................... 31 
6.5 
Protocol Registration ........................................................................................... 31 
6.6 
Patient Confidentiality ......................................................................................... 31 
6.7 
Record Retention ................................................................................................. 32 
6.8  
Investigational New Drug Exemption ................................................................. 32 
7 
Karnofsky Performance Status Scale ............................................................................... 33 
8 
Body Surface Area and Creatinine Clearance Calculations ............................................ 33 
9 
New York Heart Association Classification of Cardiac Disease ..................................... 33 
10 
Declaration of Helsinki .................................................................................................... 35 
11 
Common Terminology Criteria for Adverse Events Version 3.0 .................................... 39 
 
12        REFERENCES ................................................................................................................ 40 
  
 
 
 
 
 
 
 


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ABBREVIATIONS LIST 


Protocol, Amendment 5, 08Nov2019 
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Abbreviation 
Definition 
°C 
degrees Celsius 
µM 
Micromolar 
20S 
20S proteasome subunit 
AE 
adverse event 
ANC 
absolute neutrophil count 
Bc1-2 
B-cell lymphoma-2; a gene that inhibits apoptosis 
BSA 
body surface area 
CAM 
cell adhesion molecules  
cm 
Centimeter 
CR 
Complete Response 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DNA 
deoxyribonucleic acid 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
ht 
Height 
IκB 
I kappa B kinase; cytokine response kinase that activates 
transcription factor NF-kappa b at serine 32 and 36 
ICAM-1 
intercellular adhesion molecule 1 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
IκBα 
I kappa B alpha-associated protein kinase 
kg 
Kilogram 
Ki 
inhibitory constant 
lbs 
Pounds 
m2 
square meters 
mg 
Milligram 
min 
Minute 


Protocol, Amendment 5, 08Nov2019 
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Abbreviation 
Definition 
mL 
Milliliter 
mm3 
cubic millimeters 
mmol 
Millimole 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NF-κB 
nuclear factor-κB 
ng 
Nanogram 
nM 
Nanomole 
p21 
p21(ras) farnesyl-protein transferase 
p27 
cyclin-dependent kinase inhibitor 
p53 
tumor suppressor protein with molecular weight of 53 kDa 
SAE 
serious adverse event 
US 
United States 
USP 
United States Pharmacopeia 
VCAM-1 
vascular cell adhesion molecule 1 
w/w 
weight-to-weight ratio 
wt 
Weight 


Protocol, Amendment 5, 08Nov2019 
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1 
INTRODUCTION AND STUDY RATIONALE 
1.1 
Overview of the Disease 
Multiple myeloma is the second most prevalent blood cancer (10%) after non-hodgkin’s 
lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths. 
Although the peak age of onset of multiple myeloma is 70 years of age, recent statistics 
indicate both increasing incidence and earlier age of onset. 
Multiple myeloma affects slightly more men than women. African Americans and Native 
Pacific Islanders have the highest reported incidence of this disease in the United States 
and Asians the lowest. Results of a recent study found the incidence of myeloma to be 9.5 
cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. 
Among African Americans, myeloma is one of the top 10 leading causes of cancer death. 
1.2 
Clinical Studies of High-Dose Therapy of Multiple Myeloma 
Standard dose therapy for most plasma cell disorders includes regimens such as low-dose 
melphalan (32 mg/m2/month) with prednisone.  For patients with multiple myeloma, this 
regimen results in a 40% overall response rate, but few patients achieve a complete 
remission and the median duration of response is only 2 years.  The median survival is in 
the range of 3 years and few (<15%) survive 5 years.  More aggressive chemotherapy 
regimens, including VAD, VBMCP and M2, induce remissions more quickly but overall 
survival rates are not substantially improved (Alexanian and Dimopoulos, 1994). 
These poor outcomes led many investigators explored high-dose chemotherapy regimens.  
In 1983, McElwain used melphalan 140 mg/m2 without stem cell support as a salvage 
therapy in nine patients with refractory myeloma and noted all patients responded to 
treatment with five patients achieving complete biochemical and bone marrow responses 
(McElwain and Powles, 1983).  This observation of dose-response led to a series of phase 
I/II trials with and without stem cell support in both newly diagnosed and refractory disease 
(Attal et al., 1992; Harousseau et al, 1995). 
A matched-pair analysis by the Arkansas group and SWOG comparing dose-intense with 
standard-dose therapy demonstrated the benefit of autologous HSC transplantation for the 
treatment of multiple myeloma (Barlogie et al., 1997).  Event-free (49 vs 27 months) and 
overall survivals (62+ vs 48 months) were improved for patients treated with dose-intense 
therapy as part of the initial treatment.  
1.3 
Autologous hematopoietic stem cell transplantation for multiple myeloma 
High-dose therapy and autologous stem cell transplantation (ASCT) is an integral 
component of the myeloma treatment for patients considered eligible for the procedure. 
The majority of the randomized clinical trials demonstrated a superior progression-free and 
overall survival among patients undergoing ASCT compared with those treated with only 
conventional therapies. Currently, the “novel” agents of thalidomide, lenalidomide and 
bortezomib appear best suited to be used as first-line therapy, enhancing the quality of 
responses prior to proceeding to ASCT and diminishing early mortality from the disease. 
Tandem transplantation has been shown to improve the event-free survival and overall 
survival of patients with myeloma (4,5). A study of 399 previously untreated patients with 


Protocol, Amendment 5, 08Nov2019 
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myeloma  randomized these patients to receive either single or double transplantation. The 
probability of surviving event-free for seven years after the diagnosis was 10 percent in the 
single-transplant group and 20 percent in the double-transplant group (P=0.03). The 
estimated overall seven-year survival rate was 21 percent in the single-transplant group and 
42 percent in the double-transplant group. Therefore, as compared with single autologous 
stem-cell transplantation after high-dose chemotherapy, double transplantation improves 
overall survival among patients with myeloma, especially those who do not have a very 
good partial response after undergoing one transplantation.  Yet most patients will relapse 
at a median of three years after transplantation. 
1.4 
 Allogeneic stem cell transplantation for multiple myeloma 
Allogeneic transplantations have been performed for multiple myelomas since the 1980’s 
(6). The initial rationale in performing these transplants was to administer high-dose 
chemotherapy to eradicate myeloma cells and provide the patient with a disease-free 
marrow. It soon became apparent that a graft-versus-myeloma effect exists(7). Although 
the relapse/progression rates appeared lower, the initial enthusiasm for performing 
allogeneic transplantation in MM was tempered by the elevated treatment-related toxicity, 
approaching 40% in trials involving total body irradiation or busulfan based myeloablative 
regimens.  In an EBMT retrospective case-matched analysis of 378 patients, the overall 
survival was inferior compared to autologous transplantation as a result of this high risk 
transplant-related mortality(8). Ablative regimens were used in these original transplants 
and the main causes of death were severe infections often combined with severe GVHD.  
The EBMT database and the US Intergroup trial showed a plateau at approximately 25% 
indicating a probable cure for an otherwise incurable disease. 
1.5 
Transplant regimen intensity 
Based on the idea that the graft-versus-myeloma (GVM) effect is more important than the 
intensity of the conditioning regimens, the Seattle group developed an allogeneic transplant 
modality using considerably lower intensity in the conditioning regimen(9). Transplant-
related mortality was reduced significantly but relapses after transplantation remains a 
major concern with this approach. In a recent retrospective study by the EBMT, reduced 
intensity conditioning was compared to myeloablative conditioning(10). A dose of 
melphalan less than 140 mg/m2, a busulfan dose of 8 mg/kg or less and a 
cyclophosphamide dose less than 120 mg/kg was considered to be reduced intensity. If 
total body irradiation was used, a dose of radiation less than 6 Gy or up to 6 Gy 
fractionated was accepted as reduced intensity. With this definition, reduced intensity 
conditioning was associated with lower non-relapse mortality but a higher relapse rate 
compared to myeloablative conditioning. The progression-free survival was superior with 
myeloablative conditioning but there was no significant difference in overall survival. It is 
therefore concluded that the intensity/activity of the conditioning regimen does have an 
impact on relapse-free survival. New supportive treatment modalities in recent years and 
better GVHD prophylaxis, has lead to a reduction in mortality for patients receiving 


Protocol, Amendment 5, 08Nov2019 
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ablative regimens. The EBMT data has shown a significant reduction in mortality for 
patients transplanted after 1994(11). 
Most recently, a strategy using high dose melphalan with autologous ASCT for maximal 
cytoreduction followed by an non-myeloablative regimen to allow for eradication of 
residual disease by GVM has shown considerable promise. Response rates usually exceed 
50% with transplant-related mortality in the 10-15% range. When this approach was 
compared directly to tandem ASCT, the auto-allo patients had superior PFS and OS 
compared to tandem ASCT. A similar prospective randomized US trial which enrolled 710 
patients will provide mature data in the first quarter 2010. 
Unfortunately, even with this strategy of ASCT for maximal cytoreduction and a tandem 
reduced intensity allogeneic transplant for eradication of minimal residual disease, patients 
continue to relapse, even in the setting of GVHD. Thus, we believe the major limitation to 
improving outcomes is disease relapse after the allogeneic transplant. 
1.6 
Fludarabine- melphalan conditioning regimen for multiple myeloma 
The combination of fludarabine and melphalan has been studied as a preparative regimen 
for allogeneic transplantation for patients with multiple myeloma (12). Twenty-two patients 
with multiple myeloma between 1996 and 2000 received the combination of fludarabine 
and melphalan. Eighteen patients received fludarabine 30 mg/m2 for 5 days with melphalan 
140 mg/m2 as a single dose and 4 patients received fludarabine 25 mg/m2 for 5 days with 
melphalan 90 mg/m2 daily for 2 days. The actuarial overall survival and progression-free 
survival at 2 years was 30% and 19% respectively. Non-relapse mortality was 19% at day 
100. Similarly, Kroger et al. reported on the fludarabine-melphalan combination (13). The 
treatment-related mortality at day 100 was 11%. Fifty-five percent of the patients obtained 
a complete remission and 27% a partial remission, giving an overall response rate of 82%. 
The updated overall survival and disease-free survival was 68% and 42%, respectively. 
Kroger et al have recently published their collective results of salvage therapy after 
allogeneic transplant. Patients were treated with donor lymphocyte infusions (DLI) with 
one or more novel agents (bortezomib; thalidomide). High response rates were observed 
with prolonged progression-free survival indicating that post-transplant novel therapies can 
still achieve significant anti-myeloma effects which may enhance the efficacy of DLI (to 
induce GVM). Furthermore, this study showed the feasibility and toxicities of post-
allogeneic novel therapy administration. 
1.7 
Bortezomib  
Bortezomib is a small molecule proteasome inhibitor developed by Millennium 
Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies.  
Bortezomib is currently approved by the United States Food and Drug Administration 
(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 


Protocol, Amendment 5, 08Nov2019 
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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 induces apoptosis in cells that over express bcl-2, a genetic trait 
that confers unregulated growth and resistance to conventional chemotherapeutics. 
Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear 
factor κB (NF-κB) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, 
a direct apoptotic effect, and possibly anti-angiogenic and other effects. Bortezomib has 
shown synergy when combined with various chemotherapeutics in pre-clinical and 
clinical models (14,15).  
We are conducting a phase I/II clinical study of bortezomib with dose-intense melphalan 
with autologous peripheral blood stem cell transplantation in patients with disease 
progression or less than partial response after a prior PBSCT (tandem 
transplant).  Primary exclusion criteria are active infection at time of PBSCT, cardiac 
amyloid deposition, and creatinine clearance of <20 ml/min. Peripheral neuropathy of less 
than grade 4 is not an exclusion.  Bortezomib is given on days -4 and -1 with melphalan 
200 mg/m2 (actual weight) given on day -2 before PBSCT.  For the phase I study, 
bortezomib was given at rising doses of 1.0, 1.3, and 1.6 mg/m2.  Three patients were to 
be enrolled at each dose level, with an additional 3 patients enrolled in case of a serious 
toxicity event at any level. An additional 20 patients are being enrolled in the phase II 
portion of the study with 15 patients enrolled as of 12/1/09 (patient accrual will be 
completed before enrollment into this study).  
Twelve patients (median age, 58 yrs) were treated in the phase I study with 6 patients 
treated at the 1.0 mg/m2 level after 1 patient experienced a serious adverse event (SAE) of 
prolonged diarrhea, and 3 patients treated at each of the subsequent levels. Eleven patients 
had 1 prior and 1 patient tandem prior cycles of dose-intense melphalan. All patients 
experienced the expected pancytopenia requiring red cell and/or platelet support.  Ten 
patients had febrile neutropenia with bacteremia identified in 3 patients. One patient had 
mild tumor lysis not requiring medical intervention.  Mucositis was minimal and 
comparable to PBSCT with melphalan alone. All patients engrafted at a median time to 
ANC>500/uL of 11 days (range, 9-19) and platelet>20,000/uL of 14 days (range, 11-27). 
No other SAEs occurred in the phase I study beyond the usual events of high-dose 
therapy. No neurological SAEs, including severe peripheral neuropathies, were observed. 
A bortezomib dose of 1.6 mg/m2 was chosen for the phase II study.  
Fifteen patients (median age, 56 yrs) are now treated in the phase II study. Six patients 
had disease progression and 9 patients had less than a partial response (PR) after a prior 
PBSCT. All patients experienced pancytopenia and evaluable patients engrafted with 
median time to ANC>500/uL of 10 days (range, 8-13) and platelet>20,000 of 11 days 
(range, 9-65).  Eleven patients had febrile neutropenia with 3 patients with positive blood 
cultures and 1 patient with RSV bronchitis.  Three SAEs are reported in the phase II 
portion: 1 patient expired of complications of Candida krusei infection and 1 of MRSA 
sepsis (before ANC recovery). A third patient developed tumor lysis requiring dialysis. 
One patient had a dysphoric reaction to anti-emetics and did not receive the 2nd 


Protocol, Amendment 5, 08Nov2019 
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bortezomib dose.  No neurological SAEs attributable to this regimen were observed in 
this population.  
Patients underwent restaging studies at monthly intervals after transplantation with 
marrow examination at 3 and 12 months.  Response classification is in accordance to 
standard definitions. Three patients underwent subsequent allogeneic PBSC and 2 
patientss died of transplant-related complications and are not evaluable for response. Two 
patients succumbed to progressive disease. The remaining 20 patients are in ongoing 
follow-up. Eight patients including 6 of 11 patents with stable disease or minimal 
response after prior dose-intense melphalan achieved a CR. Six patients remain in 
continuous CR at 11+ to 23+ months (median, 15+ months) after PBSCT with 2 patients 
having disease progression at 12 and 26 months after PBSCT.  
These data indicate that bortezomib can be added to dose-intense melphalan in this 
schedule with acceptable toxicities. Strikingly, 8 of 22 pts achieved CR after minimal 
response to dose-intense melphalan alone or disease progression after a prior PBSCT, and 
2 patients showed tumor lysis, indicating a synergistic effect of adding bortezomib to 
dose-intense melphalan..  
1.8 
Bortezomib in allogeneic transplantation 
Bortezomib exerts numerous biologic effects that include blocking the activation of the 
transcription factor, nuclear factor-κB. NF-κB is implicated in the regulation of many 
genes that code for mediators of the immune and inflammatory responses. Bortezomib has 
been used as an immunomodulatory agent in the context of allogeneic transplantation. The 
Dana-Farber group used a GVHD prophylaxis regiment of bortezomib, methotrexate and 
tacrolimus in a study of patients undergoing related,unrelated donor transplantation for 
malignancies.(16). The incidence of grade II-IV acute GVHD was 13% and the incidence 
of chronic GVHD was 41%.  These results appear to compare favorably to standard 
prophylactic regimens. In addition, numerous reports of bortezomib for the treatment of 
graft versus host disease have been published.  


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2 
Study Rationale 
In this study we are proposing to treat patients with advanced multiple myeloma using the 
combination of fludarabine, melphalan and bortezomib followed by allogeneic hematopoietic stem 
cell transplantation. The hypothesis is that we can maximize the efficacy of the preparative 
regimen without increasing the regimen-related mortality. 
2.1 
Primary Objective: 
The primary objective of this study is determine if the addition of two doses of bortezomib to a 
standard regimen of fludarabine and melphalan followed by allogeneic HSC transplantation will 
improve progression-free survival at two years after transplantation for patients with multiple 
myeloma. 
2.2 
Secondary Objectives: 
To investigate: 
2.2.1 Overall survival (OS):  Defined as time from the first dose of administration to 
death from any cause 
2.2.2 Overall response rates: Defined as the composite endpoint of response to 
treatment which includes Complete Response (CR), Partial Response (PR), 
stable disease (SD) as defined in International Response Criteria. We will also 
analyze Complete Response rate 
2.2.3 Univariate analysis of the risk of progression/relapse and mortality: In addition, 
multivariate analysis of the risk of progression/relapse and overall mortality will 
be conducted to assess influence of variables measured after the start of 
treatment 
2.2.4 Regimen-related toxicity of this regimen 


Protocol, Amendment 5, 08Nov2019 
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3 
Investigational Plan 
3.1 
Overall Design and Plan of Study 
This is a single institution non-randomized phase II study to determine if allogeneic 
hematopoietic stem cell transplantation using the fludarabine, melphalan and bortezomib 
regimen is superior to historical controls.  
3.2 
Patient Inclusion and Exclusion Criteria 
3.2.1 Patient Inclusion Criteria: 
3.2.1.1 
Diagnosis of multiple myeloma 
3.2.1.2 
Have a suitable related or unrelated donor (Section 3.3) 
3.2.1.3 
Age ≥18 but <70 yrs 
3.2.1.4 
KPS of ≥70% 
3.2.1.5 
Recovery from complications of previous therapies 
3.2.2 Patient Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study. 
3.2.2.1 
Diagnosis other than multiple myeloma 
3.2.2.2 
Chemotherapy or radiotherapy within 21 days of initiating 
treatment in this study 
3.2.2.3 
Prior dose-intense therapy requiring HSC support within 56 
days of initiating treatment in this study 
3.2.2.4 
Uncontrolled bacterial, viral, fungal or parasitic infections  
3.2.2.5 
Uncontrolled CNS metastases 
3.2.2.6 
Known amyloid deposition in heart 
3.2.2.7 
Organ dysfunction 
3.2.2.7.1 
LVEF <40% or cardiac failure not responsive to therapy 
3.2.2.7.2 
FVC, FEV1, or DLCO <50% of predicted and/or receiving 
supplementary continuous oxygen 
3.2.2.7.3 
Evidence of hepatic synthetic dysfunction, or total bilirubin >2x or 
AST >3x ULN 
3.2.2.7.4 
Calculated creatinine clearance <20 ml/min 
3.2.2.7.5 
Sensory peripheral neuropathy grade 4 within 14 days of enrollment 
3.2.2.8 
Karnofsky score <70% unless a result of bone disease directly 
caused by myeloma 
3.2.2.9 
Life expectancy limited by another co-morbid illness 
3.2.2.10 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 


Protocol, Amendment 5, 08Nov2019 
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situ malignancy, or low-risk prostate cancer after curative 
therapy 
3.2.2.11 Female subject is pregnant  or breast-feeding (women) or 
unwilling to use acceptable birth control methods (men or 
women) for twelve months after treatment. Confirmation that 
the subject is not pregnant must be established by a negative 
serum β-human chorionic gonadotropin (β-hCG) pregnancy 
test result obtained during screening.  Pregnancy testing is not 
required for post-menopausal or surgically sterilized women. 
3.2.2.12 Documented hypersensitivity to fludarabine or melphalan or to 
bortezomib, boron or mannitol or any components of the 
formulation 
3.2.2.13 Patients unable or unwilling to provide consent 
3.2.2.14 Myocardial infarction within 6 months prior to enrollment or 
has New York Heart Association (NYHA) Class III or IV heart 
failure (see section 8.4), uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, or electrocardiographic 
evidence of acute ischemia or active conduction system 
abnormalities. Prior to study entry, any ECG abnormality at 
screening has to be documented by the investigator as not 
medically relevant 
3.2.2.15 Patient has received other investigational drugs with 14 days 
before enrollment 
3.2.2.16 Serious medical or psychiatric illness likely to interfere with 
participation in this clinical study 
3.3 
Donor Inclusion and Exclusion Criteria 
3.3.1 Donor Inclusion Criteria: 
3.3.1.1 
HLA 6/6 (HLA-A, B, DrB1) related donor or 7/8 (HLA-A, B, 
C, DrB1) unrelated donor 
3.3.1.1.1 
Related donors will be evaluated in accordance with HUMC 
standard practice guidelines for the evaluation and management of 
allogeneic donors 
3.3.1.1.2 
Unrelated donors will be identified, evaluated, and managed in 
accordance with National Marrow Donor Program standards 
3.3.1.2 
Age ≥18 and <70 yrs 
3.3.1.3 
KPS of ≥70% 
3.3.1.4 
Willing to donate peripheral blood HSC by leukapheresis 
3.3.1.5 
Have adequate veins for apheresis or agree to placement of a 
central venous catheter (femoral, subclavian) 
 


Protocol, Amendment 5, 08Nov2019 
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3.3.2 Donor Exclusion Criteria 
3.3.2.1 
Identical twin 
3.3.2.2 
Female donors who are pregnant or breastfeeding 
3.3.2.3 
Infection with HIV or viral hepatitis (B or C) 
3.3.2.4 
Known allergy to filgrastim 
3.3.2.5 
Current serious systemic illness 
3.3.2.6 
Uncontrolled bacterial, viral, or fungal infection 
3.3.2.7 
Receiving experimental therapy or investigational agents 
3.3.2.8 
History of cancer other than treated basal cell cancer of the 
skin or carcinoma in situ of the cervix.  Cancer treated with 
curative intent >5 yrs before donation will be reviewed on a 
case-by-case basis by the principal investigator 
3.4 
Patient Evaluation 
Pre-transplant evaluation must be performed within 30 days of transplant conditioning 
3.4.1 History with full details of the patient’s prior treatments and responses 
3.4.2 Physical exam with determination of Karnofsky score and findings related to 
underlying malignancy 
3.4.3 Chemistry profile to include serum creatinine, AST, alkaline phosphatase, and 
bilirubin 
3.4.4 CBC with differential 
3.4.5 ABO and Rh 
3.4.6 Serum pregnancy test, if female gender with child-bearing potential  
3.4.7 HIV, Hepatitis B, Hepatitis C, CMV serology 
3.4.8 Disease Staging: 
3.4.8.1 
Quantitative immunoglobulin measurement 
3.4.8.2 
Serum protein electrophoresis and immunofixation with 
measurement of monoclonal protein 
3.4.8.3 
Quantitative serum free light chain measurement 
3.4.8.4 
Serum beta 2 microglobulin (β2m) 
3.4.8.5 
24 hr urine collection for quantitation of total protein, protein 
electrophoresis and immunofixation 
3.4.8.6 
Radiological studies of any sites of bone pain or bone scan 
abnormalities 
3.4.8.7 
Skeletal survey if not performed within 6 months of start of 
study treatment 
3.4.9 Pulmonary function tests with DLCO 


Protocol, Amendment 5, 08Nov2019 
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3.4.10 MUGA scan or cardiac echo 
3.4.11 EKG 
3.5 
Donor Evaluation 
Pre-donation evaluation must be performed in accordance with HUMC Standard Operating 
Procedures for the evaluation and management of related HSC donors, or with NMDP 
Standard Operating Procedures for the evaluation and management of unrelated HSC 
donors.  
3.6 
HSC Product Evaluation 
3.6.1 TNC, CD34+, and CD3+ cell counts 
3.7 
Post-Transplant evaluation 
3.7.1 Physical exam daily until hematological recovery and resolution of serious 
regimen-related complications, 
3.7.2 History and physical exam weekly through day 100 after transplantation, then at 
6 months, 9 months, 12 months after transplantation, and then yearly until 3 yrs 
after transplantation 
3.7.2.1 
Assessment and staging of acute and chronic GvHD will be 
performed and recorded at these visits 
3.7.3 Once weekly assessment of toxicity in accordance with NCI toxicity guidelines 
from day-1 until resolution of all Grade 3/4 treatment-related toxicities 
3.7.4 CBC daily from day 0 until ANC ≥500/ul on two sequential days after nadir 
reached (engraftment).   
3.7.5 Chemistry profile 2 times per week until documentation of engraftment  
3.7.6 Chimerism evaluation at 4 weeks (+/- 1 week) then monthly for 3 months (+/- 
10 days). 
3.7.7  Record of all medications administered during inpatient course. 
3.8 
Post transplant re-staging of disease 
3.8.1 Restaging by serum and urine should be done at 4 weeks intervals (±7 days) 
starting at day +28 after transplantation for 3 months and then at 3 months 


Protocol, Amendment 5, 08Nov2019 
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intervals until 3 years after transplantation or demonstration of disease 
progression requiring therapy, if earlier.  
3.8.1.1 
Quantitative immunoglobulin measurements 
3.8.1.2 
Serum protein electrophoresis and immunofixation with 
measurement of monoclonal protein 
3.8.1.3 
Quantitative serum free light chain measurements 
3.8.1.4 
Serum beta 2 microglobulin (β2m) 
3.8.1.5 
24 hr urine collection for quantitation of total protein, protein 
electrophoresis and immunofixation 
3.9 
Study Medications 
3.9.1 Bortezomib (VELCADE) for Injection is a sterile lyophilized powder for 
reconstitution and is supplied in vials containing VELCADE and mannitol at a 
1:10 ratio.  For example, vials containing 3.5 mg of VELCADE contain 35 mg 
of mannitol. Vials containing lyophilized VELCADE for Injection should be 
stored according to the label requirements.  For the United States, store at USP 
Controlled Room Temperature which is 25ºC (77ºF); excursions permitted from 
15 to 30ºC (59 to 86ºF).  For Europe, do not store above 30ºC (86ºF).  To date, 
stability data indicate that the lyophilized drug product is stable for at least 18 
months when stored under the recommended conditions. Stability studies are 
ongoing, and Millennium Pharmaceuticals, Inc. will notify the investigator 
should this information be revised during the conduct of the study. VELCADE 
is cytotoxic.  As with all cytotoxic drugs, caution is required when preparing 
and handling VELCADE solutions.  Cytotoxic drugs should only be handled by 
staff specially trained in the safe handling of such preparations. The use of 
gloves and other appropriate protective clothing is recommended.  In case of 
skin contact, wash the affected area immediately and thoroughly with soap and 
water for at least 15 minutes.  If product contacts eye, immediately flush eye 
thoroughly with water for at least 15 minutes.  Always contact a physician after 
any form of body contact. All materials that have been used for preparation 
should be disposed of according to standard practices. A log must be kept of all 
disposed materials. The drug is available in sterile, single use vials containing 
3.5 mg of VELCADE.  Each vial of VELCADE for Injection should be 
reconstituted under a laminar flow biological cabinet (hood) within eight hours 
before dosing with 3.5 mL of normal (0.9%) saline, Sodium Chloride Injection 
USP, so that the reconstituted solution contains VELCADE at a concentration 
of 1 mg/mL.  Prior to reconstitution the vials should remain in the cartons to 
protect them from light.  Dissolution is completed in approximately 10 
seconds.  The reconstituted solution is clear and colorless, with a final pH of 5 
to 6.  Reconstituted VELCADE should be administered promptly and in no case 
more than 8 hours after reconstitution.  All materials that have been used for 
preparation should be disposed of according to standard practices.  A log must 
be kept of all disposed materials. 


Protocol, Amendment 5, 08Nov2019 
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3.9.2 Melphalan for Injection is a sterile lyophilized powder for reconstitution and 
will be obtained from the manufacturer in accordance with standard pharmacy 
purchasing criteria. Melphalan will be reconstituted by pharmacy staff, in 
accordance with usual pharmacy practices, immediately before patient infusion. 
Melphalan is a bifunctional alkylating agent that acts principally through 
covalent reactions with DNA, resulting in the formation of drug-DNA adducts 
with cross-linking of DNA strands.  Melphalan’s cytotoxic effects are related to 
its concentration and the duration of exposure to melphalan of the cell.  
Enhanced repair of DNA interstrand crosslinks may be a mechanism of 
resistance that develops after prior exposure to this drug. Melphalan is actively 
transported into cells by the high-affinity L-amino acid transport system; 
glutamine and leucine compete for carrier uptake and high levels of these amino 
acids can reduce drug uptake.  Other drugs such as tamoxifen, chlorpromazine, 
and indomethacin can also impair melphalan uptake and accumulation.  Studies 
of the pharmacokinetics of oral melphalan were complicated by the highly 
variable absorption of the drug.  Moreover, studies of intravenous melphalan 
have also showed considerable inter-patient variability in plasma clearance.   
Pinguet et al studied the pharmacokinetics of melphalan administered at a dose 
of 140 mg/m2 in combination with other chemotherapeutic agents to 20 patients 
undergoing autologous PBSC transplantation. The medians time to neutrophil 
and platelet recoveries were 16 and 14.6 days, and the majority of patients 
(80%) developed WHO grade 3/4 stomatitis.  Plasma concentration profiles 
were biphasic and fitted with a two-compartment model.  The maximal 
concentration at the end of infusion averaged 7.94±3.73 mg/l (range, 1.65-14.5).  
The mean elimination half-life and the mean residence time were 83.1±27.1 
minutes (range, 51.6-166.81) and 98.7±26.9 minutes (range 59.5-166.9), 
respectively.  The volume of distribution averaged 1.00±0.62 l/kg (range 0.46-
3.12) and total plasma clearance 548.3±300.0 ml/min/m2 (range, 218.6-1378.8).   
Plasma levels were below the limits of detection for all patients by 24 hours 
after melphalan administration.  These authors noted large inter-individual 
variability of these pharmacokinetic parameters.  Total clearance of melphalan 
was significantly correlated with creatinine clearance (r=0.49, p<0.05).   A 
relationship between melphalan clearance and renal function was also described 
by Kergueris et al., but this relationship did not explain the large variation in 
inter-individual overall clearance of the drug (Kergueris et al., 1994).  Similar 
pharmacokinetic results were reported for 20 pediatric and 10 adult patients 
treated with melphalan 140 mg/m2 as a single agent.  For the adult patients, the 
elimination half-life (t½β) was 50±7 minutes for patients treated with 140 
mg/m2 dose and 41±12 minutes for the higher dose of 180 mg/m2.  Plasma 
clearance averaged 525 ml/min/m2 at 140 mg/m2 and 532 ml/min/m2 at 180 
mg/m2.  
3.9.3 Fludarabine: Fludarabine is a fluorinated nucleotide analogue of the antiviral 
vidarabine. It acts as a purine antagonist antimetabolite. Synonyms: 2-F-ara-
AMP. Bone-marrow suppression from fludarabine is dose-limiting, manifesting 


Protocol, Amendment 5, 08Nov2019 
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as neutropenia, thrombocytopenia, and anemia. Other adverse effects include 
fever, chills, cough, Dyspnea, pneumonia, gastrointestinal disturbances, 
stomatitis, edema, the tumor lysis syndrome, skin rashes, auto-immune 
hemolytic anemia and thrombocytopenia, and hemorrhagic cystitis. 
Neurological disturbances include peripheral neuropathy, agitation, confusion, 
visual disturbances, seizures, and coma; high doses have been associated with 
progressive encephalopathy, blindness, and death.Dosage should be reduced in 
renal impairment and fludarabine should not be given if creatinine clearance is 
less than 30 mL/minute. Intravenous fludarabine phosphate is rapidly 
dephosphorylated to fludarabin, which is taken up by lymphocytes and 
rephosphorylated to the active triphosphate nucleotide. Peak intracellular 
concentrations of fludarabine triphosphate are seen about 4 hours after a dose. 
Fludarabine has a bioavailability of about 50 to 65% after doses of the 
phosphate by mouth.Clearance of fludarabine from the plasma is triphasic with 
a terminal half-life of about 20 hours. Elimination is mostly via renal excretion: 
60% of a dose is excreted in the urine. The pharmacokinetics of fludarabine 
exhibit considerable interindividual variation. 
3.9.4 Anti-thymocyte globulin (ATG) 
 
 
Antithymocyte globulins are antibodies, which act against lymphocytes, and in 
particular against T-cells, to produce suppression of cell-mediated immunity 
Common adverse reactions include fever, chills, and skin reactions including rash, 
pruritus, and urticaria, which may be manifestations of hypersensitivity. Dyspnea, 
hypotension, chest, back or flank pain may indicate anaphylaxis, which can occur in 
up to 1% of patients. Rashes and arthralgia may represent serum sickness, 
especially in patients with aplastic anemia. Use with other immunosuppressants 
may reduce the incidence or severity of hypersensitivity but increase the risk of 
acquired systemic infections, such as CMV or herpes simplex. Enhanced 
immunosuppression may also increase the incidence of post-transplant 
lymphoproliferative disease or other malignancies. Leucopenia and 
thrombocytopenia are also common. Although usually transient, dosage adjustment 
may be necessary if they become severe or prolonged, and if unremitting, they may 
warrant stopping therapy. Other adverse effects include headache, abdominal pain, 
gastrointestinal disturbances, hypertension, peripheral edema, asthenia, 
hyperkalaemia, and tachycardia. Nephrotoxicity has been reported. 
 
 
3.10 
Outline of Treatment Plan 
 
Table 1: Treatment Schema for Conditioning Regimen 


Protocol, Amendment 5, 08Nov2019 
Page 20 of 41 
 
Day of Transplant 
 
-5 
-4 
-3 
-2 
-1 
0 
+1 
+3 
+6 
+9 
+11 
Fludarabine 30mg/m2 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Bortezomib 1.6mg/m2 
 
 
X 
 
 
X 
 
 
 
 
 
 
Melphalan 140 mg.m2 
 
 
 
 
X 
 
 
 
 
 
 
 
rATG (unrelated donor) 
 
 
 
X 
X 
X 
 
 
 
 
 
 
Tacrolimus 
 
 
 
 
X→ 
 
 
 
 
 
 
 
Stem cell infusion 
 
 
 
 
 
 
X 
 
 
 
 
 
Methotrexate 5 mg/m2 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
Filgrastim 5 ug/kg 
 
 
 
 
 
 
 
 
 
 
X→ 
 
 
3.11 
Conditioning Regimen: 
3.11.1 Fludarabine will be administered at a dose of 30 mg/m2 IV daily for 4 days 
starting on transplant day -5. 
3.11.2 Melphalan will be administered at a dose of 140 mg/m2 on transplant day-2  
3.11.3 Bortezomib will be administered by rapid IV push at a dose of 1.6mg/m2 on 
days-4 and -1. The bortezomib should be given at least 20 hours after the 
melphalan. 
3.11.4 Patients receiving cells from an unrelated donor will also receive rabbit 
antithymocyte globulin (Thymoglobulin) at a dose of 0.5 mg/kg IV on day -3, 
1.5 mg/kg on day -2 and 2 mg/kg on day -1 
 
3.11.5 Dose adjustment for the fludarabine, methotrexate and antithymocyte globulin 
will be as follows: 
3.11.5.1 If patient weighs less than 100% of ideal body weight (IBW), 
dosing is based on actual body weight. 
3.11.5.2 If patient weighs 120-150% of IBW, dosing is based on 
adjusted body weight (ABW). 
3.11.5.3 If patient weighs greater than 150% of IBW, actual weight will 
be capped at 150% of ideal body weight, and this will be used 
in the adjusted body weight formula. 
3.11.5.4 Corrected body weight formula: ABW= IBW + [(0.25) x 
(actual BW-IBW)]. 
3.11.6 Melphalan and bortezomib will be dosed based on patient actual weight. 
3.12 
Stem cell infusion: 
3.12.1 Stem cell infusion will occur at least 18 hrs or later after the second bortezomib 
infusion.  Day 0 for purposes of methotrexate administration is defined as the 


Protocol, Amendment 5, 08Nov2019 
Page 21 of 41 
day the HSC infusion is completed. The infusion of peripheral blood stem cells 
will be done in accordance with the Blood and Marrow Transplant program 
standard operating procedures 
3.13 
Graft versus host disease (GVHD) prophylaxis: 
3.13.1 GvHD prophylaxis consists of tacrolimus 0.03 mg/kg ( or 0.015 mg/kg for age 
≥65) using  ideal body weight, IV total daily dose starting on transplant day -2 
and adjusted based on blood levels.  Methotrexate at a dose of 5 mg/m2 IV will 
be administered on transplant days +1, +3, +6 and +11 
3.14 
Supportive care after transplantation 
3.14.1 Supportive care including transfusions, hydration and prophylactic antibiotics 
will be provided as per current transplant program standard operating 
procedures. 
3.15 
Post-transplant cytokine administration 
3.15.1 Filgrastim will be administered at a dose of 5 mcg/kg (rounded to vial size) 
every day starting on day+9 until neutrophil engraftment  
3.16 
GvHD management 
3.16.1 Management of GvHD is not defined in this protocol.  Patients may be treated 
in accordance with usual practices and are encouraged to enroll into clinical 
studies of the management of these complications of transplantation


Protocol, Amendment 5, 08Nov2019 
Page 22 of 41 
4 
Adverse events 
4.1 
Definitions 
4.1.1 Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the treatment.  
An adverse event can be any unfavorable and unintended sign (eg, including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the drug, whether or not it is 
considered to be drug related.  This includes any newly occurring event or previous condition that 
has increased in severity or frequency since the administration of drug. 
4.1.2 Serious Adverse Event Definition 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality 
that: 
 
4.1.2.1 
Results in death. 
4.1.2.2 
Is life-threatening.  Life-threatening means that the patient was 
at immediate risk of death from the reaction as it occurred, i.e., 
it does not include a reaction which hypothetically might have 
caused death had it occurred in a more severe form. 
4.1.2.3 
Requires inpatient hospitalization or prolongation of existing 
hospitalization.  Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but 
planned prior to study entry are not considered AEs if the 
illness or disease existed before the patient was enrolled in the 
trial, provided that it did not deteriorate in an unexpected 
manner during the trial (eg, surgery performed earlier than 
planned). 
4.1.2.4 
Results in persistent or significant disability/incapacity.  
Disability is defined as a substantial disruption of a persons’ 
ability to conduct normal life functions. 
4.1.2.5 
Is a congenital anomaly/birth defect. 
4.1.2.6 
Is an important medical event.  An important medical event is 
an event that may not result in death, be life-threatening, or 
require hospitalization but may be considered an SAE when, 
based upon appropriate medical judgment, it may jeopardize 
the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the 
definitions for SAEs.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions 


Protocol, Amendment 5, 08Nov2019 
Page 23 of 41 
that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.   
Clarification should be made between the terms “serious” and “severe” since they ARE NOT 
synonymous.  The term “severe” is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as a severe headache).  This is NOT the same as 
“serious,” which is based on patient/event outcome or action criteria described above and are usually 
associated with events that pose a threat to a patient’s life or functioning.  A severe adverse event 
does not necessarily need to be considered serious.  For example, persistent nausea of several hours 
duration may be considered severe nausea but not an SAE.  On the other hand, a stroke resulting in 
only a minor degree of disability may be considered mild, but would be defined as an SAE based on 
the above noted criteria.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
4.2 
Procedures for AE and SAE Reporting 
The Principle Investigator-sponsor must report all serious adverse events (SAE) regardless of 
relationship with any study drug or expectedness to the IRB as required by the institution.  
Intensity for each adverse event, including any lab abnormality, will be determined by using the NCI 
CTCAE, version 3.0 (or later version), as a guideline, wherever possible.  The criteria are available 
online at http://ctep.cancer.gov/reporting/ctc.html.  
4.3 
Assessment of Toxicity 
4.3.1 Common Terminology Criteria for Adverse Events (CTCAE) will be used for 
the assessment and grading of all toxicities experienced by patients enrolled into 
this study (http://ctep.cancer.gov/forms/CTCAE_Index.pdf) 
4.3.1.1 
If the nature of the adverse experience is listed in the CTCAE, 
the maximum grade and time of maximum grade will be 
reported. 
4.3.1.2 
If the adverse experience is not listed on the NCI CTG 
Expanded Toxicity Criteria Appendix D, report the toxicity 
grade using the following criteria. 
4.3.1.2.1 
Grade 1 = Mild: an adverse experience which is easily tolerated by 
the patient, causing minimal discomfort and not interfering with 
everyday activities. 
4.3.1.2.2 
Grade 2 = Moderate: an adverse experience which is sufficiently 
discomforting to interfere with normal everyday activities. 
4.3.1.2.3 
Grade 3 = Severe: an adverse experience which is incapacitating and 
prevents normal everyday activities. 
4.3.1.2.4 
Grade 4 = Life Threatening: an adverse experience which places the 
patient at immediate risk of death. 


Protocol, Amendment 5, 08Nov2019 
Page 24 of 41 
4.4 
Assessment of Causality 
4.4.1 Every effort should be made by the investigator to explain each adverse 
experience and assess its relationship, if any, to study drug treatment. Causality 
should be assessed using the following categories: Not Related, Unlikely, 
Suspected (Reasonable Possibility), Probable. 
4.4.1.1 
Not related: The adverse experience is definitely not related to 
the test drug. 
4.4.1.2 
Unlikely:  There are other, more likely causes and the drug is 
not suspected as a cause. 
4.4.1.3 
Suspected (reasonable possibility): A direct cause and effect 
relationship between the drug and the adverse experience has 
not been demonstrated but there is a reasonable possibility that 
the experience was caused by the drug. 
4.4.1.4 
Probable: There probably is a direct cause and effect 
relationship between the adverse experience and the study 
drug. 
4.4.2 The degree of certainty with which an adverse experience is attributed to drug 
treatment (or alternative causes, e.g. natural history of the underlying diseases, 
concomitant therapy, etc.) will be determined by how well the experience can 
be understood in terms of one or more of the following: 
4.4.2.1 
Known pharmacology of the drug 
4.4.2.2 
Reaction of similar nature being previously observed with this 
drug or class of drug.  The experience having often been 
reported in literature for similar drugs as drug related e.g. skin 
rashes, blood dyscrasia.  The experience being related by time 
to drug ingestion terminating with drug withdrawal 
(dechallenge) or reproduced on rechallenge 
4.5 
Follow-up of Adverse Experiences 
4.5.1 Patients with grade ¾ adverse experiences will be actively followed until the 
event has subsided (disappeared) or until the condition has stabilized. 
4.5.2 Adverse events, both serious and non-serious, and deaths that occur during the 
patient’s study participation will be recorded in the source documents.  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). 


Protocol, Amendment 5, 08Nov2019 
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5 Statistical Evaluation 
This is a phase II study to determine if allogeneic hematopoietic stem cell transplantation using the 
fludarabine, melphalan and bortezomib regimen is superior to historical controls that received 
fludarabine and melphalan as the conditioning regimen.  
5.1 
Endpoints 
5.1.1 Primary Endpoint 
5.1.1.1 
The main primary endpoint of this study is two-year 
progression free survival. Patients are considered a failure with 
respect to PFS if they die or experience disease progression or 
relapse.  The time to this event is the time from transplantation 
to relapse/progression, initiation of non-protocol anti-myeloma 
therapy, or death from any cause.  Subjects alive without 
confirmed disease progression will be censored at the time of 
last disease evaluation.  Deaths without progression are treated 
as failures no matter when they occur.   
5.1.2 Secondary Endpoints 
Secondary endpoints will include: 
 
 
5.1.2.1 
Overall survival (OS):  Defined as time from the first dose of 
administration to death from any cause 
5.1.2.2 
Overall response rates: Defined as the composite endpoint of 
response to treatment which includes Complete Response 
(CR), Partial Response (PR), stable disease (SD) as defined in 
International Response Criteria. We will also analyze Complete 
Response rate 
5.1.2.3 
Univariate analysis of the risk of progression/relapse and 
mortality: In addition, multivariate analysis of the risk of 
progression/relapse and overall mortality will be conducted to 
assess influence of variables measured after the start of 
treatment 
5.1.2.4 
Regimen-related toxicity:  Graded and presented in a 
descriptive nature. 
5.2 
Descriptive analysis of baseline characteristics and demographics in this study will 
be performed in the following manner. Continuous measurements will be 
summarized as mean (SD) or median (inter-quartile range) based on whether or not 
the data come from a normal distribution as validated by Shapiro-Wilks test of 
normality. Categorical measurements will be summarized as frequency 
(percentage). Proportion of overall survival will be estimated by the Kaplan-Meier 


Protocol, Amendment 5, 08Nov2019 
Page 26 of 41 
product limit method. The univariate probability of the relapse and treatment–
related mortality (TRM) will be calculated using cumulative incidence function. 
5.3 
Accrual, Registration and Follow-up 
The targeted sample size for the single arm is 55 subjects.  It is estimated that four years of 
accrual will be necessary to enroll this number of subjects.   The Blood and Marrow 
Transplantation Program at HUMC treats about 12 patients with this diagnosis every year. 
In the last two years 28 multiple myeloma patients undergoing allogeneic hematopoietic 
stem cell transplantation (HSCT) used the fludarabine, melphalan and bortezomib 
(FluMelVel) conditioning regimen. After eligibility is established, subjects will be enrolled 
into the single arm using FluMelVel as a conditioning regimen. It is assumed that patients 
will enroll into the study uniformly over the accrual period. All subjects will be “on-study” 
for three years post-transplant, during which they will be monitored for the effects of 
treatment through regular clinic.  With four years of planned accrual, and a minimum of 
three years of additional follow-up post-transplant, subjects will be followed for 
progression-free survival for at least 36 months. 
5.4 
Sample Size and Power Calculations 
In this section, the power of the analysis of time to progression or death is considered and 
performed based on the proportion surviving without progression at two years.  The power 
of a one-sided log-rank test of surviving probability was calculated using PASS 2008.   
The study design considers PFS at two-years post-transplant ranging from 35% to 55%.  
The standard FluMel conditioning regimen is assumed to have PFS of 35%. It is posited 
that the FluMelVel conditioning regimen will increase the two year PFS to 55%. Thus, to 
detect the 20 % difference in PFS between the two groups using a desired power of 80%, 
for this one-side log rank test at 5% level of significance, four year accrual, 2 year follow-
up  and dropout rate of 10%, 55 patients on FluMelVel are required. This calculation 
achieved power of 80.06%. This calculation from PASS 2008 was obtained by treating 
subjects in arm control arm as though they were randomized. Since the subjects in this arm 
were historical controls on FluMel conditioning regimen, the method of Simon and Dixon 
(17) was also used to derive the sample size. Further, it was assumed that there are 50 
patients on FluMel available for comparison with outcomes of the new conditioning 
regimen.  Assuming an accrual rate of 1 patient per month, 80% power target, 5% level of 
significance and ratio of FluMel hazard rate to FluMelVel hazard rate of 1.7557, 50 
patients on the FluMelVel regimen are required. Furthermore, adjusting the sample size of 
the singe arm for a dropout rate of 10 % yielded a size of 55, which is the same as the 
sample obtained in PASS 2008.  
5.5 
Efficacy analysis 
In this Phase II study, we wish to ascertain if allogeneic hematopoietic stem cell 
transplantation using the fludarabine, melphalan and bortezomib regimen is superior to 
historical controls that received fludarabine and melphalan as the conditioning regimen.  


Protocol, Amendment 5, 08Nov2019 
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5.6 
Statistical Hypothesis 
The null hypothesis is that the two-year progression free survival rate in treatment 
arm A is 35%. The alternative hypothesis for this study posits that the treatment plan 
consisting allogeneic transplantation with fludarabine, melphalan-bortezomib 
(experimental arm) will increase the two-year progression free survival to 55% which 
is 20 % more than PFS in the historical arm.  
Thus, we will evaluate the hypotheses 
 HO: SC(2) ≥SE(2)  
 HA: SC(2) < SE(2)  
where SC(2) = the two-year progression free surviving proportion of historical control 
(FluMel), which is assumed to be 0.35, SE(2) = the two-year progression free surviving 
proportion of the experimental arm (FluMelVel). The patients in the FluMelVel 
conditioning regimen will be matched with patients in the FluMel by Cytomegalovirus 
(CMV) PCR status. To account for heterogeneity of outcome due to risk status of patients 
in the treatment arms, the comparative analysis will be stratified on risk status. Thus, a one-
sided log-rank test stratified on risk status will be conducted to determine if allogeneic 
transplantation with fludarabine and melphalan-bortezomib improves the progression free 
survival over that observed in the historical controls using fludarabine and mephalan alone 
at the 5% level of significance.  
5.7 
Primary endpoint 
To compare the two-year PFS between the historical control (FluMel) with the single arm 
(FluMelVel) consisting of 55 subjects. This sample size calculation is based on the 
assumption that the expected PFS of the standard transplant arm using FluMel is 35% at 2 
years (CIBMTR data). 
The primary analysis will include all eligible allogeneic transplantation subjects that 
receive the FluMelVel conditioning regimen and historical control using FluMel 
conditioning regimen. The single arm trial subjects will be matched to historical controls 
by CMV PCR status.  The treatment arms will be compared using a one-sided log-rank test. 
All tests will be performed using the significance level of 5%. 
5.8 
Secondary endpoints 
5.8.1 Response to Treatment 
The rates of complete remission (CR) and very good partial remission (VGPR) 
according to the International Uniform Response Criteria (Section 3.2) will be 
calculated at two years after transplantation.  The analyses of the two-year response 
rates are planned as soon as those data become available in all subjects, at one and 
two years after the close of accrual.  The comparison of the response rate to the 
transplant with respect to the overall and CR component will be performed using 
Fisher’s exact test at the 5% level of significance. 
 
 


Protocol, Amendment 5, 08Nov2019 
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5.8.2 Overall Survival 
The event is death from any cause.  The time to this event is the time from 
transplantation to the documented time of death, loss to follow-up or the end of the 
study, whichever comes first.  Patients alive at the time of last observation are 
considered censored.  The Kaplan-Meier estimate of survival will be estimated 
separately for each treatment-group.  For the comparison of the OS between the two 
conditioning regimens, a one-side log-rank test will be conducted at the 5% level of 
significance, analogous to the analysis of PFS described above.   
5.8.3 Association of Prognostic Factors and Risk of Progression/Relapse and 
Mortality 
A comparative analysis of risk outcomes relapse/progression, TRM, and overall 
Mortality will be conducted while adjusting for imbalance in other risk factors 
using a Cox proportional hazards model (18). To fit the multivariate model, a 
stepwise backward selection procedure will be used while considering the type of 
conditioning regimen (FluMelVel versus FluMel), relapse risk status ( low risk, 
high risk),  age at transplant and  Karnosfky performance score (<90 versus ≥90 ) , 
donor-gender, CMV, HLA match grade, and stem cell source as covariates. Graft-
versus host disease (GVHD) will be entered as a time- dependent covariate.  Both 
acute GVHD and chronic GVHD will be considered as subtypes of GVHD.  An 
examination of the goodness-of-fit will be performed using Grambsch-Therneau 
and Martingale residual plots (19) and lowess smooth of Cleveland (20). Covariates 
yielding a p-value of 0.05 or less will be an indication of statistical significance.  
The proportionality assumption for Cox regression will be validated by introducing 
a time-dependent covariate for each risk factor and outcome.  Since BM blast cell 
count, presence of peripheral blood blast, and whether or not the patient is in CR at 
transplant are collinear only one variable will be used in single model fitting 
attempt.  Thus, three different models will be considered when examining the 
association risk factors and PFS and OS. This analysis will be presented in terms of 
relative risks (RR) along with the corresponding p values for each covariate. 
5.9 
Safety Analysis 
Safety Analysis will be performed on all patients who have at least one dose of medication 
on either treatment arms over the course of this study.  The severity of the toxicities will be 
graded according to the NCI CTCAE v3.0 whenever possible.  Events during the first 100 
days after transplantation will be considered possibly related to the transplant for this 
analysis.  Regimen-related toxicity will be graded and presented in a descriptive nature as 
incidence rates and corresponding 95% confidence intervals.  
5.9.1 Safety Monitoring Endpoints 
The incidence of toxicities of grade 3 or higher toxicities (CTCAE version 3.0), the 
incidence of probable viral fungal and bacterial infections, and the incidence of 
treatment-related morality, i.e., from causes other than relapse or progression, will 
be recorded for each patient at set intervals over the course of the study.  Safety data 
will be described in a variety of ways, both graphical and tabular, and incidence 


Protocol, Amendment 5, 08Nov2019 
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will be compared across time points and treatment arms.  The Data and Safety 
Monitoring Board will be presented with a comprehensive semi-annual report that 
will contain both solicited and unsolicited adverse event reports. 
5.9.2 Stopping rules 
If the non-relapse mortality rate in the experimental group receiving Fludarabine, 
melphalan and Bortezomib within the first 3 month post transplantation exceeds 
20% then the study will be stopped. It is assumed that non-relapse mortality in the 
standard regimen is 10%.  Resumption of patient accrual will only be permitted 
after review of interim results by the Institutional Review Board and the Data 
Safety Monitoring Board. Operationally, using 10% as the acceptable rate of NRM 
and 20% as the unacceptable, Wald’s Sequential Probability Ratio Test (SPRT), the 
accrual will be halted for death occurring in: 
Table 1: Stopping Rule for Toxicity 
Stage {k} 
Maximum number of 
patients accrued by 
stage {nk} 
Stop trial if 
1 
4 
r≥4 
2 
10 
r≥5 
3 
17 
r≥6 
4 
24 
r≥7 
5 
31 
r≥8 
6 
38 
r≥9 
7 
45 
r≥10 
8 
52 
r≥11 
 
Note r is the number of non-relapse mortality events. 
This schedule of stopping rule was calculated using Wald’s SPRT algorithm in SISA (21) and 
has at least 80 power of halting the trial when the toxicity is above 20%. 
5.10 
Monitoring Compliance 
Patients enrolled into the study will monitored for treatment actually received. Failure to 
comply with study conditioning regimen would first trigger an intervention to improve 
compliance. 
5.11 
Data Management and Analysis 
Case report forms will be created for management of data collected during this study.  A 
database in Access will be created based on the case report forms. All study data will be 
imported into SAS and data management will be utilized to flag, and generate queries on 


Protocol, Amendment 5, 08Nov2019 
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out of range data issues until they are resolved. All analysis will be performed using SAS 
software version 9.2 (SAS Institute Inc. Cary, NC). 


Protocol, Amendment 5, 08Nov2019 
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6 
Administrative Requirements 
6.1 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation (ICH) 
for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The investigator will 
be thoroughly familiar with the appropriate use of the drug as described in the protocol and 
Investigator’s Brochure.  Essential clinical documents will be maintained to demonstrate the validity 
of the study and the integrity of the data 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.   
6.2 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki.  The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety and well-being of the patients.  The study will only be conducted at sites where IRB/IEC 
approval has been obtained.  The protocol, informed consent, advertisements (if applicable), written 
information given to the patients (including diary cards), safety updates, annual progress reports, and 
any revisions to these documents will be provided to the IRB/IEC by the investigator.  .   
6.3 
Patient Information and Informed Consent  
After the study has been fully explained, written informed consent will be obtained from   either 
the patient or his/her guardian or legal representative prior to study participation.  The method 
of obtaining and documenting the informed consent and the contents of the consent will 
comply with ICH-GCP and all applicable regulatory requirement(s). 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for treatment of the underlying disease.  All potential risks associated with 
the use of fludarabine , bortezomib, melphalan and HSCT will be discussed as objectively as 
possible.  It will be explained that patients offered this treatment have advanced malignancy 
with life expectancy of months to no more than 1-2 years with conventional treatments.  
Informed consent from the patient will be obtained using the IRB-approved consent form 
describing this protocol.  The patient has the right to review and correct the results of the pre-
transplant evaluation 
6.4 
Donor information and informed consent 
Related donor informed consent will be obtained in accordance with Standard Operating 
Practice 
Unrelated donor informed consent will be obtained in accordance with the Standard 
Operating Procedures of the NMDP and the donor center 
6.5 
Protocol Registration 
6.5.1 All patients will be assigned a unique patient number (UPN) in accordance with 
HUMC Standard Practice. 
6.6 
Patient 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 patient’s 


Protocol, Amendment 5, 08Nov2019 
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confidentiality will be maintained and will not be made publicly available to the extent permitted by 
the applicable laws and regulations. 
6.7 
Record Retention 
6.7.1 The investigator will maintain all study records according to ICH-GCP and 
applicable regulatory requirement(s). The licensed medical records department, 
affiliated with the institution where the patient receives medical care, maintains 
all original inpatient and outpatient chart documents. 
6.8 
Investigational New Drug Exemption 
All of the drugs employed in this protocol are commercially available and an IND exemption is not 
required for the conduct of this study.  The study will be conducted in accordance with current Good 
Clinical Practice guidelines. 


Protocol, Amendment 5, 08Nov2019 
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7 
Karnofsky Performance Status Scale 
The following table presents the Karnofsky performance status scale1: 
Points 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity 
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 
60 
Requires occasional assistance but is able to care for most of his/her needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization indicated.  Death not imminent 
20 
Very sick; hospitalization necessary; active support treatment necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
 
8 
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 = 
 
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.) 
 
9 
New York Heart Association Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease: 
 
1 
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. 
3131
)
(
)
(
lbs
Wt
inches
Ht
×


Protocol, Amendment 5, 08Nov2019 
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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. 
 


Protocol, Amendment 5, 08Nov2019 
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10 Declaration of Helsinki 
World Medical Association Declaration of Helsinki: 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended 
by the 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General 
Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, 
September 1989 48th WMA General Assembly, Somerset West, Republic of South Africa, 
October 1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as a 
statement of ethical principles to provide guidance to physicians and other participants 
in medical research involving human subjects.  Medical research involving human 
subjects includes research on identifiable human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people.  The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the patient's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the patient." 
4. Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
5. In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the 
aetiology and pathogenesis of disease.  Even the best proven prophylactic, diagnostic, 
and therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human 
beings and protect their health and rights.  Some research populations are vulnerable 
and need special protection.  The particular needs of the economically and medically 
disadvantaged must be recognized.  Special attention is also required for those who 
cannot give or refuse consent for themselves, for those who may be subject to giving 
consent under duress, for those who will not benefit personally from the research and 
for those for whom the research is combined with care. 
9. Research Investigators should be aware of the ethical, legal and regulatory 


Protocol, Amendment 5, 08Nov2019 
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requirements for research on human subjects in their own countries as well as 
applicable international requirements.  No national ethical, legal or regulatory 
requirement should be allowed to reduce or eliminate any of the protections for human 
subjects set forth in this Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
1. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
2. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and on adequate laboratory and, where appropriate, 
animal experimentation. 
3. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
4. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol.  This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
investigator, the sponsor or any other kind of undue influence.  This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed.  The committee has the right to monitor ongoing 
trials.  The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events.  The researcher should also submit 
to the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
5. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration. 
6. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  
The responsibility for the human subject must always rest with a medically qualified 
person and never rest on the subject of the research, even though the subject has given 
consent. 
7. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits 
to the subject or to others.  This does not preclude the participation of healthy volunteers 
in medical research.  The design of all studies should be publicly available. 
8. Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and 
can be satisfactorily managed.  Physicians should cease any investigation if the risks 
are found to outweigh the potential benefits or if there is conclusive proof of positive and 
beneficial results. 


Protocol, Amendment 5, 08Nov2019 
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9. Medical research involving human subjects should only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the subject.  This is 
especially important when the human subjects are healthy volunteers. 
10. Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research. 
11. The subjects must be volunteers and informed participants in the research project. 
12. The right of research subjects to safeguard their integrity must always be respected.  
Every precaution should be taken to respect the privacy of the subject, the confidentiality 
of the patient's information and to minimize the impact of the study on the subject's 
physical and mental integrity and on the personality of the subject. 
13. In any research on human beings, each potential subject must be adequately informed 
of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail.  The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal.  After ensuring that the subject has understood the information, the physician 
should then obtain the subject's freely-given informed consent, preferably in writing.  If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
14. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or 
may consent under duress.  In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
15. For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law.  
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
16. When a subject deemed legally incompetent, such as a minor child, is able to give 
assent to decisions about participation in research, the investigator must obtain that 
assent in addition to the consent of the legally authorized representative. 
17. Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population.  
The specific reasons for involving research subjects with a condition that renders them 
unable to give informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee.  The protocol should state that 
consent to remain in the research should be obtained as soon as possible from the 
individual or a legally authorized surrogate. 


Protocol, Amendment 5, 08Nov2019 
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18. Both authors and publishers have ethical obligations.  In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results.  Negative 
as well as positive results should be published or otherwise publicly available.  Sources 
of funding, institutional affiliations and any possible conflicts of interest should be 
declared in the publication.  Reports of experimentation not in accordance with the 
principles laid down in this Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
1. The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value.  
When medical research is combined with medical care, additional standards apply to 
protect the patients who are research subjects. 
2. The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods.  This does 
not exclude the use of placebo, or no treatment, in studies where no proven 
prophylactic, diagnostic or therapeutic method exists. 
3. At the conclusion of the study, every patient entered into the study should be assured 
of access to the best proven prophylactic, diagnostic and therapeutic methods identified 
by the study. 
4. The physician should fully inform the patient which aspects of the care are related to 
the research.  The refusal of a patient to participate in a study must never interfere with 
the patient-physician relationship. 
5. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent 
from the patient, must be free to use unproven or new prophylactic, diagnostic and 
therapeutic measures, if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering.  Where possible, these measures should be 
made the object of research, designed to evaluate their safety and efficacy.  In all cases, 
new information should be recorded and, where appropriate, published.  The other 
relevant guidelines of this Declaration should be followed. 
 


Protocol, Amendment 5, 08Nov2019 
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11 Common Terminology Criteria for Adverse Events Version 3.0 
http://ctep.cancer.gov/reporting/ctc.html  
 


Protocol, Amendment 5, 08Nov2019 
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12 References 
1. Attal et al. A prospective, randomized trial of autologous bone marrow transplantation and 
chemotherapy in multiple myeloma. NEJM 1996;335:91-97. 
2. Child et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple 
myeloma. NEJM 2003;348:1875-1883. 
3. Fernand et al. High-dose chemotherapy and autologous stem-cell  transplantation compared 
with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a 
randomized control trial from the Group Myeloma-Autogreffe. J Clin Oncol. 2005;23:9227-
9233. 
4. Attal et al. Single versus double autologous transplantation for multiple myeloma. NEJM 
2003 Dec25;2495-502. 
5. Barlogie et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. 
Blood. 1999;93:55-65. 
6. Maloney DG, et al. allografting with non-myeloablative conditioning following 
cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 
2003;102:3447-54 
7. Tricot et al. graft-versus-myeloma effect: proof of principle. Blood. 1996 1;87(3):1196-8 
8. Bjorkstrand et al. Allogeneic bone marrow transplantation veruss autologous stem cell 
transplantation in multiple myeloma: a retrospective case-matched study for the European 
Group for Blood and Marrow Transplantation. Blood 1996;88:4711-8 
9. Maloney DG, et al. allografting with non-myeloablative conditioning following 
cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 
2003;102:3447-54. 
10. Crawley et al. Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but 
higher relapse rates compared with myeloablative conditioning. Blood 2007;109:3588-94. 
11. Gahrton G et al. Progress in allogeneic boen marrow and peripheral blood stem cell 
transplantation for multiple myeloma: a comparison between transplants performed 1983-
1993 and 199408 at Euripean Group for Blood and Marrow transplantation centers. Br J 
Haematol 2001;113:209-16. 
12. Giralt et al. Fludarabine/melphalan conditioning for allogeneic transplantation in patients 
with multiple myeloma. Bone marrow transpl.2002;30(6):367-73. 
13. Kroger et al. Current status and perspectives of dose-reduced conditioning followed by 
related and unrelated stem cell transplantation. Haematologica 2005;90:47. 
14. Berenson et al. Phase I/II trial of assessing bortezomib and melphalan combination therapy 
for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol. 
2006 Feb 20;24(6):937-44. 
15. Richardson et al. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib 
for relapsed zand relapsed/refractory multiple myeloma. J Clin Oncol. 2009 Sep 28. [Epub 


Protocol, Amendment 5, 08Nov2019 
Page 41 of 41 
ahead of print]. 
16. Koreth et al. Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host 
disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-
mismatched unrelated donors. Blood 2009;114(18):3956-9.  
17. Dixon, DO. and Simon, R. Sample size considerations for studies comparing survival 
curves using historical controls, J Clin Epidemiol. 1988; 41: 1209-1213. 
18. Cox, DR. Regression models and life tables (with discussion). J R Stat Soc B.1972; 
34:187-220. 
19. Therneau, TM. and Grambsch, P. Modeling Survival Data. New York, NY: Springer, 2000. 
20. Cleveland, WS. Robust locally-weighted regression and smoothing scatterplots. J. Am Stat 
Assoc. 1979; 74: 829-836. 
21. Uitenbroek, DG. SISA-SPRT, online interactive program. 
http://www.quantitativeskills.com/sisa/statistics/sprt.htm   [20 May2002]