Conditions: AL Amyloidosis
Keywords: Amyloidosis Dexamethasone Bendamustine Relapsed AL Amyloidosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
The study is being done to see if the combination of bendamustine and dexamethasone will help people with amyloidosis that has returned after standard treatment, and to to estimate the partial hematologic response rate (PHR).

Detailed description:
Systemic light-chain amyloidosis (AL) is a protein conformation disorder due to a clonal plasma cell dyscrasia. There are no established and approved second-line therapies for patients with systemic AL amyloidosis who fail initial melphalan-based treatment, be it high-dose melphalan with stem cell transplant or oral melphalan and dexamethasone (MDex). Therefore new treatments are needed for those who fail initial therapy and for those who initially respond but subsequently relapse.

Therapy of AL is generally based on treatment regimens used in multiple myeloma (MM). Bendamustine achieves partial response with relapsed/refractory MM. Based on this high anti-MM activity, we anticipate that bendamustine will also be very active in clonal plasma cell disorder associated with AL.

Arms:
arm 1: Subjects with AL will receive Bendamustine and Dexamethasone

Interventions: intervention 1: Bendamustine intervention 2: Dexamethasone
Intervention descriptions: intervention 1: Patients will start bendamustine at dose level 0 and according to CrCl on day 1 and 2 of each cycle:

* CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle
* CrCl 59 - 30 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle

Available to qualifying subjects is the option to dose escalate to dose level (+)1:

* 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study)
* 100 mg/m2 (if CrCl 59-30 mL/min at the time of inclusion into the study) intervention 2: 40 mg orally on days 1, 8, 15, 22 of each cycle

Protocol document:
Prot_SAP_000.pdf: 
 
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Protocol Number 
CUMC AAAJ7800 
 
TITLE 
Phase II Study of the Combination of Bendamustine and 
Dexamethasone in Patients with Relapsed AL Amyloidosis 
 
Principal Investigator: 
Suzanne Lentzsch, M.D., PhD. 
 
 
 
 
Columbia University Medical Center 
 
 
 
 
Herbert Irving Comprehensive Cancer Center 
 
 
 
 
Herbert Irving Pavilion 
 
 
 
           161 Fort Washington Avenue 
 
 
 
 
New York, NY 10032 
 
 
 
 
sl3440@columbia.edu 
 
 
Co-Investigator: 
 
Jennifer Amengual, M.D. 
 
 
 
 
 
Columbia University Medical Center 
 
 
Black Building 
 
 
 
                   
650 West 168th Street 
 
 
 
 
 
New York, NY 10032 
 
 
 
 
 
jea2149@columbia.edu 
 
Co-Investigator: 
 
Changchun Deng, M.D. 
 
 
 
 
 
Columbia University Medical Center 
 
 
 
 
 
Center for Lymphoid Malignancies 
 
 
16 East 60th Street 
 
 
 
 
 
New York, NY 10022 
 
 
 
 
 
cd2448@columbia.edu 
 
Co-Investigator: 
 
David Diuguid, M.D. 
 
 
 
 
 
Columbia University Medical Center 
 
 
Herbert Irving Comprehensive Cancer Center 
 
 
Milstein Hospital 
 
 
 
                   
177 Fort Washington Avenue 
 
 
 
 
 
New York, NY 10032 
 
 
 
 
 
dld6@columbia.edu 
 
Co-Investigator: 
 
Andrew Eisenberger, M.D. 
 
 
 
 
 
Columbia University Medical Center 
 
 
Herbert Irving Comprehensive Cancer Center 
 
 
Herbert Irving Pavilion 
 
 
 
                   
161 Fort Washington Avenue 
 
 
 
 
 
New York, NY 10032 
 
 
 
 
 
abe6@columbia.edu 
Co-Investigator: 
 
Markus Y. Mapara, M.D. 
 
 
 
 
 
Columbia University Medical Center 
 
 
Herbert Irving Comprehensive Cancer Center 


 
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Milstein Hospital 
 
 
 
                   
177 Fort Washington Avenue 
 
 
 
 
 
New York, NY 10032 
 
 
 
 
 
mym2111@columbia.edu 
 
Co-Investigator: 
 
John Gregory Mears, M.D. 
 
 
 
 
  
Columbia University Medical Center 
 
   
Herbert Irving Comprehensive Cancer Center 
 
 
Herbert Irving Pavilion 
 
 
 
                   
161 Fort Washington Avenue 
 
 
 
 
 
New York, NY 10032 
                                                gjm2@columbia.edu 
 
Co-Investigator:                     Celia Grosskreutz, M.D. 
                                               Columbia University Medical Center   
                                               Herbert Irving Comprehensive Cancer Center 
 
       
                       Herbert Irving Pavilion 
 
 
 
                       161 Fort Washington Avenue 
 
                                       New York, NY 10032 
                                               clg2177@columbia.edu 
 
AFFILIATE SITES 
Co-Investigator: 
 
Raymond Comenzo, M.D. 
 
 
 
 
 
Tufts Medical Center 
 
 
 
 
 
Box 826800 
 
 
 
 
 
Washington Street 
 
 
 
 
 
Boston, MA  02111 
 
 
 
 
 
rcomenzo@tuftsmedicalcenter.org 
 
Co-Investigator:                   Heather Landau, M.D. 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
 
 
 
 
 
Division of Hematologic Oncology 
 
 
 
 
 
1275 York Avenue 
 
 
 
 
  New York, NY 10065 
 
 
 
 
 landauh@mskcc.org 
 
Co-Investigator:  
 
Keren Osman, M.D. 
 
 
 
 
 
Mt. Sinai Medical Center 
 
 
 
 
 
1 Gustave L. Levy Place 
 
 
 
 
 
Box 1185  
 
 
 
 
 
New York, NY 10023 
 
 
 
 
 
Keren.osman@mountsinai.org  
 
Co-Investigator: 
 
Vaishali Sanchorawala, M.D. 
 
 
 
 
 
Boston Medical Center 
 
 
 
 
 
Autologous Stem Cell Transplant Program 


 
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820 Harrison Avenue 
 
 
 
 
 
FGH-1007 
 
 
 
 
 
Boston, MA 02118 
 
 
 
 
 
Vaishali.Sanchorawala@bmc.org 
 
Co-Investigator: 
 
Jeffrey Zonder, M.D. 
 
 
 
 
 
Karmanos Cancer Insitute 
 
 
 
 
 
4th Floor 
 
 
 
 
 
Hudson Webber Cancer Research Center 
 
 
 
 
 
4100 John R. 
 
 
 
 
 
Detroit, MI 48201 
 
 
 
 
 
zonderj@karmanos.org 


 
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PROTOCOL SUMMARY 
Title: Phase II study of the bendamustine and dexamethasone in patients with relapsed AL 
amyloidosis 
Objectives: 
 
The primary objective of this study is to estimate the partial hematologic response rate 
(PHR) 
 
 
The secondary objectives of this study are to: 
o Determine overall hematologic response rate 
o Determine the organ response rate 
o Determine time to treatment failure 
o Assess toxicity of the regimen 
o Determine overall survival (OS) 
o To assess by RT-PCR the expression in clonal plasma cells of cyclin D1 (CCND1) 
and SEL1L, before treatment. To assess the bone marrow cytokine profile before and 
after treatment with bendamustine. 
 
Patient population: (Specific inclusion and exclusion criteria are detailed in section 4.2) 
Individuals are eligible for this study if they have: 
 
Primary systemic amyloidosis (biopsy proven), OR 
 
Light chain deposition disease (biopsy proven), OR 
 
Meet the IMWG definition of symptomatic myeloma with symptoms attributable only to 
associated amyloid. The patient cannot otherwise meet criteria for diagnosis of 
symptomatic MM with other disease-related symptoms not attributable to amyloid 
deposition. 
 
Either are not a candidate for autologous stem cell transplant (ASCT), have declined 
option of ASCT, or have relapsed after prior ASCT. 
 
Number of patients: 13 patients in the first stage, 16 patients in the second stage (max 29) 
Study design and methodology: 
This Phase IIa clinical trial uses a two-stage optimal Simon design.1 In the first stage, 13 patients 
are enrolled. If at least three patients experience PHR, the trial proceeds to the second stage, 
otherwise, the trial terminates with no further interest in the treatment. In the second stage, 16 
additional patients are treated. If a total of 9 or more out of the total of 29 patients experience 
PHR, the treatment will be considered worthy of further development. Patients who finish at 
least 2 cycles are eligible for evaluation of PHR. Patients with primary progressive disease after 
only receiving 1 cycle of therapy will be included in the response analysis. 
Treatments administered: 
 
Bendamustine 100 mg/m2 IV on day 1 and 2 of each cycle 
 
Dexamethasone 40 mg PO or IV on days 1, 8, 15, 22 of each cycle 


 
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 
Cycle will be 28 days. Treatment may be continued until progression of disease or a 
maximum of 6 cycles beyond CHR, after which time patients will be observed until other 
non-protocol therapy is needed. 
 
Efficacy data collected: 
 
Serial serum and urine M-protein assessment 
 
Serum and urine electrophoresis/immunofixation 
 
Serum free light chain (Freelite) assay 
 
Serial echocardiogram assessment of cardiac wall thickness and left ventricular ejection 
fraction 
 
Serial BNP/NT-proBNP and troponin I/T levels  
 
Serial assessment of non-light chain 24-hr urinary protein excretion 
 
Serial assessment of liver function tests and size of liver 
 
Change in bone marrow plasmacytosis 
 
Correlative studies: 
 
Baseline samples will be sent to Dr. Comenzo’s lab for correlative studies. The 
correlative studies are optional.  


 
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TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS .................................................................................................................... 8 
1 
BACKGROUND AND RATIONALE ................................................................................................ 10 
1.1 
Systemic Light Chain Amyloidosis ............................................................................................. 10 
1.2 
Bendamustine .............................................................................................................................. 11 
Tumor Lysis Syndrome............................................................................................................................... 14 
Skin Reactions ............................................................................................................................................... 14 
1.3 
Study Rationale and Selection of Drug Doses ............................................................................ 14 
1.4 
Correlative Studies: ..................................................................................................................... 15 
Cyclin D1 Overexpression in AL ......................................................................................................... 15 
2 
OBJECTIVES ...................................................................................................................................... 17 
2.1 
Primary Objectives ...................................................................................................................... 17 
2.2 
Secondary Objectives .................................................................................................................. 17 
3 
STUDY DESIGN ................................................................................................................................. 17 
3.1 
Study Design ............................................................................................................................... 17 
3.2 
Stopping Rule for Excess Toxicity .............................................................................................. 17 
3.3 
Justification of Sample Size and Stopping Rule.......................................................................... 18 
4 
PATIENT SELECTION ....................................................................................................................... 18 
4.1 
Patient Population ....................................................................................................................... 18 
4.2 
Inclusion and Exclusion Criteria ................................................................................................. 18 
4.2.1 Inclusion Criteria .................................................................................................................................. 19 
4.2.2 Exclusion Criteria ................................................................................................................................. 19 
5 
REGISTRATION PROCEDURES ...................................................................................................... 20 
5.1 
Assignment of Study Numbers.................................................................................................... 20 
6 
TREATMENT PLAN .......................................................................................................................... 24 
6.1 
Study Agents ............................................................................................................................... 24 
6.1.1 Bendamustine ....................................................................................................................................... 24 
6.1.2 Dexamethasone .................................................................................................................................... 26 
6.2 
Other Agents ............................................................................................................................... 27 
6.3 
General Concomitant Medication and Supportive Care Guidelines ........................................... 27 
6.4 
Dosing Delays/Modifications ...................................................................................................... 28 
6.4.1 Bendamustine Adjustments for Hematologic Toxicities ...................................................................... 28 
6.4.2 Bendamustine Adjustments for Other Toxicities ................................................................................. 29 
6.4.3 Dexamethasone Treatment Adjustments .............................................................................................. 29 
6.5 
Duration of Treatment ................................................................................................................. 30 
6.6 
Duration of Follow-Up ................................................................................................................ 31 
6.7 
Dose Modifications ..................................................................................................................... 32 
6.8 
Study Calendar ............................................................................................................................ 32 
7 
MEASUREMENT OF EFFECT .......................................................................................................... 35 
7.1 
Definition of Hematologic Response .......................................................................................... 35 
7.2 
Definition of Organ Response Rate (OrRR) ............................................................................... 37 
8 
STATISTICAL CONSIDERATIONS ................................................................................................. 37 
8.1 
Justification of Design ................................................................................................................. 37 
9 
CORRELATIVE LABORATORY STUDIES ..................................................................................... 38 
10 
ADVERSE EVENT REPORTING ................................................................................................ 39 


 
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10.1 Adverse Event Definitions .......................................................................................................... 39 
10.2 Recording/Reporting Requirements ............................................................................................ 40 
10.2.1 Eliciting Adverse Event Information .................................................................................................. 40 
10.3 Reporting of Adverse Events ...................................................................................................... 40 
10.4 Guidelines for Processing IND Safety Reports ........................................................................... 43 
10.5 Data and Safety Monitoring Committee ..................................................................................... 44 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................. 44 
11.1 Guidelines for Affiliate site prospective protocol deviation requests: ........................................ 46 
12 
DATA HANDLING AND RECORD KEEPING ......................................................................... 47 
12.1 Data Recording/Case Report Forms ............................................................................................ 47 
12.2 Record Maintenance and Retention ............................................................................................ 48 
13 
ETHICS ......................................................................................................................................... 48 
13.1 Institutional Review Board (IRB) Approval ............................................................................... 49 
13.2 Ethical and Scientific Conduct of the Clinical Study .................................................................. 49 
13.3 Subject Informed Consent ........................................................................................................... 49 
REFERENCES .......................................................................................................................................... 50 
APPENDIX A. IMWG Definitions of Asymptomatic and Symptomatic Myeloma26 ......................... 53 
APPENDIX B. ECOG Performance Status ............................................................................................ 54 
APPENDIX C. NYHA Functional Classification for Congestive Heart Failure28 .............................. 55 
APPENDIX D. Creatinine Clearance Formula ...................................................................................... 56 
APPENDIX E. KARNOFSKY PERFORMANCE STATUS ................................................................ 56 


 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AL 
systemic light-chain amyloidosis 
ALT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ASCT 
Autologous stem cell transplant 
BNP 
brain natriuretic peptide 
BP 
bendamustine and prednisone 
BUN 
blood urea nitrogen 
CLL 
chronic lymphocytic leukemia 
CHR 
complete hematologic response 
CR 
complete response/remission 
CTCAE 
NCI common terminology criteria for adverse events (version 4.0) 
DLT 
dFLC 
dose-limiting toxicity 
difference between the involved and uninvolved free light chain 
ECG 
12 lead electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ER 
endoplasmic reticulum 
FDA 
Food and Drug Administration 
G-CSF 
granulocyte colony-stimulating factor (e.g. filgrastim) 
GM-CSF 
granulocyte-macrophage colony-stimulating factor (e.g. sargramostim) 
HIV 
human immunodeficiency virus 
IV 
intravenous(ly) 
IRB 
institutional review board 
LLN 
lower limit of normal 
MDex 
melphalan and dexamethasone 
mg/m2 
milligrams per square meter 
MM 
multiple myeloma 
MP 
melphalan and prednisone 
MR 
minor response 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin lymphoma 
NIH 
National Institutes of Health 
OrRR 
organ response rate 
OS 
overall survival 
OHR 
overall hematologic response 
PLT 
platelet 
PR 
partial response 
qRT-PCR 
quantitative real-time polymerase chain reaction 
SAE 
serious adverse event 
SD 
stable disease 
SJS 
Stevens Johnson Syndrome 
SPEP 
serum protein electrophoresis 
T4 
thyroxine 
TEN  
toxic epidermal necrolysis 


 
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TTF 
time to treatment failure 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
VGPR 
very good partial response 
 


 
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1 
BACKGROUND AND RATIONALE 
1.1 
Systemic Light Chain Amyloidosis 
Systemic light-chain amyloidosis (AL) is a protein conformation disorder due to a clonal plasma 
cell dyscrasia.2  In both AL and multiple myeloma (MM), clonal plasma cells in the bone 
marrow produce monoclonal immunoglobulins.3,4 Unlike myeloma, the AL plasma cell clone in 
most patients is the equivalent of a monoclonal gammopathy of undetermined significance.5,6  In 
AL, abnormal monoclonal immunoglobulin light chains unfold and aggregate to form insoluble 
fibrils that are deposited in the kidneys, heart, liver, GI tract and peripheral nervous system.7 The 
deposits lead to multiorgan dysfunction and death. The annual incidence of AL is estimated to be 
six to nine per million. The prognosis of AL is poor, with a median survival without therapy of 
approximately 13 months from diagnosis and a 10-year survival rate of 5%. Survival can be 
prolonged with effective treatment.8,9 
Therapy of AL is generally based on treatment regimens used in MM. The aim of therapy is to 
eliminate the clonal plasma cells in order to reduce the production of abnormal light chains. 
Reduction in the amyloid-precursor light chains in the serum can lead to resorption of amyloid 
deposits in tissues and restoration of organ function. Achievement of a hematologic response is 
associated with improved outcome, and a complete hematologic response (CHR) has been shown 
to prolong survival.10 Rapid response to treatment may be important as the benefit of therapy on 
organ function typically does not become evident before months after hematologic response. 
Patients may not survive long enough if therapy is slow-acting.  
High-dose melphalan with stem cell transplant is effective in AL and in eligible patients may be 
the therapy of choice.8,11 Toxicities and treatment-related mortality are high in patients with 
involvement of multiple organs, which has led investigators to propose and develop a risk-
adapted approach to patient selection for stem cell transplant.12 Standard therapy for patients who 
do not undergo autologous stem cell transplant (ASCT) remains oral melphalan and 
dexamethasone (MDex),13 which achieves a hematologic response rate of 67%, including 33% 
complete response/remission (CR).  
Median survival for those who do not respond to initial therapy with melphalan and stem cell 
transplant is 2 years, and in those with cardiac involvement who do not respond to any 
melphalan-based initial therapy the median survival is 10 months.14 There is an urgent need in 
AL for better treatment options that would result in substantial and rapid activity, with good 
tolerability, particularly for patients with persistent plasma cell disease and progressive organ 
dysfunction despite initial therapy and for those who experience relapsed disease, two situations 
for which no standard treatment exists. 
Because the immunoglobulin light chains secreted by clonal plasma cells in AL have an 
abnormal configuration, novel agents that interfere with intracellular protein quality control 


 
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processes will likely have a role in the treatment of AL. Interference with cellular quality 
controls in cells that secrete abnormal proteins can cause increased intracellular stress and may 
trigger cell death. Recently, for example, in the phase I portion of a phase I/II trial with the 
proteasome-inhibitor bortezomib in AL patients with relapsed disease, 63% overall and 38% 
CHR rates were achieved.15 Nevertheless those patients were not heavily pretreated. Dr. 
Palladini and colleagues enrolled 24 patients with relapsed/refractory AL Amyloidosis who were 
previously treated with Melphalan, bortezomib, and thalidomide (Ann Hematol 2012 Vol 91: 89-
92).  In this protocol, patients received lenalidomide and dexamethasone. Hematologic response 
defined as partial response or higher was seen in 9 out of 24 subjects (41%). There were no 
complete responses seen. In a follow-up study (Palladini et al. Haematologica 2013; Vol 98 p 
433-5), twenty-one patients who had relapsed or refractory AL Amyloidosis received treatment 
with cyclophosphamide, lenalidomide, and dexamethasone. Hematologic response was seen in 
62% of patients, but there was only one complete response (5%). 
Since the immunoglobulin light chain proteins made by the clonal plasma cells in AL are 
abnormal in sequence and conformation, they may require optimal intracellular protein quality 
control management. Impairment of intracellular chaperone and protein-processing quality 
controls could cause increased intracellular stress due to protein misfolding and aggregation, 
thereby leading to cell death. Bendamustine may interfere with protein chaperone and quality 
controls in AL plasma cells by modulating expression of genes involved in those processes. 
1.2 
Bendamustine 
Bendamustine is a bifunctional alkylating agent. It is a mechlorethamine derivative with 
structural similarity to chlorambucil and other drugs from the nitrogen mustard class, as well as a 
benzimidazole ring, which may act as an antagonist to purines and amino acids. It has good oral 
bioavailability but has been studied almost exclusively in the intravenous formulation. It 
undergoes extensive first-pass metabolism by cytochrome P450 1A2 to active metabolites 
gamma-hydroxy bendamustine and N-desmethyl-bendamustine, but clinical activity appears to 
be associated primarily with the parent compound. The t(1/2) of bendamustine is approximately 
40 minutes. While bendamustine has 2 moieties with possible antitumor effect, it is unclear to 
what extent the benzimidazole ring enhances the efficacy of the drug.16 Numerous studies 
including in vitro assays have reported, however, that bendamustine has little cross-resistance 
with other alkylating agents and remains active even in extensively pretreated patients.  
Bendamustine has been approved in Europe for treating MM, non-Hodgkin lymphoma (NHL), 
chronic lymphocytic leukemia (CLL), breast cancer, and Hodgkin lymphoma. It is of note that 
bendamustine was developed and approved in East Germany in 1971. Dose-limiting toxicity 
(DLT) is primarily hematologic. Treatment-associated infections have been reported in some 
studies; however, nonhematologic adverse events (AEs) have rarely been dose limiting. The 
most common nonhematologic AEs include fatigue, nausea, xerostomia, and pyrexia. 


 
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Pharmacokinetic studies have shown that Bendamustine is >95% protein bound, but this binding 
is not affected by age (>70years), low serum albumen levels (<3.1 g/dl) or the presence of 
advanced tumors 33.  
Bendamustine was approved by the US Food and Drug Administration (FDA) for the treatment 
of CLL in March 2008 and for the treatment of rituximab-refractory, indolent B-cell NHL in 
October 2008. 
FDA approval for use in CLL was based on findings from a randomized, open-label, Phase III 
study comparing bendamustine with chlorambucil as single-agent therapy in treatment naive 
patients with CLL (Binet stage B or C) 29, 30. Bendamustine was administered intravenously at a 
dose of 100 mg/m2 on days 1 and 2, while chlorambucil was administered orally at 0.8 mg/kg 
daily, both over 4-week cycles for up to 6 cycles. At interim analysis (the data used for FDA 
approval), bendamustine was associated with a greater overall response (68% vs 39%; P <0.001), 
median progression-free survival (21.7 vs 9.3 months; P <0.001) and median duration of 
remission (18.9 vs 6.1 months; P <0.001) compared with chlorambucil. FDA approval for 
rituximab refractory, indolent B-cell NHL followed a Phase III, open-label, single-arm study 
evaluating bendamustine monotherapy in patients who did not respond to rituximab or who had 
progressive disease within 6 months of rituximab therapy. Bendamustine 120 mg/m2 was 
administered intravenously on days 1 and 2 of a 21-day cycle for up to 8 cycles. At interim 
analysis, the overall response rate was 84%, including 29% CR. The median progression-free 
survival was 9.7 months.  
The efficacy of bendamustine has also been reported in the treatment of MM in a large number 
of patients and several clinical trials and was first used in 1969 in Germany. A randomized phase 
III study compared bendamustine and prednisone (BP) to standard melphalan and prednisone 
(MP) treatment in previously untreated patients with MM 31. To be included, patients had to have 
histologically and cytologically proven stage II with progressive disease or stage III MM. They 
were randomly assigned to receive BP (n=68) or MP (n=63). The primary endpoint was the time 
to treatment failure (TTF). Secondary endpoints included survival, remission rate, toxicity and 
quality of life. The overall response rate was 75% in the BP and 70% in the MP group. A 
significantly higher number of patients treated with BP achieved a complete remission than did 
patients receiving MP (32 vs. 13%; P =0.007), and the maximum response was achieved more 
rapidly in patients treated with BP compared to those receiving MP (6.8 vs. 8.7 cycles; P <0.02). 
TTF and remission duration were significantly longer in the BP group. Patients receiving BP had 
higher quality of life scores and reported pain less frequently than patients receiving MP. The 
authors concluded that BP is superior to MP with respect to complete remission rate, TTF, cycles 
needed to achieve maximum remission and quality of life and should be considered the new 
standard in first-line treatment of MM patients not eligible for transplantation.17 


 
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A retrospective analysis evaluated 39 patients with relapsed or refractory MM 32, who have been 
treated with bendamustine as salvage therapy. After a median 2 lines of prior therapy (range: 1-
5) patients received a median 3 (range: 1-10) cycles of bendamustine. Bendamustine dose was 
80-150 mg/m2 on days 1 and 2 of a monthly cycle. Bendamustine was administered as 
monotherapy in 39% of patients, whereas 61% received concomitant steroids. Toxicity was mild 
to moderate. Response rates were as follows: 3% very good partial response (VGPR), 33% 
partial response (PR), 18% minor response (MR), 26% stable disease (SD) and 20% progressive 
disease. The median event-free and overall survivals (OS) were 7 and 17 months, respectively. 
The authors concluded that in patients with advanced MM, bendamustine is effective and 
associated with mild toxicity.18 
In another study, 17 patients with relapsed MM with a median age of 70 years (51-82) were 
treated with bortezomib 1-1.3 mg/m2 on days 1, 4, 8 and 11; bendamustine 60 mg/m2 on days 1 
and 8; and dexamethasone 24 mg orally days 1-3 and days 8-10. Response was evaluated 
according to the Southwest Oncology Group (SWOG) criteria. The overall response rate 
(CR+PR+MR) was 88%. CR: (n=2; 12%), PR: (n=10; 58%), MR (n=3; 18%; No Change (n=2; 
12%). A total of 28 patients with a median age (range) of 64 years (40-78) have been enrolled in 
a phase I study of bendamustine in combination with thalidomide and prednisolone in patients 
with stage II or Ill refractory or relapsed MM after transplantation or conventional 
chemotherapy.19 After at least 2 cycles of chemotherapy, 25/28 patients responded with 3 
complete remission, 1 near CR, 5 VGPR, 15 PR, and 1 MR. Two patients had stable disease and 
one was refractory. After a median follow up of 15 months, event free survival and OS at 12 
months were 34% and 92% respectively. 
Our group performed a phase 1 trial using bendamustine combined with lenalidomide. Our 
primary objective was to determine the maximum tolerated dose and safety profile of 
bendamustine and lenalidomide when administered with dexamethasone for patients with 
relapsed or refractory MM. Patients aged ≥18 years with confirmed, measurable MM that was 
refractory to or progressed after 1 or more prior therapies received bendamustine by intravenous 
infusion on days 1 and 2, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 
15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as 
defined by the International Myeloma Working Group, was reached. Study drug doses were 
escalated through 4 levels, with 3-6 patients enrolled at each level depending on whether any 
DLT occurred. Secondary endpoints included preliminary efficacy, as evidenced by objective 
responses, time to disease progression, and OS. To date, 13 patients have been enrolled; 12 
patients have been treated (median age 61 years [range, 38-75 years]). The maximum tolerated 
dose of bendamustine and lenalidomide has not been identified at this point; currently, patients 
are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, 
DLTs include 1 grade 4 neutropenia at dose level 2 and 1 grade 3 thrombocytopenia at dose level 


 
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3. Ten patients are currently eligible for response assessment. An objective response was 
observed in 70% of patients, including 3 VGPR and 4 PR. Two patients experienced stable 
disease and 1 exhibited progressive disease.20 These data suggest that bendamustine, 
lenalidomide, and dexamethasone form a well-tolerated regimen in heavily pretreated MM 
patients.  
DLT of bendamustine is primarily hematologic. Treatment-associated infections have been 
reported in some studies; however, nonhematologic AEs have rarely been dose limiting. The 
most common nonhematologic AEs include fatigue, nausea, xerostomia, and pyrexia. 
Tumor Lysis Syndrome 
Tumor lysis syndrome associated with bendamustine treatment has been reported in patients in 
clinical trials and in spontaneous reports. The onset tends to be within the first treatment cycle of 
bendamustine and, without intervention, may lead to acute renal failure and death. Preventive 
measures include maintaining adequate volume status, and close monitoring of serum chemistry, 
particularly potassium and uric acid levels. Allopurinol has also been used prior to or at the 
beginning of bendamustine therapy. However, there may be an increased risk of severe skin 
toxicity when bendamustine and allopurinol are administered concomitantly. 
Skin Reactions 
Skin reactions have been reported in clinical trials and post-marketing spontaneous reports. 
These events have included rash, toxic skin reactions, and bullous exanthema. Some events 
occurred when bendamustine was given in combination with other anticancer agents, so the 
precise relationship of the skin reactions to bendamustine treatment is uncertain. 
In a study of bendamustine (90 mg/m2) in combination with rituximab (study SDX-105-02), 1 
case of toxic epidermal necrolysis (TEN) occurred. TEN has been associated with treatment with 
rituximab. Spontaneous reports of Stevens Johnson Syndrome (SJS) and TEN, some fatal, have 
been reported when bendamustine was administered concomitantly with allopurinol and other 
medications known to cause these syndromes. The relationship to bendamustine cannot be 
determined. 
When skin reactions occur, they may be progressive and increase in severity with further 
treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions 
are severe or progressive, bendamustine treatment should be withheld or discontinued. 
1.3 
Study Rationale and Selection of Drug Doses 
There are no established and approved second-line therapies for patients with systemic AL 
amyloidosis who fail initial melphalan-based treatment, be it high-dose melphalan with stem cell 
transplant or oral melphalan and dexamethasone (MDex). Therefore new treatments are needed 
for those who fail initial therapy and for those who initially respond but subsequently relapse.  


 
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The clonal plasma cells that cause AL produce abnormal immunoglobulin light chains that are 
the precursor proteins of amyloid fibrils. These light chain proteins are abnormal in sequence and 
conformation, and have a tendency to self-assemble and aggregate. Thus eradication or the 
control of the abnormal plasma cell clone is the precondition for successful treatment of AL 
amyloidosis. Bendamustine, a bifunctional alkylating agent with high anti-myeloma activity, 
achieves a PR in 70% of patients with relapsed/refractory MM. Based on this high anti-MM 
activity, we anticipate that bendamustine will also be very active in clonal plasma cell disorder 
associated with AL. 
MM and AL are plasma cell dyscrasias which receive similar treatment, e.g. melphalan, steroids, 
high dose chemotherapy with autologous stem cell transplant. Substances testing positive for 
anti-MM activity are also used for the treatment of AL, and data on the toxicity and efficacy 
from MM trials are used for subsequent studies in amyloidosis. 
Bendamustine is a drug which is approved and has been widely used in therapy for MM, NHL, 
breast cancer and other malignancies for 46 years. Based on several phase III trials, 
bendamustine received FDA approval for CLL (100 mg/m2) and NHL (120 mg/m2 d1 and d2) in 
the US. Due to the extensive experience and large amount of safety and toxicity data on 
bendamustine in hematologic malignancies, we think it is justified and safe to use bendamustine 
in a phase II trial for patients with AL with a strict stopping rule. 
 
 
 
1.4 
Correlative Studies:  
Cyclin D1 Overexpression in AL 
The correlative studies for this trial will be performed at Tufts University Medical Center, 
Boston, MA in Dr. Raymond Comenzo’s laboratory. This group is actively investigating the 
characterization of clonal plasma cells in AL. Recent data from this lab and others indicate that 
these cells over-express CCND1 in one-half of cases, often associated with t(11;14) and or gain 
11q.21,22 In a report at the American Society of Hematology Meeting (ASH 2009), clonal plasma 
cells (CD138+) obtained at diagnosis from 58 patients with AL were evaluated for CCND1 
expression.23 Sixteen cases were assessed by Affymetrix U133A 2.0 arrays (Affymetrix; Santa 
Clara, CA) and 42 cases by quantitative real-time polymerase chain reaction (qRT-PCR) as 
previously described.7,24 With transcriptional profiles (n=16), CCND1 median loge-transformed 
quantitative expression levels were 11.08 (range, 9.6-11.55) in five versus 4.163 (3.875-5.447) in 
eleven patients (P < 0.01). With qRT-PCR (n=42), relative CCND1 expression levels were high 
in twenty [median of 4.21 (1.76-17.24)], and low in twenty-two patients, [median of 0.014 (0-
0.99)] (P < 0.0001). Overall, 43% (25/58) of patients were CCND1hi and did not differ from 


 
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CCND1lo patients with respect to organ involvement, troponin I, urine total protein, creatinine or 
alkaline phosphatase levels. The median brain natriuretic peptide (BNP) of CCND1hi patients 
was 252pg/ml (range 20-1880), significantly higher than that of CCND1lo patients (109pg/ml (5-
4210), P < 0.05). CCND1hi patients tended to have more plasma cells (13% versus 8%, P = 
0.06), higher serum free light chain levels (23.3 versus 14mg/dl, P = 0.12) and more kappa 
clones (6/25 versus 2/33, P = 0.06) than CCND1lo patients. CCND1hi patients also had 
significantly fewer intact immunoglobulin M-proteins (4/25 versus 22/33, P <0.01). Although 
there were no differences in treatment modalities used in terms of SCT or MDex as well as in the 
rates of CHR, there was a significant difference in OS (Figure 1). CCND1hi patients survived a 
median of only 27 months compared to 60 months for CCND1lo patients (P = 0.02), and had a 
risk of death of 2.86 (CI 1.18-6.94). 
CCND1 over-expressing clones then usually produce only immunoglobulin light chains and not 
intact immunoglobulins because of loss of Ig heavy chain gene loci due to t(11;14). Preliminary 
data from the Comenzo lab indicates that CCND1 over-expressing clones also over-express  
genes associated with maintenance of protein solubility and protein quality control such as 
PDIA6 and SEL1L, a phenomena possibly linked to the exclusive production of Ig light chains 
that form amyloid. The correlative studies of clonal bone marrow plasma cells selected from pre-
treatment marrow aspirates will further test the hypothesis that CCND1 over-expressing clones 
up-regulate SEL1L, a genes involved in ER-associated protein quality control. Using patient bone 
marrow specimens obtained at baseline, we will perform RT-PCR to assess the expression in 
clonal plasma cells of the genes CCND1 and SEL1L and determine whether their expression is 
correlated.  
0
6 12 18 24 30 36 42 48 54 60 66 72 78
0
25
50
75
100
CCND1hi (n=25)
CCND1lo (n=33)
P = 0.02
Months
Percent survival
Figure 1. Overall Survival is Significantly 
Decreased in CCND1hi Patients
 
Figure 1. Overall Survival is Significantly Decreased in CCND1hi Patients 
 
Quantitative RT-PCR will be performed (in duplicate and on 2 separate days) using TaqMAN 
Gene Expression Assays with RPLP0 (Hs99999902_m1) primers and probes (Applied 
Biosystems; Foster City, CA) as internal control on an Mx 3000P platform and related software 
(Stratagene; La Jolla, CA). The comparative Ct method will be used and the amount of target 
normalized to the control (2-ΔΔCt) assuming an efficiency of 2. Statistical analyses (paired t-test) 


 
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will be performed with GraphPad PRISM (GraphPad; La Jolla, CA) with P < 0.05 significance 
level for CCND1. Then CCND1hi and CCND1lo cases will be compared by paired t-test with 
respect to expression levels of SEL1L. These studies may lead to new therapies for AL by 
identifying new druggable targets.  
With patients’ consent baseline samples (5 ml) will be sent to Dr. Comenzo’s lab for these 
correlative studies. The correlative studies are optional. 
2 
OBJECTIVES 
2.1 
Primary Objectives 
Determine the CHR rate. 
2.2 
Secondary Objectives 
 
Determine the overall hematologic response (OHR) rate 
 
Determine the organ response rate (OrRR) 
 
Determine  the time to treatment failure (TTF) 
 
Assess the toxicity of the regimen 
 
Determine the distribution of OS and PFS 
 
To assess by RT-PCR the expression in clonal plasma cells of cyclin D1 (CCND1) and 
SEL1L before treatment. To assess the bone marrow cytokine profile before and after 
treatment with bendamustine.  
 
3 
STUDY DESIGN 
3.1 
Study Design 
This Phase IIa clinical trial uses a two-stage optimal Simon design.1 In the first stage, 13 patients 
are enrolled. If at least three patients experience hematologic PR or better, the trial proceeds to 
the second stage, otherwise, the trial terminates with no further interest in the treatment. In the 
second stage, 16 additional patients are treated. If a total of 9 or more out of the total of 29 
patients evaluable for response experience hematologic PR and better, the treatment will be 
considered worthy of further development. Patients who finished at least 2 cycles are eligible for 
evaluation of response. 
Patients who have not completed 2 cycles and therefore are not evaluable for response will be 
replaced. However, patients with primary progressive disease after only receiving 1 cycle of 
therapy will be included in the response analysis. A maximum of 40 patients will be consented to 
accrue the maximum of 29 patients evaluable for response. 
3.2 
Stopping Rule for Excess Toxicity 
The trial will employ a stopping rule25 for excess of drug toxicity defined as Grade 4 and 5 as 
defined in NCI CTCAE, Version 4.0 and related to the study medication. The number of patients 
experiencing toxicity during any cycle of treatment will be evaluated after 5, 10, 15, 20 and 25 
patients have completed treatment. For instance, if 4 or more patients out of the first 10 


 
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experience toxicity as defined, the trial will be paused for evaluation by the DSMB.  Accrual 
does not need to be stopped until 5, 10, etc., patients have completed their treatment per Table 1 
below.  Grade 4 thrombocytopenia and lymphocytopenia are expected events and will not be 
considered an excess of toxicity.  The protocol allows for patients to be treated with CrCl 15 – 30 
mL/min.  For patients with a baseline CrCl within this range, grade 4 Chronic Kidney Disease 
defined as a CrCl < 15 will not be considered an excess of toxicity.   
Table 1. Stopping rule for excess toxicity 
# Patients 
# Toxicities 
5 
3 
10 
4 
15 
5 
20 
6 
25 
7 
 
 
 
 
3.3 
Justification of Sample Size and Stopping Rule 
The optimal two-stage Simon design was determined from the following parameters. For the 
treatment to be of further interest, the proportion of patients experiencing clinical response 
should be at least 0.40 (p1). A proportion of responding patients of 0.20 or less is clearly 
unacceptable (p0). The probability of promoting an unacceptable drug to Stage 2 (α) is 0.10, and 
the probability of rejecting an acceptable drug at the end of Stage 2 (β) is set to 0.15. The 
resulting trial has an expected sample size of 21.0 patients if the treatment is unacceptable. The 
trial is stopped if P(π>0.1)>0.7, where π is the true probability of toxicity in the patient 
population. In Monte Carlo simulations, it was determined that, if π=0.2, the probability of 
stopping early equaled 0.3, while, if π=0.3, the probability the trial stopped early was 0.72. 
4 
PATIENT SELECTION 
4.1 
Patient Population 
Eligible patients will be 18 years old or older with AL with persistent or progressive clonal 
plasma cell disease after first line therapy. 
4.2 
Inclusion and Exclusion Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. All baseline evaluations, which assure that inclusion 
and exclusion criteria have been satisfied, must be reviewed by the Investigator or an authorized 
physician sub-investigator prior to enrollment. In addition, the patient must be thoroughly 
informed about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent. The written informed consent 


 
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must be obtained from the patient prior to enrollment. The following criteria apply to all patients 
enrolled onto the study unless otherwise specified. 
4.2.1 Inclusion Criteria 
 
Male or female patients aged ≥ 18 years old 
 
Histopathology of amyloidosis or light chain deposition disease based on detection by 
polarizing microscopy of  green bi-refringent  material in Congo red-stained tissue specimens 
or characteristic electron microscopy appearance or immunohistochemical stain with anti-
light chain anti-sera 
 
Demonstrate measurable disease as defined by one or more of the following: 
o Serum monoclonal protein ≥ 0.5 g/dL by serum electrophoresis 
o Urine monoclonal protein > 200 mg/dL in a 24 hr urine electrophoresis 
o Demonstrate clonal population of plasma cells in the bone marrow or abnormal FLC ratio 
 
ECOG performance status of 0, 1, or 2 
 
Patients had at least one prior regimen consisting of at least 1 cycle 
 
If not previously transplanted, patient should be either ineligible for ASCT, or must have 
declined the option of ASCT. Patients who have previously had ASCT and have 
subsequently progressed are eligible, provided other entry criteria are met 
 
Ability to provide written informed consent obtained prior to participation in the study 
and any related procedures being performed 
 
Patients must meet the following laboratory criteria: 
 
ANC ≥ 1.5 x 109/L 
 
Hemoglobin ≥ 9 g/dl  (May transfuse PRBC to meet parameter)   
 
Platelets ≥ 100x 109/L (Must be independent of platelet transfusion) 
 
Calculated CrCl   30 mL/min, patients with a CrCl   15 mL/min can be considered for 
the trial if patients are not in active renal failure and after discussion with the PI 
(Cockcroft-Gault Formula – see Appendix D)34  
 
AST and ALT ≤ 2.5 x upper limit of normal (ULN)  
 
Serum bilirubin <1.5 x ULN 
 
Serum potassium WNL 
 
Total serum calcium (corrected for serum albumin) or ionized calcium below ULN  
 
4.2.2 Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study. 
 
Patients meeting the criteria for symptomatic MM: 
o lytic lesions on skeletal survey or 
o plasmacytoma 
Patients meeting International Myeloma Working Group definition of symptomatic 
myeloma with symptoms only related to associated amyloidosis who would otherwise 
only meet the criteria for smoldering MM are potentially eligible. 
 
Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class IIIB or IV heart failure, uncontrolled angina, severe 


 
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uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia 
or active conduction system abnormalities (not including 1st degree AV-block, 
Wenckebach type 2nd degree heart block, or left bundle branch block. Prior to study 
entry, any ECG abnormality at Screening has to be evaluated by the investigator or an 
authorized physician sub-investigator). Note: There is no lower limit of left ventricular 
ejection fraction below which patients are excluded from participation. 
 
Patients with NT-proBNP ≥ 1800 ng/L or BNP ≥ 400 ng/L, abnormal cTnT or cTnI 26, 27 
can only be included after evaluation by cardiology to determine of the risk associate 
with the treatment. This evaluation needs to be discussed with the PI (Dr Lentzsch). 
 
Patient has received other investigational drugs within 14 days prior to enrollment 
 
Any form of secondary / familial amyloidosis 
 
Serious concurrent illness, which in the opinion of the investigator or an authorized 
physician sub-investigator would interfere with participation in this clinical study.  
 
Known HIV Infection. 
 
Inability to provide informed consent or to comply with the schedule of office and 
treatment visits 
 
Female subject is pregnant or breast-feeding. Confirmation that the subject is not 
pregnant must be established by a negative serum -human chorionic gonadotropin 
pregnancy test result obtained during screening. Pregnancy testing is not required for 
post-menopausal or surgically sterilized women (woman not of child-bearing potential is 
defined as any woman whose menstrual periods have stopped in the past 12 consecutive 
months or have had a complete hysterectomy or both ovaries surgically removed). 
 
Diagnosed or treated for another malignancy within 3 years of enrollment, with the 
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of 
the skin, an in situ malignancy, low-risk prostate cancer, or cancer after curative 
treatment. 
 
5 
REGISTRATION PROCEDURES 
5.1 
Assignment of Study Numbers 
Each patient enrolled will be assigned a unique and sequential study identifier. 
 
Registration Guidelines 
 
CUMC Research Participant Registration: 
 
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures, along with applicable institutional policies and federal regulations. 
 
Research personnel trained to consent subjects for this protocol will be required to complete a 
protocol specific Eligibility Checklist. 
 


 
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All participants must be centrally registered at CUMC prior to initiation of study 
treatment. 
 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST (excluding 
holidays). Same day patient registrations (and after hour registrations) will be accommodated on 
a case by case basis provided that the study team has expressed all time sensitive registration 
concerns/cases in a timely manner. 
 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent, a completed/signed IRB approved informed consent 
HIPAA form, and demographics forms must be submitted to the CPDM Central Registration 
Office via an email to CPDMRegistration@columbia.edu or fax to 212.305.5292, with the 
subject line “AAAJ7800 Pending Subject Registration Request (PHI)”.  Upon receipt, applicable 
subject information as well as a “pending eligibility” status will be entered into HICCC’s 
institutional database.  This status will remain until further source documentation is made 
available to determine overall patient eligibility. Required materials for all pending registration 
submissions are as follows: 
 
 Completed/signed IRB approved/stamped Informed Consent Forms, including additional 
study ICFs (i.e. tissue, DNA, etc.) as applicable 
 The completed/signed IRB approved HIPAA Authorization form 
 Completed/signed CPDM ICF checklist 
 Completed/signed HICCC personal census form 
 Completed/signed CPDM Demographics Note to File 
 
In order to confirm eligibility status, Investigators/designees (i.e., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to the 
Central Registration Office via email or fax: 
 
 The completed/signed study specific Eligibility Checklist  
 Completed/signed Velos Demographics Note to File 
 Copies of source documentation necessary for each item to be verified on the CUMC 
specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (i.e., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 


 
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o Copy of clinic note(s) or other appropriate medical records capturing the consent 
process information, along with providing source documentation of any other 
items needed for screening/eligibility that are not captured in other source 
document forms (e.g., positive investigator statements of unique eligibility items 
not captured via other direct source documentation, concomitant medication lists, 
etc) 
o Protocol deviation/waiver approvals (if applicable) 
 Please note: subject line of email or fax should include the following: “AAAJ7800 
Complete Subject Registration Request (PHI)”. 
Upon Receipt of the above mentioned documentation, participant eligibility information will be 
verified by a qualified Central Registration Registrar. If any questions arise during the review 
process, queries in the form of emails will be addressed to the applicable study team personnel 
for clarification prior to enrollment. .All applicable finalized registration/eligibility information 
will then be entered into HICCC’s institutional database by the Central Registration Registrar.  
Upon completion, an official subject registration notification email will be sent to the PI/research 
team which will include eligibility/enrollment status, as well as subject ID information.  Protocol 
therapy may not be initiated prior to receipt of this notification from the Central Registration 
Office. 
 
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 
 
Affiliate Institution Research Participant Registration Process:  
All Affiliate Institutions must register subjects with the coordinating center (CUMC) prior to 
any administration of study drug/intervention/local institution registration.  Please see 
instructions below: 
 
1. Within 48 hours of the consent visit, the Affiliate Institution CRN and/or CRC is required 
to submit the following documents to the coordinating center’s designee (CUMC’s study 
specific Clinical Research Coordinator or Clinical Research Nurse) via email at 
AAAJ7800@columbia.edu.  The coordinating center’s designee will review the 
documents for accurateness, and subsequently submit the documents to the CPDM 
Central Registration Office via email at CPDMRegistration@columbia.edu (or via fax at 
212.305.5292), with a request to register the patient “pending eligibility.” The title of the 
email should read, “AAAJ7800 Pending Subject Registration Request (PHI)”.  The 
following documents should be submitted with the pending registration request: 
a. Redacted Completed/signed IRB approved/stamped Informed Consent Forms, 
including additional study ICFs (i.e. tissue, DNA, etc.) as applicable 


 
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b. Redacted Signed HIPAA (or institutional equivalent) 
c. MCT Velos Demographics Note to File form  
 
2. The Participating Institution’s investigator/research nurse/data manager/coordinator must 
contact the coordinating center’s designee (CUMC’s study specific Clinical Research 
Coordinator or Clinical Research Nurse) via telephone or email to communicate the 
following: 
 Notify of pending registration request  
 Confirm method of registration request submission (email or fax) 
 Communicate expected time-line of registration request submission (i.e., same day, next 
day, within the hour, etc.) 
3. For a full registration, the Affiliate Institution’s investigator/research nurse/data 
manager/coordinator should then submit the following documents to the CUMC study 
specific designee: 
 A signed Affiliate Site Eligibility Checklist (signed by treating physician/investigator) 
 Copies of redacted source documentation necessary for each item to be verified on the 
CUMC specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (i.e., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) capturing the consent process information, along with 
providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms. (e.g., 
positive investigator statements of unique eligibility items not captured via other 
direct source documentation, concomitant medication lists, etc.) 
o Protocol deviation/waiver approvals (if applicable) 
 Please note: subject line of email or fax should include the following: “AAAJ7800 
Complete Subject Registration Request (PHI)”. 
4. Upon receipt of the above mentioned documents, the designated study specific Clinical 
Research Coordinator will review all documents and verify patient eligibility.  If any 
questions arise during the review process, queries in the form of emails will be addressed to 
the applicable affiliate site study team personnel for clarification prior to enrollment.  Upon 


 
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verification, the CUMC study specific designee will then forward all documents to the 
CPDM Central Registration Office for central registration (as described above). The CPDM 
Central Registration Registrar will review all applicable documents and communicate to the 
CUMC study specific designee in order to clarify any items.  The CUMC study specific 
designee will communicate with the applicable site study team personnel for additional 
clarifications necessary prior to enrollment. 
5. Upon receipt of the subject registration notification email, the CUMC study specific 
designee will forward the notification email (which will include the study specific subject 
ID) to the affiliate site’s Principal Investigator, Consenting Professional, and applicable 
research personnel.  This notification should be filed in the subject research record, medical 
record, and regulatory binders accordingly. Protocol therapy may not be initiated prior to 
receipt of this notification from the coordinating center. 
6. All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration 
office in a manner analogous to the procedures noted above. Applicable source 
documentation will be required within the corresponding submissions. 
6 
TREATMENT PLAN 
Treatment will be administered on an outpatient basis. Each treatment cycle will be 28 days. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
6.1 
Study Agents 
6.1.1 Bendamustine 
Patients will start bendamustine at dose level 0 and according to CrCl on day 1 cycle 1 and actual 
body weight:  
CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle  
CrCl 59 – 30 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle 
CrCl 15 – 30 mL/min: 70 mg/m2 IV on day 1 and 2 of each cycle 
Available to qualifying subjects is the option to dose escalate to dose level (+)1:  
120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study)  
100 mg/m2 (if CrCl 59 – 30 mL/min at the time of inclusion into the study)  
Refer to section 6.7 for detailed dose modification information.  
6.1.1.1 How Supplied 
Bendamustine is an investigational agent supplied to investigators by Teva Pharmaceuticals 
(formerly Cephalon, Inc) (See Appendix G for Study Drug Request Form).The bendamustine 
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For further details and molecule characterization, see the Cephalon IND application and/or 
Investigator’s Brochure (See Appendix E for cross reference letter).  
 
6.1.1.2 Route and Method of Administration 
The dose should be administered intravenously over 60 minutes. To insure complete delivery of 
bendamustine, the IV infusion line must be flushed with 50 mL 0.9% sodium chloride for 
injection and a volume equal to the volume contained in the tubing according to institutional 
standards.  
 
6.1.1.3 Expected Adverse Events 
Common (occurs in more than 10% of people - more than 10 out of 100 people): 
 
Blood abnormalities, such as a decrease in the number of white blood cells, red blood cells, 
platelet, and/or neutrophils. White blood cells are cells of your immune system.  A decrease 
in white blood cells and or neutrophils may lead to fever and/or a life threatening infection.  
The red blood cells carry oxygen to your organs.  A decrease in red blood cells can lead to 
fatigue.  A decrease in platelets may lead to bleeding and require stopping treatment.   An 
elevated number of eosinophils, a type of white blood cell, may also be seen. 
 
Infections (such as pneumonia) requiring antibiotic treatment 
 
Nausea 
 
Vomiting 
 
Diarrhea 
 
Constipation 
 
Dehydration 
 
Fatigue 
 
Hair loss 
 
Fever 
 
Allergic reactions 
 
Chills 
 
Pruritus (itchy skin) 
 
Rash 
 
Phlebitis 
 
Hives 
 
Hypersensitivity 
 
Mouth sores and pain 
 
Dry mouth 
 
Cough 
 
Weight loss/ lack of appetite  
 
Potential risk of temporary discomfort, bleeding, hematoma and infection after venipuncture 
 
Infrequent (occurs in 1% to 10% of people - from 1 to 10 out of 100 people): 
 
Blood clots in your arteries which may cause stroke or heart attack or other problems. These 
conditions can be life-threatening or fatal. 
 
Rare (occurs in fewer than 1% of people – fewer than 1 out of 100 people): 
 
Kidney damage 
 
Reversible changes in liver function tests that may indicate liver damage  


 
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 
Pulmonary edema (pulmonary edema is an abnormal build up of fluid in the lungs, which 
leads to swelling).  
 
Myelodysplastic syndrome, a pre-cancerous blood condition which could lead to leukemia 
 
Toxic Epidermal Necrolysis, which is a severe and frequently fatal skin reaction similar to a 
severe burn. 
 
Anaphylactic and anaphylactoid reaction (particularly in the second and subsequent cycles of 
therapy) 
 
Infection associated with septic shock and death 
 
Death 
 
Extravasation: During the intravenous infusion of bendamustine, there have been reports of 
drug escaping from the blood vessel into the tissues. This can cause redness, swelling, pain, 
infection and tissue damage. 
 
Severe skin reactions (if relationship to Bendamustine is suspected, discontinue 
Bendamustine) 
 
Tumor lysis syndrome (tends to be within the first treatment cycle and without intervention, 
may lead to acute renal failure and death) 
 
Tumor Lysis Syndrome 
Tumor lysis syndrome associated with bendamustine treatment has been reported in patients in 
clinical trials and in spontaneous reports. The onset tends to be within the first treatment cycle of 
bendamustine and, without intervention, may lead to acute renal failure and death. Preventive 
measures include maintaining adequate volume status, and close monitoring of serum chemistry, 
particularly potassium and uric acid levels. Allopurinol has also been used prior to or at the 
beginning of bendamustine therapy. However, there may be an increased risk of severe skin 
toxicity when bendamustine and allopurinol are administered concomitantly. 
 
Skin Reactions 
Skin reactions have been reported in clinical trials and postmarketing spontaneous reports. These 
events have included rash, toxic skin reactions, and bullous exanthema. Some events occurred 
when bendamustine was given in combination with other anticancer agents, so the precise 
relationship of the skin reactions to bendamustine treatment is uncertain. 
 In a study of bendamustine (90 mg/m2) in combination with rituximab (study SDX-105-02), 1 
case of TEN occurred. TEN has been associated with treatment with rituximab. Spontaneous 
reports of SJS and TEN, some fatal, have been reported when bendamustine was administered 
concomitantly with allopurinol and other medications known to cause these syndromes. The 
relationship to bendamustine cannot be determined.  
When skin reactions occur, they may be progressive and increase in severity with further 
treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions 
are severe or progressive, bendamustine treatment should be withheld or discontinued. 
6.1.2 Dexamethasone 
Will be administered 40 mg orally or intravenously on days 1, 8, 15, 22 of each cycle. Dose 
reduction is outlined under Section 6.7. 
 
6.1.1.4 How Supplied 
Decadron, Hexadrol, Dexameth, Dexone, DXM, others. 


 
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Commercially available in 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 6 mg tablets. 
 
6.1.1.5 Route of Administration 
Oral: 40 mg orally will be administered on days 1, 8, 15, 22 of each cycle. 
Individual patients will stay at the same dose level throughout study treatment unless they 
require dose reduction due to DLT. 
Intravenous: Dexamethasone can be administered intravenously at the same dose level at any 
point in the study cycle if this is more convenient for the study subject and/or the study site. 
 
6.1.1.6 Risks of Dexamethasone 
The most common side effects of dexamethasone include infection, insomnia, seizures, muscle 
weakness, particularly the thigh muscles, irritability and mood swings, weight gain, increased 
appetite, diabetes mellitus (high blood sugar), high blood pressure, thromboembolism, peptic 
ulcers, pancreatitis (inflammation of the pancreas), mucositis and fluid retention. 
 
Intravenous administration of dexamethasone may cause following side effects: 
 Temporary discomfort from the needle stick  
 Bruising  
 Bleeding 
 Infection (rare)  
 
6.2 
Other Agents 
Patients should receive full supportive care while on this study. This includes blood product 
support, antibiotic treatment and treatment of other newly diagnosed or concurrent medical 
conditions. All blood products and concomitant medications such as anti-diarrheal, analgesics, 
anti-emetics received from the first administration of study drugs until 30 days after the final 
dose are to be recorded in the subject’s research record. 
 
All patients will receive prophylaxis with either an H-2 blocker or proton pump inhibitor while 
on study medications. Prophylactic antibiotics (Bactrim, Diflucan) should be considered. All 
supportive care should be given according to institutional standards. 
 
Use of insulin and/or oral hypoglycemics to control hyperglycemia related to dexamethasone 
therapy is allowed per physician discretion. 
 
6.3 
General Concomitant Medication and Supportive Care Guidelines 
Myelosuppression: Growth factors, specifically filgrastim (granulocyte colony stimulating factor; 
G-CSF) or pegfilgrastim only (GM-CSF not allowed), can be used to treat neutropenia. The 
usual dose of filgrastim is 5 micrograms/kg/day given subcutaneously until the ANC is greater 
than 1,000 x 2 subsequent readings. G-CSF can be rounded to the nearest vial size. The usual 
dose of pegfilgrastim is a single dose of 6 mg administered subcutaneously. No additional doses 
of pegfilgrastim are permitted in the next 28-day period. Growth factors should be given 24-72 
hours after the last chemotherapy. The major adverse even with filgrastim and pegfilgrastim is 
bone pain. Other side effects are rare and include nausea, fatigue, diarrhea, vomiting, 
constipation, fever, anorexia, headache, taste perversion, dyspepsia, myalgia, insomnia, 


 
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abdominal pain, arthralgia, generalized weakness, peripheral edema, and dizziness. Reversible 
elevations in LDH, alkaline phosphatase, and uric acid, not requiring therapy have also been 
observed. 
 
Hyperglycemia: Hyperglycemia, sometimes severe, including diabetic coma or ketoacidosis can 
occur with dexamethasone therapy. Therefore blood sugars should be monitored in diabetic 
patients, borderline patients, and in patients at risk for hyperglycemia or diabetes. 
 
Anemia: Patients with hemoglobin < 8 mg/dL and/or symptomatic receive packed red blood cells 
transfusion. The final decision should be made at the discretion of the investigator or an 
authorized physician sub-investigator. 
Subjects are allowed to be treated with full dose anti-coagulation (full dose low molecular weight 
heparin or warfarin with a goal INR of 2 to 3) while on study, however the toxicity management 
guidelines as outlined below must be followed. 
 
6.4 
Dosing Delays/Modifications 
Treatment modifications are based on adverse events, which are possibly, probably, or definitely 
related to drug. All AEs should be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE, v. 4.0).  Due to the complex problems that may occur in this patient 
population, it is at the discretion of the investigator to decrease the dose level of the study drugs 
if medically indicated.  The investigator should inform the lead institution’s principal 
investigator regarding these decisions.  Dose modifications and delays different from those stated in 
the protocol, for management of toxicities, will be permitted at the discretion of the Investigator. 
6.4.1 Bendamustine Adjustments for Hematologic Toxicities  
The following treatment adjustments for hematologic toxicities are recommended. The 
investigator or an authorized physician sub-investigator may modify the recommendations if the 
clinical situation dictates a change. 
 
▪ Uncomplicated Neutropenia: On Day 1 of each cycle, if Grade 3 or 4 neutropenia is the only 
Grade 3 or 4 adverse event present, hold all study drugs, monitor CBC weekly. If neutropenia 
resolves to grade 1 or baseline within 7 days resume treatment at previous dose level and add G-
CSF or Peg-G-CSF at Day 3 of cycle.  
If neutropenia does not resolve to baseline or grade 1 within 7 days, start daily G-CSF without 
initiating next cycle of therapy. If neutropenia resolves with G-CSF at  7days of starting G-
CSF, start next cycle without dose reduction and adding G-CSF with the next cycle. If 
neutropenia does not resolve with G-CSF at  7 days of adding G-CSF, patient is off study.  
Patients who experience a Grade 3 or 4 neutropenia on Day 1 and received pegfilgrastim in the 
previous cycle should be dose-reduced for the following cycle. 
 
At any other time of each cycle (with protocol labs), if grade 3 or 4 neutropenia is the only grade 
3 or 4 adverse event, add G-CSF. Do not reduce dose for next cycle. Add G-CSF on Day 3 of 
next cycle. If patient is already receiving G-CSF, then dose is reduced by one level with 
continued use of growth factor when next cycle is initiated. 
 


 
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▪ Complex/Complicated Neutropenia: Sustained (≥ to 7 days) Grade 3 or 4 neutropenia subsequent 
to G-CSF or associated with fever/infection (temperature ≥ 38.5°C AND requiring antibiotic 
treatment) hold study drugs and follow CBC weekly. When toxicity resolves to baseline or  
Grade 1, start new cycle at next lower dose level with G-CSF. 
 
Adherence to the preceding guidelines regarding G-CSF use with neutropenia is strongly 
encouraged; however final decision regarding use of G-CSF rests with the study site investigator 
and his/her clinical judgment. 
 
▪ Thrombocytopenia:  Grade 3/4 (Plt < 50,000/mm3) hold all study drugs, follow CBC and dose 
reduce to next lower dose level. If grade 4 thrombocytopenia occurs for more than 7 days and/or 
is associated with significant bleeding (e.g., requiring transfusion) patient is off study regardless 
of the dose level. When toxicity resolves to baseline or  Grade 1, start new cycle at next lower 
dose level. 
▪ Lymphopenia: Grade 3/4 is expected and will not be graded as an AE. 
▪ Anemia: Grade 4, patient should be evaluated for other reasons of anemia such as hemolytic 
anemia, bleeding, etc.  
 
All patients should get optimal supportive therapy such as platelet or red blood cell transfusion. 
6.4.2 Bendamustine Adjustments for Other Toxicities 
There are no reductions in the bendamustine dose if bendamustine is given at dose level -2. If 
adverse events occur at dose level -2 that require holding bendamustine, the dose will remain the 
same once treatment resumes. If bendamustine is held for more than 4 weeks, the study site 
investigator should consult with the Principal Investigator of the study to assess the 
appropriateness of continuing the patient on study. If an AE occurs at a higher dose, the 
bendamustine dose will be reduced according to the table in section 6.7. 
 
6.4.3 Dexamethasone Treatment Adjustments 
It is expected given the low dose of dexamethasone that few dose modifications related to 
dexamethasone will be necessary. Refer to the dose modifications table, Section 6.7, for the dose 
reduction levels for dexamethasone. 
CTCAE Category 
Adverse Event 
Dexamethasone 
Treatment 
Bendamustine Dose Management based on Adverse Events 
CTCAE Grade 
Bendamustine Treatment Adjustment 
Hepatic or other non-hematologic toxicity 
assessed as bendamustine related ≥ Grade 3 
Hold bendamustine and follow the subject. If the 
toxicity resolves to ≤ Grade 1 restart the next cycle at 
the next lower dose level. IF AE occurred under dose 
level -2 of bendamustine and the dose is held for more 
than 4 weeks the patients will be off study. 


 
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Adjustment 
Gastrointestinal  
(All patients will be 
treated 
with 
H2 
Blockers, ranitidine, or 
omeprazole 
as 
per 
Section 6.2) 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grade 1-2 
If symptoms persist despite prophylaxis, 
decrease dexamethasone to dose level -1 
permanently. 
Dyspepsia, gastric or duodenal 
ulcer, 
gastritis 
≥ 
Grade 
3 
(requiring 
hospitalization 
or 
surgery) 
Hold dexamethasone until symptoms are 
adequately controlled. Restart at dose 
level 
-1. 
If 
symptoms 
persist, 
discontinue dexamethasone and do not 
resume 
Acute pancreatitis 
Discontinue dexamethasone and do not 
resume. 
Cardiovascular 
Edema 
≥ Grade 3 
Diuretics as needed, and decrease 
dexamethasone dose to dose level -1, if 
edema persists despite above measures, 
decrease 
dose 
to 
dose 
level 
-2; 
discontinue dexamethasone and do not 
resume if symptoms persist despite  
reduction to dose level -2. 
Neurology 
Confusion or Mood Alteration ≥ 
Grade 2 (interfering with function 
and/or ADLs) 
Hold dexamethasone until symptoms 
resolve, restart at next lower dose level. 
If symptoms persist despite above 
measures, discontinue dexamethasone 
and do not resume. 
Musculoskeletal 
Muscle Weakness ≥ Grade 2 
(symptomatic 
and 
interfering 
with ± function of ADLs) 
Decrease dexamethasone to dose level -
1, if weakness persists despite above 
measures, decrease dose to dose level -2; 
discontinue dexamethasone and do not 
resume if symptoms persist at dose level 
-2. 
Metabolic 
Hyperglycemia ≥ Grade 3 or 
higher 
Treatment 
with 
insulin 
or 
oral 
hypoglycemics 
as 
needed. 
If 
uncontrolled despite above measures, 
decrease to dose level -1, decrement 
until levels are satisfactory. 
 
6.5 
Duration of Treatment 
Therapy will be given until disease progression or for up to 6 courses after a patient has a CHR. 
Patients will come off treatment for unacceptable toxicity, patient refusal, non-response, 
progression or non-compliance.  
 


 
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6.6 
Duration of Follow-Up 
Patients who have progressed will be followed for survival for a maximum of 3 years, with 
phone calls every 3 months. Patients who have not progressed, will be followed according to the 
Study Calendar in Section 6.8. Patients removed from study for unacceptable adverse events will 
be monitored until resolution or stabilization of the adverse event. 


 
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6.7 
Dose Modifications  
Dose reduction level for bendamustine:  
 
If the AE is not described in 6.4 and cannot be attributed to a specific drug e.g. (hyperglycemia 
and dexamethasone, neutropenia and bendamustine) a dose reduction of both drugs should be 
performed. 
Patients will start bendamustine at dose level 0 according to calculated creatinine clearance 
(CrCl) result on day 1 cycle 1 and actual body weight  on day 1 of each cycle, and dose 
modifications will be based on their individual starting dose. 
When CrCl ≥ 60 mL/min: start at 100 mg/m2 IV on day 1 cycle 1  
When CrCl 59 – 30 mL/min: start at 90 mg/m2 IV on day 1 cycle 1 
When CrCl 30 – 15 mL/min: start at 70 mg/m2 IV on day 1 cycle 1 
Dose modifications will be performed according to the starting dose. 
 
 
CrCl ≥ 60 mL/min 
CrCl 
59 
– 
30 
mL/min 
CrCL 
30 
– 
15 
mL/min 
Dose Level +1 
120 mg/m2 days 1+2 
100 mg/m2 days 1+2 
 
Dose Level 0 
100 mg/m2 days 1+2 
90 mg/m2 days 1+2 
70 mg/m2 days 1+2 
Dose Level -1 
90 mg/m2 days 1+2 
70 mg/m2 days 1+2  
50 mg/m2 days 1+2 
Dose Level -2 
70 mg/m2 days 1+2 
50 mg/m2 days 1+2 
 
 
 
Dose reduction level for dexamethasone: 
 
 
Standard risk patient 
Patient 
with 
edema, 
cardiac 
symptoms 
or 
previous 
AE 
to 
dexamethasone 
Dose Level 0 
40 mg/week 
20 mg/week 
Dose Level -1 
20 mg/week 
20 mg q 14 days 
Dose Level -2 
20 mg q 14 days 
10 mg/week 
Dose Level -3 
D/C 
dexamethasone 
and 
continue 
bendamustine monotherapy 
D/C dexamethasone and continue 
bendamustine monotherapy 
 
Investigator has option of escalating dose of bendamustine to dose level +1 if no dose 
interruptions or serious adverse events (SAEs) in cycles 1 and 2. If the subject tolerates treatment 
well without serious side effects, dose escalation can be considered upon discussion with the 
Principal Investigator of the study who will make the final determination for dose escalation. 
6.8 
Study Calendar 


 
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All pre-study scans, x-rays and biopsy to be done up to 6 weeks before registration. EKG and 
Echocardiogram to be done up to 4 weeks before registration. Pre-study CBC (with differential 
and platelet count) and all required pre-study chemistries must be done up to 4 weeks before 
registration. Patients must begin therapy within 4 weeks of registration. If a cycle needs to be 
delayed due to the subject’s inability to comply with the study calendar (i.e., hospitalizations, 
business and vacation travel plans, illness, transportation issues, holidays, family emergencies, 
etc.), a one week delay is available for rescheduling of day 1 treatment and procedures per the 
discretion of the treating physician investigator. Laboratory assessments required for treatment 
must be performed on day 1 of each cycle (up to 3 days prior to or on the day of treatment 
administration is permitted).  UPEP may be performed up to two weeks prior to Day 1. After 
discontinuation of therapy, subjects who have not progressed should be followed every 3 months 
(± 1 month) for the first two years, every 6 months (± 1 month) for years 2-5, and annually 
thereafter until progression (see Section 6.6). The following parameters need to be evaluated by 
the treating physician prior to start of therapy:  History and physical examination including 
graded neuropathy, VS and AE assessment, performance status (ECOG and Karnofsky), CBC, 
Calcium, sodium, potassium, serum creatinine, BUN, EKG, BNP/NT-proBNP, Troponin I/T. 
 
Study parameters15 
 
Baseline 
Every 
Cycle  
d115, 16 
 
Every 
Cycle 
d15 ( ± 2 
days)17 
Discontinuation 
of therapy13 
Follow-
up14 
History & Physical Examination, 
orthostatic VS, Height & Weight1 
X 
X2 
 
X 
X 
VS, orthostatic VS, AE assessment 
 
X2 
X 
 
 
Performance Status (ECOG and 
Karnofsky) 
X 
X2 
 
X 
X 
CBC 
(with 
differential 
and 
platelets) 
X 
X2 
X 
X 
X 
Calcium, sodium, potassium, serum 
creatinine, BUN 
X 
X2 
 
X 
X 
Glucose 
X 
X 
 
 
 
Total Bilirubin, LDH 
X 
X 
 
X 
 
AST/ALT 
X 
X 
 
 
 
Alkaline Phosphatase 
X 
X 
 
 
 
Albumin 
X 
X 
 
 
 
PT, PTT, INR 
X 
X 
 
 
 
BNP/NT-proBNP, Troponin I/T3 
X 
X2 
 
X 
X 
B12 level 
X 
X9 
 
X9 
 
Urinalysis 
X 
X 
 
X 
X 
SPEP4 
X 
X 
 
X 
X 


 
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Study parameters15 
 
Baseline 
Every 
Cycle  
d115, 16 
 
Every 
Cycle 
d15 ( ± 2 
days)17 
Discontinuation 
of therapy13 
Follow-
up14 
Serum free light chains4 
X 
X 
 
X 
X 
24 hour urine collection for total 
protein with UPEP 4 
X 
X 
 
X 
X 
Immunofixation of serum and urine 
X 
X10 
 
X10 
X10 
Bone Marrow Aspirate/Biopsy5 
X 
 
 
X5 
 
Cytogenetics (bone marrow) 
X 
 
 
X 
 
Beta 2 Microglobulin 
X 
X 
 
X 
 
Quantitative Immunoglobulins6 
X 
X 
 
X 
 
Pregnancy test7 
X 
X 
 
 
 
EKG1  
X 
X2 
 
X 
X 
Echocardiogram1 
X 
X11 
 
X11 
X11 
X-ray: skeletal survey with CXR 
X 
 
 
 
 
CT scan/ultrasound abdomen 
X 
X11 
 
X11 
X11 
Fecal Fat8 
X 
X 
 
X 
 
Bendamustine & Dexamethasone 
 
X12 
 
 
 
 
Correlative studies (Optional)  
5mL pre-treatment bone marrow 
aspirate, shipped to Dr. Comenzo’s  
lab (Boston)  
X 
 
 
 
 
1. 
Physical exam including graded neuropathy, ECG and echocardiogram can be done up to 4 weeks before registration. 
Height is obtained at baseline only; weight is measured at baseline, day 1 (with a window of -3 days) of each treatment 
cycle, at discontinuation of therapy, and at follow-up assessment visits. 
2. 
Results should be evaluated prior to start of drug treatment. 
3. 
BNP or NT-proBNP and Troponin I or Troponin T can be used (investigator’s choice) but initial test chosen should be the 
one used throughout the study for an individual patient. 
4. 
After baseline testing, the appropriate marker should be followed to assess response. This might be either SPEP, free light 
chains and/or UPEP.  Serum immunofixation should be performed in patients in which the M-protein spike became 
undetectable. 
5. 
Bone marrow aspirate/biopsy at the end of treatment is obtained only to confirm achievement of CHR or if necessary for 
response assessment. 
6. 
Includes lgG, IgA, IgM. 
7. 
All females of childbearing potential should complete a serum pregnancy test within 7 days prior to day 1 of cycle 1. The 
pregnancy test should be repeated in week 1 of every cycle (except for cycle 1). Postmenopausal women must have been 
amenorrheic for ≥ 12 months in order to be considered “of non-childbearing potential.” 
8. 
 Twenty four to 72 hr fecal fat testing is recommended (but not required) for patients with clinical signs/symptoms of 
intestinal malabsorption, diarrhea, impaired motility, etc. If baseline results of test are abnormal, then analysis should be 
repeated every 4 cycles and at discontinuation of therapy. NOTE: Colonoscopy/endoscopy may be useful for confirmation 
of bowel involvement by amyloid and assessment of bowel-related symptoms, but will not be used in assessment of organ 
response, and is thus NOT included in the requested baseline testing. 
9. 
If baseline results of test are abnormal, then analysis should be repeated Day 1 of every cycle and at discontinuation of 
therapy. 


 
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10. Required to document CHR or PD  
11. Only if baseline results are abnormal then EKG, TTE, and/or intra-abdominal imaging will be performed again every 4 
cycles (not required to be performed on day1), at follow-up and discontinuation of therapy if clinically indicated. 
Echocardiogram must report LV ejection fraction, intra-ventricular septum wall thickness and left ventricular posterior wall 
thickness. 
12. Bendamustine is administered IV on days 1 and 2 of each cycle. Dexamethasone is administered PO or IV on days 1, 8, 15, 
22 of each cycle. 
13. To be performed within 4 weeks after completion of the last cycle. 
14. After discontinuation of therapy, subjects should be followed every 3 months (± 1 month) for the first two years, every 6 
months (± 1 month) for years 2-5, and annually thereafter.  
15. CBC, glucose,  calcium, sodium, potassium, serum creatinine, BUN, VS, AE assessment should be performed on the day of 
treatment administration (a window of minus 3 days is allowed). 
16. All other labs and tests should be performed on day 1 of each cycle (a window of minus 7 days is allowed) if not otherwise 
specified. 
17. Day 15 of each cycle can be performed by a non-physician clinician. 
 
Note: For subjects coming from great distances, follow-up may be performed by a local physician/oncologist if no 
treatment related toxicities have been noted in the prior evaluation performed at the treating institution, starting 6 
months after the last treatment, and as long as the subject remains free of treatment related toxicities. The study 
coordinator will make direct telephone contact with the subject to assure the absence of any new symptoms and will 
make arrangements to receive records from the local physician for investigator review. If the subject experiences 
any toxicities that are considered attributable to study treatment, the subject must return to the treating institution for 
examination and follow-up with the study team. 
 
7 
MEASUREMENT OF EFFECT 
Patients that received at least 2 cycles of therapy will be evaluable for response assessment such 
as SD, MR, PR, VGPR or CR.  Patients who receive less than 2 complete cycles of treatment are 
not eligible for response assessment but will be evaluable for toxicity and for OS in secondary 
analyses.  Patients with primary progressive disease after only receiving 1 cycle of therapy will 
be included in the response analysis. 
 
7.1 
Definition of Hematologic Response  
The clonal protein may be in the form of an M spike (SPEP/UPEP) or monoclonal 
protein (immunoelectrophoresis) or elevated free light chain levels with an abnormal 
ratio. Some patients have all 3 findings, some have 2 and some only 1. Some patients 
have only urine M spikes and urine immunofixation findings. One percent of patients 
have no measurable abnormal clonal protein by any blood or urine test. Therefore, 
evaluation of the clonal plasma cell disease can be based on serum protein 
electrophoresis (SPEP, M spike), immunoelectrophoresis (quantitative immunoglobulins, 
monoclonal or M protein), or serum free light chain assay, and on bone marrow biopsy 
stained for isotypic plasma cells.  Nevertheless free light chains are the most relevant 
prognostic marker and should be followed as the preferred response criteria. It is 
expected that around 15% of the patients have normal FLC or dFLC < 4 g/dL at baseline. 
For those patients standard criteria of multiple myeloma response evaluation using SPEP 
and UPEP should be applied. 
 


 
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 
Complete Response (CR): Normalization of the free light chain levels and ratio, 
negative serum and urine immunofixation. 
 
Very Good Partial Response (VGPR): Reduction in the difference between involved 
and uninvolved free light chains (dFLC) to <4 mg/dL. 
 
A  90% reduction of the M protein with persistence by immunofixation will be 
considered a VGPR. 
 
Partial Response (PR): Reduction of the difference between involved and uninvolved 
free light chains (dFLC) of ≥ 50%. 
 
A reduction of  50% of the M-protein if M-spike is  0.5 g/dL will be considered a PR. 
 
No Response (NR): Less than a PR. 
 
Progression of Disease (PD): 
•From CR: any detectable monoclonal protein or abnormal free light chain ratio 
(light chain ratio must double) 
•From PR, 50% increase in serum M protein to >0.5 g/dL or 50% increase in 
urine M protein to >200mg/day (a visible peak must be present) 
•Free light chain increase of 50% to >100 mg/L 
 
 
Bone marrow biopsy comparisons are part of the response assessment in order to confirm 
CHR or in case of not measurable m-spike or FLCs. It is for this reason that marrow 
biopsies are stained at baseline for CD138 (plasma cell marker) and isotypic light chains 
(kappa and lambda, by immunohistochemical or in situ hybridization techniques). This 
approach allows estimation of total plasma cells (CD138+) and relative kappa-to-lambda 
ratio based on isotypic staining. A normal marrow biopsy has less than 2% plasma cells in 
a diffuse distribution. The normal kappa-to-lambda ratio ranges from 4:1 to 1:1; estimates 
of the ratio outside of that range are considered indicative of clonal plasma cell disease. 
 
A CHR to therapy requires undetectability of the prior M spike and/or monoclonal 
protein and/or abnormal serum free light chain by any and all tests, and no evidence of 
the prior clonal plasma cell disease by bone marrow biopsy (normal marrow biopsy  5% 
plasma cells). 
 


 
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7.2 
Definition of Organ Response Rate (OrRR) 
Amyloid-related organ response will be evaluated on the basis of the accepted criteria described 
below. The tests and studies listed in Section 7.1 will be repeated as appropriate to assess 
patients for both organ response and progression of disease. 
Based on the criteria below, amyloid-related organ involvement will be scored as response, 
stable or progression every 4 cycles of therapy (or at the end of therapy if the patient receives 
more or less than 6 cycles). 
 
Response 
 
Kidneys: 30% reduction or drop below 0.5 g  in 24-hour urine protein excretion in the absence 
of progressive renal insufficiency.35 
Heart: NT-proBNP or BNP response (>30% and >300 ng/L decrease in patients with baseline 
NT-proBNP ≥ 650 ng/L or NYHA class response (≥ 2 class decrease in subjects with baseline 
NYHA class 3 or 4). 
Liver: 50% decrease of an initially elevated alkaline phosphatase level or reduction in the size of 
the liver by at least 2 cm (determined by physical exam, ultrasound or computer tomography).  
Neuropathy: clinical improvement supported by clinical history, neurologic exam, orthostatic 
vital signs, resolution of severe constipation or reduction of diarrhea to less than 50% of previous 
movements/day, and EMG studies if indicated. 
 
Progression 
Kidneys: 25% decrease in eGFR35 
Heart: NT-proBNP or BNP progression (>30% and >300 ng/L increase) or cTN progression 
(≥33% increase) or Ejection fraction progression (≥10% decrease). 
Liver: 50% increase in the alkaline phosphatase level above the lowest value. 
Neuropathy: clinical worsening supported by history, worsening orthostatic vital signs and 
symptoms, and EMG studies if indicated.  
Stable disease is defined when none of the criteria for improvement or for worsening disease are 
met.  Subjects with progressively worsening renal function cannot be scored for NT-proBNP 
progression 
 
8 
STATISTICAL CONSIDERATIONS 
8.1 
Justification of Design 
The optimal two-stage Simon1 design was determined from the following parameters. For the 
treatment to be of further interest, the proportion of patients experiencing clinical response 
should be at least 0.40 (p1). A proportion of responding patients of 0.20 or less is clearly 
unacceptable (p0). The probability of promoting an unacceptable drug to Stage 2 (α) is 0.10, and 
the probability of rejecting an acceptable drug at the end of Stage 2 (β) is set to 0.15. Given the 
parameters above, 13 patients are enrolled in the first stage. If at least three patients experience a 
hematologic response defined as PR or higher, the trial proceeds to the second stage with 
additional 16 patients, otherwise, the trial terminates with no further interest in the treatment. If a 
total of 9 or more out of the total of 29 patients experience a hematologic PR or better, the 
treatment will be considered worthy of further development.  In Monte Carlo simulations, it was 


 
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determined that, if π =0.2, the probability of stopping earlier is 0.5. Under this scenario, the 
expected number of patients is 21. 
 
8.2 
Data Analysis Plan 
1. Primary Objective: Determine the partial hematologic response (PHR) Only patients who 
have received at least 2 cycles of therapy are eligible for response assessment.  The 
proportion of patients with PHR two months post-treatment will be estimated, with a 95% 
exact binomial confidence interval. 
2. Secondary Objective 1: Determine overall hematologic response (OHR) rate The proportion 
of response-evaluable patients experiencing OHR will be estimated, with a 95% exact 
binomial confidence interval. 
3. Secondary Objective 2: Determine the organ response rate (OrRR) The proportion of 
response-evaluable patients experiencing OrRR will be estimated, with a 95% exact binomial 
confidence interval. 
4. Secondary Objective 3:  Determine the distribution of time to failure (TTF). Time to failure 
will be assessed for each patient from day of first treatment, where failure will be defined as 
disease progression or death.  The survival function of TTF for response-evaluable patients 
will be estimated using the product-limit (Kaplan-Meier) estimator, along with 95% 
confidence bounds. The median time to failure will be estimated from the survival function.  
The analysis will be repeated on all patients who receive any therapy. 
5. Secondary Objective 4: Assess the toxicity of the regimen Toxicities (adverse events at least 
possibly related to treatment) will be tabulated for patients who receive any therapy by NCI 
CTCAE grade and category. 
6. Secondary Objective 5:  Determine the distribution of overall survival (OS)  Survival is 
assessed as time to death from first day of treatment The OS function for response-evaluable 
will be estimated using the product-limit (Kaplan-Meier) estimator, along with 95% 
confidence bounds. The median survival will be estimated from the survival function. The 
analysis will be repeated on all patients who receive any therapy. 
7. Secondary Objective 6:  Assess by RT-PCR the effects on expression in clonal plasma cells 
of genes associated with ER stress (GADD153, BiP) and cell-cycle regulation (CCND1, p16, 
p21). Change from baseline in these endpoints will be characterized graphically (e.g., by 
boxplots) and by descriptive statistics (e.g., mean, standard deviation, median). The null 
hypothesis of no change over time will be tested by a signed-rank test, or, if appropriate, 
single-sample t-test. 
 
9 
CORRELATIVE LABORATORY STUDIES 
The laboratory of one of the co-investigators (Dr. Raymond Comenzo, Tufts Medical Center) 
will be performing correlative studies on the marrow plasma cells of consenting patients 
obtained before the first cycle of bendamustine and dexamethasone. Five (5) mL of bone marrow 
aspirate will be sent in one green to tube (heparin prefilled) at room temperature to  
 
Dr. Comenzo’s laboratory 
Raymond Comenzo, MD 
Tufts Medical Center,  
800 Washington Street 


 
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Boston, MA  02111 
 
These studies involve investigations of the character of the clonal plasma cells in AL. Recent 
data from this lab and others indicate that AL plasma cells over-express CCND1 in almost one-
half of cases, likely often associated with t(11;14) or +11q.23 In several retrospective studies, 
over-expression of CCND1 or t(11;14) have been associated with poorer survival in AL 
patients.21,22 
 
CCND1 over-expressing clones usually produce only immunoglobulin light chains and not intact 
immunoglobulins because of loss of Ig heavy chain gene loci due to t(11;14). Preliminary data 
from the Comenzo lab indicates that CCND1 over-expressing clones also over-express genes 
associated with maintenance of protein solubility and protein quality control (PDIA6, Sel1L), a 
phenomena possibly linked to the exclusive production of Ig light chains that form amyloid. The 
correlative studies of clonal bone marrow plasma cells selected from pre-treatment marrow 
aspirates will further test the hypothesis that CCND1 over-expressing clones up-regulate these 
genes involved in ER-associated protein quality control. Using patient bone marrow specimens 
obtained at baseline, we will perform RT-PCR to assess the expression in clonal plasma cells of 
the genes CCND1 and Sel1L. 
 
Quantitative RT-PCR will be performed (in triplicate and on 2 separate days) using TaqMAN 
Gene Expression Assays with RPLP0 (Hs99999902_m1) primers and probes (Applied 
Biosystems; Foster City, CA) as internal control on an Mx 3000P platform and related software 
(Stratagene; La Jolla, CA). The comparative Ct method will be used and the amount of target 
normalized to the control (2-ΔΔCt) assuming an efficiency of 2. Statistical analyses (paired t-test) 
will be performed with GraphPad PRISM (GraphPad; La Jolla, CA) with P < 0.05 significance 
level for CCND1. Then CCND1hi and CCND1lo cases will be compared by paired t-test with 
respect to expression levels of PDIA6 and SEL1A. These studies may lead to new therapies for 
AL by identifying new druggable targets. 
 
The correlative studies are optional. 
 
10 ADVERSE EVENT REPORTING 
10.1 Adverse Event Definitions 
 
Adverse event: Any untoward medical occurrence in a clinical study; regardless of the 
causal relationship of the event with the investigational drug or study treatment(s). 
 
Associated with the use of the investigational drug or study treatment(s): There is a reasonable 
possibility that the adverse event may have been caused by the investigational drug or 
study treatment(s). 
 
Disability: A substantial disruption of a person’s ability to conduct normal life functions. 
 
Life-threatening adverse event: Any adverse event that places the patient or subject, in the 
view of the investigator, at immediate risk of death from the event as it occurred (i.e., 
does not include an adverse event that, had it actually occurred in a more severe form, 
might have caused death). 
 
Serious adverse event: Any adverse event occurring at any dose that results in any of the 
following outcomes: death, a life-threatening adverse event, inpatient hospitalization or 


 
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prolongation of existing hospitalization, a persistent or significant disability/incapacity, 
or a congenital anomaly/birth defect. 
o 
Hospitalization shall include any initial admission (even if less than 24 hours) to a 
healthcare facility as a result of a precipitating clinical adverse event; to include 
transfer within the hospital to an intensive care unit. Hospitalization or prolongation 
of hospitalization in the absence of a precipitating, clinical adverse event (e.g., for a 
preexisting condition not associated with a new adverse event or with a worsening of 
the preexisting condition; admission for a protocol-specified procedure) is not, in 
itself, a serious adverse event. 
 
Unexpected adverse event: Any adverse event, the frequency, specificity or severity of 
which is not consistent with the risk information described in the clinical protocol(s). 
 
10.2 Recording/Reporting Requirements 
10.2.1 Eliciting Adverse Event Information 
 
Clinical study subjects will be routinely questioned about adverse events at study visits. 
 
10.2.2 Recording Requirements 
All observed or volunteered adverse drug events (serious or non-serious) and abnormal test 
findings, regardless of treatment group or suspected causal relationship to the investigational 
drug or study treatment(s) will be recorded in the subjects’ case histories. For all adverse events, 
sufficient information will be pursued and/or obtained so as to permit 1) an adequate 
determination of the outcome of the event (i.e., whether the event should be classified as a 
serious adverse event) and; 2) an assessment of the casual relationship between the adverse event 
and the investigational drug or study treatment(s). 
 
Adverse events or abnormal test findings felt to be associated with the investigational drug or 
study treatment(s) will be followed until the event (or its sequelae) or the abnormal test finding 
resolves or stabilizes at a level acceptable to the investigator. 
 
Abnormal Test Findings 
An abnormal test finding will be classified as an adverse event if one or more of the following 
criteria are met: 
▪ The test finding is accompanied by clinical symptoms. 
▪ The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug treatment or other therapy. 
Note: simply repeating a test finding, in the absence of any of the other listed criteria, does not 
constitute an adverse event. 
▪ The test finding leads to a change in study dosing or discontinuation of subject participation in 
the clinical study. 
▪ The test finding is considered an adverse event by the investigator-sponsor. 
 
10.3 Reporting of Adverse Events 


 
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Safety Monitoring and Adverse Event Reporting 
All participating sites are responsible for protecting the safety, rights and well-being of study 
participants. Recording and reporting of adverse events that occur during the course of a study 
help ensure the continuing safety of study participants. All participants receiving investigational 
agents and/or other protocol mandated treatment will be evaluated for safety. The safety 
parameters include all laboratory tests and hematological abnormalities, physical examination 
findings, and spontaneous reports of adverse events reported by participants.  All toxicities 
encountered during the study will be evaluated according to the criteria specified in the protocol. 
Life-threatening toxicities must be reported immediately to Columbia University, the 
Coordinating Site (lead institution). 
 
AEs and SAEs can be reported on the standard MedWatch form (FDA Form 3500A) 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/ucm082728.p
df 
 
Name of Contact:  
Suzanne Lentzsch, M.D. 
Address: 
 
Columbia University Medical Center 
 
 
 
Herbert Irving Comprehensive Cancer Center 
 
 
 
Herbert Irving Pavilion 
 
 
 
161 Fort Washington Avenue 
 
 
 
New York, NY 10032 
Email:  
 
aaaj7800@columbia.edu 
Fax: 
 
 
212-305-3035 or 212-305-4667  
 
An adverse event is any unfavorable and unintended sign, symptom, or disease temporarily 
associated with the use of a medical treatment or procedure that may or may not be considered 
related to the medical treatment. Serious adverse events are defined as complications in the 
patient’s clinical course that are outside the normal course for the underlying disease/condition 
and/or significantly increase the risk of compromising the patient’s health.  
 
Adverse Event Documentation 
Regardless of relationship to study treatment, all serious and non-serious adverse events that 
occur during the protocol-defined AE and/or SAE reporting period are to be recorded on an 
Adverse Event Log  during the study. 
The following information should be collected for adverse events: 
• 
Description of the adverse event including onset and resolution dates 
• 
Severity of Adverse Event 
• 
Relationship to study treatment or other causality 
• 
Outcome of each event 
• 
Whether event met SAE criteria 
 
Multicenter Site Investigator Reporting Responsibility 
Site investigators (affiliate sites) are responsible for knowing the policies of the local IRB, 
adhering to these policies, and maintaining a copy of the policies in the study file.  The site 


 
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investigators are also responsible for the accurate documentation, investigation and follow-up of 
all possible study-related adverse events.   
 
All serious adverse events that occur during the study, regardless of the relationship to the study 
drug, must be reported by the site investigators to the Coordinating Site within 24 hours and the 
Institutional Review Board (IRB) in accordance with institutional guidelines of being made 
aware of the SAE. For initial SAE reports, available case details are to be recorded on an SAE 
form. At a minimum, the following should be included: 
• 
Patient number 
• 
Date of event onset 
• 
Description of the event 
• 
Study treatment, if known 
 
Relevant follow-up information is to be submitted to the Coordinating Site in the form of a 
follow-up SAE report within 10 business days (if available) of the original submission.  The 
follow-up SAE report should include a re-evaluation of the original determination of grade and 
relationship of the event, along with all results supporting this assessment. 
 
The Coordinating Site will maintain documentation of all participating sites’ Adverse Event 
information and be responsible for communicating to all participating site investigators and 
notifying the funding agency or sponsor, as necessary.  Participating site investigators will 
review any distributed AE reports, send a copy to their IRB according to their local IRB’s 
policies and procedures, and file a copy with their regulatory documents. 
 
Reporting Adverse Events to the Responsible IRB 
In accordance with applicable policies of the Columbia University’s Institutional Review Board 
(IRB), the investigator-sponsor will report, to the IRB, any observed or volunteered adverse 
event that is determined to be 1) at least possibly related to participation 2) increases risk; and 3) 
unexpected. Adverse event reports will be submitted to the IRB in accordance with the 
respective IRB procedures. 
 
Applicable adverse events will be reported to the IRB as soon as possible and, in no event, later 
than 5 calendar days following the investigator-sponsor’s receipt of the respective information. 
Adverse events which are 1) associated with the investigational drug or study treatment(s); 2) 
fatal or life-threatening; and 3) unexpected will be reported to the IRB within 24 hours of the 
investigator-sponsor’s receipt of the respective information.  
 
Follow-up information to reported adverse event will be submitted to the IRB as soon as the 
relevant information is available. If the results of the sponsor-investigator’s follow-up 
investigation show that an adverse event that was initially determined to not require reporting to 
the IRB does, in fact, meet the requirements for reporting; the investigator-sponsor will report 
the adverse event to the IRB as soon as possible, but in no event later than 5 calendar days, after 
the determination was made. 
 
10.3.1 
       


 
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The Investigator will comply with all safety reporting regulations as set forth in the Code of 
Federal Regulations. The investigator being the sponsor of the study has sole responsibility for 
reporting of adverse events to the FDA. For informational purposes any correspondence to the 
FDA regarding adverse events or other safety issues will be simultaneously copied to 
us.clinops.sae@tevapharm.com or reported to Teva via facsimile at 215-619-3825. The 
Investigator will communicate the occurrence of serious adverse events to Teva within 24 hours 
of becoming aware of the event.  Reporting of Adverse Events to Teva does not preclude the 
responsibility of the investigator to report adverse events to the FDA. Please note that the 
reporting period begins when a patient signs the informed consent, and ends 30 days after the 
discontinuation of dosing or completion of the patient’s participation in the Study if the last 
scheduled visit occurs at a later time. In addition, the Investigator must notify Teva of any 
serious adverse events that may occur after this time period which he or she believes to be 
definitely, likely or possibly related to the Study Product.  Institution acknowledges that Teva is 
required to comply fully and promptly with all regulatory safety reporting requirements 
regarding its products.  
 
The MedWatch 3500A form should be utilized to report serious adverse events to the FDA.   
 
A serious adverse event or reaction is any untoward medical occurrence that at any dose:  
•     Results in death;  
•     Is life-threatening; 
•     Requires inpatient hospitalization or prolongation of existing hospitalization; 
•     Results in a persistent or significant disability/incapacity; 
•     Is a congenital anomaly or birth defect; 
•     Results in the development of drug dependency or drug abuse;  
•     Is a serious adverse event drug experience.  
 
For the purpose of this Agreement, these terms shall have the same meaning as the terms used in 
the provisions of the Code of Federal Regulations governing drug and biologic safety reporting.  
See 21 CFR 314.80(a); 600.80(a). Additionally, the following will also be deemed to be adverse 
events for purposes of this Agreement: pregnancy exposure, infant exposure during 
breastfeeding, overdose, abuse, misuse, medication errors, lack of efficacy, infectious agents, as 
well as all reports of accidental pediatric exposure, and any other safety information as 
reasonably requested by Company. Investigator shall use his/her judgment to determine the 
relationship between the serious adverse event and the Study Product. In the event the IRB 
requests additional safety information from Investigator, Investigator shall notify Teva of such 
request within one (1) business day.  
 
Investigator and Institution further agree to report all Adverse Events in compliance with all 
applicable legal and regulatory requirements, and in accordance with any requirements provided 
by Teva.   
 
 
10.4 Guidelines for Processing IND Safety Reports  
 


 
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The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies to 
notify the FDA and all participating investigators of any serious and unexpected adverse 
experiences that are possibly related to the investigational agent. The CUMC Principal 
Investigator will review all applicable IND Safety Reports and has the responsible for 
forwarding the IND Safety Reports to the Affiliate Institutions. The Affiliate Institution 
investigators are to review, send a copy to their IRB according to their local IRB’s policies and 
procedures, and file a copy with their regulatory documents. All Affiliate site INDSR 
submissions, along with IRB acknowledgment (per local policies and procedures) are to be 
forwarded to CUMC for placement within the trial master file. 
 
 
10.5 Data and Safety Monitoring Committee 
 
Every subject who receives treatment on this protocol will be monitored for toxicity by the 
Herbert Irving Comprehensive Cancer Center (HICCC), an NCI-approved Data Safety 
Monitoring Committee (DSMC). This protocol will adhere to the policies of the HICCC Data 
and Safety Monitoring Plan, version 2 guidelines in accordance with NCI regulations.  The 
committee is led by Dr. Gregory Mears and consists of HICCC members. The DSMC meets 
monthly to review adverse event reporting and the timeliness of adverse event reporting. The PI 
will submit data and safety monitoring reports to the DSMC. Upon review, the HICCC DSMC 
will disseminate the review findings to the CUMC PI.  CUMC, as the coordinating center for this 
trial, will subsequently distribute all DSMC review letters to affiliate sites for applicable local 
submission and regulatory binder maintenance. 
 
According to DSMC guidelines, all protocols managed through CUMC review and monitoring 
systems are subject to the HICCC Data and Safety Monitoring Plan. Part of the plan provides for 
monthly review of all studies in each disease center. In addition, each subject will be assessed 
periodically according to the treatment schedule (flowchart) for the development of any toxicity. 
Dose modifications will be made based on toxicities described earlier. 
All toxicities encountered during the study will be evaluated on an ongoing basis according to 
the NCI Common Toxicity Criteria version 4.0 and recorded prior to each course of therapy. In 
addition, all toxicities will be reported to the IRB along with any Data Safety meeting minutes in 
the annual renewal report. Any required modifications necessary to ensure patient safety are 
discussed and will be submitted to the IRB. All protocol violations will also be reported to the 
IRB and all other designated regulatory agencies as required. All study data reviewed and 
discussed during these meetings will be kept confidential. Any breaches in research subject 
confidentiality will be immediately reported to the IRB. 
 
 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by the CPDM Compliance Core on behalf of the HICCC DSMC.  Additionally, the 
Compliance Oversight Committee of the IRB at Columbia University Medical Center may audit 
the study at any time per institutional policies and procedures. 
 


 
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The investigator-sponsor and Columbia University Medical Center will permit direct access of 
the study monitors and appropriate regulatory authorities to the study data and to the 
corresponding source data and documents to verify the accuracy of this data. 
 
A risk-based approach will be used by the Compliance Core to determine the frequency, number 
of subject charts, and data elements to be monitored. The Compliance Coordinator will review 
the study status and summarize enrollment, toxicities, SAEs/UPs, dose escalation, statistical 
endpoints (e.g., stopping rules), etc. for the full DSMC membership at the regularly scheduled 
meetings.   
MCT Monitoring:  
 
1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted at remote clinical 
sites, as appropriate/feasible. Other sites will have monitoring performed remotely (see below for 
further details). 
 
a. The study Monitoring Visit Log will be completed and signed by the monitor and the 
PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
 
2. The Compliance Coordinator will communicate with the participating site coordinator to schedule 
the monitoring visit and arrange for access to study materials and documentation. 
 
3. The Compliance Coordinator will monitor IIT trials within 1 month after the first subject is 
enrolled at the participating site and throughout the life of the study to ensure that the study is 
being conducted in accordance with the protocol, GCP, applicable federal and local regulations, 
and per all applicable SOPs. The Compliance Coordinator is responsible to notify the 
participating site PI and CRNP/CRN/CRC of upcoming monitor visits and convey what 
information and documentation will be required for the visit(s).  The Compliance Coordinator is 
responsible for verifying that informed consent is properly obtained, eligibility is met (via the 
central registration process), and all study procedures are conducted according to the study 
protocol. The Compliance Coordinator will also verify that the data reported in the CRF’s 
accurately reflect source documents, that all toxicities have been reported to date, and that all 
SAE’s/UPs/deviations/violations have been reported according to Coordinating Center, local IRB 
and HICCC DSMC requirements. The Compliance Coordinator will issue queries and ensure 
resolution in a timely and efficient manner.  
 
4. An SIV (or) teleconference will be scheduled and conducted prior to study drug being made 
available (if applicable) and before any subjects are enrolled on a study at the participating site. 
 
MCT Remote Monitoring:  
 
1. When necessary (due to logistical constraints), participating sites will be monitored remotely by a 
designated Compliance Coordinator. Sites will be informed of this remote monitoring process on 
a site by site basis. 
 


 
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2. Participating sites will be monitored by the Compliance Coordinator on both a regulatory level, as 
well as a clinical data/source documentation review level. 
 
3. Redacted source documents (applicable to supporting the protocol specific CRF data 
requirements) will be sent to the designated Compliance Coordinator via fax or secure email for 
all subjects enrolled at participating sites. Timelines for submission procedures will be defined on 
a case by case basis.   
 
4. The Compliance Coordinator will review all submitted redacted source documents against the 
data entered on the protocol specific CRFs. The Compliance Coordinator will issue queries 
when/if necessary. 
 
5. The participating site research staff will respond to queries within 30 days. If queries remain 
outstanding, the Compliance Coordinator will send a delinquent query reminder for the 
outstanding items. 
 
6. The remote monitoring procedures will include review of applicable redacted source 
documentation and supporting applicable documents to determine compliance regarding: 
 
a. Informed consent procedures 
b. Eligibility criteria 
c. Protocol specific treatment compliance 
d. Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on study, follow-
up) 
e. Participating site IRB documents (e.g., IRB amendment approvals, annual renewals, 
SAE/UP submissions, violation/deviation submissions, INDSR submissions, etc). 
f. Required specimen submissions (e.g., tissue specimens, research blood specimens, etc.) 
g. Pharmacy accountability records 
h. Adherence to the CRF submission timeframes to CUMC (within the protocol specified 
timeframes) 
 
7. Participating site performance reports will be sent to lead PI, HICCC DSMC, and participating 
sites on a quarterly basis. Reports will include information regarding data submission 
timeliness/accuracy, query resolution status, regulatory status, and overall participating site 
performance. These reports will be generated by the Compliance Coordinator and reviewed with 
the Compliance Core Manager prior to dissemination. 
 
11.1 Guidelines for Affiliate site prospective protocol deviation requests: 
For multisite-IIT trials in which CUMC is serving as the coordinating center, the participating 
site MUST submit a prospective deviation request to the CUMC lead PI for review and 
submission to the HICCC DSMC, HICCC PRMC, and CUMC IRB. Approvals must be obtained 
from all entities prior to implementation at the participating site.  If a prospective protocol 
deviation request is submitted for review (from a participating site), the PI/site memo(s), HICCC 
DSMC approval(s) and correspondence, HICCC PRMC approval(s) and correspondence, and 


 
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CUMC IRB eligibility deviation letter(s) should be forwarded to the participating site for 
documentation. The participating site is also required to obtain prospective local IRB approval as 
per institutional policies/procedures prior to implementing the proposed deviation. All 
documents and determinations must be clearly documented in the study subject’s medical record, 
research chart and regulatory binder, as described. 
 
12 DATA HANDLING AND RECORD KEEPING 
12.1 Data Recording/Case Report Forms 
A Case Report Form will be completed for each subject enrolled into the clinical study through 
Velos eResearch. It is the investigator/sponsor’s responsibility for ensuring that all clinical and 
laboratory data entered on the CRFs are complete, accurate and authentic. 
 
Please refer to the table below regarding the form completion and source document submission 
guidelines: 
CRF Title 
Baseline/Screening 
Day 1 of 
Every Cycle 
Day 15 of 
Every Cycle 
Day 1 of Every 
4 Cycles 
Off-
Study 
Kidney Organ Response 
X 
  X* 
 
X 
X 
Med Hist Weight PS 
X 
X 
 
 
 
Neuropathy Response 
X 
  X* 
 
X 
X 
Hematologic Response 
X 
X 
X 
X 
X 
Other Lab 
X 
X 
 
X 
X 
SPEP 
X 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
CxR  
X 
 
 
 
 
Radiologic Assessment 
X 
 
 
X 
 
Urinalysis 
X 
X 
 
X 
 
Serum Pregnancy 
X 
X 
 
 
 
Bone Marrow 
X 
 
 
 
 
Consent Form 
X 
 
 
 
 
CBC Lab 
X 
X 
X 
X 
X 
Liver Organ Response 
X 
  X* 
 
X 
 
Organ Assessment 
X 
 
 
X 
X 
Radiologic Assessment 
X 
 
 
X 
X 
Cardiac Assessment 
X 
  X* 
 
X 
X 
ECHO 
X 
 
 
X 
X 
EKG 
X 
X 
 
X 
X 
Vital Signs 
 
X 
X 
 
 
Treatment  
 
X 
 
 
 
 
*  = If necessary, as deemed appropriate by an improvement demonstrating response or worsening demonstrating 
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1. At time of Central Registration, all redacted source documentation for tests required at Baseline/Screening is 
required to be submitted. 
2. For all CRF time points after registration, all redacted source documentation is required within 30 days of visit 
date.  
 
12.2 Record Maintenance and Retention 
The investigator-sponsor will maintain records in accordance with Good Clinical Practice 
guidelines; to include: 
 
IRB correspondence (including approval notifications) related to the clinical protocol; 
including copies of adverse event reports and annual or interim reports 
 
Current and past versions of the IRB-approved clinical protocol and corresponding IRB-
approved consent form(s) and, if applicable, subject recruitment advertisements 
 
Signed FDA Form 1572 Statements of Investigator listing all sub-investigators involved 
in the treatment and/or evaluation of research subjects 
 
Financial disclosure information (for the investigator-sponsor and all sub-investigators 
involved in the treatment and/or evaluation of research subjects) 
 
Curriculum vitae (investigator-sponsor and clinical protocol sub-investigators) 
 
Certificates of required training (e.g., human subject protections, Good Clinical Practice, 
etc.) for investigator-sponsor and listed sub-investigators 
 
Listing of printed names/signatures of investigator-sponsor and listed sub-investigators 
 
Normal value(s)/range(s) for medical/laboratory/technical procedures or tests included in 
the clinical protocol 
 
Laboratory certification information 
 
Signed informed consent forms 
 
Completed Case Report Forms; signed and dated by investigator-sponsor 
 
Source Documents or certified copies of Source Documents 
 
Monitoring visit reports  
 
Copies of investigator-sponsor correspondence to 
sub-investigators, 
including 
notifications of safety information 
 
Subject screening and enrollment logs 
 
Subject identification code list 
 
Investigational drug accountability records, including documentation of drug disposal. 
 
Retained biological specimen log 
 
Interim data analysis report(s) 
 
Final clinical study report 
 
Subject identity on study records will be indicated by a case number rather than by name, and the 
information linking the case numbers with the subject’s identity will be kept separate from the 
research records. All records related to this research study will be stored in a locked file cabinet. 
The investigator-sponsor will retain the specified records and reports for up to 2 years after the 
marketing application is approved for the investigational drug. 
13 ETHICS 


 
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13.1 Institutional Review Board (IRB) Approval 
The investigator-sponsor will obtain, from Columbia University Medical Center Board (IRB), 
prospective approval of the clinical  protocol and corresponding informed consent form(s); 
modifications to the clinical protocol and corresponding informed consent forms, and 
advertisements (i.e., directed at potential research subjects) for study recruitment. 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s). In such circumstances, the 
investigator-sponsor will promptly notify the CUMC IRB of the deviation.  
 
The CUMC IRB operates in compliance with FDA regulations at 21 CFR Parts 50 and 21 CFR 
56, and in conformance with applicable International Conference on Harmonization (ICH) 
Guidelines on Good Clinical Practice (CGP).  
 
13.2 Ethical and Scientific Conduct of the Clinical Study 
The clinical study will be conducted in accordance with the current IRB-approved clinical 
protocol; ICH Guidelines on GCP; and relevant policies, requirements, and regulations of the 
Columbia University Medical Center New York State Laws and applicable federal agencies. 
 
13.3 Subject Informed Consent 
The investigator-sponsor will make certain that an appropriate informed consent process is in 
place to ensure that potential research subjects, or their authorized representatives, are fully 
informed about the nature and objectives of the clinical study, the potential risks and benefits of 
study participation, and their rights as research subjects. The investigator-sponsor, or a sub-
investigator(s) designated by the investigator-sponsor, will obtain the written, signed informed 
consent of each subject, or the subject’s authorized representative, prior to performing any study-
specific procedures on the subject. The date and time that the subject, or the subject’s authorized 
representative, signs the informed consent form and a narrative of the issues discussed during the 
informed consent process will be documented in the subject’s case history. The investigator-
sponsor will retain the original copy of the signed informed consent form, and a copy will be 
provided to the subject, or to the subject’s authorized representative. 
The investigator-sponsor will make certain that appropriate processes and procedures are in place 
to ensure that ongoing questions and concerns of enrolled subjects are adequately addressed and 
that the subjects are informed of any new information that may affect their decision to continue 
participation in the clinical study. In the event of substantial changes to the clinical study or the 
risk-to-benefit ratio of study participation, the investigator-sponsor will obtain the informed 
consent of enrolled subjects for continued participation in the clinical study. 


 
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Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 
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Kyle RA. Amyloidosis: a convoluted story. Br J Haematol. 2001;114:529-538. 
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Kyle RA. Diagnosis of multiple myeloma. Semin Oncol. 2002;29:2-4. 
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Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed 
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Merlini G, Stone MJ. Dangerous small B-cell clones. Blood. 2006;108:2520-2530. 
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Comenzo RL. Managing systemic light-chain amyloidosis. J Natl Compr Canc Netw. 
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Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Kumar S. Transplantation for 
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Gertz MA, Lacy MQ, Dispenzieri A, et al. Effect of hematologic response on outcome of 
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Sanchorawala V, Seldin DC. An overview of high-dose melphalan and stem cell 
transplantation in the treatment of AL amyloidosis. Amyloid. 2007;14:261-269. 
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Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic 
amyloidosis. Blood. 2002;99:4276-4282. 
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Palladini G, Perfetti V, Obici L, et al. Association of melphalan and high-dose 
dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are 
ineligible for stem cell transplantation. Blood. 2004;103:2936-2938. 
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Lebovic D, Hoffman J, Levine BM, et al. Predictors of survival in patients with systemic 
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Zonder JA, Sanchorawala V. Melphalan and Dexamethasone Plus Bortezomib Induces 
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Dennie TW, Kolesar JM. Bendamustine for the treatment of chronic lymphocytic 
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Ponisch W, Mitrou PS, Merkle K, et al. Treatment of Bendamustine and Prednisone in 
patients with newly diagnosed multiple myeloma results in superior complete response rate, 
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Melphalan and Prednisone-a randomized phase III study of the East German Study Group of 
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Michael M, Bruns I, Bolke E, et al. Bendamustine in patients with relapsed or refractory 
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Ponisch W, Rozanski M, Goldschmidt H, etal. Treatment with bendamustine, 
thalidomide, and prednisolone (BPT) in patients with refractory or relapsed multiple myeloma 


 
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after autologous stem cell transplantation or conventional chemotherapy: Results of a phase I 
clinical trial. Blood. 2006;108:abstract 3564. 
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Lentzsch S, O’Sullivan A, Lalo S, et al. A Phase I Study of Bendamustine Combined 
with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple 
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Harrison CJ, Mazzullo H, Ross FM, et al. Translocations of 14q32 and deletions of 13q14 
are common chromosomal abnormalities in systemic amyloidosis. Br J Haematol. 2002;117:427-
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Hayman SR, Bailey RJ, Jalal SM, et al. Translocations involving the immunoglobulin 
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amyloidosis. Blood. 2001;98:2266-2268. 
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Zhou P, Hassoun H, Landau L, Comenzo R. Elevated Cyclin D1 (CCND1) expression in 
the plasma cells of patients with systemic AL Amyloidosis at diagnosis is associated with higher 
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Blood. 2009;abstract. 
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Zhou P, Teruya-Feldstein J, Lu P, Fleisher M, Olshen A, Comenzo RL. Calreticulin 
expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is 
associated with response to high-dose melphalan. Blood. 2008;111:549-557. 
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Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Stat Med. 1995;14:357-379. 
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Durie et al B. Criteria for the classification of Monoclonal gammopathies, multiple 
myeloma, and related disorders: A report of the International Myeloma Working Group. 
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Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
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Hurst JW, Morris DC, Alexander RW. The use of the New York Heart Association's 
classification of cardiovascular disease as part of the patient's complete Problem List. Clin 
Cardiol. 1999;22:385-390. 
29.  
J Clin Oncol. 2009 Sep 10;27(26):4378-84. Epub 2009 Aug 3. "Phase III randomized 
study of bendamustine compared with chlorambucil in previously untreated patients with chronic 
lymphocytic leukemia. 
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Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, Juliusson 
G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, 
Tremmel L, Merkle K, Montillo M." PMID: 19652068. 
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J Cancer Res Clin Oncol. 2006 Apr; 132(4):205-12. Epub 2006 Jan 10. “Treatment of 
bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in 
superior complete response rate, prolonged time to treatment failure and improved quality of life 
compared to treatment with melphalan and prednisone--a randomized phase III study of the East 
German Study Group of Hematology and Oncology (OSHO).” Pönisch W, Mitrou PS, Merkle K, 
Herold M, Assmann M, Wilhelm G, Dachselt K, Richter P, Schirmer V, Schulze A, Subert R, 
Harksel B, Grobe N, Stelzer E, Schulze M, Bittrich A, Freund M, Pasold R, Friedrich T, Helbig 
W, Niederwieser D; East German Study Group of Hematology and Oncology (OSHO). 
PMID: 16402269. 
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Eur J Med Res. 2010 Jan 29;15(1):13-9. “Bendamustine in patients with relapsed or 
refractory multiple myeloma.” Michael M, Bruns I, Bölke E, Zohren F, Czibere A, Safaian NN, 
Neumann F, Haas R, Kobbe G, Fenk R. PMID: 20159666. 
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Cancer Chemother Pharmacol 2010 November; 66(6) 1039-1049). 


 
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34.      Pönisch W, J Cancer Res Clin Oncol. 2013 Nov;139 (11):1937-46. 
35.     Palladini, G., et al. A staging system for renal outcome and early markers of renal response 
to chemotherapy in AL amyloidosis. Blood. 2014; 124.15: 2325-2332. 
 
 
 


 
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APPENDIX A. IMWG DEFINITIONS OF ASYMPTOMATIC AND SYMPTOMATIC 
MYELOMA26 
Symptomatic Myeloma: 
1. M-protein > 30 g/L 
2. Bone marrow plasmacytosis > 10% 
3. Myeloma related organ or tissue impairment as defined here: 
i. Calcium Elevation (Serum Calcium > 1 mg/dL above the IULN or > 11 mg/dL) 
ii. Renal Insufficiency (Serum Creatinine >2.0 mg/dL) 
iii. Anemia (hemoglobin < 10 g/dL or more than 2 g/dL below ILLN) 
iv. Bone Disease (lytic bone lesions or osteoporosis with compression fractures) 
v. Other: symptomatic hyperviscosity, amyloidosis, >2 infections annually 
 
Asymptomatic (Smouldering) Myeloma: 
Meets criteria 1 and 2, but not 3 (i.e., no disease-related organ or tissue impairment). 


 
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APPENDIX B. ECOG PERFORMANCE STATUS 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light 
or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
* As published in American Journal of Clinical Oncology.27 


 
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APPENDIX C. NYHA FUNCTIONAL CLASSIFICATION FOR CONGESTIVE HEART 
FAILURE28 
 
The New York Heart Association (NYHA) Functional Classification provides a simple way of 
classifying heart disease (originally cardiac failure), useful for preoperative assessment. It places 
patients in one of four categories, based on how much they are limited during physical activity: 
Class I: patients with no limitation of activities; they suffer no symptoms from ordinary 
activities. 
Class II: patients with slight, mild limitation of activity; they are comfortable with rest or 
with mild exertion. 
Class III: patients with marked limitation of activity; they are comfortable only at rest. 
Class IV: patients who should be at complete rest, confined to bed or chair; any physical 
activity brings on discomfort and symptoms occur at rest. 


 
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APPENDIX D. CREATININE CLEARANCE FORMULA 
 
Creatinine clearance (CrCl) can be calculated using the Cockcroft-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.)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX E. KARNOFSKY PERFORMANCE STATUS 
 


 
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Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
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 indicated. Death not 
imminent. 
 
10 
Moribund, fatal processes progressing rapidly. 
 
0 
Dead. 
 
Reference 
Karnofsky DA, Burchenal JH: In Evolution of Chemotherapy Agents, Macleod CM (ed.). Columbia 
University Press, New York, 1949: pp 191-205