Clinical trial NCT01383759
Conditions: Light Chain Deposition Disease (LCDD or MIDD) Light Chain and Heavy Chain Deposition Disease (LHCDD or MIDD) Monoclonal Immunoglobulin Deposition Disease (MIDD) Amyloidosis
Keywords: BORTEZOMIB (VELCADE) CYCLOPHOSPHAMIDE (CYTOXAN) DEXAMETHASONE MELPHALAN 11-061
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2011-06-24; Completion date: 2019-04-30
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical trial is to determine the toxicity and also the efficacy of a treatment that includes the following treatment: Two medications, bortezomib and dexamethasone (or BD), followed by autologous stem cell transplantation, and a prolonged course of treatment with bortezomib and dexamethasone after transplantation. This type of treatment has been very effective in multiple myeloma. However, there is little experience with this treatment in patients who have Monoclonal Immunoglobulin Deposition Disease (MIDD) or amyloidosis. The investigators and others have treated patients who have MIDD and amyloidosis with bortezomib and autologous stem cell transplantation and have had success with this treatment. But the combination of autologous transplant with BD given before and after the transplant is a new way of treating these diseases, which the investigators believe will be very effective.

Detailed description:

Arms: arm 1: This is a pilot study to gain information and estimate the toxicity/tolerability of 1-3 cycles of BD, followed by HDM/ASCT, and maintenance therapy with BD in patients with MIDD associated with multiple myeloma and AL amyloidosis.
Interventions: intervention 1: Bortezomib/Dexamethasone (BD), Followed By Autologous STC & Maintenance Bortezomib/Dexamethasone
Intervention descriptions: intervention 1: The treatment has three phases:

1\) Initial treatment phase: This phase consists of 1-3 21-day-cycles of a combination regimen that includes bortezomib 1.3 mg/m2, IV or Subcutaneous Injection (SQ), on days 1, 4, 8, and 11; and dexamethasone 40 mg PO or IV, on days 1, 4, 8, and 11. Stem cell mobilization and HDM/ASCT. Post-ASCT consolidation/maintenance treatment phase: This phase consists of six cycles of bortezomib 1.3 mg/m2, IV or (SQ) with dexamethasone 20 mg PO or IV administered on days 1, 8, 15, and 22 every 12 weeks +/- 2 weeks. Long Term Follow Up will cease when all patients on study have fulfilled the requirements for at least five follow up appointments.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
Pilot Study of Bortezomib/Dexamethasone  (BD), Followed By Autologous Ste m Ce ll 
Transplantation and Maintenance Bortezomib/Dexamethasone  For the Initial Tre atment of 
Monoclonal Immunoglobulin De position Disease (MIDD) Associated With Multiple Mye loma 
and AL Amyloidosis 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
Principal 
Investigator/Department: 
Hani Hassoun, MD 
Medicine /Myeloma 
Manhattan, West Harrison 
Co-Principal 
Investigator(s)/Department: 
Heather Landau, MD 
Medicine /BMT 
Investigator(s)/Department: David Chung, MD 
Sergio Giralt, MD 
Guenther Koehne, MD 
Alex Lesokhin, MD 
Nikoletta Lendvai, MD 
Neha Korde, MD 
Elyn Riedel, MS 
Carlos Flombaum 
Roni Tamari, MD 
Parastoo Dahi, MD 
Esperanza Papadapolous 
Juliet Barker, MBBS 
Hugo Castro-Malaspina, MD 
Alan Hanash, MD 
Katharine Hsu, MD, PhD 
Ann Jakubowski, MD, PhD 
Robert Jenq, MD 
Matthew Matasar, MD 
Miguel-Angel Perales, MD 
Doris Ponce, MD 
Craig Sauter, MD 
James Young, MD 
Marcel van den Brink, MD, PhD 
Boglarka Gyurkocza, MD 
Brian Shaffer, MDXi Chen, MD 
Audrey Hamilton, MD 
Han Xiao, MD 
Sree Bhavani Chalasani, MD 
Stuart Lichtman, MD 
Steven Sugarman, MD 
Jon Fiore, MD 
Avni Desai, MD 
Kenneth Ng, MD 
Medicine/BMT 
Medicine/BMT Medicine/BMT 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/Myeloma 
Epidemiology and Biostatistics 
Medicine/Renal 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT Manhattan, 
Rockville Centre 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT Medicine/Neurol 
ogy 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Rockville Centre 
 
 
 
Page 1 of 70 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
Pamela Drullinsky, MD 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Philip Caron, MD 
Carolyn Wasserheit-Lieblich, MD 
Sean M. Devlin, PhD 
Chau Dang, MD 
Diana Lake, MD 
Elizabeth Won, MD 
Karen Cadoo, MD 
Andrew Zelenetz, MD 
Kenneth Ng, MD 
Ephraim Casper, MD 
Melody Smith, MD 
Shani Irby, NP 
Megan Scott, NP 
Shannon Andersen, NP 
Abigail Cohen, NP 
Nicole Lestrange, NP 
Abigail Staible, PA 
Allison Tucker, NP 
Tara Wolff, NP 
Kara Mosesso, NP 
Sheila Kenny, NP 
Daniel McFarland, DO 
Parisa Momtaz, MD 
Michael Mauro, MD 
Chung-Han (Joe) Lee, MD 
Sham Mailankody, MD 
Juliana Eng, MD 
Gunjan Shah, MD 
Eric Smith, MD 
Jennifer Liu, MD 
Medicine: Rockville Centre 
Medicine: Rockville Centre 
Medicine: Rockville Centre 
Medicine: Rockville Centre 
Medicine: Sleepy Hollow 
Medicine: Sleepy Hollow 
Epidemiology-Biostatistics 
Medicine/Manhattan and West 
Harrison 
Medicine/Manhattan and West 
Harrison 
Medicine/Manhattan and West 
Harrison 
Medicine/Manhattan and West 
Harrison 
Medicine/Manhattan and West 
Harrison 
Medicine/Manhattan and West 
Harrison 
Medicine/All sites 
Medicine 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Medicine 
Nursing 
Nursing 
Nursing 
Nursing 
Medicine: West Harrison 
Medicine: West Harrison 
Medicine: West Harrison 
Medicine: West Harrison 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine/BMT 
Medicine/Myeloma 
Medicine/Cardiology 
Consenting 
Professional(s)/Department 
: 
Hani Hassoun, MD 
Heather Landau, MD 
Medicine/Myeloma Manhattan, 
West Harrison 
Medicine/BMT 
 
 
 
 
Page 2 of 70 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
David Chung, MD 
Sergio Giralt, MD 
Guenther Koehne, MD 
Alex Lesokhin, MD 
Nikoletta Lendvai, MD 
Neha Korde, MD 
Roni Tamari, MD 
Parastoo Dahi, MD 
Boglarka Gyurkocza, MD 
Brian Shaffer, MD 
Audrey Hamilton, MD 
Han Xiao, MD 
Sree Bhavani Chalasani, MD 
Stuart Lichtman, MD 
Steven Sugarman, MD 
Jon Fiore, MD 
Avni Desai, MD 
Kenneth Ng, MD 
Pamela Drullinsky, MD 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Philip Caron, MD 
Carolyn Wasserheit-Lieblich, MD 
Chau Dang, MD 
Diana Lake, MD 
Elizabeth Won, MD 
Karen Cadoo, MD 
Andrew Zelenetz, MD 
Kenneth Ng, MD 
Ephraim Casper, MD 
Melody Smith, MD 
Daniel McFarland, DO 
Parisa Momtaz, MD 
Michael Mauro, MD 
Chung-Han (Joe) Lee, MD 
Sham Mailankody, MD 
Juliana Eng, MD 
Gunjan Shah, MD 
Eric Smith, MD 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/ Myeloma 
Medicine/ Myeloma 
Medicine/Myeloma 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine/BMT 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Rockville Centre 
Medicine: Rockville Centre 
Medicine: Rockville Centre 
Medicine: Rockville Centre 
Medicine: Rockville Centre 
Medicine: Sleepy Hollow 
Medicine: Sleepy Hollow 
Medicine/Manhattan and West 
Harrison 
Medicine/Manhattan and West 
Harrison 
Medicine/Manhattan and West 
Harrison 
Medicine/Manhattan and West 
Harrison 
Medicine/Manhattan and West 
Harrison 
Medicine/All sites 
Medicine 
Medicine: West Harrison 
Medicine: West Harrison 
Medicine: West Harrison 
Medicine: West Harrison 
Medicine: Commack 
Medicine: Commack 
Medicine/BMT 
Medicine/Myeloma 
 
 
 
 
 
 
Page 3 of 70 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
Ple ase Note: A Consenting Professional must have completed the mandatory Human 
Subje cts Education and Ce rtification Program. 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 4 of 70 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA........................................................................3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................4 
3.0 
BACKGROUND AND RATIONALE .......................................................................................5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................15 
4.1 
Design................................................................................................................................15 
4.2 
Intervention ........................................................................................................................16 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS.............................................................................17 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY.............................................................................35 
6.1 
Subject Inclusion Criteria ...................................................................................................35 
6.2 
Subject Exclusion Criteria..................................................................................................36 
7.0 
RECRUITMENT PLAN .........................................................................................................37 
8.0 
PRETREATMENT EVALU ATION ........................................................................................38 
9.0 
TREATMENT/INTERVENTION  PLAN .................................................................................39 
10.0 EVALU ATION DURING TREATMENT/INTERVENTION....................................................47 
11.0 TOXICITIES/SIDE EFFECTS ...............................................................................................50 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................57 
13.0 CRITERIA FOR REMOVAL FROM STUDY ........................................................................61 
14.0 BIOSTATISTICS ...................................................................................................................62 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES63 
15.1 Research Participant Registration.....................................................................................63 
15.2 Randomization...................................................................................................................63 
16.0 DAT A M AN AGEMENT ISSUES...........................................................................................63 
16.1 Quality Assurance..............................................................................................................64 
16.2 Data and Safety Monitoring ...............................................................................................64 
17.0 PROTECTION OF HUMAN SUBJECTS..............................................................................65 
17.1 Privacy ...............................................................................................................................65 
17.2 Serious Adverse Event (SAE) Reporting ..........................................................................65 
17.2.1 Procedures for AE and SAE Reporting: Millennium requirements ...............................68 
18.0 INFORMED CONSENT PROCEDURES..............................................................................73 
19.0 REFERENCES ......................................................................................................................74 
20.0 APPENDICES .......................................................................................................................80 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
 
Myeloma  + MIDD 
Amyloidosis 
Biopsy proven 
 
BD x 1-3 cycles 
(21 day-cycle) 
 
stem 
cell mobilization 
 
 
HDM-ASCT #1 
MEL 100-140-200 
POD  
Off Study 
 
 
BD x 6 cycles 
(35 day-cycle) 
Every 3 months 
 
AL amyloidosis and Monoclonal Immunoglobulin Deposition Disease (MIDD) are two related entities 
associated with underlying plasma cell dyscrasia.  Although both diseases are caused by mis-folding 
and deposition in various organs of abnormal immunoglobulin light chains (sometimes intact 
immunoglobulins) secreted by proliferating plasma cells, the molecular mechanisms differ and lead 
to dissimilar pathologic and clinical findings. In both diseases however, this immunoglobulin 
deposition results in organ dysfunction, morbidity and ultimately death. 
 
Treatment of both diseases is aimed at eradicating the plasma cells that produce the pathologic light 
chain.  Because of the similarity to multiple myeloma (MM), a much more common disorder, patients 
have typically been treated with drugs used to treat multiple myeloma, most commonly melphalan, 
prednisone, dexamethasone, VAD (Vincristine, Adriamycin, and Prednisone) and more recently in 
the case of AL amyloidosis, newer agents like thalidomide, bortezomib and revlimid. While the 
treatment of MM continues to evolve and has resulted in improved outcomes for patients, the 
treatment of amyloidosis and especially MIDD has lagged behind, mainly because of the small 
number of patients reported in the literature. Nevertheless, the goal of treatment remains 
achievement of complete hematologic remission and complete suppression of light chain production, 
which is key to achieving organ response in both AL and MIDD.  However, because of distinct 
pathologic characteristics and increased susceptibility to toxicity due to organ dysfunction compared 
to MM patients, the treatment applied to MM cannot be extrapolated to these diseases. Patients with 
AL amyloidosis and MIDD would benefit from clinical studies addressing specifically these diseases. 
 
This clinical trial is a pilot, single arm study that examines the tolerability/toxicity, and estimates the 
efficacy of a comprehensive treatment approach in the management of MIDD and AL amyloidosis. 
The treatment includes 3 phases: Pre-transplant bortezomib based induction 
(Bortezomib/Dexamethasone or BD); followed by high dose melphalan and autologous stem cell 
transplantation (HD M/ASCT); and post-transplant consolidation/maintenance therapy with BD. This 
3-phase approach is highly effective in multiple myeloma but has never been tested in patients with 
MIDD or in patients with AL amyloidosis. The goal of the treatment is to achieve a high rate of 
complete hematologic remission which is necessary for organ improvement.   If this pilot study 
appears promising, we will develop a larger phase II study that we will propose as a cooperative 
group trial, adopting this comprehensive approach to these 2 rare diseases. 
 
The 3 phases of treatment include: 
 
1. Induction therapy consisting of one to three 21-day-cycles of BD (Patients achieving CR after one 
or two cycles could forgo remaining cycle(s)): 
 
Bortezomib 1.3 mg/m
2  IV or Subcutaneous Injection (SQ) on days 1, 4, 8, and 11 
 
 
6 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
• Dexamethasone 40 mg IV or po on days 1, 4, 8, and 11 
 
2. HD M/ASCT performed with risk-adapted doses of melphalan IV at 100, 140, or 200 mg/m 2. 
 
3. Post-transplant consolidation/maintenance consisting of six cycles of BD each given every 12 
weeks +/- 2 weeks: 
• bortezomib 1.3 mg/m2  IV or SQ on days 1, 8, and 15, and 22 
• Dexamethasone 20 mg IV or po administered on days 1, 8, and 15, and 22 
 
Toxicities will be tabulated by type and severity. With 20 patients, the hematologic and renal 
response rates can be estimated to within +/- 22%. 
 
2.0     OBJECTIVES AND SCIENTIFIC AIMS 
The primary objective of this study is: 
• To examine the tolerability and toxicity of a 3-phase comprehensive treatment approach 
including induction with BD, followed by risk adapted HDM/ASCT, followed by 
consolidation/maintenance therapy with BD in pat ients with MIDD and AL amyloidosis. 
 
The secondary objectives of this study are: 
 
• To estimate the hematologic response rate [Complete Response (CR), Very Good Partial 
Response (VGPR) and Partial Response (PR)], achieved at 12 month and at 24 months 
post-initiation of treatment (following the 3-phase comprehensive treatment approach 
including induction with BD, followed by risk adapted HDM/ASCT, followed by 
consolidation/maintenance therapy with BD) in patients with MIDD and AL amyloidosis. 
 
• To estimate the organ response rate at 12 months and at 24 months post-initiation of 
treatment  following the 3 phase comprehensive treatment approach including induction with 
BD, followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy 
with BD in patients with MIDD and AL amyloidosis. 
 
• To estimate the time to hematologic progression following the 3-phase comprehensive 
treatment approach including induction with BD, followed by risk adapted HD M/ASCT, 
followed by consolidation/maintenance therapy with BD in patients with MIDD and AL 
amyloidosis. 
 
3.0     BACKGROUND AND RATIONALE 
 
 
3.1     Upfront Treatment of Multiple Myeloma 
 
Multiple myeloma is a malignant plasma cell proliferative disorder that accounts for an estimated 
15,000 new cancer cases per year in the United States, as well as approximately 11,000 deaths 1. 
Based on the United Kingdom (UK) Myeloma Forum and the Nordic Myeloma Study Group 
recommendations2  and National Comprehensive Cancer Network (NCCN) Practice Guidelines 3, 
chemotherapy is indicated for the management of myeloma presenting with myeloma-related orga n 
damage (referred to as symptomatic myeloma as opposed to asymptomatic myeloma). Despite the 
potential benefits of newer treatments, multiple myeloma remains an incurable disease and relapse 
occurs in almost all patients, with a median survival period of 5 to 7 years 4,5. 
 
 
 
 
 
 
 
7 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
Standard front-line treatment for patients with symptomatic multiple myeloma who are deemed 
eligible for transplantation, consists of 2 phases of treatment: The first is referred to as the ―initial‖ 
therapy and consists of various combinations of therapeutic agents. The second consists of high 
dose melphalan followed by autologous stem cell transplant (HD M/ASCT) 4,5. 
 
3.1.1 Initial therapy 
The regimens currently recommended in the NCCN guidelines for initial therapy of MM in patients 
who are candidates for HD M/ASCT include dexamethasone, thalidomide/dexamethasone, 
revlimid/dexamethasone, liposomal doxorubicin/vincristine/dexamethasone (DVD), as well as 
several bortezomib based regimens. Indeed, In previously untreated patients, bortezomib has shown 
activity as a single agent6-8  and also in combination with dexamethasone6,9, 
thalidomide/dexamethasone10,11,  melphalan/prednisone (MP)12,13, dexamethasone/adriamycin14,15 as 
well as revlimid/dexamethasone.  There are currently several large phase III randomized studies 
ongoing worldwide examining the role of bortezomib in both the transplant and non-transplant 
settings. It is widely accepted that in patients who will undergo HDM/ASCT, melphalan-containing 
regimens should be avoided since stem cell collection may be subsequently hampered. 
 
Bortezomib, a potent, reversible, and specific inhibitor of the proteasome, is a first-in-class 
antineoplastic cytotoxic agent. It was the first proteasome inhibitor to enter the clinic and is the first 
approved for any clinical indication. Bortezomib specifically and selectively inhibits proteasome 
function by binding tightly (Ki=0.6 nM) and reversibly to the enzyme‘s chymotrypsin-like site. It is 
highly selective for the proteasome as exemplified in a screen of related and unrelated proteases 
where no significant inhibitory activity was seen. The mechanism of action of bortezomib as a 
cytotoxic agent is described in more details below. 
 
On June 20, 2008, the U.S. Food and Drug Administration approved bortezomib for injection for the 
treatment of patients with multiple myeloma. This approval results from a clinical trial using 
Bortezomib as an initial treatment for patients with multiple myeloma. 
 
3.1.2 Autologous Ste m Cell Transplantation 
 
There have been two large prospective trials in France (IFM 90) and in UK (MRC 9), and one large 
retrospective study of myeloma patients in Nordic countries, showing a survival benefit for ASCT 
compared to conventional chemotherapy16 -18. In the larger study, IFM 90, newly diagnosed untreated 
patients less than 65 years of age with DS stage II or III MM were randomized to either SCT after up 
to 6 cycles of VMCP alternating with BCNU, vincristine, doxorubicin and prednisone (BVAP) or 
conventional chemotherapy with 18 cycles of VMCP alternating with BVAP. The SCT regimen was 
MEL 140 mg/m2 and TBI, and recombinant interferon alpha (IFNα) was administered to patients in 
both groups until relapse. By intent-to-treat, SCT patients had a significantly higher response rate 
(CR+VGPR 38% versus 14%) than those receiving conventional chemotherapy. At a median follow- 
up of 37 months in the chemotherapy group and 41 months in the SCT group, the latter had 
significantly longer PFS and OS.  The other two studies have confirmed these results although the 
dose of melphalan given was 200 mg/m2  and radiation therapy was not used. Based on these trials, 
autologous stem cell transplantation using melphalan 200 mg/m 2 has become part of the standard 
treatment of symptomatic multiple myeloma. 
 
In patient with renal insufficiency, transplantation with melphalan 200 mg/m2  has resulted in high rate 
of side effects, especially severe mucositis. Lower doses have been studied in the literature for 
these patients. The dose of melphalan 140 mg/m 2 has been chosen in this clinical trial for patients 
with abnormal creatinine clearance because it has been shown to be safer than melphalan 200 
mg/m2  and has been widely used in patients with renal dysfunction 19- 22. This dose has become the 
standard of care nowadays for transplantation in patients with renal insufficiency and a creatinine 
 
 
 
 
8 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
clearance < 50 ml/min. Our experience at MSKCC also supports this observation and this dose has 
been adopted as standard of care for patients with creatinine clearance less than 50 ml/min. 
 
3.1.3 Post Transplant The rapy 
 
HDM/ASCT has improved response rate and overall survival rate in patients with MM, but all patients 
eventually relapse. Clinical trials have investigated the use of consolidation and maintenance 
therapy post-transplant to extend the duration of response. 
 
In a large study23, 2 months after ASCT, patients were randomly assigned to receive no maintenance 
(group A), pamidronate (group B), or pamidronate plus thalidomide (group C; 400 mg/day, dose 
reduction to a minimum dose of 50 mg was allowed for treatment-related toxicity). At least VGPR was 
achieved in 55% of patients (group A), 57% of patients (group B), and 67% of patients (group C; P = 
.03). The 3-year EFS was 36% (group A), 37% (group B), and 52% (group C; P < .009). The 4-year 
OS was 77% (group A), 74% (group B), and 87% (group C; P < .04). Patients received thalidomide 
for a median of 15 months and the mean dose of thalidomide was 200 mg/day. In another study
24  
thalidomide (200 mg/day for a maximum of 12 months) combined with prednisolone (50 mg on 
alternate days) was compared with prednisolone alone as maintenance after ASCT. At 12 months 
after randomization, the thalidomide group had higher PR rate (83% vs 52%; P 
< .01), better 2-year PFS (63% vs 36%; P < .001), and better 3-year OS (86% vs 75%; P = .02). In a 
more recent study25, patients with newly diagnosed MM were randomly assigned to receive either a 
single ASCT followed by thalidomide maintenance or tandem ASCT. Single ASCT followed by 
maintenance with thalidomide proved better than tandem ASCT for both 3- year PFS (85% vs 57%; P 
= .02) and 3-year OS (85% vs 65%; P = .04). 
 
Importantly, preliminary studies from two major large studies recently presented at the last ASCO 
meeting in 2010, have established maintenance therapy post HDC/ASCT as standard of care for 
MM. Both studies have shown a statistically significant improvement in the progression free survival 
when patients were treated with maintenance therapy with Revlimid after HD M/ASCT. The 
improvement in overall survival is currently not established26,27. 
A recent study using the combination of bortezomib, thalidomide and dexamethasone following a 
single autologous transplant demonstrated that it is feasible to administer 4 cycles of consolidation 
chemotherapy post-transplant.  With this approach, responses were improved and a proportion of 
patients (18%) became PCR negative for molecularly detectable residual disease.  Although the 
follow up remains short, no patient who achieved molecular remission relapsed at a median follow 
up of 42 month
28. 
 
Based on these studies, the use of post transplant maintenance and/or consolidation therapy in 
multiple myeloma is widely accepted. Several studies are currently investigating the use of 
bortezomib in the maintenance setting. 
 
3.2 
Monoclonal Immunoglobulin De position Dise ase 
 
Monoclonal immunoglobulin deposition disease (MIDD) is a broad entity encompassing several 
conditions that result from the deposition of a monoclonal paraprotein in various organs (For 
Review29-31). It includes light chain deposition disease (LCDD), the most common pathology; light 
and heavy chain deposition disease (LHCDD); and heavy chain deposition disease (HCDD). The 
latter two conditions are rare and have been poorly characterized in the literature.  The major organ 
target in MIDD is the kidney, where the monoclonal paraprotein deposits within the glomerular 
basement membranes, mesangium, tubular basement membranes and vessel walls. This deposition 
typically leads to a nodular sclerosing glomerulopathy that eventually manifests with nephrotic 
syndrome, hypertension and renal insufficiency. Less commonly, other visceral organs can be 
involved, including heart and liver
29,30,32- 36. Also classified among MIDD is another entity known as 
 
 
 
9 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
light chain crystal deposition disease (LCCDD) described initially by Terashima 37. . The pathology in 
this condition consists of light chain deposition forming intracellular crystals in histiocytes and renal 
parenchymal cells, particularly the proximal tubular epithelium, with variable involvement of other 
organs. Proximal tubular involvement typically manifests with light chain Fanconi syndrome (LCFS), 
which is characterized clinically by type 2 renal tubular acidosis (RTA) that associates a non anion 
gap metabolic acidosis with hypophosphatemia, glucosuria, and hypouricemia. 
 
MIDD results from the production of a monoclonal paraprotein (light chain, heavy chain, or both) and 
is therefore associated with an underlying plasma cell dyscrasia that may or may not be evident at 
the time patients first present. The majority of patients will ultimately be diagnosed with multiple 
myeloma29,30,38. Using the recently developed Free Light Chain Assay that is more sensitive for the 
detection of serum free light chains, it is likely that virtually all patients with MIDD will have a 
monoclonal free light chain detected in the serum. 
 
3.2.1 Tre atment of MIDD 
 
The treatment of MIDD has not been standardized and remains controversial because of the small 
number of patients reported in the literature. However, since MIDD is associated with plasma cell 
dyscrasias, patients have typically been treated with regimens used for multiple myeloma, most 
commonly melphalan and prednisone and VAD (Vincristine, Adriamycin, and Prednisone) 29,39,40. In a 
few small series, investigators have reported that high-dose chemotherapy followed by autologous 
stem cell transplantation (HD M/ASCT) can be associated with beneficial results while toxicity 
remains acceptable in this group of patients29,41-45. HDM/ASCT is a therapeutic modality currently 
accepted as the standard of care for patients with multiple myeloma who are less than 65 years of 
age. Weichman et al. described 6 patients, 5 with LCDD and 1 with LCCDD, who were treated with 
HDM/ASCT and who achieved a good outcome with acceptable and expected toxicity44. As 
described in the present report, most patients had complete hematologic remission followed by renal 
improvement and reversal of dialysis dependence in one case. Royer et al have reported their 
experience in 11 patients with LHCDD who received a variety of therapeutic regimens. They also 
observed an overall favorable outcome, including complete hematologic remission in five patients 
with improvement of kidney function in four42, and several patients with cardiac and/or hepatic 
involvement who experienced functional improvement after stem cell transplantation. More recently, 
Lorenz et al. reported the long-term outcome after autologous stem cell transplantation of six 
patients. Although one patient did not survive the procedure, 5 had a hematologic response by 
standard criteria and 4 who were not on dialysis at the time of transplantation had a renal response 
as assessment by improvement in their glomerular filtration rate
46. Thus, this experience highlights 
the potentially important role of stem cell transplantation in MIDD, in striking contrast to the minimal 
benefit when conventional chemotherapy (including melphalan and prednisone) is used in these 
patients. 
 
3.2.2 MSKCC Expe rience with HDM/ASCT in MIDD 
 
We have recently reported our retrospective review of all patients with MIDD who were treated with 
HDM/ASCT at Memorial Sloan Kettering Cancer Center between 2004 and 200747. We identified 7 
patients with monoclonal plasma cell dyscrasia and MIDD who underwent HDM/ASCT. 
 
3.2.2.1 
Patie nt Characteristics 
 
Six patients were male; the median age was 50 (range 33 to 52). All fulfilled criteria for multiple 
myeloma.  The median percentage of plasma cells in the bone marrow was 21 % (10 to 41 %) and 
immunohistochemical staining for light chain isotype showed kappa clonality in all cases. Serum 
protein electrophoresis showed a monoclonal spike in one patient, while serum immunofixation 
showed an IgG kappa monoclonal band in two patients. All seven patients, however, had elevated 
 
 
 
10 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
serum free kappa light chains and an abnormal kappa-to-lambda ratio with medians of 52.4 mg/dL 
(5.3 to 385 mg/dL) and 18.34 (3.01 to 203.7), respectively. The monoclonal protein deposited in the 
kidney consisted of free kappa light chains in all five patients with LCDD, kappa light chain and 
gamma heavy chain in the patient with LHCDD, and intratubular crystals of kappa light chain in the 
patient with LCCDD and Fanconi syndrome.  The median β2 microglobulin was 9.2 mg/L (2.3 to 18.4 
mg/L) and the median serum albumin level 4.4 gm/dL (3.5 to 4.6 mg/L). Using the International 
Staging System (ISS), five patients had stage III and two stage I disease. All patients were stage IB 
by Durie-Salmon classification. Cytogenetic analysis in all seven patients and FISH analyses in 
three demonstrated no chromosomal aberrations. 
 
All seven patients had hypertension that was controlled by antihypertensive medications. The patient 
with intracytoplasmic light chain crystal deposition (LCCDD) presented with renal insufficiency 
(serum creatinine of 1.6 mg/dl; creatinine clearance 40 ml/min) and Fanconi syndrome (with type II 
renal tubular acidosis (RTA II) and non-anion gap metabolic acidosis, glycosuria, and 
aminoaciduria). The median serum creatinine was 4.6 (1.6 to 6.1), median creatinine clearance 35 
ml/min (11 to 79 ml/min), and median 24-hour proteinuria 4373 mg (237 to 8525 mg). Three patients 
(patients 1, 6 and 7) presented with severe acute renal failure necessitating initiation of dialysis 
within 2 weeks of initial presentation. These patients continued dialysis throughout the entire 
treatment including the transplant period. 
 
3.2.2.2 
Histopathologic Findings on Re nal Biopsy 
 
All patients underwent a diagnostic renal biopsy. The five patients with LCDD and the single patient 
with LHCDD displayed a nodular sclerosing glomerulopathy with characteristic immunofluorescence 
profile and corresponding electron dense deposits.  The glomerular capillary lumina were diffusely 
narrowed by mesangial expansion forming large nodules that stained strongly periodic acid-Schiff 
(PAS)-positive, trichrome-blue and weakly argyrophilic.  There was variable thickening of glomerular 
basement membranes, Bowman‘s capsule, tubular basement membranes and vessel w alls by PAS- 
positive material.  These deposits typically formed ribbon-like, glassy thickenings of the tubular 
basement membranes, associated with focal tubular atrophy and interstitial fibrosis. One patient with 
LCDD also exhibited several atypical crystalline, lamellated casts of the myeloma type.  In 4 
patients, immunofluorescence studies showed intense and diffuse linear staining of all renal 
basement membranes and the mesangial nodules for kappa light chain, with negative staining for 
lambda light chain and immunoglobulins, consistent with kappa LCDD.  One patient had strong 
linear staining for IgG and kappa, with negative staining for lambda, consistent with IgG kappa 
LHCDD.  Electron microscopic examination typically showed expansion of mesangial areas with an 
increase in mesangial matrix forming large nodules containing finely granular mesangial electron 
dense deposits. Similar finely granular, electron-dense material formed linear band-like deposits 
involving the inner aspect of the glomerular basement membranes, the outer aspect of the tubular 
basement membranes and the areas surrounding the medial myocytes of arteries and arterioles. 
 
In contrast to the patients with LCDD/LHCDD, microscopic examination of the patient with light chain 
crystal deposition disease revealed no evidence of glomerular disease.  The proximal tubular 
epithelial cells displayed irregular cytoplasmic expansion caused by abundant intracellular crystalline 
inclusions that deformed the cells.  The intracytoplasmic crystals stained PAS-negative, trichrome- 
red and silver-negative.  The proximal tubular cells displayed acute injury, including focal shedding 
of tubular cells into the tubular lumen, loss of brush border, luminal ectasia and regenerative nuclear 
atypia.  In the medulla, a single atypical crystalline lamellated cast of the myeloma type was 
identified.  Tubular atrophy and interstitial fibrosis affected 10% of the cortex.  Immunofluorescence 
performed on pronase-digested paraffin sections showed intense diffuse staining for kappa light 
chain in the distribution of the proximal tubular intracellular crystals and the single atypical cast, with 
negative staining for lambda light chain.  By electron microscopy, glomeruli were unremarkable, and 
no electron dense deposits were identified involving renal basement membranes.  Intracytoplasmic 
 
 
 
11 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
crystals were demonstrated in proximal tubular epithelial cells.  The findings were interpreted as 
consistent with the special form of LCCDD known as kappa light chain Fanconi syndrome (KLCFS). 
 
3.2.2.3 
Tre atment Re ceived and Toxicity 
 
The initial therapy prior to HD M/ASCT included thalidomide (escalated to 200 mg daily) and 
dexamethasone in pulses (40 mg on days 1-4, 9-12, and 17-20) given for 3 cycles (n = 2), 
dexamethasone pulses alone for 3 cycles (n = 3), melphalan and dexamethasone for 5 cycles (n = 
1), and doxorubicin and dexamethasone for 2 cycles (n = 1). Following initial therapy, five patients 
were mobilized with high-dose cyclophosphamide (3 gm/m2) and G-CSF, and two with G-CSF alone 
(10 mcg/kg daily prior to leukapheresis for 10 days). All seven patients proceeded to HD M/ASCT 
and received melphalan as conditioning regimen at 140 mg/m 2 divided on days -3 and -2. Stem cells 
were infused on day 0. Patients received a mean of 5.8 x 106 CD34+ cells/kg (3.6 to 8.3 x 106 
CD34+ cells/kg). 
 
HDM/ASCT was well tolerated. There was no mortality. All patients completed the planned treatment 
without major or unusual complications. Routine transfusion of blood products, prophylactic broad- 
spectrum antibiotics, hydration, and analgesic medications for mucositis were administered to all 
patients. The non-hematologic adverse events included: Neutropenic fever (n=5); mucositis requiring 
intravenous analgesic medication administered by PCA (n=2); nausea requiring antiemetics (n=6); 
transient rash (n=2); an episode of syncope attributed to dehydration (n=1); abdominal cramps of 
uncertain etiology (n=1). Three patients who were on dialysis prior to HDM/ASCT continued dialysis 
throughout the course of transplant. In these patients, melphalan was given after dialysis. 
 
3.2.2.4 
Re sponse to Therapy 
 
At the completion of initial therapy, four patients had achieved a PR, 2 a CR, and one a uCR (no 
bone marrow biopsy available for confirmation of CR in this patient). Six of the seven patients 
achieved a hematologic CR after HDM/ASCT. The patient with LCCDD achieved a VGPR as 
reflected by persistence of low level free kappa chain in the serum (i.e. > 90% reduction in the level 
of free kappa light chain). This patient showed evidence of hematologic progression 8 months after 
transplant. He is currently being evaluated for a second autologous stem cell transplantation 
followed by allogeneic stem cell transplantation from an HLA-matched sibling. With a median follow 
up time of 23.6 months (range 7.9 to 69.8 months), all other patients remain in hematologic CR. 
 
Among the four patients who were dialysis independent at the time of HD M/ASCT, the serum 
creatinine has improved in two (patients 3 and 5), remained stable in one (patient 4) who achieved 
hematologic PR), and worsened in one (patient 2), leading to hemodialysis despite hematologic CR 
(see figure 4). Proteinuria has improved significantly in the four patients shortly after HD M/ASCT. 
However, we should caution that although an improvement in the proteinuria may reflect 
improvement of the renal function, it may also reflect worsening of the disease due to a decrease in 
the glomerular filtration, as exemplified by patient 2 whose proteinuria continued to improve despite 
worsening in his creatinine clearance. The three patients who were dialysis -dependent at the time of 
HDM/ASCT achieved hematologic CR. Two of them have undergone kidney transplantation 14.1 
and 45.7 months after HD M/ASCT (patients 1 and 7), and have a normal creatinine clearance 35.9 
and 69.8 months after HD M/ASCT. The kidney transplantation was deemed reasonable in these 
patients since they had achieved a hematologic CR and had no co-morbid condition otherwise. The 
third patient (patient 6) who also remains in hematologic CR became dialysis independent after 
HDM/ASCT for a period of 2 months following improvement in his creatinine, but has resumed 
peritoneal dialysis mainly for symptomatic relief (nausea) and despite a stable creatinine. 
Discontinuation of his peritoneal dialysis is currently being contemplated. 
 
 
 
 
 
12 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
3.3 
Amyloidosis 
 
Systemic AL amyloidosis is a plasma cell dyscrasia that results from mis -folding of abnormal 
immunoglobulin free light chains (FLC) that form fibrils and deposit as amorphous, congophilic 
extracellular deposits. These deposits occur in key viscera such as the kidneys, heart, and liver and 
in the peripheral nervous system48. As systemic deposits of amyloid fibrils accumulate, they disrupt 
organ function leading to organ dysfunction, morbidity and ultimately death. The initial presentation 
is variable depending on the organ(s) affected. Initial presentations include a nephrotic-range 
proteinuria with or without renal insufficiency, congestive cardiomyopathy, unexplained 
hepatomegaly, and sensorimotor and/or autonomic peripheral neuropathy. The disorder has an 
incidence of 8 to 13 per million persons per year, similar to that of chronic myelogenous leukemia. 
AL is approximately one-fifth as common as multiple myeloma but is more devastating in that the 
median survival of patients seen within 1 month of diagnosis is 13.2 months 49. Moreover, for those 
who present with congestive heart failure the median survival is 4 months, and historically less than 
5% of all AL patients survive 10 years or more from diagnosis 48,50. 
 
Achievement of a hematologic response with normalization of the serum FLCs is associated with 
organ responses and improved survival.. Therefore, the main goal of treatment in AL amyloidosis is 
directed at eradication of the FLC producing plasma cell clone, leading to suppression of the 
abnormal FLC production and deposition in various organs. 
 
3.3.1 Tre atment of AL amyloidosis 
 
The median survival of patients with AL was only 18 months in those treated with oral melphalan 
and prednisone in a large phase III trial conducted for newly diagnosed untreated patients; those 
receiving colchicine alone had a median survival of eight months51. These results highlight that 
limited progress had been made in reversing AL amyloidosis until the mid 1990's when HD M/ASCT 
was introduced for the treatment of this disease52,53. The effectiveness of HD M/ASCT  in reversing 
the clinical manifestations of AL amyloidosis in nearly two-thirds of surviving patients has been 
documented at numerous centers. Amyloid P component radionuclide scans have demonstrated 
resorption of amyloid deposits after reduction or elimination of the plasma cell clone(16-18). As the 
production of abnormal FLC is halted and amyloid resorbed, both the performance status and the 
quality of life of AL patients can improve54. 
 
However, in the early years of SCT for AL, the average 100 day mortality of SCT has ranged from 
13% to 43%, which demonstrated that AL patients who undergo HD M/ASCT are prone to major 
adverse events54-56. In these early studies, transplant-related mortality was high because multiple 
viscera of AL amyloidosis patients were significantly compromised by the disease, rendering 
patients susceptible to toxicity. Therefore, refinement of patient selection and improvement of peri- 
transplant clinical management became priorities. In 2007, a French group conducted a randomized 
trial comparing high-dose intravenous melphalan followed by ASCT with standard-dose melphalan 
plus dexamethasone in patients with AL amyloidosis. Fifty patients were enrolled in each group. The 
results were analyzed on an intention-to-treat basis, with overall survival as the primary end point. 
After a median follow-up of 3 years, the outcome of treatment of AL amyloidosis with ASCT similar 
to the outcome with standard-dose melphalan plus dexamethasone.  It was felt that this lack of 
benefit for the transplant arm was related to the high transplant related mortality. Of the 37 patients 
who actually proceeded with transplantation, 9 died within 100 days after ASCT — 5 from multiorgan 
failure with acute renal failure, 2 from sepsis, and 2 from cardiac arrhythmia. The transplant-related 
mortality was 24%57. However this study was criticized because ASCT was performed in small 
centers where expertise in transplantation for amyloidosis patients may have been suboptimal. 
 
 
 
 
13 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
From these studies we learned that patients with AL undergoing SCT with more than 2 major organs 
symptomatically involved or with advanced cardiomyopathy were at high risk of death during the 
peri-transplant period and, therefore, were poor risk candidates for SCT. At the same time, patients 
with 1 or 2 organs symptomatically involved and those with uncomplicated cardiac disease were 
appropriate  candidates for stem cell transplantation, provided the dose of intravenous melphalan 
was attenuated based on age and organ compromise. This risk-adapted approach based on extent 
of organ involvement,  dose-related differences in toxicity, (8,22)and on the age-related differences 
in survival has improved the safety of high dose chemotherapy (Cohen BJH publication) and has 
been adopted by experienced amyloid transplant centers in the US. 
 
3.3.2 Re cent experience with HDM/ASCT followed by consolidation/maintenance 
the rapy at MSKCC 
 
In the first of a series of trials conducted at MSKCC using the risk-adapted approach,  IRB #02-031, a 
phase II trial evaluated risk-adapted HD M/ASCT followed by dexamethasone (D) and thalidomide (T) 
in an attempt to reduce treatment related mortality (TRM) and overcome any loss of efficacy as a 
result of attenuated melphalan dosing
58.  Patients (n = 45) with newly diagnosed AL involving < or =2 
organ systems were assigned to MEL 100, 140, or 200 mg/m(2) with SCT, based on age, renal 
function and cardiac involvement. Patients with persistent clonal plasma cell disease 3 months post- 
SCT received 9 months of consolidation with TD (or D if there was a history of deep vein thrombosis 
or neuropathy). Organ involved included kidney (67%), heart (24%), liver/GI (22%) and peripheral 
nervous system (18%), with 31% of patients having two organs involved. TRM was 4.4%. Thirty-one 
patients began adjuvant therapy, with 16 (52%) completing 9 months of treatment and 13 (42%) 
achieving an improvement in hematological response. By intention-to-treat, overall hematological 
response rate was 71% (36% complete response), with 44% having organ responses. With a 
median follow-up of 31 months, 2-year survival was 84% (95% confidence interval: 73%, 94%). This 
clinical trial showed that risk-adapted HDCT/SCT with consolidation TD is feasible and results in low 
TRM and high hematological and organ response rates in patients with AL amyloidosis. 
 
Improved efficacy and toxicity profiles of bortezom ib compared to thalidomide in multiple myeloma, 
prompted us to initiate a new phase II clinical trial in amyloidosis in 2007.  We used the same 
strategy of risk-adapted HDC/ASCT followed by consolidation with bortezomib/dexamethasone (BD) 
in patients with 1 or 2 organ involvement without advanced heart disease. At the 2009 meeting of 
the American Society of Hematology, we presented the two-year update for this phase II trial 
59. 
Patients with newly diagnosed AL involving <=2 organs were assigned to HD M/ASCT with 
melphalan 100, 140 or 200mg/m2 based on age, renal function and cardiac involvement. Responses 
were assessed at 2-3 mos, 12 mos and 24 mos post-SCT. Patients with persistent clonal plasma 
cell disease at 2-3 mos post-SCT received treatment with BD for up to 6 cycles (two 21-day, four 35- 
day cycles).  Thirty-seven patients were enrolled with kidney (68%), heart (43%), liver/GI (14%) and 
peripheral nervous system (16%) involvement.  Forty-one percent had two organ involvement.  Four 
patients with advanced cardiac disease died within 100 days of SCT, resulting in a TRM of 12% 
(4/33).  With a median follow-up of 29 mos, the OS at 12 mos post-SCT was 86%.  At 12 and 24 
mos, OS in patients with cardiac involvement was 69% and 49% respectively, versus 100% at both 
time points in those without (P = 0.001).  Sixty-eight percent (19/28) received consolidation with BD 
for persistent clonal plasma cell disease. At 12 mos post-SCT, the hematologic response rate in 
evaluable patients was 95% (20/21) with 62% achieving sCR and 60% having organ improvement. 
At 24 mos post-SCT, the overall response rate was 82% (14/17) including 53% who maintained a 
sCR and 88% (15/17) who had organ improvement. Organs continued to get better over time and 
92% (11/12) of patients with kidney involvement had organ responses at 24 mos versus 50% (7/14) 
at 12 mos.  Overall, 87% of patients who received BD improved their hematologic response. There 
was no correlation between the number of cycles received (median 6; range 1.25-6) and response 
and interestingly, all responded after only 1 cycle of BD.  Of the 19 patients who received post-SCT 
BD, 79% experienced grade III- IV toxicity, which was most often hematologic toxicity with 
 
 
 
14 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
thrombocytopenia in 41%.  Grade 2 or greater peripheral neuropathy was seen in 32% and became 
more prevalent as the number of consolidation cycles increased. 
 
This trial showed that in newly diagnosed patients with systemic AL amyloidosis, consolidation with 
BD following risk-adapted SCT was safe and effective for eradicating persistent clonal plasma cell 
disease.  Hematologic responses were rapid (occurring after 1 cycle) resulting in high overall and 
unprecedented sCR rates.  Improvement in organ function was seen in the majority of patients and 
continues to occur over time.  Relapses are seen following completion of therapy, suggesting that a 
consolidation plus maintenance regimen following SCT may be worthy of further study. 
 
While consolidation following HD M/ASCT has shown promising results, a Phase II study evaluating 
the incorporation of bortezomib into the combination of melphalan and dexamethasone as initial 
therapy (i.e. before HD M/ASCT) for AL amyloidosis has been undertaken and preliminary data has 
been recently reported60. Twenty-four of 29 patients evaluable on this trial (83 %) had a hematologic 
response with 13 CR (45%) and 16 PR. Organ improvement was seen in 2/10 with cardiac AL, 7/8 
with renal and 6/12 patients with nerve involvement.  Two of 7 patients without baseline neuropathy 
developed symptoms by cycle 4.  (This trial showed that bortezomib incorporated in the initial 
therapy also shows promising activity in the treatment of AL. Importantly, this trial includes patients 
with amyloidosis as well as patients with MIDD. 
 
The data presented above in amyloidosis lays the ground for this more comprehensive approach to 
the treatment of this disease, which incorporates pre-transplant bortezomib based initial therapy, 
risk-adapted HD M/ASCT, followed by bortezomib based maintenance therapy. 
 
 
3.5 
Rationale for this Clinical Trial 
 
We believe that the comprehensive treatment approach that we propose in this trial, which borrows 
the most effective therapeutic concepts used in multiple myeloma, is very promising. This treatment 
approach includes a highly active initial combination regimen, followed by HD M/ASCT and then 
post-ASCT consolidation/maintenance therapy, which have been shown to increase the complete 
hematologic response (CR) and the overall survival (OS) in patients with multiple myeloma. The 
hematologic effectiveness of this aggressive regimen is crucial because even low levels of 
circulating free light chains may have deleterious organ consequences in MIDD and AL amyloidosis. 
Hence, one of the aims of therapy is to suppress the free light chain production to the greatest 
extent. The success of therapy in curbing organ dysfunction depends on achieving and maintaining 
a complete hematologic remission. In this context, the comprehensive and effective treatment 
approach used in this clinical trial is crucial for the achievement of a high CR rate. 
 
We and others have observed a unique sensitivity of these patients to bortezomib-based therapy 
with the majority of responses seen after only 1 cycle.  The incidence of neuropathy in this patient 
population appears similar to that reported in patients with MM.  However the morbidity of 
neuropathy in MIDD and AL patients who are also at risk for both autonomic and sensory 
neuropathy may be greater than seen in MM.  Our experience with repeated doses of BD as 
consolidation following HDM/ASCT suggests dose-dependent toxicity.  Given the rapidity of 
response to BD, risk of toxicity, and incidence of relapse, within the context of this comprehensive 
approach to treatment we propose 1-3 cycles of initial BD therapy (determined by achievement of 
CR) followed by 6 cycles of consolidation/maintenance BD after HD M/ASCT with cycles 
administered every 12 weeks. 
 
Although our experience with HD M/ASCT and bortezomib as individual therapies in MIDD and AL 
amyloidosis is encouraging, there is no precedent for such a comprehensive and aggressive 
approach that combines the three phases of therapy as proposed in this clinical trial. Whether 
 
 
 
15 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
patients with MIDD and AL amyloidosis will be able to tolerate such an aggressive and protracted 
approach, and whether the toxicity of HD M/ASCT combined with pre and post transplant 
administration of BD will be prohibitive or deleterio us to these patients will be evaluated on this pilot 
study. 
 
Regarding MIDD, although our experience with HD M/ASCT appears encouraging, there has been 
no prospective study addressing the use of this treatment modality in MIDD. All the data available on 
the subject, including the MSKCC experience, stems from retrospective analyses that have 
obviously numerous shortcomings. Despite the fact that all patients in the few series reported 
received ASCT, treatments administered have been widely variable in terms of initial therapy 
(treatment received before the ASCT) as well as conditioning regimens prior to transplantation. 
Regarding the response to treatment in MIDD, the correlation between hematologic response and 
renal response is poorly characterized, often not even reported in the literature, and much remains 
to be understood in that regard. This clinical trial represents the first prospective therapeutic clinical 
trial in MIDD examining the outcome of these patients using a comprehensive treatment that is very 
effective in multiple myeloma. 
 
In the event this comprehensive treatment strategy is safe and there is a signal of activity, we plan to 
complete a larger phase II trial which will be most feasible in a cooperative group setting. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a pilot study to gain information and estimate the toxicity/tolerability of 1-3 cycles of BD, 
followed by HD M/ASCT, and maintenance therapy with BD in patients with MIDD associated with 
multiple myeloma and AL amyloidosis. A total of 20 patientswill be accrued to the study.  We will 
estimate the hematologic response rates as well as organ response rates at the completion of 
therapy and at 24 months. 
4.2 
Intervention 
The treatment has three phases: 
1) Initial treatment phase: This phase consists of 1-3 21-day-cycles of a combination regimen that 
includes bortezomib 1.3 mg/m2, IV or SQ, on days 1, 4, 8, and 11; and dexamethasone 40 mg PO 
or IV, on days 1, 4, 8, and 11. 
At the completion of every cycle and prior to init iation of the subsequent cycle, the toxicity of the 
treatment will be assessed using CTCAE v4.0. Likewise, the hematologic response will also be 
assessed at the completion of every cycle of treatment based on standard response criteria well 
established for multiple myeloma. These criteria are based on evaluation of serum and urine M- 
spike values.  Patients who show evidence of progression of disease (POD) with confirmation at any 
time during this phase of treatment will be taken off study and will be treated at the discretion of their 
treating physician. All other patients will continue to receive treatment as per protocol and will 
proceed with the second phase of treatment after 3 cycles. Patients who achieve CR before 
completion of 3 cycles may forego the remaining cycle(s) and proceed to phase 2 of treatment 
(HDM/ASCT). A bone marrow biopsy will be performed at the completion of the first phase of 
treatment to characterize the response to induction BD. 
 
2) Stem cell mobilization and HD M/ASCT: Patients will have peripheral blood stem cells mobilized 
and collected as per MSKCC‘s institutional guidelines.  All patients will undergo risk-adapted 
conventional autologous stem cell transplantation with melphalan 100, 140, or 200 mg/m2 
(depending on risk. See section 9.0) given in a single dose on day -2 or divided doses given on days 
 
 
 
 
16 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
-3 and -2, prior to stem cell reinfusion on day 0. These procedures will be performed as per 
MSKCC‘s institutional guidelines.. 
Toxicity will be assessed during transplant and hematologic and organ responses to HD M/ASCT will 
be assessed at 12 weeks +/- 2 weeks post-transplantation using standard response criteria. 
However, organ response being delayed compared to hematologic response, we expect that 
maximum organ response will be best assessed at 12 months and 24 months from initiation of 
treatment. Patients who have hematologic POD after transplantation will be taken off study and will 
be treated at the discretion of their treating physician. All other patients will proceed to the third 
phase of treatment. 
 
3) Post-ASCT consolidation/maintenance treatment phase: This phase consists of six cycles of 
bortezomib 1.3 mg/m2, IV or SQ with dexamethasone 20 mg PO or IV administered on days 1, 8, 
15, and 22 every 12 weeks +/- 2 weeks. Although bortezomib has not been established as 
maintenance therapy in multiple myeloma (clinical trials currently in progress), the concept of 
maintenance therapy after HD M/ASCT has now been shown to increase the CR rate, PFS, and in 
few studies, OS in patients with multiple myeloma using lenalidomide or thalidomide. 
Toxicity and hematologic response will be assessed at the initiation of every cycle based on CTCAE 
4.0 criteria and standard response criteria, respectively. Patients who show evidence of POD with 
confirmation at any time during this phase of treatment will be taken off study and will be treated at 
the discretion of their treating physician. All other patients will continue to receive treatment as per 
protocol. 
The hematologic and organ responses will be assessed using standard hematologic response 
criteria in multiple myeloma (including a bone marrow biopsy to confirm CR) at 12 months and at 24 
months (+/- 2 weeks) following treatment initiation.  We anticipate that in many patients, end of 
therapy will correspond to the 24 month post-treatment evaluation. 
 
 
At the completion of treatment, patients will be seen in the clinic every three months until disease 
progression with no further intervention. 
4.3 
Outcome me asurement 
 
The primary objective of this clinical trial is toxicity/tolerability and we will use CTCAE 4.0 criteria to 
describe adverse events and measure outcome. Secondary objectives include hematologic and 
organ response rates at the completion of treatment and 24 months post treatment initiation. The 
criteria for hematologic response are well established and widely used in the myeloma field and are 
detailed in section 12.0. The criteria for organ response are also well established for amyloidosis. 
For MIDD, the response criteria have not been as well defined and are discussed in section 12.0. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
Bortezomib 
 
5.1.1  Scientific Background 
 
BORTEZOMIB ( Velcade®) for Injection is a small-molecule proteasome inhibitor developed by 
Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies. 
BORTEZOMIB is currently approved by the United States Food and Drug Administration (US 
FDA) for the treatment of patients with multiple myeloma (MM).  It is also indicated for the 
treatment of patients with mantle cell lymphoma (MCL) who have received at least 1 prior 
therapy.  In the European Union (EU), BORTEZO MIB in combination with melphalan and 
 
 
 
17 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
prednisone is indicated for the treatment of patients with previously untreated MM who are not 
eligible for high-dose chemotherapy with bone marrow transplant.  BORTEZOMIB is indicated as 
monotherapy for the treatment of progressive MM in patients who have received at least 1 prior 
therapy and who have already undergone or are unsuitable for bone marrow transplantation. 
By inhibiting a single molecular target, the proteasome, BORTEZOMIB affects multiple signaling 
pathways.  The antineoplastic effect of BORTEZOMIB likely involves several distinct 
mechanisms, including inhibition of cell growth and survival pathways, induction of apoptosis, and 
inhibition of expression of genes that control cellular adhesion, migration, and angiogenesis. 
Thus, the mechanisms by which BORTEZOMIB elicits its antitumor activity may vary among 
tumor types, and the extent to which each affected pathway is critical to the inhibition of tumor 
growth could also differ.  BORTEZOMIB has a novel pattern of cytotoxicity in National Cancer 
Institute (NC I) in vitro and in vivo assays.(See ref Appendix 20.5 i)  In addition, BORTEZOMIB 
has cytotoxic activity in a variety of xenograft tumor models, both as a single agent and in 
combination with chemotherapy and radiation.(See ref Appendix 20.5 ii,iii,iv ,v ,v i,v ii,v iii,ix,x,xi,xii,xiii,xi v ) 
Notably, BORTEZOMIB induces apoptosis in cells that over express bcl-2, a genetic trait that 
confers unregulated growth and resistance to conventional chemotherapeutics. (See ref Appendix 
20.5 
xv ) 
The mechanisms of action leading up to apoptosis have been more clearly defined and include 
initiation of the unfolded protein response and direct/indirect effects on various molecular targets 
including cell cycle control proteins p27 and p21, cyclins, signal transduction molecules, transcription 
factors c-jun and HIF1-
, tumor suppressor protein p53, angiogenesis factors, and many others. 
BORTEZOMIB is thought to be efficacious in multiple myeloma via its inhibition of nuclear factor B 
(NF-B) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct apoptotic 
effect, and possibly anti-angiogenic and other effects. (See ref Appendix 20.5 xv i,xv ii,xv iii,xix,xx,xxi ,xxii,xxiii) 
5.1.2 Non-clinical Pharmacology 
Pharmacokinetic (PK) and pharmacodynamic studies were conducted in the rat and cynomolgus 
monkey.  Upon intravenous (IV) bolus administration, bortezomib displays a rapid distribution phase 
(t½ <10 minutes) followed by a longer elimination phase (t½  5–15 hours).  Bortezomib has a large 
volume of distribution (range 5–50 L/kg).  The plasma PK profile is well described by a 
2-compartment model. 
The pharmacodynamic action of bortezomib is well established and can be measured through an ex 
vivo assay (20S proteasome activity)67.  This assay was used to determine the duration of drug 
effect in lieu of the PK data in the early preclinical toxicology studies as well as to set a guide for 
dose escalation in humans.  Following dosing with bortezomib in the rat and cynomolgus monkey, 
proteasome inhibition in peripheral blood had a half-life less than 24 hours, with proteasome activity 
returning to pretreatment baseline within 24 hours in monkey and within 48 to 72 hours in rat after a 
single dose of bortezomib.  Further, intermittent but high inhibition (>70%) of proteasome activity 
was better tolerated than sustained inhibition.  Thus, a twice-weekly clinical dosing regimen was 
chosen in order to allow return of proteasome activity towards baseline between dose 
administrations. 
5.1.3 Non-clinical Toxicity 
Single-dose IV toxicity studies were conducted with bortezomib in the mouse, rat, dog, and monkey 
to establish the single-dose maximum tolerated dose (MTD).  The MTDs were 0.25 mg/kg (1.5 
mg/m2) and 0.067 mg/kg (0.8 mg/m2) in the 2 most sensitive species, rat and monkey, respectively. 
Repeat-dose multi-cycle toxicity studies of 3 and 6 months in the rat and 9 months in the monkey, 
each with 8-week recovery periods, were conducted to characterize the chronic toxic ity of 
bortezomib when administered by the clinical route and regimen of administration.  The MTD in the 
6-month rat study was 0.10 mg/kg (0.6 mg/m
2) and the key target organs were the gastrointestinal 
 
 
 
18 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
(GI) tract, hematopoietic and lymphoid systems.  The MTD in the 9-month monkey study was 0.05 
mg/kg (0.6 mg/m
2) and the key target organs were the GI tract, hematopoietic and lymphoid 
systems, peripheral nervous system, and kidney.  Full or partial reversibility was observed for each 
of the toxicities described to date. 
In general, the nature of the toxicity of bortezomib is similar across species, and target organs of 
toxicity in animals have been largely predictive of human toxicity.  The toxicity of bortezomib in 
animals is characterized by a steep dose-response with mortality seen at dosages above the MTD. 
The cause of death at acutely lethal dosages is considered to be related to indirect cardiovascular 
(CV) effects of hypotension and vascular changes with secondary bradycardia and the cause of 
death in long-term studies has been attributed to GI or hematologic toxicity.  The pharmacologic 
effects of bortezomib on the CV system have been extensively characterized and have 
demonstrated that indirect effects on CV function occur only at acutely lethal dosages and are 
abrogated by routine supportive care. 
Additional detailed information regarding the nonclinical pharmacology and toxicology of bortezomib 
may be found in the Investigator‘s Brochure 
5.1.4 Clinical Pharmacokinetics and Phar macodynamics 
The clinical pharmacology characterization of bortezomib has been determined from phase 1 studies 
in subjects with solid tumors and hematological malignancies, and confirmed in phase 2 studies in 
subjects with multiple myeloma. 
Bortezomib demonstrates multi-compartmental pharmacokinetics. Following intravenous 
administration of 1.0 mg/m2  and 1.3 mg/m2  dose, the mean first-dose maximum observed plasma 
concentrations of bortezomib were 57 and 112 ng/mL, respectively in 11 patients with multiple 
myeloma and creatinine clearance values >50 mL/min participating in a pharmacokinetics study.  In 
subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL 
for the 1.0 mg/m2  dose and 89 to 120 ng/mL for the 1.3 mg/m2  dose.  The mean elimination half-life 
of bortezomib upon multiple dosing ranged from 40 to 193 hours.  Bortezomib is eliminated more 
rapidly following the first dose.  Mean Total Body Clearances were 102 and 112 L/h following the 
first dose for doses of 1.0 mg/m2  and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h 
following subsequent doses for doses of 1.0 and 1.3 mg/m2, respectively.  Clinical experience has 
shown that the change in clearance does not result in overt toxicity from accumulation in this 
multidose regimen in humans. 
In subjects with advanced malignancies, the maximum pharmacodynamic effect (inhibition of 20S 
activity) occurred within 1-hour post dose.  At the therapeutic dose of 1.3 mg/m 2 in subjects with 
multiple myeloma, the mean proteasome inhibition at 1-hour post dose was approximately 61%. 
The time course of proteasome inhibition in subjects is characterized by maximum inhibition 
observed within the first hour after administration, followed by partial recovery of proteasome activity 
over the next 6 to 24 hours to within 50% of the pretreatment activity.  On the Day 1, 4, 8, and 11 
schedule, variable (10%–30%) levels of proteasome inhibition have been observed at next 
scheduled dosing.  In theory, this advantage allows cells to recover proteasome activity for normal 
cellular housekeeping functions between doses. 
The relationship between bortezomib plasma concentrations and proteasome inhibition can be 
described by a maximum effect (Emax) model.  The Emax  curve is initially very steep, with small 
changes in plasma bortezomib concentration over the range of 0.5 to 2.0 ng/mL relating to large 
increases in the percent inhibition (0–60%).  After that, a plateau occurs where marginal increases of 
proteasome inhibition are observed in spite of large changes in plasma bortezomib concentrations. 
 
 
 
 
 
19 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
5.1.5 Clinical Experience 
It is estimated that as of January 2009, more than 100,000 patients have been treated with 
BORTEZOMIB, including patients treated through Millennium-sponsored clinical trials, Investigator- 
Initiated Studies, the US NC I Cancer Therapy Evaluation Program (CTEP), and with commercially 
available drug.  BORTEZOMIB has been commercially available since 13 May 2003. 
 
The overall goal of the Millennium phase 1 program was to determine the MTD and dose-limiting 
toxicity (DLT) of BORTEZOMIB in a number of therapeutic settings involving subjects with various 
advanced malignancies.  In a phase 1 trial in patients with refractory hematologic malignancies, the 
MTD for a twice weekly dosing for 4 weeks of a 42-day cycle was 1.04 mg/m2/dose, with DLTs of 
thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. (See ref Appendix 20.5 xxiv ) 
The toxicity was greatest during the third and fourth weeks of therapy.  In the 3-week schedule of 
BORTEZOMIB monotherapy (4 doses, given on Days 1, 4, 8, and 11 of a 21-day treatment cycle), 
the DLT occurred at 1.56 mg/m2/dose (3 subjects with Grade 3 diarrhea and 1 with peripheral 
sensory neuropathy).  Therefore, the MTD at this schedule was 1.3 mg/m 2/dose.  In a 35-day 
treatment cycle with 4 weekly doses of BORTEZOMIB monotherapy, the MTD was 1.6 mg/m2/dose 
and DLT included hypotension, tachycardia, diarrhea, and syncope. 
 
In phase 1 clinical studies, antitumor activity was reported in subjects with Non-Hodgkin‘s 
Lymphoma (NHL), MM, Waldenström‘s Macroglobulinemia, squamous cell carcinoma of the 
nasopharynx, bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate cancer. 
(See ref Appendix 20.5 
xxv ,xxv i,xxv ii,xxv iii) 
 
The safety and efficacy of BORTEZOMIB in subjects with MM were investigated in two phase 2 
clinical studies, studies M34100-024 (subjects with first relapse) (See ref Appendix 20.5 xxix) and 
M34100-025 (subjects with second or greater relapse and refractory to their last prior therapy). (See 
ref Appendix 20.5 xxx)  In M34100-025, 202 heavily pretreated subjects with refractory MM after at 
least 2 previous treatments received BORTEZOMIB, 1.3 mg/m2  on Days 1, 4, 8, and 11 of a 21-day 
treatment cycle.  The European Group for Blood and Marrow Transplant (EBMT) response criteria, 
as described by Blade (See ref Appendix 20.5 xxxi) were utilized to determine disease response. 
Complete responses (CRs) were observed in 4% of subjects, with an additional 6% of patients 
meeting all criteria for CR but having a positive immunofixation test.  Partial response (PR) or better 
was observed in 27% of subjects, and the overall response rate (CR, PR, and minor response [MR] 
combined) was 35%.  Seventy percent of subjects experienced stable disease or better. 
 
The phase 3 study (M34101-039) (See ref Appendix 20.5 xxxii), also referred to as the APEX study, 
was designed to determine whether BORTEZOMIB provided benefit (time to progression [TTP], 
response rate, and survival) to patients with relapsed or refractory MM relative to treatment with 
high-dose dexamethasone.  The study was also designed to determine the safety and tolerability of 
BORTEZOMIB relative to high-dose dexamethasone, and whether treatment with BORTEZOMIB 
was associated with superior clinical benefit and quality of life relative to high-dose dexamethasone. 
A total of 669 patients were enrolled and 663 patients received study drug (BORTEZOMIB:  331; 
dexamethasone:  332).  Patients randomized to BORTEZOMIB received 1.3 mg/m2  IV push twice 
weekly on Days 1, 4, 8, and 11 of a 3-week cycle for up to 8 treatment cycles as induction therapy, 
followed by 1.3-mg/m2  BORTEZOMIB weekly on Days 1, 8, 15, and 22 of a 5-week cycle for 3 
cycles as maintenance therapy.  Patients randomized to dexamethasone received oral 
dexamethasone 40 mg once daily on Days 1 to 4, 9 to 12, and 17 to 20 of a 5-week cycle for up to 
4 treatment cycles as induction therapy, followed by dexamethasone 40 mg once daily on Days 1 to 
4 of a 4-week cycle for 5 cycles as maintenance therapy.  The EBMT response criteria were utilized 
to determine disease response.  There was a 78% increase in TTP for the BORTEZOMIB arm. 
Median TTP was 6.2 months for the BORTEZOMIB arm and 3.5 months for the dexamethasone arm 
(p < 0.0001).  CR + PR was 38% with BORTEZOMIB versus 18% with dexamethasone (p  0.0001). 
 
 
 
20 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
CR was 6% with BORTEZOMIB versus  1% with dexamethasone (p < 0.0001).  The CR + nCR 
(near CR) rate was 13% with BORTEZOMIB versus 2% with dexamethasone.  In patients who had 
received only 1 prior line of treatment (BORTEZOMIB:  132; dexamethasone:  119), CR + PR was 
45% with BORTEZOMIB vs 26% with dexamethasone (p = 0.0035).  With a median 8.3 months of 
follow-up, overall survival was significantly longer (p = 0.0013) for patients on the BORTEZOMIB 
arm versus patients on the dexamethasone arm.  The probability of survival at 1 year was 80% for 
the BORTEZOMIB arm versus 66% for the dexamethasone arm, which represented a 41% 
decreased relative risk of death in the first year with BORTEZO MIB (p = 0.0005).  In patients who 
had received only 1 prior line of treatment, the probability of survival at 1 year was 89% for the 
BORTEZOMIB arm versus 72% for the dexamethasone arm, which represented a 61% decreased 
relative risk of death in the first year with BORTEZOMIB (p = 0.0098).  Updated response rates and 
survival data were reported for M34101-039. (See ref Appendix 20.5 xxxiii)  The updated CR + PR 
rate was 43% with BORTEZOMIB.  The CR + nCR rate was 16% with BORTEZOMIB.  With a 
median 22 months of follow-up, overall survival was significantly longer for patients on the 
BORTEZOMIB arm versus patients on the dexamethasone arm.  The median overall survival was 
29.8 months (95% CI:  23.2, not estimable) for the BORTEZOMIB arm vs 23.7 months (95% CI: 
18.7, 29.1) for the dexamethasone arm (hazard ratio = 0.77, p = 0.0272).  The probability of survival 
at 1 year was 80% for the BORTEZO MIB arm versus 67% for the dexamethasone arm (p = 0.0002). 
 
The safety and efficacy of BORTEZOMIB in relapsed or refractory mantle cell lymphoma (MCL) 
were investigated in an international, phase 2, multicenter study M34103-053, also referred to as the 
PINNACLE study. (See ref Appendix 20.5 xxxiv ) The single-arm study was designed to evaluate the 
response rates, duration of response (DOR), TTP, overall survival (OS), and safety of 
BORTEZOMIB treatment in patients with relapsed or refractory mantle cell lymphoma.  For 141 
evaluable patients, the response rate was 31% (8% CR/unconfirmed CR [Cru]).  Median time to 
response was 40 days (range 31-204 days).  The median number of cycles administered across all 
patients was 4; in responding patients, the median number of cycles was 8. The median DOR by 
algorithm was 9.2 months and 13.5 months in patients with CR/CRu.  Median TTP for both groups 
was 6.2 months. With a median follow-up of 13.4 months, overall survival had not been reached. 
The most commonly reported adverse events (AEs) were fatigue, peripheral neuropathy, and 
gastrointestinal events.  A time-to-event update to the PINNACLE study (See ref Appendix 20.5 xxxv ) 
was reported after a median follow-up of 26.4 months.  TTP was 6.7 months for all patients, 12.4 
months in all responders.  The median DOR was 9.2 months in all responders and had not been 
reached in patients achieving CR/Cru.  Overall survival was 23.5 months in all patients and 36 
months in patients with CR/Cru.  Survival at 12 months was 69% overall and 91% in responding 
patients. 
 
The phase 3 study (MMY 3002) known as the VISTA study, evaluated the safety and efficacy of the 
combination of BORTEZOMIB, melphalan, and prednisone in previously untreated multiple myeloma 
patients who were not candidates for stem cell transplant. (See ref Appendix 20.5 
xxxv i)  The study 
was designed to determine the ben efit of adding BORTEZOMIB to MP (melphalan and prednisone) 
as assessed by TTP.  Patients (682) were randomized to receive nine 6-week cycles of melphalan 
9mg/m2  and prednisone 60 mg/m2  on Days 1 to 4, alone or in combination with BORTEZO MIB 1.3 
mg/m2  by IV bolus on Days 1, 4, 8, 11, 22, 25, 29, and 32 during Cycles 1 to 4, and on Days 1, 8, 
22, and 29 during Cycles 5 to 9. Response was evaluated every 3 weeks using the EBMT criteria. 
At a preplanned interim analysis, the independent data monitoring committee recommended that the 
study be stopped since the prespecified statistical boundary end point of TTP had been crossed. 
Response rates were 30% with 4% CR.  The rates of partial response or better were 71% in the 
BORTEZOMIB (VMP) group compared to 34% in the MP group (p = 0.001).  With follow-up of 16.3 
months, the TTP for the VMP group was 24 months compared to 16.6 months in the MP group (p = 
0.000001) and was associated with a 52% reduced time to progression.  The median DOR was 19.9 
months in the VMP group and 13.1 months in the MP group.  Overall survival had not been reached 
in either group.  Hematologic toxicity was similar in both groups.  The incidence of peripheral 
 
 
 
21 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
sensory neuropathy and gastrointestinal symptoms was higher in the VMP group.  The incidence of 
herpes zoster was 3% in patients in the VMP group who received antiviral prophylaxis.  Fifteen 
percent of patients in the VMP group discontinued therapy due to AEs compared to 14% in the MP 
group. 
The VISTA study update after extended follow-up of 25.9 months, (See ref Appendix 20.5 xxxv ii) 
confirmed a survival benefit for the VMP group.  Overall survival was not reached in either group: 
VMP group (75) deaths, 3 year OS 72%; MP group (111) deaths, 3 year OS 59% (p = 0.0032). 
Patients on VMP were less likely to start second-line therapy (VMP 38% vs MP 57% at the time of 
data cut-off) with a longer time to next therapy (TNT) and treatment free interval (TFI).  Of the MP 
patients who received subsequent therapy, 43% went on to receive BORTEZOMIB. 
 
Based on investigator-reported best responses to subsequent therapies, patients relapsing after 
therapy with a novel agent were not intrinsically more resistant than after receiving a traditional 
agent. 
 
In the VISTA study, VMP was associated with prolonged TTP, TNT, TFI, and OS.  Patients were 
successfully treated with subsequent IMiD-based therapy and retreated with BORTEZOMIB.  After 
36.7 months follow-up, OS continued to be superior for VMP.  The OS for VMP had not yet been 
reached compared to MP (43.1 months). (See ref Appendix 20.5 
xxxv iii) 
 
5.1.6 Potential Risks of Bortezomib 
To date, more than 100,000 patients have been treated with BORTEZOMIB in both clinical trials 
investigating its use in hematological malignancies and solid tumors, and in patients who were 
treated with commercially available BORTEZOMIB. 
 
Prescribing physicians and health care practitioners are referred to their locally appro ved product 
label for BORTEZOMIB regarding Indications and Usage, Contraindications, Warnings, and 
Precautions. 
 
The known anticipated risks of BORTEZOMIB therapy are presented inTable 1 andSection 11.1. 
These risks are grouped according to the combined frequency observed in an integrated analysis 
of AEs in sponsored clinical studies of single-agent BORTEZO MIB dosed at 1.3 mg/m2  twice 
weekly on a 21-day schedule, in patients with multiple myeloma and mantle cell lymphoma. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
22 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
Table -1 
Known Anticipated Risks of BORTEZOMIB by MedDRA System 
Organ Class, Observed Incidence, and Preferred Term 
System Organ Class 
Ob served Incidence 
Preferred Term 
Blood and Lymphatic System Diso rder s 
Most common 
Thrombocytopenia*, anaemia* 
Very common 
Neut ropeni a* 
Comm on 
Lymphopenia, pancytopeni a*, leukopenia*, febrile 
neutropenia 
Cardiac Disorder s 
Comm on 
Tachycardi a, atrial fi brill ation, pal pitations, cardi ac 
failure congesti ve* 
Uncomm on 
Cardiogenic shock*, atrial flutter, cardiac 
tamponade*, bradycardia, atri oventricul ar bl ock 
complete, arrhythmi a, cardiac arrest , cardiac 
failure, arrhythmi a, peric ardi al effusion, pericarditis, 
pericardi al disease , cardiopulm onary fail ure
Ear and Labyrinth Di sorder s 
Uncomm on 
Deafness, heari ng impaired 
Eye Di so rder s 
Comm on 
Blurred vision, conjuncti vitis, conjuncti val 
haem orrhage 
Gastrointe stinal Disor der s 
Most common 
Constipation, diarrhea*, nausea, vomiti ng* 
Very common 
abdominal pain (excludi ng oral and throat) 
Comm on 
Dyspepsia, pharyngol aryngeal pain, 
gastroes ophageal refl ux, abdominal distension, 
gastritis, stomatitis, mouth ulceration, dysphagia, 
gastroint estinal haemorrhage*, lower 
gastroint estinal haemorrhage*± rectal haemorrhage 
Uncomm on 
Eructation, gastrointestinal pain, t ongue ulc eration, 
retching, upper gastrointestinal haem orrhage*, 
haem atemesis*, oral mucosal petechiae, ileus 
paralytic*, ileus, odynophagi a, enteritis, colitis, 
oesophagitis, enterocolitis, diarrhea haemorrhagic, 
acute pancreatitis*, intestinal obstruction 
General Disor der s and Administration Site Condition s 
Most common 
Fatigue, pyrexia 
Very common 
Chills, oedema peri pheral, asthenia 
Comm on 
Neural gia, lethargy, malaise, chest pai n, mucosal 
inflammation* 
Uncomm on 
Inj ection site pain, injection site irrit ation, injection 
site phlebitis, general physical health deteri oration*, 
catheter-related com plication 
Hepatobiliary Disorder s 
Uncomm on 
Hyperbilirubi naemia, hepatitis*
Immune System Di sorder s 
Uncomm on 
Drug hypersensiti vity, angi oedem a 
Infection s and Infestation s 
Very common 
Upper respiratory tract infection, nasopharyngitis, 
pneumonia*, Herpes zoster* 
Comm on 
Lower respiratory tract infection*, sinusitis, 
 
 
23 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
Table -1 
Known Anticipated Risks of BORTEZOMIB by MedDRA System 
Organ Class, Observed Incidence, and Preferred Term 
 
System Organ Class 
Ob served Incidence 
Preferred Term 
pharyngitis, oral candidi asis, urinary tract infection*, 
sepsis, bactaeremia*, cellulitis, Herpes simplex, 
bronchitis, gastroent eritis*, infection 
Uncomm on 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung 
infection, infusion site cellulitis, catheter site 
cellulitis, infusion site infection, urosepsis*, 
Aspergill osis*, tinea infection, Herpes zoster 
ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic , varicella, 
empyem a, fungal oesophagitis
Injury, Poisoning, and Procedural Complications 
Comm on 
Fall 
Uncomm on 
Subdural haem atom a 
Investigation s 
Comm on 
Weight decreased, alani ne ami notransferase (ALT) 
increased, aspartate aminotransferase (AS T) 
increased, blood alkaline phosphatase increased, 
li ver function test abnormal, bl ood creatini ne 
increased* 
Uncomm on 
Gamma-gl utamyltransferase (GGT) increased, 
oxygen saturation decreased*, bl ood albumin 
decreased, ej ection fraction decreased* 
Metabolism and Nutritional Di sorder s 
Very common 
Decreased appetite, anorexia, dehydration* 
Comm on 
Hyperglycaemi a, hypoglyca emia, hyponatraemi a, 
hypokalaemia, hypercalcaemia* 
Mu sculo skeletal and Connective Tissue Di sorder s 
Very common 
Bone pain, myalgia, arthralgia, back pain 
Comm on 
Muscular weakness 
Uncomm on 
Limb discom fort 
Neoplasm s, Benign, Malignant, and Unspecified (including cysts and polyp s) 
Uncomm on 
Tumour lysis syndrome* 
Nervou s System Di sorder s 
Most common 
Peripheral neuropat hy (includi ng all preferred terms 
under the M edDRA High -level term Peripheral 
neuropathy NE C) 
Very common 
Paresthesia, dizziness excluding vertigo, headache 
Comm on 
Polyneuropathy, syncope, dysesthesia, dysgeusia, 
postherpetic neural gia 
Uncomm on 
Convulsion, loss of consciousness, ageusia, 
encephal opat hy, paralysis*,autonomic neuropathy, 
reversibl e posterior l eukoencephal opat hy 
s yndrom e
Psychiatric Di sorder s 
Very common 
Anxiety, insomnia 
Comm on 
Confusional state 
Uncomm on 
Deliri um 
 
 
 
24 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
Table -1 
Known Anticipated Risks of BORTEZOMIB by MedDRA System 
Organ Class, Observed Incidence, and Preferred Term 
 
System Organ Class 
Ob served Incidence 
Preferred Term 
Renal and Urinary Di sorder s 
Comm on 
Renal impai rment*, renal failure*, haematuria 
Uncomm on 
Micturition disorder 
Respiratory, Thoracic, and Mediastinal Disor der s 
Very common 
Cough, dyspnoea 
Comm on 
Epistaxis, dyspnoea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary oedema
Uncomm on 
Hem optysis*, acute respirat ory distress syndrom e*, 
respiratory failure*, pneum onitis*, lung infiltration, 
pulmonary al veolar haemorrhage*, interstitial lung 
disease*, pulm onary hypertensi on*, pleurisy, 
pleuritic pain 
Skin and Subcutaneous Ti ssue Di sorder s 
Very common 
Rash 
Comm on 
Rash pruritic, rash erythem atous, urticari a, 
petechiae 
Uncomm on 
Cutaneous vasculitis, leukocytoclastic vasculitis 
Vascular Di sor der s 
Comm on 
Hypotension*, orthostatic hypotensi on 
Uncomm on 
Cerebral haem orrhage* 
Source:  BORTE ZOM IB Investigator‘s Brochure Edition 14. 
Most common =  30%, Very common = 10% to 29%, Comm on = 1% to 9%, Uncomm on = < 1%. 
*  Fatal outcom es have been reported. 
  Indicates a Preferred term not listed in the source table, however the event is deemed medically 
important and so is included. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
25 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
Table -2 
Reports of Adverse Reactions From 
Postmarketing Experience 
System Organ Class 
Preferred Term 
Blood and lymphatic system disorder s 
Ob served 
Incidence 
a 
Disseminated intravascular coagul ation 
Rare 
Cardiac Disorder s 
Atrioventricul ar b lock complete 
Rare 
Cardiac tamponade 
Rare 
Ear and labyrinth disorder s 
Deaf ness b ilateral 
Rare 
Eye Di so rder s 
Ophthalmic herpes                                           Rare 
Optic neuropathy                                             Rare 
Blindness                                                         Rare 
Gastrointe stinal Disor der s 
Acute pancreatitis 
Rare 
Ischemic colitis 
Rare 
Hepatobiliary disorder s 
Hepatitis 
Uncomm on 
Liver failure 
Unknown 
Infection s and infestation s 
Herpes meningoencephalitis  
Rare 
Septic shock 
Rare 
Immune System Di sorder s 
Angioedem a 
Rare 
Nervou s System Di sorder s 
Autonomic neuropathy 
Rare 
Dysautonomia 
Unknown 
Encephalopathy 
Rare 
Respiratory, thoracic and mediastinal 
diso rder s: 
Acute diffuse infiltrative pulmonary 
disease
b
 
Acute respiratory distress syndrom e 
Rare 
 
 
Rare 
(ARDS) 
 
 
Interstitial pneumoni a                                      Rare 
Lung infiltration                                                 Rare 
Pneum onitis                                                      Rare 
Pulmonary hypertension                                  Rare 
 
 
 
 
 
 
 
 
 
 
 
26 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
Table -1 
Known Anticipated Risks of BORTEZOMIB by MedDRA System 
Organ Class, Observed Incidence, and Preferred Term 
 
System Organ Class 
Ob served Incidence 
Preferred Term 
Skin and subcutaneou s system disorder s 
Acute feb rile neutrophilic derm atosis 
Unknown 
Toxic epi dermal necrol ysis 
Unknown 
Source:  BORTE ZOM IB Investigator‘s Brochure Edition 14. 
a  Incidence is assigned using the foll owi ng convention:   very 
common ( 1/10); common (  1/100 and  1/10); uncom mon (
1/1000 and  1/100); rare ( 1/10,000 and  1/1000 ); very rare 
( 1/10, 000, including isol ated rep orts). 
b  Acute diffuse infiltrati ve pulmonary disease is a MedDRA L ow er 
Level Term whic h corresponds to a Preferred Term of Int erstitial 
lung disease. 
 
Other medical events of interest that are considered not causally related to BORTEZOMIB 
include hepatic failure and QT prolongation.  Fatal outcomes have been reported. 
Women of childbearing potential should avoid becoming pregnant while being treated with 
BORTEZOMIB.  Genotoxicity testing has shown that BORTEZOMIB is negative in the in vitro 
Ames assay and in the in vivo micronucleus assay, but it is a clastogen in the in vitro 
chromosomal aberration assay. 
Additional details on the potential risks of BORTEZOMIB may be found in the current Investigator‘s 
Brochure. 
5.1.7 Pre paration, Handling, Storage, and Return of Bortezomib 
 
 
Bortezomib will be supplied by Millenium Pharmaceuticals, Inc. for this study. 
 
Vials containing lyophilized BORTEZOMIB (Velcade®) for Injection should be stored according to 
the label requirements.  For the United States, store at USP Controlled Room Temperature which 
is 25ºC (77ºF); for Europe, do not store above 30ºC (86ºF); excursions permitted from 15 to 30ºC 
(59-86ºF).  To date, stability data indicate that the lyophilized drug product is stable for at least 18 
months when stored under the recommended conditions.  Stability studies are ongoing, and 
Millennium Pharmaceuticals, Inc. will notify the investigator should this information be revised 
during the conduct of the study. 
 
BORTEZOMIB is cytotoxic.  As with all cytotoxic drugs, caution is required when preparing and 
handling BORTEZOMIB solutions.  Cytotoxic drugs should only be handled by staff specially 
trained in the safe handling of such preparations.  The use of gloves and other appropriate 
protective clothing is recommended.  In case of skin contact, wash the affected area immediately 
and thoroughly with soap and water for at least 15 minutes.  If product contacts eye, immediately 
flush eye thoroughly with water for at least 15 minutes.  Always contact a physician after any form 
of body contact.  All materials that have been used for preparation should be disposed of 
according to standard practices.  A log must be kept of all disposed materials. 
 
Drug is available in sterile, single-use vials containing 3.5 mg of BORTEZOMIB.  Each vial of 
BORTEZOMIB should be reconstituted under a laminar flow biological cabinet (hood) within 8 
hours before dosing with 3.5 mL of normal (0.9%) saline, Sodium Chloride Injection USP, so that 
the reconstituted solution contains BORTEZOMIB at a concentration of 1 mg/mL.  Prior to 
reconstitution the vials should remain in the cartons to protect them from light.  Dissolution is 
completed in approximately 10 seconds.  The reconstituted solution is clear and colorless, with a 
 
 
27 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
final pH of 5 to 6. Reconstituted BORTEZOMIB should be administered promptly and in no case 
more than 8 hours after reconstitution. 
 
BORTEZOMIB ( Velcade®) for Injection is a sterile lyophilized powder for reconstitution and is 
supplied in vials containing BORTEZOMIB and mannitol at a 1:10 ratio.  For example, vials 
containing 3.5 mg of BORTEZOMIB contain 35 mg of mannitol. 
 
Administration 
Drug will be administered only to eligible patients under the supervision of the investigator or 
identified sub-investigator(s).  Patients may be treated on an outpatient basis, if possible. 
The drug will be prepared under the supervision of a pharmacist, or appropriately qualified and 
trained personnel.  The amount (in mg) of drug to be administered will be determined bas ed on 
body surface area.  Body surface area is to be calculated based on body weight using a standard 
nomogram or calculation.  The dose should be calculated on Day 1 of each cycle; the dose 
administered should remain the same throughout each cycle but should be recalculated at the 
start of the next cycle.  If a patient experiences a notable change in weight within a cycle, as 
determined by an unscheduled weight assessment, then the patient‘s dose should be 
recalculated at that time based on clinical judgment. 
 
The appropriate amount of bortezomib will be drawn from the injection vial and administered as 
an IV push over 3 to 5 seconds or the drug will be administered as a subcutaneous injection if this 
method is preferred by the treating physician. Bortezomib administered as an IV push will then be 
followed by a standard saline flush or through a running IV line.  Vials are for single-use 
administration. 
There must be at least 72 hours between each dose of bortezomib. 
BORTEZOMIB Return 
For commercially-labeled BORTEZOMIB for IND-exempt studies, please contact Millennium to 
arrange for study drug return procedures.  Any unused or expired BORTEZO MIB must be 
returned to Millennium.  Drug return activity must be documented in the drug accountability log. 
 
Millennium Study Drug Product Complaints 
A product complaint is a verbal, written, or electronic expression which implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact MedComm Solutions 
(see the following contact information below) and report the event.  Whenever possible, the 
associated product should be maintained in accordance with the label instructions pending further 
guidance from a Millennium quality representative. 
 
 
For Product Complaints, call MedComm Solutions at 
+1-866-835-2233 
 
Blinding, Packaging, and Labeling 
BORTEZOMIB will be supplied in vials as open-label stock.  Both the box label and vial label will 
fulfill all requirements specified by governing regulations. 
 
Prohibited Concurrent Therapy 
 
• 
Participation in clinical trials with other investigational agents, not included in this trial, within 
14 days of the start of this trial and throughout the duration of this trial. 
  
 
 
 
 
28 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
Treatment Compliance 
All drug will be administered to eligible patients under the supervision of the investigator or 
identified subinvestigator(s).  The pharmacist will maintain records of drug receipt (if applicable), 
drug preparation, and dispensing, including the applicable lot numbers, patients‘ height, body 
weight, and body surface area (see Appendix 20.3), total drug administered in milliliters and 
milligrams, and date and time of administration.  Any discrepancy between the calculated dose 
and dose administered and the reason for the discrepancy must be recorded in the source 
documents. 
 
Precautions and Restrictions 
It is not known what effects BORTEZOMIB has on human pregnancy or development of the 
embryo or fetus.  Therefore, female patients participating in this study should avoid becoming 
pregnant, and male patients should avoid impregnating a female partner.  Nonsterilized female 
patients of reproductive age and male patients should use effective methods of contraception 
through defined periods during and after study treatment as specified below. 
Female patients must meet 1 of the following: 
 
• Postmenopausal for at least 1 year before the screening visit, or 
 
• Surgically sterile, or 
 
• If they are of childbearing potential, agree to practice 2 effective methods of contraception 
from the time of signing the informed consent form through 30 days after the last dose of 
BORTEZOMIB, or agree to completely abstain from heterosexual intercourse. 
It is strongly recommended that at least 1 of these 2 methods be highly effective (see examples 
below). 
 
Highly effective method s 
Other effective method s (barrier methods) 
Intra-uteri ne devices (IUD) 
Latex condom 
Hormonal contracepti ves (bi rth control pills/oral 
contracepti ves, injectabl e contracepti ves, 
contracepti ve patches, or contracepti ve 
 implants)  
Diaphragm with spermicide 
Cervical cap 
Sponge 
If one of the highly effecti ve m ethods cannot be used, using 2 effecti ve methods at the same time 
is recommended. 
 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following: 
 
• Practice effective barrier contraception during the entire study treatment period and through 
a minimum of 30 days after the last dose of study drug, or completely abstain from 
heterosexual intercourse. 
5.2 
Me lphalan 
 
5.2.1  Ge neral information 
 
Generic name: Melphalan, L-phenylalanine mustard 
Commercial name: Alkeran 
Chemical name: 4-[bis(chloroethyl)-amino]-L-phenylalanine 
Melphalan is an alkylating agent coupled to an amino acid. 
  
 
 
 
 
29 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
5.2.2 Formulation 
 
The drug is supplied in a sterile 50 mg vial, prepared as a lyophilized powder with 20 mg of povidone 
per vial. Ten ml of special diluent is provided for reconstitution. The composition of the diluent is 
sodium citrate (0.20 g), Propylene glycol (6.00 ml), ethanol (95%) (0.5 ml) and sterile water. The 
constituted solution is further diluted with 0.9% sodium chloride injection USP to a final concentration 
of 0.45 mg/ml. 
 
Supplier: Celgene. 
 
ALKERAN for Injection is supplied in a carton containing one single-use 
clear glass vial of freeze-dried melphalan hydrochloride equivalent to 50mg melphalan and one 10 
ml clear glass vial of sterile diluent. 
 
5.2.3 Administration 
 
The dose is administered intravenously and IV fluids may be given before and after melphalan 
administration. Furosemide may be given 1 hour aft er IV melphalan. Intravenous melphalan will be 
used at doses of 140 and 200 mg/m2. It will be administered in a single dose on 1 day. 
 
5.3 
Pe gfilgrastim (Ne ulasta(TM)) (after stem cell transplantation) 
 
Pegfilgrastim is the pegylated form of recombinant methionyl human G-CSF (filgrastim). 
Pegfilgrastim is produced by covalently binding a 20-kilodalton (kD) monomethoxypolyethylene 
glycol molecule to the N-terminal methionyl residue of filgrastim. 
5.3.1 Formulation 
 
6 MG/0.6 ML SOL. A single fixed dose of 6 milligrams (mg) subcutaneously, given once per 
chemotherapy cycle, is effective and is recommended. 
 
Supplier: Amgen, Inc 
 
5.3.2 Storage 
The manufacturer recommends storage of Neulasta(TM) syringes at 2 to 8 degrees C (36 to 46 
degrees F), avoidance of freezing or shaking, and leaving syringes in the carton provided until time 
of use to protect from light (Prod Info Neulasta(TM), 2002). 
 
5.3.3 Contraindications 
Prior hypersensitivity to Escherichia coli-derived proteins, filgrastim, or pegfilgrastim. 
 
5.4 Re combinant human granulocyte-colony stimulating factor (NEUPOGEN®, G-CSF) (for 
ste m cell collection) 
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by recombinant DNA 
technology. NEUPOGEN® is the Amgen Inc. trademark for Filgrastim, recombinant methionyl 
human granulocyte colony stimulating factor (r-metHuG-CSF). 
NEUPOGEN® is contraindicated in patients with known hypersensitivity to E. coli-derived proteins, 
Filgrastim, or any component of the product. 
 
The only consistently observed clinical toxicity described with Neupogen® is medullary bone pain. 
Other clinical toxicities that have been described include skin rash, and cutaneous vasculitis. Since 
commercial introduction of Neupogen®, there have been rare reports of allergic-type reactions. 
Biochemical abnormalities that may occur include increases in alkaline phosphatase, uric acid, and 
lactate dehydrogenase. 
 
 
30 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
If required, NEUPOGEN® may be diluted in 5% dextrose. NEUPOGEN® diluted to concentrations 
between 5 and 15 mcg/mL should be protected from adsorption to plastic materials by addition of 
Albumin (Human) to a final concentration of 2 mg/mL. 
Do not dilute with saline at any time; product may precipitate. 
NEUPOGEN® should be stored in the refrigerator at 2-8 degrees Centigrade (36-46 degrees 
Fahrenheit). Do not freeze. Avoid shaking. Prior to injection, NEUPOGEN® may be allowed to reach 
room temperature for a maximum of 24 hours. Any vial left at room temperature for greater than 24 
hours should be discarded. 
Commercial NEUPOGEN® is available in 1 mL and 1.6 mL vials at a concentration of 300 mcg/mL. 
Discard unused portions. Use only one dose per vial; do not reenter the vial. Do not save unused 
drug for later administration 
 
5.5 
De xamethasone (D) 
 
Formulation: Supplied as 4 mg tablets. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
• 
Age > 18 
 
• 
New diagnosis of MIDD or AL amyloidosis based on pathologic findings confirmed at Memorial 
Sloan Kettering Cancer Center. 
 
• 
Patients must show the ability to understand the investigational nature of the treatment and to 
give voluntary informed consent before performance of any study-related procedure not part of 
normal medical care, with the understanding that consent may be withdrawn by the subject at 
any time without prejudice to future medical care. 
 
 
• 
Female subject is either postmenopausal for at least 1 year before the screening visit, is 
surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods 
of contraception from the time of signing the informed consent form through 30 days after the 
last dose of bortezomib, or agree to completely abstain from heterosexual intercourse. 
 
• 
Male subjects, even if surgically sterilized (i.e., status post-vasectomy) must agree to 1 of the 
following:  practice effective barrier contraception during the entire study treatment period and 
through a minimum of 30 days after the last dose of study drug, or completely abstain from 
heterosexual intercourse. 
 
• 
Adequate organ function defined as follows: Absolute granulocytes > 1,000/mm
3  and platelets > 
70,000/mm3, unless low granulocyte and platelets counts are due to multiple myeloma; total 
bilirubin < 1.5 ULN; AST, ALT, and alkaline phosphatase < 3 times upper limit of laboratory 
normal; LVEF > 50% by MUGA or ECHO (the method used at baseline must be used for later 
monitoring); DLCO > 50 % confirmed at MSKCC; elevated creatinine is not a contraindication to 
enrollment 
 
• 
Performance status (ECOG) < 2 
 
 
 
 
 
 
 
31 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
6.2 
Subject Exclusion Criteria 
• 
Patient has received other investigational drugs with 14 days before enrollment 
 
• 
Prior initial treatment chemotherapy for MIDD, AL amyloidosis or multiple myeloma with the 
exception of one cycle of high dose dexamethasone 
 
• 
Prior bortezomib treatment 
 
• 
Myocardial infarction within 6 months prior to enrollment or New York Heart Association Class III 
or IV heart failure (see Appendix 20.2), uncontrolled angina, severe uncontrolled ventricular 
arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system 
abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by 
the investigator as not medically relevant. 
 
• 
Pregnant or lactating women are ineligible.  A pregnancy tes t will be performed on each fertile 
premenopausal female 2 weeks prior to entry into the study. Treatment may not begin until t he 
results of the pregnancy test are ascertained. All patients (men and women) must agree to use 
medically approved contraceptive measures for at least 4 weeks before starting therapy, during 
therapy, and for at least 3 months after therapy has stopped. 
 
• 
Pre-existing neuropathy, sensory or neuropathic pain findings, grade 2 or higher on the NC I CTC 
neurotoxicity scale. 
 
• 
Concurrent active malignancy other than non-melanoma skin cancers or carcinoma-in-situ of the 
cervix. Patients with previous malignancies, but which have not required anti-tumor treatment 
within the preceding 24 months will be allowed to enter the trial. Patients with a history of a T1a 
or b prostate cancer (detected incidentally at TURP and comprising less than 5% of resected 
tissue) may participate if the PSA has remained within normal limits since TURP. 
 
• 
Patients with known HIV positivity or AIDS-related illness. This is based upon the possibility of 
increasing HIV viral load with therapy 
 
• 
Any other medical condition or reason that, in the principal investigator's opinion, makes the 
patient unsuitable to participate in a clinical trial 
 
 
• 
Patients with a history of hypersensitivity reactions attributed to bortezomib, boron, or mannitol. 
 
• 
Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require 
concurrent radiotherapy (which must be localized in its field size) should be deferred until the 
radiotherapy is completed and 3 weeks have elapsed since the last date of therapy. 
 
 
7.0 
RECRUITMENT PLAN 
This study will be conducted at MSKCC. Patients, community hematologists/oncologists, and 
nephrologists, will be informed of this trial by the MSKCC website. Efforts will be made to ensure 
that women and minority groups are adequately represented in this trial. All patients will be seen 
by MSKCC Hematology physicians and associated MSKCC co-investigators and enrolled at 
MSKCC and registered through MSKCC. All co-investigators agree to follow the treatment in the 
 
 
 
32 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
protocol and to conduct the proposed investigation according to recognized principles of good 
clinical practice. Participation is voluntary. Each patient must be informed about the neoplastic 
nature of his/her disease and willingly consent to participation in this study. Every patient will be 
informed of the procedures to be followed, the potential benefits, side effects, risks, discomforts 
of the trial and of potential therapeutic alternatives. All participants will be required to sign 
statements of informed consent and research authorization that conform to FDA, IRB and HIPAA 
guidelines. Informed consent will be documented by the use of a written consent form that has 
been approved by the MSKCC IRB. 
8.0 
PRETREATMENT EVALUATION 
The following tests will be performed within 2 weeks prior to patient enrollment: 
• History & Physical exam, grading for neuropathy, height and weight for BSA, and NC I CTC 
Scoring 
• Serum M-spike studies: Serum protein electrophoresis (SPEP), serum immunofixation (IF) 
and quantitative immunoglobulins, and serum free light chain assay 
• Urine M-spike studies: Twenty-four hour urine for total volume and total protein (TV, TP), 
immunofixation (IF), protein electrophoresis (UPEP), and creatinine clearance 
• Serum for electrolytes, BUN, creatinine, albumin, beta2-microglobulin, C-reactive protein, 
total bilirubin, ALT, AST, LD H, alkaline phosphatase (AP), calcium, CBC with differential, 
INR/PTT, and β-HCG for women of childbearing potential, BNP, and troponin. 
• Stool for Guaiac Testing – for patients with suspicion of GI involvement 
 
 
The following tests will be performed within eight weeks prior to patient enrollment: 
• Echocardiogram or MUGA scan, and electrocardiogram (EKG) 
• Pulmonary function test (PFTs) 
• EMG/Nerve conduction studies for patients with suspected nerve involvement 
• Cardiac MR I for patients with clinically significant cardiac involvement 
• Liver Ultrasound for patients with expected liver involvement 
• Hepatitis A, B, C serologies and HIV 1/2 test (unless previously negative at MSKCC within 
the last six months) 
• A skeletal survey that should be reviewed at MSKCC if not performed at MSKCC 
• Bone marrow examination, including biopsy sample for H & E stain and 
immunohistochemical staining for CD 138, CD20, kappa and lambda light chains; bone 
marrow aspirate samples for Giemsa staining, flow-cytometry, cytogenetic analysis, and 
FISH analysis for chromosomes 1, 4, 11, 13, 14, 17 abnormalities 
 
The following test will be performed within 12 weeks prior to patient enrollment: 
• Organ biopsy (kidney, heart, GI etc…) to confirm the diagnosis of MIDD or AL amyloidosis 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1      Tre atment Plan 
There are three treatment phases to this protocol. 
9.1.1    Initial treatment phase: During this phase, the patients will receive treatment as 
outpatients and will be followed in the clinic on a regular basis as shown in the schedule 
below. The patients will receive one to three 21-day-cycles consisting of the following 
combination: 
 
 
 
33 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
Bortezomib 1.3 mg/m2IV or SQ on days 1, 4, 8, and 11 as a bolus injection 
Dexamethasone 40 mg IV or PO on days 1, 4, 8, and 11 
Drugs will be administered only to eligible patients under the supervision of the investigator 
or identified sub-investigator(s).  Patients will be treated on an out-patient basis. The 
pharmacist will prepare the drugs under aseptic conditions.  The amount (in mg) of drug to 
be administered will be determined based on body surface area.  Body surface area is to be 
calculated based on adjusted body weight (ABW ) using standard MSKCC nomogram. The 
dose should be calculated on Day 1 of each cycle; the dose administered should remain the 
same throughout each cycle but should be recalculated at the start of the next cycle. 
The appropriate amount of bortezomib will be drawn from the injection vial and administered 
as an intravenous (IV) push over 3 to 5 seconds. This injection will be followed by a standard 
saline flush or through a running IV line. Vials are for single use administration. 
Prophylaxis therapy will be initiated at the start of treatment to prevent treatment-related 
toxicity and will include the following: B-complex vitamin supplement PO containing at least 
50 mg of vitamin B6 (pyridoxine) daily; Prilosec 20 mg daily or equivalent; Bactrim DS, 1 
tablet PO, daily, three days a week; Diflucan 100 mg PO, daily, and Acyclovir 400 mg PO, 
twice a day. Doses will be adjusted for renal function. 
Toxicity and response will be assessed after every cycle of treatment, before the next cycle 
and at the completion of the 3 cycles as shown on the schedule below, section 10.1. 
Patients who achieve CR before completion of 3 cycles may forego the remaining cycle(s) 
and proceed to phase 2 of treatment. If at any point in time during this phase of treatment a 
patient shows evidence of progression of multiple myeloma with confirmation, (s)he will be 
taken off study. All other patients will proceed with the second phase of treatment. Dose 
adjustments and modifications will be made as shown in the section below entitled ―dose 
adjustments and modifications‖. 
 
9.1.2 HDM/ASCT phase: After 3 cycles of BD, patients without progression of disease 
(POD) will proceed with stem cell mobilization and collection as per institutional guidelines.  . 
A leukapheresis catheter will be placed during that admission if deemed necessary for stem 
cell collection. Leukapheresis will begin as per the SOP of the Blood Donor Room stem cell 
collection process. Once stem cell collection begins, a target of 10 x 10 6 CD34+ cells per kg 
will be sought, allowing the collection of adequate stem cells for up to three stem cell 
transplants in a patient's lifetime. We will seek a minimal acceptable collection of 2-4 x 10
6 
CD34+ cells per kg, allowing one to two ASCT procedures with the minimum acceptable 
dose of 2 x 10
6 CD34+ cells/kg, per SCT. Patients failing to collect the minimum dose may be 
mobilized a second time as per MSKCC guidelines. Patients who are mobilized twice and 
have less than 2 million stem cells (CD34+ cells) collected per kg, will be removed from 
study. The likelihood of this happening is less than 2%. Blood stem cells will be 
cryopreserved according to standard operating procedures of the Cytotherapy Laboratory. 
For HD M/ASCT, patients will be admitted to the hospital. High-dose melphalan will be 
administered in a single day -2, or split on two consecutive days on days -3 and -2 through a 
central venous catheter. Melphalan will be administered at a risk adapted dose of 100, 140 or 
200 mg/m2  using adjusted ideal body weight (AIBW) and based on risk group and age as 
follows: 
 
 
 
 
 
 
34 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
o For patients with no evidence of cardiac involvement and creatinine clearance > 
51ml/min, the dose of IV melphalan will be 200 mg/m
2  if the patient is < 60 years old, 
140 mg/m2  if 61 to 70, and 100 mg/m2  if > 71. 
  
o For patients with early cardiac amyloid and/or creatinine clearance < 51ml/min, the 
dose of IV melphalan will be 140 mg/m2  with stem cell support if the patient is < 60, 
and 100mg/m2  if >  61. 
Stem cells will be infused on day 0. Patients will receive standard supportive care measures 
during the HD M/ASCT period as per MSKCC‘s institutional guidelines 73-75. After discharge, 
patients will be followed initially weekly, then biweekly, then monthly, depending on the 
clinical condition of the patient and as deemed necessary by the treating physician. 
The patients‘ response to the HD M/ASCT will be assessed at 12 weeks +/- 2 weeks after 
HDM/ASCT as shown on the schedule below. This assessment will include serum, urine and 
bone marrow testing. Patients without POD will proceed with the third phase of treatment. If 
at any time  post transplant a patient shows evidence of POD with confirmation, (s)he will be 
taken off study. 
 
9.1.3 Consolidation/maintenance  phase: During this phase, the patients will receive 
treatment as outpatients and will be followed in the clinic on a regular basis as shown in the 
schedule below. The patients will receive six cycles , each given once every 12 weeks +/- 2 
weeks and each consisting of the following combination: 
Bortezomib 1.3 mg/m2, IV or SQ, on days 1, 8, 15, and 22 
Dexamethasone 20 mg IV or PO, on days 1, 8, 15, and 22 
The patients‘ response will be assessed with serum and urine testing after every cycle, , and 
at the completion of the 6 cycles of treatment as shown on the schedule below. If at any point 
in time during this phase of treatment a patient shows evidence of POD with confirmation or 
unacceptable toxicity to treatment, (s)he will be taken off study. All other patients will 
complete the full 6 cycles. The patient‘s toxicity will be assessed at every encounter and 
before initiation of every cycle as shown on the schedule below. Dose adjustments and 
modifications will be made as shown in the section below entitled ―dose adjustments and 
modifications‖. 
Prophylaxis therapy will be initiated at the start of this phase of the treatment and will include 
the following: B-complex vitamin supplement PO containing at least 50 mg of vitamin B6 
(pyridoxine); Prilosec 20 mg PO, daily, or equivalent; Bactrim DS, 1 tablet PO, daily, three 
days a week; Diflucan 100 mg PO, daily; and Acyclovir 400 mg PO, twice a day. Doses will 
be adjusted for renal function. 
The end of treatment assessment (which will also coincide with the end of study- 24 month 
post-treatment assessment in the majority of patients) will occur within 4-6 weeks of 
completion of the last consolidation maintenance dose as shown on the schedule below, 
section 10.3. This assessment will include blood and urine testing as well as a bone marrow 
aspirate and biopsy. Organ responses will also be graded at this time point.  The patients will 
be followed in the clinic every 3 months thereafter as per standard practice, with no further 
intervention, until progression of disease.  Long Term Follow Up will cease when all patients 
on study have fulfilled the requirements for at least five follow up appointments. 
9.2 
Cycle De lay and Dose Modification Guidelines 
 
 
 
 
 
35 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
On the first day of each new treatment cycle and before each treatment dose, the patient will 
be evaluated for possible toxicities that may have occurred due to previous doses. Toxicities 
will be assessed according to the National Cancer Institute Common Terminology Criteria for 
Adverse  Events (NCI CTCAE), version 4.0. Cycle delays and dose modifications will be 
made based on the toxicity experienced during the previous cycle of therapy or the ones 
encountered on any of the treatment days. Doses of study drug that need to be held WITHIN 
a cycle are skipped and will not be made up later in the cycle. 
 
9.2.1 Cycle De lay 
The following parameters must be met on the first day of each cycle: 
– Platelet count ≥50 x10
9/L 
– Hemoglobin ≥8 g/dL ; prior red blood cell (RBC) transfusion or recombinant human 
erythropoietin use is allowed 
– ANC ≥1.0 x109 /L 
– Non-hematologic toxicity must have recovered to Grade 1 or baseline 
If the above parameters are not met, the start of the next cycle will be held for a week for 
recovery to the specified levels. The start of the new cycle can be delayed on a weekly basis 
(for a maximum of 3 weeks) until recovery from toxicity to a level allowing continuation of 
therapy. Delay of a new cycle for more than 3 weeks can only occur if a clear clinical benefit 
has been observed from the treatment and it is felt by the treating physician that continuation 
of treatment would be advisable. Otherwise, if there is a delay in the start of a new cycle of 
more than 3 weeks due to insufficient recovery from toxicity, subjects will discontinue study 
drug and have procedures performed as outlined for the End of Treatment phase 
assessment. 
 
9.2.2 Dose Modifications 
9.2.2.1 Dose Re duction Ste ps 
Dose escalation will not be allowed in any patient, and there must be at least 72 hours 
between each dose of bortezomib. 
Before each drug dose, the patient will be evaluated for possible toxicities that may have 
occurred after the previous dose(s). Toxicities are to be assessed according to the NC I 
CTCAE, version 4.0. All previously established or new toxicities observed any time, with the 
exception of neuropathic pain and peripheral sensory neuropathy, are to be managed as 
shown below. 
Dose reductions steps represented in the following tables for bortezomib and 
dexamethasone. Patients who have an unacceptable toxicity after 2 dose reductions due to 
any of the study drugs will discontinue that study drug. 
If the patient experiences febrile neutropenia, a grade 4 hematologic toxicity (including a 
platelet count < 25 x 109/L) or any ≥ grade 3 non-hematologic toxicity considered by t he 
investigator to be related to bortezomib, then drug needs to be held. 
If the bortezomib dose is reduced during the initial treatment phase, the starting dose of 
bortezomib during the Maintenance Treatment Phase should be similarly reduced as well. 
For example, if the bortezomib dose is reduced from 1.3 mg/m 2 to 1.0 mg/m2  in the initial 
phase of treatment, the starting dose in the maintenance phase should also be reduced from 
1.3 mg/m
2  to 1.0 mg/m
2. 
 
 
 
 
36 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
For nonhematologic toxicities, bortezomib is to be held for up to 2 weeks until the toxicity 
returns to Grade 1 or better. 
 
If the toxicity resolves, as described above, bortezomib may be restarted at the same 
schedule the patient was on prior to holding therapy, and the dose must be reduced by 
approximately 25% as follows: 
 
 
 
 
 
Dose reduction steps for bortezomib 
 
Starting Dose 
First Dose 
Re duction 
Se cond Dose 
Re duction 
Third Dose 
Re duction 
Bortezomib 1.3 mg/m2 
on Days 1, 4, 8 and 
11 
Bortezomib 1.0 
mg/m2 on 
Days 1, 4, 8 and 11 
Bortezomib 0.7 
mg/m2 on 
Days 1, 4, 8 and 11 
Bortezomib 0.7 mg/m2 
on Days 1, 8, 15, and 
22 of a 35 day 
schedule 
Bortezomib 1.3 mg/m
2
 
on Days 1, 8, 15, and 
22 
Bortezomib 1.0mg/m
2
 
on Days 1, 8, 15, and 
22 
Bortezomib 0.7 mg/m
2
 
on Days 1, 8, 15, and 
22 
Bortezomib 0.7 mg/m
2
 
on Days 1 and 15 
 
Dose reduction steps for dexamethasone 
 
Tre atment 
Phase 
Starting 
Dose 
First Dose 
Re duction 
Se cond Dose 
Re duction 
Third Dose 
Re duction 
Fourth Dose 
Re duction 
Initial 
Treatment 
Phase 
40 mg QD 
on Days 1, 
4, 8 and 11 
20 mg QD on 
Days 1, 4, 8 
and 11 
12 mg QD on 
Days 1, 4, 8 
and 11 
4 mg QD on 
Days 1, 4, 8, 
and 11 
Discontinue 
dexamethasone 
Maintenance 
Treatment 
Phase 
20 mg QD 
on Days 1, 
8, 15, and 
22 
12 mg QD on 
Days 1, 8, 15, 
and 22 
4 mg QD on 
Days 1, 8, 15 
and  22 
Discontinue 
dexamethasone 
N/A 
 
9.2.2.2 Dose Modifications for Bortezomib-Related He matologic Toxicity 
 
 
On any day of bortezomib administration during a cycle, other than Day 1 of each cycle, the 
hematology results must be: 
– Platelet count ≥30 x109/L 
– ANC ≥0.75 x109/L 
If the above parameters are not met, the bortezomib dose will be skipped; the dose will not 
be made up later in the cycle. 
If in the previous cycle, 2 or more of the 4 doses of bortezomib were skipped due to 
hematologic toxicity, the dose of bortezomib will be reduced in the following cycles by one 
step. 
  
 
37 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
Dose (re-)escalations of bortezomib are not allowed. 
 
 
9.2.2.3 Dose Modifications for Bortezomib-Related Ne uropathy 
The neurotoxicity-directed questionnaire (see appendix 20.1) is a useful tool for determining 
the presence and intensity of neuropathic pain and/or peripheral neuropathy from the 
patient‘s perspective.  Neuropathic symptoms are more prominent than abnormalities on the 
clinical examination.  After the patient completes the neurotoxicity-directed questionnaire, the 
questionnaire should be reviewed to assist with the evaluation of the onset and intensity of 
peripheral neuropathy and other neuro-toxicities that may possibly require intervention or 
dose modification. The table below contains the recommended dose modification for the 
management of subjects who experience BORTEZOMIB-related neuropathic pain and/or 
peripheral neuropathy. 
 
 
Recommended Dose Modification for BORTEZOMIB related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy 
Severity of Peripheral Neuropathy 
Signs and Symptoms 
Modification of Dose and Regimen 
Grade 1 (paresthesias, weakness 
and/or loss of reflexes) 
without pain or loss of function 
No action 
Grade 1 with pain or Grade 2 
(interfering with function but not with 
activities of daily living) 
Reduce BORTEZOMIB by one level 
Grade 2 with pain or Grade 3 
(interfering with activities of daily 
living) 
Withhold* BORTEZOMIB therapy until 
toxicity resolves. 
When toxicity resolves reinitiate with 
a reduced dose of BORTEZOMIB by 
one dose level and change treatment 
schedule to once per week. 
Grade 4 (Sensory neuropathy which 
is disabling or motor neuropathy that 
is life threatening or leads to 
paralysis) 
Discontinue BORTEZOMIB 
Grading based on NC I Common Terminology Criteria CTCAE v4.0 
NCI Common Terminology Criteria website - http://ctep.info.nih.gov/reporting/ctc.html 
ADL = activities of daily living 
*Key: 
Reduce by one dose level: See above tables for reduction levels for bortezomib. 
Hold:  Interrupt BORTEZOMIB for up to 3 weeks until the toxicity returns to Grade 1 or better. 
9.2.2.5 Dose Modifications for Other Non-hematologic Toxicity 
If a patient experiences any Grade 3 or 4 non- hematologic toxicity (excluding neuropathy as 
discussed above) considered by the investigator to be related to study drug(s), then the 
treatment regimen will be held until the intensity of the side effect decreases to Grade 1 or 
baseline. After recovery from toxicity to a level allowing continuation of therapy, a dose level 
 
 
 
38 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
reduction should be instituted for bortezomib.  A dose reduction for corticosteroids should 
occur only for Grade 3 or 4 corticosteroid-related toxicities. 
Patients with cardiac toxicity: If during treatment the LVEF falls below normal limits of the 
institution, or the ejection fraction (LVEF) falls by 20% from the baseline level, bortezomib will 
be discontinued. The investigator may verify the LVEF from a MUGA by obtaining an ECHO 
with cardiac consultation. If there is no evidence of cardiac damage determined by ECHO the 
patient may continue on treatment. Treatment with bortezomib should be discontinued in 
subjects who experience new onset symptomatic congestive heart failure, or if they 
experience cardiac dysfunction as indicated by symptomatic arrhythmia, a decrease in LVEF 
to below the institutional lower limit of normal, or an absolute decrease of 15% or more from 
the subject‘s baseline value (e.g. 60% to 45%). 
Patients with mild hepatic impairment (bilirubin ≤ 1.5 x ULN) do not require a starting dose 
adjustment.  Please note that patients with bilirubin levels > 1.5 ULN are excluded from enrollment in 
this protocol.  If a patient develops moderate or severe hepatic impairment with bilirubin ≥ Grade 2 (> 
1.5 - 3.0 x ULN) while on study, the investigator should hold BORTEZOMIB until the toxicity returns 
to < Grade 2. Restarting BORTEZOMIB at the next lower dosed level could be considered at the 
Investigator‘s discretion and following exclusion of BORTEZOMIB-induced liver impairment and 
careful consideration of liver disease due to other causes, such as, but not limited to, active infection 
and multiple myeloma-related liver disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
39 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
10.1 
Ev aluation During the Initial Treatment Phase 
 
Study Proce dures 
Scree ning 
Period 
Tre atment period 
End of Initial 
Tre atment a 
D -14 to -1 
Day1
g
 
Day 4 
Day 8 
Day 11 
Inf ormed Consent 
X 
History, Complete Physical (including orthostatics) 
X 
X 
X 
interval history, physical - symptom-directed 
X 
X 
Weight 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Concomitant meds, supportive Rx assessment 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
Electrocardiogram 
X
b
 
Echocardiogram 
X
b
 
Cardiac MRI 
X
h, b
 
PFTs 
X
b
 
Neurologic Examination 
X 
X 
X 
Stool f or Guaiac Testing 
X 
i
 
EMG/ Nerve conduction studies 
X
e, b
 
Liver Ultrasound 
X
f, b
 
Skeletal Survey 
X
b
 
Karnof sky Perf ormance Status 
X 
X 
X 
Serum Mu ltiple Myeloma Disease Assessment 
• 
protein electrophoresis 
• 
Quantitative immunoglobulins 
• 
Immunof ixation 
• 
Serum Free Light Chains 
X 
X 
X 
24 hour Urine Multiple Myelo ma Disease 
assessment 
• 
protein electrophoresis 
• 
Immunof ixation 
• 
Total protein 
• 
Creatinine clearance 
X 
X 
X 
Bone Marrow Aspirate and Biopsy f or: 
• 
Morphology 
• 
Cytogenetics/FISH 
X
b, j
 
X 
Organ biopsy 
X
d
 
CBC 
X 
X 
X 
X 
X 
X 
Electrolytes 
X 
X 
X 
Glucose 
X 
X 
X 
BUN, Creatinine 
X 
X 
X 
Total protein 
X 
X 
X 
ALT, AST, LDH, Bil, AP 
X 
X 
X 
Albumin 
X 
X 
X 
Calciu m 
X 
X 
X 
 2-microglobulin 
X 
X 
X 
C-reactive protein 
X 
X 
X 
Urinalysis 
X 
X 
X 
Serum  -HCG Pregnancy Test 
X
c
 
X
c
 
BNP 
X 
X 
X 
 
 
40 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
Troponin 
X 
X 
X 
HIV/hepatitis A, B and C tests 
X
b
 
Bortezomib Dosing 
X 
X 
X 
X 
Dexamethasone 
X 
X 
X 
X 
Study Procedure s 
Pre- 
HDM /ASCT
a,b 
Post- 
HDM /ASCT
a,c
 
History, Complete Physical 
X 
X 
interval history, physical - symptom-directed 
X 
X 
Concomitant meds, supportive Rx assessment 
X 
X 
Adverse event assessment 
X 
X 
Chest X-ray 
X 
Electrocardiogram 
X 
Echocardiogram 
X 
Weight 
X 
X 
Vital signs 
X 
X 
Karnof sky Perf ormance Status 
X 
X 
Serum Mu ltiple Myeloma Disease Assessment 
• 
protein electrophoresis 
• 
Quantitative immunoglobulins 
• 
Immunof ixation 
• 
Serum Free Light Chains 
X 
X 
24 hour Urine Multiple Myelo ma Disease assessment 
• 
protein electrophoresis 
• 
Immunof ixation 
• 
Total protein 
• 
creatinine clearance 
X 
X 
Bone Marrow Aspirate and Biopsy f or: 
• 
Morphology 
• 
Cytogenetics/FISH 
Xd 
X 
CBC 
X 
X 
Electrolytes 
X 
X 
Glucose 
X 
X 
BUN, Creatinine 
X 
X 
Total protein 
X 
X 
ALT, AST, LDH, Bil, AP 
X 
X 
Albumin 
X 
X 
Calciu m 
X 
X 
 2-microglobulin 
X 
X 
C-reactive protein 
X 
X 
Urinalysis 
X 
X 
Serum  -HCG Pregnancy Test 
X 
BNP 
X 
X 
Troponin 
X 
X 
Inf ectious Disease Testing
a
 
X 
  
 
 
 
 
 
 
 
aWithin 4 w eeks of completion of initial treatment; bw ithin 8 w eeks of registration; cf or w omen of childbearing potential; dw ithin 12 w eeks 
of registration; ef or patients w ith suspected nerve involvement; ff or patients w ith expected liver involvement; gstudy procedures 
excluding Vital signs, AE assessment, CBC, and Pregnancy test can be completed ≤ 10 days prior to Day 1 of treatment; hf or patients 
w ith clinically signif icant cardiac involvement; If or patients w ith suspicion of GI involvement if clinically indicated 
10.2 Evaluation During HDM/ASCT Treatment Phase 
The management and evaluation during the transplant admission itself will be performed 
as per standard operati ng procedures i n use currently at MSKCC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aall tes t obtained as per s tandard MSKCC trans plantation SOP; bThes e tes ts can be part of the end of initial 
treatm ent phas e evaluation; cThes e tes ts will be obtained 12 w eeks +/- 2 w eeks pos t ASCT; dPer MSK SOP 
 
 
 
 
 
 
 
 
 
 
 
41 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3 Evaluation During the Maintenance Treatment Phase and beyond 
 
Study Procedure s 
Tre atme nt period 
12 month 
Ev aluation 
End of 
Tre atme nt 
Phase (and 
at 24 
months) 
Long 
te rm 
Follow up 
(every 3 
months) 
Day1 
d
 
Day 8 
Day 
15 
Day 
22 
History, Complete Physical (including 
orthostatics) 
X 
X 
X 
X 
interval history, physical - symptom- 
directed 
X 
X 
X 
X 
Concomitant meds, supportive Rx 
assessment 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Neurologic Examination 
X 
X 
X 
X 
EMG/ Nerve conduction studies 
X
bg
 
X
b
 
X
b
 
Liver Ultrasound 
X
c g
 
X
c
 
X
c
 
Karnof sky Perf ormance Status 
X 
X 
X 
X 
Electrocardiogram 
X 
X 
Echocardiogram 
X 
X 
Cardiac MRI 
X
f
 
X
f
 
X
a, f
 
Serum Mu ltiple Myeloma Disease 
Assessment 
• 
protein electrophoresis 
• 
Quantitative immunoglobulins 
• 
Immunof ixation 
• 
Serum Free Light Chains 
X 
X 
X 
X 
24 hour Urine Multiple Myelo ma 
Disease assessment 
• 
protein electrophoresis 
• 
Immunof ixation 
• 
Total protein 
X 
X 
X 
X 
Bone Marrow Aspirate and Biopsy f or: 
• 
Morphology 
• 
Cytogenetics/FISH 
X
h
 
X
h
 
X
a, h
 
CBC 
X 
X 
X 
X 
X 
X 
X 
Electrolytes 
X 
X 
X 
X 
Glucose 
X 
X 
X 
X 
BUN, Creatinine 
X 
X 
X 
X 
Total protein 
X 
X 
X 
X 
ALT, AST, LDH, Bil, AP 
X 
X 
X 
X 
Albumin 
X 
X 
X 
X 
Calciu m 
X 
X 
X 
X 
 2-microglobulin 
X 
X 
X 
X 
C-reactive protein 
X 
X 
X 
X 
Urinalysis 
X 
X 
Serum  -HCG Pregnancy Test 
X
e
 
BNP 
X 
X 
X 
X 
Troponin 
X 
X 
X 
X 
Bortezomib Dosing 
X 
X 
X 
X 
Dexamethasone 
X 
X 
X 
X 
 
 
 
42 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
aThis test w ill be obtained yearly ; bf or patients w ith suspected nerve involvement; cf or patients w ith expected liver involvement; dStudy 
procedures excluding Vital signs, AE assessment, CBC, and Pregnancy test can be completed ≤ 10 days prior to Day 1 of treatme nt; 
ef or w omen of childbearing potential; ff or patients w ith clinically signif icant cardiac involvement; g Testing to be done on Day 1 Cycle 1, 
12 months and 24 months only if clinically indicated; hper MSK SOP. 
 
 
 
 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
For toxicity scoring we will use NC I CTC Version 4.0 
(http://ctep.cancer.gov/reporting/ctc.html). 
 
11.1 
Borte zomib 
 
Most Common Bortezomib Risks: 
 
The most common risks are those that have occurred in greater than or equal to 30% of patients 
who have received bortezomib: 
• 
Feeling weak, tired, and generally uncomfortable 
• 
gastrointestinal effects such as constipation, diarrhea, nausea, vomiting, and loss of appetite. 
These may result in dehydration and/or weight loss 
• 
fever commonly with shaking chills 
• 
painful feelings or numbness and tingling in hands and feet, which may not get better after 
stopping bortezomib. Uncommonly, the nerves that control things like your heart rate, gut 
movement and urinary bladder may be affected 
• 
lowered platelets;  that may increase the chance of bleeding 
• 
lowered red cells or anemia which may make you feel tired 
 
Very Common Bortezomib Risks: 
 
The very common risks are those that have occurred in 10-29% of patients who have received 
bortezomib: 
• Neutropenia uncommonly associated with fever; commonly lymphopenia or anemia, 
leukopenia and thrombocytopenia at the same time 
• flu-like symptoms and other upper respiratory tract infections, such as chills, sore throat, and 
runny nose and sinus and throat infections 
• abdominal pain 
• aches and pains in muscles and joints, pain in bones and in arms , back and legs 
• Peripheral edema. 
• cough, feeling short of breath, lung infections including pneumonia and commonly bronchitis 
• headache 
• skin rash with itching and redness.  An uncommon risk is a severe, life-threatening or deadly 
rash with skin peeling and mouth sores. 
• Herpes virus infections such as Herpes Zoster) and herpes simplex virus Herpes Zoster can 
sometimes spread over large parts of the body.  Both may also affect the eyes or brain, but 
this is uncommon 
• Anxiety 
• Insomnia 
• Myalgia 
• Chills 
• Dehydration 
• Dizziness 
 
 
 
 
43 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
Common Bortezomib Risks: 
 
Common risks are those that have occurred in 1-9% of patients who have received bortezomib: 
• 
Hypotension that can commonly cause light headedness and orthostatic symptoms 
• 
Arrhythmias that can cause you to possibly light-headedness, dizziness, fainting, dyspnea, 
and/or chest pain.  This may also cause confusion.  An uncommon risk is a possible life 
threatening arrhythmia 
• 
new or worsening heart failure that can uncommonly be severe. 
• 
infection and/or inflammation of the eye or eyelids 
• 
painful sores of the mouth and/or throat, which may make swallowing difficult 
• 
heartburn, acid reflux  and stomach bloating 
• 
severe bleeding, including bleeding in the stomach and intestines (gut) that may be linked with 
low platelet counts, and blood clotting changes.  Uncomm only, this bleeding may cause bloody 
diarrhea and/or hematemesis. 
• 
epistaxis 
• 
Renal insufficiency; renal failure 
• 
infections of the bladder, sinuses, throat, stomach and intestines, skin and at the area of catheter 
insertion. 
• 
fungal infections in the mucous membrane such as the mouth and throat and uncommonly in the 
skin and nails 
• 
life-threatening infections in the blood (sepsis) 
• 
changes in blood sugar have been reported  in a few diabetic patients who took oral antidiabetic 
medicine. 
• 
Hematuria 
• 
Confusion 
• 
Dysgeusia 
• 
abnormal liver function tests and decreased level of serum total protein and albumin 
• 
Hypokalemia,  and hyponatremia, and hypercalcemia 
• 
Muscular weakness 
• 
Weight decreased 
• 
Muscle spasms 
• 
Gastrointestinal hemorrhage 
• 
IleusNeuralgia 
 
Uncommon bortezomib Risks: 
 
Uncommon risks are those that have occurred in less than 1% of patients who have received 
bortezomib: 
• Inflammation, pleural effusions, empyema that may cause breathing problems, and can be 
life-threatening or lead to death. Pulmonary hypertension has also been reported.  This can 
cause breathing problems and can be life-threatening. 
• Pericarditis that may cause chest pain or breathing problems and can be life-threatening or 
lead to death. 
• hepatitis, and liver failure (in patients who also got many drugs and had other serious 
medical problems). 
• pain, redness, swelling and infection in the area of the skin where bortezomib is injected into 
the vein 
• pain in the mouth and throat when swallowing 
• loss of hearing 
• intestinal obstruction that may reverse spontaneously and inflammation of the intestines, 
pancreas or stomach 
• Hemoptysis 
 
 
44 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
• 
bleeding in the brain and subdural hematoma 
• 
Tumor lysis syndrome 
• 
allergic reactions that may include skin, swelling of the face or throat and could be severe or 
life threatening 
• 
severe muscle weakness and paralysis 
• 
changes to the brain that may cause convulsions and confusion 
• 
reversible posterior leukoencephalopathy syndrome that may cause headaches, changes in 
vision, mental status, or seizures, but is usually reversible 
• 
loss of some to all vision affecting one or both eyes, which may be caused by damage to the 
nerve in the eye. Loss of vision may or may not be reversible. 
• 
Gastrointestinal perforation 
• 
Adult respiratory distress syndrome 
• 
Cardiac failure 
 
 
 
11.2 
De xamethasone 
The major potential side effects of dexamethasone are well described and well known. 
Gastrointestinal prophylaxis will be given to minimize GI upset. Antibiotic and antifungal 
prophylaxis will be given. Patients who experience toxicity from dexamethasone therapy may 
have the dose reduced as detailed in section 9.2. 
 
Most Likely S ide Effects: 
• 
Hyperglycemia, worsening of diabetes, or cause diabetes 
• 
Insomnia 
• 
Fluid retention and anasarca 
• 
Hypokalemia 
• 
Immunodeficiency. This could lead to more frequent infections, which could be severe. Old 
infections such as tuberculosis may recur. 
• 
Adrenal insufficiency on withdrawal 
 
 
Very Likely Side Effects: 
• 
Mood swings, psychosis, personality changes, and/or depression 
• 
Leukocytosis 
• 
Nausea, vomiting, 
• 
Increased appetite and weight gain, or paradoxically loss of appetite and weight loss 
• 
Headache; dizziness; seizures 
 
 
Likely Side Effects: 
• 
Hiccups 
• 
Hirsutism involving the face or other parts of the body 
• 
Acne, and/or rosacea 
• 
Increased sweating; bruising; trouble healing wounds 
• 
Menstrual cycle disruption 
• 
Infertility in men 
• 
Hypertension 
• 
Opthalmic complications: 
o Cataracts 
 
 
45 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
o Increased pressure inside the eye 
o Protrusion of the eyeballs 
o Glaucoma. 
These may cause decreased vision, blindness, or eye pain. 
• 
Cushing syndrome 
• 
Osteoporosis 
• 
Thrombosis 
• 
Capillary fragility leading to ecchymoses 
 
Uncommon Side Effects: 
• 
Steroid myopathy, which may be severe 
• 
Increased pressure inside your skull 
• 
GI complications including ulcers, esophagitis, gastritis, which may lead to bleeding 
complications 
• 
Pancreatitis 
• 
Rash, including redness of the skin, hives, itching, and swelling of the skin, face, or throat 
11.3 Me lphalan 
The major systemic toxicity of IV melphalan is bone marrow depression with secondary 
anemia, leukopenia and thrombocytopenia.  This side-effect is exacerbated by prior 
chemotherapy or radiotherapy. 
Side-effects include: 
Likely 
• 
Low blood cell counts (bone marrow suppression) that can lead to anemia that 
requires red blood cell transfusions; a decreased number of white blood cells that 
increases the risk of infections and is treated with G-CSF injections and with stem 
cells; and low platelets that increases the risk of bruising and bleeding and is treated 
with platelet transfusions. 
• 
Fatigue 
• 
Nausea, vomiting 
• 
Hair loss (temporary) 
• 
Mouth sores 
• 
Pain in the mouth requiring pain medicines 
• 
Pain with swallowing requiring pain medicines 
• 
Diarrhea and cramping 
 
Less likely 
• 
Liver damage 
• 
Allergic reactions (which could make you feel short of breath and/or have a skin rash) 
 
Rare but serious 
• Secondary leukemia 5 to 10 years after exposure 
• Lung damage 
• Blood vessel damage 
• Red blood cell damage due to an immune reaction 
• Death 
  
11.4  Ne ulasta and Neupogen (G-CSF) 
 
 
Side-effects of Neupogen include: 
 
 
 
46 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
Likely 
• Body aches 
• Pain, swelling and redness at the site of injection 
• Bone pain 
• Transient and reversible changes in alkaline phosphatase, uric acid and LDH 
• Exacerbation of preexisting autoimmune disorders 
• Fever 
• Muscle cramps and pain in your back or legs (relieved by taking Tylenol) 
 
 
Less likely 
• Inflammation, psoriasis or arthritis may get worse 
Rare but serious 
• Decreased blood pressure and risk of falling 
• Enlargement of the spleen that may lead to rupture 
• Hair thinning 
• Decreased blood platelets which may increase your risk of bruising or bleeding 
• Enlargement of the liver 
• Allergic reactions 
  
11.5 Risks and side effects during stem cell mobilization specifically associated 
with PLERIXAFOR 
Likely side effects of plerixafor 
• Erythema at the injection site 
• Nausea 
• Headache 
 
 Less Likely side effects of plerixafor 
• Dysesthesia in different parts of the body 
• Burning and swelling at the injection site 
• Diarrhea 
• Dizziness 
• Chest tightness 
• Abdominal distension 
• Abdominal pain 
All of these symptoms were mild and went away after treatment. 
Rare but serious 
• Severe decrease in blood platelet count after six days of intravenous infusion of plerixafor 
was described in one patient with HIV.  The patient's platelet count returned to normal within 
four weeks after the infusion. 
• Tachycardia and orthostasis, which can be associated with irregular heartbeats. 
 
11.6  R isks and side effects during stem cell mobilization specifically 
associated with CYCLOPHOSPHAMIDE 
 
Likely side e ffects of c yclop hosp hamide: 
 
 
47 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
• Pancytopenia 
• Fatigue 
• Hair loss 
• Nausea and vomiting 
• Hemorrhagic cystitis 
• Male i nfertility 
 
Rare b ut serious side effects o f c yc lophosp hamide: 
• Myocarditis that may result in decrease in ejection fraction 
• Pneumonitis 
• Hyponatremia 
• Bladder cancer 
• Allergic skin reactions 
• Secondary leukemia 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 
Measurement of Safety Outcome 
The primary endpoint of this study is assessment of toxicity/tolerability at the completion of 
the treatment. Toxicities will be assessed according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. All subjects will be 
evaluated for the presence of treatment related toxicity during active treatment at the end of 
each cycle as described above in section 9.1.  Safety measurements also will be evaluated 
by physical examination findings, vital signs assessments, clinical laboratory test results, and 
adverse events. Cycle delays and dose modifications will be made based on the toxicity 
experienced during the previous cycle of therapy or the ones encountered on any of the 
treatment days as described above in section 9.2. All adverse events will be reported as 
described in section 17.2 below. Comprehensive assessments of any apparent toxicity 
experienced by the subject will be performed throughout the course of the study.  Study 
center personnel will record all adverse events, whether observed by the Investigator or 
reported by the subject, on the CRF.  A physician (either the Principal Investigator or a 
physician designated by the Principal Investigator) will manage and treat any treatment- 
emergent toxicity. 
 
12.1 
He matologic Re sponse 
The hematologic response to any of the treatment cycle, treatment phase, and 
comprehensive treatment will be assessed by widely accepted standard response criteria 
detailed below. These are based on measurement of the monoclonal immunoglobulin in the 
serum and urine. Bone marrow plasmacytosis and skeletal survey are also used in these 
response criteria to confirm complete response and progression of disease as detailed in the 
table below. Serum studies include protein electrophoresis, immunofixation, quantitative 
immunoglobulin, and free light chain determination. Urine studies include 24 hour urine 
collection for protein electrophoresis, immunofixation, and total protein. All these tests will be 
performed as detailed in tables in section 10.0. The response scored within 4 weeks after the 
conclusion of all therapy is the one of the secondary endpoints of this study. 
A Response Review Group that includes a pathologist, a Clinical laboratory scientist, and 
several Hematologists from the Hematology Service will formally score the response. The 
 
 
 
48 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
group meets every Tuesday. Research study assistants prepare patient data for review and 
record response decisions. Usually the response to therapy is straightforward although there 
are instances in which the multiple tests used give somewhat equivocal results. Hence, the 
value of group reviews. 
 
 
RESPONSE 
CRITERIA FOR RESPONSE 
COMPLETE RESPONSE (CR) 
Requires all of the following: 
• 
Normalization of the free light chain (FLC) 
levels and ratio 
• 
Negative serum and urine immunofixation 
• 
<5% plasma cells in bone marrow 
VERY GOOD PARTIAL RESPONSE 
(VGPR) 
• 
Reduction in the dFLC (difference between 
involved [iFLC] and uninvolved FLC) to 
<4mg/dl 
PARTIAL RESPONSE (PR) 
• 
> 50% reduction in the dFLC 
NO RESPONSE (NR) 
• 
Less than PR 
PROGRESSION OF DISEASE (POD) 
Requires one or more of the following: 
• 
From CR, any detectable monoclonal protein 
or abnormal free light chain ratio (light chain 
must double) 
• 
From PR, 50% increase in serum M protein 
to >0.5g/dl or 50% increase in urine M 
protein to >200mg/day (a visible peak must 
be present) 
• 
Free light chain increase of 50% to >10mg/dl 
 
12.2    Organ Re sponse 
12.2.1  Amyloidosis Organ Re sponse 
Organ response criteria in AL amyloidosis have been well established by consensus panel 
and  widely  used  in  the  literature.  The  tests  and studies  listed  in  section  10.0  will  be 
performed as shown in the schedule to measure organ response using the criteria detailed 
below. Amyloid-related organ involvement will be scored as improved, stable or worsened at 
the completion of every phase of treatment. 
• 
Improvement of one or more affected organ(s) is defined by: 
Kidne ys: a 50% reduction in 24-hour urine protein excretion in the absence of progressive 
renal insufficiency (defined as 25% worsening of creatinine and creatinine clearance) which 
has to be at least 0.5 g/24hr. 
He art: a reduction of the BNP or NT-pro-BNP by 30% from baseline. 
Live r: a 50% decrease of an initially elevated alkaline phosphatase level or reduction in the 
size of the liver by at least 2 cm by imaging. 
Ne uropathy: 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. 
 
 
• 
Worsening of one or more affected organ(s) is defined by: 
 
 
 
49 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
Kidne ys: doubling  of urinary 24 hour  total  protein if <3 g/24  hours  at baseline, or  50% 
increase in urinary protein loss if > 3 g/24 hours, or reduction of creatinine clearance by > 
50%, or increase in serum creatinine of > 2 mg/dL. 
He art: evidence of decrease in ejection fraction by > 10% or increase of the BNP or NT-pro- 
BNP by > 30% from baseline or increase of Troponin by 33%. 
Live r: >50% increase in the alkaline phosphatase level above lowest value. 
Ne uropathy: 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. 
 
12.2.2  MIDD Organ Response 
It is important to highlight that the renal response criteria (since this is the organ that is by far 
the most affected and most often the only organ affected) for patients with MIDD has not 
been clearly characterized in the literature and much work needs to be done along this line. 
Some authors have borrowed the renal response criteria used for amyloidosis to assess the 
renal response in MIDD. However, we believe that there is a striking difference between 
these two diseases. In amyloidosis, renal injury mostly leads to the nephrotic syndrome and 
marked proteinuria, while renal clearance is preserved until very advanced stages of the 
disease. This is why the renal response is assessed based on the proteinuria in this disease. 
Conversely, in patients with MIDD, the main clinical feature of the disease is the decrease in 
the renal clearance. Protein wasting nephropathy is a less prominent component, usually 
reaching mild to moderate levels, and is highly variable. While 96% of the patients have renal 
insufficiency, only 40% have nephrotic range proteinuria. Furthermore, with worsening of the 
renal injury and renal filtration in MIDD, proteinuria usually decreases and no longer reflects 
the worsening pace of the disease. Overall, in MIDD the degree of proteinuria does not 
necessarily reflect the severity of the disease at presentation, and subsequent changes in 
proteinuria may be difficult to interpret. On the other hand, the creatinine clearance is a more 
reliable parameter that always reflects the renal state in this disease. 
In summary, we believe that the amyloid criteria for renal respons e cannot be used for MIDD 
We believe that the only valid parameters for response measurement in MIDD are the 
creatinine and the creatinine clearance or GFR. These parameters will be used to measure 
the renal outcome in this clinical trial. 
Renal response in MIDD will be scored as improved, stable or worsened at the completion of 
every phase of treatment. 
• Progression of renal disease is defined as a decrease in the creatinine clearance by 
more than 50%. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
Patients will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care.  The investigator also has the right to 
withdraw and in some cases is required to withdraw patients from the study for any of the 
following reasons: 
• 
If at any time during the treatment, a patient shows evidence of hematologic disease progression 
with confirmation 
 
 
 
50 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
• 
If at any time a patient develops unacceptable toxicity 
• 
If there is protocol violation 
• 
Non-compliance 
• 
Administrative reasons 
• 
Failure to return for follow-up 
• 
General or specific changes in the patient‘s condition unacceptable for further treatment in the 
judgment of the investigator 
14.0 
BIOSTATISTICS 
This is a pilot study to examine the tolerability, toxicity, and efficacy of 1-3 cycles of BD, 
followed by HD M/ASCT, and maintenance therapy with BD in patients with MIDD and 
patients with AL amyloidosis.  Twenty patientswill be accrued to the study.  Toxicities will be 
tabulated by type and severity.  Stopping rules for treatment-related mortality and grade 3 or 
4 neurotoxicity will be employed to monitor the tolerability of the regimen.  Patients will be 
followed for neurotoxicity while on treatment.  Stopping rules and the corresponding power 
calculations are provided in the table below.  The calculations for the stopping boundaries 
are based on the assumption that the endpoints are independent. 
 
 
Endpoint 
# events needed 
to stop the study 
Projected probability 
of toxicity in the 
popul ation 
Probability of s tudy 
completion (bas ed on 
proj ection) 
Treatm ent Mort ality 
3 in the fi rst 8 patients 
4 in the fi rst 14 patients 
5 in the fi rst 20 patients 
0.10 
0.92 
0.30 
0.20 
Grade 3/4 Neurotoxicity 
2 in the fi rst 10 patients 
3 in the fi rst 20 patients 
0.06 
0.83 
0.20 
0.17 
 
The hematologic and organ response rates at the end of treatment and at 24 months post 
treatment will be estimated along with their corresponding 95% confidence intervals . With 20 
patients, the response rates can be estimated to within +/- 22%.  Time to hematologic 
progression from start date of therapy will be calculated using the Kaplan-Meier method. 
Approximately one patient will be accrued per month so accrual will last approximately 20 
months.  The study duration will last approximately 4 years. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Re search Participant Re gistration 
 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000.. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
 
 
 
 
51 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.2 
Randomization 
There is no randomization in this clinical trial 
 
 
 
16.0 
DAT A M AN AGEMENT ISSUES 
All patients will be enrolled on protocol at Memorial Sloan-Kettering Cancer Center. We 
expect to be able to enroll the necessary 20 patients into this study in 2 years. 
The data manager (Research Study Assistant, RSA) will be responsible for confirming 
eligibility and assisting the MD with the registration process. All study data will be collected 
by an assigned RSA who will enter this information into the Clinical Research Database 
(CRDB). This database will be utilized for data collection and storage and for reporting 
protocol specific events such as accrual demographics, toxicities and adverse events to the 
IRB, and the sponsor. 
The RSA will collect toxicity and concomitant medication information and patient interviews. 
Adverse events, including all toxic effects of treatment will be tabulated individually according 
to severity or toxicity grade. The data manager will als o monitor laboratory testing throughout 
the study. Laboratory data will be tabulated and summarized by descriptive statistics, as well 
as on the basis of MSKCC specified normal ranges. 
 
16.1 
Quality Assurance 
Monthly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates, extent and accuracy of evaluations and follow -up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action. 
Random sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
 
 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled ―Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials‖ which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
 
 
 
52 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center‘s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NC I cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
17.0 
PROTECTION OF HUMAN SUBJECTS 
  
17.1 
Priv acy 
 
 
MSKCC‘s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form.  The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form.  A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
 
The investigator will grant monitor(s) and auditor(s) from Millennium and regulatory 
authority(ies) access to the patient‘s original medical records for verification of data gathered 
on the data capture records and to audit the data collection process.  The patient‘s 
confidentiality will be maintained and will not be m ade publicly available to the extent 
permitted by the applicable laws and regulations. 
 
17.2 
Se rious Adverse Event (SAE) Re porting 
 
 
Adv e rse Events De finition 
 
 
An adverse event is any unfavorable or unintended sign, symptom or disease temporally 
associated with the use of medical treatment or procedure regardless of whether it is 
considered related to the medical treatment or procedure.  Adverse events will be captured 
and reported at each protocol visit per the Memorial Sloan Kettering Cancer Center Adult 
Bone Marrow Transplant (BMT) Adverse Event (AE) and Serious Adverse Event (SAE) 
Guide. 
 
The following adverse events will be captured and should have corresponding source 
documentation in the medical record: 
- 
Laboratory data, grades 3-4 (automatically captured through CRDB) 
- 
Unexpected grades 1-5 
- 
Expected grades 2-5 (unless specified in table one of the MSK Adult BMT AE and 
SAE Guide) 
 
 
Se rious Adverse Event De finition 
 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
 
 
 
 
 
53 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant‘s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‗Reporting of Serious 
Adverse Events‘, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to saemskind@mskcc.org. 
  
For all other trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‘s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
 
 
 
54 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
o A explanation of how the AE was handled 
o A description of the subject‘s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The PI‘s signature and the date it was signed are required on the completed report. 
 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, t he 
report will be forwarded to the FD A by the SAE staff through the IND Office 
 
17.2.1  Procedures for AE and SAE Re porting: Millennium requirements 
All serious adverse events (SAEs) (regardless of expectedness, causality, and whether 
commercial or investigational BORTEZOMIB is used) must be reported to Millennium 
Pharmacovigilance (or designee).  See below for the reporting of SAEs. 
The sponsor-investigator is responsible to meet all regulations and requirements applicable 
to the sponsor-investigator. 
 
Adverse events (AEs) may be spontaneously reported by the patient and/or in response to 
an open question from study personnel or revealed by observation, physical examination, or 
other diagnostic procedures.  AEs which are serious must be reported to Millennium 
Pharmacovigilance (or designee) from first dose of bortezomib up to and including 30 days 
after administration of the last dose of bortezomib.  When possible, signs and symptoms 
indicating a common underlying pathology should be noted as one comprehensive event. 
Any SAE that occurs at any time after completion of bortezomib treatment or after the 
designated follow-up period that the investigator and/or sub-investigator considers to be 
related to any study drug must be reported to the Millennium Pharmacovigilance (or 
designee).  Planned hospital admissions or surgical procedures for an illness or disease that 
existed before the patient was enrolled in the trial are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was performed 
earlier or later than planned).  All SAEs should be monitored until they are resolved or are 
clearly determined to be due to a patient‘s stable or chronic condition or intercurrent 
illness(es). 
 
This is an investigator-initiated study.  The principal investigator, Dr. Hani Hassoun (who may 
also sometimes be referred to as the sponsor-investigator), is conducting the study and 
acting as the sponsor. Therefore, the legal/ethical obligations of the principal investigator 
include both those of a sponsor and those of an investigator. 
 
Sponsor-investigator must report all SAEs, regardless of expectedness or relationship with 
any study drug, to Millennium Pharmacovigilance (or designee) as soon as possible, but no 
later than 5 calendar days of the sponsor-investigator‘s observation or awareness of the 
event.  In the event that this is a multisite study, the sponsor-investigator is responsible to 
ensure that the SAE reports are sent to Millennium Pharmacovigilance (or designee) from all 
sites participating in the study.  Sub-investigators must report all SAEs to the sponsor- 
investigator so that the sponsor-investigator can meet his/her foregoing reporting obligations 
to Millennium Pharmacovigilance, unless otherwise agreed between the sponsor-investigator 
and sub-investigator(s).  Millennium Pharmacovigilance (or designee) may request follow -up 
information to a reported SAE, which the sponsor-investigator will be responsible for 
providing to Millennium Pharmacovigilance (or designee). 
 
 
 
55 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
The SAE report must include event term(s), serious criteria, and the sponsor-investigator‘s or 
sub-investigator‘s determination of both the intensity of the event(s) and the relationship of 
the event(s) to study drug administration. 
 
Intensity for each SAE, including any lab abnormality, will be determined by using the NC I 
CTCAE 4.0, as a guideline, whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
 
Relationship to all study drugs for each SAE will be determined by the sponsor-investigator 
or sub-investigator by responding yes or no to the question: Is there a reasonable possibility 
that the AE is associated with the study drug(s)? 
 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study or study drug(s), 
including, but not limited to, telephone conversation logs, as soon as possible but no later 
than 5 calendar days of such communication. 
 
 
 
Millennium Pharmacovigilance 
SAE and Pre gnancy Re porting Contact Information: 
North Ame rica 
PPD, Inc. 
Safe ty and Medical Management, US 
Fax: +1 888-488-9697 
Hotline number (available 24/7): 1-800-201-8725 
 
 
Millennium Pharmaceuticals will send to the sponsor-investigator BORTEZOMIB safety 
letters (real-time safety letters and/or the quarterly safety updates). All safety letters 
pertaining to the BORTEZOMIB program will be sent to the Investigator-Sponsor via an 
electronic distribution using Mercury, the Millennium Secure File Transfer (MFT) system. For 
each safety letter distributed, Sponsor-Investigator will receive an e-mail inviting to download 
the Adobe/PDF document from Mercury. 
To meet GCP requirements, Millennium is required to send Sponsor-Investigators the safety 
letters within 15 days after the world-wide receipt date of the safety event.  Sponsor- 
Investigators responsibility is to read the safety letter, and provide the safety letter to the 
Institutional Review Board or Ethics Committee per institution‘s policy. Sponsor-investigator 
will be responsible for forwarding such reports to any sub-investigator(s). 
Monitoring of Adv erse Events and Pe riod of Observation 
Adverse events, both serious and non-serious, and deaths that occur during the patient‘s 
study participation will be recorded in the source documents.  All SAEs should be monitored 
until they are resolved or are clearly determined to be due to a patient‘s stable or chronic 
condition or intercurrent illness(es). 
 
Proce dures for Re porting Drug Exposure During Pre gnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and must permanently discontinue study 
drug(s).  All pregnancies and suspected pregnancies must be reported to Millennium 
Pharmacovigilance (or designee; see Section 17.2.1 for contact information) immediately. 
The pregnancy must be followed for the final pregnancy outcome (i.e., delivery, still birth, 
 
 
 
56 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
miscarriage) and Millennium Pharmacovigilance will request this information from the 
investigator. 
 
If a female partner of a male patient becomes pregnant during the male patient‘s participation 
in this study, this must be reported to Millennium Pharmacovigilance (or designee) 
immediately (see Section 17.2.1 for contact information).  Every effort should be made to 
follow the pregnancy for the final pregnancy outcome. 
 
17.3 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on 
Harmonization (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory 
requirement(s).  The sponsor-investigator will be thoroughly familiar with the appropriate use 
of the drug as described in the protocol and Investigator‘s Brochure.  Essential clinical 
documents will be maintained to demonstrate the validity of the study and the integrity of the 
data collected.  Master files should be established at the beginning of the study, maintained 
for the duration of the study and retained according to the appropriate regulations.  This is 
the responsibility of the sponsor-investigator. 
 
17.4 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration 
of Helsinki).  The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will 
review all appropriate study documentation in order to safeguard the rights, safety and well- 
being of the patients.  The study will only be conducted at sites where IRB/IEC approval has 
been obtained.  The protocol, Investigator‘s Brochure, informed consent, advertisements (if 
applicable), written information given to the patients (including diary cards), safety updates, 
annual progress reports, and any revisions to these documents will be provided to the 
IRB/IEC by the investigator.  Millennium requests that informed consent documents be 
reviewed by Millennium or designee prior to IRB/IEC submission. 
 
17.5 
Patie nt Information and Informed Consent 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from 
Research Risk Reports:  Protection of Human Subjects (Code of Federal Regulations 45 
CFR46).  They must be followed to comply with FDA regulations for the conduct and 
monitoring of clinical investigations. 
 
17.6 
Institutional Review 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects 
(Code of Federal Regulations 45 CFR 46). 
 
17.6 
Patie nt Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, 
study reports, and communications will identify the patient by initials and the assigned patient 
number.  The investigator will grant monitor(s) and auditor(s) from Millennium and regulatory 
authority(ies) access to the patient‘s original medical records for verification of data gathered 
on the data capture records and to audit the data collection process.  The patient‘s 
confidentiality will be maintained and will not be made publicly available to the extent 
permitted by the applicable laws and regulations. 
 
 
 
 
 
 
 
57 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
17.7 
Protocol Compliance 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies). 
Changes to the protocol will require approval from Millennium and written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed 
to eliminate an immediate hazard(s) to patients.  The IRB/IEC may provide, if applicable 
regulatory authority(ies) permit, expedited review and approval/favorable opinion for minor 
change(s) in ongoing studies that have the approval /favorable opinion of the IRB/IEC.  The 
investigator will submit all protocol modifications to Millennium and the regulatory 
authority(ies) in accordance with the governing regulations. 
 
Any departures from the protocol must be fully documented in the source documents. 
 
17.8 
On-site Audits 
Regulatory authorities, the IEC/IRB and/or Millennium may request access to all source 
documents, data capture records, and other study documentation for on-site audit or 
inspection.  Direct access to these documents must be guaranteed by the investigator, who 
must provide support at all times for these activities. 
 
17.9 
Drug Accountability 
Accountability for the drug at all study sites (including all subsites, if applicable) is the 
responsibility of the sponsor- investigator.  The investigator will ensure that the drug is used 
only in accordance with this protocol.  Drug accountability records indicating the drug‘s 
delivery date to the site (if applicable), inventory at the site (if applicable), use by each 
patient, and return to Millennium will be maintained by the s ite and/or subsites. 
Accountability records will include dates, quantities, lot numbers, expiration dates (if 
applicable), and corresponding registered patient numbers. 
 
All material containing bortezomib will be treated and disposed of as hazardous was te in 
accordance with governing regulations. 
 
17.10   Product Complaints 
A product complaint is a verbal, written, or electronic expression which implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Indiv iduals who 
identify a potential product complaint situation should immediately contact MedComm 
Solutions (see the following) and report the event.  Whenever possible, the associated 
product should be maintained in accordance with the label instructions pending further 
guidance from a Millennium quality representative. 
For Product Complaints, call MedComm Solutions at 
+1-866-835-2233 
 
 
17.11   Pre mature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the sponsor-investigator or 
Millennium, there is sufficient reasonable cause.  Written notification documenting the reason 
for study termination will be provided to the sponsor-investigator or Millennium by the 
terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
o Determination of unexpected, significant, or unacceptable risk to patients 
o Failure to enter patients at an acceptable rate 
o Insufficient adherence to protocol requirements 
 
 
 
58 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
o Insufficient complete and/or evaluable data 
o Plans to modify, suspend, or discontinue the development of the drug 
 
17.12   Re cord Retention 
The sponsor-investigator will maintain all study records according to ICH-GCP and 
applicable regulatory requirement(s). 
 
 
 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
59 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2005 
19.0 
REFERENCES 
1. 
Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 
 
2. 
Smith A, Wisloff F, Samson D: Guidelines on the diagnosis and management of 
multiple myeloma 2005. Br J Haematol 132:410-51, 2006 
3. 
NCCN: NCCN, National Comprehensive Cancer Network, Clinical Practice Guidelines 
in Oncology- Multiple Myeloma. 2006 
4. 
Barlogie B, Shaughnessy J, Tricot G, et al: Treatment of multiple myeloma. Blood 
103:20-32, 2004 
5. 
Fermand JP, Katsahian S, Divine M, et al: High-dose therapy and autologous blood 
stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 
years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin 
Oncol 23:9227-33, 2005 
6. 
Jagannath S, Durie BG, Wolf J, et al: Bortezomib therapy alone and in combination 
with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 
129:776-83, 2005 
7. 
Richardson P, Chanan-Khan, A, Schlossman, R, Munshi, N, Oaklander,A.L., Heffner, 
L., Hassoun, H. Avigan, D. Amato,A. Anderson, K: Multicenter Phase 2 Study of Bortezomib in 
Previously Untreated Multiple Myeloma (MM); Encouraging Single-agent Activity and Tolerability 
Despite High Rates of Baseline Peripheral Neuropathy. Blood 106, 2005 
8. 
Dispenzieri A, Blood, E., Vesole, D., Fonseca, R., Callender, N., Pr, G.,  : A phase II 
study of PS-341 for patients with high risk, newly diagnosed multiple myeloma: A trial of the ECOG 
group (E2A02). Blood 106, 2005 
9. 
Harousseau JL, Attal M, Leleu X, et al: Bortezomib plus dexamethasone as induction 
treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple 
myeloma: results of an IFM phase II study. Haematologica 91:1498-505, 2006 
10. 
Wang M, Giralt S, Delasalle K, et al: Bortezomib in combination with thalidomide- 
dexamethasone for previously untreated multiple myeloma. Hematology 12:235-9, 2007 
11. 
Wang M, Weber DM, Delasalle K, et al: Thalidomide-dexamethasone as primary 
therapy for advanced multiple myeloma. Am J Hematol 79:194-7, 2005 
12. 
Mateos MV, Hernandez JM, Hernandez MT, et al: Bortezomib plus melphalan and 
prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 
study. Blood 108:2165-72, 2006 
13. 
Mateos MV, Hernandez JM, Hernandez MT, et al: Bortezomib plus melphalan and 
prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and 
prognostic factors for time to progression. Haematologica 93:560-5, 2008 
14. 
Oakervee HE, Popat R, Curry N, et al: PAD combination therapy (PS-341/bortezomib, 
doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J 
Haematol 129:755-62, 2005 
15. 
Popat R, Oakervee HE, Hallam S, et al: Bortezomib, doxorubicin and dexamethasone 
(PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up. Br J 
Haematol 141:512-6, 2008 
 
 
 
60 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
16. 
Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of 
autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe 
Francais du Myelome. N Engl J Med 335:91- 7., 1996 
17. 
Child JA, Morgan GJ, Davies FE, et al: High-dose chemotherapy with hematopoietic 
stem-cell rescue for multiple myeloma. N Engl J Med 348:1875-83, 2003 
18. 
Lenhoff S, Hjorth M, Holmberg E, et al: Impact on survival of high-dose therapy with 
autologous stem cell support in patients younger than 60 years with newly diagnosed multiple 
myeloma: a population-based study. Nordic Myeloma Study Group. Blood 95:7-11., 2000 
19. 
Badros A, Barlogie B, Siegel E, et al: Results of autologous stem cell transplant in 
multiple myeloma patients with renal failure. Br J Haematol 114:822-9, 2001 
20. 
Pineda-Roman M, Tricot G: High-dose therapy in patients with plasma cell dyscrasias 
and renal dysfunction. Contrib Nephrol 153:182-94, 2007 
21. 
Bird JM, Fuge R, Sirohi B, et al: The clinical outcome and toxicity of high-dose 
chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and 
severe renal impairment: a British Society of Blood and Marrow Transplantation study. Br J 
Haematol 134:385-90, 2006 
22. 
Carlson K: Melphalan 200 mg/m2 with blood stem cell support as first-line myeloma 
therapy: impact of glomerular filtration rate on engraftment, transplantation-related toxicity and 
survival. Bone Marrow Transplant 35:985-90, 2005 
23. 
Attal M, Harousseau JL, Leyvraz S, et al: Maintenance therapy with thalidomide 
improves survival in patients with multiple myeloma. Blood 108:3289-94, 2006 
24. 
Spencer A PH, Roberts A, et al.: Thalidomide improve survivals when use after ASCT 
Hematologica 92, 2007 
25. 
Abdelkefi A, Ladeb S, Torjman L, et al: Single autologous stem -cell transplantation 
followed by maintenance therapy with thalidomide is superior to double autologous transplantation in 
multiple myeloma: results of a multicenter randomized clinical trial. Blood 111:1805- 10, 2008 
26. 
McCarthy PL, Owzar K, Stadtmauer EA, et al: Phase III Intergroup Study of 
Lenalidomide (CC-5013) Versus Placebo Maintenance Therapy Following Single Autologous Stem 
Cell Transplant for Multiple Myeloma (CALGB 100104): Initial Report of Patient Accrual and Adverse 
Events. ASH Annual Meeting Abstracts 114:3416-, 2009 
27. 
Attal M, Harousseau JL, Marit G, et al: Lenalidomide After Autologous 
Transplantation for Myeloma: First Analysis of a Prospective, Randomized Study of the Intergroupe 
Francophone Du Myelome (IFM 2005 02). ASH Annual Meeting Abstracts 114:529-, 2009 
28. 
Ladetto M, Pagliano G, Ferrero S, et al: Major tumor shrinking and persistent 
molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in 
patients with autografted myeloma. J Clin Oncol 28:2077-84, 2010 
29. 
Pozzi C, D'Amico M, Fogazzi GB, et al: Light chain deposition disease with renal 
involvement: clinical characteristics and prognostic factors. Am J Kidney Dis 42:1154-63, 2003 
30. 
Buxbaum J, Gallo G: Nonamyloidotic monoclonal immunoglobulin deposition disease. 
Light-chain, heavy-chain, and light- and heavy-chain deposition diseases. Hematol Oncol Clin North 
Am 13:1235-48, 1999 
31. 
Buxbaum JN, Genega EM, Lazowski P, et al: Infiltrative nonamyloidotic monoclonal 
immunoglobulin light chain cardiomyopathy: an underappreciated manifestation of plasma cell 
dyscrasias. Cardiology 93:220-8, 2000 
32. 
Croitoru AG, Hytiroglou P, Schwartz ME, et al: Liver transplantation for liver rupture 
due to light chain deposition disease: a case report. Semin Liver Dis 26:298-303, 2006 
33. 
Popovic M, Tavcar R, Glavac D, et al: Light chain deposition disease restricted to the 
brain: The first case report. Hum Pathol 38:179-84, 2007 
34. 
Toor AA, Ramdane BA, Joseph J, et al: Cardiac nonamyloidotic immunoglobulin 
deposition disease. Mod Pathol 19:233-7, 2006 
35. 
Pozzi C, Locatelli F: Kidney and liver involvement in monoclonal light chain disorders. 
Semin Nephrol 22:319-30, 2002 
 
 
 
 
61 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
36. 
Michopoulos S, Petraki K, Petraki C, et al: Light chain deposition disease of the liver 
without renal involvement in a patient with multiple myeloma related to liver failure and rapid fatal 
outcome. Dig Dis Sci 47:730-4, 2002 
37. 
Terashima K, Takahashi K, Kojima M, et al: Kappa-type light chain crystal storage 
histiocytosis. Acta Pathol Jpn 28:111-38, 1978 
38. 
Lin J, Markowitz GS, Valeri AM, et al: Renal monoclonal immunoglobulin deposition 
disease: the disease spectrum. J Am Soc Nephrol 12:1482-92, 2001 
39. 
Dhodapkar MV, Merlini G, Solomon A: Biology and therapy of immunoglobulin 
deposition diseases. Hematol Oncol Clin North Am 11:89-110, 1997 
40. 
Heilman RL, Velosa JA, Holley KE, et al: Long-term follow-up and response to 
chemotherapy in patients with light-chain deposition disease. Am J Kidney Dis 20:34-41, 1992 
41. 
Firkin F, Hill PA, Dwyer K, et al: Reversal of dialysis-dependent renal failure in light- 
chain deposition disease by autologous peripheral blood stem cell transplantation. Am J Kidney Dis 
44:551-5, 2004 
42. 
Royer B, Arnulf B, Martinez F, et al: High dose chemotherapy in light chain or light 
and heavy chain deposition disease. Kidney Int 65:642-8, 2004 
43. 
Sakakima M, Fujigaki Y, Tsuji T, et al: High dose chemotherapy and stem cell support 
in a patient of light- and heavy-chain deposition disease with abnormal marrow cell surface antigens 
and no monoclonal protein. Intern Med 44:970-4, 2005 
44. 
Weichman K, Dember LM, Prokaeva T, et al: Clinical and molecular characteristics of 
patients with non-amyloid light chain deposition disorders, and outcome following treatment with 
high-dose melphalan and autologous stem cell transplantation. Bone Marrow Transplant 38:339-43, 
2006 
45. 
Salant DJ, Sanchorawala V, D'Agati VD: A case of atypical light chain deposition 
disease--diagnosis and treatment. Clin J Am Soc Nephrol 2:858-67, 2007 
46. 
Lorenz EC, Gertz MA, Fervenza FC, et al: Long-term outcome of autologous stem 
cell transplantation in light chain deposition disease. Nephrol Dial Transplant, 2008 
47. 
Hassoun H, Flombaum C, D'Agati VD, et al: High-dose melphalan and auto-SCT in 
patients with monoclonal Ig deposition disease. Bone Marrow Transplant 42:405-12, 2008 
48. 
Kyle RA, Gertz MA: Primary systemic amyloidosis: clinical and laboratory features in 
474 cases. Semin Hematol 32:45-59, 1995 
49. 
Skinner M, Anderson J, Simms R, et al: Treatment of 100 patients with primary 
amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am 
J Med 100:290-8, 1996 
50. 
Kyle RA, Gertz MA, Greipp PR, et al: Long-term survival (10 years or more) in 30 
patients with primary amyloidosis. Blood 93:1062-6, 1999 
51. 
Kyle RA, Gertz MA, Greipp PR, et al: A trial of three regimens for primary 
amyloidosis: colchicine alone, melphalan and prednisone, and melphal an, prednisone, and 
colchicine. N Engl J Med 336:1202-7, 1997 
52. 
Gertz MA, Lacy MQ, Dispenzieri A: Myeloablative chemotherapy with stem cell 
rescue for the treatment of primary systemic amyloidosis: a status report. Bone Marrow Transplant 
25:465-70, 2000 
53. 
Kyle RA: High-dose therapy in multiple myeloma and primary amyloidosis: an 
overview. Semin Oncol 26:74-83, 1999 
54. 
Comenzo RL, Vosburgh E, Falk R H, et al: Dose-intensive melphalan with blood stem- 
cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 
patients. Blood 91:3662-70, 1998 
55. 
Gertz MA, Lacy MQ, Gastineau DA, et al: Blood stem cell transplantation as therapy 
for primary systemic amyloidosis (AL). Bone Marrow Transplant 26:963-9, 2000 
56. 
Moreau P, Leblond V, Bourquelot P, et al: Prognostic factors for survival and 
response after high-dose therapy and autologous stem cell transplantation in systemic AL 
amyloidosis: a report on 21 patients. Br J Haematol 101:766-9, 1998 
 
 
 
 
62 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
57. 
Jaccard A, Moreau P, Leblond V, et al: High-dose melphalan versus melphalan plus 
dexamethasone for AL amyloidosis. N Engl J Med 357:1083-93, 2007 
58. 
Cohen AD, Zhou P, Chou J, et al: Risk-adapted autologous stem cell transplantation 
with adjuvant dexamethasone +/- thalidomide for systemic light-chain amyloidosis: results of a phase 
II trial. Br J Haematol 139:224-33, 2007 
59.      Landau H, Hassoun H, Cohen AD, et al: Adjuvant Bortezomib and Dexamethasone 
Following Risk-Adapted Melphalan and Stem Cell Transplant in Systemic Light-Chain Amyloidosis 
(AL): A Phase II Study. ASH Annual Meeting Abstracts 114:533-, 2009 
60. 
Zonder JA, Sanchorawala V, Snyder R M, et al: Melphalan and Dexamethasone Plus 
Bortezomib Induces Hematologic and Organ Responses in AL-Amyloidosis with Tolerable 
Neurotoxicity. ASH Annual Meeting Abstracts 114:746-, 2009 
61. 
Adams J, Palombella VJ, Sausville EA, et al: Proteasome inhibitors: a novel class of 
potent and effective antitumor agents. Cancer Res 59:2615-22, 1999 
62. 
Teicher BA, Ara G, Herbst R, et al: The proteasome inhibitor PS-341 in cancer 
therapy. Clin Cancer Res 5:2638-45, 1999 
63. 
Cusack JC, Jr., Liu R, Houston M, et al: Enhanced chemosensitivity to CPT-11 with 
proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res 
61:3535-40, 2001 
64. 
LeBlanc R, Catley LP, Hideshima T, et al: Proteasome inhibitor PS-341 inhibits 
human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 62:4996- 
5000, 2002 
65. 
McConkey DJ PC, Elliott P, Adam J, Papandreou C, Herrmann JL et al.: The 
proteasome as a new drug target in metastatic prostate cancer. 1999 
66. 
Hideshima T, Richardson P, Chauhan D, et al: The proteasome inhibitor PS-341 
inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. 
Cancer Res 61:3071-6, 2001 
67. 
Lightcap ES, McCormack TA, Pien CS, et al: Proteasome inhibition measurements: 
clinical application. Clin Chem 46:673-83, 2000 
68. 
Jagannath S, Barlogie B, Berenson J, et al: A phase 2 study of two doses of 
bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165- 72, 2004 
69. 
Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in 
relapsed, refractory myeloma. N Engl J Med 348:2609-17, 2003 
70. 
Blade J, Samson D, Reece D, et al: Criteria for evaluating disease response and 
progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem 
cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow 
Transplant. Br J Haematol 102:1115-23, 1998 
71. 
Richardson PG, Sonneveld P, Schuster MW, et al: Bortezomib or high-dose 
dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-98, 2005 
72. 
Reece DE, Sanchorawala V, Hegenbart U, et al: Weekly and twice-weekly 
bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. 
Blood 114:1489-97, 2009 
73. 
Comenzo RL, Hassoun H, Kewalramani T, et al: Results of a phase I/II trial adding 
carmustine (300 mg/m2) to melphalan (200 mg/m2) in multiple myeloma patients undergoing 
autologous stem cell transplantation. Leukemia 20:345-9, 2006 
74. 
Kewalramani T, Zelenetz AD, Hedrick EE, et al: High-dose chemoradiotherapy and 
autologous stem cell transplantation for patients with primary refractory aggressive non-Hodgkin 
lymphoma: an intention-to-treat analysis. Blood 96:2399-404, 2000 
75. 
Kewalramani T, Zelenetz AD, Teruya-Feldstein J, et al: Autologous transplantation for 
relapsed or primary refractory peripheral T-cell lymphoma. Br J Haematol 134:202-7, 2006 
76. 
Comenzo RL, Reece D, Palladini G, Seldin D, Sanchorawala V, et al. Consensus 
guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. 
Leukemia 26:2317-25, 2012 
 
 
 
 
63 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
77. 
Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, et al. Definition of 
organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL); a 
consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, 
France, 18-22 April 2004. Am J Hematol 79:319-328, 2005 
78. 
Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, et al. New criteria for 
response to treatment in immunoglobulin light chain amyloidosis based on free light chain 
measurement and cardiac biomarkers: Impact on survival outcomes. J Clin Oncol, 2012 [Epub 
ahead of print] 
 
 
 
 
 
 
 
 
20.0 
APPENDICES 
20.1 Neurotoxicity Assessment Tool 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
64 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
20.2 Ne w York He art Association Classification of Cardiac Disease 
 
 
 
 
65 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
The following table presents the NYHA classification of cardiac disease. 
 
Class 
Functional Capacity 
Objective 
Asse ssme nt  
I 
Patients with cardi ac disease but without resulting limitations of 
physical activity.  Ordinary physical acti vity does not caus e undue 
fatigue, pal pitation, dyspnea, or angi nal pain. 
No objecti ve evi denc e 
of cardiovascular 
disease. 
II 
Patients with cardi ac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, pal pitation, dyspnea, or angi nal pain. 
Objecti ve evi dence of 
minimal cardiovascular 
disease. 
III 
Patients with cardi ac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary acti vity 
causes fatigue, pal pitation, dyspnea, or angi nal pain. 
Objecti ve evi dence of 
moderately severe 
cardiovascul ar 
disease. 
IV 
Patients with cardi ac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or the 
angi nal syndrome m ay be present even at rest.  If any physical 
activity is unde rtake n, discomfo rt is increased.  
Objecti ve evi dence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New Y ork Heart Association.  Nom enclature and Criteri a for 
Diagnosis of Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 
1994:253-256. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
66 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
20.3 
Body Surface Are a and Creatinine Clearance Calculations 
 
 
Body surface area (BSA) should be calculated using a standard nomogram that yields the 
following results in meters squared (m2): 
  
 
BSA = 
 
or 
 
BSA = 
Ht(inches) Wt(lbs) 
3131 
 
 
Ht(cm) Wt(kg) 
3600 
 
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as follows: 
CrCl (ml/min) = (140 - age) (actual wt in kg) 
72  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.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
67 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
20.4 
Common Terminology Criteria for Adverse Events 
http://ctep.cancer.gov/reporting/ctc.html 
 
 
 
 
20.5 
Borte zomib References 
 
 
 
i Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, et al. Proteasome 
inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 
1999;59(11):2615-22. 
 
ii Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-341 in cancer 
therapy. Clin Cancer Res 1999;5(9):2638-45. 
 
iii Cusack JC, Jr., Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, et al. Enhanced 
chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic 
nuclear factor-kappaB inhibition. Cancer Res 2001;61(9):3535-40. 
iv  LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, et al. Proteasome 
inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a 
murine model. Cancer Res 2002;62(17):4996-5000. 
 
v  Williams S, Pettaway C, Song R, Papandreou C, Logothetis C, McConkey DJ. Differential effects of 
the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor 
xenografts. Mol Cancer Ther 2003;2(9):835-43. 
 
vi Nawrocki ST, Bruns CJ, Harbison MT, Bold RJ, Gotsch BS, Abbruzzese JL, et al. Effects of the 
proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic 
tumor xenografts. Mol Cancer Ther 2002;1(14):1243-53. 
v ii Satou Y, Nosaka K, Koya Y, Yasunaga JI, Toyokuni S, Matsuoka M. Proteasome inhibitor, 
bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro. 
Leukemia 2004;18:1357- 63. 
 
v iii Boccadoro M, Morgan G, Cavenagh J. Preclinical evaluation of the proteasome inhibitor 
bortezomib in cancer therapy. Cancer Cell Int 2005;5:18. 
 
ix Goel A, Dispenzieri A, Geyer SM, Greiner S, Peng KW, Russell SJ. Synergistic activity of the 
proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally targeted 
radiotherapy in an orthotopic model of multiple myeloma. Blood 2006;107(10):4063-70. 
 
x Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, et al. The proteasome 
inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional 
chemotherapeutic agents: therapeutic applications. Blood 2003;101(6):2377-80. 
xi Sayers TJ, Brooks AD, Koh CY, Ma W, Seki N, Raziuddin A, et al. The proteasome inhibitor PS- 
341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. 
Blood 2003;102(1):303-10. 
 
xii Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasome inhibitor bortezomib 
interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ 
cells sensitive and resistant to STI571. Blood 2003;102(10):3765-74. 
 
 
 
 
68 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
 
 
 
 
xiii O'Connor OA, Smith EA, Toner LE, Teruya-Feldstein J, Frankel S, Rolfe M, et al. The combination 
of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen 
sensitizes human B-cell lymphomas to cyclophosphamide. Clin Cancer Res. 
2006;12(9):2902-11. 
 
xiv  David E, Sun SY, Waller EK, Chen J, Khuri FR, Lonial S. The combination of the farnesyl 
transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic 
apoptosis in human myeloma cells that is associated with down-regulation of p-AKT. Blood 
2005;106(13):4322-9. 
 
xv  McConkey DJ, Pettaway C, Elliott P, Adam J, Papandreou C, Herrmann JL, et al. The proteasome 
as a new drug target in metastatic prostate cancer. In: 7th Annual Genitourinary Oncology 
Conference; 1999 February 1999; Houston, TX. 
 
xv i Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, et al. The 
proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug 
resistance in human multiple myeloma cells. Cancer Res 2001;61(7):3071-6. 
 
xv ii Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH. Proteasome inhibitors 
induce a terminal unfolded protein response in multiple myeloma cells. Blood 
2006;107(12):4907-16. 
 
xv iii Ling YH, Liebes L, Ng B, Buckley M, Elliott PJ, Adams J, et al. PS-341, a novel proteasome 
inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest 
and apoptosis. Mol Cancer Ther 2002;1(10):841-9. 
 
xix  Yang Y, Ikezoe T, Saito T, Kobayashi M, Koeffler HP, Taguchi H. Proteasome inhibitor PS-341 
induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c- 
Jun/AP-1 signaling. Cancer Sci 2004;95(2):176-80. 
 
xx Kaluz S, Kaluzova M, Stanbridge EJ. Proteasomal inhibition attenuates transcriptional activity of 
hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation 
domain. Mol Cell Biol 2006;26(15):5895-907. 
xxi An WG, Hwang SG, Trepel JB, Blagosklonny MV. Protease inhibitor-induced apoptosis: 
accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent 
markers of proteasome inhibition. Leukemia 2000;14(7):1276-83. 
 
xxii Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, et al. Bortezomib mediates 
antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. 
Cancer Res 2006;66(1):184-91. 
 
xxiii Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, et al. Molecular sequelae 
of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 
2002;99(22):14374-9. 
 
xxiv  Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I Trial of 
the Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic Malignancies. J 
Clin Oncol 2002;20(22):4420-7. 
 
xxv  Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I Trial of 
the Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic Malignancies. J 
Clin Oncol 2002;20(22):4420-7. 
 
 
 
 
69 


Memorial Sloan Kettering Cancer Center
IRB Number: 11-061 A(11) 
Approval date: 30-Jan-2019 
 
xxv i Aghajanian C, Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ, et al. A Phase I Trial of the 
Novel Proteasome Inhibitor PS341 in Advanced Solid Tumor Malignancies. Clin Cancer Res 
2002;8(8):2505-11. 
 
xxvii Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, et al. Phase I trial of the 
proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in 
androgen-independent prostate cancer. J Clin Oncol 2004;22(11):2108-21. 
 
xxviii Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Castritis E, Bitsaktsis A, Pangalis GA. 
Treatment of relapsed or refractory Waldenström's macroglobulinemia with bortezomib. 
Haematologic. 2005;90(12):1655-8. 
 
xxix  Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, et al. A phase 2 study of 
two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 2004;127(2):165- 
72. 
 
xxx  Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A Phase 2 Study 
of Bortezomib in Relapsed, Refractory Myeloma. N Engl J Med 2003;348(26):2609-17. 
 
xxxi Bladé J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, et al. Criteria for evaluating 
disease response and progression in patients with multiple myeloma treated by high-dose 
therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. 
European Group for Blood and Marrow Transplant. Br J Haematol 1998;102(5):1115-23. 
 
xxxii Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib 
or High-Dose Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med 
2005;352(24):2487-98. 
 
xxxiii Richardson P, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, et al. Bortezomib 
Continues Demonstrates Superior Efficacy Compared with High-Dose Dexamethasone in 
Relapsed Multiple Myeloma: Updated Results of the APEX Trail. Blood 
2005;106(11):Abstract 2547. 
 
xxxiv  Fisher R, Bernstein S, Kahl B, Djulbegovic B, Robertson M, de Vos S, et al. Multicenter Phase II 
Study of Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma. J Clin 
Oncol 2006;24(30):4867-74. 
xxxv  Goy A, Bernstein S, Kahl B, Djulbegovic B, Robertson M, Vos S, et al. Durable Responses with 
Bortezomib in Patients with Relapsed or Refractory mantle Cell Lymphoma:  Updated Time - 
to-Event Analyses of the Multicenter PINNACLE Study. Blood 2007;110:Abstract 125. 
 
xxxv i San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. 
Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl 
J Med 2008;359(9):906-17. 
 
xxxv ii San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. 
Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl 
J Med 2008;359(9):906-17. 
 
xxxv iii Mateos M-V, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, et al. 
Bortezomib plus melphalan-prednisone continues to demonstrate a survival benefit vs 
melphalan-prednisone in the phase III VISTA trial in previously untreated multiple myeloma 
after 3 years' follow-up and extensive subsequent therapy use. Blood 2009;114:Abstract 
3859. 
 
 
 
70