Clinical trial NCT01849783
Conditions: Extramedullary Plasmacytoma Isolated Plasmacytoma of Bone Light Chain Deposition Disease Primary Systemic Amyloidosis Stage I Multiple Myeloma Stage II Multiple Myeloma Stage III Multiple Myeloma
Sponsor: Margarida Magalhaes-Silverman
Start date: 2013-04-04; Completion date: 2020-09-30
Enrollment: 41 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial investigates whether patients greater than or equal to 65 years of age diagnosed with myeloma or another plasma cell malignancy will have better outcomes with transplant followed by maintenance therapy, as primarily measured by progression-free survival, versus non-transplant approaches.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the progression-free survival (PFS) from the start of dexamethasone, cisplatin, Adriamycin (doxorubicin),Cytoxan (cyclophosphamide), etoposide (DPACE) for all participants who have had at least one day of protocol treatment.

II. To evaluate how well such therapy is tolerated in patients mainly over the age of 65 years by assessing severe complications (intensive care unit \[ICU\] admission, death) and the percentage of participants able to complete the full course of therapy.

SECONDARY OBJECTIVES:

I. To evaluate Quality-Of-Life post-transplant using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire QLQ-C30 and QLC-MY20.

OUTLINE:

INDUCTION THERAPY: Patients receive dexamethasone orally (PO) on days 1-4 and 8-11, cisplatin intravenously (IV) continuously, doxorubicin hydrochloride IV continuously, cyclophosphamide IV, and etoposide IV on days 1-4. Patients then receive pegfilgrastim subcutaneously (SQ) on days 6 and 13 and undergo collection of stem cells when white blood cell (WBC) and cluster of differentiation (CD)34 counts are within program range. Following stem cell collection, patients may receive interim dexamethasone PO on days 1-4, every 14 days at the discretion of the treating physician.

TRANSPLANT: Beginning between 4 weeks to 6 months after the first day of induction therapy, patients receive as transplant conditioning regimen dexamethasone PO on days -4 to -1 and days +2 through +5, bortezomib IV bolus on days -4, -1, 2, and 5, thalidomide PO on days -4 to 5, and melphalan IV on days -4 and -1. Patients undergo autologous peripheral blood stem cell transplant (PBSCT) on day 0. Between transplant and consolidation therapy, patients receive dexamethasone PO on days 1-4 every 21 days and thalidomide PO daily.

CONSOLIDATION THERAPY: If administered, post-transplant consolidation may begin 4-6 weeks after transplant but should occur no more than 4 months later. Most patients will not receive consolidation. Those that do will receive dexamethasone PO on days 1-4 and 8-11, thalidomide PO on days 1-11, bortezomib IV on days 1, 4, 8, and 11, cisplatin IV continuously, doxorubicin hydrochloride IV continuously, cyclophosphamide IV continuously, and etoposide IV continuously on days 1-4.

MAINTENANCE THERAPY YEAR 1: Beginning 6 weeks-6 months after consolidation therapy or 4 weeks to 6 months after transplant if consolidation is skipped, patients receive bortezomib IV bolus on days 1, 4, 15, and 18, thalidomide PO QD on days 1-28, and dexamethasone PO on days 1-4 and 15-18. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY YEAR 2: Patients receive bortezomib IV on days 1, 4, 15, and 18, cyclophosphamide PO or IV on days 1 and 15, and dexamethasone PO QD on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at least once annually at the study center, but serum for MM marker results will be sent to the study site for close monitoring of PFS .

Arms: arm 1: Induction : DPACE(dexamethasone,cisplatin,doxorubicin,cyclophosphamide,etoposide) chemotherapy plus stem cell collection. Additional stem cell collection and/or chemotherapy may be required.

After collection, participants will receive dexamethasone x 4 days every 14 days.

Transplant: The transplant preparative regimen will be bortezomib/thalidomide/dexamethasone/melphalan.

Once recovered, participants start thalidomide daily and dexamethasone x 4 days every 21 days.

Consolidation (if administered): VDT-PACE(bortezomib,dexamethasone,thalidomide,cisplatin,doxorubicin,cyclophosphamide, etoposide)

Maintenance: Year 1 - VTD (bortezomib, thalidomide, dexamethasone) cycles. Year 2 - VCD (bortezomib, cyclophosphamide, dexamethasone)cycles.
Interventions: intervention 1: dexamethasone intervention 2: cisplatin intervention 3: doxorubicin intervention 4: cyclophosphamide intervention 5: etoposide intervention 6: bortezomib intervention 7: thalidomide intervention 8: melphalan intervention 9: autologous stem cell transplant
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV or PO intervention 5: Given IV intervention 6: Given IV intervention 7: Given PO intervention 8: Given IV intervention 9: None

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 74 
 
 
Single Autologous Transplant Followed by Consolidation and Maintenance for Participants ≥ 
65 Years of Age Diagnosed with Multiple Myeloma or a Related Plasma Cell Malignancy 
 
Version: 10 
Version Date:  11/6/2019 
Prior Protocol Version: 9 
 
 
 
Principal Investigator 
Yogesh Jethava, MD 
 
Sub-Investigators 
Guido Tricot, MD, PhD 
Karen Ajram, PA-C 
Umar Farooq, MD  
Sarah Feddersen, PA-C 
Gina Glass, PA-C 
Jessie Alex, ARNP 
 
Margarida Magalhaes-Silverman, MD 
 
 
Study Statistician 
Brian Smith, PhD  
 
 
 
 
Department of Internal Medicine 
200 Hawkins Drive, 5980 JPP 
Iowa City, IA  52242  
 
 
 
 
 
 
 
 
 


Page 2 of 74 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Induction DPACE 
Dexamethasone 20 mg oral days 1-4 and 8-11 
Continuous Infusion on days 1-4: 
Cisplatin 10mg/m2/day, Doxorubicin10mg/m2/day, Etoposide 40mg/m2/day, Cyclophosphamide 
400mg/m2/day (OR 600mg/m2 if high risk MM) 
 
Peripheral Blood Stem Cell Collection [plus additional collection(s) if needed]   
Dexamethasone 20mg daily on days 1-4 of a 14 day cycle 
Transplant  (VDT-Mel) 
(4 weeks - 4 months from day 1 of induction) 
* may be up to 6 months after day 1 of DPACE if hard-to-mobilize PBSC 
 
Thalidomide 100mg oral on day -4 to +5, Dexamethasone 20mg oral  
days -4 to -1 and +2 to +5, Bortezomib 1mg/m2 IV Bolus on days -4, -1, +2 and +5 
Melphalan 100mg/m2 (OR 70mg/m2 if > age 70 or creatinine > 2.0 mg/dl) on days 
-4 and –1.  PBSC Infusion 24 hrs post Melphalan on day 0. 
Thal 100mg daily + Dex 20mg daily x 4 days every 21 days 
Consolidation VDT-PACE* 
(4 weeks - 4 months after transplant) 
*Will only be given if all 4 criteria for treatment are met as described in the protocol.   
 
Bortezomib 1mg/m2 IV Bolus on days 1,4,8,11, Dexamethasone 20mg oral days 1-4 and 8-11, 
Thalidomide 100mg oral days 1-11. 
Continuous Infusion on days 1-4: 
Cisplatin 10mg/m2/day, Doxorubicin 10mg/m2/day, Etoposide 40mg/m2/day, 
Cyclophosphamide 400mg/m2/day 
Maintenance Therapy  
(4 weeks-6 months post- transplant or 6 weeks - 6 months from day 1 of consolidation if given) 
Given per standard-of-care 
 


Page 3 of 74 
 
COMMON ABBREVIATIONS 
 
AE 
Adverse Event 
ANC 
Absolute Neutrophil Count   WBC x (Segs +Bands).   
B2M 
Beta-2 Microglobulin  
CA 
Cytogenetic Abnormalities 
CBC 
Complete Blood Count 
CI 
Continuous Infusion 
CMP            Complete Metabolic Panel  
CNS 
Central Nervous System 
CR 
Complete Response 
CTCAE 
NCI Common Terminology for Adverse Events 
DEX 
Dexamethasone  
DPACE 
Dexamethasone, Cisplatin, Adriamycin®, Cytoxan®, Etoposide 
DVT  
Deep Vein Thrombosis 
EFS 
Event Free Survival 
FDA 
Food and Drug Administration 
FDG PET 
Fluorodeoxyglucose - Positron Emission Tomography 
FISH 
Fluorescence in situ hybridization 
GCP 
Good Clinical Practices 
GEP 
Gene Expression Profiling 
HIPAA 
Health Insurance Portability and Accountability Act 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IV 
Intravenous 
ME 
Microenvironment 
MEL 
Melphalan 
MGUS 
Monoclonal Gammopathy of Undetermined Significance 
MIRT 
MM 
Myeloma Institute for Research and Therapy at the University of Arkansas 
Multiple Myeloma 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
n-CR 
Near Complete Response 
OS 
Overall Survival 
PBSC 
Peripheral Blood Stem Cells 
PCP 
Pneumocystic pneumonia  
PO 
By mouth 
PR 
Partial Response 
PS 
Performance Status 
QD 
Every Day 
SAE 
Serious Adverse Event 
SC/SQ 
Subcutaneous 
SRE 
Skeletal Related Events 
REV 
Lenalidomide  
THAL 
Thalidomide 
TIW 
Three times per week  
TT II 
Total Therapy II 
VDT  
Velcade®, Dexamethasone, Thalidomide 
WBC 
White Blood Count 
 
 


Page 4 of 74 
 
Modification #8 
Modification version: 2.4  
Modification version date:  5/18/15 
Page 
Change  
Cover  
Page  
Changed version number, version date, and prior version number.   
 
 
5 
Table of Contents updated to reflect revised pagination 
 
 
3 
Added CMP (Complete Metabolic Panel) as an abbreviation  
6 
Table of Contents updated. 
66 
Expedited Adverse and Serious Adverse Events will be reported to the Medical Monitor only.  The 
assigned study monitor will not review these events in real time but will review them at the quarterly 
audits.   
67 
Background section further divided into 3 sub-sections for further clarification.    Expanded upon rationale 
for adding bortezomib and thalidomide to high-dose melphalan.  Added section 2.4 (rationale for allowing 
multiple modifications during maintenance therapy)   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 5 of 74 
 
Table of Contents 
 
1.0   Objectives ……………………………………………………            
6 
 
2.0   Background and Rationale………………………………...                      6 
 
3.0   Drug Information...............................................................                   13 
 
4.0   Staging Criteria………………………………………………      
         43 
 
5.0    Eligibility Criteria…………………………………………….                   45 
 
6.0   Treatment Plan………………………………………………                    47 
 
 7.0   Toxicities to be Monitored and Drug/Dosage Modifications…..          51 
 
8.0   Study Calendar………………………………………………                   57 
 
9.0    Criteria for Evaluation and Endpoint Definitions……….                    59 
 
10.0  Statistical Considerations………………………………….     
         62 
 
11.0  Ancillary Studies……………………………………………                    64 
 
12.0  Ethical and Regulatory Considerations………………….                    64 
 
13.0  References…………………………………………………..                  70 
 
14.0  Appendices………………………………………………….                   73 
 
 
 
 
 
 
 
 
 
 
 
 


Page 6 of 74 
 
1.0  Objectives   
The hypothesis of this study is that participants ≥65 years of age diagnosed with MM or 
another plasma cell malignancy will have better outcomes with a transplant approach followed 
by maintenance, as primarily measured by PFS, but also by OS, versus non-transplant 
approaches. 
Primary Objectives  
 
1.1     To evaluate the progression-free survival (PFS) from the start of DPACE for all  
    participants who have had at least one day of protocol treatment. It is hoped that the  
    median progression-free survival will be 48 months versus 24 to 36 months for non-     
    transplant regimens.   
 
1.2    To evaluate how well such therapy is tolerated in patients mainly over the age of 65 years 
                   by assessing severe complications ( ICU admission, death) and the percentage of  
                   participants able to complete the full course of therapy.  
 
Secondary Objectives  
          1.3     To evaluate Quality-Of-Life post-transplant using the European Organization for   
                   Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire  
                   QLQ-C30 and QLC-MY20. 
 
 Overall Survival (OS) is not an objective of this study because it is heavily influenced by the type and  
 quality of therapy initiated after relapse, and therefore becomes a confounding variable. However,  
 OS data will be collected and assessed.   
 
2.0   Background and Rationale  
2.1  Background   
Although recent tandem autologous transplantation clinical trials for newly diagnosed patients have 
projected survivals of 10+ years and complete remission rates of approximately 80%, not every newly 
diagnosed (defined as <12 months of prior therapy) multiple myeloma patient will have the option of 
receiving tandem transplants, either because of a lack of insurance approval for two transplants, or 
because of clinical comorbidities that make the administration of two transplants unsafe. Most of 
these patients that fall into this category are ≥65 years of age, and in 2009, the median age of 
diagnosis for myeloma was 70 years.  
There continues to be clear evidence in the literature that supports the superiority of a single 
autologous transplant over non-transplant chemotherapy, including chemotherapy combinations that 
employ the newer drugs (Lenalidomide, thalidomide, bortezomib, and Doxil).  There is also convincing 
evidence that post-transplantation therapy with either thalidomide or Revlimid or the combination of 
bortezomib with thalidomide prolongs the progression-free survival.   However, most of the literature 


Page 7 of 74 
 
related to myeloma treatment in patients ≥65 years of age involves non-transplant chemotherapy 
regimens. The literature related to autologous transplantation for myeloma in the elderly (i.e. ≥ 65 
years of age) is scarce.     
Our group was the first to recognize that age is not a prognostic variable with autotransplants in 
myeloma (Siegel DS et al). While 83% of younger patients collected > 5 million CD34 cells/kg, 73% of 
patients 65 years or older attained this target (p= 0.2). The treatment-related mortality with the first 
transplant was 2% for younger patients, and 8% for patients 65 years or older. In multivariate analysis 
age was not a prognostic factor for either event-free (p=0.2) or overall survival (p=0.8). These 
observations were subsequently confirmed in another single institution study by El Cheikh et al (2011) 
comparing 82 elderly patients to 104 younger patient. The feasibility of transplantation in myeloma 
patients 70 years or older was also demonstrated by Bashir et al. 
The table on the next page, taken from Gay and Palumbo’s 2011 review in Blood1, summarizes the 
results of various regimens used as frontline treatment in elderly patients diagnosed with multiple 
myeloma:  
Table 2. Efficacy of regimens used as a front-line treatment in elderly patients with multiple myeloma. 
 
N 
CR  
 
≥PR 
   
PFS/EFS/TTP 
OS 
Reference 
Thalidomide-based 
TD 
T: 200 mg 
D: 40 mg day 1–4, 15–18 for a 28-day cycle 
for 9 cycles 
145 2% 68% 
41% at 
24 months 
61% at 
24 months 
Ludwig et 
al.  
MPT 
M: 4 mg/m2 day 1–7 
P: 40 mg/m2 day 1–7 
T: 100 mg/day 
for six 4-week cycles 
Maintenance: 
T: 100 mg/day 
129 16% 76% 
50% at 
22 months 
50% at 
45 months 
Palumbo et 
al.  
MPT 
M: 0.25 mg/kg day1–4 
P: 2 mg/kg day 1–4 
T: 400 mg/day 
for twelve 6-week cycles 
125 13% 76% 
50% at 
28 months 
50% at 
52 months 
Facon et al.1 
MPT 
M: 0.25 mg/kg day 1–4 
P: 2 mg/kg day 1–4 
T: 100 mg/day 
for twelve 6-week cycles 
113 7% 62% 
50% at 
24 months 
50% at 
44 months 
Hulin et al. 


Page 8 of 74 
 
 
N 
CR  
 
≥PR 
   
PFS/EFS/TTP 
OS 
Reference 
MPT 
M: 0.25 mg/kg day 1–4 
P: 100 mg day 1–4 
T: 200–400 mg/day 
for a 6-week cycle until plateau 
Maintenance: 
T: 200 mg/day 
182 13% 57% 
50% at 
15 months 
50% at 
29 months 
Waage et al. 
MPT 
M: 0.25 mg/kg 
P: 1 mg/day 1–5 
T: 200 mg/day 
for eight 4-week cycles 
Maintenance: 
T: 50 mg/day 
165 2% 66% 
67% at 24 
months 
29% at 24 
months 
Wijermans 
et al. 
CTD 
C: 500 mg day 1, 8, 15 
T: 100–200 mg/day 
D: 40 mg day 1–4, 12–15 
for a 3 week cycle 
450 21% 91% ND 
ND 
Morgan et 
al.  
Bortezomib-based 
VMP 
M: 9 mg/m2 day 1–4 
P: 60 mg/m2 day 1–4 
V: 1.3 mg/m2 day 1, 4, 8, 11, 22, 25, 29, 32 for the 
first four 6-week cycles; day 1, 8, 22, 29 for the 
subsequent five 6-week cycles 
344 30% 71% 
50% at 
22 months 
41% at 
36 months 
San Miguel 
et al.  
Mateos et 
al.  
VMP 
M: 9 mg/m2 day 1–4 
P: 60 mg/m2 day 1–4 
V: 1.3 mg/m2 day 1, 8, 15, 22 
257 24% 81% 
41% at 
36 months 
87% at 
36 months 
Palumbo et 
al. 
VMP 
M: 9 mg/m2 day 1–4 
P: 60 mg/m2 day 1–4 
V: 1.3 mg/m2 twice weekly (day 1, 4, 8, 11; 22, 25, 
29, and 32) for one 6-week cycle, followed by 
once weekly (day 1, 8, 15, and 22) for five 5-
week cycles 
Maintenance: 
V:1.3 mg/m2 twice weekly on days 1, 4, 8, 11, 
every 3 months 
130 20% 80% 
50% at 
34 months 
74% at 
36 months 
Mateos et 
al.  


Page 9 of 74 
 
 
N 
CR  
 
≥PR 
   
PFS/EFS/TTP 
OS 
Reference 
T: 50 mg/day or V: 1.3 mg/m2 twice weekly on 
days 1, 4, 8, 11, every 3 months P: 50 mg every 
other day 
Bortezomib- and thalidomide-based 
VTP 
T: 100 mg/day 
P: 60 mg/m2 day 1–4 
V: 1.3 mg/m2 twice weekly (day 1, 4, 8, 11; 22, 25, 
29 and 32) for one 6-week cycle, followed by 
once weekly (day 1, 8, 15 and 22) for five 5-week 
cycles 
Maintenance: V: 1.3 mg/m2 twice weekly on days 
1, 4, 8, 11, every 3 months T: 50 mg/day or 
V:1.3 mg/m2 twice weekly on days 1, 4, 8, 11, 
every 3 months 
P: 50 mg every other day 
130 28% 81% 
50% at 
25 months 
65% at 
36 months 
Mateos et 
al. 
VMP
T 
M: 9 mg/m2 day 1–4 
P: 60 mg/m2 day 1–4 
V: 1.3 mg/m2 day 1, 8, 15, 22 
T: 50 mg day 1–42 for nine 5-week cycles 
Maintenance: 
V: 1.3 mg/m2 every 15 days 
T: 50 mg/day 
254 38% 89% 
56% at 
36 months 
89% at 
36 months 
Palumbo et 
al. 
Lenalidomide-based 
MPR 
M: 0.18 mg/Kg day 1–4 
P: 2 mg/Kg day 1-4 
R: 10 mg day 1-21 
for nine 4-week cycles 
Maintenance: 
R: 10 mg day 1-21 
152 16% 77% 
55% at 
24 months 
92% at 
12 months 
Palumbo et 
al. 
Rd 
R: 25 mg day 1–21 
d: 40 mg day 1, 8, 15, 22 
for a 4-week cycle 
222 4% 68% 
50% at 
25 months 
87% at 
24 months 
Rajkumar et 
al.  


Page 10 of 74 
 
N indicates number of patients; CR, complete remission; PR partial response; PFS, progression-free survival; 
EFS, event-free survival; TTP, time to progression; OS, overall survival; M, melphalan; P, prednisone; T, 
thalidomide;V, bortezomib; R, lenalidomide; C, cyclophosphamide; D, high-dose dexamethasone; d, low-
dose dexamethasone; MPT, melphalan–prednisone–thalidomide; VMP, bortezomib–melphalan–prednisone; 
VTP, bortezomib–thalidomide–prednisone; VMPT, bortezomib–melphalan–prednisone–thalidomide; CTD, 
cyclophosphamide–thalidomide–dexamethasone; MPR, melphalan–prednisone–lenalidomide; NA, not 
available. § Updated information was presented at the meeting (American Society of Clinical Oncology, 
European Haematology Association and American Society of Hematology congress). 
 
The design of this protocol centers around a single autologous transplant followed by consolidation 
and maintenance therapy in patients ≥65 years of age with <12 months of prior therapy in order to 
compare event-free and overall survival rates to those in the literature cited above .   
2.2 The Rationale for Adding Bortezomib and Thalidomide to High-Dose Melphalan 
In addition to traditional mechanisms of drug resistance such as overexpression of efflux pumps, up-
regulation of anti-apoptotic factors, down-regulation of proapoptotic factors, up-regulation of 
detoxifying enzymes and subcellular redistribution of drug targets, drug resistance is also mediated 
by binding of tumor cells to extracellular matrix proteins. This type of drug resistance is called cell 
adhesion-mediated drug resistance (CAM-DR) and is particularly relevant in hematologic 
malignancies such as multiple myeloma, where the myeloma cells interact with the bone marrow 
stroma, initiating the production of proteins that stimulate and support tumor cell survival. Myeloma 
cells bind to fibronectin in the micro-environment, which up-regulates drug resistance mainly through 
increased NF-κB activity.  Bortezomib blocks the paracrine growth of myeloma cells by decreasing 
their adherence to the bone marrow stroma and by blocking NF-κB activity (Hideshima). In addition, 
bortezomib prevents DNA repair, which is the major mechanism of drug resistance to high dose 
melphalan. The Fanconi anemia (FA)/BRCA genes are overexpressed and cause drug resistance in 
melphalan-resistant cell lines. This pathway is activated by NF-κB. Bortezomib drastically reduces 
FA/BRCA gene expression and FANCD2 protein expression in myeloma cells, resulting in diminished 
DNA repair and enhanced melphalan sensitivity (Yarde et al). Thalidomide directly induces apoptosis 
or G1 growth arrest in myeloma cells, which are resistant to melphalan. Although thalidomide does 
not alter adhesion of myeloma cells to the bone marrow stroma, it inhibits the up-regulation of IL-6 
and VEGF secretion triggered by the binding of myeloma cells to the bone marrow stroma. It also 
inhibits TNFα-induced NF- κB. TNFα increases myeloma cell adhesion to the bone marrow stroma 
(Hideshima). Our own studies have demonstrated that the combination of bortezomib with 
thalidomide induces higher response rates than each drug separately. When analyzing the bone 
marrow stroma signature by gene expression profiling, multiple genes were different between a 
normal bone marrow stroma signature and that of a myeloma bone marrow stroma. However, after 
treatment for 48 hours with bortezomib and thalidomide, the bone marrow stroma signature of 
myeloma patients almost completely normalized and the stimulatory effects of the stroma on the 
myeloma cells was abrogated.  


Page 11 of 74 
 
 
These observations formed the basis of our Total Therapy 3 trial, which included bortezomib and 
thalidomide in the maintenance phase, but not with the transplant. 
Several investigators have combined high-dose melphalan with bortezomib. They concluded that this 
combination is safe and that there was a suggestion of improved efficacy (Lonial et al; Roussel et al; 
Thompson et al).   
Palumbo et al combined intermediate dose melphalan (100mg/m2) with bortezomib, thalidomide, and 
dexamethasone in 26 relapsed/refractory patients who had all received at least one prior transplant 
 [13 (50%) received a second transplant as salvage prior to study enrollment].  Responses occurred 
in 17/26 patients, including 1 CR, 3 nCR(12%), and 2 VGPR (8%). Response rate was higher than 
that induced by the previous line of treatment in 12 patients (46%).  The authors concluded that the 
regimen had encouraging anti-myeloma activity in heavily pre-treated patients, and that the addition 
of thalidomide and bortezomib only slightly increased overall toxicity caused by IV melphalan 
100mg/m2 as a single agent.  Infections requiring IV antibiotics occurred in 50% of patients, but it was 
not clear whether this was due to the immunomodulatory effect of the added agents or the infection 
susceptibility in heavily pre-treated patients.   
 
Barlogie et al reported in 2009 on the incorporation of bortezomib, thalidomide, dexamethasone with 
the addition of cisplatin, and rapamycin into the BEAM regimen as a salvage regimen in myeloma.  
Ninety-five patients were enrolled in their study.  Patient characteristics included age >=65, 19%; 
LDH>ULN, 43%; CA, 67%; GEP high-risk, 44%; GEP MF, 15%; GEP delTP53, 22%; prior AT, 75% 
including 46% with 2 AT and 12% with 3 AT. CR and near-CR status was documented in 50%; TRM 
occurred within 100 days in 6%. Three-year estimates of overall survival (OS) and event-free survival 
(EFS) were 34% and 18%; OS/EFS were superior: (a) without CA – 60%/50% versus 15%/5% with 
CA (p=0.003/0.0005); (b) with GEP low-risk – 55%/20% versus 10%/15% with high-risk MM 
(p=0.009/0.01); (c) with GEP hyperdiploidy and low bone disease molecular subgroups – 70%/35% 
versus 20%/10% in the remainder (p=0,001/0.002); and (d) absence of progression prior to SB – 
52%/35% versus 16%/5% for the remainder (p=0.002/0.0006).  They concluded that Super-BEAM 
(SB) was safe as a salvage regimen and well-tolerated by the majority of patients in the outpatient 


Page 12 of 74 
 
setting.  Although SB was very beneficial for a subset of the study patients, pre-SB relapse (relapse 
just prior to SB) was one of the significantly adverse variables for OS and EFS, which is why we 
would like to incorporate VTD-Mel upfront in newly diagnosed patients.   
2.3 The Rationale for Post-Transplant Maintenance  
Although the role of maintenance therapy post-transplantation has been controversial for a long time, 
recent evidence clearly shows the superiority of such maintenance therapy. In a study by Attal et al, 
including 614 patients, lenalidomide given after transplantation significantly prolonged progression-
free survival in a randomized study comparing lenalidomide post-transplantation versus placebo (p˂ 
0.001). Median follow up was only 30 months, which is too short to see a difference in overall survival 
(Attal et al, 2012). A second study by McCarthy et al included 460 patients and had a median follow-
up of 34 months also showed a significant benefit in progression-free survival with lenalidomide 
maintenance compared to placebo (p<0.001). In spite of the short follow-up, this study also showed 
an overall benefit for lenalidomide maintenance (p=0.03). It should be mentioned that both studies 
noted increased toxicities related to maintenance therapy and more specifically showed a significant  
increase in secondary malignancies in the lenalidomide arms, which was 3.1 versus 1.2 per 100 
patient years in the Attal study, and 8% versus 3% in the McCarthy study. A recent consensus on 
maintenance therapy in multiple myeloma was reported by Ludwig et al. Thalidomide maintenance 
showed a benefit in progression-free survival in all 6 studies performed and an overall survival benefit 
in 3 of these studies.  In a randomized Phase III study, superior complete (CR)/near complete 
response (nCR) and extended progression-free survival were demonstrated with bortezomib-
thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) when give as induction 
and maintenance therapy after transplantation in newly diagnosed myeloma patients by Cavo and 
colleagues. The study included 321 patients. VTD maintenance significantly increased CR/nCR rates 
while TD did not. With a median follow-up of 30 months from the start of maintenance, progression-
free survival at 3 years was 60% versus 48% (p= 0.04). The benefit of VTD maintenance was seen 
irrespective of poor prognostic variables.  In newly diagnosed myeloma patients, lenalidomide/ 
dexamethasone (RD) was compared to cyclophosphamide/lenalidomide/dexamethasone (CRD) and 
bortezomib/cyclophosphamide/ dexamethasone (VCD). VCD resulted in superior responses and less 
frequent serious toxicities compared to RD and CRD. With a median follow-up of 35 months no 
difference in progression-free survival was seen yet. Bensinger and colleagues reported sequential 
VCD and VTD as frontline therapy in myeloma in a Phase II study including 44 patients. They 
concluded that this novel sequential three-drug combination therapy is effective and well tolerated in 
previously untreated myeloma patients.  
2.4 The Rationale for Allowing Multiple Modifications During Maintenance Therapy 
In this protocol, we will administer two years of maintenance therapy. Years one and two will consist 
of 12 cycles of 28 days each. During year 1, we will administer VTD, while in year 2 we will administer 
VCD.  We consider it of vital importance that patients are able to complete two years of maintenance.  
However, because of anticipated toxicity during maintenance, we allow alternate dosing schedules, 
dose reductions, or replacement with a similar categorical agent (i.e. proteasome inhibitor with a 
proteasome inhibitor, IMID with an IMID, corticosteroid with a corticosteroid) so that as many patients 
as possible will complete the two years of maintenance therapy, and with 3-drug maintenance 


Page 13 of 74 
 
regimens whenever possible,  as many studies have shown a direct correlation to the length  and 
type of maintenance therapy and its efficacy in increasing PFS.  Although the replacement drugs may 
have different and better toxicity profiles, the experience with these drugs is still limited.  
Several myeloma physicians now advocate continuing therapy until relapse. We prefer to stop all 
treatment after two years of maintenance because: 1) Patients value the amount of time without 
symptoms, therapy, and toxicity 2) If therapy is continued until relapse, these drugs will by definition 
no longer be active at that time, while it is our experience that in patients relapsing more than 2 years 
after stopping all treatment, the drugs given during maintenance remain effective 3) There is a clear 
association between prolonged use of IMIDS and secondary malignancies, including MDS and AML. 
3.0   Drug Information  
3.1 Bortezomib (Velcade) 
Bortezomib for injection is a sterile lyophilized powder for reconstitution and is supplied in vials 
containing bortezomib and mannitol at a 1:10 ratio.  For example, vials containing 3.5 mg of 
bortezomib contain 35 mg of mannitol.   
Vials containing lyophilized bortezomib for injection should be stored refrigerated at 2° to 8C.  To 
date, stability data indicate that the lyophilized drug product is stable for at least 12 months when 
stored under the recommended conditions.  Stability studies are ongoing, and Millennium 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. 
Study drug will be supplied in sterile, single use vials containing 3.5 mg of bortezomib.  Each vial of 
bortezomib for Injection should be reconstituted under a laminar flow biological cabinet (hood) within 
eight hours before dosing with 3.5 mL of normal (0.9%) saline, Sodium Chloride Injection USP, so 
that the reconstituted solution contains bortezomib at a concentration of 1 mg/mL.  Dissolution is 
completed in approximately 10 seconds.  The reconstituted solution is clear and colorless, with a final 
pH of 5 to 6.  Reconstituted bortezomib should be administered promptly and in no case more than 
eight hours after reconstitution.  In case of skin contact, wash the affected area immediately and 
thoroughly with soap and water and diluted hydrogen peroxide. Remove contaminated clothing and 
dispose of according to standard procedures. In case of contact with mucous membranes, flush 
thoroughly with water. 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. 
Clinical Experience  
It is estimated that as of June 2005, more than 24,000 participants have been treated with 
bortezomib, including participants treated through Millennium-sponsored clinical trials, Investigator-


Page 14 of 74 
 
Initiated Studies, the US NCI Cancer Therapy Evaluation Program (CTEP), and with commercially 
available drug. Bortezomib has been commercially available since 13 May 2003. 
The overall goal of the Millennium phase 1 program was to determine the MTD and dose-limiting 
toxicity (DLT) of VELCADE in a number of therapeutic settings involving subjects with various 
advanced malignancies.  In a Phase I trial in participants with refractory hematologic malignancies, 
the MTD for a twice weekly for 4 weeks of a 42 day cycle was 1.04 mg/m2/dose, with DLTs of 
thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise (Orlowski et al., 2002).  The 
toxicity was greatest during the third and fourth weeks of therapy. In the 3-week schedule of 
bortezomib monotherapy (4 doses, given on Days 1, 4, 8, and 11 of a 21-day treatment cycle), the 
DLT occurred at 1.56 mg/m2/dose (3 subjects with Grade 3 diarrhea and 1 with peripheral sensory 
neuropathy).  Therefore, the MTD at this schedule was 1.3 mg/m2/dose.  In a 35-day treatment cycle 
with 4 weekly doses of VELCADE monotherapy, the MTD was 1.6 mg/m2/dose and DLT included 
hypotension, tachycardia, diarrhea, and syncope.   
In phase 1 clinical studies, anti-tumor activity was reported in subjects with NHL, multiple myeloma, 
Waldenström’s Macroglobulinemia, squamous cell carcinoma of the nasopharynx, bronchoalveolar 
carcinoma of the lung, renal cell carcinoma, and prostate cancer. 
The safety and efficacy of bortezomib in subjects with multiple myeloma were investigated in two 
phase 2 clinical studies, studies M34100-024 (subjects with first relapse) and M34100-025 (subjects 
with second or greater relapse and refractory to their last prior therapy).  In M34100-025, 202 heavily 
pre-treated subjects with refractory multiple myeloma after at least 2 previous treatments received 
bortezomib, 1.3 mg/m2 on Days 1, 4, 8, and 11 of a 21-day treatment cycle. The European Group for 
Blood and Marrow Transplant (EBMT) response criteria, as described by Blade (Blade et al., 1998) 
were utilized to determine disease response.  CRs were observed in 4% of subjects, with an 
additional 6% of participants meeting all criteria for CR but having a positive immunofixation test.  PR 
or better was observed in 27% of subjects, and the overall response rate (CR, PR and minor 
response [MR] combined) was 35%.  Seventy percent of subjects experienced stable disease or 
better.   
The phase 3 study (M34101-039), also referred to as the APEX study, was designed to determine 
whether bortezomib provided benefit (time to progression [TTP], response rate, and survival) to 
participants 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 participants were enrolled and 
663 participants received study drug (VELCADE: 331; dexamethasone: 332).  Participants 
randomized to bortezomib received 1.3 mg/m2 I.V. push twice weekly on days 1, 4, 8, and 11 of a 3-
week cycle for up to eight treatment cycles as induction therapy, followed by 1.3 mg/m2 bortezomib 
weekly on days 1, 8, 15, and 22 of a 5-week cycle for three cycles as maintenance therapy. 
Participants randomized to dexamethasone received oral dexamethasone 40 mg once daily on days 
1 to 4, 9 to 12, and 17 to 20 of a 5-week cycle for up to four treatment cycles as induction therapy, 
followed by dexamethasone 40 mg once daily on days 1 to 4 followed of a 4-week cycle for five 
cycles as maintenance therapy. The European Group for Blood and Marrow Transplant (EBMT) 


Page 15 of 74 
 
response criteria, as described by Blade (Blade et al., 1998) were utilized to determine disease 
response.  There was a 78% increase in TTP for the bortezomib arm. Median TTP was 6.2 months 
for the bortezomib arm and 3.5 months for the dexamethasone arm (P<.0001). CR (complete 
response) + PR (partial response) was 38% with VELCADE vs. 18% with dexamethasone (P.0001). 
CR was 6% with VELCADE vs. 1% with dexamethasone (P<.0001). The CR + nCR rate was13% 
with bortezomib vs. 2% with dexamethasone. In participants who had received only one prior line of 
treatment (VELCADE: 132; dexamethasone: 119), CR + PR was 45% with bortezomib vs. 26% with 
dexamethasone (P=.0035). With a median 8.3 months of follow-up, overall survival was significantly 
longer (P=.0013) for participants on the VELCADE arm vs. participants on the dexamethasone arm. 
The probability of survival at one year was 80% for the bortezomib arm vs. 66% for the 
dexamethasone arm, which represented a 41% decreased relative risk of death in the first year with 
bortezomib (P=.0005). In participants who had received only one prior line of treatment, the 
probability of survival at one year was 89% for the bortezomib arm vs. 72% for the dexamethasone 
arm, which represented a 61% decreased relative risk of death in the first year with VELCADE 
(P=.0098). (Richardson et al., 2005) 
Studies using bortezomib as monotherapy and in combination with other chemotherapy agents are 
continuing.   
Potential Risks of Bortezomib 
Most common side effects of bortezomib (i.e., incidence 30%) observed in participants are 
weakness, fatigue, and general discomfort; gastrointestinal (GI) effects such as constipation, 
diarrhea, nausea, vomiting and anorexia, which may result in dehydration and/or weight loss; fever; 
peripheral neuropathy (including painful sensations or numbness and tingling in hands and feet that 
may not get better after discontinuation of VELCADE); thrombocytopenia that may increase the risk of 
bleeding, and anemia.  
Very common side effects of bortezomib (i.e., incidence 10–29%) observed in participants are 
neutropenia that may increase the risk of infection; abdominal pain; dyspepsia; nasopharyngitis; 
arthralgias; myalgias; skin rash that can be erythematous, pruritic and display leukocytoclastic 
vasculitis at biopsy; rigors; hypotension; dizziness; fluid retention; pain in limbs and bones; 
paresthesia; dysesthesia; dyspnea; cough; epistaxis; headache; blurred vision; changed sense of 
taste; insomnia; anxiety; herpes zoster, and lower respiratory/lung infections including pneumonia. 
Common side effects of bortezomib (i.e., incidence 1–9%) observed in participants are lymphopenia; 
pancytopenia; palpitations; tachycardia; bradycardia; atrial fibrillation; angina pectoris; acute onset of 
congestive heart failure including pulmonary edema (participants with risk factors for, or existing, 
heart disease should be closely monitored); pleural effusion; tinnitus; conjunctivitis; ; abdominal 
distension; oral and esophageal mucositis; oral candidiasis; upper and lower GI bleeding; bronchitis; 
sinusitis; urinary tract infection; gastroenteritis; sepsis; hyponatremia; hyperglycemia; hypoglycemia 
(Participants on oral antidiabetic agents may require close monitoring of their blood sugar levels.); 
dehydration; orthostatic hypotension; syncope; convulsions; renal failure; hematuria; depression; 
confusion; increases in serum AST, ALT, GGT and alkaline phosphatase.                                              


Page 16 of 74 
 
Uncommon side effects of bortezomib (i.e., incidence <1%) observed in participants are febrile 
neutropenia; atrial flutter; bradycardia; new onset of decreased left ventricular ejection fraction; 
cardiogenic shock; hearing impairment; ileus paralytic/small bowel obstruction; upper gastrointestinal 
hemorrhage; oral mucosal petechiae; liver injury including abnormal liver function tests, 
hyperbilirubinemia, hepatitis, and liver failure (reported in participants receiving multiple concomitant 
medications and with serious underlying medical conditions); drug hypersensitivity; injection site 
reaction; aspergillosis; pulmonary embolism; hemoptysis; cerebral hemorrhage; and tumor lysis 
syndrome.  Isolated cases of QT-interval prolongation have been reported, but are not thought to be 
related to bortezomib treatment. Complications arising from these bortezomib toxicities may result in 
death. 
The effect of bortezomib on reproduction and its safety in pregnancy are unknown. Laboratory tests 
show that bortezomib may damage DNA therefore it is possible that bortezomib may cause infertility 
in men and women. 
3.2 Thalidomide (Thalomid) 
Description 
Thalidomide is an N-phthaloyl-glutamic acid imide.  Its chemical name is -(N- phthalimido) 
glutarimide.  The empirical formula is C13H10N2O4 and the gram molecular weight is 258.2.  The CAS 
number of thalidomide is 50-35-1.  Thalidomide is an off-white to white, nearly odorless, crystalline 
powder that is soluble at 25C in dimethyl sulfate (50 mg/ml) and ethanol (1 mg/ml).  The glutarimide 
part of the molecule contains a single asymmetric center and, therefore, may exist in either of two 
optically active forms designated S(-) or R(+).  Thalidomide is an equal mixture of the S(-) and R(+) 
forms and therefore has a net optical rotation of zero.  The enantiomers, both the S(-) and R(+) forms 
differ from the racemic thalidomide in having higher solubility in water (Hague and Smith, 1988, 
Williams 1968, Williams et al. 1965) and undergoing faster hydrolytic cleavage (Hague and Smith, 
1988). 
Contraindications and Precautions 
Thalidomide causes severe birth defects.  It must not be taken during pregnancy or within one month 
of having sexual intercourse that could result in pregnancy.  Females of childbearing potential should 
be instructed that they must not be pregnant when thalidomide therapy is initiated.  A blood test or 
professionally conducted urine test to rule out pregnancy prior to initiating thalidomide therapy is 
required.  While taking thalidomide, all female participants of childbearing potential must use two 
methods of birth control, one barrier and one hormonal or should abstain from sexual intercourse that 
could result in pregnancy.  It is not known if thalidomide is present in semen; therefore, it is 
recommended that male participants use barrier contraception while on thalidomide.  Both males and 
females of childbearing potential should continue with the contraceptive measures described above 
for one month after dosing has been discontinued. 
 
 


Page 17 of 74 
 
Toxicology 
The most important of the adverse events reported during the administration of thalidomide are 
peripheral neuropathy, rash, drowsiness, and teratogenicity.  Other frequent adverse events that have 
been reported include constipation and xerostomia.  Increased appetite, loss of libido, dryness of the 
skin, edema of the face and limbs, nausea, pruritis, headache, gastric pain, and menstrual 
abnormalities have occasionally been observed.  In addition, hangover feeling, giddiness, or 
nervousness at higher doses, shivering, aural buzzing, and addiction after several months have been 
reported.   Some participants have had a decrease in their white blood cell count and in some HIV-
positive participants an increase in the HIV RNA load has been reported.  There have been reports of 
changes of the heart rate and rhythm.  Allergic reactions include low blood pressure, rash, fever and 
rapid heartbeat associated with thalidomide use. 
Serious dermatologic (skin) reactions including a disease called Stevens-Johnson syndrome (which 
could be fatal) have been reported with thalidomide.  Symptoms of Stevens-Johnson Syndrome 
include flu-like symptoms (fever, achiness), and a crusty rash may form on mouth, lips, nose and 
genitals.  The eyes may also become red and itchy and the disease may eventually result in 
blindness. The disease can also affect the lungs, stomach and bowel, kidneys and heart if not 
treated.  If any of the above-mentioned symptoms or a skin rash of any type develop, thalidomide 
should be discontinued until thorough evaluation of the rash can be evaluated.   
Seizures, including generalized tonic-clonic convulsions, have been reported after thalidomide was 
approved by the FDA in clinical practice, but it has not been determined that thalidomide caused 
these seizures. During therapy with thalidomide, participants with a history of seizures or with other 
risk factors for the development of seizures should be closely monitored for changes that could cause 
acute seizure activity. 
DRUG INTERACTIONS 
Drug-drug interactions do not appear to have been systematically studied but it has been reported 
that thalidomide enhances the sedative effects of barbiturates, alcohol, chlorpromazine, and 
reserpine.  Its sedative action is antagonized by methylphenidate and methylamphetamine (Somers 
1960). 
Females who require treatment with rifampin, rifabutin, barbiturates, glucocorticoids, phenytoin, or 
carbamazepine should not rely upon hormonal contraception since these agents have been shown to 
reduce the efficacy of the contraceptives. 
PHARMACOLOGY 
Thalidomide is available as 50 mg strength, hard gelatin capsules. 
Stability and Storage:  The drug product has been shown to be stable for at least one year when 
stored under ambient conditions.  Over this time period, the capsules show no significant loss in 
potency and no significant increase in degradation products.  Furthermore, the drug product has been 
shown to be stable when stored under conditions of stress (40C/75% relative humidity, 6 months). 


Page 18 of 74 
 
Based upon these results, the drug product has been assigned a tentative expiration dating period of 
2 years. 
Clinical supplies should be retained in a secure, cool, dry place. 
Label Information:  The immediate container dispensed to the participant must contain the following 
warnings: 
WARNING:  This drug causes severe birth defects.  It must not be taken during pregnancy or within 
one month of having sexual intercourse that could result in pregnancy. 
CAUTION:  This drug must only be used by the person for whom it is prescribed.  Do not share this 
drug. 
3.3 Dexamethasone (Decadron)  
DESCRIPTION 
Dexamethasone is a synthetic adrenocortical steroid and is readily absorbed from the gastrointestinal 
tract.  Chemically, dexamethasone is 9-fluoro-11ß, 17, 21-thrihydroxy-16α-methyl-pregna-1, 4-diene-
3, 20-dione. 
TOXICOLOGY 
Human Toxicology: Possible adverse effects associated with the use of dexamethasone are: fluid and 
electrolyte disturbances, congestive heart failure in susceptible persons, hypertension, euphoria, 
personality changes, insomnia, exacerbation of infection (e.g., tuberculosis), exacerbation or 
symptoms of diabetes, psychosis, muscle weakness, osteoporosis, vertebral compression fractures, 
pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, convulsions, vertigo and headache, 
endocrine abnormalities, ophthalmic changes, and metabolic changes.  Some participants have 
experienced itching and other allergic, anaphylactic or other hypersensitivity reactions.  Withdrawal 
from prolonged therapy may result in symptoms including fever, myalgia and arthralgia. Phenytoin, 
phenobarbital and ephedrine enhance metabolic clearance of corticosteroids. 
Corticosteroids should be used cautiously in participants with hypothyroidism, cirrhosis, ocular herpes 
simplex, existing emotional instability or psychotic tendencies, nonspecific ulcerative colitis, 
diverticulitis, fresh intestinal anastomoses, peptic ulcer, renal insufficiency, hypertension, 
osteoporosis and myasthenia gravis.  Immunization procedures (especially smallpox vaccination) 
should not be undertaken in participants on corticosteroids. 
PHARMACOLOGY 
Kinetics:  Natural and synthetic glucocorticoids are readily and completely absorbed from the GI tract.  
Dexamethasone is insoluble in water.  Glucocorticoids have salt-retaining properties, although 
dexamethasone nearly completely lacks this property.  The anti-inflammatory property of this drug is 
its ability to modify the body’s immune system.  On the other hand, glucocorticoids suppress the 
body’s response to viral and bacterial infections. 


Page 19 of 74 
 
Formulation:  Dexamethasone is available in six potencies (0.25 mg, 0.5 mg, 0.75 mg, 1.5 mg, 4 mg, 
and 6 mg) in capsule or tablet form. 
Storage and Stability: Dexamethasone is to be stored at room temperature. 
Administration:  The drug is administered orally. 
3.4 Melphalan (Alkeran)  
DESCRIPTION 
Chemistry:  Melphalan (L-phenylamine mustard, L-PAM, L-Sarcolysin) is an alkylating agent coupled 
to an amino acid. 
Molecular Formula:  C13H18C12N2O2   M.W.:  305 
TOXICOLOGY 
Human Toxicology:  Melphalan’s major systemic toxicity is bone marrow depression with secondary 
anemia, leukopenia and thrombocytopenia, usually occurring within three to five weeks of the onset of 
therapy and lasting four to eight weeks.  Prior chemotherapy or radiotherapy exacerbates these 
effects.  Other side-effects include nausea, vomiting, diarrhea, stomatitis, esophagitis, colitis, 
increases in liver function and kidney function tests, renal/bladder necrosis, pulmonary fibrosis, 
respiratory distress, peripheral neuropathy, paresthesia, alopecia, fever, and hypersensitivity 
including edema, rash and anaphylaxis.  The occurrence of acute leukemia has been rarely reported 
in participants treated with anthracycline/alkylator combination chemotherapy. 
PHARMACOLOGY 
Formulation:  The intravenous preparation is available in a sterile, 50 mg vial.  The product is 
prepared as a lyophilized powder with 20 mg of povidone per vial.  Also provided is 10 ml of special 
diluent for use in constituting the product.   
Solution preparation: Vial/50 mg: Constitute with 10 ml of the special diluent to yield a 5 mg/ml 
melphalan concentration.  Prior to administration, dilute the constituted solution with 0.9% Sodium 
Chloride Injection, USP, to a concentration no greater than 2 mg/ml.   
Storage and Stability: The intact packages of melphalan for intravenous administration should be 
stored at room temperature (15-30C) protected from light.  Shelf surveillance of the intact dosage 
form is ongoing. 
Constitution with the special diluent as directed results in a solution that retains at least 90% 
melphalan potency for about 3 hours at 30C.  Storage at 5C results in precipitation. 
When the constituted solution is diluted to concentrations of 0.45 or 0.1 mg/ml in 0.9% Sodium 
Chloride Injection USP, 90% melphalan potency is retained for 45 minutes at 30C.  At 20C, the 0.1 
mg/ml concentration retained 90% potency for 3 hours.  The manufacturer recommends 
administration of melphalan within one hour of constitution. 


Page 20 of 74 
 
In dilute solutions of approximately 40 g/ml, increasing amounts of chloride ion appear to enhance 
stability.  For example, increasing the chloride content of such a solution from 0.2% to 0.9% increases 
the half-life from 8 to 16 hours. 
Increased temperature as well as decreased chloride ion is associated with much higher degradation 
rates.  An increase of temperature from 20C to 25C decreased the time to 10% decomposition by 
about one-half in each case. 
Administration: melphalan will be administered intravenously. 
3.5  Cisplatin (Cis-diamminedichloroplatinum [CDDP], Platinol)  
DESCRIPTION 
Cisplatin is a heavy metal complex and is water-soluble.  It is a white lyophilized powder with a 
molecular weight of 300.1.  Mechanism of action:  It acts as a bifunctional alkylating agent. 
TOXICOLOGY 
Human Toxicology: Human toxicity includes anorexia, nausea, vomiting, renal toxicity (with an 
elevation of BUN, creatinine, serum uric acid and impairment of endogenous creatinine clearance, as 
well as renal tubular damage), ototoxicity (with hearing loss which is initially in the high frequency 
range, as well as tinnitus), and hyperuricemia.  Much more severe and prolonged toxicity has been 
observed in participants with abnormal or obstructed urinary excretory tracts.  Raynaud’s phenomena 
and digital ischemia has been described.  Anaphylactic-like reactions including facial edema, 
bronchoconstriction, tachycardia and hypotension may occur within minutes of administration.  
Myelosuppression, often delayed erythrosuppression, is expected.  In the high-dose treatment 
regimen with osmotic diuresis, the nadir of white cells and platelets occurred regularly at about two 
weeks with recovery generally at about three weeks after the initiation of therapy.  Rare complications 
are alopecia, seizures, loss of taste, allergic reactions, and loss of muscle or nerve function.  Tetany 
may occur due to hypomagnesemia and/or hypercalcemia.  Other electrolyte disturbances may occur.  
At high doses, participants have experienced optic neuritis, papilledema, cerebral blindness, blurred 
vision, and altered color perception.  Participants have also experienced cardiac abnormalities, 
elevated SGOT and rash.  Subsequent courses should not be given until serum creatinine returns to 
normal, if elevated.  Audiometric analyses should be monitored and courses withheld until auditory 
acuity is within normal limits.  The occurrence of acute leukemia has been reported rarely in 
participants treated with anthracycline/alkylator combination chemotherapy.  
PHARMACOLOGY 
Kinetics:  After a single IV dose, increased concentration is found in the liver, kidneys, and small and 
large intestines.  Plasma levels of cisplatin decay in a biphasic mode with an initial half-life of 25 to 49 
minutes, and a secondary phase ranging from 58 to 73 hours.  This prolonged phase is due to protein 
binding, which exceeds 90% of the radioactivity, excreted in the first five days.  The initial fractions of 
radioactivity are largely unchanged drugs.  Although this drug seems to act as an alkylating agent, 
there are data to indicate that its mode and sites of action are different from those of nitrogen mustard 
and the standard alkylating agents.  Cisplatin penetrates poorly into CNS. 


Page 21 of 74 
 
Formulation:  Cisplatin is available in 50 mg and 100 mg reconstituted vials. 
Storage and Stability:  The intact vials may be stored at room temperature (15-25C) for the lot life 
indicated on the package.  Do not refrigerate.  The solution may be further diluted in a chloride-
containing vehicle such as D5NS, NS, or D5½NS (precipitate occurs in D5W). 
Administration:  Cisplatin should be given as a slow intravenous infusion. Needles or intravenous sets 
containing aluminum parts that may come in contact with cisplatinum (Platinol) should not be used for 
preparation or administration, as a black precipitate is formed within 30 minutes. 
3.6 Doxorubicin (Adriamycin)  
DESCRIPTION 
Mechanism of action: Doxorubicin is a cytotoxic anthracycline antibiotic different from daunorubicin by 
the presence of a hydroxyl group in the C-14 position.  Doxorubicin is produced by fermentation from 
S. peucetius var. caesius.  Its mechanism of action is thought to be the binding of nucleic acids, 
preventing DNA and possibly RNA synthesis. 
TOXICOLOGY 
Human Toxicology: Studies with doxorubicin have shown that the major toxic effects of this drug are 
alopecia, which is often total but always reversible; nausea and vomiting, which develops shortly after 
drug administration, occasionally persisting for 2-3 days; fever on the day of administration; and 
phlebitis at the site of the drug’s injection.  Extravasation of the drug will lead to soft tissue necrosis.  
Phleboscleriosis, cellulitis, vesication and erythematous streaking have also been seen.  Mucositis 
may be seen 5-10 days after administration.  Ulceration and necrosis of the colon, particularly the 
cecum, with bleeding and severe infection have been reported with concomitant administration of 
cytarabine.  Anorexia and diarrhea have also been observed.  Hyperpigmentation of nail beds and 
dermal creases, onycholysis and recall of skin reaction from prior radiotherapy may occur.  Cardiac 
toxicity manifested as acute left ventricular failure, congestive heart failure, arrhythmia or severe 
cardiomyopathy has been reported, but appears to occur predominantly in participants who receive 
total doses in excess of 550 mg/m2.   
Myelosuppression, predominantly neutropenia, is common with nadir occurring approximately two 
weeks after a single injection; lesser degrees of anemia and thrombocytopenia have been reported.  
Rapid recovery of blood counts approximately two and a half weeks after a single injection generally 
permits an every three-week dosing schedule.   
Participants with obstructive liver disease have more severe myelosuppression due to impaired drug 
excretion.  Thus, participants with hepatic dysfunction may need to have reduced dosage or be 
excluded from therapy.  Renal excretion of doxorubicin is minimal, but enough to color the urine red; 
thus impaired renal function does no appear to increase the toxicity of doxorubicin.  Other side effects 
include fever, chills, facial flushing, itching, anaphylaxis, conjunctivitis and lacrimation.  The 
occurrence of acute leukemia has been reported rarely in participants treated with 
anthracycline/alkylator combination chemotherapy. 


Page 22 of 74 
 
Safe use of doxorubicin in pregnancy has not been established.  It is embryotoxic and teratogenic in 
rats and embryotoxic and aborticacient in rabbits.  The possible effects on fertility have not been 
adequately evaluated.  Safety in nursing women has not been proven. 
PHARMACOLOGY 
Kinetics:  Intravenous administration is followed by a rapid plasma clearance with significant tissue 
binding.  Urinary excretion is negligible; biliary excretion accounts for 40 to 50% of the administered 
dose being recovered in the bile or the feces in 7 days.  The drug does not cross the blood-brain 
barrier. 
Formulation:  Doxorubicin is supplied in 10, 20, and 50 mg single use vials, and 150 and 200 mg 
multidose vials. 
Storage and Stability: Doxorubicin is stable for 24 hours at room temperature and 15 days under 
refrigeration (2-8C).  It should be protected from exposure to sunlight.  Discard any unused solution 
from the vials.  Bacteriostatic diluents with preservatives are NOT recommended as they might 
possibly worsen the reaction to extravasated drug. 
Administration:  Doxorubicin may be further diluted in 5% dextrose or sodium chloride injection and 
should be administered slowly into tubing of a freely flowing intravenous infusion with great care 
taken to avoid extravasation. 
3.7 Cyclophosphamide (Cytoxan)  
DESCRIPTION 
2[bis (2chloroethyl)amino]tetrahydro-2H-1,3,2-oxazophosphorine 2-oxide mono-hydrate.  
Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites that cross-
link to DNA. 
TOXICOLOGY 
Human Toxicology: Toxicity from cyclophosphamide includes bone marrow suppression which 
usually occurs 10 to 12 days after administration; nausea, vomiting, anorexia, abdominal discomfort, 
diarrhea and stomatitis; reversible alopecia; hemorrhagic cystitis, which can frequently be prevented 
with increased hydration; fibrosis of the bladder; cardiac toxicity, which may potentiate doxorubicin-
induced cardiotoxicity; rare anaphylactic reaction, skin rash, hyperpigmentation, interstitial pulmonary 
fibrosis, and cross sensitivity with other alkylating agents.  Treatment with cyclophosphamide may 
cause significant suppression of the immune system. 
Secondary malignancies, most frequently of the urinary bladder and hematologic systems, have been 
reported when Cytoxan® is used alone or with other anti-neoplastic drugs.  Malignancies may occur 
several years after treatment has been discontinued.  Cyclophosphamide interferes with oogenesis 
and spermatogenesis and may cause sterility in both sexes, which is dose and duration related.  
Cyclophosphamide has been found to be teratogenic, and women of childbearing potential should be 
advised to avoid becoming pregnant.  Increased myelosuppression may be seen with chronic 


Page 23 of 74 
 
administration of high doses of phenobarbital.  Cyclophosphamide inhibits cholinesterase activity and 
potentiates the effect of succinylcholine chloride.  If a participant requires general anesthesia within 
10 days after cyclophosphamide administration, the anesthesiologist should be alerted. Adrenal 
insufficiency may be worsened with cyclophosphamide. Cyclophosphamide is excreted in breast milk, 
and it is advised that mothers discontinue nursing during cyclophosphamide administration.  The 
occurrence of acute leukemia has been reported rarely in participants treated with 
anthracycline/alkylator combination chemotherapy. 
PHARMACOLOGY 
Kinetics:  Cyclophosphamide is activated principally in the liver by a mixed function microsomal 
oxidase system.  PO administration is well absorbed, with bioavailability greater than 75%.  5-25% of 
unchanged drug is excreted in the urine.  Several active and inactive metabolites have been identified 
with variable plasma protein binding.  There appears to be no evidence of clinical toxicity in 
participants with renal failure, although elevated levels of metabolites have been observed. 
Formulation:  Cyclophosphamide is supplied in 100 mg, 200 mg, 500 mg, 1 gm and 2 gm vials as a 
white powder.  The drug should be reconstituted with sterile water for injection and may be diluted in 
normal saline or D5W.  Cyclophosphamide is also available as a reconstituted solution available in 
the same size vial as the lyophilized form.   
Storage and Stability: The reconstituted vial is stable for 24 hours at room temperature and 6 days 
when refrigerated. 
Administration:  The drug should be further diluted in saline or D5W and administered by slow IV 
infusion. 
3.8 Etoposide (VP-16), (Vepesid) (Ethylidene-Lignan P)   
DESCRIPTION 
Chemistry:  Etoposide is a semi-synthetic podophyllotoxin derivative from the plant podophyllum 
pletatum, and has antineoplastic properties in experimental animals and in humans.  The empiric 
formula C29H32O has a molecular weight of 588. 
Mechanism of Action:  The epipodophyllotoxins exert phase specific spindle poison activity with 
metaphase arrest, but in contrast to the vinca-alkaloids, have an additional activity of inhibiting cells 
from entering mitosis.  Suppression of tritiated thymidine, uridine, and leucine incorporation in human 
cells in tissue culture suggests effects against DNA, RNA and protein synthesis.   
Animal Tumor Data:  Significant antitumor effect has been demonstrated in L1210, mouse sarcoma 
37 and 180, Walker carcinosarcoma and Erlich ascites tumor.  With the L1210 system, activity was 
schedule-dependent, having greater effect with a twice-weekly administration than with daily dosing 
or the administration of single large doses.  The drug is active given intraperitoneally or orally in 
L1210.  No effect was demonstrated against intracerebrally inoculated L1210. 
 


Page 24 of 74 
 
TOXICOLOGY 
Animal Toxicology: The predominant toxicities of etoposide in animal studies involve the 
hematopoietic system, with toxicity to the liver and GI tract occurring only at doses producing 
profound myelosuppression.  Anemia, leukopenia, and lymphoid involution occur in mice, rats and 
monkeys.  Acute toxicity investigations have been complicated by the toxicity of the solvent system.  
The LD-50 of the solvent plus drug approached that of the solvent alone.  Immunosuppressive effects 
occur with an inhibition of antibody production in mice and monkeys, and prevention of experimental 
allergic encephalomyelitis in rats (cell-mediated immunity). 
Human Toxicology: Reversible myelotoxicity has been uniformly observed to be the major toxicity of 
etoposide and to represent the only clinically significant side effect.  Following a single IV injection, 
peak myelotoxicity occurs at seven to nine days.  Following daily IV injections for five to seven days, 
myelotoxicity is maximal between 12 - 16 days from the initiation of therapy.   Bone marrow 
suppression is mainly manifested as granulocytopenia, with thrombocytopenia and anemia occurring 
to a lesser extent.  Gastrointestinal toxicities including transient modest nausea, vomiting and 
diarrhea, are common.  Other reactions could include aftertaste, rash, pigmentation, pruritis, 
abdominal pain, constipation and dysphagia.  Occasional alopecia is reported.  Etoposide does not 
produce phlebitis or nephrotoxicity.  Rarely, anaphylactic-like reactions have been reported, as well 
as hypotension.  Hypotension can be managed by infusing the drug over at least a 30-minute period.  
Occasionally, chills, fever, peripheral neurotoxicity, stomatitis, hepatotoxicity, transient cortical 
blindness and radiation recall dermatitis may be a result of etoposide administration.  The occurrence 
of acute leukemia has been rarely reported in participants treated with etoposide in association with 
other antineoplastic agents.  
Pregnancy and Lactation: Etoposide can cause fetal harm when administered to a pregnant woman.  
Etoposide has been shown to be teratogenic in mice and rats.  In these studies, etoposide caused 
dose-related maternal toxicity, embryotoxicity, and teratogenicity.  Fetal abnormalities included 
decreased weight, major skeletal abnormalities, exencephaly, encephalocele, anophthalmia, and 
retarded ossification.  No information is available on excretion of this drug in human milk.  Because 
many drugs are excreted in human milk and because of the potential for serious adverse reactions in 
nursing infants, it is recommended that nursing be discontinued. 
PHARMACOLOGY 
Kinetics:  After IV administration, disposition is biphasic with initial half-life of 1.5 hours and terminal 
half-life of 4 - 11 hours.  Drug does not accumulate in plasma following daily administration of 100 
mg/M2 for 4 - 5 days.  Drug poorly crosses blood-brain barrier.  Recovery after IV administration of 
radiolabeled etoposide in the urine ranges from 42 - 67% and feces from 0 - 16%.  The mutagenic 
and genotoxic potential has been established in mammalian cells. 
Formulation:  100 mg of etoposide is supplied as 5 ml of solution in Sterile Multiple Dose Vials for 
injection.  The pH of the yellow clear solution is 3 - 4.  Each ml contains 20 mg etoposide, 2 mg citric 
acid, 30 mg benzyl alcohol, 80 mg polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 
30.5% (v/v) alcohol.  Etoposide must be diluted prior to use with either 5% Dextrose Injection, USP, 
or 0.9% sodium Chloride Injection, USP.  The time before precipitation occurs depends on 


Page 25 of 74 
 
concentration; however, when at a concentration of 0.2 mg/ml it is stable for 96 hours at room 
temperature and at 0.4 mg/ml it is stable for 48 hours. 
Storage and Stability: The drug is available as a box of 10 vials that are stored at room temperature.  
Each vial should be kept in the box to protect it from light.  Etoposide is less stable in 5% Dextrose 
injection and precipitation is reported. 
Administration:  Etoposide is administered by slow IV infusion to reduce hypotension. 
3.9 Lenalidomide (Revlimid) 
WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND 
PULMONARY EMBOLISM 
FETAL RISK 
Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study 
similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it 
may cause birth defects or death to a developing baby. 
Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the 
use of two reliable methods of contraception. 
HEMATOLOGICAL TOXICITY 
Can cause significant neutropenia and thrombocytopenia. 
DVT AND PE 
Significantly increased risk of DVT and PE in participants with multiple myeloma receiving 
lenalidomide with dexamethasone. Participants and physicians are advised to be observant for the 
signs and symptoms of thrombo-embolism. Participants should be instructed to seek medical care if 
they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not 
known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with 
lenalidomide may lessen the potential for venous thromboembolic events. The decision to take 
prophylactic measures should be done carefully after an assessment of an individual participant’s 
underlying risk. 
INDICATIONS AND USAGE 
Lenalidomide is a thalidomide analogue indicated for the treatment of multiple myeloma (MM), in 
combination with dexamethasone, in participants who have received at least one prior therapy. 
DOSING AND ADMINISTRATION 
MM: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles. Recommended dose of 
dexamethasone is 40 mg once daily on Days 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 
cycles of therapy and then 40 mg/day orally on Days 1-4 every 28 days.  Treatment is continued or 
modified based upon clinical and laboratory findings. 


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DOSE ADJUSTMENTS FOR HEMATOLOGIC TOXICITIES DURING MULTIPLE MYELOMA 
TREATMENT 
Dose modification guidelines are recommended to manage Grade 3 or 4 neutropenia or 
thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to lenalidomide. 
DOSE ADJUSTMENTS FOR RENAL IMPAIRMENT IN MM 
Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of 
lenalidomide are recommended to provide appropriate drug exposure in participants with moderate or 
severe renal impairment and in participants on dialysis.  Based on a pharmacokinetic study in 
participants with renal impairment due to non-malignant conditions, LENALIDOMIDE  starting dose 
adjustment is recommended for participants with CLcr <60 mL/min. Non-dialysis participants with 
creatinine clearances less than 11 mL/min and dialysis participants with creatinine clearances less 
than 7 mL/min have not been studied.  After initiation of LENALIDOMIDE  therapy, subsequent 
LENALIDOMIDE  dose modification should be based on individual participant treatment tolerance.   
DOSAGE FORMS AND STRENGTHS 
Lenalidomide 5 mg, 10 mg, 15 mg and 25 mg capsules will be supplied through RevAssist. 
CONTRAINDICATIONS 
Lenalidomide may cause fetal harm when administered to a pregnant woman. Limb abnormalities 
were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This 
effect was seen at all doses tested. Due to the results of this developmental monkey study, and 
lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is 
contraindicated in pregnant women and women capable of becoming pregnant. Females of 
childbearing potential may be treated with lenalidomide provided adequate precautions are taken to 
avoid pregnancy. Females must commit either to abstain continuously from heterosexual sexual 
intercourse or to use two methods of reliable birth control, including at least one highly effective 
method (e.g., hormonal contraception, tubal ligation, IUD or partner’s vasectomy) and one additional 
effective method (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks prior to initiating 
treatment with lenalidomide, during therapy, during therapy delay, and continuing for 4 weeks 
following discontinuation of lenalidomide therapy. If hormonal or IUD contraception is medically 
contraindicated, two other effective or highly effective methods may be used. 
Females of childbearing potential being treated with lenalidomide must have pregnancy testing 
(sensitivity of at least 50 mIU/mL). Pregnancy testing and counseling must be performed if a 
participant misses her period or if there is any abnormality in menstrual bleeding. If pregnancy occurs, 
lenalidomide must be immediately discontinued. Under these conditions, the participant should be 
referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling. 
Lenalidomide is also contraindicated in participants who have demonstrated hypersensitivity 
(e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide. 
 


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WARNINGS AND PRECAUTIONS 
Fetal Risk 
Lenalidomide is a thalidomide analogue. Thalidomide is a known human teratogen that causes life-
threatening human birth defects. An embryo-fetal development study in non-human primates 
indicates that lenalidomide produced malformations in the offspring of female monkeys who received 
the drug during pregnancy, similar to birth defects observed in humans following exposure to 
thalidomide during pregnancy. If lenalidomide is used during pregnancy, it may cause birth defects or 
death to a developing baby. Females of childbearing potential must be advised to avoid pregnancy 
while on lenalidomide. Two effective contraceptive methods should be used during therapy, during 
therapy interruptions and for at least 4 weeks after completing therapy. There are no adequate and 
well-controlled studies in pregnant females. 
Hematologic Toxicity 
Lenalidomide can cause significant neutropenia and thrombocytopenia.  In the pooled multiple 
myeloma studies Grade 3 and 4 hematologic toxicities were more frequent in participants treated with 
the combination of lenalidomide and dexamethasone than in participants treated with dexamethasone 
alone. 
Deep Vein Thrombosis and Pulmonary Embolism 
Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) 
have occurred in participants with multiple myeloma treated with lenalidomide combination therapy or 
treated with lenalidomide monotherapy. A significantly increased risk of DVT and PE was observed in 
participants with multiple myeloma who were treated with lenalidomide and dexamethasone therapy 
in a clinical trial. It is not known whether prophylactic anticoagulation or antiplatelet therapy 
prescribed in conjunction with lenalidomide may lessen the potential for venous thromboembolic 
events. The decision to take prophylactic measures should be done carefully after an assessment of 
an individual participant’s underlying risk factors. 
Allergic Reactions 
Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and 
toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Participants with a 
prior history of Grade 4 rash associated with thalidomide treatment should not receive lenalidomide.  
Lenalidomide interruption or discontinuation should be considered for Grade 2-3 skin rash. 
Lenalidomide must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if 
SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. 
Tumor Lysis Syndrome 
Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The 
participants at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. 
These participants should be monitored closely and appropriate precautions taken. 


Page 28 of 74 
 
Tumor Flare Reaction 
Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, 
and is characterized by tender lymph node swelling, low grade fever, pain and rash. Treatment of 
CLL or lymphoma with lenalidomide outside of a well-monitored clinical trial is discouraged. 
ADVERSE REACTIONS 
Clinical Trials Experience in Multiple Myeloma 
Data were evaluated from 703 participants in two studies who received at least one dose of 
lenalidomide/dexamethasone (353 participants) or placebo/dexamethasone (350 participants).  In the 
lenalidomide/dexamethasone treatment group, 269 participants (76%) underwent at least one dose 
interruption with or without a dose reduction of lenalidomide compared to 199 participants (57%) in 
the placebo/dexamethasone treatment group. Of these participants who had one dose interruption 
with or without a dose reduction, 50% in the lenalidomide/dexamethasone treatment group underwent 
at least one additional dose interruption with or without a dose reduction compared to 21% in the 
placebo/dexamethasone treatment group. Most adverse events and Grade 3/4 adverse events were 
more frequent in participants who received the combination of lenalidomide/dexamethasone 
compared to placebo/dexamethasone. 
Median duration of exposure among participants treated with lenalidomide/dexamethasone was 44 
weeks while median duration of exposure among participants treated with placebo/dexamethasone 
was 23 weeks. This should be taken into consideration when comparing frequency of adverse events 
between two treatment groups lenalidomide/dexamethasone vs. placebo/dexamethasone. 
Deep Vein Thrombosis and Pulmonary Embolism 
Deep vein thrombosis (DVT) was reported as a serious adverse drug reaction (7.4%) or Grade 3/4 
(8.2%) at a higher rate in the lenalidomide/dexamethasone group compared to 3.1% and 3.4% in the 
placebo/dexamethasone group, respectively. Discontinuations due to DVT adverse reactions were 
reported at comparable rates between groups. 
Pulmonary embolism (PE) was reported as a serious adverse drug reaction including Grade 3/4 
(3.7%) at a higher rate in the lenalidomide/dexamethasone group compared to 0.9% in the 
placebo/dexamethasone group. Discontinuations due to PE adverse reactions were reported at 
comparable rates between groups. 
Other Adverse Events 
In these clinical studies of lenalidomide in participants with multiple myeloma, the following adverse 
drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the 
placebo percentage rate were reported: 
Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia 
Cardiac disorders: bradycardia, myocardial infarction, angina pectoris 


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Endocrine disorders: hirsutism 
Eye disorders: blindness, ocular hypertension 
Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia 
General disorders and administration site conditions: malaise 
Investigations: liver function tests abnormal, alanine aminotransferase increased, 
Nervous system disorders: cerebral ischemia 
Psychiatric disorders: mood swings, hallucination loss of libido 
Reproductive system and breast disorders: erectile dysfunction, 
Respiratory, thoracic and mediastinal disorders: cough, hoarseness 
Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation 
DRUG INTERACTIONS 
Results from human in vitro metabolism studies and nonclinical studies show that lenalidomide is 
neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that 
lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions in man. 
DIGOXIN 
When digoxin was co-administered with lenalidomide, the digoxin AUC was not significantly different; 
however, the digoxin Cmax was increased by 14%. Periodic monitoring of digoxin plasma levels, in 
accordance with clinical judgment and based on standard clinical practice in participants receiving 
this medication, is recommended during administration of lenalidomide. 
WARFARIN 
Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single dose 
pharmacokinetics of R- and S-warfarin. Co-administration of single 25-mg dose warfarin had no effect 
on the pharmacokinetics of total lenalidomide. Expected changes in laboratory assessments of PT 
and INR were observed after warfarin administration, but these changes were not affected by 
concomitant lenalidomide administration. 
Concomitant Therapies That May Increase the Risk of Thrombosis 
Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen 
containing therapies, should be used with caution in multiple myeloma participants receiving 
lenalidomide with dexamethasone.  
 
 


Page 30 of 74 
 
GERIATRIC USE 
Lenalidomide has been used in multiple myeloma (MM) clinical trials in participants up to 86 years of 
age. Of the 703 MM participants who received study treatment in Studies 1 and 2, 45% were age 65 
or over while 12% of participants were age 75 and over. The percentage of participants age 65 or 
over was not significantly different between the lenalidomide/ dexamethasone and 
placebo/dexamethasone groups. Of the 353 participants who received lenalidomide/dexamethasone, 
46% were age 65 and over. In both studies, participants >65 years of age were more likely than 
participants ≤65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal 
failure following use of lenalidomide. No differences in efficacy were observed between participants 
over 65 years of age and younger participants. 
DESCRIPTION 
Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and 
antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H -isoindol-2-yl) 
piperidine-2,6-dione and it has the following chemical structure: 3-(4-amino-1-oxo 1,3-dihydro-2H -
isoindol-2-yl) piperidine-2,6-dione The empirical formula for lenalidomide is C13H13N3O3, and the 
gram molecular weight is 259.3. Lenalidomide is available in 5 mg, 10 mg, 15 mg and 25 mg 
capsules for oral administration. 
CLINICAL PHARMACOLOGY 
Mechanism of Action 
The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide possesses 
immunomodulatory, antiangiogenic, and antineoplastic properties. Experiments have demonstrated 
that lenalidomide inhibits the growth of cells derived from participants with multiple myeloma and del 
(5q) myelodysplastic syndromes in vitro.  Lenalidomide causes a delay in tumor growth in some in 
vivo nonclinical hematopoietic tumor models, including multiple myeloma. Lenalidomide inhibits the 
secretion of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), from peripheral 
blood mononuclear cells. Lenalidomide also inhibited the expression of cycoloxygenase-2 (COX-2) 
but not COX-1 in vitro. 
Pharmacokinetics 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with maximum 
plasma concentrations occurring between 0.625 and 1.5 hours post-dose. Co-administration with food 
does not alter the extent of absorption (AUC) but does reduce the maximal plasma concentration 
(Cmax) by 36%. The pharmaco -kinetic disposition of lenalidomide is linear. Cmax and AUC increase 
proportionately with increases in dose. Multiple dosing at the recommended dose-regimen does not 
result in drug accumulation. 
Pharmacokinetic sampling in myelodysplastic syndromes participants was not performed. In multiple 
myeloma participants maximum plasma concentrations occurred between 0.5 and 4.0 hours post-
dose both on Days 1 and 28. AUC and Cmax values increase proportionally with dose following 


Page 31 of 74 
 
single and multiple doses. Exposure (AUC) in multiple myeloma participants is 57% higher than in 
healthy male volunteers. 
Distribution 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
Metabolism and Excretion 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. The 
process exceeds the glomerular filtration rate and therefore is partially or entirely active. Half-life of 
elimination is approximately 3 hours. 
SPECIAL POPULATIONS  
Participants with Renal Impairment 
In multiple myeloma participants, those participants with mild renal impairment had an AUC 56% 
greater than those with normal renal function. Adjustment of the starting dose of lenalidomide  is 
recommended in participants with moderate or severe (CLcr <60 mL/min) renal impairment and in 
participants on dialysis. 
3.10 Carfilzomib (Kyprolis)  
For Injection, for intravenous use.  Initial U.S. Approval: 2012 
DOSAGE AND ADMINISTRATION 
 
Administer intravenously over 2 to 10 minutes, on two consecutive days each week for three weeks 
followed by a 12-day rest period.   Recommended Cycle 1 dose is 20 mg/m2/day, and if tolerated, 
increase Cycle 2 dose and subsequent cycles doses to 27 mg/m2/day.  Carfilzomib may also be 
given 56 mg/m2 on days 1, 8, 15 and 22, if deemed beneficial for patient by the treating physician. 
 
The safety of carfilzomib was evaluated in clinical studies of 526 patients with relapsed and/or 
refractory multiple myeloma. 
 
Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia  
 
Death due to cardiac arrest has occurred within a day of carfilzomib administration. New onset or 
worsening of pre-existing congestive heart failure with decreased left ventricular function or 
myocardial ischemia have occurred following administration of carfilzomib. Cardiac failure events 
(e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% 
of patients. Monitor for cardiac complications and manage promptly. Withhold carfilzomib for Grade 3 
or 4 cardiac events until recovery and consider whether to restart carfilzomib based on a benefit/risk 
assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial 
infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may 
be at greater risk for cardiac complications.  
 
 


Page 32 of 74 
 
 
Pulmonary Hypertension  
 
Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with carfilzomib and 
was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests 
as indicated. Withhold carfilzomib for pulmonary hypertension until resolved or returned to baseline 
and consider whether to restart based on a benefit/risk assessment.  
 
Pulmonary Complications 
 
Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; 
no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; 
interrupt carfilzomib until symptoms have resolved or returned to baseline.  
 
Infusion Reactions 
 
Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, 
arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, 
hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following 
infusion or up to 24 hours after administration of carfilzomib. Administer dexamethasone prior to 
carfilzomib to reduce the incidence and severity of reactions. Inform patients of the risk and 
symptoms, and to contact physician if symptoms of an infusion reaction occur.  
 
Tumor Lysis Syndrome 
 
Tumor lysis syndrome (TLS) occurred following carfilzomib administration in < 1% of patients. 
Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk 
for TLS. Prior to receiving carfilzomib, ensure that patients are well hydrated. Monitor for evidence of 
TLS during treatment, and manage promptly. Interrupt carfilzomib until TLS is resolved.  
 
Thrombocytopenia 
 
Carfilzomib causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day 
cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple 
myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. 
Thrombocytopenia following carfilzomib administration resulted in a dose reduction in 1% of patients 
and discontinuation of treatment with cariflzomib in < 1% of patients. Monitor platelet counts 
frequently during treatment with carfilzomib. Reduce or interrupt dose as clinically indicated.  
 
Hepatic Toxicity and Hepatic Failure 
 
Cases of hepatic failure, including fatal cases, have been reported (< 1%). Carfilzomib can cause 
elevations of serum transaminases and bilirubin. Withhold carfilzomib in patients experiencing Grade 
3 or greater elevations of transaminases, bilirubin, or other liver enzyme abnormalities until resolved 
or returned to baseline. After resolution, consider if restarting carfilzomib is appropriate. Monitor liver 
enzymes frequently.  
 
Embryo-fetal Toxicity 
 


Page 33 of 74 
 
Carfilzomib can cause fetal harm when administered to a pregnant woman based on its mechanism 
of action and findings in animals. There are no adequate and well-controlled studies in pregnant 
women using carfilzomib. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that 
were lower than in patients receiving the recommended dose. Females of reproductive potential 
should be advised to avoid becoming pregnant while being treated with carfilzomib. 
 
ADVERSE REACTIONS 
 
Serious adverse reactions were reported in 45% of patients. The most common serious adverse 
reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure 
(3%). Adverse reactions leading to discontinuation of carfilzomib occurred in 15% of patients and 
included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute 
renal failure (1% each). 
 
The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea 
(45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%). 
 
USE IN SPECIFIC POPULATIONS 
 
Since dialysis clearance of carfilzomib concentrations has not been studied, the drug should be 
administered after the dialysis procedure. 
 
3.11 Pomalidomide (Pomalyst)  
 
INDICATION  
 
Patients with multiple myeloma who have received at least two prior therapies including lenalidomide 
and bortezomib and have demonstrated disease progression on or within 60 days of completion of 
the last therapy. 
 
CONTRAINDICATIONS 
 
Pomalidomide can cause fetal harm and is contraindicated in females who are pregnant. If this drug 
is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should 
be apprised of the potential hazard to a fetus.  Pomalidomide is a thalidomide analogue and is 
teratogenic in both rats and rabbits when administered during the period of organogenesis.  
WARNINGS AND PRECAUTIONS 
Females of Reproductive Potential 
Must avoid pregnancy while taking pomalidomide and for at least 4 weeks after completing therapy. 
Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods 
of reliable birth control, beginning 4 weeks prior to initiating treatment with pomalidomide, during 
therapy, during dose interruptions and continuing for 4 weeks following discontinuation of 
pomalidomide therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy.  
Males 


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Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex 
or synthetic condom during any sexual contact with females of reproductive potential while taking 
pomalidomide and for up to 28 days after discontinuing pomalidomide, even if they have undergone a 
successful vasectomy. Males must not donate sperm.  
Blood Donation  
Patients must not donate blood during treatment with pomalidomide and for 1 month following 
discontinuation of the drug because the blood might be given to a pregnant female patient whose 
fetus must not be exposed to pomalidomide.   
ADVERSE REACTIONS 
In the clinical trial of 219 patients who received pomalidomide alone (n=107) or pomalidomide+ low-
dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent 
adverse reaction.  
In the pomalidomide alone versus pomalidomide + low dose dexamethasone arms, respectively, most 
common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 
47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), 
dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and 
pyrexia (19%, 30%)  
90% of patients treated with pomalidomide alone and 88% of patients treated with pomalidomide + 
low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction.  
In the pomalidomide alone versus pomalidomide+ low dose dexamethasone arms, respectively, most 
common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), 
thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides 
neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the 
previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s 
discretion.  
67% of patients treated with pomalidomide and 62% of patients treated with pomalidomide + low-
dose dex had at least one treatment-emergent serious adverse reaction.  
In the pomalidomide alone versus pomalidomide + low dose dexamethasone arms, respectively, most 
common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), 
dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%), dehydration (5%, 3%), hypercalcemia (5%, 
2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%).  
Venous Thromboembolism 
Patients receiving pomalidomide have developed venous thromboembolic events reported as serious 
adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic 
treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment 
of each patient’s underlying risk factors.  
Hematologic Toxicity 


Page 35 of 74 
 
Neutropenia of any grade was reported in 50% of patients and was the most frequently reported 
Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for 
hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks 
and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities 
based upon clinical and laboratory findings. Dosing interruptions and/or modifications are 
recommended to manage neutropenia and thrombocytopenia.  
Hypersensitivity Reactions 
Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide 
were excluded from studies and may be at higher risk of hypersensitivity.  
Dizziness and Confusional State 
18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of 
patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional 
state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to 
take other medications that may cause dizziness or confusion without adequate medical advice.  
Neuropathy 
18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no 
cases of grade 3 or higher neuropathy adverse reactions reported.  
Risk of Second Primary Malignancies 
Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an 
investigational therapy outside of multiple myeloma.  
3.12 Methylprednisolone (Medrol) 
DESCRIPTION 
Methylprednisolone tablets contain methylprednisolone which is a glucocorticoid. Glucocorticoids are 
adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the 
gastrointestinal tract. Methylprednisolone occurs as a white to practically white, odorless, crystalline 
powder. It is sparingly soluble in alcohol, in dioxane, and in methanol, slightly soluble in acetone, and 
in chloroform, and very slightly soluble in ether. It is practically insoluble in water. The chemical name 
for methylprednisolone is pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-6-methyl-, (6α,11β)-and 
the molecular weight is 374.48.  Each tablet for oral administration contains 2 mg, 4 mg, 8 mg, 16 mg 
or 32 mg of methylprednisolone. 
ACTIONS 
Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have saltretaining 
properties, are used as replacement therapy in adrenocortical deficiency states. 
Their synthetic analogs are primarily used for their potent anti-inflammatory effects in 
disorders of many organ systems. 
 
Glucocorticoids cause profound and varied metabolic effects. In addition, they modify 


Page 36 of 74 
 
the body’s immune responses to diverse stimuli. 
 
INDICATIONS AND USAGE 
Methylprednisolone tablets are indicated in the following conditions: 
1. Endocrine Disorders 
Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; 
synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy 
mineralocorticoid supplementation is of particular importance). 
Congenital adrenal hyperplasia 
Nonsuppurative thyroiditis 
Hypercalcemia associated with cancer 
2. Rheumatic Disorders 
As adjunctive therapy for short-term administration (to tide the patient over an acute episode or 
exacerbation) in: 
Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose 
maintenance therapy) 
Ankylosing spondylitis 
Acute and subacute bursitis 
Synovitis of osteoarthritis 
Acute nonspecific tenosynovitis 
Post-traumatic osteoarthritis 
Psoriatic arthritis 
Epicondylitis 
Acute gouty arthritis 
3. Collagen Diseases 
During an exacerbation or as maintenance therapy in selected cases of: 
Systemic lupus erythematosus 


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Systemic dermatomyositis (polymyositis) 
Acute rheumatic carditis 
4. Dermatologic Diseases 
Bullous dermatitis herpetiformis 
Severe erythema multiforme 
(Stevens-Johnson syndrome) 
Severe seborrheic dermatitis 
Exfoliative dermatitis 
Mycosis fungoides 
Pemphigus 
Severe psoriasis 
5. Allergic States 
Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional 
treatment: 
Seasonal or perennial allergic rhinitis 
Drug hypersensitivity reactions 
Serum sickness 
Contact dermatitis 
Bronchial asthma 
Atopic dermatitis 
6. Ophthalmic Diseases 
Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such 
as: 
Allergic corneal marginal ulcers 
Herpes zoster ophthalmicus 
Anterior segment inflammation 


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Diffuse posterior uveitis and choroiditis 
Sympathetic ophthalmia 
Keratitis 
Optic neuritis 
Allergic conjunctivitis 
Chorioretinitis 
Iritis and iridocyclitis 
7. Respiratory Diseases 
Symptomatic sarcoidosis 
Berylliosis 
Loeffler’s syndrome not manageable by other means 
Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate 
antituberculous chemotherapy 
Aspiration pneumonitis 
8. Hematologic Disorders 
Idiopathic thrombocytopenic purpura in adults 
Secondary thrombocytopenia in adults 
Acquired (autoimmune) hemolytic anemia 
Erythroblastopenia (RBC anemia) 
Congenital (erythroid) hypoplastic anemia 
9. Neoplastic Diseases 
For palliative management of: Leukemias and lymphomas in adults; Acute leukemia of childhood 
10. Edematous States 
To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the 
idiopathic type or that due to lupus erythematosus. 
11. Gastrointestinal Diseases 


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To tide the patient over a critical period of the disease in: 
Ulcerative colitis 
Regional enteritis 
12. Nervous System 
Acute exacerbations of multiple sclerosis 
13. Miscellaneous 
Tuberculous meningitis with subarachnoid block or impending block when used concurrently with 
appropriate antituberculous chemotherapy. 
Trichinosis with neurologic or myocardial involvement. 
CONTRAINDICATIONS 
Systemic fungal infections and known hypersensitivity to components. 
WARNINGS 
In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting 
corticosteroids before, during, and after the stressful situation is indicated. Corticosteroids may mask 
some signs of infection, and new infections may appear during their use. Infections with any pathogen 
including viral, bacterial, fungal, protozoan or helminthic infections, in any location of the body, may 
be associated with the use of corticosteroids alone or in combination with other immunosuppressive 
agents that affect cellular immunity, humoral immunity, or neutrophil function. 
These infections may be mild, but can be severe and at times fatal. With increasing doses 
of corticosteroids, the rate of occurrence of infectious complications increases. There 
may be decreased resistance and inability to localize infection when corticosteroids are 
used. 
 
Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma 
with possible damage to the optic nerves, and may enhance the establishment of 
secondary ocular infections due to fungi or viruses 
 
Usage in pregnancy: Since adequate human reproduction studies have not been done 
with corticosteroids, the use of these drugs in pregnancy, nursing mothers or women of 
child-bearing potential requires that the possible benefits of the drug be weighed against 
the potential hazards to the mother and embryo or fetus. Infants born of mothers who 
have received substantial doses of corticosteroids during pregnancy, should be carefully 
observed for signs of hypoadrenalism. 
 
Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt 
and water retention, and increased excretion of potassium. These effects are less likely to occur with 
the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium 
supplementation may be necessary. All corticosteroids increase calcium excretion. 


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Administration of live or live, attenuated vaccines is contraindicated in patients receiving 
immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered to 
patients receiving immunosuppressive doses of corticosteroids; however the response to such 
vaccines may be diminished. Indicated immunization procedures may be undertaken in patients 
receiving nonimmunosuppressive doses of corticosteroids. 
The use of methylprednisolone tablets in active tuberculosis should be restricted to those cases of 
fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of 
the disease in conjunction with an appropriate antituberculous regimen. 
 
If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, 
close observation is necessary as reactivation of the disease may occur. During prolonged 
corticosteroid therapy, these patients should receive chemoprophylaxis. 
 
Persons who are on drugs which suppress the immune system are more susceptible to 
infections than healthy individuals. Chicken pox and measles, for example, can have a 
more serious or even fatal course in non-immune children or adults on corticosteroids. In 
such children or adults who have not had these diseases particular care should be taken to 
avoid exposure. How the dose, route and duration of corticosteroid administration affects 
the risk of developing a disseminated infection is not known. The contribution of the 
underlying disease and/or prior corticosteroid treatment to the risk is also not known. If 
exposed, to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may 
be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may 
be indicated. If chicken pox develops, treatment with antiviral agents may be considered. Similarly, 
corticosteroids should be used with great care in patients with known or suspected Strongyloides 
(threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to 
Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied 
by severe enterocolitis and potentially fatal gram-negative septicemia. 
PRECAUTIONS 
Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of 
dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; 
therefore, in any situation of stress occurring during that period, hormone therapy should be 
reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should 
be administered concurrently. 
There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with 
cirrhosis. 
Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible 
corneal perforation. 
The lowest possible dose of corticosteroid should be used to control the condition under treatment, 
and when reduction in dosage is possible, the reduction should be gradual. 
Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, 
mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, 
existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. 


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Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of 
impending perforation, abscess or other pyogenic infection; diverticulitis; fresh intestinal 
anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis; and 
myasthenia gravis. 
Growth and development of infants and children on prolonged corticosteroid therapy should be 
carefully observed. 
Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy. 
Discontinuation of corticosteroids may result in clinical remission. 
Although controlled clinical trials have shown corticosteroids to be effective in speeding 
the resolution of acute exacerbations of multiple sclerosis, they do not show that corticosteroids affect 
the ultimate outcome or natural history of the disease. The studies do show that relatively high doses 
of corticosteroids are necessary to demonstrate a significant effect.  
Since complications of treatment with glucocorticoids are dependent on the size of the dose and the 
duration of treatment, a risk/benefit decision must be made in each individual case as to dose and 
duration of treatment and as to whether daily or intermittent therapy should be used. 
DRUG INTERACTIONS 
The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of 
metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is 
possible that adverse events associated with the individual use of either drug may be more apt to 
occur. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. 
Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the 
clearance of methylprednisolone and may require increases in methylprednisolone dose to achieve 
the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of 
methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone 
should be titrated to avoid steroid toxicity. 
Methylprednisolone may increase the clearance of chronic high dose aspirin. This could 
lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when 
methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with 
corticosteroids in patients suffering from hypoprothrombinemia. 
 
The effect of methylprednisolone on oral anticoagulants is variable. There are reports of 
enhanced as well as diminished effects of anticoagulant when given concurrently with 
corticosteroids. Therefore, coagulation indices should be monitored to maintain the 
desired anticoagulant effect. 
Information for the Patient 
Persons who are on immunosuppressant doses of corticosteroids should be warned to 
avoid exposure to chickenpox or measles. Patients should also be advised that if they are 
exposed, medical advice should be sought without delay. 
ADVERSE REACTIONS 


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Fluid and Electrolyte Disturbances 
• Sodium retention 
• Congestive heart failure in susceptible patients 
• Hypertension 
• Fluid retention 
• Potassium loss 
• Hypokalemic alkalosis 
Musculoskeletal 
• Muscle weakness 
• Loss of muscle mass 
• Steroid myopathy 
• Osteoporosis 
• Tendon rupture, particularly of the Achilles tendon 
• Vertebral compression fractures 
• Aseptic necrosis of femoral and humeral heads 
• Pathologic fracture of long bones 
Gastrointestinal 
• Peptic ulcer with possible perforation and hemorrhage 
• Pancreatitis 
• Abdominal distention 
• Ulcerative esophagitis 
• Increases in alanine transaminase (ALT, SGPT), aspartate transaminase (AST, SGOT), 
and alkaline phosphatase have been observed following corticosteroid treatment. These 
changes are usually small, not associated with any clinical syndrome and are reversible 
upon discontinuation. 
Dermatologic 
• Impaired wound healing 
• Petechiae and ecchymoses 
• May suppress reactions to skin tests 
• Thin fragile skin 
• Facial erythema 
• Increased sweating 
Neurological 
• Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after 
treatment 
• Convulsions 
• Vertigo 
• Headache 


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Endocrine 
• Development of Cushingoid state 
• Suppression of growth in children 
• Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in 
trauma, surgery or illness 
• Menstrual irregularities 
• Decreased carbohydrate tolerance 
• Manifestations of latent diabetes mellitus 
• Increased requirements of insulin or oral hypoglycemic agents in diabetics 
Ophthalmic 
• Posterior subcapsular cataracts 
• Increased intraocular pressure 
• Glaucoma 
• Exophthalmos 
Metabolic 
• Negative nitrogen balance due to protein catabolism 
The following additional reactions have been reported following oral as well as parenteral therapy: 
Urticaria and other allergic, anaphylactic or hypersensitivity reactions. 
DOSAGE AND ADMINISTRATION 
The initial dosage of methylprednisolone tablets may vary from 4 mg to 48 mg of methylprednisolone 
per day depending on the specific disease entity being treated. In situations of less severity lower 
doses will generally suffice while in selected patients higher initial doses may be required. The initial 
dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable 
period of time there is a lack of satisfactory clinical response, methylprednisolone should be 
discontinued and the patient transferred to other appropriate therapy. 
4.0 Staging Criteria 
4.1 Multiple Myeloma Durie-Salmon Staging Criteria 
High Tumor Mass (Stage III) 
One of the following abnormalities must be present: 
a. Hemoglobin <8.5 gm%, hematocrit < 25 vol. %, or 
b. Serum calcium > 12 mg% or 
c. Very high serum or urine myeloma protein production rates: 


Page 44 of 74 
 
                      1. IgG peak > 7 gm% 
                      2. IgA peak > 5 gm% 
                      3. Bence-Jones protein > 12 gm/day (24 hours), or 
                d. > 3 lytic lesions on bone survey (bone scan not acceptable) 
Low Tumor Mass (Stage I) 
All of the following must be present: 
                   a.  Hemoglobin > 10.5 gm% or hematocrit > 32 vol% 
b. Serum calcium normal 
c. Low serum myeloma protein production rates: 
                                  1. IgG peak < 5 gm% 
                                  2. IgA peak < 3 gm% 
                                 3. Bence-Jones protein < 4 gm/day (24 hours) 
                   d. Bone lesions scaled (none) or 1 normal bone structure or osteoporosis only, or solitary  
                       bone plasmacytoma. 
Intermediate Tumor Mass (Stage II) 
All other participants who do not qualify specifically for high or low tumor mass categories are 
considered to have intermediate tumor mass. 
4.2.1 Assessment of Renal Status (Renal Substage): 
A = Good renal function (creatinine < 2.0 mg %) 
B = Poor renal function (creatinine > 2.0 mg %) 
4.2 International Staging Criteria  
In 2005, a new, international classification method was utilized for myeloma prognosis, based on the 
clinical and laboratory data gathered from 10,750 previously untreated symptomatic myeloma 
patients from 17 institutions in Asia, Europe, and North America.  The International Staging System 
utilizes a combination of serum β² microglobulin and serum albumin to provide a simple, powerful, 
and reproducible three-stage classification. It was validated in patients younger and older than 65 
years; with standard therapies or autotransplant; and in comparison with the Durie/Salmon staging 
system.  
 
I Serum β2 microglobulin <3.5 mg/L  
  Serum albumin ≥ 3.5 g/dL  
 


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II Not I or III*  
 
III Serum β2 microglobulin >5.5 mg/L 
 
*There are two possibilities for stage II: 
• Serum β2 microglobulin <3.5 mg/L, but serum albumin <3.5 g/dL  
                                                      OR 
         • Serum β2 microglobulin 3.5 – 5.5 mg/L irrespective of the serum albumin  
5.0 Study Eligibility Criteria 
5.1 Inclusion Criteria 
1. Participants must have had a diagnosis of symptomatic MM, MM + amyloidosis, or 
POEMS (osteosclerotic myeloma: Polyneuropathy, Organomegaly, Endocrinopathy, 
Monoclonal protein, Skin changes) requiring treatment.  Participants with a previous 
history of smoldering myeloma will be eligible if there is evidence of progressive disease 
requiring chemotherapy.  Note that study participants do not need to have active 
disease at the time of study entry, as participants may have received up to 12 
months of prior chemotherapy, which might have induced a response.    
2. Protein criteria must be present at diagnosis (quantifiable M-component of IgG, IgA, 
IgD, or IgE and/or urinary kappa or lambda light chain, Bence-Jones protein, or Free 
Kappa Light Chain or Free Lambda Light Chain) in order to evaluate response. Non-
secretory participants are eligible provided the participant has > 20% plasmacytosis OR 
multiple (≥3) plasmacytomas or lesions on MRI at the time of diagnosis or study 
enrollment , OR the presence of lesions on PET/CT scan or skeletal survey at diagnosis 
or study enrollment. 
 
3. Participants must have received ≤12 months of prior chemotherapy for this  
disease without evidence of progressive disease with treatment.   Participants may 
have received prior radiotherapy provided approval has been obtained from the 
PI. Participants with a history of radiation who have a platelet count <150,000 due 
to radiation (disease, chemo, and other factors have been ruled out) will be 
excluded from this study.   
                 
                4.  Participants must not have had a prior transplant.  
          5.  Participants must be 65-85 years of age at the time of study entry. 
               6.  Ejection fraction by ECHO or MUGA of ≥ 40% performed. 
               7.  Participants must have adequate pulmonary function studies (PFTs), > 50% of predicted  
                    on mechanical aspects (FEV1, FVC) and diffusion capacity ( DLCO) > 50% of predicted  
                   (adjusted for hemoglobin).  If the participant is unable to complete PFTs due to  
                   disease-related pain or other circumstances that make it difficult to reliably  
                   perform PFTs, documentation of pulmonary function adequate for transplant will  


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                   occur via a CT scan without evidence of major pulmonary disease, and arterial  
                   blood gas results.     
 
             8.   Participants must have a creatinine < 3 mg/dl and a GFR >30mL/min/1.73m2.  
 
             9.   Participants must have a performance status of 0-2 based on ECOG criteria.  Participants  
                   with a poor performance status (3-4) based solely on bone pain will be eligible, provided  
                   there is documentation to verify this.  
 
          10.   Participants must sign the most current IRB-approved study ICF (Informed Consent  
                  Form).  
 
5.2 Exclusion Criteria 
           1. Prior autologous or allogeneic transplant.  
           2. Progressive disease on prior treatment.  
           3. Platelet count < 30 x 109/L, unless myeloma-related.  If MM-related (hypercellular marrow 
               biopsy of >80% and packed with at least 80% plasma cells) the enrolling investigator must  
               document this. 
  
           4. > grade 3 neuropathy.  
           5. Known hypersensitivity to bortezomib, boron, or mannitol. 
           6.  Uncontrolled diabetes on appropriate therapy.   
           7.  Recent (< 6 months) myocardial infarction, unstable angina, difficult to control congestive  
                heart failure, uncontrolled hypertension on appropriate therapy, or difficult – to-control  
                cardiac arrhythmias.   
 
           8.  Participants must not have a creatinine >3 mg/dl or a GFR <30mL/min/1.73m2.   
 
           9.  Participants must not have a concurrent malignancy unless it can be adequately treated by  
                non-chemotherapeutic intervention.  Participants may have a history of prior malignancy,  
                provided that he/she has not had any chemotherapy within 365 days of study entry AND  
                that life expectancy exceeds 5 years at the time of study entry.  
 
        10.  Participants must not have life-threatening co-morbidities. 
 
An inclusion/exclusion checklist signed by the enrolling research coordinator/nurse and the enrolling 
investigator verifying participant eligibility will be kept in each participant’s research chart.   
 


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6.0 Treatment Plan 
Throughout treatment, antibiotic/antifungal/antiviral/anticoagulant prophylaxis will be administered as 
per institutional guidelines and SOPs. 
Infectious prophylaxis will include: 
1. Antibiotics (e.g. ciprofloxacin, levofloxacin, or doxycycline) 
2. Antifungals (e.g. clotrimazole, fluconazole, voriconazole or caspofungin) 
3. Antivirals (e.g. acyclovir, famciclovir, or valacyclovir) 
The drugs listed above represent current commonly used prophylactic agents within each category, 
but these may be substituted by similar drugs as appropriate since institutional standard-of-care 
prophylaxis may change over time.   All agents used for infection prophylaxis during the course of this 
study will be captured in the concomitant medication section of the Case Report forms (CRFs).  
Throughout study treatment, supportive care will be administered as per institutional guidelines and 
SOPs.  
6.1 Induction and PBSC Collection 
Initial chemotherapy will consist of 1 cycle of combination D-PACE chemotherapy and peripheral 
blood stem cell collection. It is mandated that chemotherapy be given through a central venous 
access catheter to avoid potential complications of extravasation. 
D-PACE  
Dexamethasone 20 mg oral on days 1-4 and 8-11. 
Cisplatin 10 mg/m2/day on days 1-4 CI (Continuous Infusion).  
Doxorubicin 10 mg/m2/day on days 1-4 CI. 
Cyclophosphamide 400 mg/m2/day or 600 mg/m2 on days 1-4 CI* 
Etoposide 40 mg/m2/day on days 1-4 CI 
See Appendix I for appropriate algorithms when computing chemotherapy doses. The daily dose of 
cyclophosphamide, etoposide, and cisplatin will be infused over approximately 24 hours, for a total 
infusion time of approximately 96 hours.    
*Cyclophosphamide may be dose escalated from 400mg/m2 to 600 mg/m2 in cases of high-risk 
myeloma, based on an LDH ≥ 400 u/L or high-risk cytogenetics [ t(4,14), t(14,16) and t(14,20) and 
del17p13 on FISH; del13 or del13q on metaphase cytogenetics, as per Mayo clinic criteria].  
 


Page 48 of 74 
 
PBSC (Peripheral Blood Stem Cell) Collection Guidelines 
Pegfilgrastim will be administered at a dose of 6 mg on days +6 and +13 after D-PACE 
chemotherapy.  If peripheral CD34 cell count is <20 µL, once WBC count is >1,000/μL, G-CSF may 
be given at a dose of 10 mcg/kg/day(rounded to the nearest vial size) and divided into a morning and 
evening dose, with the larger dose given in the morning.  G-CSF will be discontinued upon 
completion of apheresis.  If patient is unable to collect by day 17 post-D-PACE, plerixafor should be 
given as per SOP until the stem cell collection is completed.  
PBSC will be collected and processed according to institutional standards. These cells will be 
assessed by flow cytometry for the presence of CD34 for a target of > 15 x 106 CD34+ cells/kg. (5 x 
106 CD34+ cells/kg minimum necessary).    
Participants unable to collect at least 5 x 106 CD34/kg may undergo other collection(s) as per 
program practice.  Participants unable to collect at least 5 x 106 CD34/kg after two attempts will be 
removed from the protocol, since it is unlikely that they will complete 2 years of maintenance.  If the 
interval between the cycle of D-PACE and transplant is > 4 months (or >6 months in a participant that 
requires > 1 PBSC collection), that participant will be removed from the study. 
In the unlikely event that the PBSC product becomes contaminated with excessive myeloma cells (≥ 
5%), participants will undergo a second round of chemotherapy with VDT-PACE (see section 6.3 of 
this protocol for chemotherapy schedule) prior to an additional collection attempt in order to decrease 
the possibility of another myeloma-contaminated stem cell collection.   The same collection guidelines 
as above apply to this second round of chemo mobilization.      
 
Pre-Maintenance Therapy Modifications 
Cisplatin doses will be modified for renal insufficiency as follows:  
Cisplatin dose 
Creatinine 
10 mg/m2 (full dose) 
 
≤1.5 mg/dl 
5 mg/m2 
 
1.6 – 2.0 mg/dl 
 
0 mg/m2 (hold Cisplatin) 
 
>2.0 mg/dl 
 
Dexamethasone:  If study participants are sensitive to steroids and experience a steroid “crash” 
when stopping the drug, dexamethasone doses may be tapered after each dosing increment.  
Depending on the severity of the symptoms, 4-8mg of dexamethasone may be given for two 
additional days before stopping the drug completely.   
 
For suspected dexamethasone-related toxicity (non-infectious) ≥ grade 2 that does not abate or 
resolve with supportive care measures or a 7-14 day drug hold, methylprednisolone 16mg every 
other day may be prescribed as substitution.   
 


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Doxorubicin: For participants with hepatic dysfunction (transaminases > 2 x ULN or direct bilirubin > 
2.0 mg/dl if performed) before the start of induction or consolidation, the doxorubicin dose should be 
reduced by 50%.  It may be raised if hepatic function improves.  For participants developing evidence 
of significant cardiac toxicity or cardiac failure, doxorubicin should be discontinued.  
Thalidomide:  For grade 2 toxicity non-infectious or non-hematologic toxicity, thalidomide may be 
dose reduced to 50mg daily, depending on the toxicity and possibility of recurrence/worsening with 
the re-introduction of therapy at full dose.  For ≥grade 3 non-hematologic toxicity, thalidomide will be 
held until toxicity resolves to a grade 2 or better.  Thalidomide may be resumed at full dose 
(100mg/day) or dose-reduced to 50mg per day, depending on the toxicity and possibility of 
recurrence/worsening with the re-introduction of therapy at full dose. The rationale for the dose 
reduction must be recorded in source notes. Dose reductions below 50mg daily are not allowed. 
 
Interim between Induction D-PACE and Transplant  
Following D-PACE and PBSC collection, participants may receive interim dexamethasone at 20mg 
days 1-4 every 14 days, but this may be omitted by the treating physician. Any planned omission of 
the dexamethasone must be documented by the treating physician.   
6.2   Transplant Phase  
Transplant (VDT-MEL) 
Transplant should preferably occur 6 weeks after the induction PACE continuous infusion has been 
completed, but can occur as early as 4 weeks and as late as 3 months if the participant fails to 
mobilize stem cells after the PACE administration.  Transplant may be given on an inpatient or 
outpatient basis. 
Dexamethasone 20 mg oral on days -4 to -1 and +2 to +5. 
Bortezomib 1mg/m2 IV Bolus on days -4, -1, +2, and +5. 
Thalidomide 100mg/day oral on days -4 to +5. 
Melphalan will be given at a dose of 100 mg/m2 on days -4 and -1 (Participants > 70 years of age or 
with a creatinine > 2.0 mg/dl will receive Melphalan 70 mg/m2  on days -4 and -1).  See Appendix I for 
appropriate algorithms when computing chemotherapy doses.  
Peripheral blood stem cell infusion will be given intravenously on day 0, i.e., at least 18 hours after 
the second dose of melphalan.  The participant will be pre-medicated according to institutional 
practice.  No less than approximately 5 x 106 /kg CD34cells will be infused with the transplant.  
If deemed medically necessary (graft failure, graft delay, inadequate platelet recovery, etc), 
and if a participant has sufficient stem cells in storage, a boost of stem cells may be given at 
any point after transplant, including subsequent treatment phases.   
 
 
 


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Interim between Transplant and Consolidation/Maintenance Therapy  
Participants will receive dexamethasone 20 mg oral days 1-4 every 21 days and thalidomide 100 mg 
oral and daily in the interim between transplant and consolidation.  
Interim therapy between transplant and consolidation may be held or dose-modified, but the reasons 
for this must be documented in source notes.  
6.3   Consolidation Therapy 
If administered, post-transplant consolidation therapy should begin 4-6 weeks after transplant, but 
should occur no later than 4 months after transplant.   Consolidation will consist of one cycle of VDT-
PACE.  
Consolidation VDT-PACE should only be given if all of the following criteria are met: 
1. Participant has high-risk disease as per Mayo clinic criteria (see induction DPACE section)  
2. Platelet count should be > 80,000/ mcl.   
3. Participant does not have a medical complication that will make it unsafe to administer  
    consolidation.   
 
4. Participant must have achieved a PR or better (as defined in this protocol in the Response   
    Categories section) after induction DPACE.   
 
Consolidation VDT-PACE  
Dexamethasone 20 mg oral on days 1-4 and days 8-11 
Thalidomide 100mg oral on days 1-11 
Bortezomib 1mg/m2 IV Bolus on days 1, 4, 8, 11 
Cisplatin 10 mg/m2 on days 1-4 CI 
Doxorubicin 10mg/m2 on days 1-4 CI 
Cyclophosphamide 400 mg/m2 on days 1-4 CI 
Etoposide 40 mg/m2 on days 1-4 CI 
See Appendix I for appropriate algorithms when computing chemotherapy doses. The daily dose of 
cyclophosphamide, etoposide, and cisplatin will be infused over approximately 24 hours, for a total 
infusion time of approximately 96 hours.   
6.4   Maintenance Therapy 


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Maintenance will begin 4 weeks to 6 months after transplant, or between 6 weeks to 6 months after 
consolidation if administered.  This is considered standard of care. Platelets must have recovered to > 
70,000µl, although a variance of 5,000 µl is acceptable if it is otherwise clinically appropriate to 
proceed to maintenance therapy.   
Participants will be evaluated at least 3 times per year (after completion of 4 cycles ± 21 days) by the 
treating investigator during maintenance therapy.  Local oncologists will be encouraged to call the 
treating investigator with any questions regarding toxicities.   
An order for a blood draw to check MM markers will be sent to the participant’s local physician’s office 
every three months during long term follow up.  If 3 consecutive serum MM markers are missed, the 
study team will follow up with the participant and/or local oncologist to reinforce the necessity of close 
disease marker tracking while on study treatment.  Subjects may be removed from study if non-
compliance with this request continues.   
Participants will be evaluated for adverse events according to the National Cancer Institute Common 
Terminology for Adverse Events (CTCAE), version 4.0.   
Any protocol treatment(s) may be delayed or held by the treating investigator if the participant's safety 
is considered to be at risk. This must be adequately documented in source notes.  For serious 
adverse events, treatment will be held until it is clinically appropriate to continue. 
 
If excessive toxicity occurs, a participant may stop maintenance treatment but will still be followed for 
event-free and overall survival.   
 
 
 
 
  
   
 
8.0    Study Calendar 
All pre-study testing necessary to determine eligibility must be performed within 60 days of study 
enrollment.  All other pre-phase testing must be done within 45 days of the start of the phase.   
 
Pre-
study 
 
Pre-
Induction2 
 
Pre-
Transplant 
4wks-4mos from 
day 1 of induction 
 
Pre- Consolidation 
4wks-4 mos post- 
transplant 
OR 
Pre-Maintenance 
 
Maintenance 
Therapy5 
 
 
Long-
term 
follow-
up6 (+/-2 
weeks) 


Page 52 of 74 
 
4 wks-6 mos post- 
transplant if no 
consolidation  
H&P1 
X 
X 
X 
X 
3 times per year 
Once 
per year 
Toxicity Evaluation 
X 
X 
X 
X 
3 times per year 
Once 
per year  
ECG 
X 
 
 
 
 
 
CBC with diff 
X 
X 
X 
X 
3 times per year 
Once 
per year 
CMP3, Mg, Phos, CRP, 
LDH  
X 
X 
X 
X 
3 times per year 
Once 
per year 
PT, INR 
X 
X 
X 
X 
3 times per year 
Once 
per year 
Serum Electrophoresis 
X 
X 
X 
X 
3 times per year 
Once 
per year 
Quantitative 
Immunoglobulins 
X 
X 
X 
X 
3 times per year 
Once 
per year 
Serum Free Light 
Chains  
X 
X 
X 
X 
3 times per year  
Once 
per year 
Serum IFE 
X 
X 
X 
X 
3 times per year 
Once 
per year  
Beta-2-Microglobulin 
X 
X 
X 
X 
3 times per year 
Once 
per year 
24 hr urine for total 
protein, electrophoresis, 
and IFE (if indicated).  
X 
 
 
 
 
 
TSH 
X 
X 
X 
X 
3 times per year  
Once 
per year 
1. H&P to include detailed medical and treatment history and performance status.  
 
2. If Induction DPACE is started within 2 weeks from study enrollment, the pre-study testing can be used to satisfy the pre-Induction 
requisite testing as well.  
3. CMP includes: ALT, AST, Albumin, total bilirubin, Ca, CO2, Cl, Creatinine, Glucose, Alk Phos, K, Na, BUN, total protein 
4. In the event that a subject had a normal bone marrow core biopsy at baseline (i.e. <5% plasma cells), bone marrow biopsies will be 
performed at intervals deemed appropriate by the treating physician.   
5. Maintenance therapy consists of 24 cycles of standard-of-care chemotherapy.  Maintenance evaluations will be done 3 times per 
year (after 4 cycles ± 21 days) at the study center.  Participants will be asked to send in blood for MM marker analysis on a monthly 
basis, preferably drawn on day 1 of each cycle.  If 3 consecutive monthly serum MM markers are missed, the study team will follow up 
Bone Marrow 
Aspirate & Biopsy4 
X 
X 
X 
X 
3 times per year 
once per 
year 
 
PFTs with DLCO 
X 
 
 
 
 
 


Page 53 of 74 
 
with the participant and/or local oncologist to reinforce the necessity of close disease marker tracking while on study treatment.  
Subjects may be removed from study if non-compliance with this request continues.   
6. During long-term follow-up, study participants will be evaluated at the study center at least once per year.     
At the first sign of progression, every attempt will be made to bring the participant back to the study center as soon as possible for 
evaluation of progressive disease.   
 
Radio-imaging studies to be performed while on study  
 
Pre-
study 
Pre-
Induction 
 
Pre-
Transplant 
 
Pre-Consolidation/Pre-
Maintenance 
Maintenance 
Long-term 
follow-up 
MRI or 
PET1 
X 
X 
X 
X 
As clinically 
indicated 
As clinically 
indicated 
Echo or 
MUGA 
X 
 
 
 
 
 
1.  Ideally, study participants will have both a PET and MRI pre-study, and then alternate between MRI and PET thereafter at the time 
points on this calendar.  However, if a participant cannot receive either an MRI or PET for any reason, the participant will receive only 
the applicable radiographic test.   
Optional Quality-of-Life Questionnaires   
 
 
See section 11.0 of this protocol for further discussion.   
 
 
 
 
Pre-study 
 
Pre-Consolidation/Pre-Maintenance 
  
Maintenance Phase 
Follow-up 
EORTC QLQ-C30 
X 
X 
2 times per year  
Once per 
year for 3 
years 
EORTC QLQ-MY20 
X 
X 
2 times per year   
Once per 
year for 3 
years  
 
 
9.0 Criteria for Evaluation and Endpoint Definitions 
 
Response Categories 
International Myeloma Working Group uniform response criteria 
 
Response 
IMWG criteria 
sCR 
CR as defined below plus normal FLC ratio, if it can be calculated, and absence of clonal cells in 
bone marrow3 by immunohistochemistry or immunofluorescence4  If the FLC ratio is abnormal 
due to the non-involved light chain, it does not exclude a sCR. 


Page 54 of 74 
 
CR 
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and < 5% plasma cells in bone marrow3 
VGPR 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 90% 
reduction in serum M-protein plus urine M-protein level < 100 mg/24 h 
PR 
> 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >90% or to < 
200 mg/24 h 
If the serum and urine M-protein are unmeasurable,5 a > 50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria 
If serum and urine M-protein are not measurable, and serum free light assay is also not 
measureable, > 50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma cell percentage was > 30% 
In addition to the above listed criteria, if present at baseline, a > 50% reduction in the size of soft 
tissue plasmacytomas is also required 
MR 
NA 
No 
change/Stable 
disease 
Not meeting criteria for CR, VGPR, PR, or progressive disease 
Plateau 
NA 
Progressive 
disease5 
Increase of > 25% from lowest response value in any one or more of the following: 
• 
Serum M-component and/or (the absolute increase must be > 0.5 g/dL)6 
• 
Urine M-component and/or (the absolute increase must be > 200 mg/24 h) 
• 
Only in patients without measurable serum and urine M-protein levels; the difference 
between involved and uninvolved FLC levels. The absolute increase must be > 10 
mg/dL 
• 
Bone marrow plasma cell percentage; the absolute percentage must be > 10%7  
• 
Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas 
• 
Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 
mmol/L) that can be attributed solely to the plasma cell proliferative disorder 
Relapse 
Clinical relapse requires one or more of: 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB features).6 It is not 
used in calculation of time to progression or progression-free survival but is listed here as 
something that can be reported optionally or for use in clinical practice 
• 
Development of new soft tissue plasmacytomas or bone lesions 
• 
Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and at least 1 cm) increase as measured serially by the 
sum of the product of the cross-diameters of the measurable lesion 
• 
Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L] 
• 
Decrease in haemoglobin of > 2 g/dL [1.25 mmol/L] 
• 
Rise in serum creatinine by 2 mg/dL or more [177 mmol/L or more] 
Relapse from 
CR5 (To be 
used only if the 
Any one or more of the following: 
• 
Reappearance of serum or urine M-protein by immunofixation or electrophoresis 


Page 55 of 74 
 
end point 
studied is DFS)8 
• 
Development of > 5% plasma cells in the bone marrow7 
• 
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, 
or hypercalcaemia) 
1 BGM Durie et al. International uniform response criteria for multiple myeloma. Leukemia (2006) 1-7.  
Adapted from Durie BGM, et al. Leukemia 2006; 20: 1467-1473; and Kyle RA, Rajkumar SV. Leukemia 2008;23:3-9. 
Note: A clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is by serum FLC 
levels: CR in such patients is defined as a normal FLC ratio of 0.26–1.65 in addition to CR criteria listed above. (If one of the serum free 
light chains is not measurable, the involved free light chain should be within or below the normal range.  VGPR in such patients is 
defined as a >90% decrease in the difference between involved and uninvolved free light chain (FLC) levels.  
3 Confirmation with repeat bone marrow biopsy not needed. 
4 Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by immunohistochemistry 
and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal 
clone is kappa/lambda of > 4:1 or < 1:2. 
5 All relapse categories require two consecutive assessments made at any time before classification as relapse or disease progression 
and/or the institution of any new therapy. In the IMWG criteria, CR patients must also meet the criteria for progressive disease shown 
here to be classified as progressive disease for the purposes of calculating time to progression and progression-free survival. The 
definitions of relapse, clinical relapse and relapse from CR are not to be used in calculation of time to progression or progression-free 
survival.  
6 For progressive disease, serum M-component increases of >1 gm/dL are sufficient to define relapse if starting M-component is >5 
g/dL. 
7 Relapse from CR has the 5% cut-off versus 10% for other categories of relapse. 
8 For purposes of calculating time to progression and progression-free survival, CR patients should also be evaluated using criteria 
listed above for progressive disease. 
Note: In ≥90% of MM patients, PD will be documented according to the above criteria.  However, in some cases, an investigator may 
document PD prior to reaching the thresholds outlined in this table if holding salvage treatment until these thresholds are reached is not 
clinically sound.  In such cases, PD may be documented earlier but must be cleared with the PI.   
MDS/AML   
All persistent cytopenias will be investigated by BM aspirate and biopsy for cytogenetics/FISH.  
Participants who develop MDS not requiring treatment will remain on study, but participants who 
develop MDS requiring treatment or AML will be taken off study.  
Survival Outcomes 
Progression-Free Survival:  measured from day 1 of DPACE for all participants who have had at 
least one day of treatment on study.   
Overall Survival:  measured as the time from initial study enrollment to death from any cause. 
Event-Free Survival:  measured as the time from initial study enrollment to progression/relapse of 
disease or death from any cause. 
Performance Status 
Participants will be graded according to the following ECOG grading scale. If a Karnofsky score is 
provided instead of an ECOG, performance status may be converted to the equivalent score.  
Grade                      Scale 
0                              Fully active; able to carry on all pre-disease activities without  
                                restriction.  (Karnofsky 90-100). 


Page 56 of 74 
 
 
1                              Restricted in physically strenuous activity but ambulatory and  
                                able to carry out work of a light or sedentary nature, e.g.,  
                                light housework, office work.  (Karnofsky 70-80). 
 
2                              Ambulatory and capable of all self-care but unable to carry  
                                out any work activities.  Up and about more than 50% of  
                                waking hours.  (Karnofsky 50-60). 
 
3                              Capable of only limited self-care; confined to bed or chair  
                                more than 50% of waking hours (Karnofsky 30-40). 
 
4                              Completely disabled.  Cannot carry on any self-care.  Totally 
                                confined to bed or chair (Karnofsky 10-20). 
 
Off Study Criteria 
Participants will be informed during the informed consent process 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 participants from study treatment or from the study for any of the following 
reasons: 
 
Off Treatment Criteria 
 
• 
Initiation of ongoing medical treatment that makes it difficult to evaluate the safety or efficacy of 
study treatment  
• 
Occurrence of an adverse event that makes it unsafe to administer further study treatment 
• 
Major or recurrent non-compliance 
• 
Participant request 
• 
Failure to return for follow-up as required per study calendar  
• 
Deterioration in the patient’s condition, which may not be study treatment-related, but which 
makes it unsafe to administer further treatment 
• 
Other  
 
 
Off Study Criteria  
 
• Participant request  
•  
• Inability to return for any further study visits, including follow-up visits.   
• Lost-to-Follow-Up  
•  
• Early termination of the study  
 
Unless the study terminates early, HIPAA consent is withdrawn, or a participant is lost to follow-up, all 
study participants will be monitored for progression-free and overall survival.   


Page 57 of 74 
 
10.0 Statistical Considerations 
Power and Sample Size   
The primary objective of this study is to evaluate progression-free survival for the proposed treatment 
regimen.  The study is powered to test the null hypothesis that median survival is no greater than 30 
months versus the alternative that it is at least 48 months.  Study power and sample size are based 
on the assumption of exponentially distributed progression times and use of maximum-likelihood 
methods (Lawless, 1982) to test the one-sided alternative hypothesis at the 5% level of significance.  
Accordingly, the planned enrollment of 41 patients accrued uniformly over 3 years and followed for 4 
additional years will ensure 80% study power. 
Reference 
Lawless, J. Statistical Models and Methods for Lifetime Data, John Wiley and Sons, 1982. 
Suspension of Study    
Stopping rule with respect to mortality: 
For subjects enrolled on Total Therapy II, the mortality rate was found to be 6% for participants under 
65, and 12% for those over 65, with an overall mortality rate of 8%. Since we will be enrolling more 
heavily-pretreated participants (up to 12 months of prior therapy versus up to 1 month in Total 
Therapy II and III), and participants over 65, a treatment-related mortality rate of up to 15% is 
considered acceptable in this participant population.  
Treatment-Related Mortality calculations will include all deaths that are deemed by the Principal 
Investigator to be possibly, probably, or definitely related to treatment, that cannot be explained by 
any other event, and are not related to relapse or progressive disease.     
 
Mortality Suspension Rules 
The study will be suspending and a DSMB review triggered if X deaths occur within the first N 
patients, for X/N = 2/4, 3/8, 4/12, 5/16, 6/20, 7/25, 8/29, 9/34, 10/39, and 11/41.  The probability of 
study suspension and the expected enrollment (if terminated) are summarized in the table below over 
a range of hypothetical true mortality rates.  In it, the suspension probability can be seen to be 7.6% 
for the mortality rate of 15% deemed to be acceptable, and 73.8% for a rate of 30%.  The 
aforementioned sequential suspension rules were based on Pocock boundaries (1977) and computed 
with the ‘clinfun’ software (Ivanova et al., 2005; Seshan, 2013). 
True Mortality Rate 
Suspension Probability 
Expected Enrollment 
15% 
7.6% 
39.1 
20% 
24.1% 
35.5 
25% 
49.4% 
30.0 


Page 58 of 74 
 
30% 
73.8% 
23.6 
 
References 
Ivanova A, Qaqish BF, Schell MJ. (2005) Continuous Toxicity Monitoring in Phase II Trials in Oncology, Biometrics, 61, 
540-545. 
Pocock SJ. (1977) Group Sequential Methods in the Design and Analysis of Clinical Trials. Biometrika, 64, 191-199. 
Seshan VE. (2013) clinfun: Clinical Trial Design and Data Analysis Functions.  R package version 1.0.5. http://CRAN.R-
project.org/package=clinfun 
Statistical Analyses  
Overall analyses 
CR rate, EFS, TTP, and OS will be calculated for all participants who have signed an informed 
consent form.   All analyses will be performed on an intent-to-treat basis.  The TTP is defined as the 
time that patient will need either to start treatment if he/she is off treatment or will need a change in 
treatment if he/she was still on treatment. The TTP study hypothesis that the median TTP is 4 years 
will be tested with an exponential survival model. TTP probabilities will be estimated with the method 
of Kaplan-Meier and modeled as functions of clinicopathological factors with Cox regression.  CR will 
be summarized with binomial proportions. 
Frequencies of toxicities will be tabulated on all participants who have completed at least one day of 
induction treatment.  Toxicities will be compared descriptively to historical controls. 
Interim analysis for efficacy  
The typical use of interim analysis for efficacy is in randomized clinical trials to assess accumulating 
evidence that one treatment is more efficacious that the other(s). The proposed single-arm registry 
trial for multiple myeloma participants proposes a treatment regimen that is more intensive than any 
other available therapy. Therefore, with only one treatment regimen being considered that is more 
intensive than applied in any other study, this study does not fit the multi-arm comparison setting, and 
it is unclear that an interim analysis for efficacy is beneficial. Toxicity assessment, and not efficacy, 
will be the main reason for prematurely stopping this study. 
A second complication to an interim efficacy analysis is the short time period that would be available 
for participant follow-up. The study proposes to enroll 41 participants in 3 years. If an interim analysis 
is performed, it would be done so during the enrollment period and at a time when most participants 
have less than two years of follow-up. Conversely, the design for statistical analysis is based on 
median TTP of 4 years. By the time the interim enrollment is reached, few of the participants will have 
been followed long enough to experience a relapse. Thus, it is unlikely that we would be able to draw 
any meaningful conclusions regarding TTP with an interim analysis. For these reasons, an interim 
analysis to evaluate treatment efficacy is not warranted for this single-arm trial. 
11.0   Ancillary Studies 


Page 59 of 74 
 
Study subjects may refuse to participate in the optional quality-of-life sub-study and still 
participate in the study treatment. 
 
The EORTC quality of life questionnaire (QLQ) is an integrated system for assessing the health-
related quality of life (QoL) of cancer patients participating in international clinical trials. The core 
questionnaire, the QLQ-C30, is the product of more than a decade of collaborative research.  It is a 
copyrighted instrument, which has been translated and validated into 81 languages and is used in 
more than 3,000 studies worldwide. Presently QLQ-C30 Version 3.0 is the most recent version and 
should be used for all new studies. 
 
It is supplemented by disease specific modules. Those for Breast, Lung, Head & Neck, Oesophageal, 
Ovarian, Gastric, Cervical cancer, Multiple Myeloma, Oesophago-Gastric, Prostate, Colorectal Liver 
Metastases, Colorectal and Brain cancer have been validated and are distributed from the EORTC 
Quality of Life Department.  
 
The QLQ-C30, the core questionnaire, and the QLQ-MY20, the myeloma module, will be 
administered at the timepoints indicated on the study calendar if participants consent to this optional 
sub-study. 
 
Appendix III contains a copy of the QLQ-30 and QLQ-MY20.   
 
12.0   Ethical and Regulatory Considerations 
Definitions 
Unanticipated Problem Involving Risks to Participants or Others: Any event that is a) unanticipated b) 
caused harm or placed a person at increased risk of harm and c) is related to the research 
procedures. 
Serious Adverse Event: An event is “serious” if it involves considerable detriment or harm to one or 
more persons (who may or may not be participants), or required intervention to prevent one or more 
persons from experiencing considerable detriment or harm. Serious adverse events include: 
• Death 
• Life-threatening experience – Disease or condition where the likelihood of death is high unless 
the course of the disease/condition is interrupted or diseases/conditions with potentially fatal 
outcomes where the end point of the clinical trial analysis is survival 
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in participant’s offspring 
• Any other important medical event that, based upon appropriate medical judgment, may 
jeopardize the participant and may require medical or surgical intervention to prevent one of 


Page 60 of 74 
 
the outcomes listed above. Examples include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result 
in participant hospitalization, the development of drug dependency or drug abuse, suicidal 
ideation or attempts, or the unintentional revealing of some genetic information to insurers. 
Related: An event is “related” if more likely than not it was caused by the research activity. 
Unexpected: An event is “unexpected” when its specificity, nature, severity or incidence are not 
accurately reflected in the consent form previously reviewed and approved by the IRB. Examples 
include a lower rate of response to treatment or a side effect that is more severe than initially 
expected. 
NCI Common Terminology Criteria for Adverse Events  
The toxicity criteria to be used in this study are the Common Terminology Criteria for Adverse Events 
(CTCAE Version 4.0). 
Investigator Reporting Responsibilities  
To the IRB:  
The following must be reported to the IRB by the Principal Investigator, and, except where noted, 
such reporting is due no later than 10 business days after the investigator’s first knowledge of the 
event: 
Deaths that are probably or definitely related to the study.  
Any event, other than death, that in the PI’s opinion is Serious or Unexpected, and Possibly, 
Probably or Definitely Related to the study, regardless of whether the participant is on or off study.  
The PI is responsible for determining the relationship between the administration of study drug and 
the occurrence of the AE. 
An accidental or unintentional change (Protocol Violation) to the IRB-approved protocol that 
increases risk or decreases benefit, affects the participant’s rights, safety, welfare, affects the integrity 
of the data, or has the potential to occur again.  (NOTE: Any protocol violation that does not meet this 
definition should be reported with the next continuing review.) 
Pregnancies occurring while the participant is on are considered immediate reportable events. The 
study regimen should be discontinued immediately.  
The treating investigator will follow the participant until completion of the pregnancy, and must notify 
the IRB of the outcome within 10 business days.  The Principal Investigator will provide this 
information as a follow-up to the initial SAE. 
Any neonatal death that occurs within thirty (30) days of birth should be reported to the IRB, without 
regard to causality.  In addition, any infant death after thirty (30) days that the PI suspects is related to 
in utero exposure to the study regimen should also be reported to the IRB. 


Page 61 of 74 
 
If an Emergency requiring a protocol occurs for a participant, a deviation will be made only for that 
participant. The Principal Investigator or other designee in such an emergency will, if circumstances 
and time permit, contact the IRB immediately by telephone. If time does not allow for this, the 
Investigator will notify the IRB of the deviation as soon as possible in writing or by phone. 
Such contacts will be made as soon as possible to determine whether or not the participant (for whom 
the deviation from protocol was effected) is to continue in the study.  The participant’s research chart 
will contain a description of the deviation from the protocol and state the reasons for such deviation. 
The following must be reported to the IRB by the Principal Investigator within 30 days of the PI’s first 
knowledge of the event:                        
The PI must notify the IRB of pending audits or inquiries by external bodies (e.g. FDA, NCI or NIH). 
This includes any communication that questions the conduct of the research or suggests an 
impending inquiry, audit or investigation.  
Any publication in the literature, interim result, or other finding that indicates an unexpected change 
to the risk/benefit ratio of the research must be reported to the IRB. 
Any breach in confidentiality that may involve risk to a participant or others (Examples include the 
loss of a laptop computer on which subject identifies are stored or inadvertent loss study records) 
must be reported by the IRB. 
Any participant complaint that indicates unanticipated risk must be reported to the IRB. 
Any incarceration of a participant if study was not previously reviewed with the anticipation of 
enrolling prisoners (NOTE: No further interactions may occur with the participant until reviewed by 
IRB Prisoner Representative.) must be reported to the IRB. 
Any change in FDA labeling or withdrawal from marketing of a drug used in this research 
protocol must be reported to the IRB. 
To the Medical Monitor:  
Expedited reports shall be completed using the SAE form in OnCore, within the timeframe noted, 
following the investigator having knowledge of the event. 
Expedited reporting requirements for Adverse Events and Serious Adverse Events that occur during 
treatment and within 30 days of last dose of commercial agent: 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Unexpected 
With Hosp** 
 
Grade 3 
Unexpected  
W/O Hosp 
Grade 3 
Expected 
With 
Hosp** 
Grade 3 
Expected 
w/o Hosp 
Grade 4 & 5 
  
Unexpected 
Grade 4 & 5  
  
Expected 
 
Prolonged * 
Hospital 
stay 
Unrelated 
Unlikely 
Not  
required 
Not 
required 
10 calendar  
days 
Not  
required 
10 
calendar 
days 
Not  
required 
10 calendar  
days 
10 calendar 
days 
Not  
required 
Possible 
Probable 
Definite 
Not  
required 
Not  
required 
10 calendar  
days  
10 calendar 
days 
10 
calendar 
days 
Not 
required 
24 hours 
10 calendar  
Days*** 
24 hours 


Page 62 of 74 
 
*Prolonged hospital stay:  Hospitalization exceeding 12 days for induction or consolidation.  Hospitalization exceeding 28 days post-transplant for 
planned transplant hospitalization.  
**Hospitalization refers to any un-planned hospitalization 
***Excluding grade 4 hematology and chemistry labs results 
 
Adverse events (AEs ≥ grade 3), for which expedited reporting is not required, will be monitored and 
recorded on the AE eCRF .AEs will not be recorded by start and stop date but by phase of treatment 
in which the AE occurred.  AEs will be recorded as the worst grade achieved during that phase of 
treatment.  AEs will be categorized by an AE term in the CTCAE, and “other” will not be used as a 
term within a system organ class unless there is no satisfactory alternative.    
Expedited reports will consist of an initial report and follow-up report when applicable (i.e. the initial 
report does not contain discharge/resolution information).  Follow up reports will be completed as 
data becomes available and within 5 days of the initial report whenever possible. Every attempt will 
be made to have a complete report submitted if reporting is required within 10 days of knowledge of 
the event.  These events will be reported as a single term (superordinate event) or syndrome.   These 
events will also be assessed for grade and causality by the treating physician or BMT attending and 
subsequently reviewed by the PI.  PI comments on the expedited reports will only be recorded in 
Oncore in those cases where a disagreement between the co-investigator and the PI exists with 
respect to the grading or causality assessment of the event.   
Monitoring of Adverse Events 
All participants will be monitored for AEs during the study. Assessments may include monitoring the 
participant's clinical symptoms; laboratory, pathological, radiological, or surgical findings; physical 
examination; or other appropriate tests and procedures. 
For this study’s purposes, ≥grade 3 toxicities that are possibly, probably, or definitely related to the 
protocol treatment will be captured in participant case report forms (CRFs) from the time of the start 
of the study regimen through 30 days after the last protocol treatment administered.   
Any toxicities that meet the above criteria, but develop >30 days after the last protocol treatment and 
are probably or definitely still related to treatment, will also be captured in the CRFs.  
 
 
Data and Safety Monitoring  
Type of Clinical Trial: 
  Investigator-initiated (UI/HCCC) 
❑ Investigator-initiated, participating 
site 
❑ Pilot study 
❑ Phase I 
❑ Phase I/II 
  Phase II 


Page 63 of 74 
 
❑ Phase III 
❑ Compassionate-use/Expanded 
Access  
  Interventional Treatment 
❑ Interventional Non-Treatment 
❑ Non-Interventional 
 
 
Study risk-level:  
❑ Level 1—low risk of morbidity or death, * <1% of death or any adverse event  
❑ Level 2—risk of death* <1% or any adverse event 1% – 5%  
❑ Level 3—risk of death* 1% – 5% or grade 4 – 5 SAE 1% – 5%  
  Level 4—risk of death* >5% or grade 4 – 5 SAE >5%  
❑ Drugs being used on a “compassionate” basis  
* Risk of death” refers specifically to 100-day treatment-related mortality 
___________________________ 
 
Reporting and Monitoring Requirements:  
All institutional investigator initiated trials (IITs), regardless of assigned risk level are subject to routine 
DSMC monitoring activities which may include but are not limited to review of signed consent 
documents, eligibility and adverse event reporting.  
 
All institutional IITs have the following reporting requirements as part of their DSMP: 
• Provide an annual progress report to the DSMC and PRMC 
• Register subjects in HCCC’s Clinical Trial Management System, OnCore 
• Document Adverse Events  
• Document protocol deviations  
 
Risk Level 4 
Interventional treatment trials involving investigational agents or devices with a risk of death* (>5% or 
grade 4 – 5 SAE >5%), e.g. all investigator initiated INDs, most Phase I/II trials, gene therapy, gene 
manipulation or viral vector systems high-risk clinical procedures if performed solely for research 
purposes.  The use of a new chemical or drug for which there is limited or no available safety data in 
humans. 
 
 
 
Study Safety Review 
An independent study monitor and/or the DSMC Chair (or designee), will review study data (provided 
by the PI/available in OnCore) and communicate with the PI at least biannually.  A copy of this 
communication will be forwarded to the DSMC and PRMC Chairs.   
 


Page 64 of 74 
 
Additional Reporting Requirements:  
- A scanned copy of the completed eligibility checklist, with screening information and PI signature, 
will be attached in OnCore for ongoing review by DSMC staff.  
- Serious adverse events will be entered directly into an OnCore SAE report by the research team.  
OnCore will send an automatic notification to the DSMC Chair/acting Chair and staff for review.  
- The DSMC utilizes a risk-based monitoring approach.  The trial's research records will be 
monitored at minimum twice per year.  Monitoring may be done more frequently depending on the 
protocol, risks to subjects, reported serious/adverse events, patient population and accrual rate.   
Records for a minimum of 25% of subjects will be monitored for the entire study.    
Monitoring will involve the following: 
• review eligibility of patients accrued to the study, 
• check for the presence of a signed informed consent, 
• determine compliance with protocol’s study plan, 
• determine whether SAEs are being appropriately reported to internal and external 
regulatory agencies,  
• compare accuracy of data in the research record with the primary source documents, 
• review investigational drug processing and documentation, 
• assess cumulative AE/SAE reports for trends and compare to study stopping rules. 
 
Routine Adverse Event Reporting 
 
For non-serious Adverse Events (AEs ≥ grade 3), documentation must begin from the first day of 
study treatment and typically continue through the 30 day follow-up period after treatment is 
discontinued.  
 
Collected information should be recorded in the electronic/Case Report Forms (eCRF/CRF) for that 
subject. A description of the event, its severity or toxicity grade (according to NCI’s Common Toxicity 
Criteria (CTCAE)), onset and resolved dates (if applicable), and the relationship to the study drug 
should be included. Documentation should occur in real time. The principal investigator has final 
responsibility for determining the attribution of the event as it is related to the study drug. 
 
 
 
 
 
Serious Adverse Event Reporting 
 
For any experience or condition that meets the definition of a serious adverse event (SAE), recording 
of the event must begin after signing of the informed consent and continue through the 30 day follow-
up period after treatment is discontinued.  
Reporting requirements are outlined on page 67. An adverse event is considered serious if it results 
in ANY of the following outcomes:   
 
1. Death 
2. A life-threatening adverse event  


Page 65 of 74 
 
3. An adverse event that results in inpatient hospitalization OR prolongation of existing 
hospitalization for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5. A congenital anomaly/birth defect.  
6. 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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
 
Data Monitoring and Management  
All studies that undergo PRMC review and/or utilize HCCC Clinical Research Services (CRS) 
resources are required to register subjects in OnCore. Subject registration includes the following: 
• Consent date and the IRB approved consent used  
• Date of eligibility and eligibility status (eligible, not eligible) 
• On study date and subject’s disease site (and histology if applicable) 
• On treatment date (if applicable)  
 
Subject Data 
 
In addition to the subject registration and subject status data entered in OnCore for all HCCC trials, 
research staff also enters the subject study data into electronic case report forms (eCRFs) for HCCC 
investigator initiated studies. eCRFs are approved by the PI and statistician prior to study activation to 
ensure the most effective data acquisition. All information on eCRFs will be traceable to the source 
documents which are generally maintained in the subject’s file. eCRF data are expected to be 
entered into OnCore within 30 calendar days after a subject’s study visit.  
 
 
 
 
Forms Monitoring 
 
OnCore eCRF data are monitored on a routine basis (dependent on accrual) to ensure all mandatory 
fields are entered completely, accurately and within time requirements. The assigned DSMC monitor 
manages the logistics associated with the data monitoring review. Once the clinical trial is identified 
for monitoring, the monitor arranges for a selection of cases to review from among the subjects 
registered in OnCore.  As part of the forms monitoring process, the assigned monitor will issue 
queries within the eCRF to resolve missing, incomplete and/or incorrect information. A member of the 
research team is expected to respond to monitoring queries within 14 business days.  
 
This process can often identify a misunderstanding or deficiency in protocol requirements early in the 
study and can improve data quality.  
 
Final Reports 
 
A summary of each subject’s data record is continually available to the PI, research staff, and DSMC 
from OnCore’s Biostat Console. The availability of this information is a valuable tool for the 
preparation of final reports and manuscripts as well as ongoing deficiency reports. 


Page 66 of 74 
 
 
 
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 Risks Reports: 
Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They must be followed in 
order to comply with FDA regulations for the conduct and monitoring of clinical investigations. 
Institutional Review 
This study must be approved by the Institutional Review Board, as defined by Federal Regulatory 
Guidelines (Ref Federal Register Vol. 46, No. 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). 
The PI will be responsible for protocol submissions (initial application, amendments, continuing 
reviews, SAEs, protocol violations, reports of information, etc) to the pertinent IRB and for obtaining 
and maintaining written IRB approval for this study.  IRB approval must be obtained prior to the 
initiation of the study.  Amendments to the protocol may not be instituted without written IRB approval.  
Drug Accountability 
Because all of the study drugs employed in this schema are commercially approved and have been 
used extensively in the treatment of multiple myeloma, investigational drug accountability logs will not 
be kept.  
Participant medication diaries will be issued to each study participant in order to track compliance 
with taking the study protocol’s oral, therapeutic medications and will be collected at clinic visits.  
Participants will have the option of faxing or e-mailing their medication diaries as well.  If a participant 
fails to return his/her medication diaries more than three times consecutively, he/she will be 
considered for removal from the study for participant non-compliance.  
Concomitant Medications  
Recording of concomitant medications will be limited to infection prophylaxis, infection treatment, and 
any newly ordered medications used to treat an event requiring expedited reporting.    
 
Study Records Requirements 
The Principal Investigator must ensure that records and documents pertaining to the conduct of the 
study be retained for a minimum of 10 years after the completion of the study.  
At any time the Principal Investigator may be subject to a field audit by regulatory authorities in order 
to validate the participation of participants in the study. Therefore, careful attention should be paid to 
ensuring that all study records are complete, accurate, filed and retained by the Investigator. 


Page 67 of 74 
 
The Principal Investigator, or a designated member of the Investigator’s staff, must be available at 
some time during auditing visits to review data and resolve any queries and to allow direct access to 
the participant’s records (e.g. medical records, office charts, hospital charts, and study related charts) 
for source data verification. All study documents must be made available to the auditing 
representative so that the accuracy and completeness may be confirmed.  
13.   References 
 1.  Gay F, Palumbo A.  Management of older patients with multiple myeloma. Blood Reviews 2011;      
     25: 65-73.   
 
 2. Siegel DS, Desikan KR, Mehta J, et al.  Age is Not a Prognostic Variable With Autotransplants for  
     Multiple Myeloma. Blood. 1999; 93(1):51-54.   
 
 3. Quach H, Miles Prince H, Spencer A. Managing multiple myeloma in the elderly: are we making  
     progress? Expert Rev Hematol. 2011; 4(3): 301-315.  
 
 4. Gay F, Larocca A, Wijermans P, et al. Complete response correlates with long-term progression- 
     Free and overall survival in elderly myeloma treated with novel agents: analysis 1175 patients. 
     Blood. 2011; 117 (11): 3025-3031.  
 
 5. Pulte D, Gondos A, Brenner H.  Improvement in Survival of Older Adults with Multiple Myeloma: 
     Results of an Updated Period Analysis of SEER data.  The Oncologist. 2011; 16: 1600-1603.  
 
 6. Harousseau JL.  Multiple Myeloma in the Elderly: When to Treat, When to go to Transplant. 
     Oncology. 2010; 24(11): 1-11. 
 
 7. Palumbo A, Mateos MV, Bringhen S, San Miguel JF. Practical management of adverse events  
     in multiple myeloma: Can therapy be attenuated in older patients?  Blood Reviews. 2011; 25:  
     181-191. 
 
 8. Migkou M, Kastritis E, Roussou M et al.  Short progression-free survival predicts poor overall  
     Survival in older patients with multiple myeloma treated upfront with novel agent-based therapy. 
     European Journal of Haematology. 2011; 87: 323-329. 
 
 9. Bashir Q, Shah N, Wei W, et al.  Feasibility of autologous hematopoietic stem cell transplant in  
     Patients aged ≥70 years with multiple myeloma.  Leukemia & Lymphoma. 2012; 53 (1): 118-122. 
 
10. El Cheikh J, Kfoury E, Calmels B, et al. Age at transplantation and outcome after autologous  
      Transplantation in elderly patients with multiple myeloma.  Hematol Oncol Stem Cell Ther. 2011; 
      4(1): 30-36. 
 
11. Cavo M, Pantani L, Petrucci MT.  Bortezomib-thalidomide-dexamethasone is superior to  
      thalidomide-dexamethasone as consolidation therapy following autologous hematopoietic stem  


Page 68 of 74 
 
      cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012; epub ahead 
      of print on April 12, 2012.   
 
12. Ludwig H, Durie BGM, McCarthy P et al. IMWG consensus on maintenance therapy in multiple  
      Myeloma.  Blood. 2012; 119(13): 3003-3015.  
 
13. McCarthy P, Owzar K, Hofmeister CC, et al.  Lenalidomide after Stem-Cell Transplantation for 
      Multiple Myeloma.  N Engl J Med. 2012; 336 (19): 1770-1781.  
 
14.  Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, Stoppa AM, Hulin C,     
       Benboubker L, Garderet L, Decaux O, Leyvraz S, Vekemans MC, Voillat L, Michallet M, Pegourie  
       B, Dumontet C, Roussel M, Leleu X, Mathiot C, Payen C, Avet-Loiseau H, Harousseau JL.  
       Lenalidomide Maintenance After Stem-Cell Transplantation for Multiple Myeloma. N Engl J Med.  
       2012 366(19): 1782-91.   
   
15.  Bensinger W, Jagannath S, Vescio R et al. Phase 2 study of two sequential three-drug  
       Combinations containing bortezomib, cyclophosphamide, and dexamethasone, followed by  
       bortezomib, thalidomide, and dexamethasone as frontline therapy for multiple myeloma.  Brit J  
       Haematology. 2009; 148: 562-568.  
 
16.  Hideshima T, Chauhan D, Podar K et al.  Novel therapies targeting the myeloma cell and its bone  
       marrow microenvironment.   Semin Oncol. 2001; 28 (6): 607-612. 
 
17.  Dalton W. The tumor microenvironment: focus on myeloma.  Cancer Treatment Reviews. 2003;  
        29 (Suppl I): 11-19. 
 
18. Yarde D, Oliveira V, Mathews L et al.  Cancer Res 2009; 69 (24): 9367-9375. 
 
19. Landowski TH, Olashaw NE, Agrawal D et al. Cell adhesion-mediated drug resistance (CAM-DR)  
       is associated with activation of NF-κB (RelB/p50) in myeloma cells. Oncogene. 2003; 22(16):  
       2417-21.  
 
21. Giralt, S.  Stem Cell Transplantation for Multiple Myeloma: Current and Future Status.  
      ASH Education book; 2011(1): 191-196.   
 
22. Barlogie B, Attal M, Crowley J et al. Long-Term Follow-Up of Autotransplantation Trials for  
      Multiple Myeloma: Update of Protocols Conducted by the Intergroupe Francophone du Myelome,  
      Southwest Oncology Group, and University of Arkansas for Medical Sciences.  J of Clin Onc  
      2010; 28 (7): 1209-1214.   
    
23. Barlogie B, Haessler J, Pineda-Roman et al. Completion of Pre-Maintenance Phases in Total  
      Therapies 2 and 3 Improves Clinical Outcomes in Multiple Myeloma.  Cancer 2008; 112 (12):  
       2720-2725. 


Page 69 of 74 
 
 
24. Waheed S, Alsayed Y, Nair B, et al.  Super-BEAM (SB): Incorporation of Bortezomib,  
      Thalidomide, Dexamethasone, Cisplatin, and Rapamycin Into the BEAM Regimen for Multiple 
      Myeloma (MM). 2009; ASH abstract 3421.  
 
25. Martino M, Olivieri A, Offidani M et al.  Addressing the questions of tomorrow: melphalan and new  
      combinations as conditioning regimens before autologous hematopoietic progenitor cell  
      transplantation in multiple myeloma.  Expert Opin Investig Drugs 2013; 22(5): 619-634.  
 
26. Lonial S, Kaufman J, Tighiouart M, et al. A Phase I/II trial combining high-dose melphalan and  
      autologous  transplant with bortezomib for multiple myeloma: a dose and schedule-finding study. 
      Clin Cancer Res 2010; 16(20): 5097-86.   
 
27. Roussel M, Moreau P, Huynh A, et al.  Bortezomib and high-dose melphalan as conditioning  
      regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: 
      a phase 2 study of the Intergroupe Francophone du Myelome (IFM). Blood 2010; 115(1): 32-37. 
 
28. Palumbo A, Avonto I, Bruno B, et al. Intermediate-Dose Melphalan (100 mg/m2)/Bortezomib/ 
      Thalidomide/Dexamethasone and Stem Cell Support in Patients with Refractory or Relapsed  
       Myeloma. Clin Lymph Myel 2006; 6(6): 475-477.    
 
29. Miyamoto T, Yoshimoto G, Kamimura T et al. Combination of high-dose melphalan and  
      Bortezomib as conditioning regimen for autologous peripheral blood stem cell transplantation  
      in multiple myeloma. Int J Hematology 2013; 98: 337-345.  
 
30. Nishihori T, Alekshun T, Shain K, et al.  Bortezomib salvage followed by a Phase I/II study of  
      Bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with 
      primary resistant myeloma. Brit J Haematology 2012: 157: 553-563.   
 
31. Wong Doo N, Thompson P, Prince HM, et al.  Bortezomib with high dose melphalan conditioning 
      for autologous transplant is safe and effective in patients with heavily pretreated and high risk  
      multiple myeloma.  Leuk & Lymph 2013 54(7): 1465-1472.   
 
32. Pineda-Roman M, Zangari M, Haessler J, et al.  Sustained complete remissions in multiple  
      Myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2.  Brit J  
      Haematology 2008; 140: 625-634.     
 
33. Cavallo F, Boccadoro M, and Palumbo A.  Review of thalidomide in the treatment of newly  
      diagnosed multiple myeloma.  Ther Clin Risk Management 2007; 3(4): 543-552.   
 
34. Van Rhee F, Szymonifka J, Anaissie E, et al. Total Therapy 3 for multiple myeloma: prognostic 
      Implications of cumulative dosing and premature discontinuation of VTD maintenance  
      Components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy. 


Page 70 of 74 
 
      Blood 2010; 116(8): 1220-1227.       
 
14.   Appendices 
 
Appendix I 
 
Instructions for Determining Body Weight  
For participants with weight <60kg, or who are under 5 ft tall, all doses will be based on actual body 
weight. 
For participants with weight >60kg and who are at least 5 ft tall, doses will be based on adjusted body 
weight, not to exceed a BSA of 2.0m2 during the D-PACE, transplant  and consolidation phases. 
However, during the maintenance phase, adjusted body weight is preferred, but not required for 
participants with weight >60 kg and who are at least 5 ft tall.   
1. Actual Body Weight (ABW) is the weight in Kg. 
2. Adjusted body weight (ABW): ABW = IBW + 0.4(actual weight - IBW). 
Ideal Body Weight (IBW): 
Males:  IBW = 50 kg + 2.3 kg for each inch over 5 feet or 60 inches 
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet or 60 inches 
 
 


Page 71 of 74 
 
Appendix II 
 
EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. The 
information that you provide will remain strictly confidential. 
Please fill in your initials:  ___________ 
Your birthdate (Day, Month, Year): ___________ 
Today's date (Day, Month, Year): ____________ 
________________________________________________________________________________ 
                                                                                                         Not at      A Little    Quite       Very  
                                                                                                           All             Bit        a Bit       Much 
1. Do you have any trouble doing strenuous activities, 
    like carrying a heavy shopping bag or a suitcase?                                 1                2              3                4 
 
2. Do you have any trouble taking a long walk?                                           1                2               3                4       
 
3. Do you have any trouble taking a short walk outside of the house?        1                2               3                4     
 
4. Do you need to stay in bed or a chair during the day?                             1               2                3               4 
 
5. Do you need help with eating, dressing, washing 
    yourself or using the toilet?                                                                       1               2               3               4 
 
During the past week:                                                                        Not at        A Little   Quite      Very 
                                                                                                                    All              Bit       a Bit      Much 
  
6. Were you limited in doing either your work or other daily activities?       1                 2              3               4 
 
7. Were you limited in pursuing your hobbies or other 
    leisure time activities?                                                                             1                 2              3               4 
 
8. Were you short of breath?                                                                       1                2              3               4 
 
9. Have you had pain?                                                                                1                 2             3               4 
 


Page 72 of 74 
 
10. Did you need to rest?                                                                           1                2              3              4 
  
11. Have you had trouble sleeping?                                                           1               2              3               4 
 
12. Have you felt weak?                                                                             1               2              3               4 
 
13. Have you lacked appetite?                                                                   1               2              3               4 
 
14. Have you felt nauseated?                                                                    1               2              3               4 
 
15. Have you vomited?                                                                              1               2              3               4 
 
16. Have you been constipated?                                                               1               2              3               4 
 
Please go on to the next page 
 
During the past week:                                                              Not at          A         Quite a      Very 
                                                                                                                All            Little         a Bit         Much 
 
17. Have you had diarrhea?                                                                     1                2               3               4 
 
18. Were you tired?                                                                                  1                2               3               4 
 
19.  Did pain interfere with your daily activities?                                      1                2               3               4 
 
20. Have you had difficulty in concentrating on things, 
      like reading a newspaper or watching television?                              1               2               3                4 
 
21. Did you feel tense?                                                                            1                2              3                4 
 
22. Did you worry?                                                                                   1               2               3                4 
 
23. Did you feel irritable?                                                                         1               2               3                4 
 
24. Did you feel depressed?                                                                    1               2               3                4 
 
25. Have you had difficulty remembering things?                                    1               2               3                4 
 
26. Has your physical condition or medical treatment 
      interfered with your family life?                                                          1              2               3                 4 
 
27.  Has your physical condition or medical treatment 
       interfered with your social activities?                                                1              2               3                4 
 
28.  Has your physical condition or medical treatment 
       caused you financial difficulties?                                                      1              2               3                4 
 


Page 73 of 74 
 
For the following questions please circle the number between 1 and 7 that 
best applies to you 
 
29.  How would you rate your overall health during the past week? 
 
              1          2          3          4          5          6          7      
 
Very poor                                                                     Excellent 
 
30.  How would you rate your overall quality of life during the past week? 
 
            1          2          3          4          5          6          7      
 
Very poor                                                                     Excellent 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 
 
 
EORTC QLQ – MY20 
 
Patients sometimes report that they have the following symptoms or problems. Please indicate 
the extent to which you have experienced these symptoms or problems during the past week. 
Please answer by circling the number that best applies to you. 
 
 
During the past week:                                                           Not at         A           Quite        Very 
                                                                                                   All         Little        a Bit          Much 
 
31. Have you had bone aches or pain?                                      1              2              3                 4 
 
32. Have you had pain in your back?                                         1              2              3                 4 
 
33. Have you had pain in your hip?                                            1             2               3                 4 
 
34. Have you had pain in your arm or shoulder?                        1            2                3                 4 
 
35. Have you had pain in your chest?                                        1            2                3                  4 
 
36. If you had pain did it increase with activity?                         1            2                3                  4 


Page 74 of 74 
 
37. Did you feel drowsy?                                                          1             2                3                  4 
 
38. Did you feel thirsty?                                                            1             2                3                  4 
 
39. Have you felt ill?                                                                 1             2                3                  4 
 
40. Have you had a dry mouth?                                               1             2                3                  4 
 
41. Have you lost any hair?                                                     1             2                3                  4 
 
42. Answer this question only if you lost any hair: 
      Were you upset by the loss of your hair?                          1             2                3                  4 
 
43. Did you have tingling hands or feet?                                 1             2                3                  4 
 
44. Did you feel restless or agitated?                                      1             2                3                  4 
 
45. Have you had acid indigestion or heartburn?                    1            2                 3                  4 
 
46. Have you had burning or sore eyes?                                1             2                 3                  4 
 
Please turn to next page 
 
During the past week:                                                     Not at          A               Quite           Very 
                                                                                             All           Little            a Bit           Much 
 
47. Have you felt physically less attractive as a result  
      of your disease or treatment?                                           1             2                 3                  4 
 
48. Have you been thinking about your illness?                     1             2                 3                  4 
 
49. Have you been worried about dying?                               1             2                 3                  4 
 
50. Have you worried about your health in the future?           1             2                 3                  4 
 
 
 
 
 
© Copyright 1999 EORTC Study Group on Quality of Life. All rights reserved. 

ICF_001.pdf: 
FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201208775 
APPROVAL DATE: 02/27/18 
EXPIRATION DATE: 02/15/19 
 
 
 
Page 1 of 18 
 
INFORMED CONSENT DOCUMENT 
 
Project Title: Single Autologous Transplant followed by Consolidation and Maintenance for 
Participants  ≥ 65 Years of Age Diagnosed with Multiple Myeloma or a Related Plasma Cell 
Malignancy.  
 
Principal Investigator:  Yogesh Jethava, MD 
 
Research Team Contact:   Meghan Chandler, RN 
 
319-467-5836  
 
This consent form describes the research study to help you decide if you want to participate.  This form 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights as a research subject.   
 If you have any questions about or do not understand something in this form, you should ask 
the research team for more information.   
 You should discuss your participation with anyone you choose such as family or friends.   
 Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study.  
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
This is a research study.  We are inviting you to participate in this research study because you have been 
diagnosed with multiple myeloma or POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, 
Monoclonal Gammopathy, and Skin changes, which is a syndrome in which patients have a plasma cell 
disease resembling multiple myeloma, and various organ changes).  
 
The purpose of this research study is to find out whether relapse or disease progression will be delayed 
when an autologous stem cell transplant (a transplant using your own stem cells) is combined with 
consolidation and maintenance treatment after transplant, and how safely this treatment can be given in 
patients with myeloma who are 65 years of age or older.     
 
All of the drugs that will be used are commercially available, are FDA approved for one or more 
cancers, and have been used in the treatment of multiple myeloma and/or other cancers. However, the 
drugs Doxorubicin, Etoposide, and Cisplatin are not FDA approved specifically for the treatment of  
multiple myeloma.  
 
HOW MANY PEOPLE WILL PARTICIPATE? 
 
Approximately 41 people will take part in this study conducted by investigators at the University of 
Iowa.  This study will only be conducted at the University of Iowa.  
 
 
 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201208775 
APPROVAL DATE: 02/27/18 
EXPIRATION DATE: 02/15/19 
 
 
 
Page 2 of 18 
HOW LONG WILL I BE IN THIS STUDY? 
 
If you agree to take part in this study, your involvement in the study treatment portion of this protocol 
will take approximately 2.3-3 years if you complete the entire study treatment schedule.  Whether you 
stop early or complete study treatment, we will continue to follow you  1-3 times per year after 
treatment is done until one or more of the following occurs: 
 your disease progresses 
 you choose to stop participating in the study 
 you become pregnant during the course of study treatment if you are a female of childbearing 
age (although we will follow you through the course of your pregnancy) 
 your treating physician or the Principal Investigator believes it is in your best interest to stop 
your participation in the study 
 you do not follow instructions for participation in the study  
 
During each follow-up visit, you will see your study physician for approximately one hour, and the 
research coordinator for approximately 15 minutes.  
 
During the first phase of study treatment, which may be completed within 3-12 months, you will have 4-
5 study visits at the following time points: 
 before the induction phase  
 before transplant  
 before consolidation treatment if you receive this study treatment step 
 before proceeding to the first year of maintenance therapy  
 
Each of these study visits will also require a time commitment of approximately one hour with your 
study physician, and approximately 15 minutes with the research coordinator.   
 
WHAT WILL HAPPEN DURING THIS STUDY? 
 
Participation in this study will involve multiple phases.  
 
Before the study treatment begins, you will have screening tests and procedures for your disease that are 
part of your regular cancer care.  Based on these results, the study team will be able to determine if you 
are a good candidate to continue in this study. 
 
Although we try to give as much of your research treatment in an outpatient setting, it is highly 
likely that you may experience one or more hospitalizations during the course of this study, either 
because of the disease itself, because of complications of the study treatment, or because the study 
treatment cannot be given safely to you as an outpatient.  Thus, some of these study treatments 
may need to be given while you are hospitalized.  Only the study treatments prior to the 
maintenance phase must be given through the University of Iowa Holden Comprehensive Cancer 
Center.   
 
Induction Phase: If you are eligible to receive study treatment, you will begin the induction phase. 
During this phase, you will receive chemotherapy, and when your blood counts recover, you will have 
your stem cells collected.  


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201208775 
APPROVAL DATE: 02/27/18 
EXPIRATION DATE: 02/15/19 
 
 
 
Page 3 of 18 
The following tests may be performed if you do not start induction treatment within 2 weeks of study 
enrollment.  If you do start study treatment within 2 weeks of study enrollment, we will use the pre-
study test and procedure results.  
 
 Blood samples (approximately 9-11 tablespoons) will be done for routine blood count, chemical 
analysis, to measure specific blood markers related to your disease, and to see how well your 
organs are functioning. If you are a woman of child-bearing age, we will also perform a 
pregnancy test.  
 You will also have a bone marrow aspirate and biopsy done.  
 The doctor may also order a PET (positron emission tomography) or MRI (magnetic resonance 
imaging) scan to assess the full extent of your disease.  
 You will have a physical examination. 
 
You will receive chemotherapy drugs that are called DPACE (dexamethasone, cisplatin, doxorubicin, 
cyclophosphamide, and etoposide). We will provide you with a study treatment calendar.  The 
chemotherapy drugs will be administered according to the following schedule: 
 
Dexamethasone 20 mg oral (by mouth) on days 1-4 and 8-11. 
 
Cisplatin 10 mg/m2/day on days 1-4 Continuous Infusion (CI).  
 
Doxorubicin 10 mg/m2/day on days 1-4 CI. 
 
Cyclophosphamide 400 mg/m2/day or 600 mg/m2 on days 1-4 CI. 
 
Etoposide 40 mg/m2/day on days 1-4 CI. 
 
An assessment of any side effects or adverse reactions will be made, and we will also review 
medications with you to ensure that you have taken the oral drugs according to the study schedule.  We 
will give you medication and side effect diaries to assist the study team with these assessments. We will 
ask you to complete these diaries on a daily basis and bring them back to the study team at your next 
study visit or you may also fax or e-mail these diaries using the contact information provided to you on 
those forms.  
 
Once you recover your blood counts after chemotherapy (usually between days 12 and 17), you will 
have your stem cell collection. The goal of this stem cell collection is to obtain enough cells for a 
transplant in the near future and to have additional stem cells in store in case you need a stem cell boost, 
or you need another stem cell transplant in the future because the myeloma has recurred. The more stem 
cells we collect, the safer your transplant will be. If the amount of stem cells collected is inadequate, you 
may need another stem cell collection.  
 
A stem cell boost refers to an additional infusion of your own stem cells after transplant (but without 
additional chemotherapy) because your blood counts have not recovered (graft failure) or are slower to 
recover (graft delay) after transplant than expected, which leaves a patient vulnerable to infections and 
an extended need for blood transfusions.  This delay or lack of recovery in your blood counts increases 
your risk of serious complications after transplant.   
 


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Although unlikely, it is possible that the first stem cell collection may contain too many myeloma cells, 
and using these contaminated cells with your transplant is riskier.  Therefore, if this would happen, you 
will undergo an additional round of chemotherapy (VDT-PACE) prior to any additional stem cell 
collections. The administration schedule for this round of chemotherapy called VDT-PACE is as 
follows: 
 
Dexamethasone 20 mg oral on days 1-4 and days 8-11 
Thalidomide 100mg oral on days 1-11 
Bortezomib 1mg/m2 IV Push (administered quickly) on days 1, 4, 8, 11 
 
Cisplatin 10 mg/m2 on days 1-4 CI 
 
Doxorubicin 10mg/m2 on days 1-4 CI 
 
Cyclophosphamide 400 mg/m2 on days 1-4 CI 
 
Etoposide 40 mg/m2 on days 1-4 CI 
 
After the stem cell collection, you will continue to receive Dexamethasone for 4 days in a row every 14 
days.   
 
Transplant: Anywhere between 4 weeks and 6 months after the first day of DPACE), you will have 
your transplant. Before the transplant takes place, you will have the following tests and procedures done 
as part of your regular care. 
 
 Blood samples (approximately 9-11 tablespoons) will be done for routine blood count, chemical 
analysis, to measure specific blood markers related to your disease, and to see how well your 
organs are functioning. A pregnancy test will be added if you are a woman of child bearing 
potential. 
 You will also have a bone marrow aspirate and biopsy done.  
 You may also have an MRI (magnetic resonance imaging) scan and/or PET (positron emission 
tomography) scan. These scans will be used to assess your response to the induction 
chemotherapy, but may also be done to see if there are any signs of infection present. 
 You will have a physical examination. 
 An assessment will be made of any side effects or adverse reactions that you have had or are 
having, and we will also review medications with you to ensure that you have taken the oral 
drugs according to the study schedule. We will give you medication and side effect diaries to 
assist the study team with these assessments. We will ask you to complete these diaries on a 
daily basis and bring them back to the study team at your next study visit or you may also fax or 
e-mail these diaries using the information provided to you on those forms. 
 
As part of the transplant, you will be receiving chemotherapy drugs called bortezomib, thalidomide, 
dexamethasone, and melphalan. The day after your second dose of melphalan, you will have the 


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Page 5 of 18 
transplant, which means that part of your previously collected stem cells will be given back to you. The 
day of your transplant is considered day 0. We will provide you with a treatment calendar.   The 
chemotherapy drugs will be administered according to the following schedule: 
 
Dexamethasone 20 mg oral on days -4 to -1 and +2 to +5. 
  
Bortezomib 1mg/m2 IV Push (administered quickly) on days -4, -1, +2, and +5. 
 
Thalidomide 100mg/day oral on days -4 to +5. 
 
Melphalan will be given at a dose of 100 mg/m2 on days -4 and -1 (Patients > 70 years of age or with a 
creatinine > 2.0 mg/dl will receive a reduced dose of Melphalan of 70 mg/m2  on days -4 and -1).   
 
Peripheral blood stem cell infusion will be given intravenously on day 0, at least 18 hours after the 
second dose of melphalan. 
 
Once you have recovered from most of the side effects of the transplant, you will restart thalidomide 
daily and dexamethasone for four days every 21 days. 
 
Consolidation Phase: Approximately 4 weeks to 4 months after transplant, you will have the following 
tests and procedures done as part of your regular care.  
 
 Blood samples (approximately 9-11 tablespoons) will be done for routine blood count, chemical 
analysis, to measure specific blood markers related to your disease, and see how well your 
organs are functioning. A pregnancy test will be added if you are a woman of child bearing 
potential. 
 You will also have a bone marrow aspirate and biopsy done.  
 You may also have an MRI (magnetic resonance imaging) scan and/or PET (positron emission 
tomography) scan. These scans will be used to assess your response to transplant, but also to see 
if there are any signs of infection present. 
 You will have a physical examination. 
 An assessment will be made of any side effects or adverse reactions that you have had or are 
having, and we will also review medications with you to ensure that you have taken the oral 
drugs according to the study schedule. We will give you medication and side effect diaries to 
assist the study team with these assessments. We will ask you to complete these diaries on a 
daily basis and bring them back to the study team at your next study visitor you may also fax or 
e-mail these diaries using the information provided to you on those forms. 
 
As part of the consolidation phase, you may receive the chemotherapy drugs dexamethasone, 
thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide.   However, most patients will 
not receive consolidation treatment. If you have high-risk disease, have recovered from transplant, and 
had at least a partial response to induction therapy, you will receive consolidation chemo. If you receive 
consolidation treatment, we will provide you with a treatment calendar.  The chemotherapy drugs will 
be administered according to the following schedule: 
    


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Dexamethasone 20 mg oral on days 1-4 and days 8-11 
 
Thalidomide 100mg oral on days 1-11 
 
Bortezomib 1mg/m2 IV Push (administered quickly) on days 1, 4, 8, 11 
 
Cisplatin 10 mg/m2 on days 1-4 CI 
 
Doxorubicin 10mg/m2 on days 1-4 CI 
 
Cyclophosphamide 400 mg/m2 on days 1-4 CI 
 
Etoposide 40 mg/m2 on days 1-4 CI 
 
Maintenance Phase Year 1 and 2: After you have completed the consolidation phase, or if you do not 
receive consolidation treatment, you will proceed to maintenance. During these two years, the following 
tests and procedures will be done as part of your regular care. 
 
 You will have a physical examination. 
 At least 3 times per year you will have certain blood tests done to measure your blood chemistry, 
disease markers, and organ function.  Other blood tests may be done, or blood tests may be 
performed more frequently, if your study doctor determines that it is necessary.  
 At least 3 times per year, you will also have a bone marrow aspirate and biopsy.  
 MRI or PET scans will be done if clinically necessary, as determined by your study doctor. 
 An assessment will be made of any side effects or adverse reactions that you have had or are 
having, and we will also review medications with you to ensure that you have taken the oral 
drugs according to the study schedule.  We will give you medication and side effect diaries to 
assist the study team with these assessments.  
 
   
 
After year 2 of maintenance treatment has been completed, we will continue to follow you 1-3 times per 
year as long as you remain on study.  
 
Long-term follow-up 
 
During all subsequent years, the following tests and procedures will be done as part of your regular care. 
 
 At least once per year, you will have a physical examination. 
 At least once per year, you will have blood tests done to measure your blood chemistry, disease 
markers, and organ function.  These blood tests, or other blood tests, may be done more 
frequently if your study doctor thinks that they are clinically necessary.  
 At least once per year, you will have a bone marrow aspirate and biopsy. 
 MRI or PET scans will only be done if clinically indicated and determined as necessary by your 
doctor.  


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Quality-of-Life Questionnaires  
 
Another optional part of this study involves the administration of quality-of-life questionnaires that the 
study team will provide you.  These questionnaires will help the study team understand what quality-of-
life is like before, during, and after this type of treatment plan when given to patients who are 65 years 
of age or older.     
 
If you agree to participate in this part of the study, you will complete 2 quality-of-life questionnaires that 
have been given to thousands of cancer patients involved in clinical trials internationally at the following 
time points: 
 
 Before you begin any study treatment but after you have signed a consent form for this study. 
 Before consolidation or maintenance treatment (if consolidation is skipped) begins  
 Three times per year at your clinic appointments during maintenance treatment  
 Once per year thereafter for as long as you continue to be enrolled in this study, even when you 
are finished with study treatment.    
 
The first questionnaire is a more generic assessment of symptoms and your overall health, while the 
second questionnaire is focused on more common myeloma-specific symptoms that not all cancer 
patients might experience. Both questionnaires should take you approximately 3-5 minutes to complete.  
Answers to the questionnaires are kept completely confidential.  There is a small possibility that you 
may be distressed by some of the questions, although a lot of the questions are very similar to those that 
a physician might ask you in order to understand how you are doing.   
 
If you agree at this time to complete these questionnaires but decide in the future that you would like to 
withdraw your participation from this part of the study, please contact Meghan Chandler, RN by phone 
(319-467-5836) or via e-mail at meghan-chandler@uiowa.edu 
 
Please place your initials in the blank next to Yes or No for each of the questions below: 
 
I agree to complete the 2 quality-of-life questionnaires throughout my involvement in this study. 
 
_____ Yes     _____ No 
_____ Initials   
 
 
WHAT ARE THE RISKS OF THIS STUDY? 
 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study.  Cancer treatments have side effects that can range from mild to severe.  With your cancer 
treatment you are likely to experience a number of side effects, and some of these may be serious.  
These may include additional hospitalizations and even death.  
 
It is expected that 5 to 10% of patients will die of complications of the study treatment.  Deaths 
with this type of treatment are usually due to infections that develop when the immune system, due to 


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Page 8 of 18 
the high doses of chemotherapy, is less able to fight off infection successfully.  It is therefore extremely 
important that you follow all of the instructions related to preventing infections closely.   
 
Based on research studies at the University of Arkansas using similar treatment, 12% of patients over 
the age of 65 died from this type of treatment.  Although we do not expect this to be the case in this 
study since this study treatment is not as intensive and includes only a single transplant, it is possible 
that we may also see a similarly higher rate (12-15%) of study-related deaths, since most of the deaths 
were observed with the first transplant or during the consolidation/maintenance therapy. However, 
although the risk of this treatment is higher, we hope that this treatment will result in better and longer 
control of your cancer (48 months versus an average of 24-36 months with non-transplant chemo) and a 
good quality-of-life.   Please consider the possible benefits and risks very carefully before deciding 
to participate in this study.     
 
Common side effects of many chemotherapy drugs include:  nausea, vomiting, hair loss, upset stomach, 
and low blood counts.  Low blood counts put a patient at risk of infection, bleeding, and anemia.  
Sometimes low blood counts may require transfusions to bring the counts back up.   
 
Rarely, a patient may have an allergic reaction to chemotherapy, or may have evidence of a serious 
condition called tumor lysis syndrome, which refers to major changes in various laboratory values as a 
result of dying tumor cells releasing their contents into the blood stream.  This could result in damage to 
various organs, including the heart, kidneys, and liver.   Sometimes patients also have complications 
from the central lines used for giving chemotherapy or collecting stem cells.   These complications can 
include developing a blood clot at the site of the line, and line-related infections.   
 
Another potential side effect of a transplant in which your own stem cells are used is a syndrome called 
engraftment syndrome.  In a paper published by University of Wisconsin researchers, engraftment 
syndrome was referred to as autologous graft-versus-host disease.  While your blood counts are 
recovering, the symptoms of engraftment syndrome may include fever, a skin rash, and fluid build-up in 
the lungs.  These symptoms are due to the interactions between the body’s cells and small proteins that 
are important in cell signaling. In its less severe form, engraftment syndrome occurs in approximately 
9% of patients.  In extremely rare cases, the fluid build-up in the lungs may lead to lung failure or other 
organ failure, but this occurs in less than 2% of patients. Steroids are used to treat the symptoms of 
engraftment syndrome, and this usually resolves the symptoms.       
 
RISKS/SIDE EFFECTS ASSOCIATED WITH THE INDIVIDUAL CHEMOTHERAPIES 
 
Bortezomib 
 
Common (equal to or greater than 30%):  fatigue, generalized weakness, peripheral neuropathy 
(numbness and/or tingling in the hands or feet, which can be painful), nausea and/or vomiting, diarrhea, 
loss of appetite, constipation, low platelet counts, fever, low red blood cell counts. 
 
Less Common (10-29%):  headache, difficulty sleeping, joint pain, swelling of the face, hands, feet, or 
legs, low white blood cell counts, shortness of breath, dizziness, rash, dehydration, respiratory tract 
infections, cough, bone pain, anxiety, muscle cramps, heartburn, abdominal pain, low blood pressure, 
itching, blurring of vision, electrolyte abnormalities (low potassium, low magnesium, etc).   


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Rare but Serious (less than 10%):  serious abnormal heart rhythms, congestive heart failure, lung 
disorders, liver failure, Reversible posterior leukoencephalopathy syndrome (a reversible condition of 
the brain that results in seizures, high blood pressure, headaches, tiredness, confusion, blindness, and 
other vision problems).   
 
Carfilzomib  
 
Common (equal to or greater than 30%): low platelet counts, fatigue, low red blood cell counts, nausea, 
shortness of breath, diarrhea, and fever.   
 
Less common (10-29%): pneumonia, low white blood cell counts, lack of appetite, pain, high blood 
sugar, higher than normal blood levels of calcium, phosphorus, and sodium, mild decrease in kidney 
function, peripheral neuropathy (numbness and tingling in your hands and feet). 
 
Rare but serious (less than 10%): decrease in heart function ranging from mild to severe, pulmonary 
hypertension (an increase of blood pressure in the lung arteries), infusion reactions ranging from mild to 
severe, tumor lysis syndrome (changes in laboratory values as a result of dying tumor cells releasing 
their contents into the blood stream.  This could result in damage to various organs, including the heart, 
kidneys, and liver), liver failure, infection requiring hospitalization, shingles.   
 
Cisplatin  
 
Common (equal to or greater than 30%): low white blood cell counts, low red blood cell counts, low 
platelet counts, electrolyte abnormalities (i.e. low magnesium, low potassium, etc), temporary kidney 
dysfunction.   
 
Less Common (10-29%): peripheral neuropathy (numbness and/or tingling in the hands or feet) which 
may be irreversible, ringing in the ears, loss of appetite, metallic taste in the mouth, temporary increases 
in liver enzymes, hair loss, infertility. 
 
Rare but Serious (less than 10%):  loss of vision, swelling of the eye(s), hearing problems, heart 
attack, stroke, inflammation of arteries in the brain, leaking of plasma from blood vessels, seizures, 
puffy face, fast heartbeat, electrolyte imbalances, hormone imbalances, changes in the brain’s white 
matter that do not have any known clinical or neurologic consequences.   
 
Cyclophosphamide  
 
Common (equal to or greater than 30%):  low white blood cell count, low red blood cell counts, low 
platelet counts, temporary hair loss, nausea and vomiting, loss of appetite, infertility, 
discoloration/darkening of the skin and nails. 
 
Less Common (10-29%): diarrhea, mouth sores, bladder problems, including bladder irritation and 
bleeding, kidney damage, hormone imbalances, sweating, temporary redness of the face and neck, head 
pain, increase in uric acid that could lead to gout or kidney stones. 
 


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Rare but Serious (less than 10%):  painful, red, or swollen mouth, hepatitis (inflammation of the liver), 
trouble breathing, allergic reaction, development of a blood cancer.   
 
Dexamethasone  
 
Common (equal to or greater than 30%):  increased appetite, irritability, insomnia (difficulty sleeping), 
swelling in the ankles and/or feet, heartburn, muscle weakness, impaired wound healing, increases in 
blood sugar levels.  
 
 
Less Common (10-29%):  headaches, dizziness, mood swings, cataracts, bone thinning, intestinal 
bleed, osteoporosis, diabetes, Cushing’s Syndrome (hormone disorder that results in too much cortisol), 
irregular menstrual periods.  
 
 
Rare but Serious (less than 10%):  depression that may lead to suicidal tendencies, mania (extreme 
sense of wellbeing), increased pressure in the eye, high blood pressure, severe muscle weakness, slow 
heartbeat, abnormal heart rhythm, blood clots, hallucinations, abnormal liver enzymes, confusion.   
 
Doxorubicin   
 
Common (equal to or greater than 30%): Low white blood cell count, low platelet count, low red blood 
cell count, nausea and/or vomiting, diarrhea, heart rhythm disturbances with no clinical consequences, 
fever and risk of infection, temporary hair loss, sores in the mouth, weakness, loss of appetite.   
 
Less Common (10-29%):  watery eyes, red-orange tint to the urine, darkening of the skin or nail beds, 
infertility.  
 
Rare but Serious (less than10%):  congestive heart failure (with higher doses), inflammation of the 
heart muscle, heart rhythm abnormalities,  ulceration of the colon, swelling/rash or other abnormality at 
the IV site, hypersensitivity/allergic reaction, kidney dysfunction, redness or swelling of  the eye, 
decreased vision, and the development of another cancer.   
 
Etoposide  
 
Common (equal to or greater than 30%):  low white blood cell counts, low platelet counts, low red 
blood cell counts, hair loss, menopause, infertility, nausea and vomiting, low blood pressure.  
Less Common (10-29%): mouth sores, diarrhea, loss of appetite, metallic taste in mouth, peripheral 
neuropathy (numbness and tingling in the hands or feet), low blood pressure, constipation. 
 
Rare but Serious (less than 10%):  allergic reactions, development of a blood cancer.   
 
Lenalidomide 
 
Common (equal to or greater than 30%):  back pain, low platelet counts, low white blood cell counts, 
diarrhea, itching of the skin, rash, mild stomach pain, stuffy or runny nose, fatigue. 
 
Less Common (10-29%):  headache, blood clots, nausea and/or vomiting, constipation, low red blood 


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cell counts, abdominal pain, dry mouth or skin, night sweats, edema (fluid retention in the feet or 
ankles), respiratory tract infections, pneumonia, shortness of breath, nosebleed, joint pain, back pain, 
muscle cramping, muscle weakness, dizziness, peripheral neuropathy (numbness and/or tingling in your 
hands or feet), urinary tract infection, low blood potassium levels, loss of appetite, trouble sleeping.     
 
Rare but Serious (less than 10%):  splenic infarction (death of spleen tissue due to a blockage of blood 
flow), myelodysplasia (condition in which the bone marrow fails to produce adequate red blood cells or 
platelets), intestinal bleeding, intestinal perforation (a hole or tear develops in the intestinal wall), 
intestinal inflammation or infections, inflammation of the pancreas, severe skin reactions, including the 
development of a skin disease called Stevens-Johnson syndrome, which may be fatal, bone fractures, 
memory impairment, stroke, migraines, kidney dysfunction or failure, kidney infections, diabetes, low 
blood sugar levels, inflammation of the gallbladder, inflammation of the liver, abnormal thyroid 
function, high blood pressure, depression, delusions, congestive heart failure, abnormal and serious heart 
rhythm abnormalities, blood clot in the lungs, and the development of another cancer.  
 
Melphalan  
 
Common (equal to or greater than 30%): low white blood cell counts, low red blood cell counts, low 
platelet counts, nausea and/or vomiting. 
 
Less Common (10-29%):  allergic reaction, mouth sores, diarrhea, infertility, hair loss, kidney 
dysfunction, abnormal heart rhythms that may or may not be clinically significant.   
 
Rare but Serious (less than 10%):  anaphylaxis (serious allergic reaction that could be life-
threatening), jaundice (yellowing of the skin or eyes), problems breathing, liver damage, development of 
another cancer.   
 
Pomalidomide 
 
Common (equal to or greater than 30%): fatigue, weakness, low white blood cell counts, low red blood 
cell counts, constipation, nausea, diarrhea, shortness of breath, lung infections, back pain, and fever. 
Less common (10-29%): muscle weakness, pneumonia, bone pain, cough, nose bleed, decrease in 
appetite, higher than normal blood sugar levels, higher than normal calcium levels, low potassium 
levels, low sodium levels, rash, itchy skin, dizziness, headache, neuropathy (numbness and tingling in 
your hands or feet), confusion, anxiety, decrease in kidney function. 
 
Rare but Serious (less than 10%):  Chills, pain, urinary tract infection, lower than normal calcium 
levels, excessive sweating, night sweats, dry skin, tremor, insomnia.     
 
Thalidomide  
 
Common (equal to or greater than 30%):  fatigue and some form of neuropathy (numbness and/or 
tingling in the hands or feet). 
 
Less Common (10-29%):  dizziness, peripheral neuropathy interfering with the daily activities of life, 
low red blood cell counts, low white blood cell counts, fever, sweating, acne, nausea, constipation or 


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much less likely diarrhea, blood in the urine, increases in liver enzymes, mood changes.  
 
Rare but Serious (less than 10%): migraines, confusion, seizures, fainting, enlarged spleen, infection, 
urinary incontinence, tremor, diabetes, increased blood cholesterol levels, high and low blood pressure, 
congestive heart failure, a slow heart rate or other serious abnormal heart rhythms, blood clots, blood 
clots in the lungs, heart attack, stroke, liver function abnormalities, enlarged liver, jaundice associated 
with gallbladder disease, liver failure, obstruction of the bile duct,  pneumonia, thyroid dysfunction, 
deafness, ringing in the ears, suicide attempts, psychosis, kidney failure, and the development of another 
cancer.   
 
OTHER RISKS ASSOCIATED WITH STUDY TREATMENT 
 
Transplant 
 
1. DSMO: when your stem cells are collected, a preservative called DSMO (dimethylsulfoxide) is added 
to them before they are frozen, and the side effects associated with this preservative are: facial flushing, 
tickling sensation in the throat, strong taste in the mouth, strong odor, diarrhea, abnormal heart rhythms, 
nausea and/or vomiting, reddish urine, and rarely, abdominal pain, seizures, and kidney failure.  To 
minimize these side effects, you will be premedicated before the infusion, and you will receive a sterile 
saline infusion after the transplant to help flush this preservative out of your body. Furthermore, your 
transplant will be split over two days if the amount of DMSO is above certain levels.    
 
2. Allergic reaction/anaphylaxis: you may experience an allergic reaction (chills, fever, and hives) to the 
proteins or other parts of the stem cell infusion.  Anaphylaxis is a severe and sometimes life-threatening 
whole-body allergic reaction.  You will be treated immediately if any signs of allergy or anaphylaxis 
arise.  
 
3. High and low blood pressure:  Blood pressure fluctuations can occur. The stem cell infusion may have 
to be slowed or temporarily interrupted to allow your blood pressure to normalize. 
 
3. Pulmonary Micro-Embolism (small clots that have traveled to the lungs):  Clumps of cell matter may 
have formed after thawing your stem cells, and these clumps could result in micro-emboli in the lungs, 
which could be very serious.  Symptoms include chest pain, shortness of breath, or coughing.  Slowing 
of the infusion and administration of oxygen may alleviate mild shortness of breath during infusion.   
 
4. Fluid build-up in the lungs:  Rarely, patients may experience fluid build-up in the lungs, which is 
generally associated with a higher volume infusion.  Slowing the stem cell infusion and supplemental 
oxygen may be necessary to treat symptoms. 
 
5. It is possible that your infused stem cells may be slow to engraft (regrow your bone marrow).  This  
may be due to infection, medications, damage to the stem cell product during freezing, or a lower 
number of stem cells infused.  This is known as graft delay.  If this occurs, your physicians may need to 
infuse additional stem cells to help your bone marrow recover faster.  The risks of this additional 
infusion are the same as the risks of transplant (not including the chemotherapy) outlined in this section.   
 
6.  Graft failure, in which bone marrow function fails to return, is extremely unusual when a patient’s 


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own stem cells are the source of the stem cell infusion.  Graft failure occurs in less than 1% of 
autologous (using one’s own stem cells) transplants.  
 
Post-transplant Transfusions 
 
After the transplant, you will have low levels of red blood cells, white blood cells, and platelets, and you 
may need transfusions.  There are risks with blood transfusions, which include transfusion reaction, 
infections, and fluid overload (too much fluid). The most frequent signs of transfusion reaction are fever, 
chills, itching, and hives. Most blood transfusions go well and without complication, and only very 
rarely do serious problems develop.  
 
Growth Factors  
 
Before your stem cell collection and after the transplant, you will receive growth factors called 
filgrastim or pegfilgrastim, which are drugs that will prompt your bone marrow to produce more white 
blood cells. The risks of receiving filgrastim or pegfilgrastim include fevers and bone pain, which may 
be severe and require pain medication. Other risks are more serious but rare. They include a very high 
concentration of white blood cells which can cause strokes and heart attacks. However, thousands of 
patients have received filgrastim and there is only one report of a patient with a heart attack.  
 
Women Capable of Becoming Pregnant 
If you are a woman who is capable of becoming pregnant, we will ask you to have a pregnancy test 
before beginning this study.  You must use effective birth control methods and try not to become 
pregnant while participating in this study.  If you become pregnant, there may be unknown risks to your 
fetus, or risks to your fetus that we did not anticipate, associated with being in the study. There may be 
long-term effects of the treatment being studied that could increase the risk of harm to an unborn child.  
If you believe or know you have become pregnant while participating in this research study, please 
contact Meghan Chandler at 319-467-5836 as soon as possible. 
 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
 
We don’t know if you will benefit from being in this study.  
 
We hope that, in the future, other people might benefit from this study from knowledge gained toward 
establishing a treatment plan for patients who are only able to receive a single autologous bone marrow 
transplant that delays disease progression or relapse longer than other currently used treatment options 
but can also be administered safely in patients age 65 and older.   
 
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
 
Before you decide whether or not to be in this study, your doctor will discuss the other options that are 
available to you.  Options available as an alternative to taking part in this study include:  
 
 Different non-transplant combinations of chemotherapy drugs commonly used in the treatment of 
multiple myeloma.  


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EXPIRATION DATE: 02/15/19 
 
 
 
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 Stem cell transplant off study (either as a single or double autologous transplant).  
 Participation in another research study 
 No treatment  
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
 
You may have costs for being in this research study.  You and/or your insurance company will need to 
pay for all of the costs of treating your cancer while in this study.  Some insurance plans will not pay 
these costs for people taking part in studies.  Check with your health plan or insurance company to find 
out what they will pay for.  Financial coordinators are available to assist you with insurance coverage 
questions or issues.  
 
WILL I BE PAID FOR PARTICIPATING? 
 
You will not be paid for being in this research study.   
           
WHO IS FUNDING THIS STUDY? 
 
The University and the research team are receiving no payments from other agencies, organizations, or 
companies to conduct this research study. 
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
 
 If you are injured or become ill from taking part in this study, medical treatment is available at the 
University of Iowa Hospitals and Clinics. 
 The University of Iowa does not plan to provide free medical care or payment for treatment of any 
illness or injury resulting from this study unless it is the direct result of proven negligence by a 
University employee.  
 If you experience a research-related illness or injury, you and/or your medical or hospital insurance 
carrier will be responsible for the cost of treatment. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will keep your participation in this research study confidential to the extent permitted by law.  
However, it is possible that other people such as those indicated below may become aware of your 
participation in this study and may inspect and copy records pertaining to this research.  Some of these 
records could contain information that personally identifies you.  
 
 federal government regulatory agencies,  
 the U.S. Food and Drug Administration  
 auditing departments of the University of Iowa, and  
 the University of Iowa Institutional Review Board (a committee that reviews and approves 
research studies)  
 
To help protect your confidentiality, we will only conduct study discussions, including the informed 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201208775 
APPROVAL DATE: 02/27/18 
EXPIRATION DATE: 02/15/19 
 
 
 
Page 15 of 18 
consent discussion, in a private area.  Hard copies of the study data will only contain de-identified 
information.  Research charts containing identifying information will be kept in a locked area and will 
only be accessible to designated study team members or those parties outlined in the above paragraph.  
Electronic study data will be username and password-protected and only accessible to study team 
members or those parties outlined in the above paragraph. Optional blood and/or tissue samples obtained 
during the course of this study will only be labeled with the date, your initials, and your unique study 
identification number.  Only the research coordinator(s) will know who donated each sample.  The lab 
team will not have access to any of your identifying information.   If we write a report or article about 
this study or share the study data set with others, we will do so in such a way that you cannot be directly 
identified. 
 
The University of Iowa Hospitals and Clinics generally requires that we document in your medical 
record chart that you are participating in this study. The information included in the chart will provide 
contact information for the research team as well as information about the risks associated with this 
study. We will keep this Informed Consent Document in our research files; it will not be placed in your 
medical record chart. 
 
If any information from this study is published in medical journals, the published results will not 
identify you by name or reveal any other identifiers that may make it possible for someone to link you to 
this study.  
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by U.S. 
Law.  This website will not include information that can identify you.  At most, the website will include 
a summary of the results.  You can search this website at any time. 
 
WILL MY HEALTH INFORMATION BE USED DURING THIS STUDY? 
 
The Federal Health Insurance Portability and Accountability Act (HIPAA) requires the University of 
Iowa Hospitals & Clinics to obtain your permission for the research team to access or create “protected 
health information” about you for purposes of this research study.  Protected health information is 
information that personally identifies you and relates to your past, present, or future physical or mental 
health condition or care.  We will access or create health information about you, as described in this 
document, for purposes of this research study and for your treatment.  Once the University of Iowa 
Hospitals & Clinics has disclosed your protected health information to us, it may no longer be protected 
by the Federal HIPAA privacy regulations, but we will continue to protect your confidentiality as 
described under “Confidentiality.” 
 
We may share your health information related to this study with other parties including federal 
government regulatory agencies, the University of Iowa Institutional Review Boards and support staff. 
You cannot participate in this study unless you permit us to use your protected health information.  If 
you choose not to allow us to use your protected health information, we will discuss any non-research 
alternatives available to you.  Your decision will not affect your right to medical care that is not 
research-related.  Your signature on this Consent Document authorizes the University of Iowa Hospitals 
& Clinics to give us permission to use or create health information about you. 
 
Although you may not be allowed to see study information until after this study is over, you may be 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201208775 
APPROVAL DATE: 02/27/18 
EXPIRATION DATE: 02/15/19 
 
 
 
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given access to your health care records by contacting your University of Iowa health care provider. 
Your permission for us to access or create protected health information about you for purposes of this 
study has no expiration date. You may withdraw your permission for us to use your health information 
for this research study by sending a written notice to Dr. Yogesh Jethava, University of Iowa Hospitals 
and Clinics, 200 Hawkins Drive, 5980 JPP, Iowa City, IA  52242.   However, we may still use your 
health information that was collected before withdrawing your permission.  Also, if we have sent your 
health information to a third party, such as the study sponsor, or we have removed your identifying 
information, it may not be possible to prevent its future use.  You will receive a copy of this signed 
document. 
 
IS BEING IN THIS STUDY VOLUNTARY? 
 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time.  If you decide not to be in this 
study, or if you stop participating at any time, you won’t be penalized or lose any benefits for which you 
otherwise qualify. 
 
What if I Decide to Drop Out of the Study? 
 
If you decide to leave the study early, we may ask you to come in for a final study visit in order to 
ensure that we have complete safety and study information up to the point of your decision to withdraw 
from the study.  We may also ask you to complete some lab tests if you have any side effects that still 
need resolution.   
 
Will I Receive New Information About the Study while Participating? 
 
Sometimes during the course of a research study, new information becomes available about the drugs or 
combinations of drugs that are part of the study design.  If this happens, a study doctor will talk to you 
about it promptly and discuss whether you will want to continue in a study.   
 
If you decide to withdraw at that time, your research doctor will make arrangements for your medical 
care to continue.  Also, on receiving new information, your research doctor might consider it to be in 
your best interest to withdraw you from the study.  He/she will explain the reasons for doing so and 
arrange for your medical care to continue.   
 
If you decide to continue in the study, you will be asked to sign an updated consent form that contains 
the new information.  
 
Can Someone Else End my Participation in this Study? 
 
Under certain circumstances, the study doctors have the right to withdraw you from the study for  
any of the following reasons: 
 
 Progression/relapse of disease 
 Occurrence of an unacceptable side event  
 Non-compliance with study requirements 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201208775 
APPROVAL DATE: 02/27/18 
EXPIRATION DATE: 02/15/19 
 
 
 
Page 17 of 18 
 Administrative reasons 
 Failure to return for follow-up 
 Changes in your condition that make further study treatment unacceptable in the judgment of the 
study doctor(s) 
 
If you are removed from the study, this will be clearly communicated to you during a clinic visit and 
noted in your research record or in a letter if you decide not to return to the University of Iowa for 
further care.   
  
WHAT IF I HAVE QUESTIONS? 
 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Yogesh Jethava (319-384-9067).  If you experience a research-related injury, please contact: 
Yogesh Jethava (319-384-9067) during business hours.  Outside of business hours, please call 319-356-
1616, and ask the hospital operator for the bone marrow transplant physician on call.    
 
If you have questions, concerns, or complaints about  your rights as a research subject or about research 
related injury, please contact the Human Subjects Office, 105 Hardin Library for the Health Sciences, 
600 Newton Rd, The University of Iowa, Iowa City, IA  52242-1098, (319) 335-6564, or e-mail 
irb@uiowa.edu.  General information about being a research subject can be found by clicking “Info for 
Public” on the Human Subjects Office web site, http://research.uiowa.edu/hso. To offer input about your 
experiences as a research subject or to speak to someone other than the research staff, call the Human 
Subjects Office at the number above.   
 
 
This Informed Consent Document is not a contract. It is a written explanation of what will happen 
during the study if you decide to participate. You are not waiving any legal rights by signing this 
Informed Consent Document. Your signature indicates that this research study has been explained to 
you, that your questions have been answered, and that you agree to take part in this study.  You will 
receive a copy of this form. 
 
 
Subject's Name (printed):  __________________________________________________________ 
 
 
Do not sign this form if today’s date is on or after the expiration date in the stamp at the top of 
this form.   
 
  
__________________________________________ 
_______________________________ 
(Signature of Subject)  
 
 
 
 
(Date) 
 
 
Statement of Person Who Obtained Consent 
 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201208775 
APPROVAL DATE: 02/27/18 
EXPIRATION DATE: 02/15/19 
 
 
 
Page 18 of 18 
I have discussed the above points with the subject or, where appropriate, with the subject’s legally 
authorized representative.  It is my opinion that the subject understands the risks, benefits, and 
procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date)