Clinical trial NCT03303950
Conditions: Anemia ASXL1 Gene Mutation EZH2 Gene Mutation IDH1 Gene Mutation IDH2 Gene Mutation Plasma Cell Myeloma Primary Myelofibrosis Recurrent Plasma Cell Myeloma Secondary Myelofibrosis Thrombocytopenia
Sponsor: University of Utah
Start date: 2018-03-30; Completion date: 2020-02-19
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well busulfan, fludarabine, donor stem cell transplant, and cyclophosphamide in treating participants with multiple myeloma or myelofibrosis. Drugs used in chemotherapy, such as busulfan, fludarabine, and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the participant they may help the participant's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving busulfan and fludarabine before and cyclophosphamide after donor stem cell may work better in treating participants with multiple myeloma or myelofibrosis.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate non-relapse mortality (NRM) up to day +100.

SECONDARY OBJECTIVES:

I. To evaluate non-relapse mortality (NRM) up to day +365. II. To evaluate the incidence of acute graft versus host disease (GVHD) and chronic GVHD up to day +365 post-transplant.

III. To evaluate the overall survival and disease free survival up to 1 year. IV. To evaluate clinical response and molecular response (complete response and partial response) up to 1 year.

OUTLINE:

Participants receive busulfan intravenously (IV) over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic cell transplantation (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.

After completion of study treatment, participants are followed up for 1 year.

Arms: arm 1: Participants receive busulfan IV over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo HSCT on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.
Interventions: intervention 1: Busulfan intervention 2: Cyclophosphamide intervention 3: Fludarabine intervention 4: Hematopoietic Cell Transplantation intervention 5: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Undergo HSCT intervention 5: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Lead Org. ID: HCI98381/IRB# 98381 
CTO#HCI-17-HEME-07 
ClinicalTrials.gov ID – NCT03303950 
Principal Investigator 
Sub-investigator(s) 
Catherine J. Lee, MD 
Blood & Marrow Transplant Program 
University of Utah 
2000 Circle of Hope, Rm 2152 
Salt Lake City, UT 84132 
Phone: (801) 587-0231 
Email:  Catherine.Lee@hci.utah.edu 
Douglas Sborov, MD 
Clinical Instructor, Department of Medicine 
Phone: (801) 581-8394 
Email: douglas.sborov@hsc.utah.edu 
Vedran Radojcic, MD 
Assistant Professor, Department of Medicine 
Phone: (801) 213-6109 
Email: vedran.radojcic@hsc.utah.edu 
Daniel R. Couriel, MD, MS 
Director, Blood & Marrow Transplant Program Professor, 
Department of Medicine 
Phone: (801) 587-4056 
Email: daniel.couriel@hci.utah.edu 
Jo-Anna Reems, PhD (Laboratory) 
Scientific Director, Cell Therapy & Regenerative 
Medicine Research Professor, Department of Medicine 
Phone: (801) 585-6262 
Email: joanna.reems@hsc.utah.edu 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 2 of 51 
Michael Boyer, MD 
Associate Professor, Department of Medicine 
Phone: (801) 585-3229 
Email: michael.boyer@hsc.utah.edu  
Josef Prchal, MD 
Professor, Department of Medicine 
Phone: (801) 585-3229 
Email: josef.prchal@hsc.utah.edu 
Tibor Kovacsovics, MD 
Associate Professor, Department of Medicine 
Phone: (801) 213-5621 
Email: tibor.kovacsovics@hci.utah.edu 
Janet Weidner, PA-C 
Physician Assistant, Division of Hematology 
Phone: (801) 587-0236 
Email: janet.weidner@hsc.utah.edu 
Mary Steinbach, DNP, APRN 
Nurse Practitioner, Division of Hematology 
Phone: (801) 587-1604 
Email: mary.steinbach@hsc.utah.edu 
Sam Shewan, PA 
Physician Assistant, Division of Hematology 
Phone: (801) 213-2069 
Email: samuel.shewan@hsc.utah.edu 
Statistician(s) 
Ken Boucher 
University of Utah  
Huntsman Cancer Institute 
2000 Circle of Hope 
Salt Lake City, UT 84112 
801-585-9544 
kenneth.boucher@hci.utah.edu 
IND Number 
Exempt 
Historical Protocol Versions 
Version 1:26APR2017 
Version 2:27OCT2017 
Version 3: 02JUL2018 
Version 4: 29JAN2019 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 3 of 51 
TABLE OF CONTENTS 
Page 
LIST OF ABBREVIATIONS ............................................................................................. 5 
PROTOCOL SIGNATURE ................................................................................................ 9 
STUDY SUMMARY........................................................................................................ 10 
OBJECTIVES ................................................................................................................... 12 
1.1 
Primary Objectives and Endpoint ...................................................................... 13 
1.2 
Secondary Objectives and Endpoint .................................................................. 13 
BACKGROUND .............................................................................................................. 13 
2.1 
Allogeneic in Stem Cell Transplantation in Multiple Myeloma ........................ 13 
2.2 
Allogeneic Stem Cell Transplant in Myelofibrosis ............................................ 13 
2.3 
Post allograft Cyclophosphamide....................................................................... 14 
2.4 
Detection of minimal residual disease (MRD) following transplantation in MM 
and MF .......................................................................................................................... 14 
DRUG INFORMATION .................................................................................................. 14 
3.1 
Busulfan ............................................................................................................. 14 
3.2 
Fludarabine ......................................................................................................... 15 
3.3 
Cyclophosphamide ............................................................................................. 15 
STUDY DESIGN.............................................................................................................. 16 
4.1 
Number of Patients ............................................................................................. 16 
4.2 
Number of Study Centers ................................................................................... 16 
4.3 
Study Duration ................................................................................................... 16 
ELIGIBILITY CRITERIA................................................................................................ 17 
5.1 
Inclusion Criteria ................................................................................................ 17 
5.2 
Exclusion Criteria ............................................................................................... 18 
5.3 
Donor Inclusion Criteria..................................................................................... 18 
TREATMENT PLAN ....................................................................................................... 20 
6.1 
Administration Schedule .................................................................................... 20 
6.2 
Treatment Administration .................................................................................. 21 
6.3 
Accountability and Compliance ......................................................................... 22 
6.4 
Prohibited Concomitant Medications ................................................................. 22 
6.5 
Duration of Therapy ........................................................................................... 22 
TOXICITIES AND DOSEAGE MODIFICATION ......................................................... 22 
7.1 
Supportive Care .................................................................................................. 23 
7.2 
Diagnosis and Treatment of Acute GVHD ........................................................ 23 
7.3 
Diagnosis and Treatment of Chronic GVHD ..................................................... 24 
STUDY CALENDAR ........................................................................................................ 25 
CRITERIA FOR EVALUATION AND ENDPOINT ...................................................... 27 
9.1 
Non-relapse mortality (NRM) up to day +365 ................................................... 27 
9.2 
Rate of acute GVHD grade II-IV at Day +100 post-transplant.......................... 27 
9.3 
Cumulative chronic GVHD rates ....................................................................... 27 
9.4 
Response (clinical and molecular, disease free survival) ................................... 28 
9.5 
Safety .................................................................................................................. 30 
9.6 
Stopping Rules ................................................................................................... 31 
STATISTICAL CONSIDERATIONS.............................................................................. 31 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 4 of 51 
REGISTRATION GUIDELINES ..................................................................................... 31 
DATA SUBMISSION SCHEDULE ................................................................................ 31 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................ 32 
13.1 
Informed consent ............................................................................................ 32 
13.2 
Institutional Review ........................................................................................ 32 
13.3 
Data and Safety Monitoring Plan ................................................................... 32 
13.4 
Adverse Events / Serious Adverse Events ...................................................... 32 
13.5 
SAE Reporting Requirements ........................................................................ 35 
13.6 
Reporting of Pregnancy .................................................................................. 37 
13.7 
Protocol Amendments .................................................................................... 37 
13.8 
Protocol Deviations ........................................................................................ 37 
13.9 
FDA Annual Reporting .................................................................................. 38 
13.10 
Clinical Trials Data Bank ............................................................................... 38 
13.11 
Record Keeping .............................................................................................. 38 
REFERENCES ................................................................................................................. 38 
Appendices ........................................................................................................................ 43 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 5 of 51 
 
 
LIST OF ABBREVIATIONS 
Abbreviation or 
Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 6 of 51 
 
 
Abbreviation or 
Term1 
Definition/Explanation 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
D/C 
Discontinue 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
Eg 
Exempli gratia (for example) 
FACS 
Fluorescence Activated Cell Sorting  
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
GLP 
Good laboratory practice  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCO3- 
Bicarbonate 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
IRB 
Institutional review board 
IU 
International unit 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 7 of 51 
Abbreviation or 
Term1
Definition/Explanation 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
LLQ 
Lower limit of quantitation 
MedRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose 
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect-level 
PD 
Pharmacodynamic(s) 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QC 
Quality control 
RBC 
Red blood cell 
QD 
Once daily 
QTc 
QT interval corrected 
QTcF 
QT interval corrected using Frederichia equation 
SAE 
Serious adverse event 
SD 
Standard deviation or stable disease 
T1/2 
Terminal elimination half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
Tmax 
Time of maximum observed concentration 
TID 
Three times daily 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 8 of 51 
Abbreviation or 
Term1
Definition/Explanation 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
UV 
Ultraviolet 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of nonchildbearing potential 
All of these abbreviations may or may not be used in protocol. 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 9 of 51 
 
 
PROTOCOL SIGNATURE 
 
I confirm that I have read this protocol, and I will conduct the study as outlined herein 
and according to the ethical principles stated in the latest version of the Declaration of 
Helsinki, the applicable ICH guidelines for good clinical practice, and the applicable laws 
and regulations of the federal government. I will promptly submit the protocol to the IRB 
for review and approval. Once the protocol has been approved by the IRB, I understand 
that any modifications made during the course of the study must first be approved by the 
IRB prior to implementation except when such modification is made to remove an 
immediate hazard to the subject. 
 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure that they are fully informed regarding the study treatment, the conduct of 
the study, and the obligations of confidentiality. 
 
Note: This document is signed electronically through submission and approval by the 
Principal Investigator at Huntsman Cancer Institute in the University of Utah IRB 
Electronic Research Integrity and Compliance Administration (ERICA) system. For this 
reason, the Principal Investigator at Huntsman Cancer Institute will not have a hand-
written signature on this signature page.  


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 10 of 51 
 
 
STUDY SUMMARY 
 
Title 
A Phase II study of Allogeneic stem cell transplantation for 
multiple myeloma and myelofibrosis 
Short Title 
Allo SCT for MM and MF 
Protocol Number 
98381 
IND 
Exempt 
Phase 
II 
Design 
Single arm, open labeled study of allogenic stem cell 
transplantation for multiple myeloma and myelofibrosis with 
related and unrelated stem cell donors. 
Study Duration 
Patients will receive treatment for 2 weeks with 1 year 
follow up 
Accrual will take 3 years 
Total study duration will be 4 years 
Study Center(s) 
Single Center: HCI 
Objectives 
Primary endpoints:  
To evaluate Non-Relapse Mortality (NRM) up to day +100. 
Secondary endpoints: 
To evaluate Non-Relapse Mortality (NRM) up to day +365. 
To evaluate the incidence of acute GVHD and chronic 
GVHD up to day +365 post-transplant. 
To evaluate the Overall Survival and Disease Free Survival 
up to 1 year. 
To evaluate Clinical Response and Molecular Response up 
to 1 year. 
Number of Subjects 
24 
Diagnosis and Main Eligibility 
Criteria 
Inclusion Criteria:  
 
Age 18-75 years. 
 
ECOG status 0-1 
 
Patients must have histologically documented Multiple 
Myeloma (MM)  
 
A) Patients in early relapse (less than 24 months from 
initiation of systemic anti-myeloma therapy which may 
include single or planned tandem autologous transplant) 
after primary therapy that included an autologous HSCT 
OR 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 11 of 51 
 
 
 
B) Later Stage 
 
 
 
 
OR 
 
C) High risk factors defined by the presence of any one of 
the following detected at any time prior to enrollment: 
deletion of chromosome 13 by conventional 
cytogenetics, hypodiploidy, abnormality in chromosome 
1 (1q amplification or 1p deletion), t(4;14), t(14;16), 
t(14;20) or deletion of 17p by fluorescence in situ 
hybridization (FISH) or conventional karyotyping; high 
risk criteria based on commercially available gene 
expression profiling 
OR 
 
D) extramedullary disease, plasma cell leukemia or high 
LDH (19)  
 
Patients must have histologically documented 
Myelofibrosis (MF)  
 
1) Patients with DIPSS plus intermediate stage 2 or higher 
risk MF  
      OR  
 
2) Subset of intermediate stage 1 patients. Defined by:  
a)  Poor-risk molecular profile (triple negative: 
JAK2, CALR, MPL)  
OR 
 
b) Presence of any of the following mutations: 
(ASXL1, SRSF2, EZH2, IDH1/2)  
OR 
 
c) Severe thrombocytopenia, severe anemia, high 
peripheral blood blasts percentage 
OR 
 
d) Unfavorable cytogenetic abnormalities 
(rearrangements of chromosome 5 or 7 or ≥ 3 
abnormalities (40)). 
 
 
 
 
 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 12 of 51 
 
 
Exclusion Criteria:  
 
a. Cardiac-left ventricular ejection 
fraction <40%, symptomatic 
coronary artery disease, or 
uncontrolled arrhythmias 
b. Pulmonary- FEV1 or DLCO < 40% or 
history of chronic use of supplemental 
oxygen. Temporary use of supplemental 
oxygen at the time of screening or 
registration is allowed if the investigator 
feels that the underlying cause of 
requiring oxygen is reversible by the time 
treatment begins 
c. Renal- calculated or measured 
GFR <30 ml/min, dialysis-
dependent, or history of renal 
transplant 
d. Hepatic- bilirubin > 2 X ULN, 
ALT> 2.5 X ULN, cirrhosis 
e. Patients with active or 
uncontrolled bacterial, viral, or 
fungal infections requiring 
systemic therapy 
f. Pregnant women, nursing 
mothers or women of child-
bearing potential who are 
unwilling to use medically 
accepted methods of 
contraception 
Study Product, Dose, Route, 
Regimen 
Allogenic transplant using a divided regimen of busulfan at 
Day-5 to Day-2 and post-transplant cyclophosphamide at 
Day +3 and Day +4.  
Duration of administration 
10 days 
Reference therapy 
Standard of care continuous conditioning regimen using 
busulfan and cyclophosphamide. 
Statistical Methodology 
Comparison of primary endpoint with historical benchmarks 
of patients treated with allogenic transplants. 
Analysis of secondary endpoints will be done descriptively. 
OBJECTIVES 
This study will investigate a variation on a proven conditioning program for allogeneic 
Hematopoietic Stem Cell Transplantation (HSCT) for treatment of patients with Multiple 
Myeloma (MM) and primary Myelofibrosis (PMF). The current protocol allows stem cell 
transplant from matched related donors (MRD), matched unrelated donors (MUD), 
mismatched unrelated donor(s) (mMUD) and haploidentical donor(s) (Haplo). 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 13 of 51 
1.1 Primary Objectives and Endpoint 
1.1.1 To evaluate Non-Relapse Mortality (NRM) up to day +100. 
1.2 Secondary Objectives and Endpoint 
1.2.1 To evaluate Non-Relapse Mortality (NRM) up to day +365. 
1.2.2 To evaluate the incidence of acute GVHD and chronic GVHD up to day +365 
post-transplant. 
1.2.3 To evaluate the Overall Survival and Disease Free Survival up to 1 year. 
1.2.4 To evaluate Clinical Response and Molecular Response (complete response 
and partial response [section 9.4]) up to 1 year 
BACKGROUND 
The proposed conditioning regimen modifies the combination of busulfan-
cyclophosphamide, one of the most successful in the treatment of Multiple Myeloma (2), 
from a continuous conditioning regimen to a divided regimen where busulfan is given 
before allogeneic HSCT and cyclophosphamide on day +3 and +4 post allogeneic HSCT. 
This is the accepted standard therapy for Graft Versus Host Disease (GVHD) prevention 
in haploidentical transplantation and has been explored in the other 3 types of transplant. 
To allow for engraftment in this combination, a moderate dose of fludarabine is given, 
since busulfan alone might not be immunosuppressive enough. 
This variation regimen is designed to maximize the antitumor effect in myeloma and 
myelofibrosis and minimizes the toxicity by PK directed busulfan administration and 
may also minimize acute and chronic GVHD by administering cyclophosphamide at day 
+3 and day +4 post allogeneic HSCT.
2.1 Allogeneic in Stem Cell Transplantation in Multiple Myeloma
Allogeneic HSCT is the only potentially curative therapy for Multiple Myeloma (MM).
The use of reduced-intensity conditioning (RIC) has broadened the use of allogeneic
HSCT in MM especially in patients with refractory disease and relapsed after an
autograft. (1,2,3,4,5) B. Andersson introduced the PK directed busulfan regimen to
optimize dose-targeting and reduced transplant related mortality.(6,15)
Risk criteria for allogeneic HSCT in MM are early relapse after primary therapy and/or
high risk factors (i.e. cytogenetics, extramedullary disease, plasma cell leukemia or
high LDH).
2.2 Allogeneic Stem Cell Transplant in Myelofibrosis
Allogeneic HSCT is the only curative treatment for primary myelofibrosis (PMF), a
clonal myeloproliferative neoplasm with a high risk for clonal evolution and mortality.
Prognostic tools have been developed that assist in therapeutic decision making. The
International Prognostic Symptom Score (IPSS) is a clinical based model to assess
prognosis at the time of primary myelofibrosis diagnosis. The IPSS score was upgraded
to the dynamic IPSS plus (DIPPS plus) score, which further clarified risk variables and
risk categories (Appendix A)  Four risk categories are included in DIPSS plus: low,
intermediate 1, intermediate 2, and high. These categories are assessed by: age,


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 14 of 51 
constitutional symptoms, hemoglobin, the basis of WBC, circulating blasts, platelet 
count, RBC transfusions needed, and unfavorable karyotype.  
Only MF patients with intermediate 2 and intermediate 1 with high risk designations 
according to DIPPS plus should be transplanted.(8) 
2.3 Post allograft Cyclophosphamide 
Post allograft cyclophosphamide (Cytoxan) has been introduced as measure for GVHD 
prevention in recipients of haploidentical, mismatched unrelated, and matched 
unrelated transplants. The results of post allograft cyclophosphamide are comparable to 
or better than other ways of immunosuppression, like ATG in mismatched and matched 
recipients of stem cell transplants. Post allograft cyclophosphamide is believed to work 
by destroying early activated donor T-cells and by sparing regulatory T-cells via 
increased expression of ALDH, one of the enzymes which metabolizes 
cyclophosphamide. (9,10,11,12,13) Post allograft cyclophosphamide as sole means of 
GVHD prophylaxis is not sufficient and should therefore be combined with other 
immunosuppressant like tacrolimus and mycophenolic acid (MMF) as standard of care.  
2.4 Detection of minimal residual disease (MRD) following transplantation in 
MM and MF 
Relapse represents the main cause of treatment failure after hematopoietic stem cell 
transplantation (HSCT). Monitoring of Minimal Residual Disease (MRD) allows for 
early detection and subsequent intervention prior to clinically detectable relapse.  
MRD-determination will be done as a standard procedure approximately every 3-6 
months in patients that achieve a complete response only.  
MRD monitoring in MM is done by Flow Cytometry (preferred), ASO-PCR, by 
determining the VDOH rearrangements or NGS.(14,15,16) 
MRD-Monitoring in MF is done by JAK2 PCR, cMPL, Calreticulin mutation PCR and 
donor-recipient chimerism determination. 
Molecular relapse will be treated by DLI infusion (1X106/kg BW for matched related 
donors as defined by the HCI BMT SOP 
(https://pulse.utah.edu/policies/FilteredFor/Blood%20and%20Marrow%20Transplant.
aspx – or consult with BMT pharmacist). Infusion of donor lymphocytes (DLI) leads 
to molecular responses in 30-50% of cases with MM and MF.(17,18) 
DRUG INFORMATION 
3.1 Busulfan 
For HSCT conditioning, intravenous busulfan is more often utilized due to less 
pharmacokinetic variability. With conditioning doses of busulfan, antiepileptic 
medication must be given. Seizure prophylaxis with levetiracetam should start prior to 
receiving busulfan and continue until at least 24 hours after the infusions are complete. 
Newer second-generation antiepileptics such as levetiracetam have become a favorable 
option due to decreased adverse effects and minimal drug interactions. Side effects of 
busulfan include nausea, diarrhea, myelosuppression, transient increase in liver 
enzymes, and rarely more serious liver and lung toxicity.(20) The pharmacokinetic levels 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 15 of 51 
of busulfan are determined by measuring levels in the blood following the first IV 
infusion according to HCI BMT SOPs: 
(https://pulse.utah.edu/policies/FilteredFor/Blood%20and%20Marrow%20Transplant.a
spx – or consult with BMT pharmacist). 
3.2 Fludarabine 
Fludarabine or fludarabine phosphate (Fludara) is a chemotherapy drug used in the 
treatment of hematological malignancies (cancers of blood cells such as leukemias and 
lymphomas). It is a purine analog, which interferes with DNA synthesis. Fludarabine is 
highly effective in the treatment of chronic lymphocytic leukemia, producing higher 
response rates than alkylating agents, such as chlorambucil, alone. Fludarabine is used 
in various combinations with cyclophosphamaide, mitoxantrone, dexamethasone and 
rituximab in the treatment of indolent non-Hodgkins lymphomas. As part of the FLAG 
regiment, fludarabine is used together with cytarabine and granulocyte colony 
stimulating factor in the treatment of acute myeloid leukemia. Because of its 
immunosuppressive effects, fludarabine is also used in some conditioning regimens 
prior to allogeneic stem cell transplant.  
3.3 Cyclophosphamide 
Cyclophosphamide is an alkylating agent of the nitrogen mustard type (specifically, the 
oxazaphosphorine group). An alkylating agent adds an alkyl group to DNA. It attaches 
the alkyl group to the guanine base of DNA, at the number 7 nitrogen atom of the 
imidazole ring. This interferes with DNA replication by forming intrastrand and 
interstrand DNA crosslinks. Cyclophosphamide is used to treat cancers, autoimmune 
disorder and AL amyloidosis. As a prodrug, it is converted by liver cytochrome P450 
(CYP) enzymes to form the metabolite 4-hydroxycyclophosphamide that has 
chemotherapeutic activity. Cyclosphosphamide has severe and life-threatening adverse 
effects, including acute myeloid leukemia, bladder cancer, hemorrhagic cystitis and 
permanent infertility, especially at higher doses. The addition of cyclophosphamide at 
day +3 and day +4 has two purposes:  a) optimizing the antineoplastic effect against 
MM and MF and b) to prevent serious life-threatening GVHD. 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 16 of 51 
 
 
STUDY DESIGN 
STUDY SCHEMA 
Description 
Patients will receive pre-transplant conditioning with busulfan (PK directed) and 
Fludarabine, followed by post-transplant cyclophosphamide on day +3 and day +4 as 
GVHD prophylaxis.  
All patients will receive additional GVHD prophylaxis with post allogeneic HSCT 
Cyclophosphamide, Tacrolimus and MMF per standard of care (HCI BMT SOPs: 
[https://pulse.utah.edu/policies/FilteredFor/Blood%20and%20Marrow%20Transplant.asp
x – or consult with BMT pharmacist]). Residual or relapse disease will be treated with 
DLI infusions.  
 
4.1 Number of Patients 
24 patients will be enrolled. There is no limit to the ratio of MM and MF patients that 
enroll. (4, 8, 12 in 1st, 2nd and 3rd year) 
4.2 Number of Study Centers 
Huntsman Cancer Institute will be the sole enrolling site.  
4.3 Study Duration  
Total Study duration will be four years.  
 
 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 17 of 51 
 
 
 
ELIGIBILITY CRITERIA 
This eligibility checklist is used to determine patient eligibility and filed with 
investigators signature in the patient research chart.  
 
 
Patient No. ______________________ 
Patient’s Initials: (L,F,M) _________________ 
5.1 Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
5.1.1 _____ Age 18-75 years   
5.1.2 _____ ECOG Performance status 0-1 
5.1.3 _____ Patients must have one of the following diagnoses of Multiple Myeloma 
(MM) or primary/secondary Myelofibrosis (MF): 
______ Patients must have histologically documented Multiple Myeloma 
(MM) Appendix A.  
A) Patients in early relapse (less than 24 months from initiation of systemic 
anti-myeloma therapy which may include single or planned tandem 
autologous transplant) after primary therapy that included and autologous 
HSCT. 
OR 
B) Later Stage. 
 
 
 
OR 
C) High risk factors defined by the presence of any one of the following 
detected at any time prior to enrollment: deletion of chromosome 13 by 
conventional cytogenetics, hypodiploidy, abnormality in chromosome 1 
(1q amplification or 1p deletion), t(4;14), t(14;16), t(14;20) or deletion of 
17p by fluorescence in situ hybridization (FISH) or conventional 
karyotyping; high risk criteria based on commercially available gene 
expression profiling. 
OR 
D) Extramedullary disease, plasma cell leukemia or high LDH (19).  
_____ Patients must have histologically documented Myelofibrosis (MF) 
Appendix A.  
A) Patients with DIPSS plus intermediate stage 2 or higher risk MF. 
OR 
B) 
Subset of intermediate stage 1 patients. Defined by:  
i) Poor-risk molecular profile (triple negative: JAK2, CALR, MPL).  


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 18 of 51 
OR 
ii) Presence of any of the following mutations: ASXL1, SRSF2, EZH2,
IDH1/2. 
OR 
C)
Severe thrombocytopenia, severe anemia, high peripheral blood blasts
percentage.
OR
D)
Unfavorable cytogenetic abnormalities (rearrangements of chromosome 5
or 7 or ≥ 3 abnormalities (40).
5.1.4 _____ Able to provide informed consent and willing to sign an approved 
consent form that conforms to federal and institutional guidelines. 
5.2 Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 
5.2.1 _____ Cardiac- left ventricular ejection fraction <40%, symptomatic coronary 
artery disease, or uncontrolled arrhythmias. 
5.2.2 _____ Pulmonary- FEV1 or DLCO < 40% or history of chronic use of 
supplemental oxygen. Temporary use of supplemental oxygen at the time of 
screening or registration is allowed if the investigator feels that the underlying 
cause of requiring oxygen is reversible by the time treatment begins. 
5.2.3 ______ Renal- calculated or measured GFR <30 ml/min, dialysis-dependent, or 
history of renal transplant. 
5.2.4 _____ Hepatic- bilirubin > 2 X ULN, ALT> 2.5 X ULN or cirrhosis. 
5.2.5 _____ Patients with active or uncontrolled bacterial, viral, or fungal infections 
requiring systemic therapy. 
5.2.6 _____ Pregnant women, nursing mothers or women of child-bearing potential 
who are unwilling to use medically accepted methods of contraception 
5.2.7 ______Male and female subjects not willing to agree to medically accepted 
methods of contraception. 
5.3 Donor Inclusion Criteria 
The evaluation of donors shall be in accordance with existing Foundation for the 
Accreditation of Cellular Therapy standards. The University of Utah Blood and 
Marrow Transplant and Myeloma Program are a FACT accredited Cellular Therapy 
programs. 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 19 of 51 
 
 
 
5.3.1 _____ A related donor –fully matched. 
5.3.2 _____ A related donor – haploidentical. 
5.3.3 _____ An unrelated donor – fully matched. 
5.3.4 _____ An unrelated donor – 9/10 matched. 
 
 
I certify that this patient meets all inclusion and exclusion criteria for enrollment 
onto this study.  
 
 
______________________________ 
 
_________ 
_______ 
Investigator Signature  
 
 
 
Date  
Time 
 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 20 of 51 
 
 
TREATMENT PLAN 
HCI BMT SOPs found: 
https://pulse.utah.edu/policies/FilteredFor/Blood%20and%20Marrow%20Transplant.aspx 
– or consult with BMT pharmacist). 
6.1 Administration Schedule 
Day  
Therapy 
Day - 6   
Start Levetiracetam1 (per standard of care dosing)  
Day - 5  
Busulfan daily dose of 3.2 mg/kg/day IV 
 
Busulfan goal Css = 800 to 900 ng/mL as determined by the PI 
(PK Blood Draw required per HCI MBT SOPs) 
 
Fludarabine 30 mg/m2 IV 
 
Levetiracetam 
Day - 4  
Busulfan  
 
Fludarabine 30 mg/m2 
 
Levetiracetam 
Day - 3  
Busulfan 
 
Fludarabine 30 mg/m2 
 
Levetiracetam 
Day - 2   
Busulfan  
 
Fludarabine 30 mg/m2 
 
Levetiracetam 
Day -1     
Rest 
 
 
Levetiracetam 
Day   0  
HPC infusion per HCI BMT Standard of Care SOP 
Day+3  
Cyclophosphamide 50mg/kg IV over 60 minutes per HCI BMT 
standard of Care SOP 
Day+4  
Cyclophosphamide 50mg/kg IV over 60 minutes 
Day +5 
Tacrolimus per standard dosing guidelines with Mycophenolate 
mofetil (MMF) 15 mg/kg IV or PO q8 hrs (max dose 3g/day) and 
continued until day +35 
1With conditioning doses of busulfan, antiepileptic medication (levetiracetam) must be given. 
Seizure prophylaxis should start prior to receiving busulfan and continue at least 24 hours after 
the infusions are complete.  
2Tacrolimus and Mycophenolate mofetil (MMF) can also be used post-transplant as GVHD 
prophylaxis per PI discretion as HCI BMT standard of care SOP.  
*Residual or relapsing disease will be treated with DLI infusions per HCI BMT SOP.  


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 21 of 51 
 
 
MF patients who take Ruxolitinib prior to transplant will continue to do so.  The dose 
of Ruxolitinib is reduced to 2 x 5 mg and continued until stable engraftment, then 
tapered and stopped around day +28.  In case of early CMV reactivation, the drug will 
be tapered earlier(41). 
6.2 Treatment Administration  
All treatments associated with protocol are commercially available agents and will be 
administered per institutional guidelines only to eligible patients under the supervision 
of the investigator or sub-investigator(s). The treatments will be prepared under the 
supervision of a pharmacist at Huntsman Cancer Institute. The amount of drug to be 
administered will be determined based on targeted PK, body surface area, ideal body 
weight, actual or adjusted body weight and calculated based on institutional standards.  
6.2.1 Busulfan:  
See HCI BMT SOP for details of busulfan administration, toxicities, PK sample 
collection and targeted level and levetiracetam prophylaxis. 
a. Dosage: the initial dose for intravenous busulfan is 3.2 mg/kg/dose IV daily. 
Busulfan Css goal is 800 ng/mL to 900 ng/mL, as per the investigator’s clinical 
judgement. Busulfan dose may need to be adjusted based on busulfan levels 
drawn after the first dose. Therefore, without dose adjustment, the total dose is 
12.8 mg/kg. Busulfan will only be given intravenously over 3 hours from Days 
–5 through –2. Doses should be rounded to the nearest 1 mg. 
b. Dosage calculation is based on actual or adjusted body weight see HCI BMT 
SOP for calculation of chemotherapy. 
6.2.2 Fludarabine:  
See HCI BMT SOP for details of Fludarabine administration and toxicities. 
a.  Dosage: 30 mg/m2/day IV on Days -5 through Day –2, for a total dose of 120 
mg/m2. The dose is rounded to the nearest 5 mg and given intravenously over 30 
minutes.  
b.   Dosage calculation is based on actual body weight. HCI BMT SOP for 
calculation of chemotherapy. 
Consider a 25% dose reduction of fludarabine in patients with creatinine clearance <50 
mL/min. Fludarabine should be avoided in patients with creatinine clearance <30 
mL/min. 
6.2.3 HPC infusion 
Source of hematopoietic progenitor cells (HPC) to be determined by BMT 
attending physician. Infusion to be given per HCI BMT SOP. 
Graft versus Host Disease prophylaxis 
6.2.4 Cyclophosphamide  
Cyclophosphamide 50mg/kg IV over 60 minutes on Day +3 and Day +4.  Post-
transplant cyclophosphamide should be started between 60-72 hours after HPC 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 22 of 51 
 
 
infusion. Dosage calculation is always based on ideal body weight, unless the patient 
weighs less than ideal body weight, then use actual body weight. 
Hydration prior to cyclophosphamide may be given according to institutional 
standards. Mesna should be started prior to cyclophosphamide at a dose of 100% of 
cyclophosphamide dose in 1 liter of 0.9% sodium chloride, given as a continuous 
infusion. Discontinue mesna approximately 24 hours after the last dose of 
cyclophosphamide.  
It is crucial that no immunosuppressive agents are given until 24 hours after the 
completion of the post-transplant cyclophosphamide. This includes corticosteroids as 
anti-emetics. 
6.2.5 Tacrolimus  
Tacrolimus will be initiated at Day +5 per standard dosing guidelines with a goal of 
being tapered to off by Day +180, in the absence of GVHD. 
• 0.01-0.03 mg/kg/day IV continuous infusion depending on age and prophylactic 
antifungal choice. In some patients, tacrolimus may be started as an oral 
formulation at a dose of 0.045-0.06 mg/kg/dose PO BID and titrated as needed. 
The conversion from IV to PO tacrolimus is approximately 1:3.  
6.2.6 Mycophenolate mofetil (MMF) WITH Tacrolimus 
MMF will be initiated at Day +5 at a dose of 15mg/kg IV or PO q8 hrs (max dose 3 
gm/day) and discontinued on Day +35 in the absence of GVHD. 
See HCI BMT SOP for details of tacrolimus plus MMF administration:  
6.3 Accountability and Compliance 
Accountability for the treatment is the responsibility of the principal investigator. The 
investigator will ensure that treatment is used only in accordance with this protocol. 
Drug accountability records will be maintained per institutional practice.  
6.4 Prohibited Concomitant Medications 
Medications will be managed at PI discretion.  
6.5 Duration of Therapy 
Patients will receive a conditioning regimen, transplant, GVHD prevention and one 
year of assessment on study.  
TOXICITIES AND DOSEAGE MODIFICATION 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 5.0 for adverse event and serious adverse event reporting. A copy of the 
CTCAE Version 5.0 can be downloaded: (http://safetyprofiler-
ctep.nci.nih.gov/CTC/CTC.aspx). 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 23 of 51 
7.1 Supportive Care 
7.1.1 Prophylactic Care 
All supportive measures consistent with optimal patient care will be given throughout 
the study. Institutional guidelines will be followed and include the following: 
•
Prophylactic antibiotics consisting of a quinolone or equivalent depending upon
patient tolerance as per institutional standards.
•
Prophylactic antifungals consisting of caspofungin, fluconazole, voriconazole, or
posaconazole as per institutional standards. The use of azole antifungals should
be avoided until Day +5 due to potential drug-drug interaction between azoles
and cyclophosphamide.
•
Prophylactic acyclovir or valacyclovir starting by day 0 and continuing until one
year post transplant.
•
Patients receiving haploidentical transplant, will receive filgrastim or filgrastim-
sndz 5 mcg/kg/day starting on Day +5 and continued until engraftment.
•
Patients should be started on ursodiol prior to transplant per institutional
standards. We will provide viral weekly screening for CMV and EBV as needed
(see study calendar). Screening and infection treatment will be instituted per HCI
BMT SOP.
7.2 Diagnosis and Treatment of Acute GVHD 
GVHD assessment should be conducted standard of care once weekly for the first 100 
days and then monthly until one year following BMT by the treating transplant 
physician or GVHD experienced members of the BMT team including midlevel 
providers using the forms provided in appendix B. Additional time points of 
assessment depend on clinical necessity and or when symptoms of GVHD arise.  
Acute GVHD can affect various target organs, predominantly the GI tract, liver and 
skin. It is not defined by time of onset but by clinical symptoms. The recommended 
staging and grading of acute GVHD, and the functional grading of acute GVHD is 
presented in HCI BMT SOP (appendix B). Whenever possible, the clinical diagnosis 
of GVHD should be confirmed by biopsy of an affected end organ, but should not 
delay management. Other complications affecting the skin, liver, and gastrointestinal 
(GI) tract should be ruled out. 
GVHD grade I: 
•
topical treatment (steroid cream, tacrolimus 0.01 – 0.03%, antihistamine
containing lotion against pruritus)
GVHD grade II: 
•
systemic treatment with corticosteroids (1mg/kg prednisolone)
GVHD grade III and IV:
•
systemic treatment with corticosteroids (2mg/kg methylprednisolone; equivalent
to prednisone 2.5mg/kg) plus calcineurin inhibitor.


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 24 of 51 
 
 
For skin involvement: additional topical agents allowed. For GI tract involvement: 
additional nonabsorbable agents (budesonide, beclomethasone) allowed. 
See HCI BMT SOP for additional treatment of acute GVHD: 
(https://pulse.utah.edu/policies/FilteredFor/Blood%20and%20Marrow%20Transplant.
aspx – or consult with BMT pharmacist). 
7.3 Diagnosis and Treatment of Chronic GVHD 
GVHD assessments should be conducted standard of care once weekly for the first 100 
days and then monthly until one year following BMT by the treating transplant 
physician or GVHD experienced members of the BMT team including midlevel 
providers.  
Additional time points of assessment depend on clinical necessity and or when 
symptoms of GVHD arise.  See HCI BMT SOP for details of chronic GVHD 
assessments and treatments.


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 25 of 51 
 
 
STUDY CALENDAR 
Examination 
Screen 
ing1 
Day 
-6 
Day 
-5 
Day 
-4 
Day 
-3 
Day 
-2 
Day 
-1 
Day 
0  
 
Day 
+3 
Day 
+4 
 
Day 
+28 
M1 
(±7 
Days) 
Day 
+100 
M4 
(±7 
Days) 
Day 
+180 
M6 
(±7 
Days) 
Day 
+365 
M12 
(±7 
Days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events7 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
 
X 
CMV, EBV test 
X10 
 
 
 
 
 
 
X10 
 
 
X 
X 
 
X 
Hematology2 
X 
X 
X 
X 
X 
X 
 
X 
Serum Chemistries3 
X 
X 
X 
X 
X 
X 
 
X 
LDH 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pulmonary Function Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Multiple Myeloma Disease 
Assessments8  
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Myelofibrosis Disease Assessment9 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Busulfan 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Busulfan PK 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Fludarabine 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Cyclophosphamide  
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 26 of 51 
 
 
1 ALL Pre-study/Screening procedures should be completed within 4 weeks of study enrollment - with the exception of laboratory tests which need to be 
completed within 2 weeks prior to study enrollment and bone marrow aspirate and biopsy which could be completed within 60 days of study enrollment.  Prior 
medical history will be assessed at screening, including assessment of comorbidities. 
2 Hematology includes CBC with differential and platelets. Assessments should be done weekly at the discretion of the investigator.  
3 Chemistry includes Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, 
Creatinine, Chloride, Glucose, Potassium, Protein, Sodium, Urea Nitrogen. 
4 Pregnancy test must be done at screening for all women of childbearing potential and repeated as clinically indicated. 
5 MRD monitoring in Multiple Myeloma done by Flow Cytometry (preferred), ASO-PCR, by determining the VDOH rearrangements or NGS. MRD-Monitoring 
in Myelofibrosis to be done by JAK2 PCR or cMPL or Calreticulin mutation PCR and donor-recipient chimerism determination. This testing should be done at 
screening to determine the molecular markers that will determine MRD after transplant. MRD-determination should be done as a standard procedure every 3-6 
months ONLY if the patient has demonstrated complete response.  Previous MRD testing results may be used for screening requirement, if performed within 60 
days of study enrollment. 
6 GVHD assessments for acute and chronic GVHD should be conducted as per standard of care once weekly from Day 0 to day +100. Assessments should 
continue monthly after day +100 until day +365. 
7 Adverse Events will start at Day-6 and continue to Day+365. 
8 Multiple Myeloma disease assessments should include evaluation of quantitative immunoglobulins, serum protein electrophoresis (SPEP), serum 
immunofixation electrophoresis (SIFE), 24-hour urine for total urine protein, urine immunofixation electrophoresis (UIFE), serum free light chains. Bone 
marrow aspirate and biopsy including cytogenetics, plasma cell FISH and other molecular testing for MM associated mutations and/or other chromosomal 
abnormalities, bone scans and/or PET/CT should be performed as clinically indicated (if supported by increased signs and symptoms). Response should be 
monitored every 3 – 6 months until disease progression.  
9 Myelofibrosis disease assessments should include evaluation of symptoms, evaluation of the spleen by physical exam, and/or CT or MRI. Bone marrow 
aspirate and biopsy including cytogenetics, flow cytometry and molecular testing for MF associated mutations and/or other chromosomal abnormalities should 
be performed as clinically indicated (if supported by increased signs and symptoms). Response should be monitored every 3 – 6 months until disease 
progression.  
10 As Needed 
 
Transplant HSCT  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Minimal Residual Disease5 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Acute and Chronic GVHD 
Assessment6 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
  
X 
Clinical CR up through 1 year8,9 
 
 
 
 
 
 
 
 
 
 
 
X 
Molecular CR up through 1 year8,9 
 
 
 
 
 
 
 
 
 
 
 
X 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 27 of 51 
 
 
CRITERIA FOR EVALUATION AND ENDPOINT 
9.1 Non-relapse mortality (NRM) up to day +365 
NRM is defined as death due to GVHD, infections, sepsis, organ (lung, liver, kidney) 
toxicity. Death from underlying disease (i.e. progression or relapse) is not considered 
NRM.  
9.2 Rate of acute GVHD grade II-IV at Day +100 post-transplant 
GVHD should be assessed according to the standard of care by the treating physician or 
other member of the BMT clinical team including mid-level providers once weekly 
through day +100 post transplant and monthly for 1 year. Acute GVHD may affect the 
skin, the gastrointestinal tract, and the liver. Diagnosis of acute GVHD is based on criteria 
established according to the criteria as described by the 1994 Consensus conference on 
acute GVHD grading. The recommended staging and grading of acute GVHD and the 
functional grading of acute GVHD is presented in HCI BMT SOP (see worksheet in 
appendix B). 
9.3 Cumulative chronic GVHD rates 
Diagnosis of chronic GVHD is based on criteria established by the National Institutes 
of Health Consensus Development Project in 2005 (Filipovich et al. 2005), and recently 
updated in 2014. Diagnostic and distinctive manifestations of chronic GVHD are 
present in the skin and appendages, mouth, eyes, female genitalia, esophagus, lungs and 
connective tissues. Diagnosis of chronic GVHD requires the presence of at least 1 
diagnostic clinical sign (e.g. poikiloderma or esophageal web) or the presence of at 
least 1 distinctive manifestation (e.g. keratoconjunctivitis sicca) confirmed by pertinent 
biopsy or other relevant tests (e.g. Schirmer test) in the same or another organs. Biopsy 
or other testing is not always feasible to confirm the presence of chronic GVHD and is 
not mandatory if the patient has at least 1 of the diagnostic findings of chronic GVHD. 
Other possible diagnoses for clinical symptoms must be excluded. 
The National Institutes of Health Consensus Development Project recognizes 2 main 
categories of GVHD each of which having 2 subcategories as shown in Table 4. The 
broad category of chronic GVHD includes (a) classic chronic GVHD without features 
characteristic of acute GVHD, and (b) an overlap syndrome in which features of 
chronic and acute GVHD appear together. 
Table 4:  Categories of GVHD 
 
Category  
Time of Symptoms 
after HSCT  
Presence of Acute 
GVHD Features*  
Presence of 
Chronic GVDH 
Features*  
Acute GVHD  
Classic acute  
≤ 100 days  
Yes  
No  
Persistent, 
recurrent or late 
onset  
>100 days  
Yes  
No  
Chronic GVHD  


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 28 of 51 
 
 
Classic chronic  
No time limit  
No  
Yes  
Overlap syndrome  No time limit  
Yes  
Yes  
No time limit is set for the diagnosis of chronic GVHD. In the absence of histological or 
clinical signs or symptoms of chronic GVHD, the persistence, recurrence or new onset of 
characteristic skin, GI tract or liver abnormalities should be classified as acute GVHD 
regardless of the time of onset after transplantation. 
Scoring of chronic GVHD (mild, moderate or severe) is similarly based upon criteria 
established by the National Institutes of Health Consensus Development Project, 
updated in 2014 (see worksheets appendix C). The following scoring system 
determines severity:  
Mild Chronic GVHD 
1 or 2 organs involved with no more than score 1  
AND 
Lung score of 0 
Moderate Chronic GVHD 
3 or more organs involved with no more than score 1  
OR 
At least 1 organ (not lung) with a score of 2 
OR 
Lung score 1 
Severe Chronic GVHD 
At least 1 organ with a score of 3 
OR 
Lung score of 2 or 3  
9.4 Response (clinical and molecular, disease free survival) 
A clinical and molecular response will be assessed up to Day +365.  
For Multiple Myeloma, the IMWG criteria will be used to assess clinical/molecular 
response:  
Complete Response (CR)  
• 
Negative immunofixation on the serum and urine 
AND 
• 
Disappearance of any soft tissue plasmacytomas 
AND  
• 
<5% plasma cells in bone marrow aspirates 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 29 of 51 
 
 
Stringent complete response (sCR) 
• 
Complete response as defined above plus normal FLC ratio1 
AND  
• 
Absence of clonal cells in bone marrow biopsy by immunohistochemistry (k/λ 
ration ≤ 4:1 or ≥ 1:2 for k and λ patients respectively after counting ≥ 100 plasma 
cells2 
Partial Response (PR):  
• 
≥ 50% reduction of serum M-protein plus reduction in 24hr urinary M-proteins by 
a ≥90% or to < 200mg per 24hr 
o 
If the serum and urine M-protein are unmeasurable,  
 
a ≥50% decrease in the difference between involved and uninvolved FLC 
levels are is required in place of the M-protein criteria 
o 
If serum and urine M-proteins are unmeasurable, and serum-free light assay is 
also unmeasurable 
 ≥50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma-cell percentage was ≥30%.   
AND 
If present at baseline, a ≥50% reduction in the size (SPD)3 of soft tissue 
plasmacytomas is also required 
1. All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based 
on results obtained with the validated Freelite test (Binding Site, Birmingham, UK).  
2. Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ ratio. An 
abnormal κ/λ ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis. 
An abnormal ratio reflecting presence of an abnormal clone is κ/λ of >4:1 or <1:2. 
3. Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, 
or dedicated CT scans where applicable. For patients with only skin involvement, skin lesions 
should be measured with a ruler. Measurement of tumor size will be determined by the SPD. 
For Myelofibrosis:  
Complete Response (CR)  
Bone marrow:1 Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF2  
AND 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; Neutrophil count ≥ 1 x 109/L and 
≥UNL; Platelet count ≥100 x 109/L and <UNL; <2% immature myeloid cells3  
AND 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence 
of EMH 
Partial Response (PR) 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; Neutrophil count ≥1 x 109/L and 
<UNL; Platelet count ≥100 x 109/L and <UNL; <2% immature myeloid cells3 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 30 of 51 
 
 
AND 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence 
of EMH  
OR 
Bone marrow:1 Age-adjusted normocellularity; < 5% blasts; ≤ grade 1 MF2 
AND  
peripheral blood: Hemoglobin ≥ 85 but ≤ 100 g/L and <UNL; neutrophil count ≥ 1 x 
109/L and < UNL; platelet count ≥50, but≤ ,100 x 109/L and <UNL; <2% immature 
myeloid cells3  
AND 
Clinical:  Resolution of disease symptoms; spleen and liver not palpable; no evidence 
of EMH 
EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or 
imaging study-proven non-hepatosplenic EMH); LCM, left costal margin; UNL, upper normal limit. 
 
1. Baseline and post-treatment bone marrow slides are to be interpreted at one sitting by a central review 
process. Cytogenetic and molecular responses are not required for CR assignment. 
2. Grading of MF is according to the European classification (Thiele et al. European consensus on 
grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90:1128). 
It is underscored that the consensus definition of a CR bone marrow is to be used only in those patients 
in which all other criteria are met, including resolution of leukoerythroblastosis. 
It should also be noted that it was a particularly difficult task for the working group to reach a consensus 
regarding what represents a complete histologic remission. 
3. Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + 
nucleated red blood cells. In splenectomized patients, <5% immature myeloid cells is allowed. 
9.5 Safety 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, and clinical 
laboratory test results. More frequent safety evaluations may be performed if clinically 
indicated or at the discretion of the investigator.  
Physical Examination 
Complete and symptom-directed physical examinations will be performed by a 
licensed physician (or physician’s assistant or nurse practitioner) 
Vital Signs 
Vital signs (blood pressure, respiratory rate, pulse rate and temperature) will be 
obtained in the sitting position.  
Safety Laboratory Determinations 
Laboratory evaluations will be performed as noted in the flow chart.  


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
Version Date: 29JAN2019 
Principal Investigator: Catherine J. Lee, MD 
Page 31 of 51 
 
 
9.6 Stopping Rules 
Stopping rules will be met when 4 out of 12 patients experience Non-relapse mortality 
(NRM) by Day+100. If the true probability of NRM is 50% there is an 81% chance that 
the trial will be stopped early for NRM. If the true probability NRM is 15% there is a 
2.4% chance that the trial will be stopped early for NRM.  
STATISTICAL CONSIDERATIONS 
The protocol proposes to study 24 patients with Myelofibrosis (MF) and Multiple 
Myeloma (MM).  
The primary outcome is non relapse related mortality (NRM) for the entire cohort. 
The outcome will be reported along with exact binomial confidence intervals for 
informal comparison to the literature. A review of the literature yielded similar results 
for NRM in 19 studies for MM and 8 studies for MF. In MM we collected 19 studies 
with 1686 allogenic transplant patients and selected the 3 largest studies with 
880 patients. These three studies reported NRM of 18%, 21.5%, and 22% for a weighted 
average of 21%. Weighted averaging revealed a benchmark of 25% for NRM. We hope 
to achieve a modest improvement over these results from the literature. We have 83% 
power to reject the null hypothesis that NRM = 25% at the one sided 0.05 significance 
level using an exact binomial test provided the true NRM = 6%. The null hypothesis will 
be rejected if ≤ 3/24 patients have NRM. If NRM is observed 3 or fewer out of 24 
patients an exact 80% upper confidence bound will exclude 22%.  
Analysis of acute and chronic GVHD and response (clinical and molecular response up 
to 1 year and disease free survival) is secondary and will be done descriptively. 
Proportions and exact binomial confidence intervals will be reported for secondary 
binary outcomes and Kaplan-Meier techniques will be used to report secondary time to 
event outcomes. Response outcomes will be reported for the entire cohort and also 
stratified by response to therapy prior to transplant, number of preceding treatment 
regimens and staging of disease at diagnosis.(21-39) 
REGISTRATION GUIDELINES 
Patients must meet all of the eligibility requirements listed in Section 5 prior to 
registration.  
Study related screening procedures can only begin once the patient has signed a 
consent form. Patients must not begin protocol treatment prior to registration. 
Treatment should start within five working days after registration. 
To register eligible patients on study, complete a Clinical Trials Office Patient Registration 
Form and submit to: CTORegistrations@hci.utah.edu.  
DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each patient 
that provides a record of the data generated according to the protocol. CRF’s should be 
created prior to the study being initiated and updated (if applicable) when amendments to 
the protocol are IRB approved. Data capture should be restricted to endpoints and 
relevant patient information required for planned manuscripts. These forms will be 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
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completed on an on-going basis during the study. The medical records will be source of 
verification of the data. During the study, the CRFs will be monitored for completeness, 
accuracy, legibility and attention to detail by a member of the Research Compliance 
Office. The CRFs will be completed by the Investigator or a member of the study team as 
listed on the Delegation of Duties Log. The data will be reviewed no less than annually 
by the Data and Safety Monitoring Committee. The Investigator will allow the Data and 
Safety Monitoring Committee or Research Compliance Office personnel access to the 
patient source documents, clinical supplies dispensing and storage area, and study 
documentation for the above-mentioned purpose. The Investigator further agrees to assist 
the site visitors in their activities. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 Informed consent  
Informed consent will be obtained from all research participants prior to performing 
any study procedures using the most recent IRB approved version.  
13.2 Institutional Review 
Study will be approved by the Institutional Review Board of University of Utah. 
13.3  Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman Cancer 
Institute (HCI) and approved by the NCI to assure the well-being of patients enrolled 
on Investigator Initiated Trials that do not have an outside monitoring review. Roles 
and responsibilities of the DSMC are set forth in the NCI approved plan. The activities 
of this committee include a quarterly review of adverse events including SAEs, 
important medical events, significant revisions or amendments to the protocol, and 
approval of cohort/dose escalations. If the DSMC and/or the PI have concerns about 
unexpected safety issues, the study will be stopped and will not be resumed until the 
issues are resolved. The DSMC also reviews and approves audit reports generated by 
the Research Compliance Office.  
All phase II studies are reviewed by the full committee at each quarterly DSMC 
meeting. This includes a review of all serious adverse events (SAEs) occurring in 
patients treated at HCI or its affiliates as well as all grade 3 or greater toxicities for 
patients on treatment and within 30 day follow-up window (only if possibly, probably 
or definitely related).  
13.4 Adverse Events / Serious Adverse Events 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 5.0 for AE and SAE reporting. An electronic copy of the CTCAE 
Version 5.0 can be downloaded from:  
http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx 
This is a protocol for allogeneic stem cell transplantation with the expected spectrum of 
transplant related SAEs like acute and chronic GVHD, life threatening infections, 
bleeding and graft rejection. A transplant related mortality of 10-20% is expected (2-5 
patients). 


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Anticipated frequent AEs during the acute transplant period (admission to day 28) are 
nausea, vomiting, diarrhea, fever, infections, mucositis. These will only be considered 
and documented as AE post engraftment 
Grade 3 and 4 cytopenias will not be considered AE or SAE (as applicable) until after 
engraftment. 
13.4.1 Adverse Events (AE) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, 
or medical condition occurring after starting the study drug even if the event is not 
considered to be related to study drug. For the purposes of this study, the terms 
toxicity and adverse event are used interchangeably. Medical conditions/diseases 
present before starting study drug are only considered adverse events if they worsen 
after starting study drug. Abnormal laboratory values or test results constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
Adverse event monitoring and collection will begin on Day -6 and end 365 days post- 
transplant. Any signs, symptoms or medical conditions occurring prior to Day -6 will 
be captured as medical history/baseline events. All adverse events will be captured in 
source documentation (with severity grading and causality noted) as defined in 
section 13.4; however, only events meeting the following criteria will be captured in 
OnCore (electronic CRFs): 
• CTCAE ≥ grade 3-4 non-hematologic toxicities related to study treatment 
• Relapse of the underlying hematological malignancy and acute/chronic GVHD will 
be documented on specific CRFs pages; this information should not be recorded on 
the CRF “Adverse Event” page and should not be treated as an adverse event (AE) 
unless leading to fatal outcome, which will trigger a SAE report (see Section 13.4.2). 
• Engraftment failure needs to be documented as an AE. In case it meets SAE 
criteria, 13.4.2, an SAE report must be sent.  
Information about all adverse events, whether volunteered by the subject, discovered 
by investigator questioning, or detected through physical examination, laboratory test 
or other means, will be collected and recorded and followed as appropriate. 
The occurrence of adverse events should be sought by non-directive questioning of 
the patient at each visit or phone contact during the study. Adverse events also may 
be detected when they are volunteered by the patient during or between visits or 
through physical examination, laboratory test, or other assessments. As far as 
possible, each adverse event should be evaluated to determine: 
1.the severity grade based on CTCAE v.5 (grade 1-5) 
2.its relationship to the study treatment (definite, probable, possible, unlikely, not 
related)  
3.its duration (start and end dates or if continuing at final exam) 
4.action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 


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medication taken; non-drug therapy given; hospitalization/prolonged 
hospitalization) 
5.whether it constitutes an SAE 
All adverse events will be treated appropriately. Once an adverse event is detected, it 
should be followed until its resolution, and assessment should be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the study treatment, the interventions required to treat it, and the 
outcome. 
Information about common side effects already known about the study treatment is 
described in the Drug Information (section 3) and the FDA-approved product labels. 
This information will be included in the patient informed consent and will be 
discussed with the patient during the study as needed. 
All adverse events will be immediately recorded in the patient research chart.  
13.4.2 Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded. A serious 
adverse event is an undesirable sign, symptom or medical condition which: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed 
above 
• causes congenital anomaly or birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition (procedures such as central line placements, 
paracentesis, pain control) 
o elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since the start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission 
o social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
The collection of SAEs will begin on Day -6 and end at Day +365.  
Any death from any cause while a patient is receiving treatment on this protocol or up 
to 365 days post-transplant, or any death which occurs more than 365 days post-
transplant but which is felt to be treatment related, must be reported.  
Grade 3 and 4 cytopenias will not be considered SAE until after engraftment. 


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Anticipated, but less frequent SAEs beyond day +28 are acute GVHD (liver, gut, skin), 
VOD, CMV activation, interstitial and fungal pneumonia, and cystitis which may 
require hospitalization 
Anticipated, but less frequent SAEs after day +100 are, chronic GVHD, relapse of MM 
or MF. 
If subjects fail to engraft by Day+28, this must be reported as an SAE.  
Graft failure after allogenic hemaopoietic cell transplantation (AHCT) may manifest as 
either a lack of initial engraftment of donor cells, or loss of donor cells after minimal 
engraftment; this may occur for a variety of reasons, including recipient T-cells, natural 
killer cells, or antibodies. Risk of graft failure can be decreased by more intense 
conditioning, increased cell dose, or more effective immunosuppression. Occurrence of 
graft failure will be confirmed by the treating transplant physician.  
Fatal relapses, fatal acute GVHD and fatal chronic GVHD are to be reported as SAEs. 
This study should be handled like a phase II study. All phase II studies are reviewed by 
the full committee at each quarterly DSMC meeting. This includes a review of all 
serious adverse events (SAEs) occurring in patients treated at HCI as well as all grade 3 
or greater toxicities for patients on treatment up to day +365 (only if possibly, probably 
or definitely related).  
Toxicities which fall within the definitions listed above must be reported as an SAE 
regardless if they are felt to be treatment related or not. Toxicities unrelated to treatment 
that do NOT fall within the definitions above, must simply be documented as AEs in the 
patient research chart.  
13.5 SAE Reporting Requirements 
SAEs must be reported to the DSMC, the FDA, the IRB, according to the requirements 
described below:  
A MedWatch 3500A form must be completed and submitted to 
compliance@hci.utah.edu within 1 business day of first knowledge or notification of 
event.  
DSMC Notifications: 
• An HCI Research Compliance Officer (RCO) will process and submit the 
MedWatch form to the proper DSMC member as necessary for each individual 
study.  
• The RCO will summarize and present all reported SAEs according to the Data 
and Safety Monitoring Plan at the quarterly DSMC meeting. 
Information about all serious adverse events will be collected and recorded. A 
serious adverse event is an undesirable sign, symptom or medical condition 
which: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 


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• is medically significant, i.e., defined as an event that jeopardizes the patient 
or may require medical or surgical intervention to prevent one of the 
outcomes listed above 
• causes congenital anomaly or birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
o routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition (procedures such 
as central line placements, paracentesis, pain control) 
o elective or pre-planned treatment for a pre-existing condition 
that is unrelated to the indication under study and has not 
worsened since the start of study treatment 
o treatment on an emergency outpatient basis for an event not 
fulfilling any of the definitions of a SAE given above and not 
resulting in hospital admission 
o social reasons and respite care in the absence of any 
deterioration in the patient’s general condition 
Toxicities which fall within the definitions listed above must be reported as an SAE 
regardless if they are felt to be treatment related or not. Toxicities unrelated to 
treatment that do NOT fall within the definitions above, must simply be documented 
as AEs in the patient research chart.  
FDA Notifications: 
• Adverse events occurring during the course of a clinical study that meet the 
following criteria will be promptly reported to the FDA: 
• Serious 
• Unexpected 
• Definitely, Probably or Possibly Related to the investigational drug 
• Fatal or life-threatening events that meet the criteria above will be reported 
within 7 calendar days after first knowledge of the event by the investigator; 
followed by as complete a report as possible within 8 additional calendar 
days. 
• All other events that meet the criteria above will be reported within 15 
calendar days after first knowledge of the event by the investigator. 
• The RCO will review the MedWatch report for completeness, accuracy and 
applicability to the regulatory reporting requirements. 
• The RCO will ensure the complete, accurate and timely reporting of the event 
to the FDA. 
• The MedWatch report will be submitted to the FDA through the voluntary 


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reporting method by the Regulatory Coordinator. 
IRB Notification: 
• Events meeting the University of Utah IRB reporting requirements 
(http://www.research.utah.edu/irb/) will be submitted through the IRB’s 
electronic reporting system within 10 working days. 
*Medwatch 3500A form can be found online 
13.6 Reporting of Pregnancy  
Although pregnancy is not considered an adverse event, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject, 
including the pregnancy of a male subjects’ female partner as an SAE. Pregnancies or 
lactation that occurs during the course of the trial or with 30 days of completing the 
trial or starting another new anticancer therapy, whichever is earlier, must be reported 
to the DSMC, IRB, FDA, and the sponsor as applicable. All subjects and female 
partners who become pregnant must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, fetal death, 
intrauterine death, miscarriage and stillbirth must be reported as serious events.  
13.7 Protocol Amendments 
Any amendments or administrative changes in the research protocol during the period, 
for which the IRB approval has already been given, will not be initiated without 
submission of an amendment for IRB review and approval.   
These requirements for approval will in no way prevent any immediate action 
from being taken by the investigator in the interests of preserving the safety of all 
patients included in the trial.  
13.8 Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and 
treatment plans as outlined in the protocol version submitted and previously approved 
by the IRB. Protocol deviations have the potential to place participants at risk and can 
also undermine the scientific integrity of the study thus jeopardizing the justification 
for the research. Protocol deviations are unplanned and unintentional events.  
Because some protocol deviations pose no conceivable threat to participant safety or 
scientific integrity, reporting is left to the discretion of the PI within the context of the 
guidelines below. The IRB requires the prompt reporting of protocol deviations 
which are: 
• 
Exceptions to eligibility criteria. 
• 
Intended to eliminate apparent immediate hazard to a research participant 
or  
• 
Harmful (caused harm to participants or others, or place them at 
increased risk of harm - including physical, psychological, economic, or 
social harm), or  
• 
Possible serious or continued noncompliance  


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13.9 FDA Annual Reporting  
This study is IND exempt therefore there are no annual reporting requirements to the 
FDA.  
13.10 
 Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical 
Trials Reporting Program) by the Clinical Trials Office. 
13.11 
 Record Keeping 
Per 21 CFR 312.57, Investigator records shall be maintained for a period of 2 years 
following the date a marketing application is approved; or, if no application is filed or 
the application is not approved, until 2 years after the investigation is discontinued and 
the FDA is notified. 
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allogeneic transplantation for multiple myeloma: an analysis of prognostic 
factors from the Chronic Leukaemia Working Party of the EBMT. Blood. 
2005; 105:4532-9. 
36.) 
Kröger N, shimoni A, Schillig G, et al. Unrelated stem cell transplantation 
after reduced intensity conditioning for patients with multiple myeloma 
relapsing after autologous transplantation. Br J Haemtol. 2010; 148: 323-
31. 
37.) 
Franssen LE, raymakers RA, Buijs A, Schmitz MF, van Dorp S, Mutis T, 
Lokhorst HM, van de Donk NW. Outcome of allogeneic transplantation in 
newly diagnosed and relapsed/refractory multiple myeloma: long-term 
follow-up in a single institution. Eur J Haematol. 2016; 97(5): 479-488. 
doi: 10.111/ejh.12758  
38.) 
Auner HW, Szydlo R, van Biezen A, et al. Reduced intensity-conditioned 
allogeneic stem cell transplantation for multiple myeloma relapsing or 
progressing after autologous transplantation: a study by the European 
Group for Blood and Marrow Transplantation. Bone marrow Transplant. 
2013; 48(11): 1395-400. doi: 10.1038/bmt.2013.73 
39.) 
El-Cheikh J, Crocchiolo R, Furst S, et al. Long-term outcome after 
allogeneic stem-cell transplantation with reduced-intensity conditioning in 
patients with multiple myeloma. Am J Hematol. 2013; 88(5): 370-4. doi: 
10.1002/ajh.23412 
40.) 
Tam CS1, Abruzzo LV, Lin KI, et. al. The role of cytogenetic 
abnormalities as a prognostic marker in primary myelofibrosis: 
applicability at the time of diagnosis and later during disease course. 
Blood. 2009 Apr 30;113(18):4171-8. doi: 10.1182/blood-2008-09-178541 
41.) 
Nicolaus Kröger, Sharifah Shahnaz Syed Abd Kadir et. al.  Ruxolitinib 
during Peritransplant Period for Myelofibrosis Patients Undergoing 
Allogeneic Stem Cell Transplantation Reduces Acute Graft-Versus-Host 
Disease. Blood 2016 128:2242 
 
 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
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Principal Investigator: Catherine J. Lee, MD 
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APPENDICES 
Appendix A (staging criteria)  
 
MULTIPLE MYELOMA 
Clinical Presentation, Diagnosis and Staging 
 
High risk disease — Approximately 15 percent of people with multiple myeloma have 
high risk disease based on cytogenetic testing (patients with translocation t (14;16)), 
translocation t (14;20) and deletion chromosome 17p). This is the aggressive form of 
multiple myeloma and may shorten survival; patients at high risk disease are treated with 
more aggressive therapy. 
 
Intermediate risk disease — Approximately 10 percent of people with multiple myeloma 
have intermediate risk disease based on cytogenetic testing (patients with translocation t 
(4;14)). With appropriate therapy, patients with this form of multiple myeloma can have 
outcomes similar to those of standard risk multiple myeloma. 
 
Standard risk disease — All patients with multiple myeloma who lack high or 
intermediate risk genetic abnormalities are considered to have standard risk multiple 
myeloma, and with appropriate therapy have an estimated median survival of 8 to 10 
years. 
 
Stage I - All of the following:  
- Hemoglobin value > 10 g/dL 
- Serum calcium value normal or ≤ 12 mg/dL 
- Bone x-ray, normal bone structure (scale 0) or solitary bone plasmacytoma only 
- Low M-component production rate (IgG value < 5 g/dL; IgA value < 3 g/dL) 
- Bence Jones protein < 4 g/24 hr 
 
Stage II - Neither Stage I nor Stage III 
Stage III - One or more of the following:  
- Hemoglobin value < 8.5 g/dL 
- Serum calcium value > 12 mg/dL 
- Advanced lytic bone lesions (scale 3) 
- High M-component production rate - (IgG value > 7 g/dL; IgA value > 5 g/dL) 
- Bence Jones protein > 12 g/24 h 
 
Sub-classifications (either A or B)  
A: Relatively normal renal function (serum creatinine value < 2.0 mg/dL) 
B: Abnormal renal function (serum creatinine value = 2.0 mg/dL) 
 
The International Staging System, which is the most recent, most reliantly used risk 
assessment system and identifies three risk groups on the basis of serum β2-
microglobulin and albumin levels (Greipp et al., 2005): 
 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
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Principal Investigator: Catherine J. Lee, MD 
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Stage I - Serum beta-2 microglobulin is less than 3.5 (mg/L) and the albumin level is 3.5 
(g/dL) or greater 
Stage II - Neither stage I or III, meaning that either: The beta-2 microglobulin level is 
between 3.5 and 5.5 (with any albumin level), OR the albumin is below 3.5 while the 
beta-2 microglobulin is less than 3.5 
Stage III - Serum beta-2 microglobulin is 5.5 or greater. 
 
MYELOFIBROSIS 
 
The prognosis of MF was initially guided by the Lille score (a.k.a., the Dupriez score), 
which used hemoglobin and white blood cell counts to classify patients as “long-lived” 
(median survival of ten years) or “short-lived” (median survival of two years) (Dupriez, 
1996). Patients were further grouped by risk, as shown in the table below: 
 
Lille risk group 
Number of risk factors Median survival (years) 
Low 
None 
7 - 8 
Intermediate 
1 
2.2 
High 
2 
1 
 
In the past decade the International Prognostic Scoring System (IPSS), which has been 
progressively updated to first the dynamic IPSS (DIPSS) and now the DIPSSplus as the 
understanding of the natural history and especially the impact of cytogenetics on the 
pathogenesis of MF has increased (Alchalby & Kroger, 2014) has gained prominence. 
The DIPSSplus prognostic score is based on eight risk factors (need for red blood cell 
transfusion, hemoglobin level, platelet count, leukocyte count, circulating blasts in the 
blood, constitutional symptoms, unfavorable cytogenetic profile and age). There are four 
risk categories based on the DIPSSplus score as show in the following table (Gangat et 
al., 2011): 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
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Principal Investigator: Catherine J. Lee, MD 
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Unfavorable karyotype:  complex karyotype or sole or two abnormalities that include 
trisomy 8, 7/7q-, i(17q), 5/5q-, 12p-, inv(3), or 11q23 
 
 


Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis 
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Principal Investigator: Catherine J. Lee, MD 
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Appendix B: ACUTE GVHD GRADING SCALE
 
 
Max
Skin
Type
%BSA
Date
LGI
Stool
Date
UGI
Emesis
Date
Liver
Tbili
Date
 
Prepared By: ______________________
Reviewed By: ___________________________
Date/Time:_______________________
Acute GVHD Grading
Other
Biopsy Date
GVHD 
Treatment, 
Drug 
changes, 
dose 
changes, 
start and end 
dates
NAME:                                                                                TX Date:
Week
Day
Date
Biopsy Results
MRN: 
Day 100:


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Principal Investigator: Catherine J. Lee, MD 
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Principal Investigator: Catherine J. Lee, MD 
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Appendix C: CHRONIC GVHD GRADING SCALE 
 
 


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