Reduce Intensity Conditioning (RIC) Allogenic Hematopoietic Stem Cell Transplantation (Allo HSCT) for Patients With Relapsed Multiple Myeloma: A Pilot Study
Phase: PHASE2
Conditions: Recurrent Plasma Cell Myeloma
Sponsor: Srinivas Devarakonda

Protocol v.4                                                                                                  
IRB Protocol Number: 2019C0218 
OSU-19190                                                                                                    
      IRB Approval date: 03/11/2021 
               Version Date: 03/03/2021 
 
 
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Reduce Intensity Conditioning (RIC) Allogeneic Hematopoietic Stem Cell 
Transplantation (allo HSCT) for Patients with Relapsed Multiple Myeloma:  
A pilot study 
 
 
 
 
 
 
Principal Investigator (PI):            
Srinivas Devarakonda, MD 
 
 
 
 
 
           Assistant Professor of Medicine 
The Ohio State University 
1800 Cannon Dr. 
Lincoln Tower 
Columbus, OH-43210 
Ph:  (614) 366-5539 
Fax: (614) 293-7526 
Email: Srinivas.Devarakonda@osumc.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol v.4                                                                                                  
IRB Protocol Number: 2019C0218 
OSU-19190                                                                                                    
      IRB Approval date: 03/11/2021 
               Version Date: 03/03/2021 
 
 
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PROTOCOL SYNOPSIS 
 
Reduce Intensity Conditioning (RIC) Allogeneic Hematopoietic Stem Cell 
Transplantation (allo HSCT) 
for Patients with Relapsed Multiple Myeloma: A pilot study  
 
Principal Investigator:  Srinivas Devarakonda M.D 
 
 
Study Design: The study is a pilot study to develop a platform for allo HSCT in 
relapsed multiple myeloma (MM) patients, with the idea of maximizing anti-myeloma 
effect and minimizing aGVHD (graft versus host disease). First, all patients will undergo 
conditioning regimen of Flu/Mel (fludarabine, melphalan). For GVHD prophylaxis, the 
investigator will use post-transplant cyclophosphamide (PTCy), mycophenolate mofetil 
(MMF) and tacrolimus. Second, the addition of a maintenance with daratumumab 
(administered for 1 year post allo HSCT), may further reduce the risk of disease relapse 
long enough in order for the graft versus myeloma to take effect. 
 
Primary Objective: 
• 
To develop a platform for allo HSCT in relapsed multiple myeloma patients to 
obtain preliminary data on the effect of combined treatment regimen on clinical 
outcomes  
 
Primary Endpoints 
To obtain preliminary data on the effect of the combined treatment regimen on clinical 
outcomes. 
 
Secondary Endpoints: 
• 
To determine the 2 year progression-free survival (PFS) 
• 
To determine 2 year overall survival (OS) 
• 
To determine the cumulative incidence of grade II-IV acute-graft-versus-host-
disease (aGVHD) at day 100 and 180. 
• 
To determine the 100 days, 1 year and 2 year cumulative incidence of treatment-
related mortality (TRM) 
• 
To assess one-year GVHD-free Relapse-free Survival (GRFS) 
• 
To determine the cumulative incidence of chronic graft-versus-host-disease 
(cGVHD) 
• 
To assess overall and best response rates 100 days after allo HCT, 6 months 
and every 6 months thereafter until end of Daratumumab maintenance. 
• 
To determine rate of relapse after allo HSCT followed by maintenance 
 
To determine Rate of MRD negativity using Next generation sequencing (FDA 
approved) in patients achieving a VGPR or better. 
 
• 
To determine immune reconstitution pattern on days +30, +100, +180 and 
+365 following allo HSCT. 
 

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IRB Protocol Number: 2019C0218 
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Patient Eligibility 
 
Patient Inclusion Criteria: 
• 
Patients age 18-75 years old 
• 
High risk relapsed MM patients   and who have received at least 2 prior lines of 
therapy, and have obtained at least a Partial response from their salvage chemo.  
  
High risk criteria are: patients are one or more of the following: 1: patients who 
progressed within 24 months from their first autologous stem cell transplant 
(Criteria from the BMT/CTN 1302( clinical trials.gov identifier:NCT02440464); 2: 
Patients with at least 2 prior lines of therapy with progression within 12 months 
from their last line of therapy.; 3: Patients with high risk markers ( del13 by conv. 
karyotyping only; hypodiploidy, 1q amplification or 1p deletion, t(4;14), t(14;16), 
t(14;20) or deletion of 17p by FISH or conv. karyotyping; R-ISS 3; or Beta-2M ≥ 
5.5 mg/L)  
• 
Patients with nonsecretory myeloma are eligible for the study. Assessments of 
response will be based on PET scans. 
• 
Prior radiation is allowed as this is a very vital management of myeloma bone 
disease. 
• 
Patients with ≥ PR prior to allo-HSCT 
• 
First allogeneic transplant 
• 
Cardiac function: Ejection fraction ≥45% 
• 
Estimated creatinine clearance greater than 40 mL/minute (using  the  Cockcroft- 
Gault formula and actual body weight) 
• 
Pulmonary function: DLCO ≥40% (adjusted for hemoglobin) and FEV1≥50% 
• 
Liver function: total bilirubin < 2x the upper limit of 
normal and ALT/AST < 2.5x the upper normal limit (Patient  who  have  been  
diagnosed  with  Gilbert’s  Disease  are permitted to exceed the defined bilirubin 
value of 2x the upper limit of normal). 
• 
Female subjects (unless postmenopausal for at least 1 year before the screening 
visit, or surgically sterilized), agree to practice two (2) effective methods of 
contraception at the same time, or agree to practice true abstinence when this is 
in line with the preferred and usual lifestyle of the subject. (Periodic abstinence 
[eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal 
are not acceptable methods of contraception.)through 90 days after the last dose 
of maintenance therapy 
• 
Male subjects (even if surgically sterilized) must agree to one of the following: 
practice effective barrier contraception, or practice true abstinence when this is in 
line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, 
calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable methods of from the time of signing the informed  
consent through 90 days after last dose of maintenance therapy• Understand and 
voluntarily sign an informed consent 
• 
Able to comply with the study visit schedule and other protocol requirements 
 

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IRB Protocol Number: 2019C0218 
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Patient Exclusion criteria: 
• 
Karnofsky Performance Score < 70% 
• 
Planned  pre-emptive/prophylactic  administration  of  donor  lymphocytes 
• 
Active Central  Nervous  System(CNS)  involvement  with  multiple  myeloma  
defined  as  csf positivity for plasma cells or a parenchymal CNS plasmacytoma 
• 
Patients with POEMS, Waldenstrom macroglobulinemia  
• 
Cannot have had prior allogeneic transplant 
• 
Uncontrolled bacterial, viral or fungal infection (currently taking medication and 
with progression or no clinical improvement) at time of enrollment 
• 
Patients with prior malignancies <3 years except resected basal cell/squamous 
cell carcinoma, treated carcinoma in-situ. Other cancers treated with curative 
intent < 3 years previously will not be allowed unless approved by the Principal 
investigator 
• 
Patients seropositive for the human immunodeficiency virus (HIV). 
• 
Patient with active Hepatitis B or C determined by serology and/or NAAT 
• 
Patients with > grade 2 sensory peripheral neuropathy 
• 
Myocardial   infarction   within   6   months   prior   to   enrollment, uncontrolled 
angina, severe  uncontrolled  ventricular  arrhythmias,  or  electrocardiographic  
evidence  of  acute ischemia  or  active  conduction  system  abnormalities.  Prior  
to  study  entry,  any  ECG abnormality  at  screening  must  be  documented  by  
the  investigator  as  not  medically relevant 
• 
Failure to have fully recovered (i.e. no toxicities > Grade 1) from the reversible 
effects of prior chemotherapy 
• 
Patient with serious medical of psychiatric illness likely to interfere with 
participation on this clinical study 
• 
Hypersensitivity to any of the drugs involved in this trial 
• 
Participation in clinical trials with other investigational agents not included in this 
trial, within 14 days of the start of this trial and throughout the duration of this trial 
• 
Enrollment of subjects who require concurrent radiotherapy (which must be 
localized in its  field size) should be deferred until  the radiotherapy is completed 
and  3 weeks have elapsed since the last date of therapy 
• 
Major surgery within 14 days of start of trial 
• 
Patients unable or unwilling to adhere to the study assessment schedule 
• 
Female patients who are pregnant or breastfeeding. A negative pregnancy test 
will be required for all women of child bearing potential 
 
 
Patient Eligibility Criteria Prior to Begin Maintenance Therapy: 
Between  Day +90  and  Day +150  after  allogeneic  HCT,  patients  will    receive  
daratumumab  maintenance.  If patients do not meet the eligibility criteria for initiating 
maintenance, they will continue to be followed per the protocol. 
 
Patient Eligibility Criteria Prior to Initiating Maintenance Therapy: 
 Platelet count ≥ 75,000/mm3 
 Absolute neutrophil count (ANC) ≥ 1000/mm3 

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 Total bilirubin < 2x the upper limit of the normal range (ULN), except in patients 
with Gilbert’s syndrome 
 ALT/AST < 2.5x the upper normal limit 
 No ≥ grade 2 visceral (gut or liver) acute GVHD. No ≥ Grade 3 any other acute 
GVHD 
 All non-hematologic toxicities should have resolved to ≤ grade 1 
 Negative for Hepatitis B virus by PCR 
 Patients must be in at least a partial response 
Stem Cell Donor and Source 
 Matched related 
 Matched unrelated  
 1 antigen mismatch related or unrelated 
 Haploidentical 
 Peripheral stem cell source will be used except in Haploidentical where Bone 
marrow stem cells will be required 
 
Donor Exclusion Criteria: 
 Donors will be excluded if they are an identical twin of the recipient 
 Females who are pregnant (positive serum β HCG) or uninterruptible 
breastfeeding will be excluded 
 HIV seropositive donors will be excluded 
 Donors receiving experimental therapy or investigational agents will be excluded 
unless approved by the protocol chair and Officer 
 Donors not willing and able to donate PBSC will be excluded 
 Related and unrelated donors will be identified according to institutional 
guidelines 
 
Disease to be Included 
• 
Relapsed Multiple Myeloma patients with a partial response (PR) or better prior 
to allo-transplantation. 
 
Treatment Plan 
Patients meeting the eligibility criteria for transplant/enrollment will be treated with 
conditioning regimen of fludarabine and melphalan. GVHD prophylaxis consists of 
cyclophosphamide, tacrolimus and mycophenolate mofetil, and post allo-HSCT 
maintenance with daratumumab: Patients will receive fludarabine 30 mg/m2 (when 
creatinine clearance 40 – 70 mL/min, reduce to 24 mg/m2) from Day -5 to Day -2 and 
melphalan 70 mg/m2 on Day -3 and Day -2 intravenously (50 mg/m2 for patients 71 and 
older). On Day 0, patients will receive the donor stem cells. GVHD Prophylaxis will be 
cyclophosphamide/tacrolimus/ mycophenolate mofetil: Cyclophosphamide 50 mg/kg will 
be given on days +3, and +4. Tacrolimus will start on day +5 at 0.05 mg/kg orally twice 
daily to achieve a target serum level of 5-10 mg/ml.  Tacrolimus may change to i.v as 
necessary. Serum levels of tacrolimus will be measured per institution guideline. 
Tapering of tacrolimus will start after day 90 post HSCT with goal of having the patient 

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receive no immune-suppressive medication by 6 months in absence of GVHD.  
Mycophenolate Mofetil (MMF) will be given at a dose of 15 mg/kg three times a day 
(based on actual body weight) with a maximum total daily dose not to exceed 3 grams ( 
1 gram TID, IV or oral), starting Day +5 to day 35 post-transplant. Patients will start 
maintenance Daratumumab between 90-150 days post allo-HSCT as long as counts 
are acceptable (absolute neutrophil ≥1000/µL; Platelets ≥ 75,000/µL) and in the 
absence of disease progression. Patients will receive daratumumab maintenance (given 
at 16 mg/kg weekly for 8 doses, followed by every 2 weeks for 8 doses, then monthly). 
Maintenance will continue for 1 year in absence of unacceptable toxicity, disease 
progression or death. 
 
Accrual 
Relapsed MM patients who are candidates for allo-HSCT will be assessed for accrual. 
20 patients will be accrued. 
 
Accrual Period 
The estimated accrual period is 2 years.  
 
Follow-up Period 
Patients will be followed for 1 year after end of Daratumumab treatment  
 
Stopping Rule:    
Monitoring of the key safety endpoint of death will be conducted. Day 100 post-
transplant mortality will be monitored. The null hypothesis that the 
Day 100 mortality rate is less than or equal to 10%. The stopping rule will be triggered if  
there is significant evidence that the overall death rate exceeds 10%, that is, if the lower 
bound of the one-sided 95% CI exceeds 10%. The rationale of a lower confidence 
bound is to be certain that the estimated true rate is not significantly higher than the 
rates deemed clinically acceptable. If the number of death equals or exceeds the 
numbers in the table below, then the study will be suspended to accrual pending further 
consultation with the DSMB. We will first enroll 3 patients and assess toxicity through 
day 100, before continuing enrollment. 
 
One year non-relapse mortality after allo-HSCT is 16-20%. Given that patients will be on 
daratumumab maintenance, while not expected, monitoring for excessive mortality is  
necessary. At one year post allo-HSCT, patients would have transitioned to the monthly 
daratumumab. The stopping rule will be triggered if the one-year non-relapse mortality  
exceeds 20%. 
 
The rate of chronic GVHD(cGVHD) occurs in 50-60% of patients undergoing allo-HSCT, 
with 30-35% being extensive cGVHD. The stopping rule will be triggered if the rate of 
extensive cGVHD exceeds 35%. 
 
Table: Incidence of death  

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IRB Protocol Number: 2019C0218 
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Number of 
patients enrolled 
Number of death 
3 
2 
4-8 
3 
9-14 
4 
15-20 
5 
 

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IRB Protocol Number: 2019C0218 
OSU-19190                                                                                                    
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Contents 
PROTOCOL SYNOPSIS................................................................................................. 2
1. 
BACKGROUND and RATIONALE ..................................................................... 11
1.1. Relapsed Multiple Myeloma and Transplantation ................................ 11
1.2. Daratumumab in Multiple Myeloma .......................................................... 12
1.3. Rational for Post-transplant Cyclophosphamide ................................. 13
2. 
STUDY OVERVIEW AND OBJECTIVE ............................................................. 14
2.1. Study Overview .............................................................................................. 14
2.2. Primary Hypotheses and Study Objectives ............................................ 15
2.2.1. 
Primary hypothesis ................................................................................... 15
2.2.2. 
Primary Objectives .................................................................................... 15
2.2.3. 
To develop a platform for allo HSCT in relapsed multiple myeloma 
patients           to obtain preliminary data on the effect of combined treatment 
regimen on clinical outcomes ................................................................................... 15
2.2.4. 
Secondary Objectives ............................................................................... 15
2.2.5. Correlative Objective .............................. Error! Bookmark not defined.
3.     PATIENT ELIGIBILITY CRITERIA ...................................................................... 15
3.1. Patient Inclusion Criteria ................................................................................ 16
3.3 Patient Eligibility Criteria Prior to Begin Maintenance Therapy: .......... 17
3.4 Stem Cell Donor and Source .......................................................................... 18
3.5 Donor Exclusion Criteria ................................................................................. 18
3.6. Diseases to be Included ................................................................................. 18
3.7. Inclusion of Women and Minorities ............................................................. 18
4.    TREATMENT PLAN ............................................................................................... 18
4.1. Administration Schedule to Patients ....................................................... 19
4.2. Stem Cell Administration ............................................................................ 21
4.3. Supportive Care ............................................................................................. 21
4.3.1. Growth Factors ....................................................................................... 21
4.3.2. Prophylaxis Against Infection ............................................................ 21
4.4. Participant Risks ............................................................................................ 21
4.4.1. Fludarabine .............................................................................................. 21
4.4.2. Melphalan ................................................................................................. 22
4.4.3. Mycophenolate mofetil (MMF) ............................................................ 22

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4.4.4. Cyclophosphamide ................................................................................ 22
4.4.5. Tacrolimus ............................................................................................... 22
4.4.6. Daratumumab Administration ............................................................ 23
5. 
Management of Toxicities .................................................................................. 24
5.1. GVHD ................................................................................................................ 25
5.2. Veno Occlusive Disease (VOD) .................................................................. 25
5.3. Idiopathic Pneumonia Syndrome/Diffuse Alveolar Hemorrhage ...... 25
5.4. Thrombotic Microangiopathy ..................................................................... 25
5.5. Engraftment Failure ...................................................................................... 26
5.6. Patient Withdrawal ........................................................................................ 26
6. 
Study Drug Supply ............................................................................................... 27
7. 
Statistical Consideration .................................................................................... 27
8. 
Stopping Rule: ...................................................................................................... 28
9. 
Accrual and Accrual Period .............................................................................. 29
10. 
Follow-Up Period ............................................................................................... 29
11. 
Follow-Up and Schedule of Events .............................................................. 29
11.1. 
Follow-up Schedule for Patients (Recipients) ................................... 29
11.2. 
Evaluation During Treatment .................................................................. 30
11.3. 
Post-Treatment Follow-up ....................................................................... 30
11.4. 
Sample Collection for Immunologic Correlative Studies ................ 30
11.5. 
Patient Study Calendar ............................................................................. 30
12. 
Analysis Definitions and Endpoints ............................................................. 36
12.1. 
Safety Endpoints ........................................................................................ 36
12.2. 
Efficacy Analysis Endpoints ................................................................... 36
12.3. 
Relapse of Malignancy ............................................................................. 37
12.3.1. 
Myeloma ................................................................................................ 37
12.3.2. 
Registration Guidelines .................................................................... 37
12.3.3. 
Assignment of Study Numbers ....................................................... 37
12.3.4. 
Study Records ..................................................................................... 37
12.3.5. 
Selection Procedures ........................................................................ 38
13. 
Correlative Studies ........................................................................................... 38
13.1. 
Correlative Studies ........................................................................................ 38
14. 
Definitions of Adverse Events and Causality ............................................ 39

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14.1. 
Monitoring of Adverse Events ................................................................ 39
14.2. 
Definitions of Adverse Events and Causality ..................................... 39
14.3. 
Serious Adverse Events ........................................................................... 41
14.4. 
Reporting of Adverse Event Information Following Study 
Completion ................................................................................................................. 42
14.5. 
Patient Withdrawal ..................................................................................... 42
15. 
References .......................................................................................................... 43
16. 
Appendices ......................................................................................................... 47
Appendix A: HCT-SPECIFIC COMORBIDITY INDEX SCORE ............................ 47
Appendix B: KARNOFSKY PERFORMANCE STATUS SCALE......................... 48
Appendix C: International Myeloma Working Group Response Criteria ...... 49
Appendix D:  Acute GVHD Grading ......................................................................... 51
Appendix E.  Ethical and regulatory ....................................................................... 52
Ethical Principles ..................................................................................................... 52
Protocol Compliance and Protocol Revisions ..................................................... 52
Informed consent ......................................................................................................... 52
Institutional Review Board (IRB) Approval ........................................................... 52
Additional Responsibilities of the Investigator .................................................... 53
Use and Completion of Case Report Forms (CRFs) ........................................... 53
Confidentiality ............................................................................................................... 53
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. BACKGROUND and RATIONALE 
 
1.1. Relapsed Multiple Myeloma and Transplantation 
 
Multiple Myeloma (MM) accounts for approximately 20% of all hematologic 
malignancies and 2% of all cancer deaths in the United States (1). Due to the improved 
PFS resulting in prolonged time off treatment without symptoms and improved quality of 
life, autologous stem cell transplantation (AHSCT) has become an integral part of 
treatment in patients with newly diagnosed MM. The introduction of the novel agents–
thalidomide, lenalidomide and bortezomib-has improved on both PFS and OS (2-10).  
The addition of maintenance treatment post AHSCT has further improved the PFS (from 
median 23-27 months to 41-53 months), and in one study, OS (3 yr. 84% versus 
80%)(11, 12). Despite this improvement in response, a vast number of patients relapse 
and treatment of relapse remains a major challenge. AHSCT and salvage therapies at 
time of relapse, has led to improvement in the survival of patients with MM (10).  
However, as MM has become a chronic disease with a longer succession of remissions 
and relapses, finding effective treatment is critical for prolonging PFS/OS. The options 
include retreatment with previous regimens, and/or moving on to more recently used 
drugs. However, despite this, patients become resistant to chemotherapy and have 
progressive MM.   
 
Allo HSCT is a reasonable upfront option in these patients and offers a potential cure 
and was found to be highest when this modality was used earlier in the disease course 
and when used as a strategy for consolidation of remission induced by salvage therapy 
(13, 14). In a prospective EBMT trial, it was shown that patients who had relapsed from 
a previous AHSCT and received allo-HSCT had an overall response rate of 90%, 
including a CR rate of 40% (15). Reduced intensity conditioning (RIC) allo HSCT offers 
the potential advantage of decreased treatment related mortality (TRM) while preserving 
the GVM effect (16, 17).  Prospective studies utilizing upfront RIC allo HSCT 
incorporated autologous HSCT prior to allo HSCT (18-21). Novel agents were not 
incorporated or available at the time. Conditioning regimen was not consistent and 
consisted of low dose total body radiation, fludarabine/busulfan/antithymoglobulin or 
fludarabine/Melphalan. aGVHD prophylaxis consisted of mycophenolate 
mofetil/cyclosporine or methotrexate/cyclosporine. The PFS and OS ranged 31-39 
months and 35-50 months respectively. TRM was 11-16%, aGVHD 32-40% and 
cGVHD up to 66%. No maintenance was done. Overall, the results of allogeneic HSCT 
have continued to improve significantly over the years as was seen in a steady decline 
in TRM by the Center for International Blood and Marrow Transplant Research 
(CIBMTR) analysis (22). However, the relapse after allogeneic HSCT remains a 
challenge (22, 23) and the emerging data suggest that the outcomes of allogeneic 
 
 
 

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HSCT could be further improved with the use of novel agents (23). BMT CTN 1302 was 
one such multicenter trial that aimed to address whether the addition of novel agent 
Ixazomib to maintenance following allo HSCT results in improved PFS and is 
associated with lower rates of GVHP, in patients with high risk multiple myeloma (BMT 
CTN1302). 
 
We here, propose a concept that, even if not curative, may improve PFS and OS, for 
haploidentical, mismatch or matched related or unrelated patients who relapse after 
autologous AHSCT.  In this study, to improve on the PFS and OS, and to reduce 
aGVHD, we propose to use allo HSCT for all transplant eligible relapsed MM patients.  
Patients obtaining a partial response or better with any salvage regimen will proceed to 
allo HSCT with a related or unrelated donor.  Conditioning regimen will consist of 
fludarabine, melphalan and aGVHD prophylaxis will consist of post-transplant 
cyclophosphamide (PTCy), mycophenolate mofetil (MMF) and tacrolimus. Maintenance 
with monthly daratumumab will be administered for 1-year post allo-HSCT starting 
between 90-150 days post allo-HSCT. 
 
1.2. Daratumumab in Multiple Myeloma 
 
The optimal intensity of conditioning regimens for allo-HSCT is still controversial for 
patients with multiple myeloma. Fully myeloablative regimens have been largely 
abandoned, whereas nonmyeloablative stem cell transplant regimens (e.g., total body 
irradiation of 2 Gy) without anti-multiple myeloma activity have been associated with 
lower transplant related mortality (TRM) risk but increased relapse (17). The pendulum 
of regimen intensity has now swung back to reduced-intensity conditioning with 
regimens that incorporate intermediate doses of active anti-multiple myeloma therapy. 
The most popular approach in the United States is a combination of fludarabine and 
melphalan at a dose of 140 mg/m2 (CIBMTR data). The addition of monoclonal 
antibody to maintenance is being explored as an additional strategy to increase the 
antineoplastic potential without incurring additional toxicity. 
 
Daratumumab has been approved by the Food and Drug Administration (FDA) to treat a 
type of blood cancer called multiple myeloma. Daratumumab is especially potent & 
highly effective in the treatment of relapsed & refractory MM, both as monotherapy and 
in combination. It is a monoclonal antibody (a type of antibody that identifies and 
attaches to certain proteins within the body to bring about an immune response, help 
the immune system work, or block signals telling the cancer cells to divide). 
Daratumumab can target tumor cells for elimination via antibody-dependent cellular 
cytotoxicity, complement-dependent cytotoxicity and phagocytosis. Daratumumab may 
also initiate CD38-mediated signal transduction, leading to cell death. In preliminary 
studies, daratumumab has demonstrated promising activity in combination with 
lenalidomide and dexamethasone. The efficacy and safety profiles of daratumumab 
monotherapy in heavily pretreated patients with RRMM were examined in the open-
label, phase 1/2 GEN501 study and the phase 2 SIRIUS study (24, 25). Daratumumab 
also demonstrated a manageable safety profile marked by a low incidence of grade ≥3 

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infusion-related reactions (IRRs) and few treatment discontinuations as a result of 
adverse events (AEs).  
 
1.3. Rational for Post-transplant Cyclophosphamide  
 
High dose cyclophosphamide is a potent immunosuppressor that has been successfully 
used to prevent GVHD in unrelated, HLA-matched sibling and haploidentical bone 
marrow/PBSC transplants in single center as well as multi-center studies (26, 27). 
Cyclophosphamide (Cy) administered early post HSCT preferentially kills allo-reactive T 
cells while sparing resting, non allo-reactive T cells leading to suppression of GVHD as 
well as graft rejection (28). Following a regimen of fludarabine, Cy and low dose TBA, 
GVHD prophylaxis consisted of Cy on days +3 and +4 post-transplant, tacrolimus, and 
MMF (27). Post transplantation immunosuppression with high-dose Cy, tacrolimus, and 
thrice-daily MMF was associated with an acceptably low incidence of fatal graft 
rejection, severe aGVHD, and extensive cGVHD, while allowing prompt engraftment, 
and low incidence of severe opportunistic infections. Cumulative incidences of grades II-
IV and grades III-IV acute GVHD by day 200 were 34% and 6% respectively. Also, the 
transplantation regimen is truly non-myeloablative, as autologous hematopoiesis 
recovered in 8 of 9 patients who rejected their grafts. There was lower incidence of 
extensive chronic GVHD among recipients of two versus one dose of post-Cy (5% 
versus 25%; p=.05). The cumulative incidences of non-relapse mortality (NRM) and 
relapse at 1 year were 15% and 51%, respectively. Overall and event-free survival 
(EFS) at two years after transplantation were 36% and 26%, respectively. In addition, 
two retrospective studies also reported encouraging results on the use of post-
transplant cyclophosphamide following Allo-HSCT. Lower rates for aGVHD and cGVHD 
were observed using post-transplant Cy (29, 30).  
 
The Blood and Marrow Transplant Clinical Trials Network conducted multicenter phase 
2 trials for individuals with leukemia or lymphoma and no suitable related donor. RIC 
was used with either unrelated double umbilical cord blood (dUCB) or HLA-
haploidentical related donor bone marrow transplantation (26). The 1-year probabilities 
of overall and progression-free survival were 54% and 46%, respectively, after dUCB 
transplantation (n=50) and 62% and 48%, respectively, after haploidentical bone 
marrow transplantation (n=50). The day +56 cumulative incidence of neutrophil recovery 
was 94% after dUCB and 96% after haploidentical bone marrow transplantation. The 
100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% 
after haploidentical bone marrow transplantation. The 1-year cumulative incidences of 
NRM and relapse after dUCB transplantation were 24% and 31%, respectively, with 
corresponding rates of 7% and 45%, respectively, after haploidentical bone marrow 
transplantation. Post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis was 
developed initially for haploidentical bone marrow transplantation after non-ablative 
conditioning but, recently, several small studies have extended the approach to 
myeloablative conditioning and to PBSC transplantation. To date, haploidentical non-
ablative transplantation with PTCy has used bone marrow as the graft source. Use of 
PBSC instead of marrow may allow wider applicability of this approach but there is 

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concern about higher risks of acute and chronic GVHD due to the 5-10 fold higher 
number of T-cells in the allograft. Recently, groups in Houston and Seattle/London 
reported small studies in which PBSC were substituted for bone marrow with post-Cy in 
the haploidentical donor setting (31). In both studies, the incidences of severe acute 
GVHD, chronic GVHD and non-relapse mortality at 1 year with PBSC were comparable 
to the rates seen with the bone marrow.  A phase II multicenter trial, PROGRESS I, was 
done in an attempt to primarily determine if the three new GVHD prophylaxis 
approaches using novel agents such as maraviroc, bortezomib, and PTCy, improve the 
rate of GVHD relapse free survival (GFRS) at one year after allo HSCT (32). An event 
for this time to event outcome is defined as time from allo HSCT to grade III-IV aGVHD, 
cGVHD requiring systemic immunosuppression, relapse, or death by any cause. Donors 
were 6/6 HLA matched related, or 7/8 or 8/8 HLA matched unrelated. Using these novel 
strategies, MMF/Tacrolimus/PTCy was shown to be associated with a superior 1-year 
GRFS (p 0.0467), lower rates of severe aGVHD (p 0.0066), cGVHD requiring 
immunosuppression (p 0.0413) and better GVHD-free survival (p 0.0121). There were 
no differences in relapse/progression, treatment related mortality, disease free survival, 
count recoveries, or overall survival compared to control. Kasamon et al (33) recently, 
demonstrated the feasibility and acceptable safety profile of non-myeloablative T-cell 
replete mismatch unrelated donor bone marrow transplantation with PTCy based GVHD 
prophylaxis for hematologic malignancies. Rates of GVHD and toxicity were low. 
Therefore, the inclusion of PTCy with MMF and tacrolimus as GVHD prophylaxis after 
non-ablative conditioning regimen seems to be justified. 
 
2. STUDY OVERVIEW AND OBJECTIVE 
 
2.1. Study Overview 
 
Patients who achieve a high quality and prolonged duration of response with initial 
therapy will ultimately relapse. Thus, management of relapsed disease is a critical aspect 
of MM management. Given the small number of relapsed myeloma patients treated with 
an allogeneic transplant, there is considerable unmet need to define the role of allogeneic 
HCT in relapsed MM population. The introduction of reduced intensity regimen has 
resulted in reduced TRM in allogeneic HCT for patients with myeloma. However, 
myeloma relapse still need to be reduced in order to maximize the efficiency of the 
therapeutic approach in relapsed myeloma population. The purpose of this study is to 
develop a platform for allo HSCT in relapsed multiple myeloma (MM) patients (34, 35), 
with the idea of maximizing anti-myeloma effect and minimizing aGVHD (graft versus host 
disease). First, all patients will undergo conditioning regimen of Flu/Mel (fludarabine, 
melphalan) for GVHD prophylaxis, the investigator will use post-transplant 
cyclophosphamide (PTCy) mycophenolate mofetil (MMF) and tacrolimus. Second, the 
addition of a maintenance with monthly daratumumab (administered for 1 year post allo 
HSCT), may further reduce the risk of disease relapse long enough in order for the graft 
versus myeloma to take effect. 
 

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2.2.  Primary Hypotheses and Study Objectives 
 
2.2.1. Primary hypothesis 
Allogeneic Stem cell transplant  with post-transplant cyclophosphamide 
(PTCy) mycophenolate 
mofetil (MMF) and tacrolimus followed 
by  
maintenance with monthly daratumumab (administered for 1 year post allo 
HSCT),  will improve  PFS and OS and reduce relapse due to graft versus 
myeloma effect. 
 
2.2.2.  Primary Endpoint 
 
To obtain preliminary data on the effect of the combined treatment regimen 
on clinical outcomes   
To develop a platform for allo HSCT in relapsed multiple myeloma patients           
to obtain preliminary data on the effect of combined treatment regimen on 
clinical outcomes  
 
2.2.3. Secondary Endpoints 
• 
To determine the 2 year progression-free survival (PFS) 
• 
To determine 2 year overall survival (OS) 
• 
To determine the cumulative incidence of grade II-IV acute-graft-versus-
host-disease (aGVHD) at day 100 and 180. 
• 
To determine the 100 days, 1 year and 2 year cumulative incidence of 
treatment-related mortality (TRM) 
• 
To assess one-year GVHD-free Relapse-free Survival (GRFS) 
• 
To determine the cumulative incidence of chronic graft-versus-host-
disease (cGVHD) 
• 
To assess overall and best response rates 100 days after allo HCT, 3 
months, 6 months and every 6 months thereafter until end of 
Daratumumab maintenance. 
• 
To determine rate of relapse after allo HSCT followed by maintenance  
• 
To determine Rate of MRD negativity using Next generation sequencing 
(FDA approved) in patients achieving a VGPR or better 
      
 
To determine immune reconstitution pattern on days +30, +100, +180 and +365 following 
allo HSCT. 
 
3. PATIENT ELIGIBILITY CRITERIA 
 

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3.1. Patient Inclusion Criteria                                                                  
• 
Patients age 18-75 years old High risk relapsed MM patients and who have 
received at least 2 prior lines of therapy, and have obtained at least a Partial 
response from their salvage chemo.  
 
 High risk patients are one or more of the following: 1: patients who progressed within 
24 months from their first autologous stem cell transplant (Criteria from the BMT/CTN  
1302( clinical trials.gov identifier:NCT02440464); 2: Patients with at least 2 prior lines of 
therapy with progression within 12 months from their last line of therapy; 3: Patients with 
with high risk markers ( del13 by conv. karyotyping only; hypodiploidy, 1q amplification 
or 1p deletion, t(4;14), t(14;16), t(14;20) or deletion of 17p by FISH or conv. karyotyping; 
R-ISS 3; or Beta-2M ≥ 5.5 mg/L)  
 
• 
Patients with nonsecretory myeloma are eligible for the study. Assessments 
of response will be based on PET scans. 
• 
Prior radiation is allowed as this is a very vital management of myeloma bone 
disease. 
• 
Patients with ≥ PR prior to allo-HSCT 
•    First allogeneic transplant 
•    Cardiac function: Ejection fraction ≥45% 
•    Estimated creatinine clearance greater than 40mL/minute (using  the  
Cockcroft- Gault formula and actual body weight) 
• 
Pulmonary function: DLCO ≥40% (adjusted for hemoglobin) and FEV1≥50% 
•    Liver function: total bilirubin < 2x the upper limit of normal and ALT/AST < 
2.5x the upper normal limit (Patient  who  have  been  diagnosed  with  
Gilbert’s  Disease  are permitted to exceed the defined bilirubin value of 2x 
the upper limit of normal) 
• 
Female subjects (unless postmenopausal for at least 1 year before the 
screening visit, or surgically sterilized), agree to practice two (2) effective 
methods of contraception at the same time, or agree to practice true 
abstinence when this is in line with the preferred and usual lifestyle of the 
subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-
ovulation methods] and withdrawal are not acceptable methods of 
contraception) through 90 days after the last dose of maintenance therapy 
• 
Male subjects (even if surgically sterilized) must agree to one of the following: 
practice effective barrier contraception, or practice true abstinence when this 
is in line with the preferred and usual lifestyle of the subject. (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable methods of from the time of signing the 
informed consent through 90 days after last dose of maintenance therapy• 
 
• 
Understand and voluntarily sign an informed consent 
• 
Able to comply with the study visit schedule and other protocol requirements 
 
3.2  
Patient Exclusion criteria: 
• 
Karnofsky Performance Score < 70% 

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• 
Planned  pre-emptive/prophylactic  administration  of  donor  lymphocytes 
• 
Active Central  Nervous  System(CNS)  involvement  with  multiple  myeloma  
defined  as  csf positivity for plasma cells or a parenchymal CNS 
plasmacytoma 
• 
Patients with POEMS, Waldenstrom macroglobulinemia  
• 
Uncontrolled bacterial, viral or fungal infection (currently    
      taking medication and with progression or no clinical improvement) at time of 
enrollment 
• 
Patients with prior malignancies <3 years except resected basal 
cell/squamous cell carcinoma, treated carcinoma in-situ. Other cancers 
treated with curative intent < 3 years previously will not be allowed unless 
approved by the Principal investigator 
• 
Patients seropositive for the human immunodeficiency virus (HIV). 
• 
Patient with active Hepatitis B or C determined by serology and/or NAAT 
• 
Patients with > grade 2 sensory peripheral neuropathy 
• 
Myocardial   infarction   within   6   months   prior   to   enrollment, 
uncontrolled angina, severe  uncontrolled  ventricular  arrhythmias,  or  
electrocardiographic  evidence  of  acute ischemia  or  active  conduction  
system  abnormalities.  Prior  to  study  entry,  any  ECG abnormality  at  
screening  must  be  documented  by  the  investigator  as  not  medically 
relevant 
• 
Failure to have fully recovered (i.e. no toxicities > Grade 1) from the reversible 
effects of prior chemotherapy 
• 
Patient with serious medical of psychiatric illness likely to interfere with 
participation on this clinical study 
• 
Hypersensitivity to any of the drugs involved in this trial 
• 
Participation in clinical trials with other investigational agents not included in 
this trial, within 14 days of the start of this trial and throughout the duration of 
this trial 
• 
Enrollment of subjects who require concurrent radiotherapy (which must be 
localized in its  field size) should be deferred until  the radiotherapy is 
completed and  3 weeks have elapsed since the last date of therapy 
• 
Major surgery within 14 days of start of trial 
• 
Patients unable or unwilling to adhere to the study assessment schedule 
• 
Female patients who are pregnant or breastfeeding. A negative pregnancy 
test will be required for all women of child bearing potential 
 
3.3 Patient Eligibility Criteria Prior to Begin Maintenance Therapy: 
 
Between  Day +90  and  Day +150  after  allogeneic  HCT,  patients  will    receive  
daratumumab  maintenance.  If patients do not meet the eligibility criteria for initiating 
maintenance, they will continue to be followed per the protocol. Starting daratumumab 
between day 120-150 post transplant is in line with BMT/CTN 1302, which started 
maintenance Ixazomib between day 60-120 post allogeneic stem cell transplant in 
patients with relapsed multiple Myeloma (clinical trials.gov identifier:NCT02440464). We 

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chose this time frame as this is the time when patients are being weaned off immune 
suppression with graft-versus-myeloma effect. 
 
Patient Eligibility Criteria Prior to Initiating Maintenance Therapy: 
• 
Platelet count ≥ 75,000/mm3 
• 
Absolute neutrophil count (ANC) ≥ 1000/mm3 
• 
Total bilirubin < 2x the upper limit of the normal range (ULN), except in patients 
with Gilbert’s syndrome 
• 
ALT/AST < 2.5x the upper normal limit 
• 
No ≥ grade 2 visceral (gut or liver) acute GVHD. No ≥ Grade 3 any other acute 
GVHD 
• 
All non-hematologic toxicities should have resolved to ≤ grade 1 
• 
Negative for Hepatitis B virus by PCR 
• 
Patients must be in at least a partial response 
 
3.4 Stem Cell Donor and Source 
• 
Matched related 
• 
Matched unrelated  
• 
1 antigen mismatch related or unrelated 
• 
Haploidentical 
• 
Peripheral stem cell source will be used except in Haploidentical where Bone 
marrow stem cells will be required 
 
3.5 Donor Exclusion Criteria 
• 
Donors will be excluded if they are an identical twin of the recipient 
• 
Females who are pregnant (positive serum β HCG) or uninterruptible 
breastfeeding will be excluded 
• 
HIV seropositive donors will be excluded 
• 
Donors receiving experimental therapy or investigational agents will be excluded 
unless approved by the protocol chair and officer 
• 
Donors not willing and able to donate PBSC will be excluded 
• 
Related and unrelated donors will be identified according to institutional guidelines 
 
3.6. Diseases to be Included 
• 
Relapsed Multiple Myeloma patients with a partial response (PR) or better 
prior to allo-transplantation 
 
3.7. Inclusion of Women and Minorities 
• 
Both men and women of all races and ethnic groups are eligible for this trial 
 
4. TREATMENT PLAN 
 

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4.1. Administration Schedule to Patients 
 
• 
Patients meeting the eligibility criteria for transplant/enrollment will be treated 
with conditioning regimen of fludarabine and melphalan.  
• 
Patients will receive fludarabine 30 mg/m2 (when creatinine clearance 40 –60 
mL/min, reduce to 24 mg/m2) from Day -5 to Day -2 and melphalan 70 mg/m2 
on Day -3 and Day -2 intravenously( Melphalan 50 mg/m2 for patients 71 
years and older) 
• 
On Day 0, patients will receive the donor stem cells.  
• 
GVHD Prophylaxis will consist of: Cyclophosphamide 50 mg/kg will be given 
on days +3, and +4.  
• 
Tacrolimus will start on day +5 at 0.05 mg/kg orally twice daily to achieve a 
target serum level of    5-10 mg/ml.  Tacrolimus may be changed to i.v as 
necessary. Serum levels of tacrolimus will be measured per institution 
guideline. Tapering of tacrolimus will start after day 90 post HSCT with goal of 
having the patient receive no immune-suppressive medication by 6 months in 
absence of GVHD.  Mycophenolate Mofetil (MMF) will be given at a dose of 
15 mg/kg three times a day (based on actual body weight) with a maximum 
total daily dose not to exceed 3 grams ( 1 gram TID, IV or oral), starting Day 
+5 to day 35 post-transplant.  
• 
Patients will start maintenance Daratumumab between 90-150 days post allo-
HSCT as long as counts are acceptable (absolute neutrophil ≥1000/µL; 
Platelets ≥ 75,000/µL) and in the absence of disease progression.  
• 
Patients will receive daratumumab maintenance (given at 16 mg/kg weekly 
for 8 doses, followed by every 2 weeks for 8 doses, then monthly) 
Maintenance will continue for 1 year in absence of unacceptable toxicity, 
disease progression or death 
 
Table 1: Fludarabine/Melphalan Conditioning 
 
 
 
 
Day -5
Day -4 
Day -3 Day-
2 
Day-
1 
Day 0 Day 
+3 
Day 
+4 
Fludarabine 30 
mg/m2, i.v 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Melphalan 70 
mg/m2 i.v 
 
 
 
X 
 
X 
 
 
 
 
Peripheral blood 
stem cell infusion 
 
 
 
 
 
 
X 
 
 
Cyclophosphamide 
50 mg/kg 
 
 
 
 
 
 
 
X 
 
X 

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4.2. Stem Cell Administration 
 
Stem cells will be administered on Day 0 to all patients according to institutional 
guidelines after appropriate processing and quantification has been performed by the 
institutional laboratory. Stem cells are administered through an indwelling central 
venous catheter.  
 
4.3. Supportive Care 
 
All supportive care will be given in keeping with BMT CTN Manual of Procedures 
(http://www.cibmtr.org/DataManagement/TrainingReference/Manuals/Pages/index.aspx 
, 
https://web.emmes.com/study/bmt2/public/MOP/BMT%20CTN%20Technical%20MOP
%20ver%202.0.pdf ), and institutional practice. 
 
4.3.1. Growth Factors 
 
Growth factors will only be used on a case-by-case basis as determined by the treating 
physician (example, if absolute neutrophil cell count (ANC) recovery to 0.5 x 109/L 
(500/µL) has not occurred by Day +14, severe infection).  
 
4.3.2. Prophylaxis Against Infection 
 
• 
Antibiotic, antifungal and antiviral prophylaxis will be given according to 
institutional guidelines. 
• 
Pneumocystis carinii prophylaxis will start on Day 30 post-transplant and 
continued according to institutional guidelines. 
• 
CMV and EBV: Monitoring and treatment strategy will be done according to 
institutional guidelines. 
 
4.4. Participant Risks 
 
4.4.1. Fludarabine 
 
Fludarabine (Flu) can lower the white blood cell count, in particular the CD4+ T-cells. 
The immunosuppression observed with the use of Flu increases the risk of infection, 
which can be life threatening. Hematopoietic suppression and immunosuppression are 
expected to occur as a direct effect of the antimetabolite. The most serious toxicity of 
Flu is neurological, and may consist of both peripheral neuropathy and encephalopathy. 
Toxicity can be manifested by fatigue, weakness, paresthesias, visual disturbances, 
somnolence and coma, that usually develop between 30 and 60 days from therapy. The 
incidence of serious neurological toxicity has been 36% in patients treated with > 96 
mg/m2 per day for 5-7 days,131 a dose > 3 times higher than used in this protocol. 

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Other adverse effects include fever, nausea, vomiting, diarrhea, stomatitis, skin rash, 
cough and idiopathic pneumonitis. 
 
4.4.2. Melphalan 
 
High dose melphalan is well tolerated by patients when they are supported with blood 
component transfusions, PBSC/marrow transplantation and broad-spectrum antibiotics. 
The duration of profound bone marrow suppression decreases with the use of PBSC 
infusion and colony stimulating factors. Gastrointestinal toxicity, which includes severe 
stomatitis, esophagitis and diarrhea, can be severe or life-threatening. Most patients 
receiving high dose melphalan will require parental narcotics for mucositis-related pain, 
IV hydration; may require IV alimentation and broad spectrum IV antibiotics. Despite 
moderate to severe symptoms in many patients, recovery is the norm, coincident with 
recovery of granulocytes. Other toxicities reported include pulmonary fibrosis and 
interstitial pneumonitis, skin hypersensitivity, vasculitis, alopecia, hemolytic anemia, and 
allergic reactions. 
 
4.4.3. Mycophenolate mofetil (MMF) 
 
MMF side effects include: Neurologic: headache, tremor, insomnia, dizziness, excessive 
fatigue, weakness, Cardiovascular: tachycardia. Pulmonary: dyspnea. Gastrointestinal: 
nausea, vomiting, dyspepsia, abdominal pain, diarrhea, hematemesis and 
hematochezia. Hematologic: Neutropenia, thrombocytopenia, unusual bruising, and 
anemia. Endocrine and metabolic: hyperlipidemia. Miscellaneous: rash, edema, change 
in vision, infection, second cancers, teratogenicity, miscarriage, limited effectiveness of 
birth control, and progressive multifocal leukoencephalopathy (PML) 
 
4.4.4. Cyclophosphamide 
 
Cyclophosphamide side effects include: Gastrointestinal: nausea, vomiting, anorexia, 
mucositis, stomatitis, abdominal pain, diarrhea. Cardiovascular: cardiomyopathy, fluid 
weight gain/edema. Hematologic: myelosuppression, hemolytic anemia. Miscellaneous: 
skin rash, alopecia, hemorrhagic cystitis, pulmonary toxicity, temporary lethargy, 
secondary cancers, gonadal function impairment, sterility, and damage to fetus if taking 
drug while pregnant. 
 
4.4.5. Tacrolimus 
 
Tacrolimus side effects include: Cardiovascular: hypertension. Neurologic: confusion, 
dizziness, insomnia, seizures, tremors, changes in how clearly one can think. 
Gastrointestinal: nausea, vomiting. Hematologic: microangiopathic hemolytic anemia, 
thrombocytopenia. Endocrine and metabolic: hypomagnesemia, hypokalemia, 
hypocalcemia, erlipidemia. Miscellaneous: unwanted hair growth, changes in vision, 

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liver problems, reversible renal insufficiency, infections and post-transplant 
lymphoproliferative disorders 
 
4.4.6. Daratumumab Administration 
 
Daratumumab will be dosed at 16mg/kg following guidelines provided in package insert.   
Dose is calculated based on actual body weight. 
 
 
Very common side effects with daratumumab (affects more than 1 in 10 patients). 
• 
Infusion related reaction (see separate section) 
• 
Infection of the upper respiratory tract infection  such as nose, sinuses throat or 
airway  
• 
Infection of the lung 
• 
Low neutrophils  
• 
Low platelets  
• 
Low red blood cells  
• 
Low lymphocytes  
• 
Numbness/tingling of the hands, feet or limbs  
• 
Headache 
• 
Cough 
• 
Shortness of breath  
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
• 
Muscle spasms 
• 
Fatigue 
• 
Fever 
• 
Swelling of hands, feet or limbs 
 
Common side effects with daratumumab (affects 1 to 10 in 100 patients). 
• 
The flu 
• 
Sepsis  
• 
Irregular heartbeat 
 
Uncommon side effects with daratumumab (affects 1 to 10 in 1,000 patients). 
• 
Shingles (Herpes zoster) 
• 
High blood pressure 
• 
Low oxygen  
• 
Swelling of the throat  
• 
Inflammation of lung tissue (pneumonitis) 
• 
Difficulty with blood testing prior to blood transfusion (Indirect Antiglobulin Testing 
positive) 
 
 

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Infusion-Related Reactions 
 
Infusion–related reactions were reported in approximately half of all patients treated with 
daratumumab and most were grade 1 or 2. It usually occurs with the first infusion and 
during or within the first few hours of the start of the infusion. 
Signs and symptoms of infusion-related reactions may include respiratory symptoms, 
such as stuffy nose, cough, throat irritation, as well as chills, vomiting and nausea. Less 
common symptoms are having trouble breathing (wheezing), runny nose, fever, chest 
discomfort, itching of the skin, and low blood pressure or high blood pressure. Most of the 
observed infusion-related reactions so far were mild or moderate, and ended by 
temporarily stopping the infusion and giving medicines to treat the side effect.  
Severe reactions include narrowing and obstruction of the respiratory airway 
(bronchospasm), low oxygen, shortness of breath, high blood pressure, swelling in the 
throat and fluid accumulation in the lungs (pulmonary edema).  
Pre-Infusion Medications: 
First infusion: Acetaminophen 325 mg orally, diphenhydramine 25 mg orally or IV, 
dexamethasone 20 mg orally or IV, montelukast 10 mg orally, and famotidine 20 mg orally 
or IV. 
Subsequent infusions: Acetaminophen 325 mg orally, diphenhydramine 25 mg orally or 
IV, and dexamethasone 20 mg orally or IV. 
Post-Infusion medication: dexamethasone 20 mg orally on day after Daratumumab 
infusion 
 
Management of infusion reactions: we will interrupt infusion for any reaction and manage 
as appropriate per USPI information and institutional guideline. We will reduce the 
infusion rate for grade 1, 2, or 3 reaction. We will permanently discontinue therapy for an 
anaphylactic reaction or life-threatening grade 4 infusion reaction and treat with 
appropriate emergency care per instirutional guideline (eg, glucocorticoids, epinephrine, 
bronchodilators, and/or oxygen as appropriate). 
Please refer to the respective USPI for each drug for management of study-drug related 
toxicities. 
5. Management of Toxicities 
 
Toxicities will be scored as per the NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0  

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Toxicities of the blood/bone marrow, gut, liver, and skin will be excluded from the 
common toxicity criteria and evaluated separately since they are likely to be affected by 
GVHD.  
 
 
5.1. GVHD 
 
Acute GVHD is graded according to the Bone Marrow Transplant Clinical Trials Network 
Methods of Procedure (BMT CTN MOP) (see Appendix D). The first day of acute GVHD 
onset at a certain grade will be used to calculate cumulative incidence curves for that 
GVHD grade (e.g. if the onset of grade I acute GVHD is on day 20 post-transplant and 
the onset of Grade II is on Day 60 post-transplant, then time to grade II is day 60). The 
endpoint of acute GVHD will be evaluated through day 180 post-transplant.  
 
Whenever possible, the diagnosis of GVHD should be confirmed with a biopsy of the 
involved organ and histological examination of a biopsy specimen by a pathologist 
experienced in the diagnosis of GVHD. Diagnosis of isolated hepatic GVHD must be 
made by liver biopsy. 
 
Specific therapy of GVHD will not be mandated by protocol, although it is recommended 
that only Grade II-IV GVHD be treated with systemic therapy. A recommendation for 
initial therapy of GVHD is methylprednisolone, 2 mg/kg/d IV (or an equivalent 
corticosteroid). If the patient responds to steroids, the steroid will be tapered as per 
institutional standards.  
 
5.2. Veno Occlusive Disease (VOD) 
 
Treatment of veno-occlusive disease of the liver will be treated per institutional 
standards.  
 
 
5.3. Idiopathic Pneumonia Syndrome/Diffuse Alveolar Hemorrhage 
 
Treatment of idiopathic pneumonia syndrome/diffuse alveolar hemorrhage will be 
treated per institutional standards.  
 
5.4. Thrombotic Microangiopathy 
 
Thrombotic microangiopathy will be defined according to BMT CTN guidelines. The 
diagnostic criteria include complement biomarker analysis and the concurrent 
occurrence of: Red cell fragmentation on a manual differential (2 + schistocytes) with a 
negative Coombs test, and LDH > normal and either renal dysfunction (doubling of 
serum creatinine or a decrease > 50% in the measured creatinine clearance) or 

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Neurological dysfunction unexplained by another etiology. Thrombotic microangiopathy 
should be managed as per institutional guidelines  
 
5.5. Engraftment Failure 
 
Engraftment will be considered to be three consecutive measurements ANC > 0.5 x 
109/L (500/µL) over three or more days. If the ANC ≤ 0.1 x 109/L on Day 28, evaluation 
for graft failure will be initiated, including bone marrow aspiration/biopsy, cytogenetics 
and/or fluorescence in situ hybridization (FISH) if appropriate. Plans for a second stem 
cell infusion will be made depending on the results of the work-up.  
 
5.6. Patient Withdrawal 
 
A patient should be removed from the treatment whenever it is necessary to safeguard 
his/her welfare. Occurrence of a significant adverse event or laboratory abnormalities 
unexpected for these patients may also necessitate discontinuation from the treatment.   
Additional reasons for removing a patient from the study are: 
 
• 
Patients who participate in another investigational drug trial 
• 
Patients’ non-compliance with the protocol 
• 
Patients who express a desire to withdraw from the study (the patient has the 
right to withdraw for any reason without prejudice) 
• 
Evidence of progressive disease would require withdrawal of the patient from the 
treatment. 
• 
Any other reasons deemed by the principal investigator and treating physician. 
 
The reason for any patient withdrawal from treatment should be recorded on the CRF 
and the occurrence should be reported to the principal investigator by email. When a 
patient is removed from treatment, he/she will receive treatment according to the 
standard of care (SOC) in the medical center and will be followed-up according to the 
study schedule whenever possible.  
 
A patient who is removed from treatment by the investigator due to an AE or SAE will be 
followed until resolution of the toxicity to Grade 1 or baseline.  All the tests that are 
required to assess the patient condition will be made as frequent as necessary until the 
AE or SAE has been resolved. Samples that have already been obtained will be 
processed. 
 
A patient who withdraws consent before starting the study will not be followed up.  
 
A patient who is removed from treatment by the investigator since he/she did not keep 
the appointments will be hard to follow given the circumstances. The extreme situation 
of this occurrence is a patient who is defined as “lost to follow-up”. Attempts to follow up 
on the subject will be made as long as the consent has not been withdrawn by the 
subject. Samples that have already been obtained will be processed. 

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6. Study Drug Supply 
 
Tacrolimus, Cyclophosphamide, Mycophenolate Mofetil and Daratumumab are 
commercially available agents and will be administered as described in section 4. 
7. Statistical Consideration  
 
This study is a pilot study focusing on developing a platform for allo-HSCT in relapsed 
multiple myeloma patients. Total of 20 patients will be expected to be enrolled across 2 
years and these patients will be followed up for 2 years. Clinical outcomes such as 
GVHD, relapse and survival data will be collected and analyzed as detailed below. 
These outcome data analysis will be purely viewed as preliminary and hypothesis 
generating and will be used to guide the design of future larger studies. 
 
The safety and tolerability of this combined treatment regimen in allo-HSCT, adverse 
events by grade will be summarized. The occurrence of grade 3+ adverse events 
according to CTCAE will be summarized as well. Adverse events will initially be 
reviewed regardless of attribution, but also according to whether adverse events are 
possibly, probably, or definitely related to treatment.  
 
 
Secondary endpoint analysis plan:  
 
The 2-year progression-free survival (PFS), will be measured from the date of transplant 
until the date of relapse or date of death from any cause. Patients who do not relapse or 
die will be censored at the date of last clinical assessment. Kaplan-Meier curves will be 
generated to estimate the PFS rates at 2 years post-transplant. To evaluate the 
potential association between patient characteristics and PFS, the log-rank test will be 
used to compare the PFS curves and Cox proportional hazard regression model will be 
used to estimate the hazard ratio. The overall survival (OS) will be defined as the time 
from the date of transplant to death or last contact date if no death. GVHD-free 
Relapse-free Survival (GRFS), measured from the date of transplant until the date of 
grade II-IV acute GVHD, chronic GVHD, disease relapse or progression, or death from 
any cause, whichever occurs first. Patients who do not experience an event will be 
censored at the date of last clinical assessment. A similar analysis approach described 
above for PFS will be applied for the GRFS analysis. 
 
To examine the cumulative incidence of grade II-IV acute GvHD (aGVHD), the event will 
be onset of grade II-IV aGvHD and time to aGvHD will be defined as the period of time 
from transplantation to the event of aGvHD. Death and early relapse without aGvHD will 
be competing risks. Cumulative incidence rate of aGVHD with 95% confidence intervals 
will be estimated from the cumulative incidence curves. To evaluate the association 
between patient characteristics and aGVHD, the Gray’s test accounting for competing 
risks will be used to compare the cumulative incidence curves and a proportional 
hazards model for the sub distribution of competing risks will be used to estimate the 

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hazard ratio. The cumulative incidence of chronic GVHD (cGVHD) will be similarly 
analyzed. To determine the rate of relapse, the event time will be from the date of 
transplant to relapse treating death from any cause as a competing risk. Patients 
without relapse or death will be censored at last clinical assessment date. The similar 
analysis approach used for outcome of aGVHD will be applied. 
 
To determine the 100-day, 1-year and 2-year cumulative incidence of treatment-related 
mortality (TRM), the event will be death due to reasons other than disease and the time 
will be measured from the date of transplant to date of death. The competing risk for 
NRM will be death due to disease. The cumulative incidence curve accounting 
competing risks will be generated to estimate the cumulative incidence rate at various 
time points.  
 
The assess the overall and best response rate at various time points, the proportion of 
each type of response with a 95% CI will be reported for all evaluable patients, 
assuming a binomial distribution. MRD status will be performed on patients with VGPR 
or better pre-transplant, day +100  and day+365 post-transplant. The rate of minimal 
residual disease-negativity is defined as the proportion of patients who achieved 
minimal residual disease-negative status at the respective time point, in accordance 
with the International Myeloma Working Group criteria.(36) Minimal residual disease 
was evaluated by next-generation sequencing using ClonoSEQ Assay 2.0.(37) 
8. Stopping Rule:    
 
Monitoring of the key safety endpoint of death will be conducted. The rate of overall 
mortality will be monitored up to Day 100 post-transplant. The null hypothesis that the  
Day 100 mortality rate is less than or equal to 10%. The stopping rule will be triggered if 
there is significant evidence that the overall death rate exceeds 10%, that is, if the lower 
bound of the one-sided 95% CI exceeds 10%. The rationale of a lower confidence 
bound is to be certain that the estimated true rate is not significantly higher than the 
rates deemed clinically acceptable. If the number of death equals or exceeds the 
numbers in the table below, then the study will be suspended to accrual pending further 
consultation with the DSMB. We will first enroll 3 patients and assess toxicity through 
day 100, before continuing enrollment. 
 
One year non-relapse mortality after allo-HSCT is 16-20%. Given that patients will be on  
daratumumab maintenance, while not expected, monitoring for excessive mortality is 
necessary. At one year post allo-HSCT, patients would have transitioned to the monthly 
daratumumab. The stopping rule will be triggered if the one-year non-relapse mortality 
exceeds 20%. 
 
The rate of chronic GVHD(cGVHD) occurs in 50-60% of patients undergoing allo-HSCT, 
with 30-35% being extensive cGVHD. The stopping rule will be triggered if the rate of 
extensive cGVHD exceeds 35%. 
 

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Table 3: Incidence of death  
Number of 
patients enrolled 
Number of death 
3 
2 
4-8 
3 
9-14 
4 
15-20 
5 
 
9. Accrual and Accrual Period 
 
Relapsed MM patients who are candidates for allo-HSCT will be assessed for accrual. A 
total of 20 patients will be accrued.  The estimated accrual period is 2 years.  
10.  Follow-Up Period 
 
Patients will be followed for 1 year after end of Daratumumab treatment  
Follow-Up and Schedule of Events 
 
10.1. 
Follow-up Schedule for Patients (Recipients) 
 
 
Study Visit 
Target Day Post-Transplant 
1 week 
7 ± 3 days 
2 week 
14 ± 3 days 
3 week 
21 ± 7 days 
4 week 
28 ± 7 days 
5 week 
35 ± 7 days 
6 week 
42 ± 7 days 
7 week 
49 ± 7 days 
8 week 
56 ± 7 days 
9 week 
63 ± 7 days 
10 week 
70 ± 7 days 
11 week 
77 ± 7 days 
12 week 
84 ± 7 days 
100 day 
100 ± 9 days 
6 month
180 ± 28 days 
12 month
365 ± 28 days 
18 month 
24 month
547 ± 28 days 
730 ± 28 days
 

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10.2. 
Evaluation During Treatment  
 
Clinical examination, ECOG/WHO PS, vital signs, toxicity assessment and 
documentation of concomitant medications will be performed at each outpatient visit. 
Toxicity will be assessed according to the NCI CTCAE.  
 
10.3. 
Post-Treatment Follow-up  
 
After the end of study treatment (whatever the reason for discontinuation), the patient 
will be followed for up to one year to evaluate the incidence of acute and chronic GVHD, 
relapse, PFS and OS. 
 
All patients who discontinue the trial secondary to an adverse event thought to be 
related to protocol therapy (probably, possible, or definite) should be followed until 
resolution, stabilization, return to a baseline condition, or death.   
 
Overall and progression free survival will be determined through clinic visits or phone 
interviews with clinical research staff. 
 
10.4. 
Sample Collection for Immunologic Correlative Studies 
 
All patients enrolled on this trial will have samples procured for all proposed laboratory 
correlative studies as summarized in Section 13.  Samples will be collected and sent to 
the appropriate research lab(s) for processing. Upon receipt, each sample will be 
recorded and coded with a unique sample number to keep patient identification 
confidential. PBMCs and plasma (and/or serum) will be aliquoted and cryopreserved. 
The vials of viably frozen cells for all time points for each patient will be thawed at the 
same time whenever possible to avoid inter-experimental variability.  
 
10.5. 
Patient Study Calendar  
 
 
 
 
 

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Schedule of Study 
Assessments 
 
Baseline 1 
 
Day 
+0 
Day 
+7 
Day 
+14 
Day 
+21 
Day 
+28 
Day 
+35 
Day 
+42 
Day 
+49 
Day 
+56 
Day 
+63 
Day 
+70 
Day 
+100 
Day 
+180 
Day 
+365 
Day 
+547 
Day 
+730 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History-
anti-cancer 
therapies
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
X
X
X
 
 
Vital Signs2
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky 
performance status
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
HCT-Specific 
Comorbidity Index 
score
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete blood 
count3
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
Serum chemistry, 
and liver function 
test4
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious disease 
panel5
X 
 
 
 
 
 
 
 
 
 
 
 
EKG and LVEF6
X 
 
 
 
 
 
 
 
 
 
 
 
Quantitative 
Immunoglobulins7
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
CD34/CD3 cell dose 
infused
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immune 
reconstitution panel 
& Other Correlative 
studies8
x 
x 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
 
 
ANC and Platelet 
recovery9
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse event 
(CTCAE) 
assessment10
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Acute GVHD 
assessment
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow 
biopsy & aspirate 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 

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(response 
assessment)`11

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1Baseline refers to the period prior to conditioning. Assessments should be made within 4 weeks prior to start of transplantation.  
2 Vital signs: blood pressure, pulse rate, respiratory rate and temperature, weight 
3 Daily during the post-infusion period while hospitalized (recommended) and once weekly after discharge until Day 28.  
4 Serum chemistries panel: electrolytes, BUN, ALT, AST, creatinine, bilirubin, alkaline phosphatase, LDH, albumin. Electrolytes to include sodium, potassium, chloride, carbon 
dioxide, and calcium.  
5 Infectious disease panel: Cytomegalovirus (CMV) antibody, Hepatitis B sAg, Hepatitis C Ab, HIV /HCV NAT, HIV Ab, HTLV Ab, Epstein-Barr Virus (EBV) IgG and IgM, herpes 
simplex virus (HSV) IgG and IgM  
6 LVEF: left ventricular ejection fraction to be determined by MUGA or echocardiogram 
7 IgG, IgM and IgA.  
8 Peripheral blood for immune reconstitution panel drawn in one-10ml EDTA or ACD-solution-A tube and sent to Dr. Lozanski in the OSU-Medical Center Clinical flow Cytometry 
Laboratory. Day 0 will be apheresis product 
9 Record time to neutrophil engraftment defined as first of three consecutive days with ANC ≥ 0.5 x 109/L, and platelet engraftment defined as first day of platelet count ≥ 20,000 x 
109/L, without transfusion for 7 consecutive days. 
10 Adverse event assessment will include a review of all toxicities experienced during the entire assessment period and the highest grade for each toxicity during the assessment 
period will be recorded on the Toxicity form in AdvantageEDC. 
11Bone marrow aspirate and biopsy required at baseline. On Days +100, +365, and +730. Other  bone marrow biopsy will be performed if clinically indicated. Other tests and/or 
imaging studies for response assessment will be performed as clinically indicated. 

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11. Analysis Definitions and Endpoints 
 
11.1. 
Safety Endpoints 
 
We will describe the safety profile of treatment by the recording of adverse events 
experienced by patients in the trial and by the monitoring of clinical laboratory values.  
Adverse events and toxicities in both donors and patients will be described using the 
NCI CTCAE V 5.0 criteria.  Frequency and severity of adverse events according to body 
system and severity criteria will be described.  In addition, frequency of grade 3 or 4 
adverse events will be described separately.  Causality will also be noted.   
 
Laboratory assessments will also be described according to the NCI CTCAE V5.0 
criteria, with separate descriptions for grade 3 or 4 laboratory abnormalities.  Clinically 
significant laboratory abnormalities will be described as well. 
 
 
11.2. 
Efficacy Analysis Endpoints 
 
Neutrophil and platelet engraftment:  Neutrophil engraftment will be defined as first of 
three consecutive days with ANC  0.5 x 109/L post-conditioning regimen induced nadir. 
Similarly platelet engraftment is defined as first day of platelet count  20,000 x 109/L, 
without transfusion for 7 consecutive days. 
 
Graft versus host disease (GVHD):  GVHD occurring anytime after day 100 post 
transplant will be termed chronic GVHD, otherwise it will be termed acute GVHD.  
Standard criteria will be used for the diagnosis and grading of acute and chronic GVHD 
(38, 39) (Appendix D).  The first day of acute GVHD onset at a certain grade will be 
used to calculate cumulative incidence curves for that GVHD grade (e.g. if the onset of 
grade I acute GVHD is on day 20 post-transplant and the onset of Grade II is on Day 60 
post transplant, then time to grade II is day 60). The endpoint of acute GVHD will be 
evaluated through day 100 post transplant.  
 
Whenever possible, the diagnosis of GVHD should be confirmed with a biopsy of the 
involved organ and histological examination of a biopsy specimen by a pathologist 
experienced in the diagnosis of GVHD. Diagnosis of isolated hepatic GVHD must be 
made by liver biopsy. 
 
Patients will be monitored for development of acute GVHD weekly until day +100.  For 
diagnosis of GVHD, biopsy is recommended, but not required.  
 
Non relapse mortality (NRM):  NRM will be defined as death from any cause other 
than relapse.  
 

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Progression free survival (PFS):  PFS will be measured from the day of allogeneic 
stem cell infusion to the day of documented relapse or progression.   
 
Overall survival (OS):   OS will be measured from the day of allogeneic stem cell 
infusion (day 0) to death from any cause, with censoring performed at date of last 
contact.   
 
 
11.3. 
Relapse of Malignancy 
 
11.3.1. Myeloma 
 
For Myeloma, relapse will be diagnosed when: 
 Development of  new soft tissue plasmacytomas or bone lesions, or 
 Definite increase in the size of existing plasmacytomas pr bone lesions. A 
definite increase is defined as a 50% (and at least 1 cm) increase as measured 
serially by the sum of the products of the cross-diameters of the measured 
lesion, or 
 Hypercalcemia (>11.5 mg/dl [2.65 mmol/l]), or 
 Decrease in  hemoglobin of .2g/dl (1.25 mmol/l) without any other known causes, 
or 
 Rise in serum creatinine by 2mg/dl or more (177µmol/l or more) without any other 
known causes, or 
 Reappearance of serum or urine M-protein by immunofixation or electropheresis 
or development of ≥ 5% plasma cells in the bone marrow in a patient with 
previous complete response. 
(See Appendix C) 
 
 
11.3.2. Registration Guidelines 
 
Eligible patients and their donors will be entered on study at the Ohio State University. 
The Study Coordinator should be called between the hours of 8:00 AM and 4:30 PM to 
verify eligibility.   
 
11.3.3. Assignment of Study Numbers 
 
Each patient and their donor enrolled in the study will be registered in the OSU’s Clinical 
Trials Management Application at study entry. Each patient enrolled will be assigned a 
sequential study identifier by the Clinical Trials Management Application. 
 
11.3.4. Study Records 
 

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Study data will be collected in standardized case report forms (CRF). The investigator 
or designate will record all patient information, including patient identification, disease 
stage, previous treatment, as well as information concerning drug administration, results 
of laboratory tests, toxicity and efficacy data.  
 
A specific form will be used for recording and reporting serious adverse events as 
defined in section 9 
 
11.3.5. Selection Procedures 
 
All eligible patients and their donors must be registered. This must be done before the 
start of treatment.  On receipt of all the necessary baseline information, a clinical 
research coordinator will assess whether the patient is eligible or not.   
 
12. Correlative Studies 
12.1. 
Correlative Studies 
 
Immune Reconstitution. Peripheral blood from patients, to assess recovery of 
quantitative immunoglobulin levels and immune reconstitution following 
transplantation will be collected in one 10 ml EDTA or ACD-solution-A tube on 
day of admission, days 0 (apheresis product),+30, +100, +180 and +365 post-
transplant.  
The peripheral blood samples will be collected and received within 12h following 
collection. A research account number (R ) will be established with the research 
billing and compliance office. Each sample will have proper permanent label with 
study identifier by the Clinical Trials Management and printed proper requisition 
that will have study R#, both on tube and requisition, patient or donor study 
identification, date and time of specimen collection, sample type blood ( 
peripheral blood,  bone marrow, pheresis product) and specific time point the 
sample represents.   Assessment will be done in Dr. Lozanski’a lab in the clinical 
flow cytometry laboratory.  Prior to staining all samples will be analyzed for 
viability using 7AAD method. Only samples with viability of at least 97% will be 
accepted for further analysis. All samples will be stained using PrepPlus2 
automated staining system (Beckman Coulter) using five color whole blood 
staining technique with panels of directly conjugated monoclonal antibodies (see 
table below) used  in predetermined quantities.  Multiparametric analysis will be 
performed with gating strategy based on OCD45 staining and light side scatter 
characteristics that allow good separation of   lymphocyte, monocyte and myeloid 
cell populations. Detailed immunophenotypic characterization of the lymphocyte 
gate will be performed using Prism plot algorithm ( Beckman Coulter). The 
results will be reported as % of lymphocyte gate and as % of total leukocytes 
analyzed. The results will also be reported as an absolute number of specific cell 
types per microliter of blood. Absolute cell number will be calculated based on 

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dual platform method using % of lymphocytes expressing specific 
immunophenotypic profile (derived from prism plot) and absolute number of 
lymphocytes derived  from analysis of  each whole blood sample using  ActDIFF 
hematology analyzer (Beckman Coulter). 
 
13. Definitions of Adverse Events and Causality 
 
13.1. 
Monitoring of Adverse Events 
 
Significant adverse events should be identified and recorded, then seriousness, 
expectedness, and causality will be assessed using the definitions that follow.  The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
 
13.2. 
Definitions of Adverse Events and Causality 
 
An Adverse Event (AE) is any untoward medical occurrence in a patient administered 
a pharmaceutical product and which does not necessarily have to have a causal 
relationship with the treatment.  For marketed products in the U.S., a Serious Adverse 
Event (SAE) is any untoward medical occurrence that at any dose:  
 
 Results in death (if the patient’s death is suspected as being a direct outcome of 
the adverse event) 
 Is life-threatening (the patient was at substantial risk of dying at the time of the 
adverse event or it is suspected that the use or continued use of the product 
would result in the patient’s death) 
 Requires inpatient hospitalization or prolongation of existing hospitalization   
 Results in persistent or significant disability/incapacity 
 Results in a congenital anomaly/birth defect (i.e., exposure to a medical product 
prior to conception or during pregnancy resulted in an adverse outcome in a 
child) 
 Requires intervention to prevent permanent impairment or damage 
 Overdosage (regardless of adverse outcome) of any study medication.  An 
overdose is defined as the accidental or intentional ingestion of any dose of a 
product that is considered both excessive and medically important. 
 Pregnancy 
 Is an important medical event, defined as a medical event(s) that may not be 
immediately life threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require medical or surgical intervention to prevent one of the other serious 
outcomes listed in the definition above.  Examples of such events include, but 
are not limited to, intensive treatment in an emergency room or at home for 

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allergic bronchospasm, or blood dyscrasias or convulsions that do not result in 
hospitalization.   
 
The SAE reporting period begins once study drug treatment is initiated to within 30 days 
following cessation of treatment.  AEs should be followed to resolution or stabilization, 
and reported as SAEs if they become serious.  This also applies to patients 
experiencing AEs that cause interruption or discontinuation of investigational product, or 
those experiencing AEs that are present at the end of their participation in the study.  
Such patients should receive post-treatment follow-up as appropriate.  If an ongoing AE 
changes in its severity or in its perceived relationship to study drug, a new AE entry for 
the event should be completed. 
 
Additionally, any serious adverse event considered by an investigator to be possibly, 
probably, or definitely related to the investigational product that is brought to the 
attention of the investigator at any time outside of the time period specified in the 
previous paragraph also must be reported immediately to the IRB  
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should also usually be considered serious. 
 
Note: The term "life-threatening" in the definition of "Serious Adverse Event" refers to an 
event in which the patient was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more severe. 
 
An Unexpected Adverse Event is not listed in the current US Package Insert may be 
mentioned in the package insert, but differs from the event because of greater severity 
or specificity.  
 
Causality is a determination of whether there is a reasonable possibility that the drug 
may have caused or contributed to an adverse event. It includes assessing temporal 
relationships dechallenge/rechallenge information, association (or lack of association) 
with underlying diseases, and the presence (or absence) or a lack of one or more likely 
causes. 
 
The Investigator must attempt to determine if an adverse event is in some way related 
to the use of the study drug.  This relationship should be described as follows: 
 
Unlikely:   
The event is clearly due to causes distinct from the use of the study drug, 
such as a documented pre-existing condition, the effect of a concomitant medication, a 
new condition which, based on the pathophysiology of the condition, and the 
pharmacology of the study drug, would be unlikely related to the use of the study drug. 
 
 

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Unrelated:  The adverse event is clearly not related to the study drug. 
 
Possible:  
The event follows a reasonable temporal sequence from administration of 
the study drug or the event follows a known response pattern to the study drug BUT the 
event could have been produced by an intercurrent medical condition which, based on 
the pathophysiology of the condition, and the pharmacology of the study drug, would be 
unlikely related to the use of the study drug or the event could be the effect of a 
concomitant medication 
 
Probable:  
The event follows a reasonable temporal sequence from administration of 
the study drug and the event follows a known response pattern to the study drug AND 
the event cannot have been reasonably explained by an intercurrent medical condition 
or the event cannot be the effect of a concomitant medication 
 
Definite: 
The event follows a reasonable temporal sequence from administration of 
the study drug, the event follows a known response pattern to the study drug and based 
on the known pharmacology of the study drug, the event is clearly related to the effect 
of the study drug 
 
Unknown:  Based on the evidence available, causality cannot be ascribed 
 
Common Terminology Criteria Adverse Events (CTCAE) – a descriptive terminology 
developed by the National Cancer Institute (NCI) for use in reporting adverse events. 
The CTCAE includes a grading (severity) scale for each adverse event term.  
 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 
Grade 0 
No adverse event or 
within normal limits
1
Mild adverse event
2 
Moderate adverse 
event
3
Severe adverse event
4 
Life-threatening or 
disabling adverse 
event
5
Fatal adverse event
 
13.3. 
Serious Adverse Events 
 
When the principal investigator has determined that a Serious Adverse Event has 
occurred, the principal investigator is responsible for providing all Serious Adverse 
Events to the IRB and within two working days of this determination.  This applies to 
initial and follow-up information. 
 

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Follow-up Reports: 
 
 The Investigator should take all appropriate measures to ensure the safety of the 
patients, notably he/she should follow up the outcome of any Serious Adverse 
Event and complete follow-up forms as necessary.  The patient must be followed 
up until recovery, stabilization or return to baseline. This may mean that follow-up 
will continue after the patient has completed the trial and that additional 
investigations may be necessary.  
 Any reportable Serious Adverse Events brought to the attention of the 
Investigator at any time after cessation of the trial and considered by him/her to 
be reasonably associated with medication administered during the period should 
also be submitted to the IRB.  As with the initial submission to the IRB, the 
principal investigator is also responsible for providing all follow-ups of Serious 
Adverse Events to the IRB.  
 
13.4. 
Reporting of Adverse Event Information Following Study Completion  
 
Collection of safety information following the end of investigational product 
administration is important in assisting in the identification of possible delayed toxicities 
or withdrawal effects.  All SAEs must be collected which occur within 30 days of 
discontinuation of dosing or completion of the patient’s participation in the study if the 
last scheduled visit occurs at a later time.   
 
13.5. 
Patient Withdrawal  
 
A patient should be withdrawn from the trial treatment if, in the opinion of the 
investigator, it is medically necessary, or if it is the wish of the patient.  If a patient does 
not return for a scheduled visit, every effort should be made to contact the patient.  In 
any circumstance, every effort should be made to document patient outcome, if 
possible. 
 
Patients should be withdrawn from therapy if any of the following occurs: 
 
 The occurrence of unacceptable toxicity indicating the need for cessation of 
treatment.  Patients may continue with correlative studies. 
 Patient has progressive disease while receiving treatment   
 The physician feels it is in the best interest of the patient to stop treatment and 
the physician may determine whether to continue with correlative studies. 
 Patient refusal to continue with therapy. 
 Non-compliance by the patient with protocol requirements. 
 Patient is lost to follow-up.  If a patient does not return for scheduled visits, every 
effort should be made to re-establish contact.  In any circumstance, every effort 
should be made to document patient outcome, if possible. 
 Patient becomes pregnant. 

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 Termination of the study. 
 
The reason and date of discontinuation are to be documented in the patient’s medical 
record and in the CRF.  
 
The investigator should complete all end of treatment procedures when a patient 
withdraws from treatment.  All patients who discontinue the trial secondary to an 
adverse event should be followed until resolution, stabilization or return to a baseline 
condition. 
 
  All patients who receive one dose of study treatment should be included in any safety 
analysis. 
 
The investigator may discontinue the trial at any time.  Reasons for early trial 
discontinuation may include, but are not limited to, unacceptable toxicity of study 
treatment, a request to discontinue the trial from a regulatory authority or an IRB, or poor 
enrollment.  
14. References 
 
1. 
Siegel R, Miller K, Jemal A. Cancer Statistics. CA: A Cancer Journal for Clinicians.2018. p. 7-30. 
2. 
Jagannath S, Durie BG, Wolf J, Camacho E, Irwin D, Lutzky J, et al. Bortezomib therapy alone and 
in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J 
Haematol. 2005;129(6):776-83. 
3. 
Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, et al. Combination 
therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 
2005;106(13):4050-3. 
4. 
Harousseau JL, Attal M, Leleu X, Troncy J, Pegourie B, Stoppa AM, et al. Bortezomib plus 
dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with 
newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica. 2006;91(11):1498-
505. 
5. 
Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Phase III clinical trial of thalidomide plus 
dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical 
trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24(3):431-6. 
6. 
Cavallo F, Boccadoro M, Palumbo A. Review of thalidomide in the treatment of newly diagnosed 
multiple myeloma. Ther Clin Risk Manag. 2007;3(4):543-52. 
7. 
Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, et al. Melphalan, 
prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--
Italian Multiple Myeloma Network. J Clin Oncol. 2007;25(28):4459-65. 
8. 
Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. Melphalan and prednisone 
plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell 
transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 
2007;370(9594):1209-18. 

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44 
 
9. 
Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D, et al. Bortezomib 
plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of 
patients with del(17p). J Clin Oncol. 2010;28(30):4630-4. 
10. 
Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in 
multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516-20. 
11. 
McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide 
after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770-81. 
12. 
Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide 
maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782-91. 
13. 
de Lavallade H, El-Cheikh J, Faucher C, Furst S, Stoppa AM, Coso D, et al. Reduced-intensity 
conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma. Bone Marrow 
Transplant. 2008;41(11):953-60. 
14. 
Michallet M, Sobh M, El-Cheikh J, Morisset S, Sirvent A, Reman O, et al. Evolving strategies with 
immunomodulating drugs and tandem autologous/allogeneic hematopoietic stem cell transplantation in 
first line high risk multiple myeloma patients. Exp Hematol. 2013;41(12):1008-15. 
15. 
Kroger N, Schwerdtfeger R, Kiehl M, Sayer HG, Renges H, Zabelina T, et al. Autologous stem cell 
transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple 
myeloma. Blood. 2002;100(3):755-60. 
16. 
Crawley C, Lalancette M, Szydlo R, Gilleece M, Peggs K, Mackinnon S, et al. Outcomes for 
reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors 
from the Chronic Leukaemia Working Party of the EBMT. Blood. 2005;105(11):4532-9. 
17. 
Kroger N, Sayer HG, Schwerdtfeger R, Kiehl M, Nagler A, Renges H, et al. Unrelated stem cell 
transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation 
antithymocyte globulin is highly effective with low transplantation-related mortality. Blood. 
2002;100(12):3919-24. 
18. 
Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, et al. Prospective 
comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) 
with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple 
myeloma. Blood. 2006;107(9):3474-80. 
19. 
Rosinol L, Perez-Simon JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ, et al. A prospective 
PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity 
conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood. 2008;112(9):3591-
3. 
20. 
Bruno B, Rotta M, Patriarca F, Mattei D, Allione B, Carnevale-Schianca F, et al. Nonmyeloablative 
allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di 
Midollo. Blood. 2009;113(14):3375-82. 
21. 
Giaccone L, Storer B, Patriarca F, Rotta M, Sorasio R, Allione B, et al. Long-term follow-up of a 
comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma. Blood. 
2011;117(24):6721-7. 
22. 
Kumar S, Zhang MJ, Li P, Dispenzieri A, Milone GA, Lonial S, et al. Trends in allogeneic stem cell 
transplantation for multiple myeloma: a CIBMTR analysis. Blood. 2011;118(7):1979-88. 
23. 
El-Cheikh J, Crocchiolo R, Boher JM, Furst S, Stoppa AM, Faucher C, et al. Allogeneic transplant 
for myeloma in the era of new drugs: have the outcomes improved? Leuk Lymphoma. 2012;53(8):1630-
2. 
24. 
Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with 
Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015;373(13):1207-19. 

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45 
 
25. 
Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in 
patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. 
Lancet. 2016;387(10027):1551-60. 
26. 
Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, et al. Alternative donor 
transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-
mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 
2011;118(2):282-8. 
27. 
Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical 
bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and 
high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641-50. 
28. 
Luznik L, Fuchs EJ. High-dose, post-transplantation cyclophosphamide to promote graft-host 
tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res. 2010;47(1-3):65-77. 
29. 
Ghosh N, Ye X, Tsai HL, Bolanos-Meade J, Fuchs EJ, Luznik L, et al. Allogeneic Blood or Marrow 
Transplantation with Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis 
in Multiple Myeloma. Biol Blood Marrow Transplant. 2017;23(11):1903-9. 
30. 
Castagna L, Mussetti A, Devillier R, Dominietto A, Marcatti M, Milone G, et al. Haploidentical 
Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Post-Transplantation 
Cyclophosphamide Graft-versus-Host Disease Prophylaxis. Biol Blood Marrow Transplant. 
2017;23(9):1549-54. 
31. 
Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R, et al. Improved early 
outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem 
cell transplantation. Biol Blood Marrow Transplant. 2012;18(12):1835-44. 
32. 
Bolaños-Meade J, Ran R, Fraser R, Fei M, Abhyankar S, Al-Kadhimi Z, et al. Novel Approaches for 
Graft-versus-Host Disease (GvHD) Prophylaxis: 
Primary Results of PROGRESS I Multicenter Trial of Matched Allogeneic Hematopoietic 
Cell Transplantation (alloHCT) Using Reduced Intensity Conditioning (BMT CTN 
1203). BMT Tandem Meetings2018. 
33. 
Kasamon YL, Ambinder RF, Fuchs EJ, Zahurak M, Rosner GL, Bolanos-Meade J, et al. Prospective 
study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation 
cyclophosphamide. Blood Adv. 2017;1(4):288-92. 
34. 
Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform 
response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-73. 
35. 
Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus 
recommendations for the uniform reporting of clinical trials: report of the International Myeloma 
Workshop Consensus Panel 1. Blood. 2011;117(18):4691-5. 
36. 
Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma 
Working Group consensus criteria for response and minimal residual disease assessment in multiple 
myeloma. Lancet Oncol. 2016;17(8):e328-e46. 
37. 
ClonoSEQ cleared for residual cancer testing. Cancer Discov. 2018;8(12):OF6. 
38. 
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus 
Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15(6):825-8. 
39. 
Pavletic SZ, Lee SJ, Socie G, Vogelsang G. Chronic graft-versus-host disease: implications of the 
National Institutes of Health consensus development project on criteria for clinical trials. Bone Marrow 
Transplant. 2006;38(10):645-51. 
 
 

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15. Appendices 
Appendix A: HCT-SPECIFIC COMORBIDITY INDEX SCORE 
 
Total score is the sum of all comorbidities present at time of transplantation. 
 
Comorbidities 
Definition 
Score
Migraine/headache 
 
0
Osteoporosis 
 
0
Osteoarthritis
 
0
Hypertension 
 
0
Gastrointestinal
Including inflammatory bowel disease 
0
Mild pulmonary 
DLCo and/or FEV1 >80% or 
Dyspnea on moderate activity 
0 
Mild renal
Serum creatinine 1.2-2 mg/dl
0
Endocrine 
 
0
Bleeding
 
0
Coagulopathy 
Deep venous thrombosis or pulmonary embolism
0
Asthma
 
0
Arrhythmia 
 
1
Myocardial 
Coronary artery disease, congestive HF, history of 
medically documented MI, EF50% 
1 
Mild hepatic 
Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN, or 
AST/ALT >ULN-2.5XULN 
1 
Cerebro-vascular 
accident 
History of transient ischemic attack or cerebro-vascular 
accident 
1 
Morbid obesity 
 
1
Diabetes 
Requiring treatment 
1
Depression/anxiety 
 
1
Infection
Requiring continuation of treatment after Day 0 
1
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, polymyalgia 
rheumatica 
2 
Moderate pulmonary 
DLCo and/or FEV1 66-80% or 
Dyspnea on slight activity 
2 
Peptic ulcer
Patients who have required treatment 
2
Moderate-severe renal 
Serum creatinine >2 mg/dl, on dialysis, or prior renal 
transplantation 
2 
Valvular heart disease 
Except mitral valve prolapse
3
Prior solid tumor 
Requiring treatment with chemotherapy 
3
Moderate-severe hepatic Liver cirrhosis, Bilirubin >1.5 X ULN, or AST/ALT 
>2.5XULN 
3 
Severe pulmonary 
DLCo and/or FEV1 65% or 
Dyspnea at rest or requiring oxygen 
3 

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Appendix B: KARNOFSKY PERFORMANCE STATUS SCALE 
Index 
Specific Criteria 
General 
100 
Normal, no complaints, no evidence of disease. 
Able to carry on normal activity; no 
special care needed. 
90
Able to carry on normal activity, minor signs or 
symptoms of disease. 
80
Normal activity with effort, some signs or 
symptoms of disease. 
70
Care for self, unable to carry on normal activity
or to do work. 
Unable to work, able to live at 
home and care for most personal 
needs, varying amount of assistance 
needed. 
60
Requires occasional assistance from others but
able to care for most needs. 
50
Requires considerable assistance from others 
and frequent medical care 
40
Disabled, requires special care and assistance.
Unable to care for self, requires 
institutional or hospital care or 
equivalent, disease may be rapidly 
progressing. 
30
Severely disabled, hospitalization indicated, but 
death not imminent. 
20
Very sick, hospitalization necessary, active 
supportive treatment necessary. 
10
Moribund
0
Dead

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Appendix C: International Myeloma Working Group Response Criteria 
 
 
 

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Appendix D:  Acute GVHD Grading 
 
 
Stage
Skin
GI
Liver
1 
<25% rash 
Diarrhea > 500 
mL/d or persistent 
nausea
Bilirubin 2-3 mg/dL 
2
25-50% rash
> 1000 mL/day
Bilirubin 3-6 mg/dL
3 
> 50% rash 
> 1500 mL/day 
Bilirubin 6-15 
mg/dL
4 
Generalized 
erythroderma with 
bullae 
Large volume 
diarrhea and 
severe abdominal 
pain ± ileus
Bilirubin > 15 
mg/dL 
 
 
 
 
Consensus GVHD Grading (Przepiorka, et al., 1995) 
Grade
Skin
GI
Liver
I
Stage 1-2
0
0
II
Stage 3 or
Stage 1 or
Stage 1
III
---
Stage 2-4
Stage 2-3
IV
Stage 4
---
Stage 4
 
 
 

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Appendix E.  Ethical and regulatory 
Ethical Principles 
The study should be conducted according to the principles outlined by the 18th World 
Medical Assembly (Helsinki, 1964) and all applicable amendments; the International 
Conference on Harmonization Guidelines for Good Clinical Practice; and FDA 
regulations regarding the conduct of clinical trials and the protection of human subjects.  
 
Protocol Compliance and Protocol Revisions 
The study must be conducted as described in this approved protocol.  The investigator 
should not implement any deviation or change to the protocol without prior review and 
documented approval/favorable opinion from the IRB of an Amendment, except where 
necessary to eliminate an immediate hazard(s) to study patients.  Documentation of 
approval signed by the chairperson or designee of the IRB(s) must be sent to 
CureTech.  If the revision is an administrative letter, the investigator(s) must inform the 
IRB. 
 
Informed consent 
It is the responsibility of the investigator to obtain written informed consent from a 
patient or a patient’s legal representative before any study related procedures are 
performed.  The Investigator will provide an informed consent in compliance with ICH 
GCP and U.S. FDA guidelines (21 CFR 50).  The informed consent document must 
clearly describe the potential risks and benefits of the trial, and each prospective 
participant must be given adequate time to discuss the trial with the Investigator or site 
staff and to decide whether or not to participate.  The informed consent must be 
approved by the IRB prior to being presented to a potential patient.    
 
One copy of the patient's signed, dated and witnessed written consent will be kept in the 
patient’s medical record and one copy will be given to the patient or the patient’s legal 
representative. 
 
Institutional Review Board (IRB) Approval 
The Investigator must obtain the approval of the protocol, the informed consent 
document and any other material used to inform the patient about the nature of the trial 
from the local IRB in the form of a written letter.  On the approval letter, which must be 
signed by the chairperson of the IRB or the chairperson’s designee, the following items 
should be clearly stated:  trial title, protocol number and version, study-related 
documents (protocol, informed consent material, advertisement when applicable), IRB 
review date, and IRB decision.  The trial should not start until a copy of this written 
approval has been received by the Investigator. If the investigator is a member of the 
IRB, the Investigator may participate in any discussion of the study, but may not 
participate in the final vote deciding whether to approve the study.  

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Annually, or more often if stipulated by the IRB, and at the completion or termination of 
the study, the Investigator will report the progress of the trial to the IRB and CureTech, 
Inc. (see contact information in section “Serious Adverse Events”) 
Additional Responsibilities of the Investigator 
The investigator(s) agrees to perform the study in accordance with ICH Good Clinical 
Practice and FDA regulations.  The Investigator is required to ensure compliance with 
respect to the investigational drug schedule, visit schedule and procedures required by 
the protocol.  
 
The investigator should be able to recruit the required number of suitable patients and 
should have sufficient time to properly conduct and complete the trial.  The Investigator 
should have available an adequate number of qualified staff and adequate facilities for 
the duration of the trial, and should ensure that all persons assisting with the trial are 
adequately informed about the protocol, the protocol-defined procedures, protocol 
therapy and trial related duties and functions.. 
 
The Investigator should be responsible for all trial-related medical decisions.  During 
and following a patient’s participation in a trial, the investigator should ensure that 
adequate medical care is provided to a patient for any adverse events related to the 
trial.   
 
Use and Completion of Case Report Forms (CRFs) 
It is the responsibility of the Investigator to monitor the preparation and accurate use of 
CRFs to record all observations and other data pertinent to the clinical investigation.  All 
CRFs should be completed in their entirety to ensure accurate interpretation of data.   
Should a correction be made, the information to be modified must not be overwritten. 
The corrected information will be transcribed next to the previous value, initialed and 
dated by the authorized person. 
 
Confidentiality 
It is the responsibility of the investigator to ensure that the confidentiality of all patients 
participating in the trial and all of their medical information is maintained.  Case report 
forms must never contain the name of a trial patient.  All case report forms and any  
identifying information must be kept in a secure location with access limited to the study 
staff directly participating in the trial.  Personal medical information may be reviewed by  
a representative of Merck & Co, Inc., of the IRB, or of regulatory authorities in the 
course of auditing the trial.  Every reasonable effort will be made to maintain such  
information as confidential.