Clinical trial NCT04635735
Conditions: Relapsed/Refractory Multiple Myeloma
Keywords: Ipilimumab Stem Cell Transplantation 20-329
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2020-01-12; Completion date: 2023-02-02
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will test the safety of ipilimumab to see what effects, if any, the drug has when used as maintenance therapy for people with relapsed/refractory multiple myeloma who have received chemotherapy and allogeneic hematopoietic stem cell transplant (AHCT). The investigators also want to find out whether giving ipilimumab after chemotherapy and AHCT is a better way to control the multiple myeloma than chemotherapy and AHCT alone.

Detailed description:

Arms: arm 1: The patient will be admitted to a single room on the Adult Transplantation Service and allogeneic CD34-selected PBSC or marrow transplantation performed as per MSKCC adult BMT guidelines. Patients will be evaluated at approximately day 100 (±2 weeks) after allo-HSCT.
Interventions: intervention 1: Ipilimumab
Intervention descriptions: intervention 1: Ipilimumab 3 mg/kg every 3 weeks for 4 doses.

Protocol documents:
Prot_SAP_001.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 20-329 A(2) 
Approval date: 14-Jan-2021 
Administrative Update 6 : 03-Jan-2023 
 
 
MSK PROTOCOL COVER SHEET 
 
A Phase I/II Trial of Ipilimumab after CD34-Selected Allogeneic Stem Cell Transplantation for 
Patients with Relapsed/Refractory Multiple Myeloma 
 
Principal Investigator/Department: Gunjan Shah, MD/Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
Page 1 of 38 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-329 A(2) 
Approval date: 14-Jan-2021 
Administrative Update 6 : 03-Jan-2023 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 2 of 38 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ...................................................................................... 4 
3.0 
BACKGROUND AND RATIONALE ........................................................................................ 4 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................... 6 
4.1 
Design ................................................................................................................................. 6 
4.2 
Intervention ......................................................................................................................... 6 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS ............... 7 
6.0 
CRITERIA FOR PARTICIPANT ELIGIBILITY ....................................................................... 10 
6.1 
Participant Inclusion Criteria .............................................................................................. 10 
6.2 
Participant Exclusion Criteria ............................................................................................. 11 
7.0 
RECRUITMENT PLAN ......................................................................................................... 11 
7.1 
Research Participant Registration ...................................................................................... 12 
8.0 
INFORMED CONSENT PROCEDURES ................................................................................ 12 
9.0 
PRE-TREATMENT/INTERVENTION .................................................................................... 12 
10.0 TREATMENT/INTERVENTION PLAN ...................................................................................... 13 
11.0 EVALUATION DURING TREATMENT/INTERVENTION ......................................................... 15 
12.0 CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 18 
13.0 
CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY .................. 18 
14.0 BIOSTATISTICS ....................................................................................................................... 21 
15.0 TOXICITIES/RISKS/SIDE EFFECTS ........................................................................................ 24 
15.3 
Assessment of Safety ........................................................................................................ 27 
15.4 Serious Adverse Event (SAE) Reporting ............................................................................ 28 
15.5 
External SAE Reporting ......................................................................................................... 29 
16.0 PROTECTION OF HUMAN PARTICIPANTS ........................................................................ 36 
16.1 Privacy .............................................................................................................................. 36 
16.2 Data Management ............................................................................................................... 36 
16.3 Quality Assurance ............................................................................................................. 36 
16.4 Data and Safety Monitoring ............................................................................................... 36 
17.0 
REFERENCES .......................................................................................................................... 38 
18.0 
APPENDICES ........................................................................................................................... 38 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-329 A(2) 
Approval date: 14-Jan-2021 
Administrative Update 6 : 03-Jan-2023 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 3 of 38 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a phase I/II, single arm, open label trial to explore the safety and efficacy of ipilimumab when used as a 
maintenance strategy after CD34-selected allogeneic hematopoietic stem cell transplant (alloHSCT) for 
relapsed/refractory multiple myeloma (MM). We hypothesize that ipilimumab used in the context of CD34- 
selected alloHSCT platform will be safe and will reduce the risk graft-versus-host disease that has been 
associated with checkpoint inhibition in conventional alloHSCT. We also hypothesize that ipilimumab used 
after alloHCT and in the absence of active disease has potential to overcome the immune dysregulation that 
drives MM relapse by directing a newly reconstituting host immune system away from immune senescence 
and toward effective anti-tumor surveillance. 
 
Patients with multiple myeloma that have undergone more than 2 lines of prior therapy, and those eligible for 
CD34-selected alloHSCT from 10/10 matched human leucocyte antigen (HLA)-compatible donors are eligible 
for enrollment. All enrolled patients will be evaluated at day 100 (±2 weeks) after alloHSCT to assess for 
eligibility to receive ipilimumab. The Phase I cohort will be made up of 6 patients treated with ipilimumab 3 
mg/kg every 3 weeks for 4 doses (assessment phase). Each patient in this group during the assessment phase 
will be evaluated twice weekly for four 3-week cycles. In the absence of dose-limiting toxicity (DLT) in a given 
patient, the patient will then be treated for 4 further doses every 3 months in a maintenance phase. The DLT 
window is from the first dose of ipilimumab until three weeks following the the fourth dose in the initial 
assessment phase. If DLTs are observed in no more than one patient during the assessment phase of Phase 
I, a single arm Phase II study will be initiated and will accrue an additional 33 patients using the same dose 
(first every 3 weeks for 4 doses in an assessment phase followed by every 3 months for 4 doses). If more than 
one patient in the initial Phase I cohort has any observed DLT with the target ipilimumab dose, a second 6- 
patient Phase I cohort at a reduced ipilimumab dose will be opened to determine the dose for Phase II. 
Patients in all cohorts will be scheduled to receive ipilimumab for 4 doses in assessment phase and four in 
maintenance phase (total therapy duration 15 months; until 18 months post alloHSCT) unless limited by 
intolerance to therapy or disease relapse. We anticipate to complete accrual in two years. 
 
Figure 1: 
 
 
 
 
 
This potentially effective relapse prevention strategy would address an unmet need in patients with high risk 
multiple myeloma in whom numerous other strategies have failed and may also provide context to incorporate 
ipilimumab as a component of combination chemotherapy strategies in this challenging patient population. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-329 A(2) 
Approval date: 14-Jan-2021 
Administrative Update 6 : 03-Jan-2023 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 4 of 38 
 
 
PFS of 44 patients 
Cumulative GVHD 2% 
Median PFS 13.5 months 
NRM at 1 yr 18%, infections 
Figure 2: MSKCC outcomes of CD34-selected HSCT in high-risk 
relapse/refractory multiple myeloma 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Phase I: 
 
The primary objective of the phase I component of this study is to identify a dose of ipilimumab administered to 
patients with relapsed refractory multiple myeloma (RRMM) following CD34-selected alloHSCT for a 
subsequent phase II trial. 
 
Phase II: 
Primary: 
The primary objective of the phase II component of this study is to estimate the 11-month (from time of 
ipilimumab) progression free survival (PFS) in patients with high-risk RRMM treated with ipilimumab 100 days 
after HSCT. 
 
Secondary: 
 
1. To describe the toxicities associated with ipilimumab. 
2. To estimate the cumulative incidence of grade II-IV acute GVHD. 
3. To estimate the cumulative incidence of chronic GVHD 
4. To describe the association between donor lymphocyte infusions (DLI) and progression-free survival. 
 
Exploratory objectives: 
 
We aim to analyze immunologic and biochemical correlates in ipilimumab recipients through characterization 
and quantification of peripheral blood and bone marrow T cell phenotype, and other mononuclear cell 
populations both before and after alloHSCT, and before and after ipilimumab administration. 
 
3.0 
BACKGROUND AND RATIONALE 
 
CD34+ selected alloHSCT for Multiple Myeloma 
 
Despite recent therapeutic advances, most MM patients will experience disease relapse during their lifetime. 
Although the advent of Immunomodulatory imide drugs and proteasome inhibitor-based therapies have 
improved MM patient outcomes the last fifteen years, outcomes in patients who develop resistance to these 
agents is universally dismal.(1) 
 
Allogeneic hematopoietic stem cell transplant remains the only curative treatment for eligible patients with 
RRMM. Although the success of alloHSCT in MM has been challenged by historical rates of non-relapse 
mortality (NRM) exceeding 40%, these rates have substantially decreased with improvements in supportive 
A 
B 
care, better patient selection, and 
modification in conditioning regimen 
components and intensity.(2) A recent 
study from our institution using 
myeloablative conditioning and CD34+ 
selected allografts in 44 patients treated 
from 2007-2013 reported 1 year NRM 
rates of 18%, and grade II-IV acute graft- 
versus-host disease (GVHD) and chronic 
GVHD rates of 2% of 0%, respectively.(3) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-329 A(2) 
Approval date: 14-Jan-2021 
Administrative Update 6 : 03-Jan-2023 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 5 of 38 
 
 
 
 
Relapse rates after alloHSCT have not seen similar improvements and have emerged as a primary challenge 
in this patient population. In our same institutional population, despite the use of high intensity conditioning to 
eradicate disease, the reinfusion of a tumor-free allogeneic stem cell source, and potential advent of graft- 
versus-myeloma effect, progression free survival (PFS) had a median duration 13.5 months and a PFS rate of 
31% at 2 years.(3) 
 
Ipilimumab use after alloHSCT in high risk Multiple Myeloma: Rationale for Use 
 
Profound immune dysfunction is observed in myeloma patients and contributes to tumorigenesis, disease 
resistance and relapse. Targeted immunotherapeutic strategies have generated excitement in the field due to 
their potential to enhance the effects of established cytotoxic strategies with marginal additional toxicity, and to 
induce long term remissions through the establishment of a more effective host immune system.(4) Checkpoint 
inhibition has also generated particular interest in alloHSCT, where this strategy has theoretic potential            
to enhance the effectiveness of the adoptive allogeneic immune system, and increase its curative    
potential.(5) Exploration of the CTLA-4 checkpoint inhibitor ipilimumab in a dose escalation and expansion 
study of 28 patients with hematologic malignancies demonstrated an overall response rate in 7/22 (32%) of 
patients who received the maximum tolerated ipilimumab dose.(6) An update on this study presented at the 
ASH 2017 annual meeting reported complete remission, very good partial remission, and partial remission in 
the 3 MM patients.(7) 
 
Concerns have been raised due to both immune mediated adverse events (IRAEs) and for increased GVHD 
rates in patients receiving checkpoint inhibitors either alone or in combination before or after alloHSCT (7, 8). 
IRAEs were also implicated in the suspension of two MM trials exploring pembrolizumab use in combination 
with pomalidomide or dexamethasone. Davids et al, have addressed these concerns by exploring lower dosing 
strategies in the context of alloHSCT.(7, 8) At these doses, the toxicities including GVHD were substantially 
reduced, although at the expense of efficacy. We nonetheless hypothesize that ipilimumab in the context of this 
proposal will be safe in that we are using it as a single agent, we are using it in the absence of active disease 
and are using it in a platform depleted of alloreactive donor T Cells, in which we have previously reported 
exceedingly low rates of GVHD. 
 
Ipilimumab after alloHSCT: Rationale for Dosing 
 
Ipilimumab is a CTLA-4 inhibitor, currently FDA approved in melanoma and renal cell carcinoma. The dosing 
for ipilimumab is based on prior Phase I/II trials. Bashey and others reported a Phase I trial with 29 patients 
with malignancies that were recurrent or progressive after alloHSCT, who received ipilimumab as a single 
infusion at dose cohorts between 0.1 and 3.0 mg/kg.(NCT00060372).(9) Dose-limiting toxicity was not 
encountered, and ipilimumab did not induce GVHD or graft rejection. However, organ-specific immune adverse 
events (IAE) were seen in 4 patients (grade 3 arthritis, grade 2 hyperthyroidism, recurrent grade 4 
pneumonitis). This was further studied in a Phase I/Ib multicenter study, where 28 patients with relapsed 
hematologic cancer after allogeneic HSCT received induction therapy with ipilimumab at a dose of 3 or 10 
mg/kg of body weight every 3 weeks for a total of 4 doses, with additional doses every 12 weeks for up to 60 
weeks in patients who had a clinical benefit (6). While substantial IAE and GVHD was noted with 10mg/kg, at a 
dose of 3mg/kg, minimal side effects were seen. Chronic GVHD of the liver developed in one patient; this was 
the only dose-limiting toxic effect in that cohort. Immune-related adverse events were observed in two patients 
(grade 2 pneumonitis in one patient and grade 2 diarrhea in one patient). These events were rapidly reversed 
with glucocorticoids and did not preclude further administration of ipilimumab. Additionally, a Phase II        
study has been reported with ipilimumab and lenalidomide in 17 patients with relapsed lymphoid malignancies 
after alloHSCT and in high-risk patients after autologous HSCT. Patients received 10 mg of oral lenalidomide 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-329 A(2) 
Approval date: 14-Jan-2021 
Administrative Update 6 : 03-Jan-2023 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 6 of 38 
 
 
 
 
daily for 21 days followed by intravenous ipilimumab at 3 mg/kg body weight. The regimen was repeated 4 
weeks later for a total of 4 treatments. Immune-mediated toxicity was limited to 1 patient with asymptomatic 
hypothyroidism and 1 with dermatitis in the allogeneic and autologous groups, respectively. One allogeneic 
transplant recipient had a flare of prior graft-versus-host disease (GVHD) while taking lenalidomide that 
precluded further treatment. All others finished treatment without GVHD. Four of 10 patients in the allogeneic 
group had complete responses, and 3 had partial responses. Of note, all these patients had active disease, 
and were being treated for a relapse and were post conventional (T cell replete) alloHSCT. 
 
Based on the above and ongoing MSKCC adult BMT protocol, we hypothesize that ipilimumab dosed at 3 
mg/kg every 3 weeks followed by a maintenance phase of every 3 months dosing for 4 further doses will be 
safe and well tolerated in our cohort of patients. As ipilimumab has not been explored in MM, as a 
maintenance strategy after alloHSCT, or after CD34+ selected alloHSCT, we will initiate a dose de-escalation 
cohort should we find DLT in more than one patient at the currently accepted clinical dose, as outlined in 
Figure 1 and Table 1. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This phase I/II trial is designed to assess the safety and efficacy of ipilimumab administered to patients with 
relapsed refractory multiple myeloma (RRMM) following CD34-selected allogeneic hematopoietic stem cell 
transplantation (alloHSCT). The phase I cohort of 6 patients will be treated with ipilimumab 3 mg/kg every 3 
weeks for 4 doses. If DLTs (defined in section 10.2) are observed in no more than 1 patient, a single arm 
Phase II study will be initiated and will accrue an additional 33 patients using the same dose. If the initial 
Phase I cohort has an observed toxicity rate of more than 1 out of the six patients with the target ipilimumab 
dose, a second 6-patient Phase I cohort at a reduced ipilimumab dose will be opened to determine a lower 
dose for the Phase II. Patients in all cohorts will be scheduled to receive ipilimumab for 4 doses, once every 3 
weeks, followed by 4 doses, once every 3 months, unless limited by DLT or disease relapse. 
 
 
4.3 
Intervention 
 
Intervention 1: Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) 
 
This protocol will enroll patients with multiple myeloma that has relapsed or remained refractory despite 
administration of more than 2 lines of therapy. The patient will be admitted to a single room on the Adult 
Transplantation Service and allogeneic CD34-selected PBSC or marrow transplantation performed as per 
MSKCC adult BMT guidelines. Patients will also be required to meet organ and comorbidity based alloHSCT 
eligibility criteria and have a 10/10 matched eligible donor. All patients will be conditioned for transplantation 
with busulfan (3.2mg/kg/day with pharamacokinetic dosing adjustment to achieve an average daily busulfan 
AUC of 3700 mmol/min as described in Section 10.1), melphalan (70 mg/m2/day x 2 doses) and fludarabine 
(25mg/m2/day x 5 doses), according to the trial diagram outlined in Figure 1. Patients with a measured or 
calculated creatinine clearance of 40-70ml/min will have the fludarabine dose reduced to 80% (20mg/m2/day). 
Donor stem cells will be mobilized by administration of granulocyte-colony stimulating factor (G-CSF) for 5 or 6 
days and harvested from peripheral blood. No drug prophylaxis against GVHD will be administered after 
transplant. 
 
Intervention 2: Ipilimumab 
Patients will be evaluated at approximately day 100 (±2 weeks) after allo-HSCT and those meeting the criteria 
in sections 6.1.2 and 6.2.2.will be eligible to receive the first dose of ipilimumab. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-329 A(2) 
Approval date: 14-Jan-2021 
Administrative Update 6 : 03-Jan-2023 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 7 of 38 
 
 
 
 
Following administration of ipilimumab patients will be evaluated clinically according to MSKCC BMT standard 
of care. Subsequent doses will be given every 3 weeks for 4 doses as per the schedule outlined in Table 1 and 
will be administered only in the absence of DLTs. A DLT will be defined as any grade 3 or greater expected 
immune adverse effect attributable to ipilimumab described in the BMS brochure v2019 as graded by the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, or unexpected grade 3 (CTCAE v. 
5.0) or greater adverse event developing within 3 weeks of ipilimumab administration attributable to ipilimumab 
within the assessment phase as determined by the PI, or new development of grade 2-4 acute GVHD from 
start of ipilimumab to 3 weeks after 4th dose of ipilimumab administration during the assessment phase that 
requires treatment with systemic glucocorticosteroids, or loss of chimerism. 
 
Patients not eligible to receive ipilimumab will continue to be followed in the trial as per standard MSK 
guidelines. Patients who do not receive ipilimumab will be considered non-evaluable for the primary objective 
and replaced. Patient who receive at least one dose of ipilimumab will be considered evaluable for the primary 
objective. 
 
The phase I cohort of 6 patients will be treated with ipilimumab 3 mg/kg every 3 weeks for 4 doses. If no DLTs 
are observed, a single arm Phase II study will be initiated and will accrue an additional 33 patients using the 
same dose. If the initial Phase I cohort has an observed toxicity rate of more than 1 out of the 6 patients with 
the target ipilimumab dose, a second 6-patient Phase I cohort at a reduced ipilimumab dose of 1mg/kg will be 
opened to determine the appropriate lower dose for Phase II. Patients in all cohorts will be scheduled to 
receive ipilimumab for 4 doses, once every 3 weeks, followed by 4 doses, once every 3 months unless limited 
by DLT or disease progression. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS 
 
5.1 Busulfan (Busulfex®) 
a. Source and pharmacology: Supplier: Otsuka Pharmaceutical; Busulfan is a bifunctional alkylating agent 
known chemically as 1, 4-butanediol, dimethanesulfonate. BUSULFEX® (busulfan). This is an agent in which 
two labile methanesulfonate groups are attached to opposite ends of a four carbon alkyl chain. In aqueous 
media, busulfan hydrolyzes to release the methanesulfonate groups. This produces reactive carbonium ions 
that can alkylate DNA. DNA damage is thought to be responsible for much of the cytotoxicity of busulfan. 
 
b. Formulation and stability: It is supplied as a clear, colorless, sterile, solution in 10 mL single use 
ampoules. Each ampoule of BUSULFEX contains 60 mg (6 mg/mL) of busulfan, the active ingredient, a white 
crystalline powder with a molecular formula of CH3SO2O (CH2)4OSO2CH3 and a molecular weight of 246 
g/mole. Busulfan is dissolved in N, N-dimethylacetamide (DMA) 33% wt/wt and polyethylene glycol 400, 67% 
wt/wt. Busulfan‟s solubility in water is 0.1 g/L and the pH of a >0.5% solution in 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP as recommended for infusion reflects the pH of the diluent used 
and ranges from 3.4 to 3.9. 
 
c. Solution preparation: Prepare and Mix per MSKCC Guideline. 
 
d. Storage and stability: Unopened ampules of BUSULFEX must be stored under refrigerated conditions 
between 2° -8° C (36° -46° F). 
 
e. Clinical considerations: Busulfan is emetogenic. Busulfan is administered intravenously over 3 hours. 
Seizure prophylaxis is co-adminstered according to institutional guidelines. Acetaminophen and metronidazole 
should not be given 24 hours pre or post busulfan administration. 
 
5.2. Melphalan (Evomela®) 
a. Source and pharmacology: Supplier: Spectrum Pharmaceuticals. A derivative of nitrogen mustard, an 
analog of mustard gas. It is a polyfunctional alkylating agent that causes miscoding, cross-linkage of DNA, and 
single-strand breakage of DNA. It inhibits cellular glycolysis, respiration, and protein synthesis. It is cell cycle- 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-329 A(2) 
Approval date: 14-Jan-2021 
Administrative Update 6 : 03-Jan-2023 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 8 of 38 
 
 
 
 
phase non-specific. 
 
b. Formulation and stability: A lyophilized powder of 50 mg melphalan per vial. 
 
c. Solution preparation: . Prepare and Mix per MSKCC Guideline. 
 
d. Storage and stability: The intact packages should be stored at room temperature (15- 30°C) protected 
from light. 
 
e. Administration: Intravenous, over 30 minutes. 
 
5.3 Fludarabine (FLUDARA®) 
a. Source and pharmacology: Supplier: Berlex Laboratories, Inc. FLUDARA FOR INJECTION contains 
fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-ß-D- 
arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. The 
chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-ß-D- 
arabinofuranosyl). Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then 
phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This 
metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, 
thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized 
and may be multi-faceted. 
 
b. Formulation and stability: Each vial of sterile lyophilized solid cake contains 50 mg of the active ingredient 
fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7. The pH range for the  
final product is 7.2-8.2. Reconstitution with 2 mL of Sterile Water for Injection USP results in a solution 
containing 25 mg/mL of fludarabine phosphate intended for intravenous administration. FLUDARA FOR 
INJECTION is supplied in a clear glass single dose vial (6 mL capacity) and packaged in a single dose vial 
carton in a shelf pack of five 
 
c. Solution preparation: Prepare and mix per MSKCC Guideline. 
 
d. Storage and stability: As per MSKCC Guideline. 
 
e. Administration: Intravenous, over thirty minutes. 
 
5.4. Anti-Thymocyte Globulin (Rabbit) (Thymoglobulin®) 
a. Source and pharmacology: Supplier: Sangstat, The Transplant Company®. Thymoglobulin® [Anti- 
thymocyte Globulin (Rabbit)] is a purified, pasteurized, gamma immune globulin, obtained by immunization of 
rabbits with human thymocytes. This immunosuppressive product contains cytotoxic antibodies directed 
against antigens expressed on human T-lymphocytes. 
 
b. Formulation and stability: Thymoglobulin is a sterile, freeze-dried product for intravenous administration 
after reconstitution with sterile Water for Injection, USP (WFI). Each package contains two 7 mL vials: Vial 1: 
Freeze-Dried Thymoglobulin Formulation Active ingredient: Anti-thymocyte Globulin (Rabbit) 25 mg - Inactive 
ingredients: Glycine (50 mg), mannitol (50 mg), sodium chloride (10 mg); Vial 2: Diluent Sterile Water for 
Injection, USP 5 mL. The reconstituted preparation contains approximately 5 mg/mL of Thymoglobulin, of 
which >90% is rabbit gamma immune globulin (IgG). The reconstituted solution has a pH of 7.0± 0.4. Human 
red blood cells are used in the manufacturing process to deplete cross-reactive antibodies to non-T-cell 
antigens. The manufacturing process is validated to remove or inactivate potential exogenous viruses. All 
human red blood cells are from US registered or FDA licensed blood banks. A viral inactivation step 
(pasteurization, i.e., heat treatment of active ingredient at 60°C/10 hr) is performed for each lot. Each 
Thymoglobulin lot is released following potency testing (lymphocytotoxicity and E-rosette inhibition assays), 
and cross-reactive antibody testing (hemagglutination, platelet agglutination, anti-human serum protein 
antibody, antiglomerular basement membrane antibody, and fibroblast toxicity assays on every 5th lot). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-329 A(2) 
Approval date: 14-Jan-2021 
Administrative Update 6 : 03-Jan-2023 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 9 of 38 
 
 
 
 
 
c. Solution preparation: Prepare and mix per MSKCC Guideline. 
 
d. Storage and stability: As per MSKCC Guideline. 
 
e. Administration: Infuse through a 0.22-micron filter. Set the flow rate to deliver the dose over 12 hours. : 
Patients will receive pre-hydration and anaphylaxis prophylaxis to include diphenhydramine and 
acetaminophen according to institutional guidelines. Methylprednisolone 1 mg/kg may be administered 
concurrently with ATG. 
 
5.5 Ipilimumab (Yervoy) 
a. Source and pharmacology: 
Ipilimumab (BMS-734016, MDX010, MDX-CTLA4) is a fully human monoclonal immunoglobulin (Ig) G1 
specific for human cytotoxic T-lymphocyte antigen 4 (CTLA-4, cluster of differentiation [CD] 152), which is 
expressed on a subset of activated T cells. CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a 
monoclonal antibody (mAb) that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, 
CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the 
activation and proliferation of tumor-infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce 
T-regulatory cell (Treg) function, which may contribute to a general increase in T-cell responsiveness, 
including the anti-tumor response. Ipilimumab 3 mg/kg has been approved for use in advanced melanoma in 
over 47countries, including the United States (US, 25-Mar-2011), the European Union (EU, 13-Jul-2011), and 
Australia (Jul-2011). Yervoy 10 mg/kg is approved as adjuvant treatment of unresectable or metastatic 
melanoma in the US. 
 
The pharmacokinetics of ipilimumab were studied in 785 patients with unresectable or metastatic melanoma 
who received doses of 0.3, 3, or 10 mg/kg once every three weeks for 4 doses. Peak concentration (Cmax), 
trough concentration (Cmin), and area under the plasma concentration versus time curve (AUC) of ipilimumab 
increased dose proportionally within the dose range examined. Upon repeated dosing every 3 weeks, the 
clearance (CL) of ipilimumab was found to be time-invariant, and systemic accumulation was 1.5-fold or less. 
Steady-state concentrations of ipilimumab were reached by the third dose; the mean Cmin at steady-state was 
19.4 mcg/mL following repeated doses of 3 mg/kg. The mean value for terminal half-life was 15.4 days and for 
CL was 16.8 mL/h 
 
b. Formulation and stability: Ipilimumab currently comes packaged in a concentrated form in either a 50 mg 
(5 mg/mL) or 200 mg (5 mg/mL) single use vial. This concentrated solution should be diluted with 0.9% 
Sodium Chloride or 5% Dextrose Injection to prepare a diluted solution with a final concentration ranging from 
1 mg/mL to 4 mg/mL. 
 
c. Solution preparation: Ipilimumab injection, 50 mg/10 mL (5 mg/mL) or 200 mg/40 mL (5 mg/mL), can be 
used for intravenous (IV) administration without dilution after transferring to a polyvinyl chloride (PVC), non- 
PVC/non-di(2-ethylhexyl)phthalate (DEHP), or glass container and is stable for 24 hours at 2°C to 8°C or room 
temperature/room light. Ipilimumab injection may be diluted in 0.9% sodium chloride injection or 5% dextrose 
injection to concentrations between 1 mg/mL and 4 mg/mL and stored in PVC, non-PVC/non-DEHP, or glass 
containers for up to 24 hours at 2°C to 8°C or room temperature/room light. 
 
d. Storage and stability: Ipilimumab injection may be stored undiluted (5 mg/mL) or following dilution in 0.9% 
sodium chloride injection or 5% dextrose injection in PVC, non-PVC/non-DEHP, or glass containers for up to 
24 hours at 2°C to 8°C or room temperature/room light. Vials should be protected from light and should not be 
frozen. 


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e. Administration: The diluted solution may be infused over 90 minutes using a volumetric pump at the 
protocol- specific dose(s) and rate(s) through a PVC IV solution infusion set with an in-line, sterile, 
nonpyrogenic, low protein binding filter (pore size of 0.2 m to 1.2 m) as per manufacturer’s guidelines. 
Ipilimumab injection must not be administered as an IV push or bolus injection. Care must be taken to assure 
sterility of the prepared solutions since the drug product does not contain any antimicrobial preservatives or 
bacteriostatic agents. 
 
 
 
6.1 
CRITERIA FOR PARTICIPANT ELIGIBILITY 
 
6.2 
Participant Inclusion Criteria 
 
6.2.1 Inclusion Criteria prior to Allogeneic Hematopoietic Stem Cell Transplantation 
(alloHSCT) 
• 
Willing and able to participate as a research subject and provide informed consent (Note: an LAR 
may sign the consent form on the partipant’s behalf) 
• 
Diagnosis of relapsed refractory multiple myeloma defined as more than 2 lines of prior 
therapywith at least a very good partial remission to most recent salvage therapy. 
o Patients should have R-ISS stage II or III disease at diagnosis or high risk cytogenetics by 
IMWG criteria (t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q)) at 
any time since diagnosis 
 
Note:. A line of therapy is treatment between diagnosis and progression or between two progressions 
 
• 
Eligible for CD34-selected HSCT according to MSKCC adult BMT guidelines. 
• 
Have a 10/10 matched donor 
• 
Age ≥ 21, < 73 years. 
• 
Karnofsky (adult) Performance Status ≥ 70%. 
• 
Patients must have adequate organ function measured by: 
a) Cardiac: LVEF at rest must be ≥ 50% 
b) Hepatic: 
▪ 
< 3x ULN ALT 
▪ 
< 1.5 ULN total serum bilirubin, unless there is congenital benign hyperbilirubinemia. 
c) Renal: serum creatinine <1.2 mg/dl or if serum creatinine is outside the normal range, then 
CrCl > 40 ml/min (measured or calculated/estimated) with dose adjustment of Fludarabine 
for <70ml/min as per section 4.2. 
d) Pulmonary: DLCO > 50% of predicted (corrected for hemoglobin). 
 
6.2.2 Inclusion Criteria prior to Ipilimumab 
 
• 
Non progressive myeloma (partial response or better) as defined by International Myeloma 
Working Group (IMWG) criteria 
• 
Engraftment of all cell lines without transfusion dependence, defined as 
o 
absolute neutrophil count > 1.0K/mcL x 3 consecutive days 
o 
platelets > 50K/mcLx 7 consecutive days without platelet transfusion 
o 
no platelet or RBC transfusions within the preceding 7 days 
• 
≥ 80% donor chimerism in the bone marrow 


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6.3 
Participant Exclusion Criteria 
 
6.3.1 Exclusion Criteria prior to Allogeneic Hematopoietic Stem Cell Transplantation 
(alloHSCT) 
 
• 
Patients ineligible for therapy with ipilimumab, for example:. 
a) Active autoimmune disease or any condition requiring systemic treatment with either 
corticosteroids (>10 mg daily of prednisone equivalents) or other immunosuppressive 
medications at enrollement. Inhaled or topical steroids and adrenal replacement doses > 10 
mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 
b) History of motor neuropathy considered to be of autoimmune origin (e.g., Guillain-Barre 
Syndrome, Myasthenia Gravis). 
• 
Female patients who are pregnant or breast-feeding. 
• 
Patients with plasma cell leukemia at the time of diagnosis. 
• 
Patients who have undergone prior allogeneic hematopoietic stem cell transplantation. 
• 
Patients who have had a previous malignancy that is not in remission. 
 
 
6.3.2 Exclusion Criteria prior to Ipilimumab 
 
• 
Active infection or treatment for infection (patients on Cytomegalovirus (CMV) therapy will be 
considered eligible; patients with CMV viremia by PCR or disease with end-organ involvement will 
not be eligible) 
• 
Active GVHD of any grade or prior grade 3-4 GVHD 
• 
Active immune suppression, defined as 
o 
active use of calcineurin inhibitors, mycophenolate mofetil, or other immunomodulators 
o 
steroid dosing exceeding 10 mg/d prednisone or equivalent 
• 
Receiving immunomodulatory agents (ex. thalidomide, lenalidomide, pomalidomide) 
 
 
7.1 
RECRUITMENT PLAN 
 
This study will be conducted at MSKCC. Information regarding this study will be made available on the 
MSKCC web site, and the trial will be listed on www.clinicaltrials.gov. 
 
Potential research subjects will be identified by members of the patient’s treatment team or research team 
during clinical visits and weekly multidisciplinary meetings. The investigator will use information provided by 
the patient and/or medical record to confirm that the patient is eligible and contact the patient regarding study 
enrollment. Physicians will discuss with the patient his/her diagnosis, prognosis, risks and benefits of study 
participation, as well as treatment alternatives which will include standard treatment options and may include 
other investigational options. All patients will be required to sign an IRB approved informed consent prior to 
enrollment on study. All eligible patients, regardless of sex and race, will be approached for participation. The 
investigators are aware of the NIH policy concerning inclusion of women and minorities in clinical research 
populations. All patients will be seen by MSKCC BMT physicians and associated MSKCC co-investigators, 
enrolled, and registered at MSKCC. All co-investigators agree to follow the treatment in the protocol and to 
conduct the proposed investigation according to recognized principles of good clinical practice. Participation is 
voluntary. If the patient turns out to be ineligible for the research study, the research staff will destroy all 
information collected on the patient during the initial conversation and medical records review, except for any 
information that must be maintained for screening log purposes. 
 
This protocol will be the priority study for patients with multiple myeloma who are undergoing allo HSCT. 


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7.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain informed 
consent, by following procedures defined in section entitled Informed Consent Procedures. During the 
registration process registering individuals will be required to complete a protocol specific Eligibility 
Checklist. The individual signing the Eligibility Checklist is confirming whether the participant is eligible 
to enroll in the study. Study staff are responsible for ensuring that all institutional requirements 
necessary to enroll a participant to the study have been completed. See related Clinical Research 
Policy and Procedure #401 (Protocol Participant Registration). 
 
7.2 
Randomization 
 
Not applicable. 
 
 
 
8.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their inclusion 
in the study. Participants will also be informed that they are free to withdraw from the study at any 
time. All participants must sign an IRB/PB-approved consent form indicating their consent to 
participate. This consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to withdraw 
from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to signing 
the IRB Informed Consent, all patients must agree to the Research Authorization component of the 
informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must receive a 
copy of the signed informed consent form. 
 
 
9.1 
PRE-TREATMENT/INTERVENTION 
 
The patient will receive an extensive medical evaluation within approximately 45 days prior to starting 
preparatory cytoreduction as per MSKCC adult BMT guidelines. This evaluation includes: 
• 
Complete physical exam and medical history 
• 
Dental evaluation (not required within 45-day window) 
• 
CBC with differential 


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• 
Coagulation profile (PT, PTT, INR) 
• 
Blood Type and screen (any time prior to enrollment) 
• 
Myeloma specific analyses include – Serum protein electrophoresis (SPEP), Serum 
Immunofixation (IF), quantitative immunoglobulins, Serum Free Light Chain assay, β -2 
microglobulin, LDH; 24 hr urine collection for total protein, creatinine clearance, urine protein 
electrophoresis (not required if total protein is < 10.0 mg/dl), urine immunofixation. 
• 
Serum chemistries including BUN, creatinine, electrolytes, glucose, total protein, albumin, liver 
function tests (AST, ALT, bilirubin, and alkaline phosphatase). 
• 
Infectious disease markers will be performed as per each department’s guidelines or at the 
discretion of the treating attending. 
• 
HTLV-1 and 2 as well as HIV-1 and 2 serology 
• 
Pregnancy test for women of childbearing age (and repeated as necessary per institutional 
guidelines prior to starting conditioning) 
• 
Urinalysis 
• 
Electrocardiogram, echocardiogram or a gated pool scan if needed 
• 
Pulmonary function test 
• 
FDG-PET/CT (for patients with positive bone lesions at baseline; may be substituted by PET/MRI 
at the discretion of the investigator) 
• 
Chest X-ray (Chest CT scan and FDG-PET scan if indicated) 
• 
Samples of bone marrow and/or blood cells will be obtained to assess disease status and to 
define donor/host differences. 
• 
An additional blood will be drawn in 2 CPT tubes and 1 SST tube once prior to conditioning for 
laboratory correlative studies and banked in HOTB. 
• 
Bone marrow assessment will be performed as follows: 
1. Biopsy will be stained with CD138, CD20 and kappa/lambda. 
2. Aspirate will be sent for the following tests: 
a. Routine staining and cell counts 
b. One heparinized syringe with 5ml of marrow for flow cytometry for routine 
myeloma markers 
c. Two syringes with EDTA and 2-4ml of marrow in each syringe for karyotype for 
chromosomal abnormalities and FISH. 
d. An additional 3-6ml marrow in EDTA will be drawn for correlative studies 
 
 
10.0 TREATMENT/INTERVENTION PLAN 
 
10.1. Preparative cytoreduction 
 
The patient will be admitted to a single room on the Adult Transplantation Service and allogeneic 
CD34-selected PBSC or marrow transplantation performed as per MSKCC adult BMT guidelines. 
Patients can co-enroll on MSK protocols with busulfan, melphalan, and fludarabine conditioning in 
which the protocol intervention ends prior to day 100. For co-enrolled patients, busulfan, melphalan, 
fludarabine, and rabbit antithymocyte globulin (rATG) dosing will follow the co-enrolled protocol. For 
patients not co-enrolled on another protocol, patients will receive: 
 
On day -6, patients will receive the Busulfan 3.2mg/kg/day with PK levels drawn per standard of 
practice. Busulfan PK modeling will be done using these levels using an in-house liquid 
chromatography tandem mass spectrometry assay, per current standard of care. If necessary, 
dose adjustments will be made based on the first dose kinetics to ensure that patients achieve a 
target average daily busulfan AUC goal of 3400 – 4400 mmol/min. Busulfan will be administered 
on days -6, -5, and -4. 


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Melphalan (70mg/m2/day IV) will be administered on days -3 and -2.  
Fludarabine (25mg/m2/day IV) will be administered on days -6, -5, -4, -3, and -2. 
Patient will also receive rATG (thymoglobin 2.5mg/kg/day IV) on day -3 and -2 with a total ATG 
dose cap of 450mg. 
 
Adjusted body weight will be used for busulfan, melphalan, and rATG if the patient’s actual 
weight is >125% of adjusted body weight. Patients with a measured or calculated creatinine 
clearance of 40-70ml/min will have the fludarabine dose reduced to 80% (20mg/m2/day). 
 
10.2 Therapy with ipilimumab 
 
Ipilimumab 
Safety Assessment Phase 
Ipilimumab 
Maintenance Phase 
 
 
Phase I 
Phase 
Is* 
Phase II 
Pts 
Dose 
Freq 
Doses 
Duration 
Dose 
Freq 
Doses 
Duration 
Table 1: Ipilimumab Dosing Schedule in Expansion and *Safety Cohorts. (Freq = frequency; Mo = Month;; Pts = 
number of patients; wk(s) = week(s).) * Phase I safety cohort, if needed 
 
Following administration of ipilimumab patients will be evaluated clinically according to MSKCC BMT 
standard of care. Subsequent doses will be given every 3 weeks for 4 doses as per the schedule 
outlined in Table 1 and will be administered only in the absence of dose-limiting toxicities (DLT). DLT 
will be defined as: any grade 3 or greater expected immune adverse effect attributable to ipilimumab 
described in the BMS brochure v2019 as graded by the NCI Common Terminology Criteria for  
Adverse Events (CTCAE) version 5.0, or unexpected grade 3 (CTCAE v. 5.0) or greater adverse event 
developing within 3 weeks of ipilimumab administration during the assessment phase attributable to 
ipilimumab as determined by the safety monitoring board, or new development of grade 2-4 acute 
GVHD within 3 weeks of ipilimumab administration during the assessment phase that requires 
treatment with systemic glucocorticosteroids, or loss of chimerism. 
 
For dose 2 and onwards, within 48 hours prior to ipilumimab dose, patients should have 
Platelet count >50K/mcL, Hemoglobin >= 7g/dL, Total Bilirubin <= 1.5 x ULN, and AST/ALT <= 1.5 x 
ULN. Tyroid function tests should be drawn prior to each dose. 
 
Patients who do not receive ipilimumab will be considered non-evaluable for the primary objective and 
replaced. Patients who discontinue treatment due to DLT will continue to be followed in the trial as per 
standard MSK guidelines and their blood and their archived for research. Patient who receive at least 
one dose of ipilimumab will be considered evaluable for the primary objective. 
 
To receive maintenance doses of ipilimumab, patients should: 
1. Phase I – not have had DLT in DLT window 
Phase II – not have had any grade 3 or greater expected immune adverse effect attributable 
to ipilimumab or unexpected grade 3 or greater adverse event developing within 3 weeks of 
ipilimumab administration 
2. Not have new development of acute GVHD within 3 weeks of ipilimumab administration during 
the assessment phase that requires treatment with systemic glucocorticosteroids 
3. ≥ 80% donor chimerism in the bone marrow 
6 
3 mg/kg 
q3 
wks 
4 
12 wks 
3 mg/kg 
q3 
mo 
4 
12 mo 
6 
1 mg/kg 
q3 
wks 
4 
12 wks 
1 mg/kg 
q3 
mo 
4 
12 mo 
33 
from Phase 
I/Is 
q3 
wks 
4 
12 wks 
from Phase 
I/Is 
q3 
mo 
4 
12 mo 


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4. Clinical benefit with at least a partial remission by IMWG criteria 
 
Prophylactic DLI should not be given prior to Day 180 after alloHSCT and should be separated from 
maintenance ipilimumab doses by 2-4 weeks. Patients who have not achieved a complete remission 
by Day 180 are eligible for prophylactic DLI. DLI for disease progression should only be given once 
patient is removed from the treatment portion of the study, but the patient will be monitored for toxicity 
and efficacy. 
 
10.3. Supportive Care 
 
a. Prophylaxis against infections Standard of care guidelines will be followed for prophylaxis against post- 
transplant infections by opportunistic organisms, including Pneumocystis jiroveci, fungal organisms, DNA 
herpesviruses and more specifically CMV. 
b. Prophylaxis against menorrhagia All post-pubertal females will receive prophylaxis against menorrhagia 
according to our standard of care guidelines. 
c. Transfusions All blood product transfusions will be performed as per standard of care and BMT guidelines. 
d. Nutritional support Nutritional status will be carefully monitored by the physician, and high-calorie 
parenteral alimentation will be introduced as clinically indicated. Vitamin supplements will be as clinically 
indicated. 
 
10.4 Clinical Lab Work 
 
CBC with differential and CMP will be checked at day 28, at day 100, prior to each dose of Ipi, and at the 6, 9, 
12, 18, and 24 month visits. 
 
Chimerism at baseline (pretreatment) can be either blood or bone marrow (through the diagnostic molecular 
pathology order). Additionally, baseline chimerism may be done at any time pre-transplant. For the day+28 
time point, only bone marrow chimerism is required. Chimerism will be studied in peripheral blood prior to 
ipilimumab administration during days 100-180 and complete donor loss (i.e. loss of chimerism) is considered 
a DLT. Chimerism will be checked monthly from 6-12 months and ongoing as clinically indicted until normal 
values are reached. 
 
T cell donor chimerism, reconstitution and function will be assessed starting day 100 prior to each ipilimumab 
dose then monthly from 6 months to 12 months if the absolute lymphocyte count is equal to or greater than 0.5 
K/mcL or if clinically indicated. T-cell chimerism analysis is not required when a patient’s absolute lymphocyte 
count is less than 0.5 K/mcL. Additional subset chimerism is at the discretion of the clinical team. 
 
10.5 Concomitant Medications 
 
Immunomodulatory medications such as thalidomide, lenalidomide, or pomalidomide may not be given during 
the ipilimumab treatment period. 
 
 
11.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
11.1 
Clinical Tests: 
All patients will be closely monitored and evaluated as per MSKCC BMT standard of care guidelines. Study 
specific assessment schedule listed below. 


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Table 2: Schedule of Assessments 
Procedures 
Pre- 
treat 
Days post-transplant 
Months post-transplant 
7 
14 
21 
28 
35 
42 
56 
70 
84 
100 
100-180 
6 
9 
12 
18 
24 
36 
Window 
45 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
7d 
± 
7d 
± 
7d 
± 
14d 
Prior to each 
cycle of Ipi 
± 
14d 
± 
14d 
± 
30d 
± 
30d 
± 
30d 
± 
30d 
Eligibility 
X 
X10 
Informed 
consent 
X 
H&P 
X 
X12 
Dental eval 
X 
CBC w/ 
differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
profile 
X 
Blood type 
& Screen 
X 
Serology1 
X 
Pregnancy 
test2 
X 
HTLV-1/2, 
HIV-1/2 
X 
Urinalysis 
X 
EKG, Echo 
or gated 
pool scan 
X 
PFT 
X 
X 
Chest X ray 
X 
BM biopsy 
and 
aspirate3 
X 
X 
X 
X 
X 
X 
X 
X 
BM 
Chimerism4 
X 
X 
X 
X 
X 
X 
X 
X 
Peripheral 
Blood 
Chimerism4 
X 
X 
X 
X 
X 
X 
X 
X 
Myeloma 
analysis5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune 
function6 
X 
X 
X 
X 
X 
X 
X 
Research 
Bloods7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FDG- 
PET/CT8 
X 
X 
X 
X 
X 


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GVHD 
eval9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity 
assessment 
X 
X 
X 
X 
X 
X 
X 
Phone call 
X9 
1. 
Infectious disease markers will be performed as per BMT service guidelines or at the discretion of the treating attending. 
2. 
For women of child-bearing potential, only. Serum pregnancy test is required within 14 days prior to treatment. 
3. 
Bone marrow biopsy will be stained with CD138, CD20 and kappa/lambda. Aspirate will be sent for the following tests: 
a. 
Routine staining and cell counts 
b. 
One heparinized syringe with 5ml of marrow for flow cytometry for routine myeloma markers 
c. 
Two syringes with EDTA and 2ml of marrow in each syringe for FISH for chromosomal abnormalities 
d. 
An additional 3-6ml marrow in EDTA will be drawn for correlative studies 
4. 
Chimerism at baseline (pretreatment) can be either blood or bone marrow. Additionally, baseline chimerism may be done at any 
time pre-transplant. For the day+28 time point, only bone marrow chimerism is required. Chimerism will be studied in peripheral 
blood prior to ipilimumab administration during days 100-180 and complete donor loss (i.e. loss of chimerism) is considered a 
DLT. Chimerism will be checked monthly from 6-12 months and ongoing as clinically indicted until normal values are reached. 
5. 
Myeloma analyses includes: serum protein electrophoresis (SPEP), serum immunofixation (IF), quantitative immunoglobulins, 
serum free light chain assay, β -2 microglobulin, LDH; 24-hour urine collection for total protein, creatinine clearance, urine 
protein electrophoresis (not required if total protein is < 10.0 mg/dl), urine immunofixation. β -2 microglobulin will only be 
performed pre-treatment. 
6. 
IgG, IgA, IgM, Lymphocyte subsets, B naïve memory translational, T naïve memory effectory, T regulatory (RNB), mitogen 
proliferation 
7. 
Blood will be drawn in 2 CPT tubes and 1 SST tube for laboratory correlative studies and stored in HOTB for batch testing as 
defined in section 11.2.2. 
8. 
Patients with positive bone lesions at baseline will have repeat imaging with FDG-PET/CT (can be substituted by PET/MRI at 
investigator discretion) at day 100, 6 months, and 12 months post-transplant 
9. 
GvHD evaluations will be performed as per the ABMT service guidelines. GvHD evaluations may be conducted by phone for 
remote patients. This will be appropriately documented in EMR. 
10. Refer to section 4.2 for eligibility criteria to be assessed prior to starting the first cycle of ipilimumab. 
11. Patients will be called at 36 months post-enrollment to assess for second primary malignancies. 
12. For the Phase 1 portion, patients will be seen prior to each dose of ipilmumab and will receive twice weekly phone calls to 
assess for DLTs. 
 
11.2. 
Research Tests: 
 
11.2.1. Peripheral Blood Evaluations: During treatment, peripheral blood samples (2 CPT and 1 SST ) will 
be obtained immediately prior to conditioning therapy (pre-treatment baseline), immediately prior to ipilimumab 
infusions,and at 6, 9, 12,18 and 24 months after alloHSCT (windows above). Collected blood samples may be 
analyzed for research purposes, including but not limited to: 
• 
T cell phenotype: Immunophenotype will be assessed by multi-parameter FACS and/or CyTOF 
including but not limited to markers to determine CD4/CD8 ratio, Th1/Th2/Th17/Treg/Tfh subtype, 
activation/exhaustion markers, and memory/effector status. mRNA expression analysis of sorted T 
cells will also be performed. 
• 
Cytokine analysis: Concentrations of cytokines including but not limited to proinflammatory (IFN, 
TNF, GM-CSF, IL-2, IL-4, IL-5, IL-8) and immune suppressive cytokines (TGF, IL-10) will be 
assessed (10). 
 
11.2.2 Bone Marrow Evaluations: Collected bone marrow aspirate/biopsy samples may be analyzed for 
research purposes, including but not limited to: 
• 
Phenotype of T cells by FACS and gene expression analysis (see Section 10.2.1) 
• 
Anti-tumor response by clinical pathologic assessment of bone marrow aspirate and biopsy including 
MRD assessment by MSKCC clinical 10-marker flow and/or PCR based monitoring of malignant IgH 
rearrangement. 
• 
Characterize the MM microenvironment and PC immuno-phenotype including but not limited to by 
multiparameter-flow, CyTOF, quantitative immunofluorescence, MM cell DNA mutation analysis, 
and/or GEP. 
• 
Assess for plasma and B cell and PC aplasia by FACS and/or IHC 


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11.2.3 Plasmacytoma Analysis: In patients with an extramedullary plasmacytoma, a biopsy of the 
responding and/or refractory plasmacytoma(s) may be requested if easily accessible and the patient is 
agreeable. Obtained tissue will be banked for future analysis that may include but not limited to analysis by 
FACS, RT-PCR and/or immunohistochemistry to assess the presence of modified T cells and for tumor 
microenvironment assessment. 
 
 
12.0 CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient is found to be ineligible for the protocol as designated in the section on Criteria for 
patient/subject eligibility (e.g. a change in diagnosis), the patient will be removed from the study. Also, patients 
may be removed from the study if requested by the patient. Management will depend on where they are in their 
treatment course. Such patients will receive appropriate supportive care. The PI may also remove patients 
from the study form noncompliance. Additionally, patients who experience recurrence of disease prior             
to ipilimumab will be removed from study and replaced. 
 
 
13.0 
CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY 
 
13.1 Criteria for Therapeutic Response/Outcome Assessment 
DEFINITIONS OF DISEASE STATUS Patients at each data collection period are classified into one of the 
following states as defined by the revised International Myeloma Working Group consensus criteria for 
response and minimal residual disease assessment in multiple myeloma(11). 
 
Standard 
IMWG 
response 
criteria 
Stringent 
complete 
response 
Complete response as defined below plus normal FLC ratio ** and absence of clonal cells 
in bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ 
patients, respectively, after counting ≥100 plasma cells) †† 
Complete 
response 
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and <5% plasma cells in bone marrow aspirates 
Very good 
partial 
response 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 
≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 h 
Partial 
response 
≥50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by ≥90% or to 
<200 mg per 24 h; 
If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria; 
If serum and urine M-protein are unmeasurable, and serum-free light assay is also 
unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma-cell percentage was ≥30%. In addition to these criteria, if 
present at baseline, a ≥50% reduction in the size (SPD) §§ of soft tissue plasmacytomas is 
also required 
Minimal 
response 
≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 
50–89%. In addition to the above listed criteria, if present at baseline, a ≥50% reduction in 
the size (SPD) §§ of soft tissue plasmacytomas is also required 
Stable 
disease 
Not recommended for use as an indicator of response; stability of disease is best 
described by providing the time-to-progression estimates. Not meeting criteria for 


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complete response, very good partial response, partial response, minimal response, or 
progressive disease 
Progressive 
disease 
Any one or more of the following criteria: 
Increase of 25% from lowest confirmed response value in one or more of the following 
criteria: 
Serum M-protein (absolute increase must be ≥0·5 g/dL); 
Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL; 
Urine M-protein (absolute increase must be ≥200 mg/24 h); 
In patients without measurable serum and urine M-protein levels, the difference between 
involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); In patients 
without measurable serum and urine M-protein levels and without measurable involved 
FLC levels, bone marrow plasma-cell percentage irrespective of baseline status (absolute 
increase must be ≥10%); 
Appearance of a new lesion(s), ≥50% increase from nadir in SPD §§ of >1 lesion, or ≥50% 
increase in the longest diameter of a previous lesion >1 cm in short axis; 
≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the only 
measure of disease 
Clinical 
relapse 
Clinical relapse requires one or more of the following criteria: 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB features) 
related to the underlying clonal plasma-cell proliferative disorder. It is not used in 
calculation of time to progression or progression-free survival but is listed as something 
that can be reported optionally or for use in clinical practice; 
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do 
not constitute progression); 
Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and ≥1 cm) increase as measured serially by the SPD §§ of 
the measurable lesion; 
Hypercalcemia (>11 mg/dL); 
Decrease in hemoglobin of ≥2 g/dL not related to therapy or other non-myeloma-related 
conditions; 
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable 
to myeloma; 
Hyperviscosity related to serum paraprotein 
Relapse from 
complete 
response (to 
be used only 
if the end 
point is 
disease-free 
survival) 
Any one or more of the following criteria: 
Reappearance of serum or urine M-protein by immunofixation or electrophoresis; 
Development of ≥5% plasma cells in the bone marrow; 
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, or 
hypercalcemia see above) 
Relapse from 
MRD negative 
(to be used 
only if the end 
point is 
disease-free 
survival) 
Any one or more of the following criteria: 
Loss of MRD negative state (evidence of clonal plasma cells on NGF or NGS, or positive 
imaging study for recurrence of myeloma); 
Reappearance of serum or urine M-protein by immunofixation or electrophoresis; 
Development of ≥5% clonal plasma cells in the bone marrow; 
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, or 
hypercalcemia) 


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13.2 Criteria for Study Endpoint Evaluability 
13.2.1 Regimen-related and transplant-related mortality 
 
Regimen related toxicity (RRT) refers to those toxicities that can be attributed directly to the 
preparative regimen (including chemotherapeutic agents, ATG, and ipilimumab). 
 
Transplant-related mortality (TRM) includes the RRT and other fatal complications resulting from the 
allogenic transplant such as graft failure, GvHD, hemorrhages, and infections. 
 
The grading for monitoring the morbidity and mortality will be based on the NCI/CTEP common toxicity 
criteria version 5.0. This will include assessment of severity and duration of oral mucositis and 
sequelae specifically parenteral opioid analgesic use, TPN use, febrile neutropenia, hospital days and 
intubation. 
 
13.2.2 Immunologic Reconstitution 
 
T cell chimerism and activity will be closely monitored following ipilimumab administration. 
Immunophenotyping of T-cells, B-cells, and NK cells will be performed at approximately 100 days, and 
then every month post-transplant until normal values are reached. T-cell proliferations in response to 
PHA will be performed at approximately 3 months post-transplant and every 3-6 months thereafter until 
normal values are reached. These tests are not required when a patient’s absolute lymphocyte    
count is less than 0.5 K/mcL. 
Immunoglobulin levels will be tested at 3, 6, 9, 12, and 18 months post-transplant and thereafter as 
clinically indicated. The patient will be revaccinated as per MSKCC adult BMT guidelines 
 
13.2.3 Engraftment and chimerism 
 
Engraftment will be documented by analysis of peripheral blood and bone marrow cells for chimerism 
by standard diagnostic molecular pathology studies at 1 month, 100 days, and thereafter in the blood 
prior to ipilimumab administration, and then every 3 months in blood and bone marrow until 18 months 
post-transplant, and then as needed thereafter. T-cell chimerism analysis is not required when a 
patient’s absolute lymphocyte count is less than 0.5 K/mcL. 
 
 
13.2.4 Graft failure or rejection 
 
Primary non-engraftment is diagnosed when the patient fails to achieve an ANC 500/mm3 at any time 
in the first 28 days post-transplant. If the patient's myeloma recurs during this interval, the patient is 
scored as having refractory myeloma. In such a situation, the absence of donor hematopoiesis is not 
evaluable for graft failure or rejection. If host T-cells capable of specifically inhibiting donor 
hematopoietic progenitor growth in vitro are concurrently detected during graft failure, a presumptive 
diagnosis of immune mediated rejection is made. If (1) after achievement of an ANC >500/mm2 the 
ANC declines to <500/mm3 for more than 3 consecutive days in the absence of relapse, or, (2) there is 
absence of donor cells in the marrow and/or blood as demonstrated by chimerism assay in the 
absence of relapse, a diagnosis of secondary graft failure is made. If, however, recurrence of host 
myeloma is detected concurrently, the patient is not evaluable for graft failure or rejection. 
 
Patients with evidence of graft failure without evidence of recurrence of host myeloma will have 
additional studies drawn under 06-107. A separate biospecimen research protocol will be submitted to 
ascertain cause and define relevant histoincompatibilities. These analyses may include (1) Evaluation 
of bone marrow aspirates and biopsies for residual or recurrent myeloma, when indicated, (2) Culture 
and/or molecular analyses of marrow and blood for viral pathogens potentially causing graft failure 
including CMV, HHV6 and parvovirus B 19, (3) Immunophenotypic and genetic analysis of circulating 
T-cells and NK cells to ascertain their origin and potential function, (4) Analysis of the functional 


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activity of residual circulating lymphocytes to determine whether and to what degree they exhibit 
cytotoxic or cyto-inhibitory activity against donor host or third party PHA-stimulated blasts or 
clonogenic hematopoietic progenitor cells. If donor-specific reactivity is identified, attempts will be 
made to identify targeted specificities (HLA or minor alloantigens) whenever possible. 
 
Patients who suffer graft failure will be considered for a secondary transplant. The need for additional 
immunosuppression or treatment for viral infection prior to the secondary transplant will be determined 
by the results obtained from chimeric and viral studies and will be done off study. 
 
13.2.5. Graft-versus-host disease 
 
Standard BMT-CTN and IBMTR systems clinical criteria as defined by Rowlings, et al will be used to 
establish and grade acute GvHD (13). To determine the severity of acute GvHD, data will be collected 
approximately weekly to characterize the severity of symptoms and signs caused by GvHD and to 
evaluate possible confounding factors. Real time data collection will include descriptive characteristics 
of rash and estimated body surface area involved, extent of dermal/epidermal separation, identification 
of concomitant causes of increased bilirubin other than GvHD, presence or absence of nausea, 
vomiting or anorexia persistent after engraftment, peak diarrhea volume with annotations concerning 
the presence after engraftment, peak diarrhea volume with annotations concerning the presence or 
absence of urinary mixing and estimates of true diarrhea volume, presence or absence of abdominal 
cramps, presence or absence of frank stool blood or melena, concomitant causes of GI symptoms 
other than GvHD, biopsy results, identification of any agents used for treatment and autopsy results. 
Patients will be observed for acute and/or chronic GvHD. Graft-versus-host disease occurring after 
ipilimumab infusions will be analyzed separately. 
 
Patients with moderate to severe acute GvHD (grade I2-4) will be treated in standard fashion with 
high-dose IV methylprednisolone (1-2mg/kg/day) or in combination with other immunosuppressants as 
per ongoing trials on GvHD. Patients failing to respond to steroids will be considered for treatment with 
experimental treatments available at the time of diagnosis of GvHD. 
 
Chronic GvHD will be diagnosed and graded according to the criteria of Sullivan(14) treated with 
standard or experimental immunosuppressive therapy. Treatment will consist of corticosteroids, 
cyclosporin A or azathioprine, or combinations of these agents. Other novel treatments could be used 
if available at the investigator’s discretion, i.e. thalidomide and psoralen/ultraviolet A phototherapy 
(PUVA). 
 
 
14.0 BIOSTATISTICS 
 
This is a phase I/II study designed to examine the efficacy and safety of ipilimumab for patients with relapsed 
or high-risk multiple myeloma. The primary objective of Phase I is to determine the dose of ipilimumab for the 
Phase II and that of Phase II is to assess the efficacy of ipilimumab. 
 
Phase I: A maximum of 12 patients will be accrued and DLTs will be assessed in these patients. DLTs are 
defined in Section 4.2 and the DLT evaluation window is three weeks from the final q3 week dose of the initial 
intense phase. If any DLT is observed in more than one of the six patient cohort, a lower dose of ipilimumab 
will be evaluated in a new six patient cohort. The phase II study will commence if no more than one patient in 
the cohort has a DLT. The proportion of patients who have a DLT among the six will be reported along with an 
exact 95% confidence interval. 
 
DLT are defined in Section 10.2. The table below shows the probabilities of de-escalation for different true 
underlying rates of toxicity. 


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True Toxicity Rates 
0.1 
0.15 
0.2 
0.25 
0.3 
0.35 
0.4 
Probability of De-escalation 
0.11 
0.22 
0.34 
0.47 
0.58 
0.68 
0.77 
 
If the dose is reduced and more than one patient in the six patient reduced-dose cohort has a DLT, the trial will 
stop. 
 
Phase II The primary endpoint of the phase II study is progression-free survival (PFS). PFS is defined as time 
from of initiation of ipilimumab to progressive disease or death from any cause. Response and progression are 
based on the criteria of the International Myeloma Working Group (Section 13). Based on historical MSKCC 
data on patients who would have been eligible to receive ipilimumab based on this protocol (based on critiera 
under Intervention 2, in Section 4.2), the estimate of median PFS is 11 months. The intervention will be 
considered promising if the 11-month PFS improves to 70% or higher. A total of 39 patients will accrue onto the 
phase II study. This includes the six patients treated at the same dose level in the phase I study. Using the 
nonparametric Kaplan-Meier survival estimate, the study will be considered promising if the PFS-estimate at  
11 months surpasses the critical value of 62%. Allogeneic patients are closely followed in this setting per 
standard of care evaluations. However, the study design conservatively allows for 15% dropout (patients 
censored prior to the 11-month time period). The one-sided type I error for this design is 0.10 and the the 
power is 0.86. In addition to the 11-month PFS estimate, the median PFS along with the corresponding 
confidence interval will be reported. Patient who receive at least one dose of ipilimumab will be considered 
evaluable for the primary objective. 
 
Sequential Stopping Rules for Phase II Assessment Phase: 
 
These stopping rules will be applied to the 33 phase II patients who were not included in the initial phase I 
study during the assessment phase. 
 
Immune related adverse events (irAE): 
 
The stopping rule is as follows: if 2 in the first 8 patients, 3 in the first 17 patients, 4 in the first 29 patients, or 5 
anytime develop AE the study will stop. If the true toxicity rate is 5%, the probability the study will be declared 
unsafe is 0.107; the probability increases to 0.97 if the true toxicity rate is 25%. 
 
Grade 4 Non-Hematologic Adverse Events: 
 
The stopping rule is as follows: if 2 in the first 8 patients, 3 in the first 17 patients, 4 in the first 29 patients, or 5 
anytime develop AE the study will stop. If the true toxicity rate is 5%, the probability the study will be declared 
unsafe is 0.107; the probability increases to 0.97 if the true toxicity rate is 25%. 
 
Grade II-IV GVHD: 
 
The stopping rule is as follows: if 2 in the first 8 patients, 3 in the first 17 patients, 4 in the first 29 patients, or 5 
anytime develop AE the study will stop. If the true toxicity rate is 5%, the probability the study will be declared 
unsafe is 0.107; the probability increases to 0.97 if the true toxicity rate is 25%. 
 
Treatment-related Mortality: 
 
The stopping rule is as follows: if 3 in the first 8 patients, if 4 in the first 14 patients, if 5 in the first 20 patients, if 
6 in the first 27 patients, or if 7 anytime have TRM the study will stop. If the true TRM rate is 10%, the 
probability the study will be declared unsafe is 0.10; the probability increases to 0.82 if the true toxicity rate is 
25%. 


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Sequential Stopping Rules for Safety During Maintenance Phase: 
 
These stopping rule will be applied to the 39 phase I-II patients and will include any events during the phase II 
assessment phase.. If the dose is de-escalated in the phase I study, the protocol will be amended, and the 
stopping rules will be extended to include all 12 phase I patients. 
 
Immune related adverse events (irAE): 
 
The stopping rule is as follows: if 3 in the first 12 patients, 4 in the first 22 patients, 5 in the first 32 patients, or 
6 anytime develop irAE the study will stop. If the true toxicity rate is 5%, the probability the study will be 
declared unsafe is 0.04; the probability increases to 0.87 if the true toxicity rate is 20%. 
 
Grade 4 Non-Hematologic Adverse Events: 
 
The stopping rule is as follows: if 3 in the first 12 patients, 4 in the first 22 patients, 5 in the first 32 patients, or 
6 anytime develop irAE the study will stop. If the true toxicity rate is 5%, the probability the study will be 
declared unsafe is 0.04; the probability increases to 0.87 if the true toxicity rate is 20%. 
 
Grade II-IV GVHD: 
 
The stopping rule is as follows: if 3 in the first 12 patients, 4 in the first 22 patients, 5 in the first 32 patients, or 
6 anytime develop grade II-IV GVHD the study will stop. If the true toxicity rate is 5%, the probability the study 
will be declared unsafe is 0.04; the probability increases to 0.87 if the true toxicity rate is 20%. 
 
Treatment-related Mortality: 
 
The stopping rule is as follows: if 3 in the first 8 patients, if 4 in the first 13 patients, if 5 in the first 20 patients,  
if 6 in the first 26 patients, if 7 in the first 33, or 8 anytime have TRM the study will stop. If the TRM rate is 10%, 
the probability the study will be declared unsafe is 0.1; the probability increases to 0.86 if the true toxicity rate  
is 25%.If one of these stopping rules is crossed, accrual to the study will be suspended and patients will not 
receive additional doses. The decision to either reopen or terminate the study will made after all safety data is 
reviewed by the study team in collaboration with the IRB and the FDA. 
 
Secondary: 
 
1. The toxicities associated with ipilimumab will be summarized. Descriptive statistics will be used to 
summarize toxicities by grade and phase of treatment. 
2. The cumulative incidence of grade II-IV acute GVHD will be estimated using cumulative incidence 
functions. This will be estimated from the time of ipilimumab administration. Competing risks include 
relapse and death. 
3. The cumulative incidence of chronic GVHD will be estimated using cumulative incidence functions. 
This will be estimated from the time of ipilimumab administration. Competing risks include relapse and 
death. 
4. The association between donor lymphocyte infusions (DLI) and progression-free survival will be 
estimated. PFS is measured from the time of ipilimumab administration, similar to the primary 
objective. This will be explored using a time-dependent covariate within Cox proportional hazards 
regression. 
 
Exploratory: 
 
Descriptive analysis of T cell phenotype and other mononuclear cell populations both before and after 
alloHSCT, and before and after ipilimumab administration will be done. Changes in T cell subpopulations 
before and after alloHSCT and ipilimumab administration will be analyzed descriptively; a Wilcoxon rank sum 
test may be used to further evaluate an association. 


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15.0 TOXICITIES/RISKS/SIDE EFFECTS 
 
Prior to consideration for transplant, all patients will undergo a series of consultations discussing the risks and 
potential benefits of an allogeneic stem cell transplantation as a standard of care and the added risks 
associated with enrollment in this study. The risks and potential benefits of the transplant procedure, as well as 
the participation in any given research, experimental, or therapeutic protocol will be discussed. 
 
15.1 General Description of Risks to Recipients 
 
Infections and hemorrhage constitute major and continuing risks throughout the period of marrow aplasia. 
These are, however, also the major risks associated with the primary disease. Certain opportunistic infections 
remain a risk in transplant patients beyond recovery of circulating leukocytes, for at least 9-12 months post- 
transplant, e.g. Pneumocystis carinii, cytomegalovirus and Epstein Barr virus. 
 
Common: 
 
Busulfan: Myelosuppression (causing anemia, neutropenia, and thrombocytopenia), fatigue, difficulty 
sleeping, anorexia, nausea, vomiting, diarrhea, abdominal pain, mucositis, weight gain and swelling (edema), 
alopecia, fever, infection, headache, worry, and sterility may be seen. 
 
Melphalan: Myelosuppression (causing fatigue, dizziness, headache, bruising, bleeding and infection) 
nausea, vomiting, diarrhea, mucositis, alopecia, fever, transient liver dysfunction, and sterility may be seen. 
 
Fludarabine: Myelosuppression (causing anemia, neutropenia, and thrombocytopenia), cough, tiredness, 
anorexia, nausea, vomiting, diarrhea, mucositis, fever, infection, bruising, bleeding, and pain may be seen. 
 
Reproductive risks: Sterility. Male patients may be offered sperm banking before admission for the 
transplant. Possibilities of preserving the ability to have children for female patients can be discussed with the 
doctor. Patients should not become pregnant or father a baby while on this study because the drugs in this 
study can affect an unborn baby. Women should not breast feed a baby while on this study. A pregnancy test 
is required of all females of childbearing age before starting the transplant. 
 
ATG: is a rabbit protein that may induce an immune response in humans. Fever, chills, changes in blood 
pressure, skin rash and itching, neutropenia, headache, and thrombocytopenia may be seen. Pre-medications 
(Benadryl, Tylenol and steroids before ATG) have been shown to be effective therapy. Side effects are usually 
only severe after the first dose. 
 
Ipilimumab: Diarrhea, fatigue, skin itchiness, skin rash, nausea, decreased appetite, fever, vomiting, and 
infusion site reaction (skin rash or hives) may be seen. 
 
Occasional: 
 
Busulfan: Seizures that are generally preventable by phenytoin therapy started 24 hours prior to 
administration and continued for 24 hours post busulfan. Abnormal liver function, pulmonary fibrosis, internal 
bleeding, menopause, cataracts, and hypothyroidism may be seen. 
 
Melphalan: Pneumonitis, pulmonary fibrosis, infection, bruising, bleeding, anemia, hepatitis, renal or bladder 
dysfunction (increased BUN, creatinine, necrosis), allergic reaction (edema, rash, shortness of breath, low 
blood pressure), cancer of the bone marrow and secondary cancer (specifically, when treated for a previous 
cancer) may be seen. 
 
Fludarabine: Damage to brain, lungs, and other organs, which may cause tiredness, changes in thinking, or 
shortness of breath, confusion, anemia, chills, numbness, increased ALT/AST, buildup of fluid causing 
swelling, skin rash 


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ATG: Prior exposure to rabbit proteins may predispose subjects to allergic reactions or serum sickness. Such 
reactions will be treated with epinephrine and anti-histamines. Serum sickness is an immune disease usually 
appearing 3-10 days after injection of a foreign serum or serum protein, with reactions such as hives, fever, 
swollen lymph nodes, edema, arthritis, protein in the urine, or severe inflammation of the kidney. In the event 
of a severe systemic allergic reaction, a trial of an alternative horse ATG will be administered. If a similar 
reaction occurs with the equine ATG, no further ATG will be administered. Tachycardia may also be seen. 
 
Ipilimumab: Hypopituitarism, hypophyitis, dehydration, confusion, nerve damage, intestinal/abdominal 
bleeding, colitis, constipation, heartburn, abdominal pain, abnormal liver function, inflammation of mucous 
membranes, inflammation of the skin (causing vitiligo, hives, hair loss or thinning, excessive sweating, dry 
skin), arthralgia, muscle spasms, shivering, fatigue, edema, pain, flu-like illness, weight loss, and shortness of 
breath may be seen 
 
Rare, and serious: 
 
Busulfan: high doses of Busulfan can cause Veno-Occlusive Disease (VOD), also called sinusoidal 
obstruction syndrome. Symptoms include jaundice,tiredness, weight gain, swelling, fluid retention in the 
abdomen, enlarged liver, and pain . This complication is managed by aggressive supportive care with 
monitoring of fluids and administration of diuretics and infusions of plasma and albumin. Veno-Occlusive 
Disease in its severe form can be life threatening. There is also a medication, Defibrotide, which has shown to 
be helpful in treating VOD. Additional rare side effects include buildup of excess fluid around the heart, 
inflammation of the liver, and cancer of the bone marrow. 
 
Melphalan: Serious hypersensitivity reactions, causing anaphylaxis (which may lead to drop in blood 
pressure, difficulty breathing, or even death), cardiac arrest, seizures, kidney failure, and VOD may be seen. 
 
Fludarabine: Kidney damage, which may require dialysis, neurotoxicity, including peripheral neuropathy, 
severe liver injury and/or liver failure, autoimmune hemolytic anemia, phlebitis, and deep vein thrombosis may 
be seen. 
 
ATG: Severe allergic reaction (anaphylaxis), which may lead to drop in blood pressure, difficulty breathing, or 
even death may be seen. 
 
Ipilimumab: Sepsis, septic shock, encephalitis, myelitis, urinary tract infection, respiratory infection, 
paraneoplastic syndrome, mild or severe allergic reactions, adrenal insufficiency, hyperthyroidism, tumor lysis 
syndrome, changes in mental health status, Guillain-Barré syndrome, fainting, conjunctivitis, abnormal 
heartbeat, inflammation of the blood vessels, inflammation of the lungs, bowel perforation, inflammation of the 
gut, ulcers and/or stomatitis, intestinal blockage, pancreatitis, inflammation of the liver and/or liver failure, toxic 
epidermal necrolysis, inflammation of the thyroid, kidney or CNS, inflammation of skeletal muscles, muscle 
weakness, kidney failure, absence of menstrual period, change in hair color, Giant cell arteritis, proctitis, 
psoriasis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS), and serous 
retinal detachment may be seen. 
 
Transplant related risks: 
 
Blood transfusions: Transfusions may induce allergic reactions. Small, subclinical pulmonary emboli may 
occur, but these rarely if ever require any intervention. Standard pre-medications for blood products may be 
used before administration of the marrow graft. Fluid overload can be managed with diuretics. Allergic 
reactions of variable severity can be prevented or mitigated by premedication with antipyretics, antihistamines, 
and narcotics. These products may also serve as vectors of serious infection (e.g., CMV, hepatitis, AIDS). To 
circumvent this, prospective blood and marrow donors will be screened per AABB and FAHCT guidelines. 
CMV antibody (-) blood products will be used in CMV (-) individuals, whenever possible, regardless of the 
antibody status of the marrow donor. All blood products are irradiated (3000r, 137Cs) to circumvent the risk 


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of GvHD caused by contaminating lymphocytes in the transfused fractions. 
 
Receiving peripheral blood stem cells: The volume of the T-cell depleted peripheral blood stem cells 
infused is approximately 30-50 cc. Possible side effects include: changes in blood pressure, fever, headache, 
shortness of breath, chills, sweats, nausea/vomiting, bad taste in the mouth. Pre-medications are given to 
reduce these side effects. 
 
Graft-versus-host-disease (known as GvHD): This condition happens when the transplanted donor cells 
recognizes the patient’s body as foreign and attacks it. At least 1-2 out of 10 patients receiving a T cell- 
depleted transplant will get mild to moderate GvHD. GvHD can be treated with medications (either IV or 
tablets). A biopsy may be necessary to make the diagnosis of GvHD. 
 
Acute GvHD usually occurs in the first 3 months and may cause: skin rashes, nausea, vomiting, diarrhea, 
hepatitis, increased risk of infection, ulceration of the surfaces of the oral cavity, esophagus, and intestines, 
and suppressed or delayed recovery of the hematopoietic and immune system It may be fatal in at least 20- 
50% of cases and may also predispose to lethal infections which contribute to an additional mortality of 10- 
25%.. In patients transplanted and engrafted with cliniMACS sorted CD34+ stem cells, this complication has 
been observed in fewer than 20% of patients and has rarely been severe. 
 
Chronic GvHD can occur any time after the first 3 months. Approximately 50% of patients with acute GvHD 
may also develop chronic GvHD, manifested to varying degrees by scleroderma-like changes of the skin, 
cirrhosis of the liver, sclerosis of lacrimal and salivary ducts, chronic inflammation and scarring of the 
gastrointestinal tract with consequent malabsorption and diarrhea, chronic bronchitis, and suppression of the 
immune system. This can be treated with standard or protocol-based experimental immunosuppression but 
may be refractory. 
 
Severe graft-versus-host disease: Rarely, GvHD can be severe or deadly. Severe acute GvHD could 
involve a severe skin rash like a burn, severe vomiting and/or diarrhea, liver failure and infections or bleeding. 
Severe acute GvHD will be treated with intense immunosuppressive therapy according to standard clinical 
practice or other experimental protocol. Severe chronic GvHD could involve similar symptoms but may 
produce other symptoms such as severe skin changes, severe dry eyes and weight loss. 
 
Infections or bleeding: Full recovery of blood counts may take months. Full recovery of the immune system 
may take months to a few years. For this reason, patients will be at increased risk of infections and bleeding. 
Medications are given to reduce the chance of those infections. Patients will receive treatment if they do get an 
infection and most infections can be treated successfully with antibiotics. Patients will stay in the hospital  
longer or be readmitted if found to have an infection. Patients are watched closely for bleeding and given 
platelet transfusions to prevent serious bleeding, but minor bleeding may occur. 
 
Serious infections or bleeding: Some infections are very difficult to treat, even with strong antibiotics. 
Rarely, serious infections can be passed on by the transfusion of blood products. Serious bleeding can 
happen in spite of platelet transfusions. Rarely infections or bleeding are lethal. 
 
Potential sensitization to murine proteins: Mouse protein (the anti CD34 antibody used in this device is of 
murine derivation) is used in the CliniMACS processing procedure. Marrow cells are also separated on bovine 
serum albumin gradients and exposed to sheep red cells to remove rosetting populations. It is possible that 
patients may have pre-existing immunity to these proteins and may be at risk for allergic reactions during 
infusion of the processed marrow and/or peripheral blood. No allergic reactions have been noted with infusions 
of cells processed by the CliniMACS system in clinical studies or from infusion of cells recovered by depletion 
of SRBC-rosette-positive cells. Precautions for an allergic event will be taken during the infusion of the 
processed cells. 
 
Pneumocystis jiroveci prophylaxis: The risk of trimethoprim and sulfamethoxazole in the doses given are 
primarily hypersensitivity reactions and signs of folate deficiency. Any patient with known hypersensitivity to 


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these compounds will not receive these drugs. The risks of parenteral pentamidine are primarily hypotension 
and hypoglycemia both of which will be monitored during and following administration of the drug. 
Hypokalemia or hypomagnesemia associated with prolonged QT syndrome or Torsade de pointe necessitates 
strict electrolyte monitoring. The risks of aerosolized pentamidine are mild bronchospasm primarily observed in 
(prior) tobacco abusers and easily managed with bronchodilator therapy. 
 
Risk of a secondary cancer different from multiple myeloma may happen after chemotherapy. The risk of 
developing a secondary cancer of the skin, cervix, etc., which has been seen in other studies of similar 
transplants, is less than 5%. There is a special concern in patients who receive a T cell-depleted transplants 
because there is a risk of having a cancer of the lymph nodes (lymphoma) caused by the Epstein Barr virus 
(EBV). This virus causes mononucleosis in healthy people. Treatment of EBV lymphoma includes Donor 
Leukocyte Infusion and Rituximab. 
 
Graft Failure: Bone marrow graft may fail to grow. Past experience suggests that this may occur in about 10% 
of patients. This number might be higher in patients treated with checkpoint inhibitor like ipilimumab by 
activating residual host T cells. Although not reported with ipilimumab in the post-llogeneic transplantation 
setting, this has been observed with PD-1 inhibitors are also immune checkpoint inhibitors (12). If graft failure 
occurs, it is unlikely that bone marrow will recover and a second transplant with stem cells from the same donor 
or a different donor will be needed. We will be monitoring T cell chimerism at monthly intervals whist the 
patients are on ipilimumab therapy starting day 100 – if the absolute lymphocyte count is equal to or greater 
than 0.5 K/mcL. – until 18 months post alloHSCT or if clinically indicated. T-cell chimerism analysis is not 
required when a patient’s absolute lymphocyte count is less than 0.5 K/mcL. 
 
Progression of Disease and Relapse of Multiple Myeloma is a risk even if the transplant is initially 
successful. Patients who have relapsed or progressed will be removed from study and be treated as per the 
investigator choice. 
 
15.2 ASSESSMENT OF SAFETY 
 
Toxicities during the transplant portion of the study will be graded and collected as per MSKCC Adult and 
Pediatric BMT Adverse Event Reporting Guide. 
 
Ipilimumab Safety 
 
The safety profile of ipilimumab was consistent with the pharmacology of the target and other agents in the 
immune checkpoint inhibitor class. No tumor types appeared to be associated with unique AEs. Immune- 
related AEs (irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
ipilimumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, 
endocrinopathy, dermatitis, and nephritis. These events are manageable by available/established treatment 
guidelines as described in the study protocol. 
 
15.3 
Investigational Scan Considerations 
 
Patients on study may have optional biopsies any time after a scan shows response to treatment. Patients 
undergoing investigational CT guided biopsies are exposed to an additional 0.626 Gy (+/- 0.132) 
dermatologically, an additional 29.9 mSv in for scan done in helical mode and an additional 18.9 mSv for 
scans done in axial mode. 
 
It is estimated that each patient with plasmacytoma(s) will have up to 3 additional scans for CT-guided 
biopsies. 
 
The informed consent will include the necessary risk language on contrast use and low-level radiation. 


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15.4 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant starts investigational treatment/intervention. SAE 
reporting is required for 30-days after the participant’s last investigational treatment/intervention. Any 
event that occur after the 30-day period that is unexpected and at least possibly related to protocol 
treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention and is 
related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per IRB SOP 
RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted within 5 calendar 
days of the event. All other SAEs must be submitted within 30 calendar days of the event. 
 
The report should contain the following information: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o 
An explanation of how the AE was handled 
o 
A description of the participant’s condition 
o 
Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
For IND/IDE protocols: 
The SAE report should be completed as per above instructions. If appropriate, the report will be forwarded to 
the FDA by the IND Office 


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The reportable serious adverse events during the transplant portion of the study will be defined according to 
the current MSKCC Adult BMT Adverse Event Reporting Guide. 
 
15.5 External AE/SAE Reporting 
 
Adverse Event Reporting 
 
Adverse Event intensity and/or severity will be graded using CTCAE Version 5.0 for toxicity and adverse event 
reporting. A copy of the CTCAE Version 5.0 can be downloaded from CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). All appropriate treatment 
areas should have access to a copy of the CTCAE Version 5.0. All adverse clinical experiences, whether 
observed by the investigator or reported by the patient, must be recorded, with details about the duration and 
intensity of each episode, the action taken with respect to the test drug, and the event’s outcome, including lab 
abnormalities. The investigator must evaluate each adverse experience for its relationship to the test drug and 
for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical significance. If any abnormal 
laboratory result is considered clinically significant, the investigator must provide details about the action taken 
with respect to the test drug and about the event’s outcome or lab abnormality. 
 
Monitoring, recording and reporting adverse events 
 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or 
worsen in a subject during a study. It may be a new intercurrent illness, a worsening concomitant illness, an 
injury, or any concomitant impairment of the subject’s health, including laboratory test values, regardless of 
etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a pre- 
existing condition) should be considered an AE. A diagnosis or syndrome should be recorded rather than the 
individual signs or symptoms of the diagnosis or syndrome. 
 
Abuse, withdrawal, sensitivity or toxicity to the investigational product should be reported as an AE. An 
overdose, accidental or intentional, whether it is associated with an AE, should be reported. Any sequela of an 
accidental or intentional overdose of the investigational product should be reported as an AE. If the sequela of 
an overdose is an SAE, then the sequela must be reported on an SAE report form and as an AE. 
 
All subjects will be monitored for AEs during the study. Assessments may include monitoring of any or all of 
the following parameters: the subject’s clinical symptoms, laboratory, pathological, radiological or surgical 
findings, physical examination findings, or findings from other tests and/or procedures. 
 
All AEs will be recorded by the Investigator from the time the subject signs informed consent until 90 days after 
the last dose of IP and those SAEs made known to the investigator at any time thereafter that are suspected of 
being related to IP. AEs and serious adverse events (SAEs) will be recorded in the subject’s source 
documents. All SAEs must be reported to BMS Drug Safety within 24 hours of the Investigator’s knowledge of 
the event by facsimile, or other appropriate method, using a redacted MSK SAE Report Form. 
 
Evaluation of adverse events 
 
A qualified Investigator will evaluate all adverse events as to: 
 
Seriousness 
 
A serious adverse event (SAE) is defined in section 15.3 
 
Events not considered to be SAEs are hospitalizations for: 
 
− 
A standard procedure for protocol therapy administration. However, hospitalization or prolonged 
hospitalization for a complication of therapy administration will be reported as an SAE. 


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− 
Routine treatment or monitoring of the studied indication not associated with any deterioration in 
condition. 
 
− 
The administration of blood or platelet transfusion as routine treatment of studied Indication. However, 
hospitalization or prolonged hospitalization for a complication of such transfusion remains a reportable 
SAE. 
 
− 
A procedure for protocol/disease-related investigations (e.g., surgery, scans, endoscopy, sampling for 
laboratory tests, bone marrow sampling). However, hospitalization or prolonged hospitalization for a 
complication of such procedures remains a reportable SAE. 
 
− 
Hospitalization or prolongation of hospitalization for technical, practical, or social reasons, in absence of 
an AE. 
 
− 
A procedure that is planned (i.e., planned prior to starting of treatment on study); must be documented 
in the source document and the CRF. Hospitalization or prolonged hospitalization for a complication 
remains a reportable SAE. 
 
− 
An elective treatment of or an elective procedure for a pre-existing condition unrelated to the studied 
indication. 
 
− 
Emergency outpatient treatment or observation that does not result in admission, unless fulfilling other 
seriousness criteria above. 
 
If an AE is considered serious, the SAE Report Form must be completed. For each SAE, the Investigator will 
provide information on severity, start and stop dates, relationship to IP, action taken regarding IP, and 
outcome. 
 
Definition of adverse events of special interest (AESI) 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to understanding of 
the Investigational Product and may require close monitoring and rapid communication by the investigator to 
the sponsor. An AESI may be serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance 
of these events in order to characterize and understand them in association with the use of this investigational 
product. 
 
AESIs for ipilimumab include but are not limited to events with a potential inflammatory or immune-mediated 
mechanism and which may require more frequent monitoring and/or interventions such as steroids, 
immunosuppressants and/or hormone replacement therapy. These AESIs are being closely monitored in 
clinical studies with ipilimumab monotherapy and combination therapy. An immune-related adverse event 
(irAE) is defined as an adverse event that is associated with drug exposure and is consistent with an immune- 
mediated mechanism of action and where there is no clear alternate etiology. Serologic, immunologic, and 
histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis. Appropriate efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE. 
 
AESIs observed with ipilimumab include those specified in the IB section 5.5.2. 
 
Assessment of safety parameters 
Assessment of severity 
For both AEs and SAEs, the Investigator must assess the severity / intensity of the event. 
 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the current active 
minor version of the Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0);  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 


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AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to the following 
scale: 
 
− 
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical intervention/therapy 
required 
 
− 
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be needed; no or 
minimal medical intervention/therapy required 
 
− 
Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible 
 
− 
Grade 4 = Life-threatening – extreme limitation in activity, significant assistance required; significant 
medical intervention/therapy required, hospitalization or hospice care probable 
 
− 
Grade 5 = Death - the event results in death 
 
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as 
severe headache). This criterion is not the same as “serious” which is based on subject/event outcome or 
action criteria associated with events that pose a threat to a subject’s life or functioning. 
 
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
 
Causality 
 
The Investigator must determine the relationship between the administration of IP and the occurrence of an 
AE/SAE. 
 
Causality should be assessed and provided for every AE/SAE based on currently available information. 
Causality is to be reassessed and provided as additional information becomes available. 
 
Duration 
 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the event. 
 
Action Taken 
 
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable (e.g., 
discontinuation, interruption of IP, as appropriate) and report if concomitant and/or additional treatments were 
given for the event. 
 
Outcome 
 
The Investigator will report the outcome of the event for both AEs and SAEs. All SAEs that have not resolved 
upon discontinuation of the subject’s participation in the study must be followed until recovered (returned to 
baseline), recovered with sequelae, or death (due to the SAE). 
 
Overdose 
 
Overdose, as defined for this protocol, refers to ipilimumab. 
 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified dose of 
ipilimumab assigned to a given patient, regardless of any associated adverse events or sequelae. 
 
PO 
any amount over the protocol-specified dose 


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IV 
10% over the protocol-specified dose 
SC 
10% over the protocol-specified dose 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the protocol 
required schedule or frequency. 
 
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified rate. 
 
Complete data about drug administration, including any overdose, regardless of whether the overdose was 
accidental or intentional, should be reported. 
 
Pregnancy 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease 
state) of a female subject occurring while the subject is on IP, or within 28 days of the subject’s last dose of IP, 
are considered immediately reportable events. IP is to be discontinued immediately. The pregnancy,  
suspected pregnancy, or positive pregnancy test must be reported to BMS Drug Safety immediately by 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved equivalent form. 
The female subject may be referred to an obstetrician-gynecologist (not necessarily one with reproductive 
toxicity experience) or another appropriate healthcare professional for further evaluation. 
 
The Investigator will follow the female subject until completion of the pregnancy and must notify BMS Drug 
Safety immediately about the outcome of the pregnancy (either normal or abnormal outcome) using the 
Pregnancy Follow-up Report Form or approved equivalent form. 
 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator 
should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, it 
must be reported as an SAE to BMS Drug Safety immediately by facsimile, or other appropriate method, within 
24 hours of the Investigator’s knowledge of the event using the SAE Report Form or approved equivalent form. 
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male subject taking 
IP should notify the Investigator, and the pregnant female partner should be advised to call their healthcare 
provider immediately. 
 
Second Primary Malignancies 
 
Second primary malignancies will be monitored as events of interest and must be reported as serious adverse 
events. This includes any second primary malignancy, regardless of causal relationship to IP (alloHSCT and 
ipilimumab), occurring at any time for the duration of the study, from the time of signing the informed consent 
document for at least 3 years from the date the last subject is randomized into the study. Events of second 
primary malignancy are to be reported using the SAE report form and must be considered an “Important 
Medical Event” if no other serious criteria apply; these events must also be documented in the appropriate 
page(s) of the CRF (i.e., AE and SPM CRF) and subject’s source documents. Documentation on the diagnosis 
of the second primary malignancy must be provided at the time of reporting as a serious adverse event (e.g., 
any confirmatory histology or cytology results, X-rays, CT scans, etc.). 
 
Collection and Reporting Information: 
• 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through (100 days) of discontinuation of dosing must be reported to 
BMS Worldwide Safety, whether related or not related to study drug. If applicable, SAEs must 
be collected that relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy). 


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• 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, are collected, including those thought to be associated with protocol- 
specified procedures. The investigator should report any SAE occurring after these 
aforementioned time periods, which is believed to be related to study drug or protocol-specified 
procedure. 
• 
An SAE report should be completed for any event where doubt exists regarding its 
seriousness; 
• 
If the investigator believes that an SAE is not related to study drug but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report 
Form. 
 
A redacted MSK SAE report will be used to report SAEs to BMS. The BMS Protocol number should 
be on the SAE form or on the cover sheet with the SAE form transmission. 
 
• 
The Sponsor will reconcile the clinical database AE cases (case level only) transmitted to 
BMS Global Pharmacovigilance (Worldwide.Safety@bms.com). 
▪ 
The Investigator will request from BMS GPV&E, 
aepbusinessprocess@bms.com the SAE reconciliation report and include the 
BMS protocol number every 3 months and prior to data base lock or final data 
summary 
▪ 
GPV&E will send the investigator the report to verify and confirm all SAEs 
have been transmitted to BMS GPV&E. 
▪ 
The data elements listed on the GPV&E reconciliation report will be used for 
case identification purposes. If the Investigator determines a case was not 
transmitted to BMS GPV&E, the case should be sent immediately to BMS 
(Worldwide.Safety@bms.com). 
• 
In addition to the Sponsor Investigator’s responsibility to report events to their local HA, 
suspected serious adverse reactions (whether expected or unexpected) shall be reported by 
BMS to the relevant competent health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate reports). 
• 
In accordance with local regulations, BMS will notify sponsor investigators of all reported SAEs 
that are suspected (related to the investigational product) and unexpected (i.e., not previously 
described in the IB). An event meeting these criteria is termed a Suspected, Unexpected 
Serious Adverse Reaction (SUSAR). Sponsor investigator notification of these events will be in 
the form of either a SUSAR Report or a Semi-Annual SUSAR Report. 
✓ Other important findings which may be reported by BMS as an Expedited Safety Report 
(ESR) include: increased frequency of a clinically significant expected SAE, an SAE 
considered associated with study procedures that could modify the conduct of the study, 
lack of efficacy that poses significant hazard to study subjects, clinically significant safety 
finding from a nonclinical (e.g., animal) study, important safety recommendations from a 
study data monitoring committee, or sponsor or BMS decision to end or temporarily halt a 
clinical study for safety reasons. 


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✓ Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the IB. Where required by local regulations or when there is a central IRB/IEC for the 
study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and 
IRB/IEC will determine if the informed consent requires revision. The investigator should 
also comply with the IRB/IEC procedures for reporting any other safety information. 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 
24 hours \ 1 Business Day of becoming aware of the event. SAEs must be recorded on either 
CIOMS, MedWatch, or approved site SAE form. 
Pregnancies must be reported and submitted to BMS. BMS will perform due diligence follow-up 
using the BMS Pregnancy Form which the investigator must complete. 
 
SAE Email Address: Worldwide.Safety@BMS.com 
 
SAE Facsimile Number:  +1 609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day to BMS 
using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The casual relationship can be one of the following: 
 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
 
Not related: There is not a reasonable causal relationship between study drug administration and the 
AE. 
 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. 
 
NONSERIOUS ADVERSE EVENT 
• 
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or final 
study reports as specified in the agreement or, if a regulatory requirement [e.g., IND US trial] 
as part of an annual reporting requirement. 
• 
Non-serious AE information should also be collected from following the subject’s written 
consent to participate in the study. 


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Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin following the subject’s written consent to 
participate in the study. All non-serious adverse events (not only those deemed to be treatment- 
related) should be collected continuously during the treatment period and for a minimum of (100 
days) following the last dose of study treatment. 
 
Non-serious AEs should be followed to resolution or stabilization or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 
 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as such. 
 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy. 
 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value). 
 
AEs of Special Interest 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half-lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for participant). 
 
The investigator must immediately notify Worldwide.Safety@bms.com of this event and complete 
one of the following forms within 24 hours of awareness of the event via either the CIOMS, 
MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE reporting 
procedures. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, X- 
rays, and any other potential safety assessments, whether or not these procedures are required by 
the protocol, should also be recorded as a non-serious or serious AE, as appropriate, and reported 
accordingly. 


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16.1 PROTECTION OF HUMAN PARTICIPANTS 
 
Participation in this trial is voluntary. All patients will be required to sign a statement of informed consent, 
which must conform to MSKCC IRB guidelines. Patients who do not wish to participate in the study may 
receive a conventional transplant. The study will protect the rights of all human subjects and an informed 
consent will clearly define the risks, benefits toxicities and side effects of treatment. We will also thoroughly 
explain the alternative options for treatment. 
 
The patients will be aware of the potential financial costs and burdens of enrolling on a clinical trial. The 
patient’s health plan/insurance company will need to pay for all of the costs of treatment in this study excluding 
the ipilimumab and research specimen collection/analysis. The patient will be responsible for the costs of 
standard medical care, all hospitalizations and any transplant complications. Patients will not be paid for taking 
part in this study. 
 
16.1 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information pursuant to a 
completed and signed Research Authorization form. The use and disclosure of protected health 
information will be limited to the individuals/entities described in the Research Authorization form. A 
Research Authorization form must be approved by the IRB and Privacy Board (IRB/PB). 
 
The consent indicates that individualized de identified information collected for the purposes of this 
study may be shared with other qualified researchers. Only researchers who have received approval 
from MSK will be allowed to access this information which will not include protected health information, 
such as the participant’s name, except for dates. It is also stated in the Research Authorization that 
their research data may be shared with others at the time of study publication. 
 
 
16.2 
Data Management 
 
A Clinical Research Coordinator (CRC), a Clinical Research Associate (CRA), and a Research 
Regulatory Associate (RRA) will be assigned to the study. The responsibilities of these positions will 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolutions, and coordination of the activities of the protocol study team. The data 
collected for this study will be entered into a secure database: Clinical Research Database (CRDB) 
and Medidata. Source documentation will be available to support the computerized patient record. 
 
Final data sets for publication are required to be locked and stored centrally for potential future access 
requests from outside entities. 
 
16.3 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and accuracy of evaluations and follow-up will be monitored periodically 
throughout the study period and potential problems will be brought to the attention of the study team 
for discussion and action. Full sample data quality and protocol compliance audits will be conducted  
by the study team, at a minimum of two times per year, and more frequently if indicated. 
 
16.4 
Data and Safety Monitoring 
 
The Data and Safety Monitoring Plan utilized for this study must align with the MSK DSM Plan, where 
applicable. 


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The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering were approved by the 
National Cancer Institute in August 2018. The plans address the new policies set forth by the NCI in  
the document entitled “Policy of the National Cancer Institute for Data and Safety Monitoring of Clinical  
Trials.” 
 
There are several different mechanisms by which clinical studies are monitored for data, safety and 
quality. At a departmental/PI level there exists procedures for quality control by the research team(s). 
Institutional processes in place for quality assurance include protocol monitoring, compliance and data 
verification audits, staff education on clinical research QA and two institutional committees that are 
responsible for monitoring the activities of our clinical trials programs. The committees: Data and 
Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety 
Monitoring Board (DSMB) for Phase III clinical trials, report to the Deputy Physician-in-Chief, Clinical 
Research. 
 
During the protocol development and review process, each protocol will be assessed for its level of 
risk and degree of monitoring required. 
 
The MSK DSMB monitors phase III trials and the DSMC monitors non-phase III trials. The DSMB/C 
have oversight over the following trials: 
 
• 
MSK Investigator Initiated Trials (IITs; MSK as sponsor) 
• 
External studies where MSK is the data coordinating center 
• 
Low risk studies identified as requiring DSMB/C review 
 
The DSMC will initiate review following the enrollment of the first participant/or by the end of the year 
one if no accruals and will continue for the study lifecycle until there are no participants under active 
therapy and the protocol has closed to accrual. The DSMB will initiate review once the protocol is open 
to accrual. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-329 A(2) 
Approval date: 14-Jan-2021 
Administrative Update 6 : 03-Jan-2023 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 38 of 38 
 
 
 
17.0 
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2. 
Giralt S, Koehne G. Allogeneic hematopoietic stem cell transplantation for multiple myeloma: 
what place, if any? Current hematologic malignancy reports.2013;8:284-290. 
3. 
Smith E, et al. CD34-Selected Allogeneic Hematopoietic Stem Cell Transplantation for 
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8. 
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Bashey A, et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after 
allogeneic hematopoietic cell transplantation. Blood.2009;113:1581-1588. 
10. 
Brentjens R, Yeh R, Bernal Y, Riviere I, Sadelain M. Treatment of chronic lymphocytic 
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12. 
Bryant AR, Perales MA, Tamari R, Peled JU, Giralt S. Severe pembrolizumab-associated 
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Rowlings PA, et al. IBMTR Severity Index for grading acute graft-versus-host disease: 
retrospective comparison with Glucksberg grade. Br J Haematol.1997;97:855-864. 
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Sullivan K, et al. Prednisone and azathioprine compared with prednisone and placebo for 
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allogeneic marrow transplantation. Blood.1988;72:546-554. 
 
18.0 
APPENDICES 
 
Not applicable.