Clinical trial NCT01131169
Conditions: Multiple Myeloma
Keywords: Myeloma Busulfan Melphalan Fludarabine T-Cell Stem Cell Transplantation 10-051
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2010-05-01; Completion date: 2020-05-15
Enrollment: 66 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The patients are being offered a stem cell transplant. Stem cells are very early blood cells. They have not yet matured to become red or white blood cells or platelets. They have already received the standard treatment of chemotherapy and an autologous stem cell transplant. An autologous stem cell transplant is when the patient receives their infusion of their own cells. Thi will give the patient a better chance of curing the disease, this protocol includes an infusion of stem cells from the blood (or the bone marrow) of another person. This is called an allogeneic stem cell transplant. The stem cells will begin to grow in the bone marrow and produce new blood cells.

Allogeneic stem cell transplants can cause a condition called graft-versus-host disease or GVHD. In GVHD, a kind of white blood cell from the donor (graft) begins to attack the body (host). That blood cell is called a T-cell. It is a cell that normally helps to protects against things like bacteria and viruses. In this case, the donor's T-cells see the body as foreign in the same way they would see bacteria as foreign. GVHD can be fatal. In order to lower the chance that the patient will get GVHD this protocol treatment will remove the T-cells from the donor's cells. This is called T-cell depletion. The T cells are removed by a system called "Clinimacs". This method is still being evaluated through clinical trials and not been approved by the Federal Drug Administration (FDA) at this time.

Before the transplant, the physician will treat the bone marrow to get rid of the cancer. The physician uses three chemotherapy drugs plus ATG. The chemotherapy drugs (Busulfan, Melphalan and Fludarabine) kills the cancer. ATG gets rid of any of the patients T cells that survive the chemotherapy. This ensures that the donor stem cells are not rejected. The patient will also receive additional white blood cells called lymphocytes from the donor. This is called a donor lymphocyte infusion or DLI. These additional infusions will help cause a graft-versus-myeloma effect and can help the donor stem cells grow.

Detailed description:

Arms: arm 1: This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma. arm 2: This is a two arm phase II trial to assess the progression-free and overall survival as well as the safety and efficacy of allogeneic hematopoietic stem cell transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with relapsed or high-risk multiple myeloma.
Interventions: intervention 1: busulfan, melphalan and fludarabine intervention 2: busulfan, melphalan and fludarabine
Intervention descriptions: intervention 1: Patients will be cytoreduced with IV busulfan, melphalan and fludarabine. Busulfan will be administered at a dose of 0.8mg/Kg q6hrs for 10 doses on days -9, -8, -7. Doses for busulfan should be adjusted according to pharmacokinetic studies. Melphalan will be administered at a dose of 70 mg/m2/day for 2 days on days -7, -6. Fludarabine will be administered at a dose of 25 mg/m2/day for 5 days on days -6, -5, -4, -3, -2. Patients will also receive rabbit anti-thymocyte globulin (ATG) to prevent immune mediated graft rejection. The ATG will be administered at a dose of 2.5 mg/Kg/day IV on days -3 and -2. Doses for busulfan, melphalan and ATG should be adjusted if patient is \> 125% ideal body weight and should be calculated on adjusted ideal body weight. intervention 2: Patients will be cytoreduced with IV busulfan, melphalan and fludarabine. Busulfan will be administered at a dose of 0.8mg/Kg q6hrs for 10 doses on days -9, -8, -7. Doses for busulfan should be adjusted according to pharmacokinetic studies. Melphalan will be administered at a dose of 70 mg/m2/day for 2 days on days -7, -6. Fludarabine will be administered at a dose of 25 mg/m2/day for 5 days on days -6, -5, -4, -3, -2. Patients will also receive rabbit anti-thymocyte globulin (ATG) to prevent immune mediated graft rejection. The ATG will be administered at a dose of 2.5 mg/Kg/day IV on days -3 and -2. Doses for busulfan, melphalan and ATG should be adjusted if patient is \> 125% ideal body weight and should be calculated on adjusted ideal body weight.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
Page 1 of 46 
 
 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
A Trial of Busulfan, Melphalan, Fludarabine and T-Cell Depleted All 
Cell Transplantation Followed by Post Transplantation Donor Lymph
with Relapsed or High-Risk Multiple Myelo 
MSKCC THERAPEUTIC/DIAGNOSTIC PRO 
Principal 
Sergio Giralt, M.D. 
Investigator/Department: 
ogeneic Hematopoietic Stem 
ocyte Infusions for Patients 
ma 
TOCOL 
Medicine, ABMT 
Co-Principal 
Hugo Castro-Mal
Investigator(s)/Department: 
aspina, M.D. 
Medicine, ABMT 
Investigator(s)/Department: 
Juliet Barker, M.B.B.S 
David Chung, MD, PhD 
Christina Cho, M.D. 
Parastoo Dahi, MD 
Boglarka Gyurkocza, M.D. 
Alan Hanash, M.D., Ph.D. 
Hani Hassoun, M.D. 
Katharine Hsu, M.D., Ph.D. 
Ann Jakubowksi, M.D., Ph.D. 
Scott James, MD. Ph.D. 
Neha Korde, M.D. 
Oscar Lahoud, M.D. 
Heather Landau, M.D. 
Nikoletta Lendvai, M.D., Ph.D. 
Alexander Lesokhin, M.D. 
Matthew Matasar, M.D. 
Esperanza Papadapoulos, M.D. 
Jonathan Peled, M.D. 
Miguel Perales, M.D. 
Ioannis Politikos, M.D. 
Doris Ponce, MD 
Craig Sauter, MD 
Michael Scordo, MD 
Brian C. Shaffer, M.D. 
Gunjan Shah, M.D. 
Melody Smith, M.D. 
Roni Tamari, M.D. 
Marcel R.M. van den Brink, M.D. Ph.D. 
James Young, M.D. 
Elaina Preston, P.A. 
Marci Andrejko, N.P. 
Jason Batalha, N.P. 
Abigail Cohen, N.P. 
Melissa Cortes, N.P. 
Stefanie Kelly, N.P. 
Sheila Kenny, N.P. 
Christina Kiss, N.P. 
Nicole Lestrange N.P. 
Courtney McElrath, N.P. 
Chelsea Mintz, N.P. 
Meighan Palazzo, N.P. 
Dayna Palumbo, N.P. 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, Lymphoma/Myeloma 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, Lymphoma/Myeloma 
Medicine, ABMT 
Medicine, ABMT 
Medicine, Lymphoma/Myeloma 
Medicine, Lymphoma/Myeloma 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, ABMT 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
 


Page 2 of 46 
Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
 
 
 
 
 
Megan H. Scott, N.P. 
Tara Doga, N.P. 
Naomi Cazeau, N.P. 
Carter Hibbs, N.P. 
Emily Patterson, N.P 
Allison Tucker, N.P. 
Shani Irby, N.P. 
Natasia Rodriguez, R.N. 
Achim Jungbluth, M.D. 
Sean Devlin Ph.D. 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Medicine, Nursing 
Nursing Pathology 
Epidemiology and Biostatistics 
Consenting 
Juliet Barker, M.B.B.S 
Medicine, ABMT 
Professional(s)/Department: 
Hugo Castro-Malaspina, M.D. 
Medicine, ABMT 
Christina Cho, M.D. 
Medicine, ABMT 
David Chung MD, PhD 
Medicine, ABMT 
Parastoo Dahi, M.D. 
Medicine, ABMT 
Sergio Giralt, M.D. 
Medicine, ABMT 
Boglarka Gyurkocza, M.D. 
Medicine, ABMT 
Alan Hanash, M.D., Ph.D. 
Medicine, ABMT 
Hani Hassoun, M.D. 
Medicine, Lymphoma/Myeloma 
Katharine Hsu, M.D., Ph.D. 
Medicine, ABMT 
Ann Jakubowksi, M.D., Ph.D. 
Medicine, ABMT 
Scott James, M.D., Ph.D. 
Medicine, ABMT 
Neha Korde, M.D. 
Medicine, Lymphoma/Myeloma 
Oscar Lahoud, M.D. 
Medicine, ABMT 
Heather Landau, M.D. 
Medicine, ABMT 
Nikoletta Lendvai, M.D., Ph.D. 
Medicine, Lymphoma/Myeloma 
Alex Lesokhin, M.D. 
Medicine, Lymphoma/Myeloma 
Matthew Matasar, M.D. 
Medicine, ABMT 
Esperanza Papadapoulos, M.D. 
Medicine, ABMT 
Jonathan Peled, M.D. 
Medicine, ABMT 
Miguel Perales, M.D. 
Medicine, ABMT 
Ioannis Politikos, M.D. 
Medicine, ABMT 
Doris Ponce, MD 
Medicine, ABMT 
Craig Sauter, MD 
Medicine, ABMT 
Michael Scordo, MD 
Medicine, ABMT 
Brian C. Shaffer, M.D. 
Medicine, ABMT 
Gunjan Shah, M.D. 
Medicine, ABMT 
Melody Smith, M.D. 
Medicine, ABMT 
Roni Tamari, M.D. 
Medicine, ABMT 
Marcel R.M. van den Brink, M.D., Ph.D. 
Medicine, ABMT 
James Young, M.D. 
Medicine, ABMT 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 3 of 46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 4 of 46 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................ 6 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 14 
4.1 
Design................................................................................................................................. 14 
4.2 
Intervention .............................................................................................................................. 14 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 15 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................... 18 
6.1 
Subject Inclusion Criteria ..................................................................................................... 18 
6.2 
Subject Exclusion Criteria ................................................................................................... 19 
7.0 
RECRUITMENT PLAN .................................................................................................................... 19 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 19 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 20 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 25 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 27 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 31 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 36 
14.0 
BIOSTATISTICS ............................................................................................................... 36 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
38 
15.1 
Research Participant Registration ....................................................................................... 38 
15.2 
Randomization .................................................................................................................... 39 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 39 
16.1 
Quality Assurance............................................................................................................... 39 
16.2 
Data and Safety Monitoring .................................................................................................... 39 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 40 
17.1 
Privacy ................................................................................................................................ 40 
17.2 
Serious Adverse Event (SAE) Reporting ................................................................................ 40 
17.2.1  ........................................................................................................................................  42 
18.0 
INFORMED CONSENT PROCEDURES................................................................................... 42 
19.0 
REFERENCES ....................................................................................................................... 43 
20.0 
APPENDICES ................................................................................................................... 46 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 5 of 46 
 
 
1.0     PROTOCOL SUMMARY AND/OR SCHEMA 
This is a two arm phase II trial to assess the progression-free and overall survival as well as the 
safety and efficacy of allogeneic hematopoietic stem cell transplantation using a  preparative 
regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell 
depleted stem cell transplant from a histocompatible related or unrelated donor in patients with 
relapsed or high-risk multiple myeloma. The administration of calculated doses of donor 
lymphocyte infusions post transplantation is designed to decrease the rate of relapse or to induce 
complete remissions in patients with residual disease following the allogeneic transplant. 
Candidates for this trial will include patients with multiple myeloma with relapsed disease following 
autologous stem cell transplantation who achieved at least a partial response (PR) following prior 
chemotherapy (cohort 1) and patients with high-risk cytogenetics at diagnosis achieving at least a 
very good partial response (VGPR) following prior autologous stem cell transplantation (cohort 2). 
Patients with plasma cell leukemia or patients achieving less than PR/VGPR are not eligible for 
this trial. Hematopoietic stem cell donors for this trial will include individuals who are 10/10 HLA 
matched or one antigen or allele mismatched at the HLA-A, B, C, DRB1 or DQB1 locus, as 
defined by high resolution methods. Donors who are 8/10 HLA matched with an antigen or allele 
mismatched at HLA-DQB1 and at one other locus will also be eligible for the trial. All patients will 
be conditioned for transplantation with busulfan (Busulfex®) (0.8 mg/Kg/dose Q6H x 10 doses), 
melphalan (70 mg/m2/day x 2 doses) and fludarabine (25mg/m2/day x 5 doses).  Doses  of 
busulfan and melphalan will be adjusted according to ideal body weight, busulfan will be adjusted 
according to first dose pharmacokinetic studies and doses of fludarabine will be adjusted 
according to measured creatinine clearance. Patients will also receive ATG (Thymoglobulin®) 
prior to transplant to promote engraftment and to prevent graft-versus host disease post 
transplantation. The preferred source of stem cells will be peripheral blood stem cells (PBSC) 
mobilized by treatment of the donor with G-CSF for 5-6 days. PBSC will be isolated, and T-cells 
depleted by positive selection of CD34+ progenitor cells, using the CliniMACS Cell Selection 
System. The CD34+ T-cell depleted peripheral blood progenitors will then be administered to the 
patients after they have completed cytoreduction. If the use of CD34+ PBSC is not possible, the 
alternative graft will consist of bone marrow derived stem cells T-cell depleted by CD34 selection 
of bone marrow using the Milteni CliniMACS device. This system has recently been validated and 
implemented for T-cell depletion of bone marrow, and will replace the Lectin/SRBC T-cell 
depletion procedure. No drug prophylaxis against GvHD will be administered post transplant. All 
patients will also receive G-CSF post-transplant to foster engraftment. Patients will also receive 
donor lymphocyte infusions following transplantation derived from the same hematopoietic stem 
cell donor. Donor lymphocytes will be administered prophylactically at calculated doses of 5x105 
CD3+  cells/kg 4-6 months and a second dose 5x105  CD3+ cells/kg 3-4 months post initial infusion 
to recipients from HLA-matched donors. The second infusion will be administered in the absence 
of graft-versus-host disease. A third infusion of 1x106 CD3+ cells/kg can be administered 2-4 
months following the second infusion, if the patient did not achieve a complete remission and 
lacks signs of graft-versus-host disease. Recipients of HLA-mismatched allografts will be infused 
with donor lymphocytes preemptively at disease relapse or progression of disease, if no complete 
remission was obtained following the transplant. These patients will then receive 1x105 CD3+ 
cells/kg at diagnosis of relapse or progression, but no sooner than 4-6  months  post 
transplantation. A second infusion of 5x105 CD3+ cells/kg will be administered  1-3  months 
following the first infusion provided the patient lacks signs of graft-versus-host disease. A third 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 6 of 46 
 
 
 
 
infusion of 1x106 CD3+ cells/kg can be administered 3-4 months following the second infusion, if 
the patient did not achieve a complete remission and lacks signs of graft-versus-host disease. 
Recipients of HLA-matched allografts will be treated preemptively at diagnosis of relapse or 
progression and according to the treatment plan described for those recipients of HLA- 
mismatched allografts. Patients will be monitored post transplant for donor engraftment, 
chimerism, incidence and severity of acute and chronic GvHD, regimen-related toxicity, 
characteristics of hematopoietic and immune reconstitution; transplant related and  relapsed 
related mortality, overall and disease-free survival. 
A maximum of 30 patients per cohort will be accrued to the study and the accrual period is 
expected to last 3 years with an additional 24 months of follow up after the accrual has been 
completed. The primary endpoint of the study is to assess one-year progression free survival from 
the time of transplant. An event is defined as a disease progression or death. For the relapsed 
multiple myeloma cohort, a single stage design that differentiates between one-year PFS rates of 
0.30 and 0.54 will be used to assess treatment efficacy. For the high-risk multiple myeloma 
cohort, a single stage design that differentiates between one-year PFS rates of 0.45 and 0.69 will 
be used to assess treatment efficacy. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
To study in a prospective phase II trial the progression-free survival, efficacy and safety of a 
chemotherapy-based cytoreduction using busulfan, melphalan, fludarabine, and ATG with T-cell 
depleted hematopoietic stem cell transplants from histocompatible related and unrelated donors, 
in patients with relapsed or high-risk multiple myeloma. This trial also incorporates prophylactic or 
preemptive post transplantation administrations of calculated doses of donor lymphocyte infusions 
derived from the same hematopoietic stem cell donor. 
 
Primary objectives of this trial are: 
 
1.   To determine the rates of progression-free (PFS) and of overall survival (OS) at 12 
months post transplant. 
 
Secondary objectives of this study are: 
 
1. To  assess  the  transplant-related  morbidity  and  mortality  for  patients  with  multiple 
myeloma. 
2. To assess the incidence of and severity of acute and chronic GvHD. 
3. To compute the current multiple myeloma free survival curve in order to account for 
patients who relapse and are restored to remission through DLI. 
4.  To explore the associations between progression free survival and the CT antigens - 
CT7, CT10, MAGE-A3 and NY-ESO-1. 
 
3.0     BACKGROUND AND RATIONALE 
 
3.1. 
Advanced Multiple Myeloma 
 
Multiple Myeloma (MM) is a malignant disease of plasma cells that accumulate in bone marrow, 
leading to bone destruction and bone marrow failure 1-2. The disease accounts for approximately 
10% of all hematologic malignancies, with an estimated 20,000 new MM diagnoses in 2007, and 
about 11,000 projected to die of the disease this year. The median survival of patients with high- 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 7 of 46 
 
 
 
 
risk myeloma is <2–3 years compared with a median survival of 6–7 years for patients with 
standard-risk MM.
2 Several independent prognostic factors have been developed to stratify 
standard-risk and high-risk myeloma patients in order to estimate median survival and justify 
treatment approaches. High-risk prognostic factors can be determined by molecular classifications 
such as deletion 13, deletion 17p, and immunoglobulin-heavy chain translocations t (4; 14) or t (14; 
16). Despite the introduction of promising novel agents including thalidomide, bortezomib, and 
lenalidomide, patients with high-risk myeloma continue to do poorly, even with tandem autologous 
bone marrow transplantation.2-3 Multiple previous studies have demonstrated a median 
progression-free survival of only 7-8 months in patients with high-risk cytogenetics after high-dose 
therapy and autologous stem cell transplantation.4-6 This translates into progression-free survival of 
35% at one year of this patient cohort. 
 
3.2. 
Hematopoietic Stem cell Transplantation for Multiple Myeloma 
 
Conventional treatments with chemotherapy and radiation therapy for patients with 
multiple myeloma (MM) are non-curative but improve quality of life and duration of survival. High- 
dose chemotherapy with autologous  transplantation  is  safe and has  low TRM (< 5%),  but  is 
associated with a continuing and nearly universal risk of disease progression and relapse. Even 
so, autologous transplantation is superior to continued conventional chemotherapy.
7 Although 
recent data indicate that tandem autologous transplants are superior to a single procedure,8 even 
with this approach, patients remain at risk of relapse and additional approaches are needed. 
Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative 
treatment available for patients with multiple myeloma. However, at this time, allogeneic 
hematopoietic stem cell transplantations are not standard of care for multiple myeloma patients as 
the success rate in these patients has been compromised by a high incidence of transplant- 
related mortality and high incidence of acute and/or chronic graft-versus- host disease (GvHD).
9-10 
This protocol uses T-cell depleted allogeneic stem cell infusions to reduce the risk of transplant- 
related mortality and graft versus host disease. 
 
3.2.1. Autologous Hematopoietic Stem cell Transplantation for Multiple Myeloma 
 
Barlogie et al
11- 13 demonstrated that the toxicity of high-dose melphalan could be 
decreased by autologous stem cell transplantation and that the use of peripheral blood 
hematopoietic stem cells led to wider application of high-dose therapy using autologous stem cell 
support. With autologous hematopoietic stem cell support following high-dose melphalan,  the 
toxic death rate was less than 3% in most studies14-15. At a dose of 200 mg/m2, high response 
rates in both untreated and previously treated patients are reported.16-21 In addition, recent data 
indicate melphalan 200 mg/m2 is less toxic but equally effective as  melphalan  with  TBI.22- 23 
Barlogie et al also demonstrated the feasibility of tandem autologous PBSC transplants using 
melphalan 200 mg/m2 for the first transplant and melphalan 200 mg/m2 (79 patients) or melphalan 
140 mg/m
2 plus TBI (1,125 cGy) (10 patients) for the second transplant. Of 123 patients, 87% 
completed one autologous transplant and 76% completed a tandem second autologous 
transplantation by 7.5 and 13 months, respectively, with a median interval between autologous 
transplantations of 4.5 months. The group reported 40% CR to tandem transplants and a median 
event-free survival of 49 months, based on intent to treat analysis in this single center experience. 
For responding patients, high-dose therapy followed by autologous PBSC  rescue  has  been 
shown to be superior  to continued treatment with conventional  chemotherapy, leading  to  the 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 8 of 46 
 
 
 
 
widespread use of autologous transplantation for myeloma patients up to and beyond the age of 
70.
24-25 In the IFM study, the progression free and overall survival curves separated after 3 years 
with improved disease free and overall survival at 6 years post-transplantation for the group that 
received tandem autologous transplants compared to those receiving single transplants.  Overall 
the median event free survival was 31 versus 37 months, 6-year event free survival was 19% 
versus 28% and 6-year overall survival 26% versus 46% for single versus tandem transplants, 
respectively. While TRM rates observed in these studies are low, patients continued to remain at 
risk for disease relapse and progression, with only a minority of patients remaining disease free at 
six years. Importantly, when Rajkumar et al assessed progression-free and overall survival based 
on risk category of standard versus high-risk patients, progression-free and overall survival were 
only 8 months and 14 months, respectively, in patients with high-risk disease who did not achieve 
a CR following high-dose Melphalan and autologous stem cell transplantation. Patients in the 
high-risk category achieving a CR following ASCT had a progression-free and overall survival of 
only 12 months and 23 months, respectively.2, 7 
 
3.2.2. Allogeneic Hematopoietic Stem cell Transplantation for Multiple Myeloma 
 
Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment 
available for patients with multiple myeloma. Despite the potential advantages of graft-versus- 
tumor immune responses and a tumor free source of stem cells, conventional high-dose 
conditioning with allogeneic bone marrow or PBSC transplantation, the success rate in these 
patients has been compromised by a high incidence of transplant-related mortality and high 
incidence   of   acute   and/or   chronic   graft-versus-   host   disease   (GvHD)   and   associated 
complications with transplant-related mortalities (TRM) exceeding 40%.
9-10   The TRM associated 
with allogeneic hematopoietic stem cell transplantation for MM exceeds that reported after 
allotransplantation for hematologic malignancies such as acute and chronic myeloid leukemias for 
unclear reasons. It possibly reflects the high incidence of co morbid disease, especially renal 
failure. The largest group of myeloma patients treated  with  allogeneic  bone  marrow 
transplantation, reported by Gahrton et al, 9-10 included 162 patients treated in  35  different 
European centers from 1983 to 1993. Early toxicity was high with an approximate 40% mortality 
within the first six months. Bensinger et al7 reported on 80 patients treated between 1987 and 
1994. Seventy-one percent of these patients were considered to have refractory disease at the 
time of transplant. TRM was high, with 42% deaths within the first 100 days and a few additional 
treatment-related deaths later. When used, it is generally limited to younger patients, in contrast 
to the advanced age profile of MM patients at diagnosis. In the experience at Fred Hutchinson 
Cancer Research Center (FHCRC), Day 100 TRM after conventional allografting exceeded 50% 
in patients ≥ 50 years of age. The inability of myeloma patients to tolerate allografting remains 
largely unknown, but may relate to an inability of generally elderly  and  immune  suppressed 
patients to tolerate the combined effects of high-dose therapy and allografting in a single 
procedure. In contrast, a Phase II study using a two-step approach where high-dose melphalan 
and autologous stem cell transplantation was followed by a non-myeloablative allogeneic 
transplant showed that donor engraftment can be established with a conditioning regiment of low 
dose total body irradiation (TBI) (200 cGy), cyclosporine (CSA) and mycophenolate mofetil (MMF) 
combined with peripheral blood stem cell (PBSC) allografting. This study demonstrated that 
allografting can be safely and effectively performed if the high-dose regimen is administered 
separate  from  the  allografting  procedure.    In  this  study,  approximately  60%  of  the  patients 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 9 of 46 
 
 
 
 
achieved complete remission (CR) with an overall-survival of approximately 85% at one year. 26 
One of the objectives of the study to reduce TRM at three months to < 20%, was achieved, as 
only 13% of patients experienced treatment-related mortality.26-27 Overall, the introduction of non- 
myeloablative for conditioning therapies in the treatment of myeloma has demonstrated reduced 
toxicity and transplant-related mortality.13-1 6, 20 However, results from transplants with non- 
myeloablative regimens were poor if the patient had failed prior autologous bone marrow 
transplantations or had developed chemotherapy-resistant disease.17, 20 
To extend the potential benefits of allogeneic  transplants to the full range of patients 
developing disorders for which a transplant is indicated, particularly older patients (> 50 years of 
age), who constitute the majority of patients with MM, as well as patients lacking HLA-matched 
sibling donors, major emphasis has been focused on the development of approaches which could 
circumvent severe acute and chronic GvHD so as to reduce its morbidity and mortality in both 
HLA-matched 
and 
HLA-non-identical 
transplant 
recipients. 
While 
no 
combination 
of 
immunosuppressive drugs administered to recipients of HLA-matched related or unrelated 
unmodified hematopoietic stem cells grafts has prevented the development of acute and chronic 
GvHD, this serious transplant related complication can be prevented by the depletion of T 
lymphocytes from the allograft prior to administration in HLA matched related and unrelated 
recipients as well as in HLA-disparate recipients.28-35 In our own series, among 232 consecutive 
adult leukemic patients (median age 41) engrafted with marrow transplants from HLA-matched 
siblings depleted of T-cells by soy bean agglutinin and E rosette depletion, the incidence of grade 
II-III GvHD was 3% and the incidence of chronic graft vs. host disease was 5%.36     Similarly, in 
over 100 unrelated marrow grafts transplanted using this T-cell depletion technique, the incidence 
of grade II-IV GvHD and of chronic GvHD has been 8%.
37
 
 
Initially, the central limitation to the effectiveness of T-cell depleted marrow transplants 
was a high risk for graft rejections  or late graft failures. Studies conducted at our institution 
demonstrated that such graft failures are principally caused by residual host T-lymphocytes which 
regenerate early after transplant and are able to reject donor hematopoietic cells through their 
cytotoxic interactions with major class I or class II HLA alloantigens in recipients of HLA-disparate 
transplants, or minor alloantigens presented by HLA class I determinants in recipients of HLA- 
matched grafts.38-39 Based on these findings, our group conducted a sequence of trials combining 
myeloablative doses of either total body irradiation, thiotepa and fludarabine or busulfan, 
melphalan and fludarabine with antithymocyte globulin (ATG) which reduced the incidence of graft 
failures following HLA-matched T cell depleted transplants to less than 2% and the incidence of 
graft failure following unrelated and 1-2 allele disparate marrow grafts to less than 8%.36-37, 40 
These rates of graft failure are comparable to those observed following unmodified transplants 
from such donors.41 Additionally, Aversa et al42- 44 demonstrated that when G-CSF mobilized 
peripheral blood stem cells are utilized as the source of hematopoietic stem cells for  T-cell 
depleted graft, the doses of stem cells provided are 5-10 fold higher than those that can be 
achieved in a marrow transplant and allow a  durable  engraftment  and  hematopoietic 
reconstitution even in HLA-haplotype disparate leukemic recipients.42 Based  upon  this 
observation, G-CSF mobilized peripheral blood stem cells are currently the preferred source of 
hematopoietic cells for T cell depleted transplants. 
 
3.2.3. Donor Lymphocyte Infusions 


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Initial proof of donor lymphocytes derived from the same hematopoietic stem cell donor to exert a 
graft-versus-leukemia effect resulted from the pioneering findings of Kolb et al45 and was later 
confirmed by several centers.46-50 Patients who developed relapses of chronic myelogenous 
leukemia (CML) following an allogeneic marrow transplant were induced into durable molecular 
remissions by high doses of peripheral blood mononuclear cells derived from the original HLA- 
matched transplant. These studies provided the first evidence that enhanced resistance to 
leukemia, accrued through a marrow allograft by comparisons of relapse rates following 
syngeneic vs HLA-matched allogeneic transplants, was indeed mediated by cells in the donor 
graft.46 
 
Several observations suggest the existence of graft-versus-myeloma immune activity following 
allogeneic transplantation. Bjorkstrand demonstrated indirect evidence in a case-matched 
analysis of 189 myeloma patients treated with either autologous transplant or allogeneic 
transplantation. He found a significantly higher rate of relapse from CR or disease progression 
from PR in the autologous transplant group compared to patients who underwent allogeneic 
transplantation.51 In addition, the quality of remission appeared greater following allogeneic 
transplantation as molecular remissions were rarely (7%) achieved after autografting (n=15) 
compared to a 50% molecular remission rate seen after allografting (n=14).52 These data suggest 
that the chemoresistance of myeloma cells might be overcome by immune antitumor effects of the 
allograft. The existence of a graft-versus-myeloma effect has been more directly confirmed by 
results of donor lymphocyte infusion (DLI) in patients who relapse after failure of conventional 
allografts.53-55 Salama reported results on 25 patients who received DLI (median dose 1x108 
mononuclear cells/kg) for MM relapsing after an allograft. Some patients received chemotherapy 
prior to the DLI and some received multiple escalating doses of DLI. Overall, 7 of 15 achieved a 
CR and 3, a partial response (PR). Lokhorst53 reported on 27 patients receiving DLI following 
partially T-cell  depleted  allo  transplants.    The  DLI were  given  a  median  of  30  months post- 
transplant. Overall, 14 of 27 patients responded with 5 CRs. Responding patients received at 
least 1x10
8 mononuclear  cells/kg. All responding patients developed graft-versus-host disease 
following administration of the relatively high doses of donor T lymphocytes. 
 
Alyea et al. combined a CD6 T-cell-depleted allogeneic BM  with prophylactic 
administration of CD4+ DLI 6 to 9 months after BMT in an effort to reduce TRM and to induce a 
GVM response after BMT. Twenty-four patients with matched sibling donors and chemotherapy- 
sensitive disease underwent BMT following a TBI, Cytoxan or Cytoxan, Busulfan conditioning 
regimen. CD6 T-cell depletion of donor bone marrow was the sole method of graft-versus-host 
disease (GvHD) prophylaxis. GvHD after BMT was minimal, 1 (4%) grade III and 4 (17%) grade II 
GvHD. Fourteen patients received DLI (1-3x107/kg CD4+ cells), 3 in complete response and 11 
with persistent disease after BMT. Significant GVM responses were noted after DLI in 10 patients 
with persistent disease, resulting in 6 complete responses and 4 partial responses. After DLI, 50% 
of patients developed acute (> or = II) or extensive chronic GvHD. Two-year estimated overall 
survival and current progression-free survival (PFS) for all 24 patients is 55% and 42%, 
respectively. The 14 patients receiving DLI had an improved 2-year current PFS (65%) when 
compared with a historical cohort of MM patients who underwent CD6-depleted BMT survived 6 
months with no GvHD and did not receive DLI (41%) (P =.13). Although this study suggested that 
prophylactic DLI induced significant GVM responses after allogeneic BMT, only 58% of patients 


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were able to receive DLI despite T-cell depleted BMT due to transplantation associated toxicities. 
The authors of this study therefore suggested that less toxic transplantation strategies are needed 
to allow a higher proportion of patients to receive DLI and the benefit from the GVM effect after 
transplantation.56 
 
3.3. Rationale for Study 
 
This study aims at improving progression-free survival while reducing the transplantation-related 
complications in patients with relapsed or high-risk multiple myeloma. To achieve these goals, we 
propose to perform T-cell depleted allogeneic hematopoietic stem cell transplantation from related 
or unrelated matched or one HLA-antigen/allele mismatched donors with chemotherapy only 
conditioning and prophylactic/preemptive administrations of calculated doses of donor lymphocyte 
infusions, derived from the same hematopoietic stem cell donor. Our initial experience with T-cell 
depleted transplants has been in patients with myelodysplastic syndrome and acute leukemia. 
Our results summarized below showed that patients with advanced MDS have better transplant 
outcomes if they are transplanted in remission after chemotherapy. Because MDS patients are 
mostly older patients (>age 40), as are patients with multiple myeloma, and some of them are not 
eligible to receive total body irradiation, our institution developed a chemotherapy only preparative 
regimen including busulfan, melphalan, fludarabine and anti-thymocyte globulin for these patients 
who could also benefit from T-cell depleted SCT from HLA matched or HLA disparate related and 
unrelated donors. The results of our experience of T-cell depleted SCT in patients with advanced 
MDS with the chemotherapy only preparative regimen are summarized in the next paragraph. 
 
A phase II trial with a chemotherapy only conditioning was performed from August 2001 – 
June 2007 (Boulad et al ASH 2007). This trial demonstrated that the use of busulfan, melphalan 
and fludarabine followed by T-cell depleted transplants from matched related,  mismatched 
related, matched unrelated or mismatched unrelated donors in patients with advanced MDS is 
safe and has a significant efficacy as demonstrated by the improved DFS. This trial included 63 
patients; 7 children and 56 adults. The median age was 55.4 years with a range of 0.6 to 71.3; 
forty pts were 50 with 12 pts older than 60 years. The diagnoses included: primary MDS (33 
patients) and AML evolved from MDS (20 patients), de novo AML in CR1 (9 patients) or CR 2 (1 
patient). The donors were HLA matched (A, B, C, DR, DQ by high resolution) related (13), 
mismatched related (4), matched unrelated (46). Except in two patients, the source of stem cells 
was peripheral blood. Sixty two patients were evaluable for outcomes and had at least 6 months 
of post transplant followup. Results of this trial demonstrated that this preparative regimen was 
safe as determined by the low incidence of graft rejection, and GvHD. All but 2 patients achieved 
durable engraftment. One recipient of unrelated HLA disparate transplant experienced primary 
graft failure and one of unrelated HLA disparate transplant experienced graft rejection. Acute 
GvHD II- IV developed in 7 patients (18%) and chronic GvHD in 4 patients (7%) (3 extensive), 
despite the advanced age of this group. Moreover, oral mucositis was less severe as compared to 
the mucositis seen after myeloablative doses of TBI-containing regimens. Thus, the objectives of 
securing consistent engraftment with graft failure <10% and grade II-IV acute GvHD in 1 HLA 
disparate locus recipient have been met in this trial. 
 
The prophylactic/preemptive administration of calculated doses of donor lymphocyte 
infusions  has  been  integrated to  reduce potential  relapses  of the disease.  Historically, donor 


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lymphocyte infusion were performed at time of relapsed disease, requiring doses  of 1x107  - 
1x10
8/kg CD3
+ cells to induce a remission. As detailed above under 3.2.3. Donor Lymphocyte 
Infusions, these doses have also been associated with development of acute and chronic graft- 
versus-host disease. As proposed in this trial, doses of donor-derived CD3+ T-cells will be given in 
the range of 5x105/kg CD3+ cells from matched donors and 1x105/kg CD3+ cells from one 
allele/antigen mismatched donors with a first dose administered 5-6 months post transplantation. 
Finally, the addition of ATG to the chemotherapy only conditioning regim en with busulfan, 
melphalan and fludarabine in our previous trial has shown to reduce the incidence of graft failures 
following HLA-matched T-cell depleted transplants to less than 2% and the incidence of graft 
failure following unrelated with 1-2 allele disparate marrow grafts to less than 8%. 
 
Pilot trial 
 
To assess whether this chemotherapy only preparative regimen including busulfan, 
melphalan, fludarabine and anti-thymocyte globulin could be safely administered to patients with 
relapsed high-risk multiple myeloma and whether these patients who could benefit from T-cell 
depleted allogeneic hematopoietic stem cell transplantation from HLA matched related or 
unrelated donor, we performed an initial pilot trial. Five patients with high-risk MM, all of which 
relapsed following multiple chemotherapy regimen and after one or two preceding autologous 
stem cell transplantations underwent T-cell depleted transplants from HLA-matched  siblings 
(3pts), matched unrelated (1pt) or mismatched unrelated (1pt) donors. Details of the individual 
patients and their outcomes are described in the paragraph below,  but  in  summary,  all  five 
patients durably engrafted with 100% donor chimerism with patients being 22, 16, 14, 10 and 4 
months following the allogeneic stem cell transplantation. None of the patients developed acute, 
chronic graft-versus-host disease or graft failure at this time. Three of these patients achieved a 
complete remission, one patient remains in near complete remission and one patient had stable 
disease with M-spike of 0.2g/dl for 20 months following the transplant. 
 
UPN #1 is a 40+ y/o male, diagnosed with stage III IgG kappa MM. He was treated with 
Thalidomide and Dexamethasone followed by his 1st autologous SCT with Mel 200 and 2nd 
autologous SCT 4 months later. He relapsed after 15 months and was treated with Lenalidomide 
and Dexamethasone x 3 cycles. He underwent allogeneic HSCT from 9/10 unrelated female with 
HLA-DQB1 antigen mismatch 22 months post autologous SCT. The patient had 7% Plasma cells 
in his marrow at admission. The patient tolerated the transplantation very well, engrafted promptly 
without requiring readmission following discharge from this hospitalization. The patient received 
infusion of low doses of donor lymphocytes (5x104/kg) at 5 months and 12 months post transplant 
and remained at very stable disease with low levels of M-protein ranging between 0.2 and 0.3 
mg/d x 20 months. This patient has recently developed signs of progression of disease and 
received 1x106 /kg CD3+ donor T cell infusion two months ago and it is currently too early to 
assess the response, but he has not developed signs of GvHD. 
 
UPN #2 is a 30+ y/o male, who was diagnosed with stage III IgA lambda with high-risk 
cytogenetics, (del 13, t (4; 14). He was treated with Velcade and Dexamethasone x 6 cycles 
followed by an autologous SCT. He relapsed 3 months later. The patient was given 1 cycle of 
Lenalidomide and Dexamethasone, which he tolerated very poorly and was switched to Velcade 
and Dexamethasone x 2 cycles. He underwent allogeneic HSCT from his 10/10 identical sister in 


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Page 13 of 46 
 
 
 
 
9 months post autologous SCT. He is currently 16 months post transplant in complete remission 
without complaints. The patient received two doses of 5x 10
5/kg CD3
+ donor lymphocytes at 7 
and 14 months without signs of acute or chronic graft-versus-host disease. 
 
UPN #3 is a 30+ y/o male with stage III IgG kappa MM diagnosed with deletion 13. He 
was initially treated with Lenalidomide and Dexamethasone x 5 cycles without a response. He 
was then treated with VAD x 5 cycles with only limited response (28% plasma cells in marrow), 
and 
continued 
with 
autologous 
SCT 
with 
minimal 
response. 
He 
 
was 
 
given 
Velcade/Dexamethasone and Thalidomide x 4 cycles with partial response. He underwent 
allogeneic HSCT from his 10/10 identical sister 7 months post autologous SCT. The patient 
tolerated the transplantation without complications, stably engrafted with 100% donor chimerism 
and is back to work fulltime. He is currently 14 months post transplant in near complete remission. 
The patient received two doses of 5x 105/kg CD3+ donor lymphocytes at 6 and 10 months without 
signs of acute or chronic graft-versus-host disease. 
 
UPN #4 is 50+ y/o male, diagnosed with stage III IgG lambda MM with high-risk 
cytogenetics (del 17p, del 13q, t11; 14). He was treated with Thalidomide and Dexamethasone x 
4 months with progression of disease + renal failure, followed by Velcade, interrupted by 
development of myocardial infarction followed by CAGB in the setting of CHF, EF 35%. 
Afterwards he was continued on Velcade x 1 cycle followed by VP-16 + Cytoxan with PR. He 
underwent autologous SCT with Melphalan 200 and relapsed after one year. He was given VAD 
with PD and VP-16/Cytoxan x 3 cycles with partial response. He underwent allogeneic SCT from 
10/10 unrelated donor 17 months post autologous SCT and engrafted promptly without 
complications. The patient is currently 10 months post transplant with all donor chimerism and in 
complete remission. The patient received a first dose of 5x 105/kg CD3+ donor lymphocytes at 6 
months and has currently no signs of acute or chronic graft-versus-host disease. 
 
UPN #5 is a 60+ y/o male, diagnosed with stage III IgG kappa MM. He was initially treated 
with Revlimid, Dexamethasone and /Biaxin (BIRD) with PR. Autologous SCT was performed with 
good response, but the patient relapsed after one year. He was started on Revlimid, Velcade and 
Dexamethasone x 4 cycles followed by Revlimid maintenance therapy, which he tolerated poorly. 
Allogeneic SCT from 10/10 HLA matched brother was performed 2 years post autologous SCT. 
This patient engrafted promptly with all donor chimerism and achieved complete remission post 
transplantation, but unfortunately passed away in 5 months post allogeneic SCT with respiratory 
failure as a consequence of pneumonia. The cause of the pneumonia was likely viral, but the 
patient had refused to be intubated and a bronchoscopy could not be performed. 
 
These results can be compared to the outcome of patients enrolled by our group onto the 
national BMT CTN trial #04-024. On this protocol, all patients with multiple myeloma, 
independently of risk category of cytogenetics of their disease, who had an HLA-identical sibling, 
were treated with an autologous stem cell transplant with Melphalan 200mg/m
2  conditioning 
followed by a non-myeloablative allogeneic transplant from the sibling with 200cGy Total Body 
Irradiation as conditioning regimen. The complete and official analyses of this national trial are still 
pending, but there were 9 patients enrolled onto the auto/allo arm of this trial by our group. Seven 
of these 9 pts actually underwent allogeneic transplantation. Of these 7 pts, 3 pts developed 
acute  graft-versus-host  disease,  of  which  2  pts  also  developed  chronic  GvHD.  2  of  7  pts 


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developed chronic GvHD without preceding acute GvHD. Two of 7 patients died. One patient died 
7 months following the transplant secondary to complications of acute GvHD, the other patient 
died of progression of disease. 
 
 
3.5. 
Summary 
 
The success of allogeneic SCT in patients with relapsed or high-risk multiple myeloma depends 
on multiple variables. Our  approach involving T-cell depleted, reduced-intensity, myeloablative 
allogeneic transplant has the potential to overcome two major obstacles limiting the success of 
allogeneic transplantation for patients with multiple myeloma, namely graft-versus-host disease 
and associated morbidity and mortality. The prophylactic/preemptive administration of low doses 
of donor lymphocyte infusions is designed to reduce the relapse mortality post transplant and to 
improve the PFS with this treatment. In the pilot trial of 5 patients treated with high-risk multiple 
myeloma, as described in detail above, this approach has been well tolerated in these patients 
with high-risk and relapsed MM. None of these patients has development of graft-versus-host 
disease or graft failure. Furthermore, 3 of the 5 patients transplanted achieved a  complete 
remission and 2 patients obtained near complete remissions with lasting durations. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a two arm phase II trial to assess overall survival, progression-free survival, efficacy 
(decrease the transplant related mortality) and safety of allogeneic hematopoietic stem cell 
transplantation using a preparative regimen with busulfan, melphalan, fludarabine, and anti- 
thymocyte globulin (ATG), and T-cell depleted stem cell transplant from a histocompatible related 
or unrelated donor in patients with relapsed or high-risk multiple myeloma. The prophylactic or 
preemptive administration of donor lymphocyte infusions is performed to decrease the rate of 
relapse and thus to prolong event-free and overall survival. 
 
4.3 
Intervention 
 
Patients will be cytoreduced with IV busulfan, melphalan and fludarabine. Busulfan will be 
administered at a dose of 0.8mg/Kg q6hrs for 10 doses on days -9, -8, -7. Doses for busulfan 
should be adjusted according to pharmacokinetic studies. Melphalan will be administered at a 
dose of 70 mg/m2/day for 2 days on days -7, -6. Fludarabine will be administered at a dose of 25 
mg/m2/day for 5 days on days -6, -5, -4, -3, -2. Patients will also receive rabbit anti-thymocyte 
globulin (ATG) to prevent immune mediated graft rejection. The ATG will be administered at a 
dose of 2.5 mg/Kg/day IV on days -3 and -2. Doses for busulfan, melphalan and ATG should be 
adjusted if patient is > 125% ideal body weight and should be calculated on adjusted ideal body 
weight. Doses of fludarabine should be reduced to 80% of dose for measured creatinine 
clearance of 40-70ml/min. Day -1 will be a day of rest before receiving the T-cell depleted stem 
cell product on day 0. The preferred stem cell product will be peripheral blood stem cells but if the 
donor is unable or unwilling to donate peripheral blood stem cells, bone marrow will be used as 
the stem cell source. Patients will receive post-transplant G-CSF starting on day +7. 


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Historically, under the multicenter BMTCTN trial 0303 (IRB 06-005 ) which employed the 
CliniMACS device, GCSF mobilized PBSC, after washing, were suspended in buffered 
saline only and then incubated with antiCD34 coated paramagnetic beads prior to 
separation of the CD34+ cells bound to the beads by adherence to an electromagnet in 
the CliniMACS device. A provision recommended as an adjunct but not required or 
known to be necessary was that the diluent in which the washed GCSF-mobilized PBMC 
were incubated with the antiCD34 coated beads also include 30% autologous plasma or 
intravenous gamma globulin at a concentration of 1.5 mg/ml. This provision was not  
used by the centers participating in the BMTCTN trial, including our own. That trial 
recorded an incidence of acute grade II-IV GVHD of 20.5% and a 7.6% incidence of 
extensive GVHD. While these findings were significantly better than any results recorded 
with drug prophylaxis or methods of T-cell depletion developed at other centers, the 
incidence of acute GVHD was higher than what we had published using SBA-E-  T-cell 
depleted marrow or CD34+ (ISOLEX) E- T-cell depleted PBSC. Since we did not see 
significant GVHD in the small number of patients that we contributed to the trial, we 
ascribed the higher incidence to limited experiences with the CliniMACS device and to 
recent changes in the grading system used for acute GVHD. Accordingly, no changes in 
procedures were made to protocol 10-051. 
 
However, as accrual to 10-051 proceeded, we observed an increase in GVHD even in 
HLA-matched cases, and severe acute GVHD in some patients who received partially 
HLA-matched transplants. Again, the data were not different from the BMT CTN trial 
results, but these results were different compared to our experience with patients 
previously transplanted with T-cell depletion by the ISOLEX  method. However, the rate 
of acute GVHD was higher than that reported by 2 European groups using the 
CliniMACS device for HLA disparate grafts. We subsequently learned that the largest of 
these centers, Perugia U., did incorporate IVIG in the incubation step. 
 
Considering the possibility that in the absence of plasma or IVIG, cells can non- 
specifically adsorb to paramagnetic beads, the cytotherapy laboratory validated 
separation of CD34
+ cells on the CliniMACS in the presence or absence of IVIG in the 
incubation period, demonstrating comparable yields of CD34+ cells and similar levels of 
T-cell depletion. Thereafter, on 7/25/12, the procedure was modified to include the IVIG. 
In February 2013, we evaluated the incidence of acute grade II-IV GVHD and chronic 
GVHD in patients treated since then. The incidence of acute grade II-IV GVHD has been 
significantly lower approximating 5%. 
 
In order to be able to meaningfully compare the incidence of acute GVHD in patients 
receiving transplants fractionated in the presence or absence of IVIG and therefore 
obtain a better overall understanding of the actual rate of acute GvHD, we wish to 
continue to enroll patients on the relapsed arm and increase the number of pts by 17 pts 
to a total of 47 pts. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1. 
Busulfan (Busulfex
®) 
 


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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: BUSULFEX is supplied as a sterile solution in 10 mL single-use 
clear glass ampoules each containing 60 mg of busulfan at a concentration of 6 mg/mL for 
intravenous use. BUSULFEX must be diluted prior to use with either  0.9%  Sodium 
Chloride Injection, USP (normal saline) or 5% Dextrose Injection, USP (D5W). The diluent 
quantity should be 10 times  the volume of BUSULFEX, ensuring that the final 
concentration of busulfan is approximately 0.5 mg/mL 
 
d. Storage and stability: Unopened ampules of BUSULFEX must be stored under 
refrigerated conditions between 2° -8° C (36° -46° F). 
 
e. 
Administration:  Intravenous, over 2 hours. 
 
5.2. 
Melphalan (Alkeran®) 
 
a. Source and pharmacology: Supplier: Glaxo Wellcome. 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-phase non-specific. 
 
b. Formulation and stability: A lyophilized powder of 50 mg melphalan and 20 mg 
povidone per vial. Also provided is 10 ml of sterile diluent for use in reconstituting the 
product and a 0.45 micron filter. The special diluent has the following composition: 
Sodium citrate 0.2 g, Propylene glycol 6.0 ml, Ethanol (95%) 0.5 ml, and sterile water 10 
ml. 
 
c. Solution preparation: Vial/50 mg: Reconstitute by rapidly injecting 10 ml of the supplied 
diluent into the vial to yield a final concentration of 5 mg/ml. Shake vigorously until the 
solution is clear.  Immediately dilute the dose to be administered in 0.9% Sodium Chloride, 
USP, to a concentration no greater than 0.45 mg/ml 
 
d. Storage and stability: The intact packages should be stored at room temperature (15- 
30°C) protected from light. Shelf-life surveillance of the intact dosage form is ongoing. 
Constitution with the special diluent as directed results in a solution that retains at least 
90% potency for about three hours at 30°C.  Storage at 5°C results in precipitation. 


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e. Administration:   Intravenous, over 30 minutes. Complete infusion within 60 minutes of 
preparation. 
 
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: FLUDARA should be prepared for parenteral use by aseptically 
adding Sterile Water for Injection USP. When reconstituted with 2 mL of Sterile Water for 
Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the 
resulting solution will contain 25 mg of fludarabine phosphate, 25 mg of mannitol, and 
sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2-8.2. In 
clinical studies, the product has been diluted in 100 cc or 125 cc of 5% Dextrose Injection 
USP or 0.9% Sodium Chloride USP 
 
d. Storage and stability: FLUDARA is supplied as a white, lyophilized solid cake. Each vial 
contains 50 mg of 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. Store under refrigeration, 
between 2°-8° C (36°-46° F). 
 
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 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 18 of 46 
 
 
 
 
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). 
 
c. Solution preparation: 
Each reconstituted vial contains 25 mg or 5 mg/mL of 
Thymoglobulin. Transfer the contents of the calculated number of Thymoglobulin vials into 
the bag of infusion solution (saline or dextrose). Recommended volume: per one vial of 
Thymoglobulin use 50 mL of infusion solution (total volume usually between 50 to 500 
mL). Mix the solution by inverting the bag gently only once or twice. 
 
d. Storage and stability: Store in refrigerator between +2° C to +8° C (36° F to 46° F). 
Protect from light. Do not freeze. Do not use after the expiration date indicated on the 
label. Reconstituted vials of Thymoglobulin should be used within 4 hours. Infusion 
solutions of Thymoglobulin must be used immediately. Any unused drug remaining after 
infusion must be discarded. 
 
e. Administration: Infuse through a 0.22-micron filter. Set the flow rate to deliver the dose 
over 12 hours. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
Diagnosis: 
 
Patient must have multiple myeloma that has either relapsed or has high risk cytogenetics. 
 
1. Patients  with relapsed multiple myeloma following autologous  stem  cell transplantation 
must have achieved at least partial response following additional chemotherapy (cohort 1): 
a. Patients are eligible if relapse occurs with complex/high-risk cytogenetics or occurs with 
normal cytogenetics but within 15 months following the autologous transplant. 
 
2. Patients with high risk cytogenetics at diagnosis must have achieved at least very good 
partial response following autologous stem cell transplantation (cohort 2): 
a. Patients must have complex karyotype, 1q25, del17p, t4;14 and/or t14;16 by FISH and/or 
del13 by karyotyping. 
 
DONOR: Patients must have a healthy HLA matched or mismatched related or unrelated 
donor who is willing to receive G-CSF injections and undergo apheresis for PBSC 
collection, or undergo a marrow harvesting procedure. 
 
1. HLA-matched related and unrelated donors 


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IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 19 of 46 
 
 
 
 
Patients who have an HLA-matched related or unrelated donor are eligible for entry on this 
protocol. This will include a healthy donor who is genotypically matched at all A, B, C, 
DRB1 and DQB1 loci, as tested by DNA analysis. 
 
2. HLA- mismatched related and unrelated donors 
Patients who do not have an HLA-matched donor but have a related or unrelated donor 
who have one antigen or one allele mismatch at the HLA A, B, C, DRB1 or DQB1 loci; or 
who have two mismatches, at HLA-DQB1 and at one other locus, will be eligible for entry 
on this protocol. 
 
The following inclusion criteria are also required: 
• 
Patients should be ≥ 21, < 73 years old. 
• 
Patients may be of either gender or any ethnic background. 
• 
Patients must have a Karnofsky (adult) or Performance Status > 70% 
• 
Patients must have adequate organ function measured by: 
a) Cardiac:   asymptomatic or if symptomatic then LVEF at rest must be > 50% and must 
improve with exercise. 
b) Hepatic:  < 3x ULN ALT and < 1.5 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. 
d) Pulmonary: 
asymptomatic  or if symptomatic, DLCO  > 50% of predicted (corrected for 
hemoglobin) 
• Each  patient  must  be  willing  to  participate  as  a  research  subject  and  must  sign  an 
informed consent form. 
 
6.3 
Subject Exclusion Criteria 
 
• 
Patients achieving < Partial Response following preceding chemotherapy (cohort 1) or < 
Very Good Partial Response following autologous stem cell transplantation (cohort 2). 
• 
Patients with Plasma Cell Leukemia. 
• 
Female patients who are pregnant or breast-feeding 
• 
Active viral, bacterial or fungal infection 
• 
Patient seropositive for HIV-I/II; HTLV -I/II 
• 
Patients who have undergone prior allogeneic hematopoietic stem cell transplantation. 
• 
Patients who have had a previous malignancy that is not in remission. 
• 
Patients with known hypersensitivity to mouse proteins (murine antibodies in ISOLEX) if 
receiving SBA-E- bone marrow, or chicken egg products. 
 
7.0       RECRUITMENT PLAN 
 
Patients with high-risk and relapsed multiple myeloma are referred from collaborating outside 
institutions and hematology services within MSKCC. All prospective patients are reviewed during 
the weekly Bone Marrow Transplant meetings. These meetings are attended by the doctors, 
nurses and members of the research team. Patients who fulfill the eligibility criteria as listed in 
Section 6.0 will be recruited for this study by Attending Physicians of the Allogeneic BMT service. 
This protocol will take due notice of NIH/ADAMHA policies concerning inclusion of women and 
minorities in clinical research populations. 
 
8.1 
PRETREATMENT EVALUATION 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 20 of 46 
 
 
 
 
8.1. 
Pretreatment evaluation of the patient 
 
The patient will receive an extensive medical evaluation within approximately 45 days prior 
to starting preparatory cytoreduction. This evaluation includes: 
- 
Complete physical exam and medical history 
- 
Dental evaluation (not required within 45 day window) 
- 
CBC 
- 
Coagulation profile 
- 
Blood Type and screen (not required within 45 day window) 
- 
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. 
- 
Blood will also be tested for HTLV-1 and 2 as well as HIV-1 and 2 
- 
Pregnancy test for women of childbearing age 
- 
Urinalysis, 
- 
Electrocardiogram, echocardiogram or a gated pool scan if needed 
- 
Pulmonary function test 
- 
Skeletal Survey 
- 
Chest X-ray (CT scan and 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 3-4 GTTs of blood will be drawn for laboratory correlative studies during 
routine blood tests. 
 
- 
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 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1. 
Preparative cytoreduction 
 
The patient will be admitted to a single room on the Adult Transplantation Service. The patient will 
be maintained in reverse isolation until the day of discharge. Prior to the administration of the pre 
transplant cytoreductive regimen, a double or triple lumen central venous catheter will be inserted 
by the Surgical or Interventional Radiology Services. 
The preparative cytoreduction will include the following: 
Days –9 to –7 Busulfan* 0.8 mg/Kg/dose Q6H X 10 doses/3 days IV over 2 hours 
Days -7 to -6   Melphalan** 70 mg/m2/day x 2 days IV over 30 minutes 
Days -6 to -2   Fludarabine*** 25 mg/m
2/day x 5 days IV over 30 minutes 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 21 of 46 
 
 
BU 
BU 
BU 
ATG 
ATG 
MEL   MEL 
FLU  FLU  FLU  FLU 
FLU 
PBSCT/BMT 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
+1 
+2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCHEMA OF CYTOREDUCTION AND PREPARATION FOR ALLOGENEIC PBSCT 
 
DONOR: 
-6 
-5 
-4 
-3 
-2 
-1 
 
 
 
 
 
 
 
PATIENT: 
LEUKAPHERESIS 
T-cell Depletion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Donor Lymphocyte Infusions – 
 
a. Recipients of HLA-matched allografts will be treated prophylactically with 5x105 CD3+/kg 
at 4-6 months post transplant. The second infusion of 5x105 CD3+/kg will be administered 
3-4 months following the first infusion. A third dose of 1x106 CD3+/kg from matched donors 
can be administered 2-4 months  following the second infusion, if the patient is  not in 
complete remission. All infusions will be administered only in the absence of graft-versus- 
host disease. 
 
b. Recipients of HLA-mismatched allografts will be treated preemptively with 1x105 
CD3+/kg at diagnosis of relapse or progression, but no sooner than 4-6 months post 
transplant. A second infusion of 5x105 CD3+ cells/kg will be administered 1-3 months 
following the first infusion. A third infusion of 1x106  CD3+  cells/kg can be administered 3-4 
G-CSF 
*Donor Lymphocyte Infusions 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 22 of 46 
 
 
 
 
months following the second infusion, if the patient did not achieve a complete remission. 
Chemotherapy can be given prior to any DLI if it is clinically appropriate.  All infusions will 
be administered only in the absence of graft-versus-host disease. 
 
c. Recipients of HLA-matched allografts will be treated preemptively at diagnosis of 
relapse or progression and according to the treatment plan described for those recipients 
of HLA-mismatched allografts. 
 
The below patients will be taken off treatment and treated according to the standard of 
care. These patients will remain on study and continue to be evaluated according to the 
protocol: 
-Patients who relapse or have progression of disease before they are eligible to receive 
their DLI. 
-Patients who are unable to get 2 of their DLIs as specified by the protocol. 
 
 
EXAMPLE OF ROAD MAP OF PREPARATION FOR TRANSPLANT 
 
-10 
Keppra 
-9 
Busulfan IV 
X4 
Keppra 
-8 
Busulfan IV 
X4 
Keppra 
-7 
Busulfan IV 
X2 
Melphalan 
70 
mg/m2/day 
IV X 1 
Keppra 
-6 
Fludarabine 
25 mg/m2/day 
IV X 1 
Melphalan 
70 mg/m2/day 
IV X 1 
Keppra 
Donor G-CSF 
-5 
Fludarabine 
25 
mg/m2/day 
IV X 1 
Donor 
G-CSF 
-4 
Fludarabine 
25 mg/m2/day 
IV X 1 
Donor G-CSF 
-3 
Fludarabine 
25 mg/m2/day 
IV X 1 
Rabbit ATG 
2.5 mg/Kg/d 
IV over 12 H 
Donor G-CSF 
-2 
Fludarabine 
25 mg/m2/day 
IV X 1 
Rabbit ATG 
2.5 
mg/Kg/d 
IV over 12 H 
Donor G-CSF 
Leukapheresi 
s1 
-1 
Donor G-CSF 
Leukapheresis 
2 
0 
T-cell 
depleted 
Stem cell 
transplant 
+ 1 
+2 
+3 
+4 
+5 
+6 
+7 
Start G-CSF 
 
* busulfan dosing and administration: 
Patients will have busulfan levels drawn after the first dose on day 1, with adjustments in 
dosing based on the pharmacokinetics of the first dose.. Dose should be adjusted if 
patient is >125% ideal body weight and should be calculated on adjusted ideal body 
weight per MSKCC‟s standard of care and BMT busulfan guidelines. 
 
** melphalan dosing and administration: 
Dose should be adjusted if patient is > 125% ideal body weight and should be calculated 
on adjusted ideal body weight per MSKCC standard of care guidelines. 
 
*** fludarabine dosing and administration: 


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IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 23 of 46 
 
 
 
 
Dose should be reduced to 80% (20mg/m2  per day) of dose for measured creatinine clearance of 
40-70ml/min. 
 
Anti-seizure prophylaxis with Keppra will be administered to all patients starting day –10 or 24 
hours prior to starting busulfan for the prevention of busulfan-associated seizures. 
 
9.2. 
Peri-transplant treatment to promote engraftment 
 
a. 
Rabbit anti-thymocyte globulin* (Thymoglobulin®) and methylprednisolone 
(MPD) will be administered in the pre-transplant period for all patients. Patients will receive 
rabbit ATG (Thymoglobulin®) at 2.5 mg/Kg/day x 2 days on days -3 and -2. 
Methylprednisolone will be given at 2 mg/Kg/day x 2 days with the ATG administration and 
will be discontinued thereafter. ATG dose should be adjusted if patient is > 125% ideal 
body weight and should be calculated on adjusted ideal body weight and will be 
administered as per MSKCC standard of care guidelines. 
 
Side-effects of ATG may occur (see section 11.0 "Toxicities/Side Effects"). If a reaction 
consisting of fever and chills occurs, then the infusion will be slowed down, meperidine 
could be given for the relief of the chills, and when the reaction improves the infusion rate 
could be slowly escalated again. Should a severe significant systemic reaction to the 
rabbit ATG occur, then the alternative equine ATG will be administered at doses of 15 
mg/Kg/day x 2 days. 
 
b. 
All patients will be treated with G-CSF (filgrastim) at 300 g SC QD for patients 
<60kg or 480 g SC QD for patients >60Kg. G-CSF administration will begin on day +7 
and will continue until the ANC is >2000. 
 
9.3. 
Prophylaxis against acute graft-versus-host disease 
 
No further GvHD prophylaxis will be administered. 
 
9.4. 
Stem Cell Transplantation   
 
9.4.1. PBSCT 
 
Donor peripheral blood progenitor cells: stimulation, harvesting, isolation and T-cell depletion. 
 
For related donors, beginning 5-6 days before the day of transplant, the normal donor will receive 
10 mcg/kg of GCSF, administered subcutaneously daily for at least 5 days. On the fifth and sixth 
days of this course of G-CSF, the donor will undergo daily leukapheresis designed to provide a 
minimum of 10
9 mononuclear cells/kg of the transplant recipient's weight. For unrelated donors, 
the G-CSF will be administered and the leukapheresis obtained according to the National Marrow 
Donor Program protocol and IND. 
 
Isolation of CD34+ hematopoietic progenitor cells with the CliniMACS TM System, Miltenyi 
Biotec. 
The apheresis product is collected from a blood of related or unrelated donors. Aliquots of the 
apheresis product are collected and then tested and screened as per blood banking guidelines. 
The apheresis product is then prepped for the CliniMACS Cell Selection System. The mechanism 
of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting, 
which can select or remove specific cell types depending on the cell-specific immunomagnetic 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 24 of 46 
 
 
 
 
label used as further detailed below. The apheresis product is first co-incubated with the 
CliniMACS CD34 reagent (antibody-coated paramagnetic  particles).  Prior  to  and  during 
incubation of the antiCD34 beads with the mobilized PBSC, intravenous gammaglobulin is added 
to the incubation fluid at a concentration of 1.5 mg IVIG/ml. After magnetic labeling and washing, 
the cells are passed through a high-gradient magnetic separation  column  in  the  CliniMACS 
clinical cell selection device. Magnetically labeled CD34+ cells are retained in the magnetized 
column, and CD34-negativ e cells flow through as the effluent fraction and will be discarded. The 
CD34+positiv e cells  retained in the column are eluted by removing the magnetic field from  the 
column, then washing the cells through the column and collecting them. The final CD34+ cell 
enriched product is concentrated by centrifugation and tested before  final  release  for 
administration as per SOPs from the MSKCC Cytotherapy Lab Manual. 
 
Before infusion, the CD34+ cells will be washed in normal saline for intravenous infusion 
containing 1% human serum albumin, and suspended in a volume of 25-50 ml for intravenous 
administration. Aliquots of the product are taken for in-process and final product testing will be 
performed as per SOPs from the Cytotherapy Lab Manual. 
 
This study (protocol) will be conducted under BB-IND #14060. BB-IND #14060 is an existing IND 
that was approved by the FDA and we are currently using the Miltenyi device in the same way. 
 
9.4.2. BMT (if PBCST not possible) 
 
Twenty\ four to forty-eight hours after the patient has completed treatment with fludarabine, bone 
marrow will be harvested from the donor in the operating room according to standard procedure. 
The procedure for T cell depletion with soybean agglutinin (SBA) and sheep red blood cells (E) 
has been previously described36, 40  as per the SOP from the MSKCC Cytotherapy Laboratory. 
 
The amount of marrow harvested will be such to provide a minimum of 1 x 10
7  SBA-E- 
mononuclear cells/kg of the transplant recipient's weight. In very rare instances, the amount of 
marrow cells harvested from the donor may be inadequate to provide a high enough cell yield 
after the complete T-cell depletion procedure outlined above, to ensure engraftment. This can be 
predicted at any of the initial steps before the final RBC rosetting. In such  a  situation,  the 
physician in charge of the study and/or the attending physician of the BMT service, in consultation 
with the laboratory investigators performing the T-cell depletion, may elect to administer either an 
unmodified or a partially T-cell depleted (SBA-) marrow transplant. The patient would then receive 
drug prophylaxis against GvHD. These patients will be statistically evaluated as recipients of T- 
cell depleted marrow, but will be analyzed separately in evaluation of the efficacy of the SBA-E- 
marrow grafts. 
 
Transplantation of the T-cell depleted stem cells. 
The CD34+T-cell depleted peripheral blood progenitor cells or the SBA-E- fraction of the bone 
marrow, suspended in a volume of approximately 20-50 ml will be infused intravenously over 15 
minutes with monitoring of vital signs. The patient is premedicated as for blood product 
transfusions. 
 
9.5. 
Supportive Care 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 25 of 46 
 
 
 
 
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 needed. Vitamin supplements will be as clinically 
indicated. 
 
Administration of Donor Lymphocyte Infusions 
Calculated doses of donor lymphocytes suspended in a volume of approximately 10-30 ml 
will be infused intravenously over 5-10 minutes with monitoring of vital signs. The patient  
is premedicated as for blood product transfusions. 
 
 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
All patients will be closely monitored and evaluated as per MSKCC BMT standard of care 
guidelines. Study specific assessment schedule listed in table below. 


 
Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
 
 
Schedule of Study Assessments 
 
Procedures 
Pre- 
treat 
Days Post-Trans plant 
7 
14 
21 
28 
35 
42 
56 
70 
84 
100 
6 
months 
9 
months 
12 
months 
18 
months 
24 months 
Window 
45 
(+/-) 
(+/-) 
(+/-) 
(+/-) 
(+/-) 
(+/-) 
(+/-) 
(+/-) 7 
(+/-) 7 
(+/-) 7 
(+/-) 14 
(+/-) 14 
(+/-) 30 
(+/-) 30 
(+/-) 30 
2 
2 
2 
2 
2 
2 
7 
Eligibility 
X 
Informed consent 
X 
History/Physical 
X 
Dental Evaluation 
X 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
Blood Type and 
screen 
X 
Serology Testing (1) 
X 
Pregnancy test if 
applicable 
(childbearing age) 
X 
HTLV-1/2, HIV-1/2 
X 
Urinalysis 
X 
EKG, ECG or 
MUGA as needed 
X 
Skeletal survey (5) 
X 
X 
X 
PFT 
X 
Chest x-ray 
X 
Bonemarrow aspirate 
and biopsy (2) 
X 
X 
X 
X 
X 
X 
Chimerism (Blood 
and BM) (3) 
X 
X 
X 
X 
X 
X 
X 
X 
Myeloma Analyses 
(4) 
X 
X 
X 
X 
X 
X 
X 
X 
GvHD evaluation (6) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 26 of 46 


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IRB Number: 10-051 A(13) 
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Page 27 of 46 
 
 
 
 
 
(1) Infectious disease markers will be performed as per each department‟s guidelines or at the 
discretion of the treating attending. 
(2) 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 karyotype and FISH for chromosomal abnormalities, d. An 
additional 3-6ml marrow in EDTA will be drawn for correlative studies 
(3) 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 done at 9 months only if clinically 
indicated 
(4) 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.  Myeloma  analyses  at  9 
months only if clinically indicated 
(5) Patients with positive skeletal surveys at baseline will have repeat skeletal surveys 
performed at 6 months and 12 months post transplant 
(6) 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. 
 
 
 
11.0   TOXICITIES/SIDE EFFECTS 
 
Patients recruited to this transplantation trial are individuals who are either referred by physicians or 
self-referred for marrow transplantation as a potentially curative treatment for their malignancy. Prior 
to consideration for transplant, all patients undergo a series of 1-3 hour consultations discussing the 
risks and potential benefits of an allogeneic stem cell transplantation and the different procedures 
which will be a normal part of the transplant course. The risks and potential benefits of the transplant 
procedure, as well as the participation in any given research, experimental, or therapeutic protocol 
are also discussed. 
 
11.1. 
Risks to Related Peripheral Blood Stem Cell Donors 
 
The risks of short-term treatment with G-CSF are likely negligible. However, administration of G-CSF 
is frequently associated with low grade fever and low back pain which usually resolves within one 
day following cessation of G-CSF treatment. Furthermore, there has now been one recorded patient 
who developed acute splenomegaly and splenic rupture in response to high dose G-CSF. The bone 
pain may require treatment with analgesics. The risks of a leukapheresis are negligible, involving an 
occasional vasovagal response to venipuncture and  the  minimal  hemodynamic  alterations 
associated with single unit phlebotomies. To protect against these risks, leukophoreses are 
conducted in the Blood Bank Donor Room with full medical and nursing supervision and support 
systems to address adverse events. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-051 A(13) 
Approval date: 14-May-2018 
Page 28 of 46 
 
 
 
 
For donors undergoing bone marrow harvest, the risks for the donor will mainly be those risks 
associated with general anesthesia. The side effects of the harvest itself will include pain at the site 
of harvest, i.e. posterior and/or anterior superior iliac crests, as well as minimal risks of bleeding at 
the site. There have been no problems with localized infections at the sites in the extensive 
experience of our service with marrow harvests over the last 20 years. 
 
11.2. 
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. 
 
Likely: 
 
Busulfan: Myelosuppression, fatigue, not sleeping well, anorexia, nausea, vomiting, diarrhea, 
mucositis weight gain and swelling, changes in blood sodium level, alopecia, needing transfusions of 
platelets and red blood cells, fever, needing antibiotics to treat infection. 
 
Melphalan: Myelosuppression, fatigue, not sleeping well, anorexia, nausea, vomiting, diarrhea, 
mucositis weight gain and swelling, changes in blood sodium level, alopecia, needing transfusions of 
platelets and red blood cells, fever, needing antibiotics to treat infection, transient liver dysfunction. 
 
Fludarabine: Myelosuppression, tiredness, not sleeping well, anorexia, nausea, vomiting, diarrhea, 
mucositis weight gain and swelling, changes in blood sodium level, alopecia, needing transfusions of 
platelets and red blood cells, fever, needing antibiotics to treat infection, jaundice and elevations of 
liver enzymes. 
 
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, rash. 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. 
 
Growth factor (G-CSF): bone pain, headache, body ache, feeling tired, swelling of hands/feet, 
nausea. These are generally mild and will go away when the growth factor is stopped. 
 
Less Likely: 
 
Busulfan,  melphalan,  fludarabine:  Late  effects  of  these  three  chemotherapy  agents  include: 
cataracts and under-activity of the thyroid gland. Both of these side effects can be easily treated. 


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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 
 
Melphalan: Renal or bladder dysfunction (increased BUN, creatinine, necrosis) may be seen. 
 
Fludarabine: confusion, numbness, loss of vision, loss of balance, difficulty walking 
 
ATG: Prior exposure to rabbit proteins may predispose subjects to serious allergic reactions such as 
a drop in blood pressure, hives, bronchospasm, 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. 
 
Rare but serious: 
 
Busulfan: high doses of Busulfan can cause Veno-Occlusive Disease (VOD). Symptoms include 
jaundice, liver enlargement with pain, fluid retention and increase risk of bleeding. 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. 
 
Melphalan: 
pulmonary 
fibrosis, 
respiratory 
distress has been 
rarely 
reported. 
Serious 
hypersensitivity reactions: Edema, rash, anaphylaxis 
 
ATG: renal toxicity, managed by Prednisone. Drop in white blood cells; drop in platelet count will be 
managed by transfusion therapy. 
 
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  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, 


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fever, headache, shortness of breath, chills, sweats, nausea/vomiting, bad taste in the mouth. Pre- 
medications are given to reduce these side effects. 
 
Receiving donor lymphocyte infusions: The volume of the donor lymphocyte infusions infused is 
approximately 10-30 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. In patients transplanted and engrafted with SBA-E- T-cell depleted marrow from HLA 1-3 
allele disparate related donors, this complication has been observed in fewer than 20% of patients 
and has rarely been severe. 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%. 
 
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. 
 
Steroids, as treatment for GvHD: inability to sleep, high blood sugar, puffiness of the face, changes 
in the skin, high blood pressure, increased risk of infection, weight gain, reduced growth in children, 
thinning of the bones 
 
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. 


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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 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 (DLI) and Rituximab. 
 
Graft Failure: Bone marrow graft may fail to grow. Past experience suggests that this may occur in 
about 10% of patients. 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. 
 
Progression of Disease and Relapse of Multiple Myeloma is a risk even if the transplant is 
initially successful. Patients on the relapsed cohort may be treated prophylactically with Revlimid 
maintenance therapy post transplant. 
 
12.0   CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
DEFINITIONS OF DISEASE STATUS 
 
Patients at each data collection period are classified into one of the following states. 
 
1. 
Complete Response (CR) 
CR requires all of the following: 


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- Absence of the original M-protein in serum and urine by routine electrophoresis and by 
immunofixation maintained for a minimum of six weeks. The presence of new monoclonal bands 
consistent with oligoclonal immune reconstitution does not exclude CR. 
- Less than 5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy, if biopsy 
is performed. Confirmation with repeat bone marrow studies is not needed if the last bone marrow 
assessment was negative. 
- No increase in size or number of lytic bone lesions on radiological investigations, if performed 
(development of a compression fracture does not exclude response). 
 
Patients in whom some, but not all, the criteria for CR are fulfilled are classified as very good partial 
response or partial response (see below), providing the remaining criteria satisfy the requirement for 
partial response. This includes patients in whom routine electrophoresis is negative but in whom 
immunofixation has not been performed. 
 
2. 
Very Good Partial Response (VGPR) 
- Reduction  of  serum  M-protein  on  electrophoresis  by  at  least  90%  with  a  urine  M-protein 
<100mg/24hours, but detectable immunofixation. 
 
3. 
Partial Response (PR) 
PR requires the following: 
- Greater than or equal to 50% reduction in the level of the serum M-protein, maintained for a 
minimum of six weeks. 
OR 
- Reduction of urine M-protein to less than 200 mg/24 hours, maintained for a minimum of six weeks 
- No increase in size or number of lytic bone lesions on radiological investigations, if performed 
(development of a compression fracture does not exclude response). 
 
For patients with nonsecretory myeloma, free light chain (FLC) levels can be used to determine a 
partial response. A 50% decrease in the difference between kappa and lambda FLC levels denotes 
a PR. If the FLC levels were unmeasurable at baseline, a 50% reduction in bone marrow plasma 
cells is acceptable as long as the original bone marrow contained at least 30% plasma cells. All PR 
require a 50% reduction in size of any soft tissue plasmacytomas 
 
Patients in whom some, but not all, the criteria for PR are fulfilled are classified as minimal response 
(see below), providing the remaining criteria satisfy the requirements for minimal response. 
 
4. 
Minimal Response (MR) 
Minimal response requires the following: 
- 25-49% reduction in the level of the serum M-protein. 
OR 
- Urine M-protein which still exceeds 200 mg/24 hours 
- 25-49% reduction in the size of soft tissue plasmacytomas (by radiography or clinical examination). 
- No increase in the size or number of lytic bone lesions on radiological investigations, if performed 
(development of a compression fracture does not exclude response) 


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5. 
Stable Disease (SD) 
Stable values (within 25% above or below value at time response is assessed) maintained for at 
least three months. 
 
6. 
Relapse 
Relapse from CR requires one or more of the following: 
• 
Reappearance of serum or urine paraprotein on immunofixation or routine electrophoresis, 
confirmed by at least two further consecutive investigation with 2-4 weeks and excluding 
oligoclonal immune reconstitution 
• 
Greater than or equal to 5% plasma cells in a bone marrow aspirate or on trephine bone biopsy 
• 
Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase in the 
size of residual bone lesions. Development of a compression fracture does not exclude 
continued response and may not indicate progression 
• 
Development  of  hypercalcemia  (corrected  serum  Ca  >  11.5  mg/dL  or  >  2.8  mmol/L)  not 
attributable to any other cause 
 
7. 
Progressive Disease (PD) 
For patients not in CR, progressive disease requires one or more of the following: 
• 
> 25% increase in the level of the serum M-protein, which must also be an absolute increase of 
at least 0.5 g/dL and confirmed by at least one repeated investigation 
• 
An absolute increase in urine M-protein of at least 200 mg/24 hours and confirmed by at least 
one repeated investigation 
• 
> 25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must 
also be an absolute increase of at least 10% 
• 
Definite increase in the size of existing bone lesions or soft tissue plasmacytomas 
• 
Development of new bone lesions or soft tissue plasmacytomas 
• 
Development  of  hypercalcemia  (corrected  serum  Ca  >  11.5  mg/dL  or  >  2.8  mmol/L)  not 
attributable to any other cause 
• 
Development of  a compression fracture does  not  exclude  continued  response and may  not 
indicated progression 
 
Definition of events in the post-transplant course important for analysis and treatment 
 
12.1. 
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 donor lymphocyte infusion). 
 
Transplant-related mortality (TRM) includes the RRT and other fatal complications resulting from 
the allogenic transplant such as graft failure, GvHD, hemorrhages, and infections. One year post 
TRM is the primary endpoint of this study. 


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The grading for monitoring the morbidity and mortality will be based on the NCI/CTEP common 
toxicity criteria version 4.0. 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. 
 
12.2. 
Immunologic Reconstitution 
 
Our previously reported analyses have identified time points at which the various  immunologic 
functions can be expected to return. Patients receiving T-cell depleted transplants  from  HLA- 
identical related donors can be monitored at fewer time points without compromising our ability to 
obtain critical information. However, patients receiving transplants from partially  HLA-matched 
related donors will be evaluated more frequently, as graft rej ection, late graft failures, more 
pronounced immune dysfunction, and more patient to patient variability have been observed. 
 
Immunophenotyping of T-cells, B-cells, and NK cells, will be performed at approximately 3, and 
every 3-6 months 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 6 months, 9 months (if clinically indicated), 12 and 18 
months post-transplant and thereafter as clinically indicated. Patients with normal total IgG levels 
and PHA response within the 25th percentile of normal may be re-immunized with diphtheria and 
tetanus toxoid, killed polio vaccine, hepatitis B vaccine, as well as the Haemophilus influenzae type 
B conjugate vaccine. Specific antibody production to tetanus and Hepatitis B is then measured. 
 
Antigen-specific  T-cell  immune  reconstitution  will  be  performed  as  described  in  detail  under 
„correlative studies‟. 
 
12.3 Engraftment and chimerism 
 
Engraftment will be documented by analysis of T cells and bone marrow cells for chimerism by 
standard cytogenetic studies at 1 month, 100 days, 6 months, 9 months (if clinically indicated), and 
12 months, 18 months, 24 months (if clinically indicated) post transplant or as needed thereafter. T- 
cell chimerism analysis is not required when a patient‟s absolute lymphocyte count is less than 0.5 
K/mcL. 
 
12.4 Graft failure or rejection 
 
Primary non-engraftment is diagnosed when the patient fails to achieve an ANC 500/l 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/mm3, the 


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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 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 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. 
12.5.    Graft-versus-host disease 
Standard BMT-CTN and IBMTR systems clinical criteria as defined by Rowlings, et al68 will be used 
to establish and grade acute GvHD. 
 
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 
DLI infusions will be analyzed separately. 
 
Patients with moderate to severe acute GvHD (grade II-IV) will be treated in standard fashion with 
high-dose I.V. 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
69 treated with 
standard or experimental immunosuppressive therapy. Treatment will consist of corticosteroids, 


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cyclosporin A or azathioprine, or combinations of these agents. Other novel treatments could be 
used if available, i.e. thalidomide and psoralen/ultraviolet A phototherapy (PUVA). 
 
13.0 
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 for noncompliance. 
14.0 
BIOSTATISTICS 
 
This is a phase 2 study designed to examine the efficacy and safety of chemotherapy followed by T- 
cell depleted transplant and donor leukocyte infusions for patients with relapsed or high-risk multiple 
myeloma. The primary objective is to assess the overall and progression free survival from the time 
of transplant in the relapsed and high-risk groups. A maximum of 30 patients will be accrued into 
each group. The primary endpoint of the study is one-year progression-free survival from the time of 
transplant. An event is defined as a disease progression or death. The accrual period will be 
approximately three years with an additional 24 month follow up after the accrual has been 
completed. 
For the relapsed multiple myeloma cohort, a single stage design that differentiates between one - 
year PFS rates of 0.30 and 0.54 will be used to assess treatment efficacy. At the conclusion of the 
study, if at least 13/30 patients were recorded progression-free at 1 year, then the treatment will be 
declared a success. The probability of declaring the treatment a success is  0.10 when the one- 
year PFS in the population is 0.30 and increases to  0.90 when the one-year progression-free 
survival is 0.54. 
 
Recent data at MSKCC suggests that the addition of immune gammaglobulin (IVIG) added to the 
incubation fluid at a concentration of 1.5 mg IVIG/ml during incubation of the antiCD34 beads with 
the mobilized PBSC results in a reduction in the rate of grade 2-4 acute graft versus host disease 
(GVHD).  A total of 17 out of the 30 patients in the relapsed cohort were treated without the IVIG 
addition. 
Since DLI and the lack of IVIG may both increase a patient‟s risk of GVHD, it is imperative to 
understand the risk that is attributable to the TCD+DLI treatment strategy and not the change in 
CD34+ preparation. Therefore this cohort will be expanded so that the outcomes can be evaluated 
on patients who all receive the IVIG addition. The outcomes for the N=17 cohort who did not receive 
IVIG will be reported separately. The stopping rules below have been extended to the 47 patients 
enrolled in the relapsed arm. 
 
For the high-risk multiple myeloma cohort, a single stage design that differentiates between one- 
year PFS rates of 0.45 and 0.69 will be used to assess treatment efficacy. At the conclusion of the 
study, if at least 18/30 patients were recorded progression-free at 1 year, then the treatment will be 
declared a success. The probability of declaring the treatment a success is  0.10 when the one - 
year PFS in the population is 0.45 and increases to 0.89  when  the  one-year  progression-free 
survival is 0.69. 


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In order to reduce patient risk, the study design includes early termination in the event of excessive 
graft failure, graft versus host disease, or early treatment related mortality during the accrual period. 
Stopping rules for excessive failure and the corresponding power calculations are applied to each 
patient cohort separately. The stopping rules are provided in the tables below and consider only the 
univariate failure probabilities. 
 
 
Relapsed Multiple Myeloma 
 
 
 
 
Graft failure 
2 in the first 26 patients 
3 in the first 47 patients 
0.15 
0.03 
0.02 
0.92 
Treatment 
Related 
Mortality 
3 in the first   8 patients 
4 in the first 14 patients 
5 in the first 20 patients 
6 in the first 27 patients 
7 in the first 34 patients 
8 
in 
the 
first 
41 
patients 
9 at any point 
0.30 
0.02 
0.10 
0.88 
Acute Graft 
Versus Host Disease 
(Grade 4) 
3 in the first 12 patients 
4 in the first 20 patients 
5 in the first 29 patients 
6 in the first 38 patients 
7 at any point 
0.25 
0.02 
0.07 
0.89 
Chronic Graft 
Versus Host 
Disease (Severe) 
3 in the first   8 patients 
4 in the first 14 patients 
5 in the first 20 patients 
6 in the first 27 patients 
7 in the first 34 patients 
8 
in 
the 
first 
41 
patients 
9 at any point 
0.30 
0.02 
0.10 
0.88 
 
 
 
 
 
 
 
 
 
 
 
High-risk Multiple Myeloma 
 
# of failures needed 
Projected probability of 
Probability of study 
to stop the study 
failure in the population 
completion (based 
# of failures needed 
Projected probability of 
Probability of study 
Failure type 
to stop the study 
failure in the population 
completion (based 
on projection) 


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Failure type 
on projection) 
 
Graft failure 
2 in the first 26 patients 
3 in the first 30 patients 
0.15 
0.08 
0.02 
0.90 
Treatment 
Related 
Mortality 
3 in the first   8 patients 
4 in the first 14 patients 
5 in the first 21 patients 
6 in the first 27 patients 
7 in the first 30 patients 
0.30 
0.10 
0.10 
0.90 
Acute Graft 
Versus Host Disease 
(Grade 4) 
3 in the first 12 patients 
4 in the first 20 patients 
5 in the first 29 patients 
6 in the first 30 patients 
0.25 
0.09 
0.07 
0.92 
Chronic Graft 
Versus Host 
Disease (Severe) 
3 in the first   8 patients 
4 in the first 14 patients 
5 in the first 21 patients 
6 in the first 27 patients 
7 in the first 30 patients 
0.30 
0.10 
0.10 
0.90 
 
 
At the conclusion of the study, Kaplan-Meier estimates of overall and progression-free survival will 
be computed over time. In addition, the probability of treatment related mortality and acute and 
chronic graft-versus-host disease will be calculated using the cumulative incidence function. 
 
Correlative studies are undertaken to explore the role of four CT antigens (CT7, CT10, MAGE-A3, 
and NY-ESO-1) for disease progression. The antigen expression, evaluated by quantitative PCR, 
will be recorded at baseline and multiple time points post-baseline (section 10) and a time- 
dependent Cox model will be used to assess the association of each antigen with progression free 
survival. 
 
Finally, to account for patients that relapse and are put back into remission through DLI, the current 
myeloma free survival curve will be computed. This curve estimates the probability a patient is alive 
in an original remission or in subsequent remission after treatment with DLI at a given time after 
transplant.70 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
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 or not the participant is eligible to enroll in the study. 


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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). 
15.3 
Randomization 
 
This research study does not require a randomization. 
 
16.1 
DAT A M ANAGEMENT ISSUES 
 
A research study assistant (RSA) will be assigned to the study. The responsibilities of the RSA will 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem and 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. Source documentation will 
be available to support the computerized patient record. 
 
16.2 
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. 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring Plans (DSM) at Memorial Sloan-Kettering cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new policies 
set forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data and 
Safety Monitoring of Clinical Trials” which can be found at: 
Http://cancertrials.nci.nih.gov/r esearchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety 
Monitoring Plans can be found on the MSKCC Intranet at: http://mskweb2.mskcc.org/irb/index.htm. 
 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research QA) and departmental procedures for quality control, plus there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials programs.  The 
committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the 
Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the Center‟s 
Research Council and Institutional Review Board. 


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During the protocol development and review process, each protocol will be assessed for its level of 
risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed, and the monitoring 
procedures will be established at the time of protocol activation. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Consent Process: Participation in this study is  voluntary. All patients will be required to sign a 
statement of informed consent which must conform to MSKCC IRB guidelines and explain the risks 
and potential benefits of the transplant procedure. 
 
Alternatives: Enrollment in this study is voluntary. Alternative treatment options will be presented to 
the patient prior to taking part in this study. Alternative treatment options may include getting a 
transplant from a volunteer unrelated donor, if one is available; getting treatment for the cancer with 
either chemotherapy or a transplant without being on a study; taking part in another study; or getting 
no treatment. 
 
Costs: The patient‟s health plan/insurance company will need to pay for all of the costs of treatment 
in this study. The patient will be responsible for the costs of standard medical care, all 
hospitalizations and any transplant complications. Pre-authorization for the transplant will be cleared 
with the health plan/insurance company prior to admission. Patients will not be paid for taking part in 
this study. Research tests will be done at no cost to the patient. 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and hospital 
records are confidential. 
17.2 
Privacy 
 
MSKCC‟s Privacy Office may allow the use and disclosure of protected health information pursuant 
to a completed and signed Research Authorization form. The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization form. A 
Research Authorization form must be completed by the Principal Investigator and approved by the 
IRB and Privacy Board (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
 
Potentially serious toxicities are an expected part of transplant therapy. Grade 4 toxicities will be 
recorded and reported as part of the analysis of study outcome. In addition, the reportable serious 
adverse events (SAEs) will be defined according to current MSKCC BMT program guidelines which 
is included as an appendix. 
 
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 


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


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o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The PI‟s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office 
 
 
17.2.1 
 
This protocol has an IND therefore, the SAE will also be reported to the FDA through the IND Office 
and the report will include the FDA assigned IND number and name. 
 
 
18.1 
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. 


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19.0 
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20.0 
APPENDICES 
 
Appendix A:  The Adult and Pediatric BMT Adverse Event Reporting Standard Operating 
Procedures.