Clinical trial NCT01174082
Conditions: Myeloma
Keywords: Multiple Myeloma Vaccine Lymphocyte Infusion
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-07-20; Completion date: 2017-02-23
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if vaccinating a donor with your purified myeloma protein and then injecting it back into you will help your immune system control the multiple myeloma.

Detailed description:
A vaccine will be made of tumor protein taken from your plasma (liquid part of the blood) and KLH (a protein designed to increase the immune response of the vaccine). By vaccinating your brother or sister with protein made from the tumor, researchers hope to increase the antitumor effect of the stem cells. KLH is used to help the immune response.

Study Treatment Schedule:

If you are found to be eligible to take part in this study, you and your brother or sister will receive a vaccine with KLH. This research involves various steps. In Step 1, a large sample of your plasma will be collected through a vein using a blood separator device. This plasma will be sent to the MD Anderson GMP lab to prepare the vaccine. It takes about 3 months to create your myeloma-specific vaccine. It takes about 3 months to prepare enough vaccine for the next phases of the study.

In Step 2, your brother or sister will receive the vaccine with KLH as an injection under the skin 8 weeks, 6 weeks, and 2 weeks before collection of his/her lymphocytes (immune fighting cells). After each injection, your brother or sister will receive an injection of a medication called GM-CSF that helps the body's response to the vaccine. GM-CSF is given under the skin near the site of the vaccination every day for 4 days, starting the day of the vaccination.

In Step 3, your brother or sister will have apheresis. During apheresis, their blood is passed through a "cell separator" and the lymphocytes (immune fighting cells) are collected. A portion of these cells will be given to you on this day. You will get these cells through a vein while the remainder is stored and frozen for research and/or use later on if you fail to respond to the first infusion.

In Step 4, you will receive the vaccine with KLH. It will be given under the skin immediately after you get the infusion of donor cells, and again 4 and 8 weeks after the lymphocyte infusion. After each vaccine, you will receive an injection of a medication called sargramostim (GM-CSF) that helps the body's response to the vaccine. GM-CSF is given under the skin near the site of the vaccination every day for 4 days, starting the day of the vaccination.

If after 6 months you are not responding to the vaccine, you will be allowed to receive 3 additional vaccines, as long as you did not develop graft versus host disease or any other serious side effects to the first vaccine. The vaccines and follow-up schedule is exactly like the first.

Study Visits:

Within 10 days before you receive the infusion of your donor's cells and within 72 hours before each vaccine injection, the following tests and procedures will be performed:

* Your medical history will be recorded.
* You will have a physical exam, including measurement of your vital signs.
* You will be checked for possible reactions to your treatment, including graft-versus-host disease (GVHD). Infused donor cells may react against your body.
* You will be asked about any side effects you may have had since the first vaccine injection.
* Blood (about 6-12 teaspoons) will be drawn for routine tests and to check your kidney and liver function, as well as the status of your immune system. Part of the blood will be used to test for CMV, hepatitis B, hepatitis C, HIV, HTLV, syphilis, West Nile virus, sickle cell anemia, and Chagas disease. Part of the blood collection will also be used for a pregnancy test for females who are able to have children. To continue to receive infusions of your donor's cells, the pregnancy test must be negative.
* You will have x-rays or bone marrow aspirates and biopsies to assess the response of your disease.

These visits will require 1 day of your time.

Long-Term Follow-Up:

Once a month during Months 3, 6, 12, 18, and 24 months after your last vaccine, the following tests and procedures will be performed:

* Your medical history will be recorded.
* You will have a physical exam, including measurement of your vital signs.
* You will be checked for possible reactions to your treatment, including GVHD.
* Blood (about 6-12 teaspoons) will be drawn to check your kidney and liver, function as well as the status of your immune system. Part of the blood collection will also be used for a pregnancy test for females who are able to have children. To continue to receive infusions of your donor's cells, the pregnancy test must be negative.
* You will have a bone marrow biopsy and aspiration. It may be repeated more often, if your doctor thinks it is needed.

If you are not able to return to MD Anderson, your study doctor may agree to allow you to have these tests and procedures at your local doctor's office. Your local doctor will need to send the results to research staff at MD Anderson.

Once a year, starting 2 years after you receive the last infusion of your donor's cells, you will be contacted by phone to check on your health status.

Length of Study Participation:

You will be considered off study after 5 years. You will be taken off study at any time if lymphocytes cannot be collected, not enough lymphocytes can be collected, your doctor thinks it is needed, the recipient is not able to receive the vaccine, the study doctor thinks it is in your best interest, you need a treatment that is not allowed while on this study, you are unable to keep appointments, or you have intolerable side effects.

This is an investigational study. The myeloma-specific vaccine is not FDA approved or commercially available, and it has been authorized for use in research only. Up to 10 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: After DLI on same day, patients receive vaccine according to donor randomization (the same type of vaccine that their donors received). arm 2: After DLI on same day, patients receive vaccine according to donor randomization (the same type of vaccine that their donors received). arm 3: Donor Group 1: (non-specific vaccination) vaccinated with KLH only vaccine 0.5 cc subcutaneously, 3 times on weeks -8, -6 and -2 prior to donor lymphocyte collection. arm 4: Donor Group 2: (myeloma specific vaccination) vaccinated with KLH-id vaccine 0.5 cc subcutaneously, 3 times on weeks -8, -6 and -2 prior to donor lymphocyte collections.
Interventions: intervention 1: KLH Vaccine intervention 2: KLH-id Vaccine intervention 3: GM-CSF intervention 4: Apheresis intervention 5: Donor Lymphocyte Infusion (DLI)
Intervention descriptions: intervention 1: Donor: 0.5 cc subcutaneously, 3 times on weeks -8, -6 and -2 prior to lymphocyte collection.

Patient: 0.5 cc subcutaneously, 3 times immediately after infusion of donor cells (DLI), and again 4 and 8 weeks post DLI. intervention 2: Donor: 0.5 cc subcutaneously, 3 times on weeks -8, -6 and -2 prior to donor lymphocyte collection.

Patient: 0.5 cc subcutaneously, 3 times immediately after infusion of donor cells (DLI), and again 4 and 8 weeks post DLI. intervention 3: 250 mcg/m2 subcutaneously daily for 4 days after each vaccine intervention 4: Day 0 (day of lymphocyte collection) donors undergo a steady state pheresis to obtain lymphocytes. intervention 5: Day 0, infusion to patient of collected donor cells.

Protocol documents:
Prot_SAP_000.pdf: 
2004-0660
November 19, 2012
Page 1
Protocol Page
PHASE II TRIAL OF ID-SPECIFIC DONOR VACCINATED LYMPHOCYTE 
INFUSION FOR PATIENTS WITH MYELOMA RELAPSING OR FAILING TO 
ACHIEVE A COMPLETE REMISSION AFTER AN ALLOGENEIC 
TRANSPLANT
2004-0660
Core Protocol Information
Short Title 
ID-SPECIFIC DLI FOR MYELOMA
Study Chair: 
Muzaffar H. Qazilbash
Additional Contact:
Beryl M. Tross
Peggy S. LeCompte
Department:
Stem Cell Transplantation and Cellular Therapy
Phone:
713-792-8750
Unit:
423
Study Manager:
Full Title: 
PHASE II TRIAL OF ID-SPECIFIC DONOR VACCINATED LYMPHOCYTE INFUSION FOR 
PATIENTS WITH MYELOMA RELAPSING OR FAILING TO ACHIEVE A COMPLETE 
REMISSION AFTER AN ALLOGENEIC TRANSPLANT
Public Description:
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 02/23/2017
Version:
15
Submitted by:
Peggy S. LeCompte--11/19/2012 4:57:09 PM
OPR Action:
Accepted by:  Rosheta McCray -- 12/6/2012 10:44:27 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2004-0660
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Protocol Body
1.0 Objectives
Primary
1.
1.1
Determine whether transfer of myeloma specific immunity is enhanced by vaccinating donors 
prior to donor lymphocyte infusion with an id-specific vaccine.
2.
Secondary
2.1
To determine the rate of partial response (PR) and complete response (CR) in patients receiving 
donor lymphocytes (recipients) from an id-specific vaccinated donor. 
2.2
To determine the GVHD rates after donor lymphocyte infusion from an id-specific vaccinated 
donor.
2.0 Background
Current Results with Allografting in Myeloma
Although high dose chemotherapy and autologous transplant has improved the outcome for myeloma 
patients (1), most patients with myeloma will eventually relapse after high-dose therapy and autologous 
transplantation and die of their disease. Allogeneic transplantation has been explored in younger patients 
as a mean for overcoming stem cell contamination with myeloma cells and with the hope of obtaining a 
graft-versus tumor effect that could eradicate the malignant clone. A large report from the European 
Transplantation Registry showed disappointing results for patients undergoing allogeneic transplantation. 
Median survival was only 18 months, and the transplant-related mortality (TRM) was prohibitive at 41% 
(2,3). The HOVAN group recently published the results of its initial experience using T cell depleted 
myeloablative bone marrow transplant in patients with HLA identical sibling donors. After initial therapy 
with VAD regimen, patients younger than 55 with an HLA-identical sibling underwent allogeneic 
transplantation with cyclophosphamide (Cy) and TBI (N=47) or Cy/TBI plus idarubicine (N=5). All patients 
received ex-vivo T-cell depleted transplantation with the goal of reducing TRM. Eleven percent of patients 
developed grade III acute graft-versus host disease (GVHD), and 30% developed chronic extensive 
GVHD. Transplant-related mortality was 34%; median OS was 25 months from the time of transplantation 
and was significantly inferior to survival for same patients in other arms of the trial (47 months). Despite 
T-cell depletion, TRM remained elevated and a graft-versus myeloma effect was not apparent in this trial 
(4). Thus high transplant-related mortality precludes the use of myeloablative conditioning regimens for 
myeloma patients. 
Allogeneic stem cell transplantation with reduced-intensity or non-myeloablative conditioning regimens 
has been attempted in patients with multiple myeloma. Table 1 summarizes the results of various phase 
two trials that have been published over the past few years. (5-11) Relapse was the most important 
cause of treatment failure, particularly for patients with chemorefractory disease. However, the 
observation that a  small percentage of refractory myeloma patients can achieve long term disease 
control support further exploration of reduced intensity allografting as a curative strategy for myeloma. 
Patients receiving a non ablative allograft as part of their initial therapy, have been reported to have TRM 
of less than 15%, however, relapse is a common cause of treatment failure with 33% of patients receiving 
reduced intensity allografts as part of their initial therapy. 


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Table 1: Results Of Nonmyeloablative Transplantation. 
Reference
N 
Regimen
RR 
(CR)
Agvhd > 
Grade II
CGVHD
TRM
DFS
OS @ 
2years
5
22
FM
72% 
(32)
46%
27%
40%
19% @ 2 
years
30%
6
45
Mel 100
FM/TBI
61% 
(31)
42%
58%
38%
13% @ 3 
years
36% 
7
29
FM
45% 
52%
51%
21%
33% @ 2 
years
60%
8
41
Fbu
ATG
50% 
(25)
40%
51%
17%
NR
62% 
9
64
FM/ATG
90% 
(45)
39%
47%
23%
38% @ 
2years
55% 
10
31
Mel
FM/TBI
61% 
58%
NR
30%
31% @ 2 
years
31%  
11
54
TBI
52%
39%
46%
15%
55% @ 2 
years 
78% 
RR: Response Rate. CR: Complete Response. aGVHD: acute Graft-Versus-Host Disease. cGVHD: chronic Graft-Versus-Host 
Disease. TRM: Transplant Related Mortality. DFS: Disease-Free Survival. OS: Overall Survival. FM: Fludarabine/Melphalan. TBI: 
Total Body Irradiation. ATG: Anti-Thymocyte Globulin. NR: Not Reported.  
Non-myeloablative transplantation for myeloma is increasingly being explored as part of a tandem 
strategy, in which patients are treated with autologous transplantation followed by planned allogeneic 
transplantation. Maloney et al, recently published their experience with fifty-four patients receiving an 
autologous transplantation with melphalan (200 mg/m²), and after a median of two months, low-dose total 
body irradiation (single fraction 2Gy) followed by stem cell transplantation from an HLA-identical sibling. 
Estimated 2-year overall survival and disease-free survival were 78% and 52%, respectively (11). This, 
although encouraging, these results show that myeloma relapse will continue to be a major cause of 
treatment failure post-allograft, treatment of relapse with donor lymphocyte infusion has been successful 
but only in a minority of patients. Therefore strategies aimed at enhancing the graft vs myeloma effect 
without increasing toxicity need to be developed. 
Donor Lymphocyte Infusions (DLI) for Myeloma
Interest in allografting for myeloma increased due to the demonstration of a graft versus myeloma effect 
(GVM) demonstrated by responses to donor lymphocyte infusions. (12-16) Up to 50% of patients respond 
to DLI, including some with sustained complete remission; however, incidence of acute and chronic 
GVHD is elevated and limits the widespread use of this strategy (15). The results of the largest DLI series 
for myeloma are summarized in Table 2.
Table 2: Results of Largest Donor Lymphocyte Infusion Series for Myeloma
Reference
N
Response Rate
CR+PR
GVHD >2
(>Grade 2)
Comments
13
27
52% (22+30)
56% (15%)
Primarily T cell depleted transplant recipients
14
25
44% (28+16)
48% (24%)
Only 3 responders without GVHD
15
54
52% (17+35)
46% (20%)
T cell depleted patients primarily
16
11
90% (54+36)
50% 
CD8 depleted DLI
Thus, in myeloma graft versus tumor responses seem to correlate with GVHD, possibly due to the fact 
that myeloma associated antigens that have been shown to be targets for the GVM effect are also 


2004-0660
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expressed in other tissues (17). Therefore, one possible strategy is to divert the GVM effect towards 
targets that are expressed primarily in myeloma cells and not in other tissues. This could increase the 
therapeutic efficacy of donor lymphocyte infusions. Vaccination with myeloma specific antigens is such an 
approach.
Vaccination therapy for Myeloma
Vaccination against tumor specific antigens could enhance the graft versus myeloma effect of donor 
lymphocyte infusions. Immunoglobulin (Ig) molecules are composed of heavy and light chains, which 
possess highly specific variable regions at their amino termini. These variable regions contain 
determinants (molecule shapes) that can themselves be recognized as antigens or idiotypes, and are 
patient specific. Thus the idiotypic determinants of the surface Ig of a B-cell lymphoma or myeloma can 
thus serve as a tumor-specific marker for the malignant clone.
Studies in experimental animals, as well as in man, have demonstrated that active immunization against 
idiotypic determinants on malignant B-cells can produce resistance to tumor growth in a number of 
syngeneic experimental tumor models, as well as specific anti-tumor therapy against established tumors 
(18-27). These results, taken together, provided the rationale for testing autologous tumor-derived 
idiotypic surface Ig (Id) as a therapeutic "vaccine" against human B cell malignancies. Furthermore, 
preclinical studies in subhuman primates demonstrated that optimal immunization with human 
lymphoma-derived Id required conjugation of the protein to an immunogenic protein carrier (keyhole 
limpet hemocyanin; KLH) and emulsification in an adjuvant (28).
Kwak et al immunized nine patients with B cell lymphoma with autologous idiotype protein.  These 
patients received no anti-tumor therapy during the time of the study.  They were either in complete 
remission or in a state of minimal residual disease following conventional chemotherapy. In addition, 
three patients with rapidly progressive recurrent lymphoma were enrolled in a separate safety study; all 
three required re-institution of chemotherapy shortly after enrollment, did not complete the immunization 
series, and were not studied further. They received intramuscular injections of 0.5 mg of Id conjugated to 
KLH at 0, 2, 6, 10, and 14 weeks, followed by two booster injections at 24 and 28 weeks. The KLH carrier 
provided a convenient internal control for immunocompetence of the patients, and all patients 
demonstrated both humoral and PBMC proliferative responses to the KLH protein, with the exception of 
one patient, who demonstrated only the latter.  Seven of the nine patients demonstrated either a humoral 
(n=2) or a cell-mediated (n=4) anti-idiotypic immunological response, or both (n=1) (29). Toxicity was 
minimal in all twelve patients. All patients experienced transient local reactions characterized by mild 
erythema, induration, and discomfort, without skin breakdown, at the injection s. Id immunization was 
associated with a mild elevation (less than twice the normal value) of serum creatine phosphokinase 24 
hours after immunization in an occasional case. These results demonstrate that patients with B cell 
lymphomas can be induced to make sustained idiotype-specific immune responses by active 
immunization with purified autologous tumor-derived surface Ig. They show that autologous Id, made 
immunogenic by conjugation to KLH, can serve as an immunogen (antigen) to elicit host immunological 
responses. 
Similar clinical results were observed in multiple myeloma patients. At the University of Turin 12 patients 
with myeloma received high-dose chemotherapy and autologous stem cell transplantation followed by 
vaccination with Id-specific proteins conjugated to KLH and GM-CSF or IL-2 as immunoadjuvants (30). 
Id-specific T cell proliferative responses were documented in 2 patients, and a positive Id-specific 
delayed-type hypersensitivity reaction was observed in 8 of the 10 patients studied. Twelve patients with 
multiple myeloma were treated at Stanford University with high-dose therapy and peripheral blood stem 
cell transplantation followed by Id immunizations (31). Following transplantation patients received a series 
of monthly immunizations consisting of Id-pulsed autologous dendritic cells followed by subcutaneous 
(S.C.) boosts of Id conjugated to KLH. The administration of Id-pulsed DC and Id-KLH vaccines was well 
tolerated with patients experiencing only minor and transient side effects. Two of 12 patients developed 
an Id-specific, cellular proliferative immune response, and one of three patients studied developed a 
transient but Id-specific cytotoxic T cell response. Similarly, investigators at the University of Wales were 
able to generated dendritic cells from six patients with IgG myeloma, and the cells were pulsed with the 


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autologous Id (32). Id-specific responses were also observed. PBMC proliferative responses to Id were 
observed in five of the six patients following treatment. These initial trials demonstrate that the 
vaccination of patients was relatively safe and capable of producing Id-specific T cell responses.
Granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) has emerged as a 
promising adjuvant for idiotypic Ig antigen. Syngeneic mice (10 mice per group) were immunized with 50 
mcg Id-KLH derived from the tumor either alone or in combination with GM-CSF mixed together with the 
antigen and administered subcutaneously. Three additional daily doses of GM-CSF were administered 
S.C. as close to the original  of immunization as possible.  Mice immunized with an irrelevant Id-KLH 
(4C5 IgM) served as negative controls for the vaccine. Two weeks after this single immunization, all mice 
were challenged with a single preparation of 38C13 tumor cells (5 x 103 cells i.p.) and followed for 
survival.  The results demonstrate that the augmented survival benefit afforded by immunization with 
relevant Id-KLH alone can be significantly enhanced by the addition of GM-CSF at either the 100 or 
10,000 unit dose.  A curious but reproducible observation has been the loss of this protective effect at a 
higher dose of GM-CSF of 50,000 units (data not shown).  These data suggest that GM-CSF may have a 
potent adjuvant effect in vivo for Id-KLH antigen, especially at relatively low doses (33). 
Idiotype protein vaccine in combination with GM-CSF as an adjuvant was evaluated in 20 lymphoma 
patients in first clinical complete remission (34). GM-CSF administration was well tolerated with minimal 
side effects. Tumor-specific cytotoxic CD8+ and CD4+ T cells were found in 19 of 20 patients. This data 
seem to indicate that GM-CSF may be an essential component of this vaccine formulation's potency. 
Donor Vaccination with Idiotype-KLH vaccine
Most vaccination protocols have attempted to vaccinate the patient against their own malignancy. 
Intuitively, however, this strategy has the main obstacle that the patients immune system has already 
failed to respond to the tumor in an effective manner. The availability of a vaccine derived from the 
immunoglobulin idiotype as a tumor-specific antigen, opened the opportunity to study the transfer of 
antigen-specific antitumor immunity from an immunized stem cell donor to the SCT recipient. Kwak et al 
have explored this strategy of transferring tumor idiotypic-specific immunity with bone marrow from 
specifically immunized donors in a preclinical murine model (35).  The 38C13 B cell tumor is a 
carcinogen-induced C3H cell line, which both expresses and secretes idiotypic Ig both in vitro and in vivo.  
Thus, it can serve as a model for well differentiated B cell malignancies, such as lymphomas or 
myelomas.  Mice serving as syngeneic marrow donors were immunized with tumor-derived Id protein or 
with a control immunoglobulin of matched isotype.  Naive lethally irradiated recipients reconstituted with 
marrow from immune donors showed serologic tumor idiotype-specific immunity, as well as protection 
against subsequent lethal tumor challenge.  The immunoprotective effect of immune marrow was also 
shown in the setting of combined donor and recipient immunizations. These results demonstrate the 
successful transfer of tumor antigen-specific immunity with immune marrow as a protective element and 
provide support for testing this approach in humans.
This approach has been tested in a single human patient with myeloma; however, a myeloablative 
conditioning regimen was used (36). The goal of BB-IND 4999 was to induce myeloma idiotype-specific 
immunity in the allogeneic donor and to evaluate the transfer of idiotype-specific immunity to the myeloma 
patient following allogeneic bone marrow grafting.  FDA approval was granted for this study.  
Idiotype-specific humoral and cellular immunity in both the donor and the recipient were evaluated using 
the serum antibody and peripheral blood mononuclear cell proliferative assays already established and 
described in the phase I lymphoma trial. This was the first time a normal BMT donor was immunized 
against a tumor protein. Successful donor immunization was demonstrated by serum antibodies, which 
bound specifically to patient-derived myeloma IgG and specific proliferation of peripheral blood 
mononuclear cells (PBMC) to the IgG in vitro. Donor toxicity consisted only of mild reactions at injection s. 
Bone marrow was used as the stem cell source. Engraftment was normal and accompanied by grade 2 
skin GVHD responsive to therapy. 60 days post-SCT, recipient PBMC proliferated both to the KLH control 
protein (stimulation index [S.I.] 48.3 at 50 mcg/ml) and to Id (S.I. 4.8) when assayed independently in 5 
day in vitro cultures.  An Id-specific T-cell line has also been established from recipient PBMC.  Specificity 
was demonstrated by the lack of proliferation to a panel of isotype-matched Ig of unrelated idiotypes.  No 


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humoral anti-idiotypic response has been detected in the recipient.  The recipient demonstrated complete 
clinical response (absence of M-protein, absence of dysplastic marrow plasma cells at day 100).
 
Dr Michael Bishop at the NCI together with Dr. Kwak have gone on to immunize 9 donors and proceed to 
stem cell collection and transplantation using a non ablative transplant regimen. In this study donor 
immunity was documented in all 9 donors, however the effects of donor immunization on transplant 
outcomes will be difficult to assess in the context of  the primary allograft. 
Thus, in order to define the role of id-specific donor vaccinations, we propose to do a phase II trial of 
donor lymphocyte infusions coming from an id-specific-KLH vaccinated donor. Such a trial will allow us to 
answer the following questions which are essential to move the field of id-specific vaccination forward.
1)
Will id specific donor vaccination translate into a skewing of lymphocyte repertoire to a more 
myeloma specific spectrum?
2)
Is it possible to quantify the degree that myeloma specific immunity is enhanced by id-specific 
vaccination?
3)
Do ex-vivo measures of id-specific immunity correlate with disease control?
4)
Will id specific vaccination of donors prior to lymphocyte collection enhance the efficacy of donor 
lymphocyte infusions for myeloma patients not in remission after allogeneic transplantation 
without increasing the risk of GVHD.
3.0 Background Drug Information
3-A Id-KLH Vaccine Myeloma Immunoglobulin Idiotype Vaccine (NSC-678327, BB IND 5779)
Availability - Individual Myeloma immunoglobulin are obtained from each patient and individual vaccine is 
prepared for each patient at the GMP Facility of MDACC.
Idiotype Vaccine Preparation - Idiotype vaccines are prepared using a recipient's idiotype protein.  The 
patient-specific protein will be isolated from the recipient's plasma (via plasmapheresis), purified by 
protein A or anti-Hu IgA affinity chromatography, and covalently coupled to a keyhole limpet hemocyanin 
(KLH) as described in Appendix G.  The preparation of the final vaccine product (myeloma idiotype 
protein conjugated with KLH) will be performed by GMP Facility of MDACC.  Each  batch of 
patient-specific vaccines will be produced according to Good Manufacturing Practices (GMP) standards 
and will be tested for sterility, endotoxin contamination, and general safety, prior to its use in any patient. 
The final vaccine product (myeloma idiotype protein conjugated with KLH) will be manufactured (and 
vialed) by the GMP Facility of MDACC. Each patient-specific vaccine will be labeled to include the 
following information:
a)
myeloma immunoglobulin idiotype vaccine: patient-specific lot
b)
final volume and concentration of  vaccine product
c)
KLH and patient-specific immunoglobulin subtype
d)
storage conditions
e)
fill date
f)
patient identification (first name/last initial)
Storage and Stability - The final product is available as a solution containing  1.1 mls of conjugated 
protein diluted in sodium chloride 0.9% (NS). The solution is contained in a 1.8 ml insert inside a sterile 
vial. The final solution contains 0.5 mg/ml of KLH conjugated to 0.5 mg/ml of the patient-specific 
immunoglobulin idiotype protein. Intact vials are stored at -20 C. 
Administration - The patient (recipient) and donor will receive 3 subcutaneous injections of the 
patient-specific vaccine preparation containing 0.5 mg of the myeloma protein at the protocol specified 
timepoints. Both individuals will receive GM-CSF as an adjuvant to the vaccine preparation.  GM-CSF will 
be administered as a subcutaneous injection at a dose of 250 mcg/m2 (rounded up to the nearest vial)  


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daily for four consecutive days (day 0-day 3).
Adverse events- described with Id-KLH vaccine administration include local  reactions (erythema, 
induration, swelling and tenderness), fever, chills, rash, myalgias and arthralgias. Mild elevations in 
creatinine phosphokinase (CPK) have been observed.  Fever and chills, associated with vaccine 
administration will be treated with acetominophen and/or meperidine.
3-B Unconjugated KLH
Availability – KLH according to GMP standards as described above, will also be vialed as a separate 
product by the MDACC GMP facility and will be supplied by the investigational pharmacy. This vialed 
product will be tested separately for sterility, endotoxin, and general safety, prior to its use in any patient. 
Each vial of KLH will be labeled to include the following information:
a)
Patient-specific lot
b)
Final volume and concentration of product
c)
Patient-specific immunoglobulin subtype
d)
Storage conditions
e)
Fill date
f)
Patient identification (first name/last initial)
Adverse events– The toxicities associated with the administration of unconjugated KLH are anticipated to 
be identical to those described with the Id-KLH vaccine. The safety issues regarding the injection of 
heterologous idiotype protein isolated from other patients’ B-cell tumors have already been fully 
addressed in CC Protocol 96-C-0133 (NCI T93-0164; Id Vaccination in Previously Untreated Patients with 
Follicular Lymphoma) and are felt to be minimal, because of the highly purified nature of the protein. 
Briefly an immune response of any consequence to the isotype used as a negative control during the skin 
test is not likely, based on:
a)
Any immune response specifically directed against the idiotype (i.e., variable region) on the 
control idiotype protein is not likely to cross-react with host cells and is therefore not likely to be of 
any consequence.
b)
An autoimmune response against constant region or allotype determinants shared between the 
idiotype of patient’s own tumor and that of the control idiotype is theoretically possible. However, 
no evidence of such autoimmune responses have been observed either in vivo or in vitro during 
the course of immunization of the normal donors so far treated or in the patients who underwent 
autologous transplantation. Furthermore, a safety precedent exists for immunizing patients with 
material derived from tumor cells from other patients. For example in attempting to develop 
immune responses against metastatic melanomas, patients were immunized with 1) intact 
melanoma cells: 2) shed antigens fractionated be detergent treatment and ultracentifugation: 3) 
melanoma cells infected with vaccinia virus and melanoma cells freeze thawed and mechanically 
disrupted, all using a pool of allogeneic melanoma cell lines.
3-C Sargramostim (granulocyte-macrophage colony-stimulating factor; NSC - 613795; BB-IND 
2632, Leukine)
Availability - The GM-CSF to be used in this study is a glycosylated, recombinant human GM-CSF. This 
GM-CSF is an altered form of the native molecule; the position 23 arginine has been replaced with a 
leucine to facilitate expression of the protein in yeast (Saccharomyces cerevisiae). Manufactured by 
Immunex.  GM-CSF will be provided by the protocol from a commercial source.
Storage and Stability - The GM-CSF is formulated as a white lyophilized cake and is provided in vials 
containing 500 mcg of the GM-CSF protein as well as 10.0 mg of sucrose, 40.0 mg of mannitol, and 1.2 
mg of Tris (Trimethamine). The unreconstituted material should be kept refrigerated at 2-8
oC and is stable 
for at least eighteen months.  Once reconstituted, the solution is stable for at least 24 hours at 2-8
oC or at 


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18-25
o C.  Because the product does not contain a preservative, vials should be treated as unit-dose 
containers; reconstituted solution should be held at 2-8
oC and discarded after no more than six hours.  Do 
not freeze GM-CSF.
Preparation - To prepare a vial of GM-CSF for direct subcutaneous use, aseptically inject 1.0 ml of Sterile 
Water for Injection, USP, into the vial to dissolve the lyophilized cake.  The dilutent should be directed 
against the side of the vial to avoid excess foaming.  Avoid vigorous agitation of the vial; do not shake.  
This yields a solution containing 500 mcg/ml.
Administration - The appropriate total dose is withdrawn into and administered from a plastic tuberculin 
syringe.  The GM-CSF will be injected subcutaneously as close as possible to the Id-KLH injection .  All 
GM-CSF doses for each patient will be administered by the nursing staff in the outpatient unit.
Adverse events- Toxicities described in patients receiving GM-CSF include:  fever, chills, diaphoresis, 
myalgias, fatigue, malaise, headache, dizziness, dyspnea, bronchospasm, pleural effusion, anorexia, 
indigestion, nausea, vomiting, diarrhea, injection  tenderness, urticaria, rash, pruritus, hypersensitivity 
reactions, bone pain, thromboembolic events, phlebitis, hypotension, peripheral edema, leukocytosis, 
thrombocytosis or thrombocytopenia, hepatic enzyme abnormalities, and bilirubin elevation.  The first 
administration of GM-CSF has provoked a syndrome of dyspnea and hypotension within two hours after 
GM-CSF injection in a single patient receiving yeast-derived GM-CSF; this type of reaction has more 
frequently been observed in patients receiving GM-CSF produced in E. coli.  One report of a vascular 
leak-like syndrome occurring after autologous bone marrow transplant in a patient receiving continuous 
IV (intravenous) infusion of GM-CSF has been recorded.
4.0 Patient Eligibility
Recipient Criteria for Vaccine Production
1.
Recipient for vaccine production: Patient with IgG1, IgG2, or IgG4 Multiple Myeloma who has 
received or is planning to receive an allogeneic progenitor cell transplant from a HLA compatible 
related donor (either 6/6 or 5/6 related donor). 
2.
Recipient for vaccine production: Have evidence of persistent or relapsing disease as 
demonstrated by persistent serum peak (by either standard protein electrophoresis, immune 
fixation or free light chain assays) or marrow infiltration. Serum peak must be greater or equal 
than 0.2 gm/dl and represent more than 70% of the specific immunoglobulin subtype. Patients 
who have adequate amount of monoclonal idiotype protein previously cryopreserved on prior 
departmental laboratory protocols are also eligible to be registered for vaccine production using 
the cryopreserved samples. 
3.
Able to sign written informed consent.
4.  
Age up to 70 years.
5.
Zubrod PS 2.
6. 
Have no serious organ dysfunction as defined by serum creatinine <2.5 mg/dL, serum bilirubin <3 
x upper limit of normal, SGPT <4 x upper limit of normal.
7.
Negative donor infectious disease panel: 
- Hepatitis B surface antigen (HBsAg)
- Anti-Hepatitis B core antibody (HBcAb)
- Anti-Hepatitis C Virus antibody (HCV Ab)
- Anti-Human Immunodeficiency Virus (HIV) antibody (HIV 1/2 type O Ab)
- Anti-Human T cell lymphotrophic Virus (HTLV) antibody (HTLV I/II Ab)
- Rapid Plasma Reagen (RPR)
- Cytomegalovirus antibody (CMV)
- HCV/HIV Nucleic Acid Test
- West Nile Virus Nucleic Acid Test
- Sickledex
- T Cruzi AB


2004-0660
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Additional tests shall be performed as required to assess the possibility of transmission of 
other infectious or non-infectious diseases.
8.
Negative serum Beta HCG test in a women with child bearing potential (not post-menopausal for 
12 months or no previous surgical sterilization) and willing to use an effective contraceptive 
measure while on study. Mothers should not breastfeed during the study.
Exclusion Criterion
1.
Recipient with IGg3 Multiple Myeloma.
Donor Criteria 
1.
Able to sign written informed consent and be willing to provide donor lymphocytes.
2.
Age 18 – 75 years 
3.
No physical contraindications to lymphocyte collection (i.e., severe atherosclerosis, auto-immune 
disease, cerebrovascular accident, prior malignancy less than 5 years ago other than 
non-melanoma skin cancer treated with surgery).  Donors with severe atherosclerosis by history 
will receive a cardiology consult and be judged eligible on a case by case basis. 
4.
Negative donor infectious disease panel:
- Hepatitis B surface antigen (HBsAg)
- Anti-Hepatitis B core antibody (HBcAb)
- Anti-Hepatitis C Virus antibody (HCV Ab)
- Anti-Human Immunodeficiency Virus (HIV) antibody (HIV 1/2 type O Ab)
-Anti-Human T cell lymphotrophic Virus (HTLV) antibody (HTLV I/II Ab)
- Rapid Plasma Reagen (RPR)
- Cytomegalovirus antibody (CMV)
- HCV/HIV Nucleic Acid test
Additional tests shall be performed as required to assess the possibility of transmission of 
other infectious or non-infectious diseases.
5.
Negative serum Beta HCG test in a woman with child bearing potential (not post-menopausal for 
12 months or no previous surgical sterilization) must use an effective method of contraception 
until at least 1 month after lymphocyte collection.  Mothers should not breastfeed during the 
study.


2004-0660
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Donor Eligibility Undetermined
All products obtained from donors where eligibility has not been determined must be stored in quarantine 
until eligibility has been assessed. Products in quarantine are clearly labeled to prevent release. If 
product must be released prior to eligibility determination then urgent medical need must be documented. 
These products must be labeled "NOT EVALUATED FOR INFECTIOUS SUBSTANCES" and 
"WARNING: Advise patient of communicable disease risks".
Release of Products from Ineligible Donor
The release of products from an ineligible donor requires the documentation of urgent medical need and 
the consent of the patient. Products are labeled with a "Biohazard" Label including "WARNING: Advise 
patient of communicable disease risks".  Screening and test results must accompany the product and 
provided to the infusing physician in an envelope for review.  These documents are to be properly 
disposed of after infusion to protect the privacy of the donor.
Ineligible Donors
If donor is deemed to be ineligible, finding must be documented on the Donor Certificate.  
An "Urgent Medical Need" order including reason for ineligibility must be provided to the laboratory.
5.0 Pretreatment evaluation
The procedures and tests listed below are standard of care and are performed to determine recipient and
donor eligibility. 
A.  Both recipient and donor:
1)
History and physical (H&P).  
2)
Albumin, total protein, calcium, glucose, BUN, creatinine, bilirubin, ALT, alkaline 
phosphatase, LDH, CBC with differential, PT/PTT. Serum B-HCG for female donor 
and recipient.
B.  Recipient only:
1)
Immunodeficiency panel: Quantitative immunoglobulins, quantification of lymphocyte 
subsets (CD4 and CD8).
2)
Cyclosporine or tacrolimus level as appropriate.
3)
Disease restaging: SPEP, UPEP, serum and immunofixation electophoresis, serum 
for free kappa and lambda light chain assay, Beta 2 Microglobulin, and C reactive 
protein.
4)
Bone survey, Magnetic resonance imaging (MRI), or Positive Emission Tomography 
(PET)/Computed tomography(CT) as clinically indicated.
5)
Bone marrow aspiration and biopsy for cytogenetics, chimerism, myeloma panel, and 
IgG subpanel.
6)   Negative donor infectious disease panel: 
- Hepatitis B surface antigen (HBsAg)
- Anti-Hepatitis B core antibody (HBcAb)
- Anti-Hepatitis C Virus antibody (HCV Ab)
- Anti-Human Immunodeficiency Virus (HIV) antibody (HIV 1/2 type O Ab)
- Anti-Human T cell lymphotrophic Virus (HTLV) antibody (HTLV I/II Ab)
- Rapid Plasma Reagen (RPR)
- Cytomegalovirus antibody (CMV)
- HCV/HIV Nucleic Acid Test
- West Nile Virus Nucleic Acid Test
- Sickledex
- T Cruzi AB


2004-0660
November 19, 2012
Page 11
Additional tests shall be performed as required to assess the possibility of 
transmission of other infectious or non-infectious diseases.
C.  Donor only:
1)  Negative donor infectious disease panel:
- Hepatitis B surface antigen (HBsAg)
- Anti-Hepatitis B core antibody (HBcAb)
- Anti-Hepatitis C Virus antibody (HCV Ab)
- Anti-Human Immunodeficiency Virus (HIV) antibody (HIV 1/2 type O Ab)
-Anti-Human T cell lymphotrophic Virus (HTLV) antibody (HTLV I/II Ab)
- Rapid Plasma Reagen (RPR)
- Cytomegalovirus antibody (CMV)
- HCV/HIV Nucleic Acid test
Additional tests shall be performed as required to assess the possibility of 
transmission of other infectious or non-infectious diseases.
6.0 Treatment Plan
Idiotype Procurement 
6.1
Recipient will undergo steady state plasmapheresis procedure to provide idiotype protein 
necessary to produce the vaccine. This is a standard procedure. Plasma (60-100 cc) from the 
plasmapheresis procedure will be sent to the MD Anderson Cancer Center GMP lab were it will 
be processed. The MDACC GMP lab will be responsible for producing the id-KLH conjugated 
vaccine according to the supplied standard operating procedure (see PDOL Appendices H and I). 
The vaccines will be kept in the GMP lab until requested.  Alternatively vaccine can be produced 
using previously collected idiotype monoclonal protein collected on ongoing laboratory protocols 
and cryopreserved.  
6.2
Donor will be vaccinated with an id-KLH vaccine 0.5 cc subcutaneously, once during weeks -8, 
-6, and –2 prior to donor lymphocyte collections. 
The preferred site for the vaccine injection are the deltoid area (upper arm) and thigh.  Sites 
should be alternated with each vaccine administration.
All donors will be observed in the clinic for two hours following vaccine administration.  During the 
observation period, vital signs will be taken every 15 minutes during the first hour and then every 
30 minutes during the second hour following vaccine administration. 
6.3
GM-CSF 250 mcg/m2 (dose rounded up to the nearest vial) S.C. will be given daily for four days 
(days 0-3) after each vaccine. All GM-CSF injections will be given in close proximity to the 
vaccination, as close to the exact  of injection as possible to ensure optimal recruitment of 
dentritic cells. The first dose of GM-CSF will be given by a nurse, and the remaining three doses 
will be given by the donor. Research staff will provide educational instructions regarding 
subcutaneous injection administration.
6.4
Recipient must meet the following criteria in order to receive the vaccine:
- Recipient to receive vaccine must be greater or equal than 3 months post allograft and with 5% 
or greater donor cell engraftment
- On a prednisone or prednisone equivalent dose of no more than 10 mg every other day at 
the time of registration, and with tacrolimus levels of <5 ng/dl or cyclosporine levels of < 100 
ng/dl.
- Have no uncontrolled GVHD. 


2004-0660
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- Negative serum Beta HCG test in a woman with child bearing potential (not post-menopausal 
for 12 months or no previous surgical sterilization) and willing to use an effective contraceptive 
measure while on study.
If the recipient does not meet the above "pre-vaccine" criteria, the recipient and donor will be 
taken off the study. The donor will have follow-up tests and procedures performed, as described 
in Section 7.0.
6.5
On day 0 (day of lymphocyte collection) donors will undergo a steady state pheresis to obtain 
lymphocytes.  Donor target cell dose will be to  2 x 10e7 CD3+ cells /kg recipient weight. If the 
target dose is not reached after 3 collections, then the door and the recipient will be taken off the 
study and the apheresis product will be discarded.
6.6
If successful collection, on day 0: 1 x 10e7 CD3+/cells per kg will be infused into the recipient. 
The rest of the cells will be cryopreserved in 5 x 10e7 CD3+ cells /kg recipient weight alliquot. 
Premedication will include only acetaminophen 650 mg po (orally) and benadryl 25 mg iv once. 
NO STEROIDS ARE TO BE GIVEN PRIOR TO LYMPHOCYTE INFUSION.
6.7
After DLI on same day, recipient will receive id-KLH vaccine. The vaccine will be also 
administered on week 4 and week 8 post DLI. The recipient will receive a total of 3 vaccines. 
6.8
For the donor the time of active treatment will begin the day of the first vaccine and finish 30 days 
after donor lymphocyte collection. 
6.9
For the recipient the time of active treatment will begin the day of the donor lymphocyte infusion 
and finish 30 days after the last vaccination.  
6.10
Recipients will receive GM-CSF 250 mcg/m2 (rounded up to the nearest vial) S.C.daily for four 
days (days 0-3) after each vaccine. All GM-CSF injections will be given in close proximity to the 
vaccination, as close to the exact site of injection as possible to ensure optimal recruitment of 
dentritic cells. The first dose of GM-CSF will be given by a nurse, and the remaining three doses 
will be given by the recipient. Research staff will provide educational instructions regarding 
subcutaneous injection administration.
6.11
Donors and/or recipients: Fever and chills associated with vaccine administration and/or GM-CSF 
will be treated with acetominophen and/or meperidine. The use of non-steroidal anti-inflammatory 
drugs and/or steroids should be avoided.
6.12
Recipients should not receive steroid premeds, or high dose steroids for other indications unless 
approved by the Study Chair or his designee.
6.13
Recipients failing to respond 6 months after the last vaccination can receive up to 3 subsequent 
doses of 5 x 10e7 CD3+ cells/kg of the remaining cryopreserved cells, if no active GVHD is 
present. The additional lymphocyte infusions and follow up will be exactly like the first infusion.
7.0 Evaluation During Study
A. Donor: 
Prior to each vaccination: Within 72 Hours:
1)
H&P, vital signs.
2)
Albumin, total protein, calcium, glucose, BUN, creatinine, bilirubin, ALT, alkaline
phosphatase, LDH, CBC with differential, PT/PTT.


2004-0660
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Page 13
3)   Toxicity assessment after first vaccination.
4)
Immunodeficiency panel: Quantitative immunoglobulins, and quantification of 
lymphocyte subsets (CD4 and CD8).
            5)   Negative serum pregnancy test if of child bearing potential if of child bearing potential.
6)
Leukopheresis will be performed to obtain 2 x 10^9 mononuclear cells (MNC) from  
donor and recipient.
7)
Collect 10 cc serum and 60 cc whole blood in preservative-free heparin for 
idiotype-specific antibody and cellular proliferative responses once during weeks -8, 
-6, -4, -2, and 0.
8)  Negative donor infectious disease panel: 
- Hepatitis B surface antigen (HBsAg)
- Anti-Hepatitis B core antibody (HBcAb)
- Anti-Hepatitis C Virus antibody (HCV Ab)
- Anti-Human Immunodeficiency Virus (HIV) antibody (HIV 1/2 type O Ab)
- Anti-Human T cell lymphotrophic Virus (HTLV) antibody (HTLV I/II Ab)
- Rapid Plasma Reagen (RPR)
- Cytomegalovirus antibody (CMV)
- HCV/HIV Nucleic Acid Test
Additional tests shall be performed as required to assess the possibility of 
transmission of other infectious or non-infectious diseases.
Prior to lymphocyte collection: Within 72 Hours:
1)
H&P, vital signs.
2)
Albumin, total protein, calcium, glucose, BUN, Creatinine, bilirubin, ALT, Alkaline 
phosphatase, LDH, CBC with differential, PT/PTT.
3)
Toxicity assessment.
4)    Collect 10 cc serum and 60 cc whole blood in preservative-free heparin for 
idiotype-specific antibody and cellular proliferative responses.
5)   Negative donor infectious disease panel: 
- Hepatitis B surface antigen (HBsAg)
- Anti-Hepatitis B core antibody (HBcAb)
- Anti-Hepatitis C Virus antibody (HCV Ab)
- Anti-Human Immunodeficiency Virus (HIV) antibody (HIV 1/2 type O Ab)
- Anti-Human T cell lymphotrophic Virus (HTLV) antibody (HTLV I/II Ab)
- Rapid Plasma Reagen (RPR)
- Cytomegalovirus antibody (CMV)
- HCV/HIV Nucleic Acid Test
Additional tests shall be performed as required to assess the possibility of 
transmission of other infectious or non-infectious diseases.
B. Recipient:
Within 10 days prior to lymphocyte infusion and within 72 hours prior to each 
vaccine:
1)   H&P, vital signs.
2)   Albumin, total protein, calcium, glucose, BUN, creatinine, bilirubin, ALT, alkaline 
 phosphatase, LDH, CBC with differential, PT/PTT.
      3)  GVHD assessment.
4)   Immunodeficiency panel.
5)   Negative serum pregnancy test if of child bearing potential.
6)   Disease specific assessment: 
             - SPEP, UPEP, serum and immunofixation electophoresis, serum for free kappa and 
lambda light chain assay, Beta 2 Microglobulin, and C reactive protein.


2004-0660
November 19, 2012
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7)  Collect 10 cc serum and 60 cc peripheral blood in preservative-free heparin for 
idiotype-specific antibody and cellular proliferative responses, immediately prior to 
donor lymphocyte infusion, 1 hour after the donor lymphocyte infusion.
8)  Idiotype-specific humoral and cellular responses will be assessed in both donor and in 
the recipient post-transplantation. 
9)  Negative donor infectious disease panel: 
- Hepatitis B surface antigen (HBsAg)
- Anti-Hepatitis B core antibody (HBcAb)
- Anti-Hepatitis C Virus antibody (HCV Ab)
- Anti-Human Immunodeficiency Virus (HIV) antibody (HIV 1/2 type O Ab)
- Anti-Human T cell lymphotrophic Virus (HTLV) antibody (HTLV I/II Ab)
- Rapid Plasma Reagen (RPR)
- Cytomegalovirus antibody (CMV)
- HCV/HIV Nucleic Acid Test
- West Nile Virus Nucleic Acid Test
- Sickledex
- T Cruzi AB
Additional tests shall be performed as required to assess the possibility of 
transmission of other infectious or non-infectious diseases.
C.  Donor Long-Term Follow-Up:
Procedures and Tests:
Donors will have the following procedures and tests at 1, 12, and 24 (+ 1 week) post 
donor lymphocyte collection at MD Anderson Cancer Center if possible.
1)
H&P, vital signs.
2)
Albumin, total protein, calcium, glucose, BUN, creatinine, bilirubin, ALT, Alkaline 
phosphatase, LDH, CBC with differential, PT/PTT.
      3)   Immunodeficiency panel. 
If the donor is not able to return to MD Anderson Cancer Center for long-term follow-up, 
the donor should have the procedures and tests performed with a local physician, as 
approved by the Study Chair.  The results should be sent to research staff at MD 
Anderson Cancer Center. 
Telephone Follow-Up:
Donors will receive a telephone follow-up call once a year for 5 years, starting at month 
24 (+ 1 week) post donor lymphocyte infusions. The telephone follow up will include 
questions regarding interim history, hospitalizations, new medications, and new allergies.
D.  Recipient Long-Term Follow-Up:
      
Procedures and Tests:
Recipients will have the following procedures and tests at 3, 6, 12, 18, and 24 months 
post last vaccine (+ 1 week)
1)  H&P, vital signs.
2)  Albumin, total protein, calcium, glucose, BUN, creatinine, bilirubin, ALT, alkaline 
phosphatase, LDH, CBC with differential, PT/PTT.
      3) GVHD assessment.
4)  Immunodeficiency panel
5)  Disease specific assessment:
-SPEP, UPEP, serum and immunofixation electophoresis, serum for free kappa and 
lambda light chain assay, Beta 2 Microglobulin, and C reactive protein.


2004-0660
November 19, 2012
Page 15
-Bone marrow aspiration and biopsy for cytogenetics, chimerism, and myeloma panel: 
Kappa, Lambda, CD138 staining. 
6) Collect 10 cc serum and 60 cc peripheral blood in preservative-free heparin for 
idiotype-specific antibody and cellular proliferative responses, immediately prior to donor 
lymphocyte infusion, and months (+ 1 week) 1, 2, 3, 4, 6, 12, 18 and 24.
7) Idiotype-specific humoral and cellular responses will be assessed in both donor and in 
the recipient post-transplantation. 
If the recipient is not able to return to MD Anderson Cancer Center for long-term 
follow-up, the recipient should have the procedures and tests performed with a local 
physician, as approved by the Study Chair.  The results should be sent to research staff 
at MD Anderson Cancer Center. 
Telephone Follow-Up:
Recipients will receive a telephone follow-up call once a year for 5 years, starting at 
month 24 (+ 1 week) post donor lymphocyte infusions. The telephone follow up will 
include questions regarding interim history, hospitalizations, new medications, and new 
allergies.
OPTIONAL PROCEDURE
Recipients will be asked for permission to obtain additional blood samples for future 
testing as well as a punch skin biopsy using standard techniques in an area around the 
vaccination  to identify types of cellular infiltrates.
Unused cells or vaccines generated for this study which are not infused into the recipients
will be used for research purposes. 
      E.
Evaluation of Toxicity and Data Collection (Donors and Recipients)  
The severity of the adverse events observed in the proposed treatment will be graded 
according to the Common Terminology Criteria v3.0 (CTCAE). 
Events not included in the CTCAE chart will be scored as follow:
General grading:
Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment 
required beyond prophylaxis.
Grade 2: Moderated: discomfort present with some disruption of daily activity, require 
treatment.
Grade 3: Severe: discomfort that interrupts normal daily activity, no responding to first 
line treatment. 
Grade 4: Life Threatening: discomfort that represents immediate risk of death.
Expected adverse events (AEs) related to the vaccine injection :
1. Local  reactions (erythema, induration, swelling and tenderness), 
2. Fever, chills, 
3. Rash, 
4. Myalgias and arthralgias. 
5. Mild elevations in creatinine phosphokinase (CPK).  
Expected adverse events (AEs) related to GM-CSF:
1. Fever, chills, diaphoresis
2. Myalgias, fatigue, malaise
3. Headache, dizziness
4. Dyspnea, bronchospasm, pleural effusion
5. Anorexia, indigestion, nausea, vomiting, diarrhea


2004-0660
November 19, 2012
Page 16
6. Urticaria, rash, pruritus, hypersensitivity reactions 
7. Bone pain
8. Thromboembolic events, phlebitis
9. Hypotension
10.Peripheral edema
11.Leukocytosis, thrombocytosis or thrombocytopenia
12.Hepatic enzyme abnormalities and bilirubin elevation have been recorded.
Expected adverse events (AEs) related to the vaccine:
1.Autoimmune reactions (hypogammaglobulinemia, collagen vascular diseases, 
cytopenias).
2.Local reactions
Expected adverse events (AEs) related to the DLI:
1.Graft versus host disease
Casualty Assessment:
For the purpose of this study adverse events known to be caused by the vaccine 
administration, GM-CSF, donor lymphocyte infusion and to the vaccine and its direct 
consequences will be scored as definitive related.
Adverse events known to be related to drugs used for the treatment of Medical problems 
arise as direct consequences of known adverse events will be scored as probable related
.
When the relationship of the adverse event cannot be ruled out with certainty the AE may 
be considered possible related. 
Adverse Events Data Collection :
At each evaluation time point adverse events will be assessed and only 
those related to the vaccine and donor lymphocyte infusion will be collected. 
The donor and recipient will be provided a diary to collect any adverse 
events following administration of the vaccines and GM-CSF.  The donor 
and recipient will bring the diary to each scheduled visit for review by 
research staff.
Adverse events related to the injection site and GM-CSF won’t be capture 
unless these are considered serious. The data collection will reflect the 
onset and resolution date and maximum grade; beyond this point some 
events considered late complications post treatment might be recorded with 
the first date of its awareness and grade or resolution date when able to be 
documented. 
Intermittent events should be labeled as such and followed until resolution.If 
a patient is taken off study while an event still ongoing, this will be followed 
until resolution unless another therapy is initiated.  Pre-existing medical 
conditions will be recorded only if an exacerbation occurs during the active 
treatment period.  Co-morbid events will not be scored separately.
Serious Adverse Event Reporting (SAE)
A serious adverse event is – any adverse drug experience occurring 
at any dose that results in any of the following outcomes: 
·
Death
·
A life-threatening adverse drug experience – any adverse experience 


2004-0660
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Page 17
that places the patient, in the view of the initial reporter, at immediate risk 
of death from the adverse experience as it occurred. It does not include an 
adverse experience that, had it occurred in a more severe form, might have
caused death.
·
Inpatient hospitalization or prolongation of existing hospitalization
·
A persistent or significant disability/incapacity – a substantial 
disruption of a person’s ability to conduct normal life functions.
·
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate 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. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32).
·
Important medical events as defined above, may also be 
considered serious adverse events. Any important medical 
event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, the 
Investigational New Drug (IND) Office.
·
All events occurring during the conduct of a protocol and meeting
the definition of a SAE must be reported to the IRB in accordance
with the timeframes and procedures  outlined in “University of Texas 
M. D. Anderson Cancer Center Institutional Review Board Policy on 
Reporting Serious Adverse Events”.  Unless stated otherwise in the 
protocol, all SAEs, expected or unexpected, must be reported to 
the IND office, regardless of attribution (within 5 working days of knowledge
of the event).
·
All life-threatening or fatal events, expected or unexpected, 
and regardless of attribution to the study drug, must have a written 
report submitted within 24 hours (next working day) of knowledge 
of the event to the Safety Project Manager in the IND Office.  
·
The MDACC “Internal SAE Report Form for Prompt Reporting” 
will be used for reporting to the IND Office. 
·
Serious adverse events will be captured from the time the 
patient signs consent until 30 days after the last dose of drug. 
Serious adverse events must be followed until clinical recovery 
is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been 
acceptable resolution of the event.
·
A research nurse will document information regarding the adverse event 
into the patient's/donor's medical record.  The Study Chair will review and 
sign the documentation.

Additionally, any serious adverse events that occur
after the 30 day time period that are related to the study


2004-0660
November 19, 2012
Page 18
treatment must be reported to the IND Office. This may Include
the development of a secondary malignancy.
Reporting to FDA:
·
Serious adverse events will be forwarded to FDA by the 
IND Sponsor (Safety Project Manager IND Office) according to
21 CFR 312.32.
It is the responsibility of the Study Chair and the research team to 
ensure serious adverse events are reported according to the
Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy.
8.0 Criteria for Response
The primary clinical endpoints for this study are anti-myeloma response to donor lymphocyte 
1.
infusions and GVHD.
CRITERIA FOR RESPONSE: Consensus EBMT/IBMTR Response Criteria for Myeloma are to be 
2.
used. Appendix E.(37) 
Acute and Chronic GVHD will be graded according to Appendix F.  Patients who develop any form of 
3.
GVHD may be treated according to standard care or any extant protocol.
RELAPSE/PROGRESSION will be recorded by the day of detection.
4.
SURVIVAL will be recorded by the day and cause of death, and measured from the date of DLI.
5.
9.0 Criteria for Removal from the Study
Patient/Donor withdrawal of informed consent
1.
Patient death
2.
Disease progression requiring anti-myeloma therapy
3.
Patient/ Donor not being compliant
4.
5 years post donor lymphocyte infusion
5.
If the recipient does not meet the "pre-vaccine" criteria in Section 7.0 B., the recipient and donor will 
6.
be taken off the study.
Donor lymphocyte collection failure
7.
An increasing or unexpected pattern of toxicity observed deemed unacceptable by the study 
8.
chairman
Investigator judgment when the well being and best interest of the patient is compromised.
9.
Inability of donor to provide lymphocytes after study registration
10.
10.0 Statistical Considerations
Preliminaries. This is a single-arm feasibility trial of Id Specific vaccinated DLI for treatment of multiple 
myeloma patients post allograft from a matched sibling donor who are not in CR or relapsing after 
transplant at least 3 months after stem cell transplant.  The last myeloma therapy must be at least 3 
weeks prior to entry. Labeling time of DLI as week 0, each donor will be vaccinated at weeks  -8, -6, 
-2 and each patient will be vaccinated at weeks, 0, 4, and 8. Toxicity (TOX) will be defined as the 
event that the patient suffers grade 2, 3 or 4 GVHD or death within 6 months post DLI.  The historical 
rate of TOX is 50% (54/107).  The primary aim is to determine whether transfer of myeloma specific 
immunity is enhanced by vaccinating donors prior to donor lymphocyte infusion with an id-specific 
vaccine.
Trial Conduct.  A maximum of 10 patients will be treated.


2004-0660
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Page 19
Analysis of Myeloma Specific CTLs over time. A generalized linear mixed model (Diggle, et al., 1998) 
will be fit to the longitudinal measurements of myeloma specific CTLs.  For patient j = 1,…, 20 at 
observation time t = -8, -6, -2, 0, 4, 8, 12, denote the myeloma specific CTL count by Yj,t and covariate 
vector by Zj.  The model is given by 
g{E(Yj,t)} =   m  + fj(t)  + b Zj  + error
where g is a suitable link function, m is the overall mean, fj is a patient-specific function of t = time from 
day of DLI, accounting for the manner in which Y varies over time and includes a patient effect to account 
for correlation among the successive observations on each patient, Zj is a component accounting for 
patient covariates with b is a covariate parameter vector, and "error" is the usual measurement of error. 
Additional analyses of the final data will include analysis of survival times as functions of the treatments 
and patient prognostic covariates using an appropriate survival regression model determined by 
goodness-of-fit analyses.
Toxicity Monitoring Rule. For the purpose of safety monitoring, “toxicity” will be defined as Grade 2-4 
acute GVHD within 6 months of DLI. Based on an historical toxicity rate of 50%, denoting q = Pr(toxicity), 
it will be assumed that q follows a beta(.50, .50) prior. The trial will be stopped early for safety if Pr(Q > 
.50|data) > .90.  This rule will stop the trial  early if [# toxicities]/ [# patients] is greater than or equal to 2/2, 
3/3, 4/4, 5/6, 6/7, or 7/9. The operating characteristics of this rule are as follows: 
True Pr(Toxicity)
Pr(Stop Early)
Median Sample Size
.50
.35
10
.60
.52
8
.70
.70
5
.80
.88
2
PROTOCOL COMPLIANCE Patients will be reviewed by the study investigators who will score the 
patient for toxicity, and GVHD. Data must be entered in PDMS and the Study Chairman will be the final 
arbiter of toxicity and other outcomes should a difference of opinion exist. 
References
1.
Thall, P.F., Simon, R., and Estey, E.H. Bayesian sequential monitoring designs for single-arm clinical 
trials with multiple outcomes. Statistics in Medicine 14:357-379, 1995.
2.
Thall, P.F. and Sung, H.G. Some extensions and applications of a Bayesian strategy for monitoring 
multiple outcomes in clinical trials.  Statistics in Medicine, 17:1563-1580, 1998.
3.
Diggle, PJ, Heagerty, P, Liang, K-Y and Zeger, SL: Analysis of Longitudinal Data, 2nd Edition. 
Oxford, UK, Oxford University Press.
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