Clinical trial NCT03782064
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Sponsor: Beth Israel Deaconess Medical Center
Start date: 2019-02-22; Completion date: 2021-01-31
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying a cancer vaccine called Dendritic Cell/MM Fusion vaccine (DC/MM vaccine) in combination with nivolumab, as a possible treatment for multiple myeloma (MM).

The drugs involved in this study are:

* Dendritic Cell/MM Fusion vaccine (DC/MM vaccine)
* Nivolumab, an immunotherapy drug

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved the DC/MM vaccine as a treatment for any disease.

The FDA has not approved nivolumab for multiple myeloma. A similar immunotherapy drug used in combination with IMiDs (drugs that regulate or modify the immune system) was associated with higher risk of death in another research trial in patients with multiple myeloma; however, nivolumab has been approved for use in several other types of cancers.

The FDA has not approved the combination of nivolumab with the DC/MM vaccine as a treatment for any disease.

In this research study, the investigators wish to determine whether nivolumab administered in combination with the DC/MM vaccine will help promote an immune response against multiple myeloma cells.

An immune response is any reaction by the immune system. It helps the body distinguish itself from substances foreign to it, such as infections and dangerous substances. Cancer cells have unique markers that distinguish them from normal cells, which can potentially serve as targets for the immune system.

The DC/MM vaccine is an investigational agent that tries to help the immune system recognize and fight against cancer cells, utilizing those unique markers. Unlike a standard vaccine that is used to prevent infections, cancer vaccines are being studied to see if they can fight cancers that are already in the body. Laboratory studies suggest that when dendritic cells (a type of immune cell that helps to tell your immune system what is good and what is bad) and tumor cells are brought together, the dendritic cells can stimulate immune responses against the tumor.

Nivolumab is a monoclonal antibody. Antibodies are part of your immune system; they are a type of protein that protects the body against foreign invaders, called antigens, by grabbing hold of antigens to stop them from invading your system. Monoclonal indicated that this antibody was made in a lab. Nivolumab has been shown to react against cancer cells, including MM cells. The investigators hope that the addition of nivolumab with the DC/MM vaccine will help the body fight MM

Arms: arm 1: * Nivolumab will be given every two weeks
* The DC/myeloma fusion vaccine/GM-CSF is administered 4 days per cycle
Interventions: intervention 1: Nivolumab intervention 2: DC/myeloma fusions/GM-CSF
Intervention descriptions: intervention 1: Nivolumab is a monoclonal antibody. Antibodies are part of your immune system; they are a type of protein that protects your body against foreign invaders, called antigens, by grabbing hold of antigens to stop them from invading your system. Nivolumab has been shown to react against cancer cells, including MM cells. intervention 2: The DC/MM vaccine is an investigational agent that tries to help the immune system recognize and fight against cancer cells, utilizing unique markers.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Page 1 
 
 
TITLE: A Phase II Trial of Vaccination with Dendritic Cell (DC)/Myeloma Fusions in Combination with 
Nivolumab in Patients with Relapsed Multiple Myeloma 
 
NCT Number: NCT03782064 
 
Protocol Date: 10/17/2020


DF/HCC Protocol #: 18-280 
Protocol Version Date: 10.17.2020 
 
2 
DF/HCC Protocol #: 18-280 
 
 
TITLE: A Phase II Trial of Vaccination with Dendritic Cell (DC)/Myeloma Fusions in Combination with 
Nivolumab in Patients with Relapsed Multiple Myeloma 
 
 
Coordinating Center: 
 
 
Beth Israel Deaconess Medical Center 
 
*Principal Investigator (PI): 
Jacalyn Rosenblatt, MD 
 
Beth Israel Deaconess Medical Center 
 
jrosenb1@bidmc.harvard.edu 
 
Other Investigators: 
David Avigan, MD 
 
Beth Israel Deaconess Medical Center 
 
davigan@bidmc.harvard.edu 
 
 
 
 
 
 
 
 
 
Responsible Research Nurse: 
 
 
Study Coordinator:  
Chelsey Gibson 
Brendan Mackey 
Beth Israel Deaconess Medical Center 
Beth Israel Deaconess Medical Center 
617-667-1957 
617-667-9923 
eknudsen@bidmc.harvard.edu 
bmackey@bidmc.harvard.edu 
 
 
 
IND #: BB8184 
IND Sponsor: David Avigan, MD   
 
 
Protocol Type / Version # / Version Date: 
Amendment 10 / October 17, 2020


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Protocol Version Date: 10.17.2020 
 
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TABLE OF CONTENTS 
 
1. 
OBJECTIVES ......................................................................................................................5 
1.1 
Study Design ............................................................................................................5 
1.2 
Primary Objectives...................................................................................................5 
1.3 
Secondary Objectives...............................................................................................5 
2. 
BACKGROUND .................................................................................................................5 
2.1 
Therapeutic approaches in Multiple Myeloma ........................................................5 
2.2 
Vaccine Therapy for Multiple Myeloma .................................................................6 
2.3 
Vaccination with DC/Myeloma fusion cells following autologous 
transplant  ................................................................................................................6 
2.4 
Checkpoint Blockade ...............................................................................................7 
2.5 
Nivolumab................................................................................................................7 
2.6 
Checkpoint Blockade in Myeloma...........................................................................8 
2.7 
Rationale ..................................................................................................................8 
2.8 
Correlative Studies Background ............................................................................10 
3. 
PARTICIPANT SELECTION ...........................................................................................11 
3.1 
Eligibility Criteria ..................................................................................................11 
3.2 
Exclusion Criteria ..................................................................................................11 
3.3 
Eligibility Prior to Vaccination with DC/MM fusions and nivolumab..................13 
3.4 
Inclusion of Women and Minorities ......................................................................13 
4. 
REGISTRATION PROCEDURES ...................................................................................13 
4.1 
General Guidelines for DF/HCC Institutions ........................................................13 
4.2 
Registration Process for DF/HCC Institutions .......................................................13 
5. 
TREATMENT PLAN ........................................................................................................13 
5.1 
Evaluations Prior to Enrollment.............................................................................13 
5.2 
Tumor Collection ...................................................................................................14 
5.3 
Dendritic Cell Collection .......................................................................................14 
5.4 
SOC Anti-Myeloma Bridging Therapy .................................................................14 
5.5 
Evaluation Prior to Initiation of Immunotherapy...................................................14 
5.6 
Day 1 of Cycles 1-3 (+/- 3 days) ............................................................................15 
5.7 
Day 15 of Cycles 1-3 (+/- 3 days) ..........................................................................16 
5.8 
Day 1 of Cycle 4 (+/- 3 days) ................................................................................16 
5.9 
Day 1 of Cycles 4-6 (+/- 3 days) ............................................................................16 
5.10 
Day 15 of Cycles 4-6 (+/- 3 days) ..........................................................................16 
5.11 
Follow Up ..............................................................................................................17 
5.12 
Agent Administration.............................................................................................18 
5.13 
General Concomitant Medication and Supportive Care Guidelines ......................19 
5.14 
Criteria for Taking a Participant Off Protocol Therapy .........................................19 
5.15 
Criteria for Taking a Participant Off Study ...........................................................19 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................19 


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6.1 
Dose Delays ...........................................................................................................20 
6.2 
Management of Nivolumab-Related Infusion Reactions .......................................21 
6.3 
Management of Other Nivolumab-Related AEs ....................................................21 
6.4 
Management of DC/MM Vaccine Site Reaction ...................................................22 
7. 
Identification of Treatment Limiting Toxicities ................................................................22 
8. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................22 
8.1 
Expected Toxicities ................................................................................................22 
8.2 
Adverse Event Characteristics ...............................................................................23 
8.3 
Adverse Event Reporting .......................................................................................24 
8.4 
Reporting to the Food and Drug Administration (FDA) .......................................25 
8.5 
Reporting to the Institutional Biosafety Committee (IBC) ....................................25 
8.6 
Reporting to Hospital Risk Management ...............................................................25 
8.7 
Routine Adverse Event Reporting .........................................................................25 
9. 
PHARMACEUTICAL INFORMATION ..........................................................................25 
9.1 
Nivolumab..............................................................................................................25 
9.2 
DC/MM Fusion Vaccine ........................................................................................27 
9.3 
GM-CSF .................................................................................................................28 
10. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................28 
10.1 
Correlative Studies .................................................................................................28 
10.2 
Sample Collection time points ...............................................................................29 
11. 
STUDY CALENDAR .......................................................................................................31 
12. 
MEASUREMENT OF EFFECT........................................................................................34 
12.1 
Definition of Disease Status...................................................................................34 
12.2 
Response Categories ..............................................................................................34 
13. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................36 
13.1 
Data Reporting .......................................................................................................36 
13.2 
Data Safety Monitoring..........................................................................................36 
14. 
STATISTICAL CONSIDERATIONS...............................................................................36 
14.1 
Study Design ..........................................................................................................37 
15. 
PUBLICATION PLAN .....................................................................................................38 
REFERENCES ..............................................................................................................................39 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................40 
APPENDIX B: Dose Modifications for Nivolumab-related AEs..................................................41 
 


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1. OBJECTIVES 
 
1.1 
Study Design 
 
The study is a phase II study to evaluate vaccination with DC/myeloma fusions/GM-CSF and nivolumab in patients 
diagnosed with relapsed multiple myeloma previously treated with a proteasome inhibitor, IMiD, and anti-CD38 
mAb therapy. Patients meeting initial eligibility will be enrolled and vaccine production will be initiated via the 
harvesting of autologous tumor cells and generation of DCs from adherent mononuclear cells. During the period of 
vaccine generation, patients will undergo therapy with 1-2 cycles of standard of care therapy. Patients without 
disease progression will then undergo monthly vaccination with DC/MM fusions for cycles 1, 2, and 3 in 
conjunction with nivolumab administered on day 1 and 15 and will then receive nivolumab alone for 3 addition 
cycles, for a total of 6 cycles of treatment. 
 
1.2 
Primary Objectives 
 
1.2.1 
Primary Immunologic Endpoint 
 
 
The primary endpoint is to define the immunologic response to nivolumab and the DC/MM fusion vaccine with 
respect to the induction of myeloma-specific immunity in patients with relapsed disease after prior proteasome 
inhibitor, IMiD, and anti-CD38 mAb therapy.  Specifically, we will quantify the expansion of treatment-induced 
myeloma-specific T cells in the circulation as measured by pre-therapy and peak post-treatment levels of CD4 and 
CD8 T cells expressing IFNγ following ex-vivo exposure to autologous tumor lysate. The percentage of patients 
achieving at least a 3 and 10-fold expansion of myeloma-specific T cells will be determined.   
 
 
1.3 
Secondary Objectives 
 
1.3.1 
Secondary Immunologic Endpoints   
 
We will determine the effect of therapy on the percent of marrow-infiltrating myeloma-specific T cells as measured 
by pre-therapy and peak post-treatment levels of CD4 and CD8 T cells expressing IFNγ following ex vivo exposure 
to autologous tumor lysate. We will also quantify T cells specific to shared myeloma antigens potentially including 
MUC1, NY-ESO, PRAME, Survivin, XPB-1, SOX2, and WT1 by pentamer analysis.  Assessment of the immune 
landscape will consist of quantifying T cell subsets in the circulation and marrow, presence of MDSCs, PD-1 
expressing T cells, Tregs, and immunoregulatory microRNAs and will be correlated with immunologic response.   
 
 
1.3.2 
Secondary Clinical Endpoints 
 
To determine the clinical response and safety of nivolumab and the DC/MM fusion vaccine in patients with relapsed 
disease.  The percentage of patients achieving complete, very good partial and partial response will be quantified.  
Minimal residual disease (MRD) status will be determined.  Progression free survival (PFS) will be assessed.    
 
 
2. BACKGROUND 
 
2.1 
Therapeutic approaches in Multiple Myeloma 
 
Despite major recent advances in therapeutic options for patients with multiple myeloma (MM), curative outcomes 
remain elusive.   While the introduction of IMIDs, proteasome inhibitors, and antibody-mediated therapies have 
dramatically improved progression free and overall survival in MM patients, progressive resistance to biologic 
agents ultimately develops and often results in disease-associated mortality.1 Novel approaches are needed to 
improve patient outcomes.  Cancer therapeutics has undergone a dramatic change with the observation that cellular 


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immunotherapy results in sustained disease response in a subset of patients with previously incurable disease.2 This 
approach potentially harnesses native immunity to provide specific targeting of tumor cells and the development of 
memory responses critical to prevent relapse. 
 
2.2 
Vaccine Therapy for Multiple Myeloma 
 
Immune therapy has emerged as a leading area of cancer therapeutics due to its potential to recruit multiple effectors 
that broadly target malignant cells and overcome mechanisms of resistance.3,4 Multiple myeloma (MM) is 
characterized by the loss of critical mediators of immune surveillance, resulting in the suppression of antigen-
presenting and effector cell function and the development of an immunologic milieu that fosters disease 
progression.5–7 We have developed a tumor vaccine in which patient-derived myeloma cells are fused with 
autologous dendritic cells (DCs), such that a broad array of myeloma antigens are presented in the context of DC-
mediated costimulation.8–10 In diverse tumor models that include MM, vaccination of animals with DC/tumor 
fusions results in protection from an otherwise lethal challenge of malignant cells and, more significantly, 
eradication of disease in the setting of advanced metastatic involvement.11 In a phase I study, 17 patients with 
advanced myeloma (median of 4 prior regimens) underwent vaccination with DC/MM fusions in conjunction with 4 
days of GM-CSF administered at the vaccine site. In this study, MM cells were isolated from bone marrow aspirates 
and fused with autologous DCs generated from adherent mononuclear cells cultured with GM-CSF, IL-4, and 
TNFα.8 Vaccine production was successful in all patients and was well-tolerated without evidence of clinically 
significant autoimmunity. Vaccination resulted in a mean 10-fold expansion of CD4 and CD8 myeloma-specific T 
cells, as determined by the percentage of cells expressing IFNγ in response to ex-vivo exposure to autologous tumor 
lysate. Similarly, vaccination resulted in the development of myeloma-specific antibody responses as documented 
by SERAX analysis.8 
 
2.3 
Vaccination with DC/Myeloma fusion cells following autologous transplant  
 
Vaccination with DC/Myeloma fusion cells following autologous transplant is associated with potent immune 
response and conversion from PR to CR in a subset of patients.10  We completed a clinical trial in which MM 
patients were vaccinated with DC/MM fusion cells in conjunction with autologous transplantation (ASCT).8,10 In the 
first cohort of the study, twenty-four patients received serial vaccinations following post-transplant hematopoietic 
recovery. A second cohort of 12 patients received a pre-transplant vaccine followed by post-transplant vaccinations. 
Vaccine preparation was successful in all patients. Mean yield of the DC and MM cells was 1.74 x 108 
and 6.5 x 107 
cells, respectively. Mean fusion efficiency, as determined by the percentage of cells that co-expressed unique DC 
(CD80, CD86, and/or CD83) and MM (CD38 and/or CD138) antigens, was 38%. The mean dose administered was 
3.6 x 106 
fusion cells. Mean viability of the DC, myeloma, and fusion preparations was 87%, 87%, 79%, 
respectively. The DC/MM fusion preparations exhibited potent antigen presenting capacity, as evidenced by their 
stimulation of allogeneic T cell proliferation, with a mean stimulation index of 36.6, similar to that observed with 
the DC preparation prior to fusion (mean stimulation index of 52.3). In contrast, the unfused myeloma cells 
demonstrated minimal capacity for T cell stimulation (mean stimulation index of 13.7). All vaccine-associated 
toxicities were of grade I-II intensity. The most common toxicity was erythema and induration at the vaccine 
injection site associated with T cell infiltration on biopsy. The other common side effects were transient pruritus, 
rash, fatigue, fever, and myalgias. One patient had a transiently elevated ANA level without clinical evidence of 
autoimmunity. One patient developed transient grade 2 leukopenia, but no evidence of graft compromise was 
observed following vaccination.  
 
Consistent with prior reports, the post-transplant period was associated with the relative suppression of general 
measures of cellular immunity as manifested by decreased T cell proliferative responses to mitogen or recall 
antigens. In contrast, the period of post-transplant lymphopoietic reconstitution was associated with the expansion of 
myeloma-specific T cells that was further boosted following vaccination, as determined by percentage of CD4+ and 
CD8+ T cells expressing IFNγ in response to ex-vivo exposure to autologous tumor lysate. In the first cohort that 
received only post-transplant vaccination, the mean log10-fold increase in myeloma-specific CD4+ T cells from pre-
mobilization to post-transplant and from pre-mobilization to peak post-vaccination was 3.55 (95% CI 0.81;15.49) 
and 10.72 (95% CI 3.89;29.51), respectively. Similarly, the mean log10-fold increase in myeloma-specific CD8+ T 
cells from pre-mobilization to post-transplant and from pre-mobilization to peak post-vaccination was 6.76 (95% CI 
3.02;15.49) and 11.48 (95% CI 4.17;32.36), respectively. A smaller subset of patients underwent a single pre-


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transplant vaccination followed by post-transplant boosting. Of note, no difference in peak levels of CD4+ or CD8+ 
circulating myeloma-specific T cells was observed between the cohort receiving a pre-transplant vaccine and that 
undergoing post-transplant vaccination alone (p=0.185 and p=0.689, respectively). For the entire study population, 
the mean log10-fold increase in myeloma-specific CD4+ T cells from pre-mobilization to post-transplant and from 
pre-mobilization to peak post-vaccination was 3.55 (95% CI 1.58;8.13) and 9.55 (95% CI 5.37;16.98), respectively. 
The mean log10 fold increase in myeloma-specific CD8+ T cells from pre-mobilization to post-transplant and from 
pre-mobilization to peak post-vaccination was 4.37 (95% CI 2.40;7.76) and 8.32 (95% CI 4.68;15.14), respectively. 
Notably, vaccination was associated with the expansion of T cells targeting the myeloma-specific antigen, MUC1, 
as determined by tetramer analysis. In a cohort of patients who were HLA-A2, the median percentage of MUC1-
specific T cells was 0.12 pre-transplant and increased to 1.84 at 3 months after completion of vaccination (p<0.05), 
representing a median fold increase of 17.5. The expansion of T cells targeting MUC1 in response to vaccination is 
of particular interest, as we have identified a population of CD34+/MUC1+ cells in the bone marrow of patients 
with myeloma that demonstrate myeloma-initiating capacity.  Seventy-eight percent of patients achieved a CR or 
VGPR (47% CR/nCR; 31% VGPR). Thirty-one percent achieved a CR/nCR in the early post-transplant period, 
whereas an additional 17% (6 patients: 4 from VGPR, 2 from PR) achieved CR/nCR as best response only after day 
100 post- transplant and after undergoing vaccination. The presence of late responses several months after ASCT is 
consistent with an impact of vaccine therapy on post-transplant residual disease.  
 
2.4 
Checkpoint Blockade  
 
A remaining challenge to develop sustained and clinically effective immune therapy for myeloma involves 
overcoming the immunosuppressive milieu characteristic of the tumor microenvironment.12  A critical component of 
this tolerizing environment is the upregulation of negative costimulatory molecules such as programmed death 
receptor 1 (PD-1) that induced a state of T cell exhaustion.3,13,14 Two ligands specific for PD-1 have been identified: 
PD-ligand 1 (PD-L1, also known as B7-H1 or CD274, expressed on tumor, antigen-presenting cells [APCs], and 
dendritic cells [DCs]) and PD-L2 (also known as B7-DC or CD273, expressed on endothelial cells). The interaction 
of PD-1 with PD-L1 and PD-L2 results in negative regulatory stimuli that down-modulate the activated T-cell 
immune response through SHP-1 phosphatase.15   In health, ligation of PD-1 is associated with protection from 
autoimmune sequelae of immune overstimulation. For example, PD-1 knockout mice develop strain-specific lupus-
like glomerulonephritis (C57BL/6)16 and cardiomyopathy (BALB/c)17. In the setting of malignancy, upregulation of 
PD-L1 on tumor cells and ligation of PD-1 on tumor associated lymphocytes results in a state of immune tolerance 
and escape facilitating tumor growth.  In contrast, blockade of the PD-1/PD-L1 pathway has been associated with 
dramatic and sustained disease responses in a subset of patients with malignancy including malignant melanoma, 
Hodgkin disease, renal, lung, bladder, and head and neck cancer.2,18   
 
2.5 
Nivolumab 
 
Nivolumab (BMS-936558, MDX-1106, and ONO-4538) is a fully human monoclonal immunoglobulin G4 (IgG4) 
antibody (HuMAb) that is specific for human programmed death-1 (PD-1, cluster of differentiation 279 [CD279]) 
cell surface membrane receptor. PD-1 is a negative regulatory molecule that is expressed transiently following T-
cell activation and on chronically stimulated T cells characterized by an “exhausted” phenotype. Nivolumab binds to 
cynomolgus monkey PD-1 but not mouse, rat, or rabbit molecules. Clinical activity of nivolumab has been observed 
in patients with melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and recently in 
hematologic malignancies. This clinical experience has demonstrated that endogenous immune responses can 
mediate effective tumor regression and/or improved survival even in patients with large volume tumors resistant to 
other forms of therapy. It is not yet clear what factors with respect to the tumor cells, their surrounding 
microenvironment, and the nature of immune dysregulation are determinative of response to the class of checkpoint 
inhibitors. 
 
2.5.1 
Nonclinical Development of Nivolumab  
 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab alone was well tolerated 
(Investigator Brochure, 2015). Nivolumab bound specifically to PD-1 (and not to related members of the CD28 
family such as CD28, ICOS, CTLA-4, and BTLA) with a Kd = 3.06 nM. A surrogate rat anti-mouse PD-1 antibody 
(4H2) was derived and expressed as chimeric IgG1 murine antibody. Antitumor activity was seen for several tumor 


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models, including colon carcinoma and fibrosarcoma.  
 
2.5.2 
Clinical Development of Nivolumab  
 
Nivolumab is being evaluated as monotherapy and in combination with cytotoxic chemotherapy, other 
immunotherapy (such as ipilimumab), anti-angiogenesis therapy, and targeted therapies in completed and ongoing 
BMS-sponsored clinical trials in NSCLC, melanoma, RCC, hepatocellular carcinoma (HCC), gastrointestinal (GI) 
malignancies including microsatellite instability (MSI) in colorectal cancer, and triple- negative breast cancer 
(TNBC) with an expanding group of indications in hematologic malignancies (Investigator Brochure, 2015). 
Investigator-sponsored trials (ISTs) of nivolumab in combination with a peptide vaccine in melanoma are being 
conducted in the adjuvant setting and advanced disease.  
 
2.5.3 
Pharmacokinetics  
  
Pharmacokinetics (PK) of nivolumab was linear in the range of 0.3 to 10 mg/kg, with dose-proportional increases in 
maximum serum concentration (Cmax) and area under the concentration-time curve from time zero to infinity 
(AUC0-∞), with low to moderate inter-subject variability observed at each dose level (Investigator Brochure, 2015). 
Clearance of nivolumab is independent of dose in the dose range (0.1 to 10 mg/kg) and tumor types studied. Body 
weight normalized dosing showed approximately constant trough concentrations over a wide range of body weights. 
The mean terminal elimination half-life of BMS-936558 is 17 to 25 days consistent with the half-life of endogenous 
IgG4.   
 
2.5.4 
Efficacy   
 
In a phase 1 (1, 3, and 10 mg/kg nivolumab doses) dose-escalation study, the 3 mg/kg dose was chosen for expanded 
cohorts. Among 236 patients, objective responses (ORs) (complete or partial responses [CR or PR]) were seen in 
NSCLC, melanoma, and RCC. Ors were observed at all doses.18 Median OS was 16.8 months across doses and 20.3 
months at the 3 mg/kg dose. Median OS across all dose cohorts was 9.2 months and 9.6 months for squamous and 
non-squamous NSCLC, respectively.19 In the RCC cohort, median duration of response was 12.9 months for both 
doses with 5 of the 10 responses lasting ≥1 year.  
 
2.5.5 
Toxicology   
 
A maximum tolerated dose (MTD) of nivolumab was not defined.18 Serious adverse events (SAEs) occurred in 32 of 
296 patients (11%) similar to the immune-related inflammatory events seen with ipilimumab: pneumonitis, vitiligo, 
colitis, hepatitis, hypophysitis, and thyroiditis (with noted pulmonary toxicity resulting in 3 deaths. Renal failure, 
symptomatic pancreatic and DM, neurologic events, and vasculitis have also been reported.).   
 
2.6 
Checkpoint Blockade in Myeloma 
 
PD-1 expression is upregulated on T-cells isolated from patients with MM,14,20,21 suggesting that this pathway is of 
importance in mediating the immunosuppressive state in this patient population.  However, PD-1 blockade has 
demonstrated minimal single agent activity in MM due to the lack of the intrinsic anti-tumor immunity in this 
setting.3,22,23 Efforts are underway to assess the activity of combination therapy with immunomodulatory agents and 
PD-1 antibody.24  Phase II studies demonstrated that PD-1 blockade in conjunction with IMID therapy resulted in 
clinical activity in a subset of patients with advanced disease who were refractory to single agent therapy with 
IMIDs.  However, a randomized trial demonstrated increased morbidity and mortality was noted in patients treated 
with combination IMID therapy and PD-1 blockade.  We postulate that the DC/MM fusion vaccine will act 
synergistically with checkpoint blockade by inducing the expansion of myeloma specific T cells that can be further 
activated by exposure to checkpoint blockade.  Indeed, preclinical studies from our laboratory demonstrated that 
PD-1 blockade enhances T-cell response to DC/MM fusions in vitro.25 
 
2.7 
Rationale 
 


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MM is associated with immune suppression, including defects in antigen presentation and effector cell function that 
are thought to play a role in disease progression. Although the outcomes for myeloma patients have improved 
greatly over the past decade, the majority of patients relapse even after autologous stem cell transplant and post-
transplant maintenance therapy with lenalidomide. We have demonstrated that vaccination with DC-MM fusions 
induces the expansion of myeloma reactive T cells and is associated with the conversion of partial to complete 
responses following high dose chemotherapy with stem cell rescue.  We are currently conducting a national 
randomized multicenter trial under the auspices of the CTN cooperative oncology group, to assess the clinical and 
immunologic impact of vaccination with lenalidomide maintenance as compared to maintenance alone in myeloma 
patients undergoing autologous stem cell transplantation.  
 
In a phase 1 trial published in 2011, we previously studied the role of personalized DC/MM fusion vaccination in 
the setting of relapsed MM. In this patient experience, we did observe an encouraging immunologic signal. 
However, only a subset of these relapsed MM patients had stable disease post-vaccination and no patient 
demonstrated a reduction in disease burden.8 For this reason, we postulate that in the relapsed MM disease setting, 
the combination of vaccination along with a second immunologic agent may yield disease response in addition to 
immunologic activation against MM. In the present proposal, we hypothesize that the efficacy of checkpoint 
blockade in myeloma is dependent on the initial expansion of myeloma-reactive T cells in the immune repertoire 
that can then be further activated and expanded in the context of nivolumab therapy.  We propose a clinical trial to 
examine the toxicity, immunologic effect and clinical response of nivolumab administered in conjunction with the 
DC/MM vaccine, as vaccination alone in this patient population has not previously yielded clinical disease response.   
We hypothesize that the study will illuminate the nature of the immunologic response to a therapeutic strategy that 
incorporates vaccine-mediated expansion of myeloma specific T cell immunity and antibody-mediated targeting of 
negative checkpoints that will alter the tumor microenvironment and favor the generation of a productive immune 
response targeting myeloma cells.   
 
 
 


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2.8 
Correlative Studies Background 
2.8.1 
Impact of therapy on the immunologic response in the peripheral blood and bone marrow 
 
The primary immunologic endpoint is to define the immunologic response to nivolumab and the DC/MM fusion  
vaccine with respect to the induction of peripheral blood myeloma-specific immunity in patients with relapse disease  
after prior proteasome inhibition, IMiD, and anti-CD38 mAb therapy. Specifically, we will compare the expansion 
of 
treatment-induced myeloma-specific T cells in the circulation as measured by pre-therapy and peak post-treatment 
levels of CD4 and CD8 T cells expressing IFNγ following ex-vivo exposure to autologous tumor lysate.  Similarly, 
as a secondary endpoint and correlative study, we will quantify the percentage of myeloma-reactive lymphocytes in  
the bone marrow prior to cycles 1, 3, 6 and at the off-treatment time. The expansion of myeloma-specific T cells in  
the circulation and bone marrow will be calculated individually for each patient so that the specific baseline levels 
prior to vaccination will serve as an internal control value for each patient. To control for intrinsic variability of the  
assay, samples are cryopreserved and all time points are analyzed in a single experiment. To control for nonspecific  
reactivity against normal marrow elements, T cell expression of IFNγ will be measured following pulsing with 
lysate from CD38- BMMCs (when feasible). We will determine the mean fold increase in myeloma- 
specific T cells and the percentage of patients demonstrating 3 and 10 fold threshold increases in response to  
vaccination in the circulation and the bone marrow. 
 
 
We hypothesize that patients will demonstrate enhanced myeloma-specific immunity following exposure to vaccine 
plus nivolumab as compared to the pre-treatment time point. In a prior study, we observed that patients with 
multiple myeloma exposed to a MM/DC fusion vaccine had a mean log10-fold increase in myeloma-specific CD4+  
T cells from pre-mobilization to post-transplant and from pre-mobilization to peak post-vaccination was 3.55 (95%  
CI 1.58;8.13) and 9.55 (95% CI 5.37;16.98), respectively. The mean log10 fold increase in myeloma-specific CD8+  
T cells from pre-mobilization to post-transplant and from pre-mobilization to peak post-vaccination was 4.37 (95%  
CI 2.40;7.76) and 8.32 (95% CI 4.68;15.14), respectively.8,10 Similarly, in an early phase clinical trial of AML  
patients receiving AML/DC fusion vaccination following  a chemotherapy-induced remission, we also observed  
enhanced leukemia-specific immunity as evidenced by increased circulating lymphocytes targeting leukemia cells.26 
 
2.8.2 
Effect of treatment on circulating T cells binding the MUC1, NY-ESO, Survivin, PRAME, WT1 tetramers 
in HLA-A2.1 patients 
 
We have previously observed enhanced antigen-specific reactivity in patients treated with personalized dendritic cell 
fusion vaccine therapy.10,26 We will examine antigen-specific reactivity by tetramer analysis in prior to and after 
exposure to the vaccine and nivolumab in HLA-A2.1 positive patients. This assay utilizes tetrameric proteins to 
detect and quantify T-cells that are specific for a given antigen within a peripheral blood sample. We hypothesize 
that patients treated with the combination of vaccine and nivolumab will elicit immune-specific responses against 
myeloma cells and thereby, we will observe increased T cells against common myeloma antigens including WT-1 
and MUC-1. Functional characteristics of the pentamer positive cells will be determined by quantifying expression 
of IFNγ, granzyme B, IL-4, and IL-10 expression by intracellular FACS staining. 
 
2.8.3 
Immune microenvironment including T cell subsets, T cell checkpoint receptors and myeloid-derived 
suppressor cells (MDSCs) 
 
We plan on quantifying T cell subsets, T cell checkpoint receptors, and MDSCs via flow cytometry. Bone marrow 
aspirate and peripheral blood samples will be obtained prior to and after initiating immunotherapy and the 
microenvironment will be assessed with respect to the presence of Tregs, PD-1 expressing T cells, central memory 
(CD4/CD62L/CD27), effector memory (CD4/CD62L/CD27), and naïve T cells and granulocytic (CD11B+ CD33+ 
HLADRLOW/ CD15+) and monocytic (CD11B+ CD33+ HLADRLOW/ CD15-) MDSCs. We hypothesize that 
exposure to vaccine and PD-1 blockade with nivolumab will shift T cells from an immunoregulatory into an 
immune-activated phenotype and will also decrease MDSC burden in the microenvironment. 
 
2.8.4 
Optional Vaccine Site Biopsy 
 


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In patients who develop a vaccine site reaction, an optional biopsy of the vaccine site may be performed. Biopsy of 
the vaccine injection site will undergo immunohistochemical staining to assess for infiltrating lymphocytes which 
will be further characterized by mechanical disruption and flow cytometry to quantify recruitment of myeloma and 
antigen specific T cells. Presence of effector (CD62L/CD27) and central memory cells (CD62L/CD27) within the 
myeloma-specific and pentamer+ T cell populations will be determined by multichannel flow cytometry. 
 
2.8.5 
Optional Aspirate and Peripheral Blood Samples for future research 
 
In patients who consent to optional bone marrow aspirate and peripheral blood samples, we will cryopreserve these 
samples in the Avigan laboratory for future possible use in biomarker discovery and correlative studies including 
genomic analysis, whole exome sequencing, RNA sequencing, neoantigen discovery, proteomics, microRNA 
profiling, as well as additional immunologic assays. 
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 
Participant must have multiple myeloma and have relapsed following or are refractory to  proteasome 
inhibitors, IMiDs and anti-CD38 mAb therapy 
 
3.1.2 
Participant must have at least 3 prior lines of therapy 
 
3.1.3 
Age ≥18 years.   
 
3.1.4 
ECOG performance status ≤2  
 
3.1.5 
Participant must have > 20% plasma cells in the bone marrow core or aspirate differential <30 days prior to 
enrollment. 
 
3.1.6 
ANC > 1K/uL; Platelets > 50 K/uL  without transfusional support   
 
3.1.7 
Participant  must have normal organ function as defined below: 
 
 
total bilirubin ≤1.5 × institutional upper limit of normal 
 
AST(SGOT)  ≤3 × institutional upper limit of normal  
 
ALT(SGPT) ≤3 × institutional upper limit of normal 
 
creatinine clearance ≥40 mL/min for participants with creatinine levels above institutional normal. 
 
3.1.8 
The effects of DC/MM fusion and nivolumab on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study participation.  Should 
a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately.  Men treated or enrolled on this protocol must also 
agree to use adequate contraception prior to the study, for the duration of study participation, and 5 months 
after completion of treatment. 
 
3.1.9 
Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
 


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12 
3.2.1 
Participants who are receiving any other investigational agents. 
 
3.2.2 
Participants with purely non-secretory MM [absence of a monoclonal protein (M protein) in serum as 
measured by electrophoresis and immunofixation and the absence of Bence-Jones protein in the urine 
defined by use of conventional electrophoresis and immunofixation techniques and the absence of involved 
serum free light chain >100 mg/L]. Patients with light chain MM detected in the serum by free light chain 
assay are eligible.   
 
3.2.3 
Participants with Plasma Cell Leukemia   
 
3.2.4 
Because of compromised cellular immunity, patients who have a known human immunodeficiency virus 
(HIV), active hepatitis C virus (HCV) or active hepatitis B virus (HBV). 
 
3.2.5 
Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class 
III or IV heart failure (see Appendix H), uncontrolled angina, severe uncontrolled ventricular arrhythmias, 
or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to 
study entry, any ECG abnormality at screening will be documented by the investigator as not medically 
relevant.   
 
3.2.6 
Active or prior documented autoimmune or inflammatory disorders including but not limited to the 
following: 
 
GI Disorders: (including inflammatory bowel disease [e.g. ulcerative colitis, Crohn’s disease], 
diverticulitis (with the exception of a prior episode that has resolved), celiac disease, or other 
serious gastrointestinal chronic conditions associated with diarrhea. 
 
Systemic lupus erythematosus 
 
Wegener’s syndrome [granulomatosis with polyangiitis] 
 
Myasthenia gravis 
 
Graves’ disease 
 
Rheumatoid arthritis 
 
Hypophysitis 
 
Uveitis 
 
The following are exceptions to this criterion: subjects with vitiligo or alopecia; subjects with 
hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement; or subjects with 
psoriasis not requiring systemic treatment. 
 
3.2.7 
Individuals with a history of a different malignancy are ineligible except for the following circumstances. 
Note: Individuals with a history of other malignancies are eligible if they have been disease-free for at least 
5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals 
with the following cancers are eligible if diagnosed and treated within the past 5 years: non-invasive cancer 
(such as, any in situ cancers) and basal cell or squamous cell carcinoma of the skin. 
 
3.2.8 
Female patients who are pregnant (positive β-HCG) or breastfeeding 
 
3.2.9 
Prior organ transplant requiring immunosuppressive therapy.  
 
3.2.10 Patients who previously received PD-1 antibody and have experienced toxicities resulting in treatment 
discontinuation.  
 
3.2.11 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations 
that would limit compliance with study requirements. 
 


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13 
3.3 
Eligibility Prior to Vaccination with DC/MM fusions and nivolumab 
 
3.3.1 
Resolution of all chemotherapy related grade 3-4 toxicity as per CTC criteria 4.0 
 
3.3.2 
Successful production of at least 2 vaccines of a minimum of 1 x106 fusion cells 
 
3.3.3 
Absence of disease progression to standard of care therapy during the period of vaccine generation.   
 
3.3.4 
ECOG performance status ≤2  
 
3.3.5 
Participants must have normal organ function as defined below: 
 
 
total bilirubin ≤1.5 × institutional upper limit of normal 
 
AST(SGOT). ≤3 × institutional upper limit of normal 
 
ALT(SGPT) ≤3 × institutional upper limit of normal 
 
creatinine clearance ≥40 mL/min for participants with creatinine levels above institutional normal. 
 
3.3.6 
No myeloma therapy within 7 days of initiation of study treatment with the exception of steroids 
 
3.4 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES  
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) OnCore. 
Registrations must occur prior to the initiation of any protocol-specific therapy or intervention. Any participant not 
registered to the protocol before protocol-specific therapy or intervention begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the protocol-specific 
eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If the subject does not receive 
protocol therapy following registration, the subject must be taken off-study in the CTMS (OnCore) with an 
appropriate date and reason entered.   
 
4.2 
Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed.   
 
5. TREATMENT PLAN 
 
On this study, patients will be enrolled and undergo tumor collection and dendritic cell collection per protocol. 
Patients will undergo 1-2 cycles of standard of care therapy during the period of vaccine preparation. Patients for 
whom vaccine production is successful will undergo vaccination with DC/MM fusions on day 1 of cycle 1, 2, and 3.  
Subsequent cycles (following cycle 3) will consist of Nivolumab alone on Days 1 and 15 for a total of 6 cycles.   
 
5.1 
Evaluations Prior to Enrollment 
 


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14 
The following evaluations must be performed within 2 weeks prior enrollment  
1. History, physical examination, height and weight   
2. ECOG Performance Status 
3. Baseline AE Evaluation 
4. CBC with differential 
5. Liver Functions and blood chemistries: Na, K, Cl, CO2, Ca, Mg, PO4, Creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, AST, ALT, LDH 
6. Beta-2 Microglobulin, CRP 
7. TSH, Free T4, Free T3 
8. Evaluation of creatinine clearance  
9. Pregnancy test in FOCBP   
10. Laboratory Disease Evaluation:  
 
Quantitative serum immunoglobulin levels.   
 
Serum protein electrophoresis (SPEP).   
 
24-hour urine collection to determine creatinine clearance and protein excretion, urine 
electrophoresis (UPEP).  
 
Immunofixation of urine and serum protein regardless of SPEP and UPEP results.  
 
Serum free light chain ratios (FLC)   
11. Bone marrow to assess plasma cell involvement in the marrow as per eligibility criteria. Unilateral bone 
marrow biopsy and aspirate are required. If performed within 30 days it does not need to be repeated.  
12. Skeletal bone survey to include cranium, axial skeleton and proximal long bones or alternative imaging to 
capture areas of bone disease 
13. EKG 
14. Vital signs (including ambulatory O2 sat) 
 
 
5.2 
Tumor Collection 
 
Following registration, patients will undergo collection of multiple myeloma cells through bone marrow aspirate 
collection. Bone marrow aspirates will be obtained (20-30cc) under local anesthesia. If there is an insufficient yield 
of tumor cells a second collection will be permitted.  
 
At the time of tumor collection, 50ml of plasma in sodium heparin tubes will be collected from the peripheral blood. 
This will be repeated if a second collection is indicated. Standard infectious serologies will be drawn as per BIDMC 
practice for storage of cellular products (drawn in 2 red top tubes and 3 pink top tubes and sent to the Stem Cell Lab 
at BIDMC). 
 
5.3 
Dendritic Cell Collection 
 
Patients may receive up to 1 cycle of bridging therapy prior to undergoing leukapheresis. Leukapheresis will be 
performed when after recovery of blood counts (an ANC >1000 K/uL and PLT >50 K/uL). When possible, 
leukapheresis will be performed via peripheral access. If peripheral access is inadequate, patients will undergo 
placement of a temporary central venous catheter. Standard infectious serologies will be drawn within 8 days of 
isolation dendritic cells as per BIDMC practice for storage of cellular products (drawn in 2 red top tubes and 3 pink 
top tubes and sent to the Stem Cell Lab at BIDMC). 
 
5.4 
SOC Anti-Myeloma Bridging Therapy During Period of Vaccine Preparation 
 
Patients may  receive up to 2 cycles of standard of care therapy following leukapheresis. Bridging therapy is at the 
discretion of the physician, however the use of IMiDs (ie. Lenalidomide or pomalidomide) is prohibited. 
 
5.5 
Evaluation Prior to Initiation of Immunotherapy 
 
Patients will be evaluated within 14 days prior to initiation of immunotherapy. The following tests will be performed 


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15 
at that time: 
 
1. History, physical examination, height and weight   
2. ECOG Performance Status   
3. AE Assessment 
4. Medications 
5. CBC with differential, platelet count   
6. Liver Functions and blood chemistries: Na, K, Cl, CO2, Ca, Mg, PO4, Creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, AST, ALT, LDH 
7. Beta-2 Microglobulin, CRP 
8. TSH, Free T4, Free T3 
9. Evaluation of creatinine clearance  
10. Pregnancy test in females of child bearing potential 
11. Laboratory Disease Evaluation:  
 
Quantitative serum immunoglobulin levels.   
 
Serum protein electrophoresis (SPEP).   
 
24-hour urine collection to determine creatinine clearance and protein excretion, urine 
electrophoresis (UPEP).  
 
Immunofixation of urine and serum protein regardless of SPEP and UPEP results.  
 
Serum free light chain ratios (FLC)   
12. Bone marrow biopsy and aspirate for re-staging, Note, if marrow was done within prior 6 weeks then this 
does not need to be repeated.  
13. EKG 
14. Skeletal bone survey or alternative imaging to include cranium, axial skeleton and proximal long bones or 
alternative imaging to capture areas of bone disease, if clinically indicated  
15. Evaluation of Pre-Treatment Eligibility Criteria and registration to second time point on study. 
 
 
5.6 
Day 1 of Cycles 1-3 (+/- 3 days) 
 
1. History, physical examination, height and weight   
2. ECOG Performance Status   
3. AE Assessment 
4. Medications 
5. CBC with differential, platelet count   
6. Liver Functions and blood chemistries: Na, K, Cl, CO2, Ca, Mg, PO4, Creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, AST, ALT, LDH 
7. Beta-2 Microglobulin, CRP 
8. TSH, Free T4, Free T3 
9. Evaluation of creatinine clearance   
10. Pregnancy test in FOCBP  
11. Laboratory Disease Evaluation:  
 
Quantitative serum immunoglobulin levels.   
 
Serum protein electrophoresis (SPEP).   
 
24-hour urine collection to determine creatinine clearance and protein excretion, urine 
electrophoresis (UPEP).  
 
Immunofixation of urine and serum protein regardless of SPEP and UPEP results.  
 
Serum free light chain ratios (FLC)   
12. EKG 
13. Nivolumab infusion (Per Section 5.12.1) 
14. Vaccine administration (Per Section 5.12.2) 
15. Vital Signs (including ambulatory O2 sat) per Section 11 
16. Study tubes as per Section 10 will be drawn at the pre-immunotherapy visit. They will not be repeated at 
the start of C1, but will be drawn on day 1 of C2 and C3. 


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16 
 
5.7 
Day 15 of Cycles 1-3 (+/- 3 days) 
 
1. History, physical examination, height and weight   
2. ECOG Performance Status   
3. AE Assessment 
4. Medications 
5. CBC with differential, platelet count   
6. Liver Functions and blood chemistries: Na, K, Cl, CO2, Ca, Mg, PO4, Creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, AST, ALT, LDH 
7. EKG 
8. Nivolumab infusion (Per Section 5.12.1) 
9. Vital Signs (including ambulatory O2 sat) per Section 11 
 
 
5.8 
Day 1 of Cycle 4 (+/- 3 days) 
 
1. Bone marrow and aspirate to assess disease response. 
2. Bone marrow aspirate for research samples 
 
5.9 
Day 1 of Cycles 4-6 (+/- 3 days) 
 
1. History, physical examination, height and weight   
2. ECOG Performance Status   
3. AE Assessment 
4. Medications 
5. CBC with differential, platelet count   
6. Liver Functions and blood chemistries: Na, K, Cl, CO2, Ca, Mg, PO4, Creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, AST, ALT, LDH 
7. Beta-2 Microglobulin, CRP 
8. TSH, Free T4, Free T3 
9. Evaluation of creatinine clearance   
10. Pregnancy test in FOCBP  
11. Laboratory Disease Evaluation:  
 
Quantitative serum immunoglobulin levels.   
 
Serum protein electrophoresis (SPEP).   
 
24-hour urine collection to determine creatinine clearance and protein excretion, urine 
electrophoresis (UPEP).  
 
Immunofixation of urine and serum protein regardless of SPEP and UPEP results.  
 
Serum free light chain ratios (FLC)   
12. EKG 
13. Nivolumab infusion (Per Section 5.12.1) 
14. Vital Signs (including ambulatory O2 sat) per Section 11 
15. Study tubes as per Section 10  
 
 
5.10 
Day 15 of Cycles 4-6 (+/- 3 days) 
 
1. History, physical examination, height and weight   
2. ECOG Performance Status   
3. AE Assessment 
4. Medications 
5. CBC with differential, platelet count   


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17 
6. Liver Functions and blood chemistries: Na, K, Cl, CO2, Ca, Mg, PO4, Creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, AST, ALT, LDH  
7. EKG 
8. Nivolumab infusion (Per Section 5.12.1) 
9. Vital Signs (including ambulatory O2 sat) per Section 11 
 
 
5.11 
Follow Up 
 
Participants will be followed monthly for the first 6 months following their last dose of treatment. Participants who 
complete treatment per protocol will be followed as outlined in section 5.11.1 and then followed for Progression 
Free Survival as outlined in section 5.11.2.   
 
Participants taken off treatment due to toxicity will be followed as outlined in section 5.11.1 and will continue to be 
followed for Progression Free Survival as outlined in section 5.11.2.   
 
Participants taken off treatment due to disease progression or to start alternative anti-myeloma therapy per MD 
discretion will be required to do a toxicity assessment visit 30 days after the last dose of study treatment. 
Participants then will continue to be followed for Survival for 5 years. Requirements for the toxicity assessment visit 
are outlined in section 5.11.3. 
 
 
5.11.1 Active Follow Up (+/- 7 days) 
 
Participants will be followed monthly for 6 months following the last dose of treatment on study. 
 
1. History, physical examination, height and weight   
2. ECOG Performance Status   
3. AE Assessment 
4. Medications 
5. CBC with differential, platelet count   
6. Liver Functions and blood chemistries: Na, K, Cl, CO2, Ca, Mg, PO4, Creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, AST, ALT, LDH 
7. Beta-2 Microglobulin, CRP 
8. TSH, Free T4, Free T3 
9. Evaluation of creatinine clearance   
10. Laboratory Disease Evaluation:  
 
Quantitative serum immunoglobulin levels.   
 
Serum protein electrophoresis (SPEP).   
 
24-hour urine collection to determine creatinine clearance and protein excretion, urine 
electrophoresis (UPEP) required for participants with +UPEP at baseline. Otherwise, random 
UPEP is permitted. If the random UPEP is positive, a 24-hour urine collection is required.  
 
Immunofixation of urine and serum protein regardless of SPEP and UPEP results.  
11. Vital Signs (including ambulatory O2 sat) per Section 11 
12. Bone marrow and aspirate as per Section 11 
13. Skeletal bone survey to include cranium, axial skeleton and proximal long bones or alternative imaging to 
capture areas of bone disease at months 1 and 6 
14. Study tubes as per Section 10  
 
5.11.2 Progression Free Survival (+/- 14 days) 
 
Participants will be followed every 3 months for 5 years. Participants will be followed until time of disease 
progression, at which time they will be followed for survival as outlined 5.11.4. At the time of disease progression 


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18 
patients will have disease assessments and study bloods/aspirate as outlined in section 10. 
  
1. Laboratory Disease Evaluation:  
 
Quantitative serum immunoglobulin levels.   
 
Serum protein electrophoresis (SPEP).   
 
24-hour urine collection to determine creatinine clearance and protein excretion, urine 
electrophoresis (UPEP) required for participants with +UPEP at baseline. Otherwise, random 
UPEP is permitted. If the random UPEP is positive, a 24-hour urine collection is required. 
 
Immunofixation of urine and serum protein regardless of SPEP and UPEP results.  
 
 
5.11.3 Toxicity Assessment Visit (+/- 7 days) 
 
Participants taken off treatment due to disease progression or to start alternative anti-myeloma therapy at MD 
discretion will be required to do a toxicity assessment visit 30 days after the last dose of study treatment. 
 
1. History, physical examination, height and weight   
2. ECOG Performance Status   
3. AE Assessment If patients have ongoing related AEs at the toxicity assessment visit, this should continue to 
be followed at least monthly, or as clinically indicated, until resolution.) 
4. Medications 
5. CBC with differential, platelet count   
6. Liver Functions and blood chemistries: Na, K, Cl, CO2, Ca, Mg, PO4, Creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, AST, ALT, LDH 
7. TSH, Free T4, Free T3 
8. Evaluation of creatinine clearance   
9. Vital Signs (including ambulatory O2 sat) per Section 11 
 
5.11.4 Survival Follow-Up 
 
Participants will be followed in clinic or by phone every 6 months for 5 years from the last dose of treatment.   
 
 
5.12 
Agent Administration 
 
5.12.1 Nivolumab 
 
Patients will be treated with Nivolumab 240 mg on days 1 and 15 of a 28-day cycle. Nivolumab will be given every 
two weeks (±3 days). Patients may be dosed no less than 12 days from the previous dose of drug.  
 
Nivolumab is to be administered as a 60-minute IV infusion (+/- 10 minutes), using a volumetric pump with a 
0.2/1.2 micron in-line filter at the protocol-specified dose. The drug can be diluted with 0.9% normal saline for 
delivery but the total drug concentration of the solution cannot be below 1.0 mg/mL. It is not to be administered as 
an IV push or bolus injection.  
 
Vital signs (BP, HR, Temp, RR, O2 sat) will be taken within 15 minutes prior to start of nivolumab infusion and 
within 15 minutes following completion of the infusion. 
 
5.12.2 DC/MM Fusion Vaccine 
 
Patients will receive the DC/myeloma fusion vaccine/GM-CSF (vaccine) on day 1 of cycles 1, 2, and 3. Vaccine will 
be administered by subcutaneous injection with 100 ug GM-CSF given subcutaneously at the vaccine site on day of 
vaccination and daily for a total of 4 days of each cycle.  The vaccine will be administered at least 1 hour following 


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19 
Nivolumab infusion.  On the first day of GM-CSF administration, 100 ug of GM-CSF subcutaneously will be 
administered subcutaneously. The patient will be trained to inject the remaining three GM-CSF injections (100ug 
dose once a day at the vaccination site) for self-administration subcutaneously at home.   
 
5.13 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients started on systemic anti-neoplastic chemotherapy or immune suppression while on treatment will be taken 
off the study drug. The administration of live vaccinations while on treatment is prohibited. Short courses of 
corticosteroids for adverse events may be permitted after discussion with the Study Chair, Jacalyn Rosenblatt, MD. 
 
5.14 
Criteria for Taking a Participant Off Treatment 
 
Duration of therapy will depend on individual response, evidence of disease progression and tolerance. In the 
absence of treatment delays due to adverse event(s), treatment may continue for up to 6 cycles of nivolumab or until 
one of the following criteria applies: 
 
 
Disease progression by IMWG criteria, after the administration of study treatment 
 
 
Intercurrent illness that prevents further administration of treatment 
 
 
Unacceptable adverse event(s) 
 
 
Participant demonstrates an inability or unwillingness to comply with the oral medication regimen 
and/or documentation requirements 
 
 
Participant decides to withdraw from the protocol therapy 
 
 
General or specific changes in the participant's condition render the participant unacceptable for further 
treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The reason for removal 
from protocol therapy, and the date the participant was removed, must be documented in the case report form (CRF). 
Alternative care options will be discussed with the participant. 
 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-Treatment/Off-
Study information will be updated in OnCore. 
 
5.15 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
 
Lost to follow-up 
 
Withdrawal of consent for data submission 
 
Death 
 
Disease progression by IMWG criteria, prior to the administration of study treatment 
 
The reason for taking a participant off study, and the date the participant was removed, must be documented in the 
case report form (CRF). In addition, the study team will ensure Off Treatment/Off Study information is updated in 
OnCore in accordance with DF/HCC policy REGIST-101. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following sections. The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for dose delays and dose modifications. A copy of the CTCAE version 4.0 can be downloaded from the 


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20 
CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
  
6.1 
Dose Delays 
 
To initiate cycle 1 of therapy with vaccine and nivolumab, participants must meet the eligibility criteria outlined in 
section 3.3.  
 
Patients experiencing any of the following toxicities judged to be possibly or definitely related to study treatment 
will not receive further therapy. 
 
Grade 3 or higher non-hematologic toxicities that do not resolve within 14 days of onset; 
o 
Please note the following exceptions indicated in Appendix B that necessitate immediate 
discontinuation of therapy: 
 
Grade 4 creatinine elevation 
 
Grade 3 or higher pulmonary toxicity  
 
ALT/AST or total bilirubin grade 3 or higher elevation 
 
Grade 3 or higher adrenal insufficiency 
 
Grade 3 or higher neurological adverse event  
 
Grade 3 or higher myocarditis  
 
Grade 4 or higher non-hematologic toxicities; 
 
Grade 4 or higher hematologic toxicities that do not resolved within 7 days of onset; 
o 
Please note that this excludes lymphopenia, as mentioned in section 5.9.3; 
 
Grade 4 or higher nivolumab infusion reactions. 
 
Laboratory abnormalities that are not thought to be clinically significant (i.e. lymphopenia) will not be 
included in criteria for holding of therapy 
 
Patients experiencing grade 3 non-hematologic toxicity, grade 2 immune associated toxicity as outlined in Appendix 
B, and grade 4 hematologic toxicity will have therapy held.   
 
Patients not meeting these criteria may have therapy held for clinical reasons with the approval of the study PI or 
designee. 
 
Patients who experience grade 4 hematologic toxicity that resolves to grade 1 or baseline within 7 days OR grade 3 
non-hematologic toxicity that resolves to grade 0-1 within 14 days OR grade 2 immune associated toxicity requiring 
hold of therapy as outlined in Appendix B that resolves to grade 0-1 within 14 days may have therapy restarted 
UNLESS otherwise specified in Appendix B. 
 
Therapy is restarted at the point of dose interruption so that all intended doses of vaccine and nivolumab are 
administered.   
 
Patients experiencing recurrence grade 3 non-hematologic toxicity, grade 2 immune associated toxicity as outlined 
in Appendix B, and grade 4 hematologic toxicity will have therapy discontinued UNLESS otherwise specified in 
Appendix B.   
 
To initiate cycles 2-6 of therapy, subjects must not have any evidence of TLT as outlined above or in section 7. In 
the event that the toxicity is clearly related to nivolumab alone (such as infusion reactions) and meets criteria for 
discontinuation, patients may continue to receive vaccine alone per protocol. Patients experiencing immune-related 
adverse events may be treated with corticosteroids (up to prednisone of 1 mg/kg or equivalent).  Patients who 
improve to grade 1 or less in this context as outlined above AND who can be tapered to prednisone of 10 mg or 
equivalent or less may continue on therapy. There will be no dose modifications. 
 
Treatment may be held for up to 14 days for unrelated adverse events, or as clinically indicated, at the discretion of 
the treating physician. 
 


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21 
6.2 
Management of Nivolumab-Related Infusion Reactions 
 
Infusion reactions to Nivolumab may consist of fever, chills, rigors, headache, rash, urticaria, angioedema, pruritus, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. Infusion reactions should be graded according 
to NCI CTCAE version 4.0 guidelines.  
 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not indicated) Infusion 
rate may be slowed or interrupted and restarted at 50% of the original infusion rate when symptoms resolve; if no 
further complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. 
Monitor patient closely.  
 
The following prophylactic pre-medications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before additional nivolumab 
administrations, slowing infusion rate as above.  
 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds promptly to 
symptomatic treatment [e.g., antihistamines, non-steroidal anti- inflammatory drugs, narcotics, corticosteroids, 
bronchodilators, IV fluids]; close observation for recurrence and treatment medications may need to be continued 
for 24-48 hours), and no further nivolumab will be administered at that visit.  
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with diphenhydramine 50 
mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and monitor patient 
until resolution of symptoms. Corticosteroid or bronchodilator therapy may also be administered as appropriate.  
If the infusion is interrupted, then restart the infusion at 50% of the original infusion rate when symptoms resolve; if 
no further complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. 
Monitor patient closely. If symptoms recur, re administer diphenhydramine 50 mg IV, and remain at bedside and 
monitor the patient until resolution of symptoms.  
 
The following prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and (acetaminophen) (or paracetamol) 325 to 1000 mg should be administered at least 30 minutes before 
additional nivolumab administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used.  
 
For Grade 3 or Grade 4 symptoms: (Severe reaction): 
 
Grade 3 symptoms: prolonged [i.e., not rapidly responsive to symptomatic medication and/or brief interruption of 
infusion]; recurrence of symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [e.g., renal impairment, pulmonary infiltrates]).  
 
Grade 4 symptoms: (life threatening; pressor or ventilatory support indicated). Nivolumab will be permanently 
discontinued:  
 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and 
bronchodilators, epinephrine 0.2 to 1 mg of a 1: 1,000 solution for subcutaneous administration or 0.1 to 
0.25 mg of a 1: 10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV 
with methylprednisolone 100 mg IV (or equivalent), as needed. Patient should be monitored until the 
investigator is comfortable that the symptoms will not recur.  
 
In the event of anaphylaxis, follow institutional guidelines.  
 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., oral antihistamine, or 
corticosteroids). Additional treatment prior to next dose as per guidelines above.  
 
Please note that late occurring events including isolated fever and fatigue may represent the presentation of 
systemic inflammation. Please evaluate accordingly.  
 
6.3 
Management of Other Nivolumab-Related AEs 
 


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22 
Please refer to Appendix B: Dose Modifications for Nivolumab-related AEs.  
 
6.4 
Management of DC/MM Vaccine Site Reaction 
 
If a patient experiences a grade 2 or higher (graded according to CTCAE v4.0) injection site reaction during the days 
when GM-SCF is administered, subsequent doses of GM-CSF may be held until the injection site reaction improves 
to grade 1 or less at the discretion of the treating investigator. On the day of subsequent vaccine administrations, 
patients will receive pre-medication with diphenhydramine (Benadryl) 25-50 mg and/or acetaminophen (Tylenol) 
650-1000 mg to minimize potential allergic-related symptoms.  
 
7. IDENTIFICATION OF TREATMENT LIMITING TOXICITIES  
 
Treatment limiting toxicities (TLT) will be defined as toxicity judged to be possibly or definitely related to the study 
treatment and meeting the following criteria: 
 
Grade 3 or higher non-hematologic toxicities that do not resolve within 14 days of onset; 
o 
Please note the following exceptions that necessitate immediate discontinuation of therapy: 
 
Grade 4 creatinine elevation 
 
Grade 3 or higher pulmonary toxicity  
 
Grade 3 or higher ALT, AST or total bilirubin elevation 
 
Grade 3 or higher adrenal insufficiency 
 
Grade 3 or higher neurological adverse event  
 
Grade 3 or higher myocarditis  
 
Grade 4 or higher clinically significant non-hematologic toxicities; 
 
Grade 4 or higher hematologic toxicities that do not resolve to grade 1 or baseline within 7 days of onset; 
o 
Please note that this excludes lymphopenia, as mentioned in section 5.9.3; 
 
Grade 4 or higher nivolumab infusion reactions. 
 
Patients experiencing TLT will not receive further therapy 
 
If 3 or more patients experience a TLT within the first 28 days of initiating therapy among the first 10 patients 
enrolled, then accrual will be suspended.  TLTs will be defined per the above criteria with grades determined by 
CTCAE version 4.0 that are possibly, probably or definitely related to the study treatment. Patients will be 
monitored for the occurrence of TLTs during the first 28 days of treatment.  
 
Once the 10th participant is enrolled, accrual will be paused until the 10th participant completes a full cycle of 
treatment (28 days) without experiencing any TLTs.  
 
8. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list of reported 
and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether 
the event requires expedited reporting in addition to routine reporting. 
 
8.1 
Expected Toxicities 
 
8.1.1 
Adverse Events Lists 
 
8.1.1.1 
Adverse Event List(s) for Nivolumab 
 
Events that are listed as very common (experienced in ≥10% of patients) according to the current IB 
(Version 16 dated June 23, 2017) include the following: fatigue and diarrhea 
 
Events that are listed as common (experienced in ≥1% to <10% of patients) include: hypothyroidism, 
hyperthyroidism, hyperglycemia, nausea, vomiting, chills, colitis, stomatitis, asthenia, gastritis, 


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23 
abdominal pain, constipation, dry mouth, pyrexia, edema peripheral, infusion related reactions, 
increased lipase, increased amylase, increased aspartate aminotransferase, increase alanine 
aminotransferase, increased creatinine, increased thyroid stimulating hormone, hyponatremia, 
decreased appetite, back pain, myalgia, arthralgias, pain in extremity, headache, pruritis, dizziness,  
pneumonitis, dyspnea, cough, rash, vitiligo, dry skin, erythema, maculopapular rash 
Events that are listed as uncommon ≥0.001% of patients to < 1% include the following: 
musculoskeletal pain, arthritis, neck pain, musculoskeletal chest pain, bone pain, polyarthritis, 
peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, vasculitis,  lung 
infiltration, tubulointerstitial nephritis, renal failure, acute kidney injury, hypertension, hypotension, 
alopecia, dermatitis acneiform, macular rash, urticaria, dermatitis, erythematous rash, generalized rash, 
papular rash, psoriasis, pustular rash, drug eruption, bronchitis, hypersensitivity, upper respiratory 
infections, edema, facial edema, peripheral swelling, localized edema, nephritis, autoimmune hepatitis, 
hepatitis, pancreatitis, uveitis, diabetes mellitus, thyroiditis, autoimmune hypophysitis, increased blood 
bilirubin, hypopituitarism, adrenal insufficiency, tachycardia, autoimmune colitis, atrial fibrillation, 
vertigo, dry eye, vision blurred, mucosal inflammation, generalized edema, respiratory failure, lung 
infiltration 
 
Events that are listed as rare risk (experienced by ≥0.00001% to <0.001% of patients) include 
arrhythmias, Stevens Johnson Syndrome, dermatitis exfoliative, allergic dermatitis, rosacea, erythema 
multiforme, diabetic ketoacidosis, autoimmune hypothyroidism,  iridocyclitis, periorbital edema, 
mouth ulceration, acute pancreatitis, acute hepatitis, sarcoidosis, anaphylactic reaction, myositis, 
musculoskeletal discomfort, osteoarthritis, pain in jaw, polymyalgia rheumatica, polymyositis, 
rhabdomyolysis, polyneuropathy, burning sensation, encephalitis, Guillain-Barre syndrome, 
myasthenia gravis, demyelination, autoimmune nephritis, organizing pneumonia, acute respiratory 
distress syndrome, vasculitis 
 
Events that are listed as very rare (experienced by < 0.0001%) include ventricular arrhythmias, 
mucosal ulceration, demyelinating polyneuropathy, myasthenic syndrome, and toxic epidermal 
necrolysis   
 
8.1.1.2 
Adverse Event List(s) for DC/MM Fusion Vaccines 
 
Toxicities related to the vaccine are:  
 Hematologic: Leukopenia  
 Neurologic: Headache  
 Gastrointestinal: Diarrhea, decrease appetite.  
 Constitutional: Weakness chills and fever.  
 Musculoskeletal: arthralgia and myalgia.  
 Dermatologic: rash, itching, periorbital edema and local reaction in the site of infusion 
(swelling, pain, erythema and pruritus).  
 Endocrine: elevated TSH.  
 Other: ANA positivity  
 
8.1.1.3 
Adverse Event List(s) for GM-CSF 
 
Potential side effects of GM-CSF treatment include fever, chills, nausea, vomiting, diarrhea, fatigue, 
weakness, headache, decreased appetite, facial flushing, bone and muscle pain, local reaction at the site 
of injections, rashes, low blood pressure, shortness of breath and low blood counts. Rarely patients 
may develop blood clots, rapid or irregular heartbeats, feeling of faintness, kidney and liver problems, 
allergic reactions or fluid retention, including potential fluid retention in lungs or around the heart, and 
keratitis (inflammation of the cornea).  
 
 
8.2 
Adverse Event Characteristics 
 


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24 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event varies in nature, 
intensity or frequency from the expected toxicity information which is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the next section 
(Expedited Adverse Event Reporting) under the sub-heading of Protocol-Specific Expedited Adverse 
Event Reporting Exclusions. 
 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
8.3 
Adverse Event Reporting  
 
8.3.1 
In the event of an unanticipated problem or life-threatening complications treating investigators must 
immediately notify the Overall PI. 
 
8.3.2 
Investigators must report to the Overall PI any adverse event (AE) that occurs after the initial dose of study 
treatment, during treatment, or within 30 days of the last dose of treatment on the local institutional SAE 
form.  
 
 
8.3.3 
DF/HCC Adverse Event Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human Research Studies 
(OHRS) per the DFCI IRB reporting policy.  
 
 
 
 
Attribution 
DF/HCC Reportable Adverse Events(AEs)
Gr. 2 & 3 AE
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE 
Expected 
Gr. 4 AE
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days#
5 calendar days
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days
 
5 calendar days#
 
5 calendar days
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be 
reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of 
the last intervention, the AE should be reported within 1 business day of learning of the event. 
 
 
 


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25 
8.3.4 
Protocol-Specific Adverse Event Reporting Exclusions 
 
AEs that occur prior to initiation of vaccine will not be captured or reported with the exception of AEs and SAEs 
that are related to tumor cell harvest and dendritic cell collection. Events that are thought to be related to tumor cell 
harvest or dendritic cell collection will be captured and reported as an SAE should it meet the DF/HCC as per 
DF/HCC guidelines. 
 
AEs and SAEs will be captured and reported after initiation of vaccine will be captured and reported as per DF/HCC 
guidelines.  
Laboratory abnormalities that are not clinically significant and are not related to study treatment will not be captured 
or reported. 
 
8.4 
Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The Overall PI will 
report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the FDA’s criteria for 
expedited reporting following the reporting requirements and timelines set by the FDA. 
 
 
8.5 
Reporting to the Institutional Biosafety Committee (IBC) 
 
Participating investigators will register and report on research protocols involving biohazards (i.e., recombinant 
DNA or infectious agents) according to the reporting requirements set by their respective IBC.  
 
8.6 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant safety reports, sentinel 
events or unanticipated problems that require reporting per institutional policy.  
 
8.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the toxicity case report 
forms.  AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must also be reported 
in routine study data submissions. 
 
 
9. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent administered in this study 
can be found in Section 7.1. 
 
9.1 
Nivolumab 
 
9.1.1 
Description 
 
Nivolumab is a fully human monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that 
targets the PD-1 cell surface membrane receptor. Nivolumab inhibits the interaction of PD-1 with its 
ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation and interferon- gamma (IFN-γ) 
release in vitro. 
 
9.1.2 
Form 
 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is a clear to opalescent, colorless to pale yellow liquid, 
which may contain light (few) particulates. The drug product is a sterile, nonpyrogenic, single-use, isotonic 


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26 
aqueous solution formulated at 10 mg/mL in sodium citrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80, pH 6.0 and includes a 0.7 mL overfill 
to account for vial, needle, and syringe (VNS) holdup. It is supplied in 10-cc Type I flint glass vials, 
stoppered with butyl rubber stoppers and sealed with aluminum seals. 
 
9.1.3 
Storage and Stability 
 
The product does not contain a preservative. Vials of nivolumab injection must be stored at 2-8°C (36°-
46°F) and protected from light, freezing, and shaking.  
After preparation, store the nivolumab infusion either: At room temperature for no more than 8 hours from 
the time of preparation. This includes room temperature storage of the infusion in the IV container and time 
for administration of the infusion or under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 
hours from the time of infusion preparation. Do not freeze. If a temperature excursion is noted, sites should 
follow institutional policies for notifying Bristol-Myers Squibb and assessing if the drug is still able to be 
used.  
 
9.1.4 
Compatibility 
 
Do not co-administer other drugs through the same intravenous line. Flush the intravenous line at end of 
infusion. No incompatibilities between nivolumab and polyvinyl chloride (PVC), non-PVC/non DEHP 
(di(2-ethylhexyl)phthalate) IV components, or glass bottles have been observed. 
 
9.1.5 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic agent 
in a self-contained and protective environment.  
 
9.1.6 
Availability 
 
Nivolumab for injection will be supplied free of charge by BMS. 
 
9.1.7 
Preparation 
 
Visually inspect drug product solution for particulate matter and discoloration prior to administration. 
Nivolumab is a clear to opalescent, colorless to pale-yellow solution. Discard the vial if the solution is 
cloudy, is discolored, or contains extraneous particulate matter other than a few translucent-to-white, 
proteinaceous particles. Do not shake the vial.  
Withdraw the required volume of nivolumab and transfer into an intravenous container.  
Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, to 
prepare an infusion with a final concentration greater than or equal to 0.35mg/ml .. Mix diluted solution by 
gentle inversion. Do not shake.  
 
9.1.8 
Administration 
 
Administer the infusion over 60 minutes (+/- 10 minutes) through an intravenous line containing a sterile, 
non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). 
 
9.1.9 
Ordering 
 
Each institution will order nivolumab directly from the supplier Bristol Myers Squibb Pharmaceuticals 
(BMS). A study specific order form will be supplied by the lead site. 
 
9.1.10 Accountability 
 


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27 
The investigator, or a responsible party designated by the investigator, should maintain a careful record of 
the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) or 
another comparable drug accountability form.  (See the NCI Investigator’s Handbook for Procedures for 
Drug Accountability and Storage.) 
 
9.1.11 Destruction and Return 
 
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially used 
study drug containers, vials and syringes may be destroyed on site.  
 
On-site destruction is allowed provided the following minimal standards are met:  
 
On-site disposal practices must not expose humans to risks from the drug.  
 
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. BMS 
will be notified of all Nivolumab drug destructions. 
 
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.  
 
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification (ID) of the person disposing the containers. 
The method of disposal, (e.g., incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor) must be documented.  
 
9.2 
DC/MM Fusion Vaccine 
 
9.2.1 
Isolation of Tumor Cells 
 
Patients will undergo aspiration of 30 mL of bone marrow from which myeloma cell preparations will be generated. 
Bone marrow will be aspirated into sterile heparinized syringes with approximately 5-8 mL aspirated per syringe to 
avoid significant hemodilution of bone marrow mononuclear cells. Bone marrow aspirate samples will be 
transferred in sterile syringes to the cell manipulation facility, and mononuclear cells will be isolated by ficoll 
density gradient centrifugation. Autologous plasma will be obtained by harvesting supernatant following 
centrifugation of 50 mL of peripheral blood. Bone marrow mononuclear cells will be cultured in media with 10% 
autologous plasma. An aliquot of the tumor cells will undergo immunohistochemical staining as detailed below. 
Tumor lysate will be prepared by freeze/thawing or sonication of an aliquot of tumor cells for immunological 
analysis. Myeloma cells may be frozen in 10% DMSO/90% autologous plasma stored in liquid nitrogen for potential 
subsequent vaccine generation.  
 
9.2.2 
DC Generation 
 
Patients will undergo leukapharesis for DC and vaccine generation. The leukapheresis product will be transferred in 
a sterile container to the cell manipulation facility, and PBMC will be isolated from the leukapheresis product and 
cultured in the presence of autologous plasma for 1- 2 hours and then cultured for 5-7 days with GM-CSF and IL-4. 
Cultures are re-fed with cytokines after 3 days. Twenty-five ng/mL of TNFα will be then be added for 48-72 hours 
to induce DC maturation. An aliquot of the DC preparation will undergo immunocytochemical staining for 
immunophenotypic analysis. 
 
9.2.3 
DC/MM Fusion Vaccine Preparation 
 
Tumor cells will be thawed (when relevant).  Tumor cells and DC preparations will be co-cultured at ratio of 1:3 and 
washed in serum-free medium. After low-speed centrifugation, the cell pellet will be re-suspended in 50% solution 
of polyethylene glycol (PEG) and will be progressively diluted by the slow addition of serum-free medium. An 
aliquot of the DC, tumor, and fusion cell preparations will undergo immunocytochemical analysis for vaccine 
characterization. Dependent on cell yields, 3 doses of 1-5 x 106 fusion cells will be prepared. The fusion cells will 
then be separated into appropriate aliquots of fusion cells, radiated at 30 Gy, and frozen in 10% DMSO/90% 
autologous plasma in liquid nitrogen. A minimum of 2 doses will be required to proceed with treatment. An aliquot 


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28 
of the vaccine product will be sent for microbiological assessment consisting of endotoxin, mycoplasma and sterility 
testing as detailed in the CMC section. Release criteria for vaccine administration are:  
1) > 50% of DC prep express CD86  
2) Viability of DC prep > 70% 
3) Fusion efficiency > 15% 
4) Fusion viability > 50%  
5) Sterility, mycoplasma, and endotoxin assays are negative  
 
9.2.4 
Administration 
 
Patients will be vaccinated with 1-5x106 fusion cells in the upper thigh region. The site will be alternated for each 
vaccine administration (right and left extremity). Vaccination will be administered subcutaneously using a 25-gauge 
5/8-inch needle. Tumor vaccine will be administered first, followed by GM-CSF injection. 
 
9.2.5 
Ordering 
 
Vaccine will be ordered from the Stem Cell Lab at BIDMC on the day of treatment. The lab should be notified of all 
scheduled treatment days at least 1 week in advance. 
 
9.3 
GM-CSF 
 
GM-CSF is commercially available and will be purchased in bulk from commercial supply by the research 
pharmacy and billed to grant.  On the day of vaccination, the clinical research nurse/physician assistant will 
administer 100 ug of GM-CSF subcutaneously at the site of the vaccine. Research pharmacy will reconstitute the 
drug with bacteriostatic water at the appropriate dose for the patient. The patient will be trained to inject the 
remaining three GM-CSF injections (100ug dose once a day) for self-administration subcutaneously at home. Tumor 
vaccine will be administered first, followed by GM-CSF injection. 
 
 
 
10. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
10.1 
Correlative Studies 
10.1.1 Myeloma-reactive T cells in the peripheral blood 
 
10 mLs of peripheral blood will be collected in a green top tube at the pre-immunotherapy 
visit, prior to cycles 2-6, at each active monthly follow up visit, and at time of progression. 
 
Specimens will be delivered to the Avigan lab at BIDMC. 
 
Samples will be processed in the Avigan lab.  Ficoll centrifugation of the peripheral blood 
sample will be performed to isolate peripheral blood mononuclear cells (PBMCs). PMBCs 
will be co-cultured with autologous tumor lysate prepared from the enrollment bone marrow 
aspirate. Surface antibody staining for CD4 and CD8 positive lymphocytes in addition to 
intracellular staining for IFN gamma will be performed on this co-culture to quantify IFN 
gamma producing T cells. 
 


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29 
10.1.2 Myeloma-reactive T cells in the bone marrow 
 
5 mLs of bone marrow aspirate will be collected in a green top tube at the pre-immunotherapy 
visit, prior to cycle 4, at one, three, and six month active follow up visits and at time of 
progression. 
 
Specimens will be delivered to the Avigan lab at BIDMC. 
 
Samples will be processed in the Avigan lab. Ficoll centrifugation of the aspirate sample will 
be performed to isolate bone marrow mononuclear cells (BMMCs). BMMCs will be co-
cultured with autologous tumor lysate prepared from the enrollment bone marrow aspirate. 
Surface antibody staining for CD4 and CD8 lymphocytes in addition to intracellular staining 
for IFN gamma will be performed on this co-culture to quantify IFN gamma producing T 
cells. 
 
 
 
 
 
10.1.3 Effect of treatment on circulating T cells binding the MUC1, NY-ESO, Survivin, PRAME, and WT1 
tetramers in HLA-A2.1 patients 
 
10 mLs of peripheral blood in a green top tube at the pre-immunotherapy visit, prior to cycles 
2-6, at each active monthly follow up visit, and at time of progression. 
 
Specimens will be delivered to the Avigan lab at BIDMC. 
 
Samples will be processed in the Avigan lab using a tetramer assay to isolate tetramer-specific 
T cells. Functional characteristics of the pentamer positive cells will be determined by 
quantifying expression of IFNγ, granzyme B, IL-4, and IL-10 expression by intracellular 
FACS staining.  
 
10.1.4 T cell subsets , T cell checkpoint receptors, and MDSCs 
 
10 mLs of peripheral blood  in a green top tube at the pre-immunotherapy visit, prior to cycles 
2-6, at each active monthly follow up visit, and at time of progression. 
 
5 mLs of bone marrow aspirate will be collected in a green top tube prior to cycle 4, at one, 
three, and six month active follow up visits and at time of progression. 
 
Specimens will be delivered to the Avigan lab at BIDMC. 
 
Samples will be processed in the Avigan lab.  The PB and BM aspirate samples will undergo 
ficoll centrifugation to obtain PBMCs/BMMCs. From the PBMCs/BMMCs, T cell subsets 
and MDSCs will be isolated by antibody staining and quantified by flow cytometric analysis. 
 
10.1.5 Optional vaccine site biopsy 
 
Patients will be referred to dermatology clinic for a punch biopsy of vaccine site reaction. 
 
The biopsy specimen will be delivered to the Avigan lab at BIDMC. 
 
Specimens will be stained using immunohistochemistry for T cell, DC, and myeloma markers 
to assess for immune cell infiltrate and possible tumor infiltrate. 
 
10.1.6 Optional samples for future research studies 
 
10 mLs of PB in a green top tube at the pre-immunotherapy visit, prior to cycles 2-6, at each 
active monthly follow up visit, and at time of progression. 
 
5 mLs of bone marrow aspirate will be collected in a green top tube prior to cycle 4, at one, 
three, and six month active follow up visits and at time of progression. 
 
These specimens will be delivered to the Avigan lab at BIDMC. 
 
The specimens will be cryopreserved in the Avigan lab for possible future research studies. 
 
 
10.2 
Sample Collection time points 
 
Sample Collection for Stem Cell Lab 
Required1 
At enrollment (at the time of 
tumor collection) 
Bone marrow aspirate for tumor collection (30 mL)  
X 


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30 
Plasma for Vaccine Production (50 mL)  
X 
Infectious Serologies  
X 
 
1. Total tubes: 3 of the 10mL Na-Hep green top tubes aspirate, 5 of the 10mL Na-Hep green top tubes, 2 of 
the 6mL red top tubes and 3 of the 6mL pink top tubes peripheral blood 
 
Sample Collection for Avigan Lab 
Required 
At the pre-
immunotherapy 
visit1 
Prior to each 
cycle1, 3 
Months 1-6 
Active 
Follow-up2 
Disease 
Progression1 
Bone Marrow Aspirate for 
Myeloma Reactive T Cells (5 mL)  
X 
X               
(cycle 4 only) 
X (months 1, 3 
and 6 only) 
X 
Bone marrow aspirate for tetramer 
reactivity (5 mL)  
X 
X                
(cycle 4 only) 
 
X 
Bone marrow aspirate for T cell 
subsets, T cell checkpoint receptors, 
MDSCs (5 mL) 
 
X                
(cycle 4 only) 
X (months 1, 3 
and 6 only) 
X             
Peripheral Blood for Myeloma 
Reactive T Cells (10 mL) 
X 
X 
X 
X 
Peripheral blood for tetramer 
analysis (10 mL)  
X 
X 
X 
X 
Peripheral blood for T cell subsets, 
T cell checkpoint receptors, MDSCs 
(10 mL)  
X 
X 
X 
X 
 
1. Total tubes: 3 of the 10mL Na-Hep green top tubes peripheral blood and 2 of the 10mL Na-Hep green top 
Aspirate 
2. Total tubes: 3 of the 10mL Na-Hep green top tubes peripheral blood 
3. These samples do not need to be collection at cycle 1, as they were collected at the pre-immunotherapy 
visit. 
 
 
 
 
 
 
 
 
 
 
 
Optional Sample Collection for Avigan Lab 
Required 
At enrollment 
(at the time of 
tumor 
collection)1 
Prior to each 
cycle1 
Months 1-6 
Active 
Follow-up2 
Disease 
Progression1 
Optional Peripheral Blood Samples 
for Future Research (10 mL) 
X 
X 
X 
X 
Optional Bone Marrow Aspirate 
Samples for Future Research (5 mL) 
 
 
 
X                
(cycle 4 only) 
 
 
X (months 1, 3 
and 6 only) 
X 
 


DF/HCC Protocol #: 18-280 
Protocol Version Date: 10.17.2020 
 
31 
1. Total tubes: 1 of the 10mL Na-Hep green top tube peripheral blood; 1 of the 10mL Na-Hep green top tube 
aspirate 
2. Total tubes: 1 of the 10mL Na-Hep green top tube peripheral blood 
 
11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 2 weeks prior to registration.   
 
Assessments must be performed prior to administration of any study agent. Study assessments and agents should be 
administered within + 3 days of the protocol-specified date, unless otherwise noted. 
 
Cycles 1-3 
 
 
Study Assessments 
 
 
Pre-
Enrollment 
 
At 
Enrollment 
(at the time 
of tumor 
collection) 
 
Pre-
Immunotherapy 
 
 
Day 1 
 
Day 15 
Day 21 
History, physical 
exam, weight and 
height 
X 
 
X 
X 
X 
 
Vital Signs1 
X 
 
X 
X 
 
 
Ambulatory O2 sat2 
X 
 
X 
X 
X 
 
CBC, differential, 
platelet count, and 
blood chemistries 
X 
 
X 
X 
X 
 
TSH, Free T4, Free 
T3 
X 
 
X 
X 
 
 
Evaluation of 
Creatinine Clearance 
X 
 
X 
X 
X 
 
Pregnancy test 
X 
 
X 
X 
 
 
Quantitative serum 
immunoglobulins 
X 
 
X 
X 
 
 
SPEP and 
immunofixation 
X 
 
X 
X 
 
 
24 Hour Urine for 
UPEP, protein 
excretion and 
immunofixation 
X 
 
X 
X 
 
 
Serum free light chain 
ratio 
X 
 
X 
X 
 
 
B2M, CRP 
X 
 
X 
X 
 
 
Skeletal Survey or 
alternative imaging 
X 
 
 
 
 
 
Bone marrow aspirate 
and biopsy 
X 
 
X6 
 
 
 
EKG 
X 
 
X 
X 
X 
 
Toxicity Assessment 
X 
 
X 
X 
X 
 
Con Meds 
X 
 
X 
X 
X 
 
DC/MM Fusion 
Vaccine and GM-CSF 
Administration3 
 
 
 
X 
 
 
Nivolumab Infusion 
 
 
 
X 
X 
 
Study Tubes4 
 
 
X 
X 
 
 


DF/HCC Protocol #: 18-280 
Protocol Version Date: 10.17.2020 
 
32 
1. Vitals (BP, HR, Temp, RR, O2 sat) to be taken within 15 minutes prior to start of nivolumab infusion and 
within 15 minutes following completion. 
2. Pulse oximetry should be obtained prior to each dose of nivolumab and at any time a subject has any new 
or worsening respiratory symptoms. A reading at rest and on exertion should be obtained at each time 
point. The extent of the exertion should be based on the judgment of the investigator, but should remain 
consistent for each individual subject throughout the study. If the patient’s status changes the investigator 
can alter the extent of exertion based on their medical judgment. If a subject shows changes on pulse 
oximetry or other pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, fever) 
consistent with possible pulmonary adverse events, the patient should be immediately evaluated to rule out 
pulmonary toxicity. An algorithm for the management of suspected pulmonary toxicity can be found in 
Appendix 2 of the IB. Not all results are required to be collected by BMS. 
3. GM-CSF will be administered at home by the patient on days 2-4 and recorded on the GM-CSF body chart. 
4. Please refer to section 10 
5. Skeletal survey/alternative imaging is only needed at the pre-immunotherapy visit if the patient received 
bridging therapy and this is needed for re-staging.  
6. If marrow was done within prior 6 weeks then this does not need to be repeated.  
 
 
 
 
Cycles 4 - 6 
 
 
Study Assessments 
 
 
Day 1 
 
Day 15  
History, physical exam, weight and 
height 
X 
X 
Vital Signs1 
X 
X 
Ambulatory O2 sat2 
X 
X 
ECOG performance score 
X 
 
CBC, differential, platelet count, and 
blood chemistries 
X 
X 
TSH, Free T4, Free T3 
X 
 
Evaluation of Creatinine Clearance 
X 
X 
Pregnancy test 
X 
 
Quantitative serum immunoglobulins 
X 
 
SPEP and immunofixation 
X 
 
24 Hour Urine for UPEP, protein 
excretion and immunofixation 
X 
 
Serum free light chain ratio 
X 
 
B2M, CRP 
X 
 
Skeletal Survey or alternative 
imaging 
 
 
Bone marrow aspirate and biopsy4 
X 
 
EKG 
X 
X 
Toxicity Assessment 
X 
X 
Con Meds 
X 
X 
Nivolumab Infusion 
X 
X 
Study tubes3 
X 
 
 
1. Vitals (BP, HR, Temp, RR, O2 sat) to be taken within 15 minutes prior to start of nivolumab infusion and 
within 15 minutes following completion. 
2. Pulse oximetry should be obtained prior to each dose of nivolumab and at any time a subject has any new 


DF/HCC Protocol #: 18-280 
Protocol Version Date: 10.17.2020 
 
33 
or worsening respiratory symptoms. A reading at rest and on exertion should be obtained at each time 
point. The extent of the exertion should be based on the judgment of the investigator, but should remain 
consistent for each individual subject throughout the study. If the patient’s status changes the investigator 
can alter the extent of exertion based on their medical judgment. If a subject shows changes on pulse 
oximetry or other pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, fever) 
consistent with possible pulmonary adverse events, the patient should be immediately evaluated to rule out 
pulmonary toxicity. An algorithm for the management of suspected pulmonary toxicity can be found in 
Appendix 2 of the IB. Not all results are required to be collected by BMS. 
3. Please refer to section 10 
4. Bone marrow aspirate and biopsy only required on day 1 of cycle 4. 
 
Follow Up 
 
 
Study Assessments 
 
 
Toxicity 
Assessment 
Visit (+/- 7 
days)0 
Months 
1-6 
(+/- 7 days) 
Progression 
Free 
Survival1    
(+/- 14 days) 
Survival 
Follow-Up 
(every 6 
months for 5 
years) 
History, physical exam, 
weight and height 
X 
X 
 
 
Vital Signs2 
X 
X 
 
 
Ambulatory O2 sat3 
X 
X 
 
 
ECOG performance score 
X 
X 
 
 
CBC, differential, platelet 
count, and blood 
chemistries 
X 
X 
 
 
TSH, Free T4, Free T3 
X 
X 
 
 
Evaluation of Creatinine 
Clearance 
X 
X 
 
 
Quantitative serum 
immunoglobulins 
 
X 
X 
 
SPEP and 
immunofixation 
 
X 
X 
 
24 Hour Urine for UPEP, 
protein excretion and 
immunofixation 
 
X 
X4 
 
Bone Marrow Biopsy and 
Aspirate 
X 
X5 
X5 
 
Serum free light chain 
ratio 
 
X 
X 
 
B2M, CRP 
 
X 
 
 
Toxicity Assessment 
X 
X 
 
 
Skeletal Survey or 
alternative imaging 
 
X6 
 
 
Con Meds 
X 
X 
 
 
Survival status 
X 
 
 
X 
Study tubes 
 
X7 
 
 
 
0. Only required for patients who are removed from treatment due to progressive disease or to start alternative 
anti-myeloma therapy per MD discretion 
1. Every 3 months after 6 month follow up visit for 5 years 
2. Vitals (BP, HR, Temp, RR, O2 sat) to be taken within 15 minutes prior to start of nivolumab infusion and 
within 15 minutes following completion. 
3. A O2 saturation reading at rest and on exertion should be obtained during each study visit. 


DF/HCC Protocol #: 18-280 
Protocol Version Date: 10.17.2020 
 
34 
4. Only required for participants with +UPEP at baseline, otherwise random UPEP is permitted. If the random 
UPEP is positive, a 24-hour urine collection is required. 
5. At Months 1, 3 and 6 follow up and at time of progression.   
6. Months 1 and 6 only 
7. Please refer to section 10 
 
At Time of Disease Progression 
 
 
 
Study Assessments 
 
 
At Time of 
Disease 
Progression 
Quantitative serum 
immunoglobulins 
X 
SPEP and 
immunofixation 
X 
24 Hour Urine for UPEP, 
protein excretion and 
immunofixation1 
X 
Bone Marrow Biopsy and 
Aspirate 
X 
Serum free light chain 
ratio 
X 
Study tubes2 
X 
1. Only required for participants with +UPEP at baseline, otherwise random UPEP is permitted. If 
the random UPEP is positive, a 24-hour urine collection is required. 
2. Please refer to section 10 
 
 
12. MEASUREMENT OF EFFECT 
 
12.1 
Definition of Disease Status  
Patients’ disease status at each data collection period will be evaluated based on the International Uniform Response 
Criteria. Until disease progression, all disease classifications are relative to the patient’s disease status prior to 
autologous transplant (i.e. study entry). At time of disease progression, disease classifications are relative to the 
patient’s best response since time of study entry.  
 
12.2 
Response Categories 
 
12.2.1 Stringent Complete Response (sCR):  
 
 
 
 
 
                   sCR requires, in addition to CR (defined below), all of the following: 
• 
Normal free light chain ratio (FLC). 
• 
Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.  
 
12.2.2 Complete Response (CR):  
 
 
 
 
 
 
 
CR requires all of the following:  
 
• Absence of the original monoclonal paraprotein in serum and urine by routine electrophoresis and by 
immunofixation. 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.  


DF/HCC Protocol #: 18-280 
Protocol Version Date: 10.17.2020 
 
35 
• No increase in size or number of lytic bone lesions on radiological investigations (development of a 
compression fracture does not exclude CR)*.  
• Disappearance of soft tissue plasmacytomas. 
*If not clinically indicated, radiographs are not required to document CR.  
Patients in whom some, but not all, the criteria for CR are fulfilled are classified as partial responses (see below), 
providing the remaining criteria satisfy the requirements for partial response. This includes patients in whom routine 
electrophoresis is negative but in whom immunofixation has not been performed.  
 
12.2.3 Very Good Partial Remission (VGPR):  
 
 
 
VGPR requires, in addition to PR (defined below), all of the following: 
 
• Serum or urine paraprotein detectable by immunofixation but not on electrophoresis. OR  
• Greater than or equal to 90% reduction in serum paraprotein plus urine paraprotein <100 mg/24hrs.  
• For free light chain only disease, VGPR requires a 90% reduction of involved light chain  
 
12.2.4 Partial Response (PR)  
 
 
 
 
 
 
 
 
                      
PR requires one of the following: 
• Greater than or equal to 50% reduction in the level of the serum monoclonal paraprotein and reduction in 
24 hour urinary monoclonal paraprotein either by greater than or equal to 90% or to <200 mg/24 hours in 
light chain disease.  
• If the only measurable non-bone marrow parameter is FLC, greater than or equal to 50% reduction in the 
difference between involved and uninvolved FLC levels or a 50% decrease in level of involved FLC with 
50% decrease in ratio,  
• If the bone marrow is the only measurable parameter, greater than or equal to 50% reduction in bone 
marrow plasma cells given that the baseline count was greater or equal to 30%,  
• Greater than or equal to 50% reduction in the size of soft tissue plasmacytomas if present at baseline (by 
radiography or clinical examination).  
12.2.5 Stable Disease (SD)  
 
• Patients who do not meet criteria for sCR, CR, VGPR, partial response or progressive disease (section 
3.1.1.2) are considered to have stable disease (SD).  
 
12.2.6 Disease Progression (PD)  
 
 
 
 
 
 
 
                   
Progression from CR or sCR requires one or more of the following:  
 
• 
A reappearance of serum monoclonal paraprotein, with a level of at least 0.5 g/dL.   
• 
24-hour urine protein electrophoresis with at least 200 mg paraprotein/24 hours.   
• 
Abnormal FLC levels of >10 mg/dl, only in patients without measurable paraprotein in the serum and 
urine.   
• 
At least 10% plasma cells in a bone marrow aspirate or on trephine biopsy.   
• 
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.   
 
12.2.7 Progressive Disease (PD)  
 
 
For patients not in CR or sCR, progressive disease requires one or more of the following measured from the time of 
randomization:  
• 
>25% increase in the level of the serum monoclonal paraprotein, which must also be an absolute increase 
of at least 0.5 g/dL.   


DF/HCC Protocol #: 18-280 
Protocol Version Date: 10.17.2020 
 
36 
• 
>25% increase in 24-hour urine protein electrophoresis, which must also be an absolute increase of at least 
200 mg/24 hours.   
• 
Absolute increase in the difference between involved and uninvolved FLC levels (absolute increase must 
be >10 mg/dl), only in patients without measurable paraprotein in the serum and urine.   
• 
>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 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.   
 
12.2.8 Minimal residual disease assessment 
 
Absence of evidence of clonal myeloma population based on multichannel flow cytometry with discrimination of 
1:1x104 – 1x105 
 
 
13. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: List 
and Reporting Requirements). 
 
13.1 
Data Reporting 
 
13.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data for this 
study. 
 
13.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data forms to the 
Office of Data Quality (ODQ) in accordance with DF/HCC policies. 
 
13.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data 
from this study. The committee is composed of medical oncologists, research nurses, pharmacists and 
biostatisticians with direct experience in cancer clinical research.  Information that raises any questions about 
participant safety will be addressed with the Overall PI and study team. 
 
The DSMC will review each protocol up to four times a year with the frequency determined by the outcome of 
previous reviews. Information to be provided to the committee may include: up-to-date participant accrual; current 
dose level information; TLT information; all grade 2 or higher unexpected adverse events that have been reported; 
summary of all deaths occurring within 30 days of intervention for Phase I or II protocols; for gene therapy 
protocols, summary of all deaths while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
14. STATISTICAL CONSIDERATIONS 
 


DF/HCC Protocol #: 18-280 
Protocol Version Date: 10.17.2020 
 
37 
14.1 
Study Design   
 
 
 
 
  
The study is designed as a Phase II open label study of vaccination with DC/myeloma fusions/GM-CSF plus 
nivolumab therapy as part of treatment for patients with relapsed multiple myeloma. Patients meeting initial 
eligibility will undergo harvesting tumor cells and undergo vaccine production. During this period patients will 
receive an initial cycle of nivolumab and will then undergo a series of vaccinations on day 1 of cycles 1-3. 25 
evaluable patients will be enrolled. Therapy with nivolumab will continue for three additional cycles.  Based on a 
prior phase II study of vaccination of myeloma patients with the DC/MM fusion vaccine approximately 50% 
patients demonstrated a >10-fold increase in IFNγ expression to the baseline. Therefore, the combination of 
vaccination and nivolumab will be considered promising if the study shows evidence of at least 75% patients with 
>10-fold increase in IFNγ expression, and would not be considered promising if >10-fold increase is observed in 
50% or less patients. With total n=25 patients, the combination will be considered promising for further study if 17 
or more patients demonstrate significant immune response. This decision rule has a 0.1 (significance level) 
probability of accepting the combination for further study if the true underlying significant immune response is 50% 
and a 0.85 (power) probability of accepting the combination if the true underlying immune response is 75%. For the 
absolute increase in IFNγ expression, with n=25 patients, we will have at least 90% power to detect an effect size of 
0.66 (one-sided Wilcoxson rank sum test, significant level of 0.05), which corresponds to a 0.36 difference in log10 
IFNγ fold increase assuming a standard deviation of 0.54 or a 2.3 difference in IFNγ expression fold increase 
assuming a standard deviation of 3.5. We estimate the median fold increase in IFNγ expression of vaccination alone 
be 14 (DFCI trial 04098). Therefore, the fold-change that can be detected in the combination is at least 16.1.  
 
As a secondary clinical endpoint, response will be assessed according to IMWG response criteria. In a prior phase I 
trial of DC/MM vaccination in patients with relapsed MM, 69% (11/16) patients had disease stabilization. No 
patients demonstrated disease response (PR, VGPR, or CR). In the present phase II trial, overall response rate per 
IMWG criteria will be assessed. An exact binomial test with a 10% one-sided significance level will have 82% 
power to detect the difference between the ORR proportion of 0.15 (null hypothesis) and the alternative ORR 
proportion of 0.35 when the sample size is 25. An ORR of 35% is considered worthy of further study in a larger 
trial. 
 
If 3 or more patients experience a TLT, accrual will be suspended.  
 
True but Unknown Rate of DLT 
0.10 
0.20 
0.25 
0.30 
0.40 
Probability of continuation of enrollment (≤ 2 TLT in 10 pts)  
0.930 
0.678 
0.526 
0.383 
0.167 
If the true rate of TLT is 25%, the probability of observing 2 or fewer TLTs within a cohort of 10 patients is 0.526.  
14.1.1 Primary Immunologic Endpoint 
 
Myeloma reactive T-cells: Log transformations will be used to induce normality in quantitative measurements, and 
if still non-normal, then nonparametric tests will be used. The primary endpoint of log 10 peak change in tumor 
reactive T cells from baseline will be quantified. A secondary analysis of peak change in tumor reactive T cells will 
be done by comparing the proportions of patients who experience >10-fold increase in IFNγ expression, using a chi-
squared test. Peak immune response will be correlated with clinical response in an exploratory fashion to assess the 
relationship between immune response and clinical response. 
 
14.1.2 Secondary Immunologic Endpoints 
 
 
 
 
 
Additional exploratory analyses will be conducted in a similar fashion to examine a number of secondary 
immunologic endpoints, including: myeloma specific T cells in the bone marrow, antigen specific reactivity by 
tetramer analysis, and quantification of T-cell subsets and PD-1 expressing lymphocytes by flow cytometry. In each 
case, log transformations will be considered to induce normality, and if still non-normal then nonparametric tests 
will be used. Profiles of these secondary immunologic endpoints will be described at each time point. The 


DF/HCC Protocol #: 18-280 
Protocol Version Date: 10.17.2020 
 
38 
correlation between the immune environment measures and the myeloma specific T-cell response will be assessed 
and reported using Spearman rank correlation at each time point.  
 
14.1.3 Duration of follow-up 
 
 
 
 
 
Patients will be followed monthly  for the first 6 months following the end of treatment and then every 3 months for 
5 years to assess disease status. 
 
 
15. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of the study is the 
time point at which the last data items are to be reported, or after the outcome data are sufficiently mature for 
analysis, as defined in the section on Sample Size, Accrual Rate and Study Duration. If a report is planned to be 
published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. A full report of the outcomes should be made public no later 
than three (3) years after the end of the study.  


DF/HCC Protocol #: 18-280 
Protocol Version Date: 10.17.2020 
 
39 
 
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3. 
Armand P. Immune checkpoint blockade in hematologic malignancies. Blood. 2015;125(22):3393–3400.  
4. 
Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 
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5. 
Rosenblatt J, Avigan D. Role of Immune Therapies for Myeloma. J. Natl. Compr. Canc. Netw. 
2015;13(11):1440–1447.  
6. 
Hoyos V, Borrello I. The immunotherapy era of myeloma: monoclonal antibodies, vaccines, and adoptive T-
cell therapies. Blood. 2016;128(13):1679–87.  
7. 
Bianchi G, Munshi NC. Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood. 
2015;125(20):3049–58.  
8. 
Rosenblatt J, Vasir B, Uhl L, et al. Vaccination with dendritic cell/tumor fusion cells results in cellular and 
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9. 
Rosenblatt J, Kufe D, Avigan D. Dendritic cell fusion vaccines for cancer immunotherapy. Expert Opin. 
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10. 
Rosenblatt J, Avivi I, Vasir B, et al. Vaccination with dendritic cell/tumor fusions following autologous 
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11. 
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12. 
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480–489.  
13. 
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on 
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14. 
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Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by 
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Tarrio ML, Grabie N, Bu D, Sharpe AH, Lichtman AH. PD-1 protects against inflammation and myocyte 
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Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in 
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Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with 
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Luptakova K, Rosenblatt J, Glotzbecker B, et al. Lenalidomide enhances anti-myeloma cellular immunity. 
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Atanackovic D, Luetkens T, Kröger N. Coinhibitory molecule PD-1 as a potential target for the 
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Rosenblatt J, Avigan D. Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or a reality? Blood. 
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2016;8(368):368ra171.  


DF/HCC Protocol #: 18-280 
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40 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable to 
carry out any work activities.  Up and 
about more than 50% of waking hours. 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization indicated.  
Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B: DOSE MODIFICATIONS FOR NIVOLUMAB-RELATED AES  
 
 
 
 
 


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Adverse Reaction 
Severity 
Dose Delays 
Other – excluding 
hematologic toxicities 
Other Grade 3 adverse reaction: First 
occurrence 
Withhold dose and resume 
when AE returns to Grade 0 
or 1 
Recurrence of same grade 3 adverse 
reaction1 
Permanently discontinue 
Life-threatening or Grade 4 adverse 
reaction 
Permanently discontinue 
Requirement for 10 mg per day or 
greater prednisone or equivalent for 
more than 12 weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse 
reactions lasting 12 weeks or longer 
Permanently discontinue 
1. Laboratory abnormalities determined to be not clinically significant are not subject to this criteria, 
hematologic in nature or otherwise.