Clinical trial NCT03875495
Conditions: Multiple Myeloma
Keywords: Temferon Gene Therapy Immunotherapy Hematological malignancy
Sponsor: Genenta Science
Start date: 2019-03-06; Completion date: 2021-04-02
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a non-randomized, open label, phase I/II, dose-escalation study, involving a single injection of Temferon, an investigational advanced therapy consisting of autologous CD34+-enriched hematopoietic stem and progenitor cells exposed to transduction with a lentiviral vector driving myeloid-specific interferon-ɑ2 expression, which will be administered to up to 9 patients affected by multiple myeloma in early relapse after intensive front line treatment.

Detailed description:
This is a non-randomized, open label, single center, phase I/II, therapeutic exploratory, dose-escalation, prospective study, involving a single intravenous infusion of Temferon, an investigational advanced therapy consisting of autologous CD34+-enriched hematopoietic stem and progenitor cells (HSPCs) exposed to transduction with a third-generation, vesicular stomatitis virus-G (VSV-G) pseudo-typed lentiviral vector driving myeloid-specific interferon-ɑ2 (IFN-ɑ2) expression, which will be administered to up to 9 patients affected by multiple myeloma in early relapse after intensive front line treatment. The study will recruit, treat and follow-up patients at a specialist hematology and bone marrow transplantation unit at Ospedale San Raffaele (OSR) in Milan, Italy.

The study will enrol multiple myeloma patients that have experienced an early relapse after intensive front line treatment, have been treated with an approved second line combination treatment regimen and obtained at least a very good partial remission (VGPR) according to International Myeloma Working Group (IMWG) criteria. Once the written informed consent is obtained, and screening procedures have been completed, harvesting of HSPCs will occur. Patients will be offered maintenance treatment during Temferon production and release. Upon Temferon release for clinical use, patients will be admitted to the transplantation unit for receipt of a reduced-intensity conditioning regimen consisting of melphalan. This will be followed by autologous stem cell transplant (ASCT) and administration of Temferon. In-patient monitoring will occur until hematological recovery occurs. Thereafter, regular follow-up of patients will occur up to 2 years (+730 days). At the +730 day visit, patients will be invited to participate in a long term follow-up study which will last for an additional 6 years.

3 cohorts of 3 patients will receive escalating doses of Temferon.

In the event that MM disease progression occurs, patients will be managed according to best clinical practice.

Arms: arm 1: Autologous CD34+-enriched hematopoietic progenitor cells exposed ex vivo to a specific lentiviral vector encoding for the human IFN-ɑ2 gene.

Its expression is tightly controlled by the human TIE2 enhancer/promoter sequence and by a post-transcriptional regulation layer represented by target miRNA sequences. This enables suppression of IFN-ɑ2 expression in HSPCs, thereby further increasing the specificity of the delivery strategy for their Tie2 expressing myeloid cell progeny.
Interventions: intervention 1: Temferon
Intervention descriptions: intervention 1: Genetically modified autologous HSPCs

Protocol documents:
Prot_000.pdf: 
Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
Protocol Synopsis 
Protocol Title 
A phase I/II dose escalation study evaluating safety and activity of 
autologous CD34+-enriched hematopoietic progenitor cells genetically 
modified with a lentiviral vector encoding for the human interferon-α2 
gene in multiple myeloma patients with early relapse after intensive 
front line therapy 
Protocol 
Number 
TEM-MM-101 
EudraCT 
Number 
2018-001741-14 
Study 
Sponsor 
Ospedale San Raffaele (OSR) 
via Olgettina 60 
20132 Milano, Italy 
Financial 
Sponsor 
Genenta Science 
via Olgettina 58, 
20132 Milano, Italy 
Study Phase 
I/II 
Study Site 
Ospedale San Raffaele (OSR), Milan, Italy 
Indication 
Multiple Myeloma (MM) 
Objectives 
• To evaluate safety and tolerability of escalating doses of Temferon1  
in multiple myeloma patients with early relapse after intensive front 
line therapy. 
• To evaluate biological activity and efficacy of escalating doses of 
Temferon as maintenance/consolidation treatment in multiple 
myeloma patients with early relapse after intensive front line 
therapy. 
 
1 Temferon = Investigational Advanced Therapy Medicinal Product (ATMP) consisting of autologous 
CD34+-enriched Hematopoietic Stem and Progenitor Cells (HSPCs) exposed to transduction with a Lentiviral 
Vector (LV) encoding the human interferon-α2 (IFN-α2) gene (TIA126-LV). 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
Study Design 
Non-randomized, open label, single center, phase I/II, therapeutic-
exploratory, dose-escalation, prospective study, involving a single 
intravenous infusion of autologous CD34+-enriched hematopoietic 
stem and progenitor cells (HSPCs) exposed to transduction with a 
third-generation, vesicular stomatitis virus-G (VSV-G) pseudo-typed 
lentiviral vector driving myeloid-specific interferon-α2 (IFN-α2) 
expression in 9 patients affected by multiple myeloma in early relapse 
after intensive front line treatment. 
The study will enrol multiple myeloma patients that have experienced 
an early relapse after intensive front line treatment, have been treated 
with an approved second line combination treatment regimen and 
obtained at least a very good partial remission according to 
International Myeloma Working Group (IMWG) criteria.  
Intensive front line treatment is defined as: 
- 
Triplet induction (at least 3 cycles including a proteasome 
inhibitor and/or immunomodulatory drug [IMID]) followed by 
single or double autologous stem cell transplantation.  
 OR 
- 
Triplet or quadruplet induction including at least a proteasome 
inhibitor and an IMID, followed by consolidation/maintenance 
treatment. 
Early relapse is defined as disease progression, according to the 
IMWG response criteria, occurring within 24 months from the end of 
induction/consolidation treatment.  
Any currently approved second line treatments is considered 
appropriate for the study and may including the following:  
- 
Carfilzomib 
(Kyprolis) 
+ 
lenalidomide 
(Revlimid) 
+ 
dexamethasone (KRd);  
- 
Daratumumab (Darzalex) + lenalidomide (Revlimid) + 
dexamethasone (DaraRd); 
- 
Elotuzumab (Empliciti) + lenalidomide (Revlimid) + 
dexamethasone (EloRd);  
- 
Daratumumab 
(Darzalex) 
+ 
bortezomib 
(Velcade) 
+ 
dexamethasone (DaraVd). 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
- 
Other approved combinations are also permitted as second line 
treatment. 
HSPC Mobilization. Patients who experience a very good partial 
response (VGPR) or better will undergo up to 2 stem cell mobilization 
attempts with lenograstim and plerixafor to reach the mobilization 
target of ≥ 4.5 x106 CD34+ cells/kg for Temferon production. Each 
mobilization attempt may require 1-3 days of apheresis in order to 
harvest sufficient cells for Temferon production, unmanipulated 
CD34+ cells and backup. In the event of insufficient HSPCs for backup,  
allogeneic backup will be permitted (providing a donor has already 
been identified) according to the Investigator’s judgement. For the first 
attempt, a minimum harvest of 2.5 x106 CD34+ cells/kg (in 1 or 2 
collections on consecutive days) is required to proceed with CD34+ cell 
selection. If the number of recovered CD34+ cells is above the 
minimum amount defined for each dose level, Temferon production 
will proceed from freshly isolated CD34+ cells.  
For patients failing this target, CD34+ cells will be frozen, and a second 
mobilization attempt will be conducted. Cyclophosphamide may be 
used in addition to lenograstim and plerixafor for the second 
mobilization attempt. For the second attempt, a minimum harvest of 
2.0 x106 CD34+ cells/kg (in 1 or 2 collections on consecutive days) is 
required to proceed with CD34+ cell selection. Fresh CD34+ cells 
isolated from second harvest will be pooled with frozen CD34+ cells 
from first harvest for Temferon production. In case of further 
mobilization failure preventing the production of the Drug Product, 
patients will be withdrawn from the study and proceed with treatment 
according to alternative options of care. 
Patients meeting the mobilization target will be offered maintenance 
treatment 
while 
Temferon 
is 
being 
produced 
and 
until 
conditioning/ASCT. Patients may receive any approved 2nd line 
treatment/maintenance regimen. 
Once the Investigator receives confirmation that Temferon has been 
released for clinical use, patients will undergo reduced intensity 
conditioning (RIC) with melphalan (100 mg/m2), followed by 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
autologous stem cell transplant (ASCT) with non-manipulated and/or 
CD34+-enriched HSPCs.  
After ASCT, patients will receive a single intravenous infusion of the 
experimental gene transfer treatment, Temferon (within 3h to 16h 
post ASCT). 
After Day +100 from Temferon infusion, patients will resume anti-
myeloma consolidation/maintenance treatment according to best 
clinical practice, unless the following criteria are fulfilled: 
• Documented Temferon engraftment (vector copy number 
[VCN] ≥ 0.07 in myeloid cells at the Day +100 visit); 
AND 
• Absence of disease on Day +100 evaluations, documented by 
stringent complete response (sCR) according to the IMWG 
response criteria, imaging negativity, AND bone marrow 
minimal residual disease (MRD) < 10-4 by multi-parameter 
flow cytometry (MFC), to be confirmed by next generation 
sequencing (NGS). 
In case the above-mentioned criteria are fulfilled on Day +100, patients 
may stay off maintenance treatment, as long as the following criteria 
are fulfilled: 
• MRD ≤ 10-5 documented on bone marrow aspirates performed 
every 3 months, starting from the Day +180 visit. 
Patients will restart preemptive maintenance if either MFC or NGS 
suggests the presence of monoclonal plasma cells above the 10-
5 threshold.  
Description of the Study Phases 
Six phases are foreseen in the study: 
1) Enrolment, with signing of the informed consent form. 
2) Screening phase (approximately 3 weeks, up to 12 weeks prior to 
Temferon infusion), during which inclusion/exclusion criteria will be 
assessed. Patients may complete another cycle of salvage therapy 
during this phase. 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
3) Temferon production, release and baseline evaluation  phase 
(approximately 7 weeks in case of a single mobilization attempt. This 
may be extended up to 7 months in case of multiple mobilization 
attempts, or need for 3rd line salvage treatment at the discretion of the 
Principal Investigator): from the beginning of HSPC mobilization and 
harvest, including Temferon production and release for clinical use by 
qualified person (QP), and baseline evaluations. Patients will be 
offered maintenance treatment from successful HSPC collection until 
conditioning/ASCT. 
4)  ASCT (Day -2 to Day 0): from the end of the Temferon production, 
release and baseline evaluation phase until completion of the ASCT. 
Once the Investigator receives confirmation that Temferon has been 
released for clinical use, the reduced intensity conditioning regimen 
will be administered to the patient at Day -2, followed by ASCT at Day 
0. 
5) Experimental Gene Transfer phase (Day 0): Temferon infusion (3h 
to 16h post ASCT) at Day 0. 
6) Follow-up phase: from Day +1 until Day +730 post Temferon 
infusion. 
Patients 
will 
resume 
anti-myeloma 
consolidation/maintenance treatment after Day +100, according to best 
clinical practice, unless patients show documented Temferon 
engraftment (VCN ≥ 0.07 in myeloid cells) and a deep molecular, 
biochemical and imaging response. 
Upon completion of the follow-up phase, patients will be invited to 
participate in a separate long-term follow-up study (according to 
applicable regulations) to further assess the long-term safety and 
efficacy of Temferon treatment. 
A Data Monitoring Committee (DMC) will review safety outcomes for 
all patients who have been administered Temferon. Dose-escalation 
will not occur until the DMC has reviewed safety and vector copy 
number (VCN) data at Day +30 of the last patient enrolled in the 
cohort, along with dose-limiting toxicities (DLTs) together with 
cumulative safety data from preceding cohorts when available. 
A DLT is defined as any CTCAE Grade 3-5 non-hematological adverse 
event (AE), as rated by the National Cancer Institute’s Common 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
Terminology Criteria for Adverse Events (CTCAE) version 5.0, 
deemed by the Investigator and confirmed by the DMC to be attributed 
to Temferon during the DLT observation period of 30 days post 
Temferon infusion. Any CTCAE ≥ Grade 4 hematological AE meets 
the DLT definition if it persists at Day +30 post-Temferon infusion, 
despite supportive therapy, and is deemed by the Investigator and 
confirmed by the DMC to be attributed to Temferon.  
Inclusion / 
Exclusion 
criteria 
Inclusion Criteria 
1. Multiple myeloma patients with early relapse after intensive front-
line treatment and disease measurable by serum biomarkers, who 
have obtained at least a VGPR after second-line salvage treatment. 
• Early relapse is defined as progressive disease within 24 
months from the end of induction/consolidation treatment.  
• Progressive disease is defined according to the IMWG 
consensus criteria 2: increase of 25% from lowest confirmed 
response value in one or more of the following criteria:  
 Serum M-protein (absolute increase must be ≥ 0.5 g/dL); 
 Serum M-protein increase ≥ 1 g/dL, if the lowest M 
component was ≥ 5 g/dL; 
 Urine M-protein (absolute increase must be ≥ 200 mg/24 h); 
 Appearance of a new lesion(s), ≥ 50% increase from nadir 
in SPD 3 of > 1 lesion, or ≥ 50% increase in the longest 
diameter of a previous lesion >1 cm in short axis; 
 ≥ 50% increase in circulating plasma cells (minimum of 200 
cells per μL), if this is the only measure of disease. 
• 
VGPR is defined as a serum and urine M-protein detectable by 
immunofixation but not on electrophoresis, or a ≥ 90% 
reduction in serum M-protein plus urine M-protein level < 100 
mg/24h, according to the IMWG consensus criteria.  
2. Able and willing to provide written informed consent. 
3. Able to comply with study protocol and procedures. 
 
2 Kumar et al. International Myeloma Working Group consensus criteria for response and minimal residual 
disease assessment in multiple myeloma. Lancet Oncology 2016. 
3 Sum of the products of the greatest diameters (SPD) 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
4. Male or Female. 
5. Age 18-70 years. 
6. Fit patients: 
• Performance status scores: ECOG 4 < 2 and Karnofsky > 70%; 
• Life expectancy of ≥ 6 months. 
7. Adequate cardiac, renal, hepatic and pulmonary functions as 
evidenced by (at screening and prior to conditioning): 
• Left ventricular ejection fraction (LVEF) ≥ 45% by 
echocardiography and normal electrocardiogram (ECG) or 
presence of abnormalities not significant for cardiac disease. 
Absence of severe pulmonary hypertension; 
• Diffusing capacity of the lung for carbon monoxide (DLCO) 
>50% and forced expiratory volume in 1 sec (FEV1) and 
forced expiratory vital capacity (FVC) > 60% predicted (if non 
cooperative: pulse oximetry > 95 % in room air); 
• Serum creatinine < 2x upper limit normal (ULN) and estimated 
glomerular filtration rate (eGFR) > 30 ml/min/1.73m2; 
• Alkaline phosphatase (ALP), alanine aminotransferase (ALT) 
and/or aspartate aminotransferase (AST) ≤ 2.5 x ULN, and 
total bilirubin ≤ 2.0 mg/dl. 
8. Women of child-bearing potential enrolled in the study must have 
a negative pregnancy test at screening and agree to use two distinct 
acceptable methods of contraception during the trial. 
9. Men enrolled in the study with partners who are women of child 
bearing potential, must be willing to use an acceptable barrier 
contraceptive method during the trial or have undergone successful 
vasectomy at least 6 months prior to entry into the study. Successful 
vasectomy needs to have been confirmed by semen analysis. 
Exclusion Criteria 
1. Use of other investigational agents within 4 weeks prior to 
experimental treatment (within 6 weeks if use of long-acting 
agents). 
 
4 Eastern Cooperative Oncology Group (ECOG) 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
2. Severe active viral, bacterial, or fungal infection at eligibility 
evaluation. 
3. Active autoimmune disease or a history of clinically relevant  
autoimmune 
manifestations 
requiring 
immunosuppressive 
treatment, i.e. psoriasis, systemic lupus erythematosus, rheumatoid 
arthritis, vasculitis, immune-mediated peripheral neuropathies.  
4. Active sarcoidosis requiring steroid or immunosuppressive 
treatment. 
5. Primary amyloidosis. 
6. History of neuropsychiatric illness including severe depression, 
schizophrenia, bipolar disorders, impaired cognitive function, 
dementia or suicidal tendency. 
7. Neuropathy > grade 2. 
8. History of severe cardiovascular disease such as prior stroke, 
coronary artery disease requiring intervention, unresolved 
arrhythmias. 
9. Malignant neoplasia (except local skin cancer or cervical 
intraepithelial neoplasia) or family history of familial cancer 
syndromes. 
10. Myelodysplasia, cytogenetic or molecular alterations specifically 
associated with clonal hematopoiesis of the myeloid lineage, or 
other serious hematological disorder other than the plasma cell 
dyscrasia. 
11. Other clinical conditions judged by the Investigator non-
compatible with the study procedures. 
12. Positivity for human immunodeficiency virus type 1 or 2 (HIV-1, 
HIV-2) (serology or RNA), and/or Hepatitis B Virus Surface 
Antigen (HbsAg) and/or Hepatitis B Virus (HBV) DNA and/or 
Hepatitis C Virus (HCV) RNA (or negative HCV RNA but on 
antiviral treatment) and/or Treponema Pallidum or Mycoplasma 
active infection. 
13. Active alcohol or substance abuse within 6 months of the study. 
14. Pregnancy or lactation. 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
15. Previous allogeneic bone marrow transplantation, kidney or liver 
transplant, or gene therapy. 
16. Prior to conditioning: inability to meet the target mobilization cell 
number needed to manufacture the Drug Product after at least 2 
attempts of HSPC collection. 
Endpoints 
Primary Endpoints 
• Engraftment of Temferon after reduced intensity conditioning 
(vector copy number [VCN] ≥ 0.07 in myeloid cells between Day 
+30 and Day +100 in at least 2 patients). 
• The proportion of patients achieving hematologic recovery by 
Day +30 from ASCT with non-manipulated and/or CD34+-
enriched autologous HSPC 5 and infusion of Temferon.  
Hematologic recovery is defined as the first of at least 3 
consecutive days with a neutrophil count > 0.5 x 109/L and platelet 
count > 20 x 109/L. 
• Safety of Temferon. This will be measured through the 24 months 
post Temferon infusion as:  
1) 
Short-term tolerability of Temferon (through 24 hours 
post Temferon infusion);  
2) 
Stable blood counts and absence of cytopenias > grade 2, 
unless related to myeloma progression or concomitant 
medications; 
3) 
Absence of systemic interferon-alpha (IFN-α) toxicity 
including: 
a. Constitutional or neurologic symptoms requiring 
medical treatment; 
b. Emergence of autoimmune manifestations requiring 
treatment;  
 
5 Non-manipulated and/or CD34+-enriched autologous HSPCs = autologous non-selected or CD34+-enriched 
HSPCs that did not undergo any genetic manipulation. 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
c. Any organ toxicity (> grade 2 according to CTCAE 
v5.0) that can be ascribed to IFN-α exposure;  
4) 
Absence of Replication Competent Lentivirus (RCL);  
5) 
Absence of hematologic malignancy that is distinct from 
progression of the primary neoplasm. 
Secondary endpoints 
• Presence of an IFN-α gene signature in the bone marrow (BM) 
of Temferon-treated patients. 
• Presence of transduced myeloid cells in BM aspirate and 
peripheral blood (PB) at Day +30 and Day +100 post Temferon 
infusion as determined by VCN.  
• Persistence of transduced myeloid cells in PB and BM as 
assessed by VCN. Persistence is defined as a VCN above the level 
of detection evident for at least 12 weeks. 
• Overall response rate (ORR): proportion of patients that obtain 
partial response (PR), very good partial response (VGPR), 
complete response (CR) and stringent complete response (sCR) 
according to IMWG response criteria.    
• Fraction of patients achieving complete response (CR) with 
minimal residual disease (MRD) levels ≤ 10-5 and 10-6 on BM 
aspirate.  
• Duration of maintenance of response during the 24 months post 
Temferon infusion, according to the IMWG extended criteria 6.  
• Progression-free survival (PFS) and overall survival (OS) at 24 
months post Temferon infusion. 
• Change in health-related quality of life (HRQOL) at 6, 12 and 
24 months post Temferon infusion compared to screening. 
• Change over time in performance status scores (ECOG and 
Karnofsky) through 24 months post Temferon infusion. 
Exploratory endpoints 
 
6 Kumar et al. International Myeloma Working Group consensus criteria for response and minimal residual 
disease assessment in multiple myeloma. Lancet Oncology 2016. 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
BM and PB samples will be collected and stored frozen for subsequent 
optional exploratory analyses, according to feasibility: 
• Characterization of myeloid BM subpopulations. 
• Characterization of marrow-infiltrating lymphocytes in the BM and 
PB T cells at diagnosis, pre- and post Temferon infusion.  
• IFN-α response signature in monoclonal plasma cells. 
• Assessment of plasma cell neoantigen load and single cell 
transcriptomic analysis of the Tie-2 expressing monocytes (TEM) 
pre- and post Temferon infusion.  
• IFN-α2 concentration in blood and BM plasma/serum.  
• Histopathologic analysis of BM biopsy for vessel density and 
immune infiltrates. 
• Clonal tracking of hematopoiesis derived from Temferon infusion. 
• Assessment of MRD levels in the CD34 negative cell fraction and 
in Temferon by NGS. 
ATMP, 
Dosage, and 
Treatment 
Plan 
Temferon is an investigational Advanced Therapy Medicinal Product 
(ATMP) consisting of autologous CD34+-enriched HSPCs exposed to 
transduction with a Lentiviral Vector (LV) encoding the human IFN-
α2 gene (TIA126-LV). 
HSPC mobilization and harvest, as per institutional practice 
The first HSPC mobilization attempt will be done with lenograstim and 
plerixafor as follows: 
- 
Lenograstim (Myelostim) 10 µg/kg/day divided in 2 
administrations (5 µg/kg each) by subcutaneous injection (s.c.) 
until a sufficient number of CD34+ cells is mobilized and the 
leukapheresis/-es has/have been concluded. Monitoring of 
CD34+ cells in the PB will be performed daily every morning 
from day 4.  
- 
Plerixafor (Mozobil) 0.40 mg/kg s.c. 5h before commencement 
of leukapheresis, starting from day 4.  
If required, additional leukaphereses will be performed the following 
day(s), preceded by additional plerixafor dose(s) 5 hrs before.    
Mobilization target is ≥ 4.5 x106 CD34+ cells/kg (pool of 2 collections 
on consecutive days): 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
• 
The following are the minimum cell numbers (CD34+/kg after 
CD34+ cell enrichment) required for Temferon production:  
o Dose cohort 1: 1.5 x106 CD34+ cells/kg 
o Dose cohort 2: 2.5 x106 CD34+ cells/kg 
o Dose cohort 3: 3.5 x106 CD34+ cells/kg  
• 
CD34+ cells exceeding the dose cohort-specific target will be 
frozen as non-transduced cells.  
In case the dose cohort-specific minimum cell number will not be 
reached, CD34+-enriched cells will be frozen and a second 
mobilization will be attempted. Cyclophosphamide may be used in 
addition to lenograstim and plerixafor for the second mobilization 
attempt, as follows: 
- 
Cyclophosphamide (Endoxan) 4 g/m2 by intravenous infusion 
(i.v.) on day 1; 
- 
Lenograstim (Myelostim) 5 µg/kg/day s.c. from day +5; 5 
µg/kg/bid from hematologic recovery (leukocytes > 1000 
cells/μL) to apheresis; 
- 
Plerixafor 
(Mozobil) 
0.40 
mg/kg 
s.c., 
5h 
before 
commencement of leukapheresis. 
If required, CD34+-enriched cells from second remobilization will be 
pooled with thawed CD34+-enriched cells from first remobilization to 
produce a single batch of Temferon.  
An aliquot of the CD34-negative fraction from the harvest(s) and 
Temferon may be tested for MRD by Clonoseq, to prospectively 
acquire data on potential contamination by monoclonal plasma cells, 
as exploratory analyses (for information only). 
Patients meeting the mobilization target will be offered maintenance 
treatment until conditioning/ASCT. Patients may receive any approved 
2nd line treatment/maintenance regimen. 
ASCT following non-myeloablative chemotherapy 
Once the Investigator has received confirmation that Temferon has 
received QP release for clinical use and the patient is ready for 
treatment, the following RIC regimen will be implemented: 
- 
Melphalan 100 mg/m2 i.v. on Day -2; 
Followed by:  


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
- 
ASCT on Day 0, as an i.v. infusion of autologous HSPCs into 
a central vein. Target dose is 3.0 x106 CD34+ cells/kg, with a 
minimum dose of 2.0 x106 CD34+ cells/kg. HSPCs for ASCT 
can be obtained from an exceeding number of non-manipulated 
and/or CD34+-enriched cells collected during the HSPC 
mobilization and harvest phase of the study, from a prior non-
manipulated front-line harvest (unfractionated apheresis), or 
from a combination of both. 
Experimental Gene Transfer Treatment 
Infusion of Temferon on Day 0, as an i.v. infusion into a large 
peripheral vein or, if not feasible, into a central vein, within 3 hours to 
16 hours post ASCT.  
Granulocyte colony stimulating factor (G-CSF) will not be given on a 
routine basis, but will be reserved to patients showing prolonged 
neutropenia (grade 3/4 neutropenia beyond day 21 post chemotherapy). 
The following dosing scheme for Temferon infusion will be applied: 
 
 
 
Temferon 
(CD34+ cells/kg body weight) 
Dose level 1 
0.5* x106 
Dose level 2 
1.0* x106 
Dose level 3 
2.0* x106 
* The actual Temferon dose to be administered will be rounded to the 
nearest available aliquot size (maximum tolerance: +10%). 
Temferon dose adjustments will be performed by the Sponsor of the 
manufacturing of Temferon (Genenta Science), in agreement with the 
Principal Investigator, according to the VCN indicated in the release 
documents. Should the VCN indicated in the release documents fall 
onto the dose-adjustment cutoffs, a VCN value expressed with 2 
decimals will be considered for decision-making. The adjusted dose 
will be released to the Investigator for administration: 
VCN 
Level 1 
Level 2 
Level 3 
< 0.4 
0.8 x106 
1.5 x106 
3.0 x106 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
0.4-1.0 
0.5 x106 
1.0 x106 
2.0 x106 
1.1-1.5 
0.4 x106 
0.8 x106 
1.5 x106 
>1.5 
0.3 x106 
0.5 x106 
1.0 x106 
Follow up treatment: 
After the evaluation on Day +100 post Temferon infusion, patients will 
resume anti-myeloma consolidation/maintenance treatment according 
to best clinical practice, unless patients show documented Temferon 
engraftment (VCN ≥ 0.07 in myeloid cells) and a deep molecular, 
biochemical and imaging response. 
At any time upon suspected disease progression, patients will undergo 
a complete disease re-evaluation (including biochemical response, BM 
analysis, MRD assessment, positron emission tomography [PET], 
computerized tomography [CT]), and nuclear magnetic resonance 
[NMR] imaging at Investigator’s discretion) and, in the case of 
documented progressive disease (PD), will be treated according to best 
clinical practice, at the discretion of the treating physician. 
Management of potential side effects from Temferon: 
The cell-based gene therapy approach that is being utilized in this study 
is designed to allow local, low dose IFN-α2 release at the tumor site, 
reducing the potential for systemic side effects. 
As a benchmark for a “worst case scenario”, potential adverse drug 
reactions related to systemic delivery of IFN-α (well described in the 
Summary of Product Characteristics of approved medicines such as 
IntronA 7 ), for which warnings exist, are listed below and will be 
managed as appropriate: 
• Central nervous system and psychiatric effects; 
• Hypersensitivity reactions ; 
• Abnormal liver function and prolongation of coagulation 
markers ; 
• Myelosuppression ; 
• Hypotension & need for adequate hydration ; 
• Pyrexia ; 
 
7 IntronA SPC: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000281/WC500034679.pdf 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
• Pulmonary conditions ; 
• Ocular adverse events ; 
• Obtundation, coma and encephalopathy ; 
• Patients with pre-existing cardiac abnormalities ; 
• Hypertriglyceridemia ; 
• Auto-antibodies and autoimmune disorders ; 
• Thyroid disorders. 
All patients are required to dispose of a non-manipulated and/or 
CD34+-enriched autologous back-up of at least 2.0 x106 CD34+ 
cells/kg, harvested during front line treatment and/or during the HSPC 
mobilization and harvest phase of the study. In the event of insufficient 
autologous CD34+ cells for backup, allogeneic backup will be 
permitted (providing a donor has already been identified) according to 
the Investigator’s judgement. In the event that hematological recovery 
does not occur, or in case of severe/persisting side effects not 
satisfactorily managed by the indicated treatments, patients may 
undergo transplant from back-up cells, ablating the genetically 
engineered graft with myeloablative conditioning regimen, as a rescue 
strategy. 
Sample Size 
Up to 9 patients in 3 cohorts. 
There can be less or more than 3 patients per cohort, for the following 
reasons: 
• 
In case the first 2 patients treated with dose level 1 show 
minimal in vivo engraftment of Temferon (VCN < 0.07 at Day 
+30 in BM myeloid cells), the third patient planned for dose 
level 1 will become the first patient in dose level 2.  
• 
In case the first 2 patients treated with dose level 2 show 
minimal in vivo engraftment of Temferon (VCN < 0.07 at Day 
+30 in BM myeloid cells), the third patient planned for dose 
level 2 will become the first patient in dose level 3.  
• If the minimum cell number for a cohort-specific dose is not 
reached, but is reached for a lower Temferon dose production, 
the patient may be assigned to a lower-dose cohort, even if 3 
patients have already been dosed in the cohort, providing that 
adequate Temferon engraftment (≥ 0.07 VCN/genome on BM 


Ospedale San Raffaele 
Temferon 
Clinical Protocol No. TEM-MM-101  
                   v3.0 of 26 November 2019 
 
myeloid cells) has been demonstrated at Day +30 for at least 
one patient in that cohort. 
Duration of 
Patient 
Participation 
Each patient’s study participation duration is expected to be 
approximately 28 months from time of consent (including 24 months 
of follow-up post Temferon infusion). Patients will then be invited to 
consent for a long-term follow-up study of another 6 years. 
Estimated 
Study 
Duration 
From enrollment of the first patient to post Temferon infusion follow-
up of the last patient enrolled, the study duration is expected to be up 
to 49 months (including a 22-month enrollment period). 
Data 
Monitoring 
Committee 
(DMC) 
A DMC with a minimum of 3 members with relevant medical and 
scientific expertise will be constituted before the study start. A charter 
describing the composition and conduct of the DMC will be issued by 
Ospedale San Raffaele and Genenta Science and agreed to by all DMC 
members prior to the DMC’s initial meeting.  
The DMC will review safety and efficacy data within a dosing cohort 
and make a recommendation about proceeding to the next dosing 
cohort. 
Enrollment 
Suspension 
Criteria 
In the event that a patient death that is attributed to Temferon occurs 
within 90 days of Temferon administration, further enrollment will be 
suspended.  
All other SAEs that result in death and are attributed to Temferon, will 
be reviewed by the DMC who will advise on whether recruitment into 
the study should be suspended. 
Statistical 
Methods 
This is a Phase I/II gene therapy study for which no formal statistical 
analysis is required.