A Pilot Study on the Efficacy of Daratumumab in Multiple Myeloma (MM) Patients in >VGPR/MRD-positive by Next Generation Flow
Phase: PHASE2
Conditions: Myeloma Multiple
Sponsor: Azienda Ospedaliera Universitaria Senese

 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1,  6 December 2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
1 
 
 CLINICAL STUDY PROTOCOL 
DART4MM 
 
Title: 
A Pilot study on the efficacy of Daratumumab in 
Multiple Myeloma (MM) patients in >VGPR/MRD-
positive by next generation flow (NGF) 
 Study code: 
DART4MM 
 
Eudract Number: 
 
2018-000386-36 
Version: 
 
1.1 
Release Date: 
 
6 December 2018 
Financing: 
CO-FINANCING BY JANSSEN CILAG S.p.A. 
Promoter: 
AZIENDA OSPEDALIERA UNIVERSITARIA SENESE 
 
Coordinator site: 
 
SIENA 
Principal Investigator: 
Dr. Alessandro Gozzetti, Ematologia,AOUS, tel. 
0577-586798, fax 0577-586185, e-mail: 
gozzetti@unisi.it 
 
Other Investigator of the coordinator 
site: 
Prof.  Monica Bocchia 0577-586798,e-
mail:bocchia@unisi.it 
Dr. Donatella Raspadori, 0577-586798, 
email:raspadori@unisi.it 
Dr. Sara Ciofini, 0577-586798. s.ciofini@gmail.com 
Dr. Francesca Bacchiarri, 0577-586798, email: 
francesca.bacchiarri@hotmail.it 
 
 
 
 
Mod. B9 
Vers_20160118 

 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1,  6 December 2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
2 
 
List of participating sites 
 
 
UOC Hematology Firenze 
Prof. Alberto Bosi, e-mail: alberto.bosi@unifi.it 
UOC Hematology Pisa 
Dr Gabriele Buda, e-mail: ga.buda@libero.it 
UOC Hematology Terni 
Prof. Anna Marina Liberati, email: 
marina.liberati@unipg.it 
UOC Hematology Ascoli Piceno 
Dr. Piero Galieni, e-mail:  
piero.galieni@sanità.marche.it 
 Contacts 
Contact Name Promoter 
Dr Alessandro Gozzetti, UOC Ematologia , AOUS 
 
Contact Name for pharmacovilance 
Dr Silvano Giorgi, UOC Farmacia, e-
mail:s.giorgi@ao-siena.toscana.it 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1,  6 December 2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
3 
 
 
PROTOCOL APPROVAL 
 
The Investigators: 
- Approve this protocol 
 
- declare that the study will be conducted in compliance with the provisions of this 
protocol 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December 2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
4 
 
 
INDEX 
 
Study background ...................................................................................................................................... 6 
Study objectives ....................................................................................................................................... 10 
Primary objective  ................................................................................................................................ 10 
Secondary objective  ........................................................................................................................... 10 
Study design  ............................................................................................................................................ 11 
Patient population  .................................................................................................................................. 11 
Subject eligibility  ..................................................................................................................................... 12 
Subject inclusion criteria ..................................................................................................................... 12 
Subject exclusion criteria  ................................................................................................................... 12 
Treatment ................................................................................................................................................. 16 
Study drug  ........................................................................................................................................... 16 
Treatment scheme .............................................................................................................................. 18 
Study drug management .................................................................................................................... 18 
Adherence to the treatment  .............................................................................................................. 18 
Concomitant medication  .................................................................................................................... 19 
Prohibited concomitant medication  .................................................................................................. 20 
Risk-benefit potential evaluation in the patient population  ............................................................ 20 
Withdrawal of the study subject ........................................................................................................ 20 
Subject completion/discontinuation of study treatment  ................................................................. 20 
Early termination or suspension of the study .................................................................................... 21 
Study endpoints  .................................................................................................................................. 21 
Primary endpoint  ................................................................................................................................ 21 
Secondary endpoint  ........................................................................................................................... 21 
Study assessments  .................................................................................................................................. 22 
Study flowchart  .................................................................................................................................. 22 
Screening phase  ................................................................................................................................. 24 
Data management  .................................................................................................................................. 26 
Statistical methods and data analysis  .................................................................................................... 28 
Safety management  ................................................................................................................................ 30 
Adverse events recording  ................................................................................................................... 32 
Causal link ............................................................................................................................................ 34 
Adverse events reporting .................................................................................................................... 35 
Anomalies in the laboratory parameteres  ........................................................................................ 35 
Administrative procedures  ..................................................................................................................... 35 
Study  financing ................................................................................................................................... 35 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December 2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
5 
 
Insurance coverage  ............................................................................................................................ 35 
Indipendent data monitoring committee(IDMC)  .............................................................................. 35 
General revision  .................................................................................................................................. 35 
Amendments to the protocol  ............................................................................................................ 36 
Ethical consideration  .............................................................................................................................. 36 
Acquisition of informed consent  ....................................................................................................... 36 
Confidentiality  .................................................................................................................................... 37 
Conflict of interest  .............................................................................................................................. 37 
Responsibility and publication policy ..................................................................................................... 37 
Data properties  ................................................................................................................................... 38 
Publication  .......................................................................................................................................... 38 
Bibliography ..........….....….........……...............….............................…...............…........................………….38

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
6 
 
STUDY BACKGROUND  
 
Multiple myeloma (MM) is a plasma cell malignancy characterized by clonal proliferation of plasma 
cells in the bone marrow microenvironment and associated organ damage (CRAB= increased 
calcium, renal insufficiency, anemia, bone lesions) (1). The organ damage is due to a monoclonal 
protein produced in the blood or urine. It represents about 10% of hematological cancers and 1% of 
all cancers. Median age at diagnosis is 70 years. In the last decades we experienced a great 
improvement in myeloma survival both in young and old patients (2,3). A more evident increase was 
seen in the age group younger than 65 years, leading to 5- and 10-year relative survival of 56% and 
41%. By contrast, only moderate improvement was seen in the age group >65 years, and no 
substantial improvement was achieved among patients older than 75 years (3).  
 
 
New drugs era 
The clinical progresses are due to the introduction of novel drugs (bortezomib, thalidomide, 
lenalidomide) and to autologous stem cell transplantation (ASCT). These approaches resulted in an 
increased rate of complete response (CR) that translated into prolonged survival(4). Nonetheless a 
better understanding of plasma cell biology and myeloma pathways has resulted in the 
identification of novel targets for therapy. New agents deriving from already approved and active 
agents (such as second- and third generation proteasome inhibitors, thalidomide, lenalidomide) 
have been developed and also new drugs with novel mechanisms of action are under investigation 
in clinical trials. Although advancements have been outstanding in the field of myeloma, there is still 
a small group of patients (10-15%) that has a dismal prognosis, i.e. .del 17p and t(4;14) patients, in 
which novel therapeutic approaches are urgently warranted (5-7).  
 
CR and MRD  
The introduction of novel therapies for the treatment of MM patients has significantly improved 
clinical outcome, but it has been difficult to define precisely a complete response  since until few 
years ago CR was defined by negative immunofixation and less than 5% bone marrow plasma cells. 
This definition of clinical response criteria and clinical end points has largely remained the same 
over the past 15 years and presents several relevant limitations. The challenge is to identify the 
patients that despite reaching CR status relapse very quickly (unsustained response) compared to 
other patients that only achieve partial response but have prolonged survival. Moreover, within the 
treatment options, new drugs are becoming available  that seem to increase the depth of response. 
Improving CR rates have made the measurement and monitoring of MRD in MM a relevant task. 
Most patients who achieve MRD-negative status eventually relapse, indicating that the sensitivity 
and specificity of traditional techniques for MRD assessment can be improved. Flow studies have 
been employed in latest years, with 4-6 colours cytometry and sensitivity of 10-3 or 10-4.  Recent 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
7 
 
data suggest that a lower cut-off provided by more sensitive assays like next generation flow at 8 
colours will likely improve outcome prediction further. Accordingly, 10−5 should currently be 
considered as the target cut-off level for definition of MRD negativity. 
 
To achieve a complete remission (CR) is a prerequisite for long term progression free survivals (PFS) 
and ultimately overall survivals (OS) and cure both in young and old patients with MM. CR rate can 
be up to 85% after single or double autologous transplant (ASCT) and up to 40% in the ASCT 
ineligible (old) patient with new drugs regimens (such as bortezomib, thalidomide, lenalidomide, 
carfilzomib)(8-10). Nonetheless a minimal residual disease (MRD positive) can be demonstrated in 
the majority of patients in CR with molecular or flow methodologies. Moreover most patients who 
achieve MRD-negative status eventually relapse, indicating that the sensitivity and specificity of 
traditional techniques for MRD assessment can be improved. Recent data suggests that a lower cut-
off provided by more sensitive assays (e.g., next generation sequencing (NGS) or high-sensitive flow 
cytometry (NGF)) can improve outcome prediction further. Two 8 colours tubes panel developed by 
the EuroFlow Consortium can detect MRD-positive cases with a sensitivity near to the molecular 
detection and can be applied as standardized method. The IMWG guidelines  for response criteria 
definitions of MRD recommend NGF or NGS as complementary methods or both and by PET/CT as 
imaging methods. 
NGF is more convenient than NGS in terms of applicability in daily laboratory practice. 
 Long term remission have been reported to be frequent in MRD neg MM patients only after 
allogeneic transplant and few studies have been done in other drug settings.  
The combination of bortezomib-thalidomide-dexamethasone (VTD) has proved to be superior to 
thalidomide-dexamethasone (TD) as induction therapy before ASCT resulting in a 3-year PFS of 68 % 
for the VTD arm vs. 56% for the TD arm (11). CR rate was 55%.  VTD was also superior in a spanish 
study associated with thalidomide maintenance (12).Novel drugs have been explored in clinical 
trials in the induction therapy of younger patients (13-18). 
 
Novel therapeutic strategies: consolidation  
 Therapy consolidation (usually two cycles after ASCT to increase responses) and maintenance 
(continuous therapy until progression) are being explored to improve outcome after ASCT as an 
alternative to perform a second autotransplant with the idea to achieve the same efficacy but with 
less toxicity. In one study VTD consolidation increased CR from 15 % to 49 % in patients who had 
previously achieved VGPR after double ASCT (19). Molecular remissions by allele- specific 
polymerase chain reaction (AS-PCR) following VTD treatment had a better outcome: the PFS at 
42 months for patients with a low tumor load was 100% versus 57% for patients with a higher tumor 
load after VTD. Another study confirmed these findings (20-21). Two cycles of consolidation therapy 
with TD or VTD were given after the second ASCT. In the TD arm, consolidation improved the CR rate 
from 40% to 47%. In the VTD arm, the CR rate increased from 49% to 61%. Several studies are 
ongoing to better evaluate the role of consolidation therapy.  

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
8 
 
 
Initial treatment of non-transplant eligible myeloma patients 
About two-thirds of MM patients are more than 65 years old at the time of the first diagnosis (22). 
Therefore the majority of patients are usually not eligible for high-dose therapy followed by ASCT. 
Achieving at least a very good partial response (VGPR) has been demonstrated to be related to an 
improvement of the long-term outcome also in the elderly patients (23-33). Standard frontline 
treatment for elderly patients has been for long time the combination of the oral alkylating agent 
melphalan with prednisone (MP). This schedule  is well tolerated even in frail patients and can be 
administered as outpatient regimen with maintenance of a good quality of life but the overall 
response rate obtained is dismal. The introduction of novel agents, such as thalidomide, 
lenalidomide and bortezomib, has led to better responses also in this setting of patients. Since the 
CR is an independent predictor of longer PFS and OS regardless of age and International Staging 
System (ISS), a novel agent is recommended in the induction therapy (34).  A randomized phase III 
study compared bortezomib-melphalan-prednisone (VMP) to MP in the elderly. VMP significantly 
increased the CR rate (from 4% to 30 %), PFS (from 16 to 23 months), and OS (from 43 to 
56 months) with respect to MP (34). Subsequently a reduced bortezomib schedule (from twice- to 
once-weekly administration) was shown to be better tolerated without affecting the outcome (35). 
Today, both MPT and VMP are considered the standard therapies for elderly patients (Table 2). 
Daratumumab in clinical trials and study rationale 
Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human mAb against CD 38 antigen, 
produced in a mammalian cell line (CHO) using recombinant DNA technology. (see Investigational 
Brochure, IB) 
Daratumumab has been explored as a single agent in relapsed and refractory patients 
(GEN501,NCT00574288. In the dose-expansion phase 30 patients received 8 mg/kg and 42 patients 
16 mg/kg once weekly (8 doses), twice monthly (8 doses) then monthly up to 24 months. Patients 
had received a median number of 4 to 5 lines of therapy with 54% of patients refractory to 
bortezomib and 72% to lenalidomide. Low grade infusion-related reactions were initially observed in 
up to 75% of patients but were considerably attenuated by the delivery in a large infusion volume. 
Thirty five percent of patients receiving a dose of 16 mg/kg responded, with 15% of complete or 
very good partial responses. These encouraging results were confirmed in the multicenter phase 2 
study SIRIUS (NCT01985126). In this study, 106 heavily pretreated myeloma patients received 
daratumumab monotherapy (16 mg/kg). Patients had received a median of 5 prior therapies and 
the majority of them were refractory to bortezomib, lenalidomide and pomalidomide. Partial 
response was achieved by 29.2% of patients and the median duration of response was 7.4 months. 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
9 
 
A pooled analysis of the patients of the GEN 501 and the SIRIUS trials who had received 
daratumumab monotherapy at the dose of 16 mg/kg (n=148) showed an overall response rate of 
31.1% and a median PFS and OS of 4 and 20 months, respectively. Patients achieving only stable 
disease or minimal response reached a promising median overall survival of 18.5 months, which is  
unexpected in this population of very advanced myeloma patients. The quality of response was 
correlated with the expression intensity of CD38 by neoplastic plasmocytes. Daratumumab was 
granted accelerated approval in 2015 by the FDA to treat patients with multiple myeloma who had 
received at least three prior treatments. 
Daratumumab is also being studied in combination with many other agents including lenalidomide, 
bortezomib, carfilzomib or pomalidomide. The phase 3 randomized trial CASTOR recently confirmed 
a strong advantage of the addition of daratumumab to bortezomib/dexamethasone, in 498 relapsed 
myeloma patients (NCT02136134). The triplet combination was associated with a significantly 
better response rate, including 82.9% of PR or better and 19.2% of CR or better. The 1-year rate of 
progression free survival was 60.7% in the daratumumab group versus 26.9% in the control arm. 
The updated results of this trial have confirmed this strong PFS benefit for the patients in the 
daratumumab arm, especially for the patients in first relapse (12-months PFS : 77.3% vs 24.7%, 
p<10-4). Daratumumab also clearly improved the median PFS of patients with high-risk cytogenetic. 
In this relapse setting, the POLLUX trial also demonstrated a strong advantage of the addition of 
daratumumab to lenalidomide and dexamethasone, in terms of both response rate and PFS 
(NCT02076009) . In this trial, patients in the daratumumab group reached an overall response rate 
of 93% (including 43% CR) and had a 63% reduction in the risk of progression. The updated results 
of this trial confirmed this significant PFS advantage even in lenalidomide-naïve patients and in 
patients with high-risk cytogenetic. Minimal Residual disease (MRD) assessed by NGS analysis in 
patients included in CASTOR and POLLUX trials revealed an unprecedently observed rate of patients 
with MRD negative disease. Indeed, 32% (vs 9%) and 18% (vs 4%) of patients reached a 10-4 MRD 
negative in the daratumumab (versus control) arms of POLLUX and CASTOR, respectively. In 
particular the rate of MRD negativity (10-5) has increased continuosly after month 6 in patients 
receiving Daratumumab monotherapy  in the CASTOR trial. (36) 
The addition of daratumumab is currently being assessed in the context of previously untreated 
myeloma patients. The phase 3 randomized study Cassiopeia is currently evaluating the role of 
daratumumab in combination with VTD in induction, and its role as maintenance after high-dose 
therapy (NCT02541383). In patients not eligible for transplant, the phase 3 randomized trial MAIA is 
evaluating the addition of daratumumab to lenalidomide-dexamethasone (NCT02252172).  
In the ALCYONE trial  (Dara-VMP vs VMP) in patients inelegible to transplant MRD negativity (10-5) 
has increased continuosly after cycle 10 with daratumumab monotherapy.(37) 
The potential benefit of daratumumab has also been recently evaluated in high-risk smoldering 
myeloma patients in the phase 3 randomized CENTAURUS (NCT02316106). 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
10 
 
Daratumumab monotherapy can increase response and in particular MRD negativity, which 
correlates with PFS and OS. To our knowledge the use of daratumumab in multiple myeloma 
patients  with suboptimal response (in particular with a >VGPR/MRD+)  has not yet been explored. 
To achieve a better response can ameliorate patient outcome and survival. 
 
STUDY OBJECTIVES  
 
 
Aim of this study is to evaluate Daratumumab effect on MRD-positive patients with MM who 
achieved >VGPR after any therapy (ASCT, VMP, Rev-Dex). Daratumumab 16 mg/kg administered at 
weekly intervals for 8 weeks, +every 2 weeks for an additional 16 weeks, will be given to 50 MM 
patients who achieved a >VGPR defined by monoclonal component disappearance in serum or 
urine, immunofixation positive/negative and MRD-positivity (by NGF). Free light chain (FLC) and 
CT/PET will be evaluated at time 0. NGF will be done on marrow aspirate at time 0, at 2 months and 
every 6 months for 2 years. If patients will be still MRD positive after 6 months of therapy , 
treatment will be continued up to 2 years. 
 
 
Primary objectives 
Primary objective of the study is Daratumumab efficacy: in particular capacity to determine 
increase of response by MRD negativity, detected by NGF assessment on bone marrow 
specimens 
 
Secondary objectives  
 
 Rate of acute and late toxicity according to National Cancer Institute Common Terminology              
Criteria for Adverse Events (NCI CTCAE) criteria. 
 
 
STUDY DESIGN 
STUDY DESIGN: DART4MM
DARATUMUMAB 16 mg/kg weekly for 8 weeks
then
DARATUMUMAB 16 mg/kg every 2 weeks  for 8 week
MRD EVALUATION AT MONTH 6
DARATUMUMAB MONTHLY UP TO 2 YEARS
MRD POSITIVE
MRD NEGATIVE
STOP THERAPY 
No -profit, , prospective , uncontrolled, multi-institutional phase II study, open label, single arm. 
Start of recruitment: June 2018 
Planned termination of recruitment: December 2019 
Planned termination of follow-up: June 2020 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
11 
 
Final study report: December  2020 
Patient population 
Hospital setting, outpatient. 50 patients are planned to be enrolled and treated 
Other satellite centers that will enroll patients and treat patients 
UOC Hematology Firenze 
Dr.ssa 
Elisabetta 
Antonioli,e-mail 
: 
elisabettaantonioli@libero.it 
UOC Hematology Pisa 
Dr Gabriele Buda,e-mail: ga.buda@libero.it 
UOC Hematology Terni 
Prof.ssa 
Anna 
Marina 
Liberati, 
e-
mail:marina.liberati@unipg.it 
UOC Hematology Ascoli Piceno 
Dr Piero Galieni,e-mail: piero.galieni@sanità.marche.it 
 
SUBJECT ELIGIBILITY 
 
Inclusion criteria 
Patients are eligible to be included only if they meet all of the following criteria: 
 Age 18-85 years at the time of signing the informed consent form 
 Able to adhere to the study visit schedule and other protocol requirements 
 >VGPR/MRD-positive by NGF measured by 2-tubes optimized 8-color antibody panel, 
(OneFlow PCST e  PCD BD Biosciences)  
 Patients should be at enrollment at least  12 weeks from any therapy for myeloma after 
diagnosis or at any subsequent relapse 
 Eastern Cooperative Oncology Group performance status score of 0, 1, or 2 
 Laboratory values and electrocardiogram within protocol-defined parameters at screening 
 All previous MM therapy, including radiation, cytostatic therapy and surgery, must have been 
terminated at least 4 weeks prior to treatment in this study, without corticosteroid therapy. 
 Laboratory test results within these ranges: 
- Absolute neutrophil count  1.0 x 109/L 
- Platelet count  75 x 109/L 
- Creatinine clearance > 30 ml/h) 
- Total bilirubin  1.5 mg/Dl 
- Aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT)  2 
x ULN  

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
12 
 
 Disease free of prior malignancies for  5 years with exception of curatively treated basal cell, 
squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix or breast 
 Fertile patients must use effective contraception during and for 6 months after study 
treatment 
 Patients must sign on an Informed Consent Form 
No study treatment or any other procedure within the framework of the trial (except for 
screening) will be performed in any patient prior to receipt of written informed consent. 
 
 
Exclusion criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
 Received daratumumab or other anti-CD38 therapies previously 
 Nonsecretory multiple myeloma 
 Previously received an allogenic stem cell transplant or has received an autologous 
stem cell transplantation within 12 weeks 
 Known chronic obstructive pulmonary disease, persistent asthma, or a history of 
asthma within 5 years 
 Absence of the Informed Consent Form signed by the patient 
 Pregnant or breast feeding females 
 Use of any other experimental drug or therapy within 28 days of baseline. 
 Known hypersensitivity to the study drugs 
 Known positive for human immunodeficiency virus (HIV) or infectious hepatitis, type A, 
B or C.  
 Plasma 
cell 
leukemia, 
Waldenstrom's 
macroglobulinemia, 
POEMS 
syndrome 
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin 
changes), or amyloidosis 
 
Contraception 
 
No clinical or preclinical studies have been performed to evaluate the potential effects of 
daratumumab on reproduction or development. 
Non-sterilized female patients of reproductive age group and male patients should use effective 
methods of contraception through defined periods during and after study treatment as below 
specified. 
Female patients must meet 1 of the following: 
 Postmenopausal for at least 1 year before the screening visit 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
13 
 
 Surgically sterile 
 If of childbearing potential, agree to practice 2 effective methods of contraception from the 
time of signing of the step 2 informed consent form through 6 months after the last dose of 
study drug 
 Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Male patients, even if surgically sterilized (i.e., status post vasectomy) must agree to 1 of the 
following: 
 Practice effective barrier contraception during the entire study treatment period and 
through 6 months after the last dose of study drug 
 Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptom-thermal, post 
ovulation methods for the female partner) and withdrawal are not acceptable methods of 
contraception. 
Examples of Contraceptives 
 
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
USER INDEPENDENT 
Highly Effective Methods That Are User Independent Failure rate of ≤1% per 
year when used consistently and correctly. 
Implantable progestogen-only hormone contraception associated with 
inhibition of ovulationb 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided 
that the partner is the sole sexual partner of the woman of childbearing 
potential and the absence of sperm has been confirmed. If not, additional 
highly effective method of contraception should be used. Spermatogenesis 
cycle is approximately 74 days.) 
USER DEPENDENT 
Highly Effective Methods That Are User Dependent Failure rate of <1% per 
year when used consistently and correctly. 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
14 
 
Combined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulationb 
oral 
intravaginal 
transdermal 
injectables 
Progestogen-only hormone contraception associated with inhibition of 
ovulationb 
oral 
injectable 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk 
associated with the study intervention. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject.) 
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY 
(not considered to be highly effective - failure rate of >1% per year) 
Progestogen-only oral hormonal contraception where inhibition of 
ovulation is not the primary mode of action. 
Male or female condom with or without spermicidec 
Cap, diaphragm, or sponge with spermicide 
A combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double-barrier methods)c 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
Withdrawal (coitus-interruptus) 
Spermicides alone 
Lactational amenorrhea method (LAM) 
a) Typical use failure rates may differ from those when used consistently 
and correctly. Use should be consistent with local regulations regarding 
the use of contraceptive methods for subjects participating in clinical 
studies. 
b) Hormonal contraception may be susceptible to interaction with the 
study intervention, which may reduce the efficacy of the contraceptive 
method. In addition, consider if the hormonal contraception may 
interact with the study intervention. 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
15 
 
c) Male condom and female condom should not be used together (due 
to risk of failure with friction). 
 
 
 
 
 
 
 
 
 
STUDY TREATMENT 
 
 
Patients will receive: 
Daratumumab  16 mg/Kg day every week for 8 weeks intravenous (8 infusions) 
Daratumumab 16mg/kg day every 2 weeks for 16 weeks intravenous (8 more 
infusions) 
If MRD positive by NGF: 
Daratumumab 16 mg/kg every 4 weeks for 80 weeks intravenous 
Treatment duration will be 6 months total  
(8 infusions = 2 months; + 8 infusions = 4 months) for patients achieving MRD 
negativity after 6 months; 
2 years for patients MRD positive after 6 months  
 
 
 
Treatment Duration: interim analysis of bone marrow MRD will be done at months 2 and 6 . Patients 
achieving an MRD negative status at 6 months can stop treatment (as per primary endpoint). As exit 
strategy patients still with detectable MRD will continue Daratumumab until MRD negativity is 
confirmed after 6 months and every 6 months up to two years. Hence, pts still MRD-positive after 6 
months dara treatment will continue until MRD turns to negative (i.e. at intermediate MRD 
evaluations planned at 6,12,18 months), with a maximum treatment duration of 24 months. 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
16 
 
 
STUDY DRUG  
Please See IB 
General drug characteristics and mechanism of action 
Description of Daratumumab 
Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human mAb against CD 38 antigen, 
produced in a mammalian cell line (CHO) using recombinant DNA technology. 
Pharmacological Properties 
Daratumumab binds to the C-terminus of CD38. While binding of daratumumab antibody to 
CD38 in vitro has some effect on enzyme activity (inhibiting cyclase and stimulating hydrolase 
activity), the main effect of daratumumab antibody binding to CD38+ myeloma cell lines is cell lysis 
through CDC, ADCC or ADCP, or by direct apoptosis following crosslinking of the antibody molecules. 
These mechanisms are likely to be involved in daratumumab activity in vivo, although the primary 
mechanism of action in patients is not fully elucidated. Elevated expression of CD38 on myeloma 
cells allows daratumumab to bind relatively selectively to those cells. Thus daratumumab produces 
a potent immunologic antitumor effect. 
 
Dosage and Administration 
Daratumumab has been administered as monotherapy at doses up to 24 mg/kg and as combination 
therapy at doses up to 16 mg/kg.  
The daratumumab infusion should be intravenously administered at the appropriate initial infusion 
rate, as presented in Table below. Incremental escalation of the infusion rate should be considered 
only if the previous infusion of daratumumab was well-tolerated as defined in Table below. 
 Infusion Rates for Daratumumab Administration via IV 
 
a Consider incremental escalation of the infusion rate only in the absence of infusion reactions 
b Dilution volume of 500 mL should be used only if there were no Grade 1 (mild) or greater infusion 
reactions during the first 3 hours of the first infusion. Otherwise, continue to use a dilution volume 
of 1000 mL and instructions for the first  infusion. 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
17 
 
c Use a modified initial rate for subsequent infusions (i.e. third infusion onwards) only if there were 
no Grade 1 (mild) or greater infusion reactions during a final infusion rate of ≥100 mL/hr in the first 
two infusions. Otherwise, continue to use instructions for the second infusion. 
 
 
 
 
 
Treatment scheme 
Patients will receive: 
Daratumumab  16 mg/Kg day every week for 8 weeks intravenous (8 infusions) 
Daratumumab 16mg/kg day every 2 weeks for 16 weeks intravenous (8 more 
infusions) 
If MRD positive by NGF: 
Daratumumab 16 mg/kg every 4 weeks for 80 weeks intravenous 
Treatment duration will be 6 months total  
(8 infusions = 2 months; + 8 infusions = 4 months) for patients achieving MRD 
negativity after 6 months; 
2 years for patients MRD positive after 6 months  
 
 
 
Treatment Duration: interim analysis of bone marrow MRD will be done at month 2 and 6 . Patients 
achieving an MRD negative status at 6 months can stop treatment (as per primary endpoint). As exit 
strategy patients still with detectable MRD will continue Daratumumab until MRD negativity is 
confirmed on two bone marrow consecutive determination one month apart up to two years. 
Hence, pts still MRD-positive after 6 months Dara treatment will continue until MRD turns to 
negative (i.e. at intermediate MRD evaluations planned at 6,12,18 months confirmed after 1 month 
each for MRD neg Pts), with a maximum treatment duration of 24 months. 
 
 
Study drug management 
The relevant information on the drug characteristics, storage, application, mode of action and 
adverse reactions is included in the Summary of Product Characteristics (SmPC). Hospital Pharmacy 
will prepare the drug as usually in daily routine. 
 
Adherence to treatment 
NA 
 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
18 
 
RECOMMENDED CONCOMITANT THERAPIES 
 
Pre-infusion therapy 
In order to reduce the risk of IRRs, a pre-infusion therapy should be administered to all patients 1-3 
hours before each infusion of DARZALEX as follows: 
• Corticosteroids (with long or intermediate action) 
Monotherapy: 
Methylprednisolone 100 mg, or equivalent, administered intravenously. After the second infusion, 
the dose of corticosteroids may be reduced (methylprednisolone 60 mg orally or intravenously). 
Combination therapy: 
Dexamethasone 20 mg, given before each infusion of DARZALEX (see section 5.1). 
Dexamethasone is administered intravenously before the first infusion of DARZALEX and oral 
administration may be considered before subsequent infusions. 
• Antipyretic (paracetamol 650-1.000 mg by mouth) 
• Antihistamine (diphenhydramine 25-50 mg or orally or intravenously equivalent). 
 
Post-infusion therapy 
To reduce the risk of delayed infusion-related reactions, post-infusion therapies should be 
administered as follows: 
Monotherapy: 
The oral corticosteroid (methylprednisolone 20 mg or equivalent dose of an intermediate or long-
acting corticosteroid according to local standards) should be administered in each of the following 
two days all infusions (starting from the day after the infusion). 
Combination therapy: 
Consider administration of low-dose methylprednisolone (≤ 20 mg) by the oral route or equivalent 
the day after the DARZALEX infusion. However, if a regimen-specific base corticosteroid (eg, 
dexamethasone) is given the day after infusion of DARZALEX, additional post-infusion medications 
may not be necessary (see section 5.1 rcp). 
In addition, for patients with a history of chronic obstructive pulmonary disease, post-infusion 
therapy including short- and long-acting bronchodilators and inhaled corticosteroids should be 
considered. After the first four infusions, if the patient does not have major IRRs, these post-infusion 
inhaler medicines may be discontinued at the discretion of the physician. 
 
Prophylaxis of reactivation of the Herpes zoster virus 
Antiviral prophylaxis should be performed to prevent the re-activation of herpes zoster virus. 
 
Pneumocystis Cariini (PCP) Prophylaxis should be considered with TRIMETHOPRIM/SULFAMETAZOL 
800mg po twice a day  for two days consecutive weekly 
 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
19 
 
Concomitant medication 
Per le specifiche vedi sezione del prodotto sperimentale.  
In general, the patients should continue to take their previous therapies (for non-malignant 
conditions) according to the recommendations of the responsible physician. The following 
concomitant therapies will not be allowed: 
 any other antineoplastic treatment 
 other investigational therapies 
 initial prophylactic use of G-CSF, GM-CSF and other growth factors 
Concomitant medication, which is relevant for the study assessments, have to be recorded. 
Additionally, any diagnostic, therapeutic or surgical procedure performed during the study period 
should be reported.  
Supportive care for treatment-related symptoms will be offered as needed to all patients in this 
study. Prophylactic treatment with antibiotics is not recommended, even in case of grade 4 
neutropenia (without fever), but the decision is up to the local investigator’s preference. 
Prophylactic hematopoietic growth factors (i.e., G- or GM-CSF) are not recommended, but 
secondary prophylaxis after a previous episode of neutropenia is up to the discretion of the 
investigator. Use of any supplementary growth factor must be documented in the patient record. 
Growth factors must be discontinued at least 48 hours prior to initiation of the next cycle of 
chemotherapy. 
 
Emergency management 
In case of an emergency the coordinating investigator can be approached via the following 
phone/fax connection:+39  0577- 586798/+39 0577-586185 
 
Prohibited concomitant medication 
Other drugs active in multiple myeloma (chemotherapy, proteasome inhibitors, IMID’s, 
radiotherapy) 
 
Risk-benefit evaluation in the patient population 
The benefit should be superior to risks in this population of patients. In fact the potential MRD 
negativity for patients can translate in longer survivals. The risks are derived mainly from infectious 
complications that can arise in MM patients.   
 
Subject completion/discontinuation of study treatment 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
20 
 
A subject will be considered to have completed the studt if he or she has finished all protocol-
specified procedures before the end of the study, has not been lost to follow up, and has not 
withdrawn consent for study partecipation before the end of the study 
 
Withdrawal of the study subject and treatment modifications 
Patients will be removed from protocol treatment for the following reasons: 
• 
disease progression  
                •        development of unacceptable toxicity 
        •    treatment delay more than four weeks or if three consecutive planned doses of                      
Daratumumab are missed for reasons other than toxicity 
• 
administration of any other anti-neoplastic medication or any other experimental 
drug 
• 
consent withdrawn 
• 
investigator decision in the best interest of the patient 
• 
pregnancy or insufficient contraception 
• 
loss to follow-up 
• 
death 
 
The time point of and reason for removal of a patient must be documented on the case report form. 
The investigator will attempt to complete all discharge procedures at the time a patient is 
discontinued from study treatment and to record further follow-up data, if required.  
 
Early termination or suspension of the study 
At any time, the sponsor/coordinating investigator of the study may terminate the trial participation 
of an individual patient, as well as the whole trial, provisionally or permanently, if this is required by 
stringent medical, administrative or legal reasons (including insufficient patient recruitment), 
especially if severe and/or frequent adverse events occur, requiring a new risk/benefit evaluation  
 
STUDY ENDPOINTS 
 
MRD negativity will be the primary endpoint  
Primary endpoint: MRD negativity will be measured at time 2, 6, 12, 18, 24 months by Flow 
cytometry on bone marrow aspirate. MRD negativity will be defined as absence of monoclonal 
plasma cells with a sensitivity of 1x105 cells analyzed by Euro flow protocols. 
Time point assessments: primary endpoints will be at 2,6,12,18 and 24 months. 
 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
21 
 
Secondary endpoints:.  Complete remission rate (CR), Duration of response (DoR) and  progression 
free survival (PFS). 
Time point assessments: primary endpoints will be at 2,6,12,18 and 24 months. 
 
 
 
STUDY ASSESSMENTS 
Study flowchart  
 
STUDY 
PARAMETERS 
pre-study 
day 
1 
of 
each cycle 
day 8, 15, 22 
of cycle 1-2 
Day 1 cycle 3-
4-5-6 
Response 
evaluatio
n 
after 
cycles 2 
and 
6 
(EoT) 
Follow-
up6 
 
Informed consent 
X1 
 
 
 
 
 
Medical history 
X1 
 
 
 
 
 
Physical exam 
X2 
X 
 
X 
X 
X 
Height, 
body 
weight 
X2 
X 
 
X 
X 
X 
Vital signs 
X2 
X 
X 
X 
X 
X 
Neurological exam 
X2 
 
 
 
X 
 
Performance status X2 
X 
 
X 
X 
X 
Pregnancy test4 
X1 
X 
 
X 
 
 
CBC/differential 
blood count7 
X2 
X 
X 
X 
X 
 
Serum 
chemistry, 
general8 
X2 
X 
 
X 
X 
 
Serum 
chemistry, 
myeloma-specific9 
X2 
X 
 
X 
X 
X 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
22 
 
Beta-2 
microglobulin 
X 
 
 
 
 
 
Urinalysis10 
X2 
X 
 
X 
X 
X 
Free light chains 
X 
X 
 
X 
X 
X 
Bone biopsy 
X3 
 
 
 
X 
X5 
BM aspiration 
X3 
 
 
 
X 
X6b 
FISH (opt.) At dx 
X 
 
 
 
 
 
Next 
Generation 
flow 
X3 
 
 
 
X 
X6b 
Toxicity/symptoms 
(NCI CTC, app. 3) 
X2 
X 
X 
X 
X 
X 
Concomitant 
medication 
X 
x 
X 
X 
X 
X 
Tumor assessment, 
incl. skeletal status  
X3 
 
 
 
X 
 
Chest X ray 
X3 
 
 
 
 
 
ECG  
X2 
 
 
 
 
 
Echocardiography 
X3 
 
 
 
 
 
PET/CT 
X 
 
 
 
X11 
X6b 
 
 
1. Within 14 days prior to the start of therapy. 
2. Within 7 days prior to the start of therapy. 
3. Within 21 days prior to the start of therapy. 
4. In case of women with childbearing potential. 
5. As clinically indicated. 
6. Every 3 months for two years (or until last dose of study treatment or confirmed 
disease progression) 
6b  Every 6 months for two years 
7. Hb, WBC, granulocytes, platelets 
8. Calcium, creatinine, uric acid, SGOT, SGPT, LDH, alk. phosphatase, total protein, albumin, blood sugar, 
CRP, VES 
9. M protein, immunelectrophoresis, immunoglobulins 
 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
23 
 
10. Urine electrophoresis (Bence-Jones protein), immunelectrophoresis, sugar  
     11.    If complete response after cycle 6 (End of Treatment) 
 
Screening phase 
Patient will be referred to study after obtaining at least VGPR to prior treatment. The following 
baseline assessments will be conducted or obtained within three weeks prior to start of study 
treatment unless otherwise indicated: 
 A condition from prior treatment of >VGPR/ CR-MRD positivity by NGF should be met. In 
particular: 
 >VGPR: Serum and urine M protein detectable by immunofixation but not on electrophoresis 
or  90% reduction in serum M protein plus urine M protein level <100mg per 24 h ; 
 CR/MRD positive by NGF: Negative immunofixation on the serum and urine and 
disappearance of any soft tissue plasmacytomas and 5% PCs in BM, positive flow by 8 colour 
analysis and >1 million BM cell analyzed 
 Signed written informed consent (within 14 days prior the start of therapy) 
 Complete medical history including dates and description of initial diagnosis of multiple 
myeloma, pre-treatment, ISS and Durie Salmon stage, FISH at diagnosis when available, 
documentation and measurement of tumor parameters and lesions, tumor related 
symptoms, relevant concurrent illnesses and relevant concomitant medication (within 14 
days prior the start of therapy) 
 .Physical examination including: weight, height, WHO performance status and complete 
neurological examination (within 7 days prior to treatment). 
 Vital signs: blood pressure, pulse rate and oral temperature within 7 days prior to treatment. 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
24 
 
 Residual toxicities from prior therapies should be recorded using the NCI Common Toxicity 
Criteria. 
 12 lead ECG. 
 Urine or serum HCG if patient is of childbearing potential. 
 Hematological tests: Complete blood count (CBC) including neutrophil and platelet count 
within 7 days prior to treatment. 
 General serum chemistry: Calcium, creatinine, uric acid, SGOT, SGPT, LDH, alk. phosphatase, 
total protein, albumin, blood sugar, CRP, VES 
 Myeloma-specific serum chemistry: M protein, immunelectrophoresis, immunoglobulins  
 Free Light Chains (FLC) 
 Urinalysis: Urine electrophoresis (Bence-Jone protein), immunelectrophoresis, sugar,  
 Bone marrow analysis : percentage of plasma cells, percentage of cellularity, Next generation 
flow (centralized  to Siena LAB) 
 Recent Skeletal status, recent chest X ray, echocardiography within four weeks prior to 
treatment 
 PET/CT within 4 weeks prior to treatment. 
The above tests and procedures are summarized in the Study Flow Sheet in section 6.1. 
Tumor response evaluation 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
25 
 
Tumor response will be assessed according to the “International uniform response criteria for 
multiple myeloma” issued in 2006 by the International Myeloma Working Group and the 
International Myeloma Foundationi. 
 
Time to best response 
Time to best response is defined as the time from treatment start to the first detection of the 
best response category according to Tab. 2, calculated for all patients, which are not primarily 
refractory. 
Progression-free survival 
Progression-free survival (PFS) will be defined as the time from the initial dose of chemotherapy to 
the time of disease progression (cf. Table 3) or death, or to the date of last assessment without any 
such event (censored observation). 
Time to progression 
This will be defined as the time from baseline to the development of progressive disease, as defined 
in Table 3. 
 
Overall survival 
The duration of survival will be determined by measuring the time interval from initial dose to the 
date of death or last observation (censored). 
 
DATA MANAGEMENT 
 
Data collection 
All patient-related data are recorded in a pseudonomized way. Each patient is unequivocally 
identified by a trial subject number, attributed at recruitment into the study. The investigator has to 
keep a patient identification log, including the full name and address of the subject and eventually 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
26 
 
additional relevant personal data such as hospital record number, home physician etc. In addition, 
patients who were screened in order to be entered into the study, but who could not be recruited 
for whatever reason (informed consent not given, not fulfilling selection criteria etc.) are recorded 
in a "patient reject log". 
All the data retrieved during the conduct of the study are entered into the appropriate case record 
forms (CRF) by the investigator or another person authorized by the investigator (co-investigator). 
The CRFs are provided by the study secretariat and are explained to the investigator by the study 
monitor.  
All recorded data have to be plausible and complete. Please respect the following technical details 
when using the CRFs: 
- 
Use black or blue ballpoint pens only in order to insure that all copies are legible. 
- 
Write only one letter or numeral into each of the open boxes of the respective data 
fields. Closed boxes have to be crossed only (check boxes). 
- 
All data fields have to be filled, except for those referring to open questions. If a 
specific test was not performed or an information item is definitely not available or 
applicable, information on this should be provided (not done= ND, not applicable, not 
available = NA, unknown= UK). 
- 
If a date is not known exactly, please fill in the respective field according to the 
following example: - - 08 05. 
- 
If any corrections have to be performed in the CRF by the investigator or co-
investigator, they have to be performed according to GCP principles, i.e. the original 
entry has to be crossed out but remain legible.  
- 
The correct version is then written legibly beside or above the original one.  
- 
The correction (or addition) has to be dated and signed or initialed. 
 
 
 
 
                  Version to be corrected: 
       corrected version: 
                                                                                                                             2 date, initials     
 
1 
2 
1 
3 
0 
3 
 
1 
2 
1 
3 
0 
3 
   day 
month year 
 
   day 
month year 
 
- 
Please write legibly and use printing letters 
The investigator is obliged to complete the case report forms within a reasonable time period after 
retrieval of the data (i.e. usually within 2 weeks). The completed forms are signed by the 
investigator, where necessary. The original has to be sent to the data management office or handed 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
27 
 
over to the monitor in case of on-site visits. A copy remains with the investigator. The study office or 
monitor checks the forms for completeness and plausibility. In case of queries, the form or a 
photocopy of it will be sent or given back to the investigator for clarification/correction/ completion. 
Queries have to be handled within 4 weeks. 
After finalization of the data checks by the study office/monitor the originals or fair copies are sent 
to the biostatistical center. If additional queries arise there during computer data entry, they are 
handled by the investigator via monitor or study office contacts. 
 
Data archiving 
The original forms of all relevant study documents including CRFs are stored at the office of the 
coordinating investigator/sponsor for at least 10 years after completion of the final study report. 
The investigators have to archive major administrative documents (correspondence with ethical 
committee, authorities, sponsor etc.), the patient identification log, the signed informed consent 
forms, and the main study documents (protocol,  amendments) for the same time period. The 
original patient records have to be archived according to the standard procedures of the respective 
institution, but at least for 10 years. 
 
 
STATISTICAL METHODS AND DATA ANALYSIS 
General design 
The present trial is designed as a phase II study that aims at estimating the activity of Daratumumab 
as consolidation therapy after initial therapy. The achievement on MRD negative status defined by 
next generation flow (NGF), divided by the total intent-to-treat patient number is chosen as primary 
activity endpoint. 
The estimation of the activity rate is to be based on an explorative pilot study, since immediate 
embarking on a large-scale comparative activity trial would not be acceptable from the point of view 
of resources. Moreover, this would induce ethical objections, as it does not seem to be justifiable to 
expose a large number of patients to an experimental approach without sufficient exploratory 
indications of an improved risk-benefit ratio. 
 
Sample size calculation  
The main objective of the trial is to assess, whether the experimental regimen shows a promising 
activity profile in treatment of MM minimal residual disease. The primary endpoint is the response 
rate.  

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
28 
 
Multiple myeloma patients achieving CR and MRD negativity after autotransplant are around  60% 
and 20% of the total, respectively. MM patients that achieve an MRD negative status after VMP 
(velcade , melphalan prednisone) are not known. Since CR achievement after VMP is 30%, MRD 
negativity is probably < 5% of the patients. Statistical analysis will be provided on 50 patients, 
assuming the power to show an increase in MRD negativity from 20% to at least 50% of the patients 
treated.  
In summary, the trial design is based on the following assumptions: 
The activity of the experimental therapy would be rated as insufficient, if the actual response rate 
was only 20% or lower. 
On the other hand, the regimen would be considered to be a promising candidate for further 
development (e.g. in a phase III trial), if the true ORR amounted to 50% or more. 
To show effectiveness of daratumumab to give a negative MRD; only descriptive statistics will be 
performed. 
Statistical Power Calculations:* 
This is a phase 2 interventionalopen-label, single arm study, thus no formal calculation of sample 
size and statistical power is necessary. This notwithstanding, a sample size of 50 patients produces a 
two-sided 95% confidence interval with a width equal to 16.6% when the sample proportion (eg, for 
percentage of patients with MRD negative at months 2) is 10%, equal to 25.4% when the sample 
proportion is 30%, and a maximum width equal to 27.7% when the sample proportion is 50%. This 
calculation was performed using PASS v.11 software (NCSS, LLC. Kaysville, Utah, USA). 
 
All parameters will be evaluated in an explorative or descriptive manner, providing means, medians, 
ranges, standard deviations and/or confidence intervals. If p values are calculated (e.g. in subgroup 
comparisons), they will be presented explicitly without referring to hypotheses or a significance 
level. Usually, no error adjustment for multiple testing will be performed. Thus the p values will 
reflect the comparison-wise error and not the experiment-wise error.  All p values will be two-sided 
if not stated otherwise. The statistical methods described in this section are suited for the data and 
distributions usually expected in this type of trials. The suitability will be checked after data entry. If 
necessary, the statistical method will be modified accordingly, with critical discussion of the original 
and modified results. 
Response, toxicity and event rates at pre-specified time points are calculated, providing confidence 
intervals. In case of comparison between patient groups, these rates will be analyzed by Fisher´s 
exact test, ² test or Mantel-Haenszel test (or trend test according to COCHRAN/ARMITAGE), 
respectively.  
Event related data like time to response, progression-free or overall survival will be estimated by the 
product limit methodii and compared using the log-rank test. If the Peto log-rank test is not 
appropriate because of violation of the proportional hazard assumptioniii, Gehan's generalization of 
the Wilcoxon rank sum test for censored data (GEHAN 1965) will be applied, preferably in its 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
29 
 
modification by PETO (1972) and PRENTICE (1978). If appropriate, prognostic strata will be taken 
into account (PETO, 1977). 
Multivariate analyses will eventually be performed by suitable regression models (logistic 
regression, proportional hazard regression model. 
 
The main biometrical evaluation of the study and the compilation of the statistical report as part of 
the integrated clinical/biometrical report will be performed two years after termination of patient 
recruitment as well as after completion and/or correction of all case report forms.  
 
 
SAFETY MANAGEMENT 
 
Definition 
An adverse event is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An adverse 
event does not necessarily have a causal relationship with the treatment. An adverse event 
can therefore be any unfavorable and unintended sign (including an abnormal finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational or 
non-investigational) product, whether or not related to that medicinal (investigational or 
non-investigational) product. (Definition per International Conference on Harmonisation 
[ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. 
Collection of adverse events starts with the signing of the ICF until the last study related 
procedure. A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance 
for Medicinal Products for Human Use is any untoward medical occurrence that at any 
dose: 
 Results in death 
 Is life-threatening 
(The subject was at risk of death at the time of the event. It 
does not refer to an event that hypothetically might have caused death if it were 
more severe.) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is a suspected transmission of any infectious agent via a medicinal product 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
30 
 
 Is Medically Important* 
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that 
may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should usually be considered serious. 
If a serious and unexpected adverse event occurs for which there is evidence suggesting a 
causal relationship between the study drug and the event (eg, death from anaphylaxis), the 
event must be reported as a serious and unexpected suspected adverse reaction even if it 
is a component of the study endpoint (eg, all-cause mortality).  
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For Daratumumab, the expectedness of 
an adverse event will be determined by whether or not it is listed in the Investigator's 
Brochure.  
Adverse Event Associated With the Use of the Drug 
An adverse event is considered associated with the use of the drug if the attribution is 
[possible, probable, or very likely] by the definitions listed in Section Attribution 
Definitions. 
Severity Criteria  
 
An assessment of severity grade will be made using the following general categorical 
descriptors: 
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and 
not interfering with everyday activities. 
Moderate: Sufficient discomfort is present to cause interference with normal activity. 
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities. 
The investigator should use clinical judgment in assessing the severity of events not 
directly experienced by the subject (eg, laboratory abnormalities). 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
31 
 
 
 
 
Adverse events recording 
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's 
last study-related procedure, which may include contact for follow-up of safety. Serious 
adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study drug, must be reported using the Serious Adverse Event Form. 
The sponsor will evaluate any safety information that is spontaneously reported by an 
investigator beyond the time frame specified in the protocol. 
All events that meet the definition of a serious adverse event will be reported as serious 
adverse events, regardless of whether they are protocol-specific assessments. Anticipated 
events will be recorded and reported as described in Safety Reference Information section.  
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
drug, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion 
should be reported as "upper respiratory infection"). Investigators must record in the CRF 
their opinion concerning the relationship of the adverse event to study therapy. All 
measures required for adverse event management should be recorded in the source 
document and reported according to sponsor instructions. 
The Sponsor-Investigator assumes responsibility for appropriate reporting of adverse 
events to the regulatory authorities. The sponsor-Investigator will also report to the 
investigators (and the head of the investigational institute where required) all suspected 
unexpected serious adverse reactions (SUSARs).  
Serious Adverse Events 
All serious adverse events occurring during the study must be reported to the appropriate 
Sponsor-Investigator contact person by study-site personnel within 24 hours of their 
knowledge of the event. 
Information regarding serious adverse events will be transmitted to the sponsor using the 
Serious Adverse Event Form, which must be completed and signed by a physician from the 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
32 
 
study site, and transmitted to the sponsor within 24 hours. The initial and follow-up 
reports of a serious adverse event should be made by facsimile (fax). 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, should be 
followed until any of the following occurs: 
 
The event resolves 
 
The event stabilizes 
 
The event returns to baseline, if a baseline value/status is available 
 
The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct 
 
It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of 
hospitalization) that occurs during the course of a subject's participation in a study must be 
reported as a serious adverse event, except hospitalizations for the following: 
 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social 
reasons such as pending placement in long-term care facility) 
 
Surgery or procedure planned before entry into the study (must be documented in 
the CRF). [Note: Hospitalizations that were planned before the signing of the ICF, and 
where the underlying condition for which the hospitalization was planned has not 
worsened, will not be considered serious adverse events. Any adverse event that results in 
a prolongation of the originally planned hospitalization is to be reported as a new serious 
adverse event.] 
 
For convenience the investigator may choose to hospitalize the subject for the 
duration of the treatment period.  
Disease progression should not be recorded as an adverse event or serious adverse event 
term; instead, signs and symptoms of clinical sequelae resulting from disease 
progression/lack of efficacy will be reported if they fulfill the serious adverse event 
definition (refer to Section Adverse Event Definitions and Classifications). 
Pregnancy  

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
33 
 
All initial reports of pregnancy in female subjects or partners of male subjects must be 
reported to the sponsor-investigator by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form. Abnormal 
pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered serious adverse events and must be 
reported using the Serious Adverse Event Form.  
Any subject who becomes pregnant during the study must be promptly withdrawn from 
the study.  
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported as noted above. 
Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
 
Causal link 
Not Related 
An adverse event that is not related to the use of the drug 
Doubtful 
An adverse event for which an alternative explanation is more likely, eg, concomitant 
drug(s), concomitant disease(s), or the relationship in time suggests that a causal 
relationship is unlikely. 
Possible 
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event that might be due to the use of the drug. The relationship in time is 
suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely, 
eg, concomitant drug(s), concomitant disease(s). 
Very Likely 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
34 
 
An adverse event that is listed as a possible adverse reaction and cannot be reasonably 
explained by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). 
The relationship in time is very suggestive (eg, it is confirmed by dechallenge and 
rechallenge). 
 
 
Adverse events reporting 
The names (and corresponding telephone numbers) of the individuals who should be 
contacted regarding safety issues or questions regarding the study are listed in the Contact 
Information page(s), which will be provided as a separate document. 
 
 
Anomalies in the laboratory parameters 
 
Please see IB 
 
ADMINISTRATIVE PROCEDURES 
 
Study financing 
The sponsor/coordinating investigator will take care of the financing/funding of the study. The 
funding is based partially from the pharmaceutical industry (Jansenn). 
 
Insurance coverage 
Insurance will be given by AOUS 
 
Indipendent data monitoring committee (IDMC) 
Since the study is a phase2 including 50 patients as total , IDMC is not required. 
 
General revision 
The study will be monitored externally by regular site visits, query letters and telephone calls to the 
investigator by authorized personnel of the principal investigator. Queries or monitoring visits may 
take place before, during and after recruitment of patients into the study. The number of contacts 
will depend on the characteristics of the respective center, e.g. the number of recruited patients. 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
35 
 
According to the investigator's agreement, the monitor is allowed to access the trial documentation 
and the patients' personal medical records in the participating center. 
In order to assure the quality of the data, all entries into the CRFs are formally inspected for 
completeness and plausibility. During site visits, an additional control with respect to identity of the 
data recorded in the personal patient records and in the CRF (Source Data Verification) may be 
performed. In addition, the monitor should review original patient records, drug accountability 
records and document retention (study file). Additionally, the monitor should observe study 
procedures and will discuss any problems with the investigator. 
 
 
Amendments to the protocol 
Any modifications to the protocol which may impact on the conduct of the study, potential benefit 
of the study, or may affect patient safety, including changes of study objectives, study design, 
patient population, sample sizes, study procedures, or significant administrative aspects will require 
a formal amendment to the protocol. Such amendment will be agreed upon by the investigators and 
the sponsor. It requires a new application to the competent authority and to the competent ethical 
committee prior to implementation, according to EC regulations. 
Administrative or technical changes of the protocol such as minor corrections and/or clarifications 
that have no effect on the way the study is to be conducted, nor on the risk-benefit-ratio, will be 
agreed upon by the sponsor and the investigator(s) and will be documented in a memorandum to 
the protocol. The competent ethical committee may be notified of such changes at the discretion of 
the sponsor/coordinating investigator. 
 
The sponsor/coordinating investigator has to assure, that all amendments have been added to the 
study documents at any site involved in the trial. 
 
 
Ethical considerations 
The study will be conducted according to the principles of Good Clinical Practise (GCP) as reported 
in current Italian and European legislation and in agreement with the last revision of the declaration 
of Helsinki and current the Italians laws and regulations. Patients will be enrolled only after giving a 
free written informed consent (see attach). The patient’s confidentiality will be maintained and will 
not be made publicly available to the extent permitted by the applicable laws and regulations 
(Decreto Legislativo 30/6/2003 n. 196 e successive modificazioni). Each participating Hematology 
Unit must submit the study protocol to local Ethics Committee/IRB for approval. 
 
Acquisition of the informed consent  

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
36 
 
Before recruitment into the clinical trial each patient will be informed, that participation in the study 
is completely voluntary, and that he or she may withdraw the participation in the trial at any time 
without any declaration of reasons. This will not lead to any disadvantage for the respective patient. 
If the withdrawal is caused by any adverse drug events, the patient should inform the investigator 
about this fact. 
The treating physician will inform the patient about the drugs to be used and their possible adverse 
effects. At the same time he/she will be informed on the nature and objectives of the study, 
expected advantages of the participation, possible hazards of the study and alternatives of 
treatment. The patient will also receive the necessary information on the trial specific insurance and 
his obligations with this respect. The patient will have sufficient time for his decision and 
opportunity to ask additional questions. Moreover, the patient will receive a written “patient 
information”, containing all relevant information for the patient's decision and the course of the 
study. Information about all biological sampling during the study will be given. 
The consent of the patient to participate must be obtained in writing before recruitment into the 
study. The informed consent form must be dated and signed by the patient. Thereby, he declares his 
voluntary consent to participate in the study and his willingness to comply with the requirements of 
the trial and the instructions of the treating investigator during the course of the study. 
There are two copies of the informed consent form: one for the patient and one to be kept by the 
investigator in his study documents. The informed consent is only valid after receiving the patient's 
signature. Thereafter, the patient can be entered into the study if he/she fulfils the selection 
criteria. 
With the declaration of consent the patient agrees that data on his disease are recorded within the 
framework of the clinical trial and that they are transferred to the sponsor in a pseudonymized way. 
Moreover, the patient agrees that delegates from the responsible authorities or the sponsor may 
have direct access to his/her original medical records for trial related monitoring, audit, review and 
regulatory inspection. 
 
Confidentiality 
All Investigators in the study will maintain confidentiality about all data coming from the trial , 
personal data regarding patients involved before, during and after trial. 
 
Conflicts of interest 
No conflicts of interest are present by investigators. 
 
RESPONSABILITY AND PUBLICATION POLICY 
 
No Profit Promoter  

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
37 
 
The promotor of the study is a no profit public institution (UOC Ematologia, Azienda Ospedaliera 
Universitaria Senese) 
 
 
Data properties 
 
All data produced are property of study Promoter. Each participating center will send all requested 
patients data to the study promoter (in anonymous form); after publication of experimental results, 
collected data (always in anonymous form) may be transferred also to Countries outside UE.  
 
Publication  
 
The promoter only will decide how and when to publish the results of the research.  
 
 Other financing 
 
Even if private subjects will contribute with additional funds to the project, this would not give any 
right of data property to the private subject or right of veto for data publication. 
Bibliography 
 
1) Kyle RA, Rajkumar SV. Multiple Myeloma. Blood (2008) 11: 2962-72.doi: 10.1182/blood-
2007-10-078022. 
2) Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of 
younger patients with multiple myeloma. Blood  (2008) 111: 2521–6. 
3) Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK et al. Improved 
survival in multiple myeloma and the impact of novel therapies. Blood (2008) 111:2516–
20. 
4) Gozzetti A, Cerase A, Lotti F, Rossi D, Palumbo A, Petrucci MT, et al. GIMEMA (Gruppo 
Italiano Malattie Ematologiche dell'Adulto) Myeloma Working Party Extramedullary 
intracranial  localizations of multiple myeloma and treatment with novel agents: a 
retrospective survey of 50 patients. Cancer (2012) 118:1574-84. doi: 10.1002/cncr.26447 
5) Ocio EM, Richardson PG, Rajkumar SV, Palumbo A, Mateos MV, Orlowski R, et al. New 
drugs and novel mechanisms of action in multiple myeloma 2013: a report from the 
International Myeloma Working group (IMWG). Leukemia (2014) 28:525-42. doi: 
10.1038/leu.2013.350. 
6) Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA, et al. Clinical and biologic 
implications of recurrent genomic aberrations in myeloma. Blood (2003) 101: 4569-75. 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
38 
 
7) Gozzetti A, Le Beau MM. Fluorescence in situ hybridization: uses and limitations. Semin 
Hematol (2000) 37:320-33. 
8) Stewart AK, Richardson PG, San-Miguel JF. How I treat multiple myeloma in younger 
patients. Blood (2009) 114:5436–43. doi: 10.1182/blood-2009-07-204651. 
9) Moreau P, Avet-Loiseau H, Harousseau JL, Attal M. Current trends in autologous stem-cell 
transplantation for myeloma in the era of novel therapies. J Clin Oncol (2011) 29: 1898–
906. doi: 10.1200/JCO.2010.32.5878. 
10) Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, et al. Bortezomib 
plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as 
induction treatment prior to autologous stem-cell transplantation in newly diagnosed 
multiple myeloma: results of the IFM 2005–01 phase III trial. J Clin Oncol (2010) 28: 
4621–9. doi: 10.1200/JCO.2009.27.9158. 
11) Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M et al. Bortezomib with 
thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as 
induction therapy before, and consolidation therapy after, double autologous stem-cell 
transplantation in newly diagnosed multiple myeloma: a randomized phase 3 study. 
Lancet (2010) 376: 2075–85. doi: 10.1016/S0140-6736 (10) 61424-9. 
12)  Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J,et al. 
Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction 
pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM 
study. Blood (2012) 120: 1589–96. 
13) Sonneveld P, Schmidt-Wolf IGH, van der Holt B, El Jarari L, Bertsch U, Salwender H, et al. 
Bortezomib induction and maintenance treatment in patients with newly diagnosed 
multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J 
Clin Oncol (2012) 30:2946–55. doi: 10.1200/JCO.2011.39.6820. 
14) Reeder CB, Reece DE, Kukreti V, et al. Chen C, Trudel S, Laumann K, Once versus twice 
weekkly bortezomib indusction therapy with CyBordD in newly diagnosed multiple 
myeloma. Blood (2012) 115:3416-7. doi: 10.1182/blood-2010-02-271676. 
15) Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. 
Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with 
newly diagnosed multiple myeloma. Blood (2010) 116:679–86. doi: 10.1182/blood-2010-
02-268862 
16) Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ,et al. Randomized, 
multicenter, 
phase 
2 
study 
(EVOLUTION) 
of 
combinations 
of 
bortezomib, 
dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple 
myeloma. Blood (2012) 119:4375–82. doi: 10.1182/blood-2011-11-390658. 
17) Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, et al. A phase 
1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
39 
 
as a frontline treatment for multiple myeloma. Blood (2012) 120:1801–9. doi: 
10.1182/blood-2012-04-422683 
18) Sonneveld P, Asselbergs E, Zweegman Carfilzomib combined with thalidomide and 
dexamethasone (CTD) is a highly effective induction and consolidation treatment in 
newly diagnosed patients with multiple myeloma who are transplant candidates. Blood 
(ASH Annual Meeting Abstracts) (2012) 120: 333.  
19) Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L, et al. Major tumor 
shrinking and persistent molecular remissions after consolidation with bortezomib, 
thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol 
(2010) 28:2077–84. doi: 10.1200/JCO.2009.23.7172 
20) Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D,et al. Bortezomib-
thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation 
therapy following hematopoietic stem cell transplantation in patients with newly 
diagnosed multiple myeloma. Blood (2012) 120: 9–19. doi: 10.1182/blood-2012-02-
408898. 
21) Mateos MV, San Miguel JF. How should we treat newly diagnosed multiple myeloma 
patient? Hematology Am Soc Hematol Educ Program. (2013) 2013:488-95. doi: 
10.1182/asheducation-2013.1.488. 
22) Cerrato C, Palumbo A. Initial treatment of nontransplant patients with multiple myeloma. 
Semin Oncol. (2013) 40:577-84. doi: 10.1053/j.seminoncol.2013.07.003. 
23) Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic 
comorbidity in longitudinal studies: development and validation. J Chronic Dis. (1987) 
40:373-83. 
24) Gay F, Larocca A, Wijermans P, Cavallo F, Rossi D, Schaafsma R, et al. Complete response 
correlates with long-term progression-free and overall survival in elderly myeloma 
treated with novel agents: analysis of 1175 patients. Blood (2011) 117: 3025-31. doi: 
10.1182/blood-2010-09-307645. 
25) Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. Melphalan and 
prednisone plus thalidomide versus melphalan and prednisone alone or reduced-
intensity autologous stem cell transplantation in elderly patients with multiple myeloma 
(IFM 99-06): a randomized trial. Lancet (2007) 370 :1209-18. 
26) Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, et al. Oral melphalan 
and prednisone chemotherapy plus thalidomide compared with melphalan and 
prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. 
Lancet (2006) 367:825-31. 
 
27) Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V,et al. Oral melphalan, 
prednisone, and thalidomide in elderly patients with multiple myeloma: updated results 
of a randomized controlled trial. Blood. (2008) 112: 3107-14. doi: 10.1182/blood-2008-
04-149427 

 
 
 UOC HEMATOLOGY – Director Prof Monica Bocchia 
 
 
 
Protocol version 1.1, 6 December2018 
A Pilot study on the efficacy of Daratumumab in Multiple Myeloma (MM) patients in >VGPR/MRD-positive by next 
generation flow (NGF) 
40 
 
28) Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige Het al. 
Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly 
patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol 
(2010) 28: 3160-6. doi: 10.1200/JCO.2009.26.1610 
29) Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C et al. Efficacy of melphalan 
and prednisone plus thalidomide in patients older than 75 years with newly diagnosed 
multiple myeloma: IFM 01/01 trial. J Clin Oncol (2009) 27:3664-70. doi: 
10.1200/JCO.2008.21.0948 
30) Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, et al. Melphalan 
and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. 
Blood. (2010) 116:1405-12. doi: 10.1182/blood-2009-08-237974. 
31) Beksac M, Haznedar R, Firatli-Tuglular T, Ozdogu H, Aydogdu I, Konuk N,et al. Addition of 
thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible 
for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. 
Eur J Haematol (2011)86:16-22. doi: 10.1111/j.1600-0609.2010.01524.x. 
32) Fayers PM, Palumbo A, Hulin C, Waage A, Wijermans P, Beksaç M et al. Thalidomide for 
previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 
individual patient data from 6 randomized clinical trials. Blood (2011) 118:1239-47. doi: 
10.1182/blood-2011-03-341669. 
33) Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, et al. 
Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients 
with multiple myeloma unsuitable for autologous transplantation. Blood (2011) 118: 
1231–8. doi: 10.1182/blood-2011-02-338665. 
34) San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. 
Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N 
Engl J Med. (2008) 359:906–17. doi: 10.1056/NEJMoa0801479. 
35) Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S,et al. Efficacy and 
safety of once-weekly bortezomib in multiple myeloma patients. Blood (2010) 116:4745–
53. doi: 10.1182/blood-2010-07-294983. 
36.   Palumbo et all. N Engl J Med 2016;375:754-66 
                                                     
i 
ii 
 
iii