Study of Daratumumab in Multiple Myeloma (MM) Patients in >VGPR/MRD-positive
Study of Daratumumab in Multiple Myeloma (MM) Patients in >VGPR/MRD-positive
Aim of this study is to evaluate Daratumumab effect on MRD-positive patients with Multiple
 Myeloma (MM) who achieved >VGPR after any therapy (ASCT, VMP, Rev-Dex). Daratumumab 16 mg/kg
 administered at weekly intervals for 8 weeks, then 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. If
 MRD negative by NGF, the patients can stop the treatment.
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.

 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). Daratumumab monotherapy can increase response and in particular MRD
 negativity, which correlates with PFS and OS. To the investigator's 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.

 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 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.

 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. 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 AE 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.
Inclusion Criteria:

 -  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

 -  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:

 -  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