Study of Daratumumab in Multiple Myeloma (MM) Patients in >VGPR/MRD-positive (DART4MM)

A Pilot Study on the Efficacy of Daratumumab in Multiple Myeloma (MM) Patients in >VGPR/MRD-positive by Next Generation Flow

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.

Patients will receive Daratumumab (16 mg/Kg day) every week for 8 weeks intravenous (8 infusions) and then every 2 weeks for 16 weeks intravenous (8 more infusions). If MRD positive by NGF, the patients will receive Daratumumab every 4 weeks for 80 weeks intravenous; if MRD negative by NGF, the patients can stop the treatment.

Patients will receive Daratumumab (16 mg/Kg day) every week for 8 weeks intravenous (8 infusions) and then every 2 weeks for 16 weeks intravenous (8 more infusions). If MRD positive by NGF, the patients will receive Daratumumab every 4 weeks for 80 weeks intravenous; if MRD negative by NGF, the patients can stop the treatment.

Daratumumab is a human monoclonal antibody (mAb) IgG1 that binds to the highly expressed CD38 protein on the surface of multiple myeloma cells and, at various levels, also in other types of cells and tissues. The CD38 protein has multiple functions, such as receptor-mediated adhesion, signal transduction activity and enzymatic activity.

The fraction of patients who experience a Minimal Residual Disease (MRD) negativity per IMWG 2016 criteria

PFS determined using the Kaplan-Meier method, considering those who progress or die without progression as failures, and censoring those who do not

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

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