Daratumumab Intensified Treatment to Eligible MM New Patients CTD-Dara Induction, Follow by Dara Consolidation (MAXDARA)

Daratumumab Intensified Treatment to Eligible MM New Patients CTD-Dara Induction, Follow by Dara Consolidation

A Conceptual Study of Daratumumab Intensified Treatment to Eligible Multiple Myeloma New Patients- Cyclophosphamide, Thalidomide, Dexamethasone and Daratumumab Induction, Follow by Daratumumab Consolidation and Maintenance

The best induction protocol to eligible multiple myeloma patients was not established. Combination of three drugs demonstrated better outcomes than two drugs combo. Nevertheless, until now four drugs combo did not prove gain against three drugs One of the three drugs protocol studied as induction was CTD scheme (cyclophosphamide+ thalidomide+dexamethasone). Daratumumab has a novel mechanism of action that results in enhanced activity in combination with existing standards of care, including first-generation novel agents, such as thalidomide, as well as other therapeutics. Considerable responses have been observed in a cohort of heavily pretreated patients with relapsed/refractory MM. The use of a treatment combination with monoclonal antibody associated with immunomodulator (in a four drug combo) can lead to a improvement in response rates and in survival, reflects on a better free time interval. This trial will represent a new option of treatment with a combination of anti CD38 monoclonal antibody (DARATUMUMAB) as induction regimen with CTD protocol (four drug combination). And It use as consolidation and maintenance to give better immunomodulatory response and extended survival and disease control.

Multiple Myeloma (MM) is a molecularly heterogeneous disease with a high degree of genomic instability. Despite improvements in event-free survival and overall survival with the use of autologous stem cell transplantation and novel agents, MM remains an incurable disease (1,2). The best induction protocol to eligible patients was not established. Combination of three drugs demonstrated better outcomes than two drugs combo. Nevertheless, until now four drugs combo did not prove gain against three drugs One of the three drugs protocol studied as induction was CTD scheme (cyclophosphamide+ thalidomide+dexamethasone) (3). This is an induction protocol commonly used in Brazil , with largely access in the brazilian public health system. Several new molecules have been developed in an attempt to improve treatment. One of these new treatment is an anti CD38 (Daratumumab). This potential target is present on plasma cells. The CD38 is a transmembrane glycoprotein recognized by combining several functions including adhesion, receptor and enzymatic function. (4-6) The expression of CD38 is finely regulated during ontogenesis of B cells and is expressed by progenitors and early stages hematopoietic cells with loss during maturation and only re- expressed during cellular activation .(4) With the information derived from tissue distribution and from pioneer experience in vitro indicates that very early precursors of the hematopoietic stem cells do not express CD38.(7) Despite the description of CD38 on progenitor cells, there was no myelosuppressive effect observed in studies to date. Apart from immune cells, the molecule CD38 has also been found in the brain, pancreatic acinar cells, smooth muscle and osteoclasts although expression in these tissues is in the cytosol or nucleus rather than the cell membrane. (8). Daratumumab has shown a strong signal in preclinical modeling with broad-spectrum killing activity through complement-mediated cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and ADC phagocytosis . (9) Daratumumab was first evaluated clinically in a phase I trial involving patients with relapsed/refractory multiple myeloma (10). In combination with others agents (lenalidomide + dexamethasone) preliminary analysis involving 20 patients, the rate of partial response or better was 75% with 3 patients achieving complete response and 6 patients a very good partial response (VGPR). The most common adverse reactions were infusion- related events (IREs) such as fever, cough, nausea, dizziness, and bronchospasm. A total of 9% occurred during predosing and 26% during the first full infusion with a gradual decrease with subsequent infusions. The onset of IREs was within 3-4 hours of infusion. Prophylactic steroids were administered to reduce the incidence of IREs (up to a maximum dose equivalent of 27 mg of dexamethasone per week). There were six serious adverse events (SAEs) related to daratumumab. Treatment-related adverse events included anemia, thrombocytopenia, and infusion reactions. All patients recovered from their SAEs with treatment and the maximum tolerated dose has not yet been reached. There was a dose-dependent decrease in peripheral-blood NK cells that was noted, with full recovery after treatment (11). Daratumumab has a novel mechanism of action that results in enhanced activity in combination with existing standards of care, including first-generation novel agents, such as thalidomide, as well as other therapeutics. Considerable responses have been observed in a cohort of heavily pretreated patients with relapsed/refractory MM. (12) However, in order to harness the full potential of the antimyeloma effect of daratumumab, the identification of synergistic drug combinations that target various mechanisms to overcome drug resistance will be vital. The potential role of cytotoxicity induced by the anti-CD38 antibody and the activation of effector cells with the immunomodulatory drugs could make this a very attractive antimyeloma combination therapy. Thalidomide, an oral immunomodulatory drug (IMID), has revolutionized clinical management of patients with MM with responses rates of 30% at relapse (alone) and higher rates at first line and at relapse when in combinations (50-65%) . The mechanism of action of thalidomide in myeloma cells remains under investigation. Thalidomide was found to potently inhibit the proliferation of endothelial cells and angiogenesis. Thalidomide has direct cytotoxic effects on myeloma cells lines. In addition to its direct effect, IMIDs appear to modulate the bone marrow microenvironment. They can inhibit the up regulation of IL-6, necrose factor-α production and Vascular Endothelial Growth Factor (VEGF). It has a direct effect on the T-lymphocytes stimulating cytotoxic T cell proliferation, and induction of secretion of interferon γ and IL-2. The authors mentioned that as thalidomide does not show haematological toxicity, it may be used in advance disease when the platelet count is low . Thalidomide and the iMIDs have been used in combination with other chemotherapeutic agents with known and investigational activity in myeloma in several clinical trials. In vitro studies have suggested synergy between these agents and dexamethasone. The use of a treatment combination with monoclonal antibody associated with immunomodulator (in a four drug combo) can lead to a improvement in response rates and in survival, reflects on a better free time interval. Another interesting point is the use of Daratumumab intensified during consolidation and maintenance. This trial will represent a new option of treatment with a combination of anti CD38 monoclonal antibody (Daratumumab) as induction regimen with CTD protocol (four drug combination). And It use as consolidation and maintenance to give better immunomodulatory response and extended survival and disease control.

Eligible patients will be enrolled and treated according to the following elicited schema: Cyclo Thal Dex- Daratumumab (cyclophosphamide 500mg D1-8-15 + thalidomide 100-200mg D1-28 + dexamethasone 40mg/week (28 days cycle)- 4 cycles. ) + Daratumumab 16mg/Kg every week on cycles 1 and 2 and every other week at cycles 3 and 4- (total of 12 doses). Then Daratumumab 16mg/Kg after D+30, every other week as pre consolidation until starts full consolidation D+90-120 every other week (total of 4 doses) + thal100mg D1-28 during sixteen weeks as full consolidation. Follow by Daratumumab 16mg/Kg once a month as maintenance until progression or limiting adverse event (total of 28 planning doses). Total scheme Daratumumab doses= 50 doses = PROTOCOL MAXDARA.

Evaluate response rate as defined by the International Myeloma Working Group) IMWG- Minimal residual Disease (MRD), stringent complete Response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), and minimal response (MR) in patients treated with this protocol.

Evaluate duration of response in patients treated with Daratumumab Cyclophosphamide thalidomide and dexamethasone treatment

Evaluate the specific moment of time of partial response observed after Daratumumab Cyclophosphamide thalidomide and dexamethasone treatment

Number of bone and extra bone marrow disease observed by PET CT image at diagnosis and after consolidation therapy by International Myeloma Working Group recommendations

Measurement of neutrophil number in peripheral blood sample to evaluate the time of bone marrow engraftment

Time to Disease Progression (TTP). The TTP is defined as time from date of randomization to date of first documented evidence of PD, as defined by IMWG criteria

Progression-Free Survival (PFS) and PFS on Next Line of Therapy (PFS2).The PFS2 is defined as time from randomization to progression on next line of treatment or death, whichever occur first. Disease progression will be based on IMWG guide

The MRD assessment will be done by flow cytometry in bone marrow aspirate and in stem cell collected pack of participants four pre specified times- after induction, after ASCT, after consolidation and 1 year of maintenance

Peripheral blood lymphocytes analysis will be done by Flow cytometry in spite of look at T and B population. The analysis will be performing at the same time as MRD

Time To Next treatment. Time to next treatment is defined as the time from randomization to the start of next-line treatment.

Duration of Response (DR). The DR is time from date of initial documentation of response (PR or better) to date of first documented PD, as defined by IMWG criteria

Overall Survival (OS). The OS is the time from date of randomization to date of participant's death or follow- up lost

Inclusion Criteria: Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 Participants who are newly diagnosed considered for high-dose chemotherapy due to: being age <=65 years; without presence of important comorbidity condition(s) likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation. Committee review and approval of participants is required before inclusion Women of childbearing potential must commit to either abstain continuously from sexual intercourse or to use 2 methods of reliable birth control simultaneously as deemed appropriate by the Investigator. Contraception must begin 4 weeks prior to dosing and must continue for 4 months after the last dose of DARATUMUMAB Man, who is sexually active with a woman of child-bearing potential potential must agree to use a latex or synthetic condom, even if he had a successful vasectomy, must agree to use an adequate contraception method as deemed appropriate by the Investigator, and must also agree to not donate sperm during the study and for four weeks after last dose of thalidomide and DARATUMUMB Participants with known or suspected COPD or asthma must have a FEV1 test during Screening Exclusion Criteria: Participant has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance (presence of serum M-protein <3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein), or smoldering multiple myeloma (asymptomatic multiple myeloma with absence of related organ or tissue impairment end organ damage, and absence of biomarkers activity) Participant has a diagnosis of Waldenström's disease, or other conditions in which IgM M protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions Participant has a history of malignancy (other than multiple myeloma) within 5 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the Investigator, with concurrence with the medical monitor, is considered cured with minimal risk of recurrence within 5 years) Participant has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids 30 days before treatment Participant has had radiation therapy within 14 days of randomization Participant has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume in 1 second [FEV1] <50% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (controlled intermittent asthma or controlled mild persistent asthma is allowed) Participants with heart block defined by electrocardiogram or not treated arrhythmia Participant is known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C or Chagas disease positivity with cardiac involvement Key exclusion criteria: Patient has malignancy , 3 years of first dose of study treatment (except basal or squamous cell carcinoma or in situ cancer of the cervix) Patients has not recovered from all therapy-related toxicities , grade 2 CTCAE; patients has undergone major surgery < 2 weeks prior to starting drug All patients must agree to follow the regional requirements for Thalidomide counseling, pregnancy testing and birth control. For women of childbearing potential (WOCBP) this includes pregnancy testing prior to prescribing thalidomide and to either commit to continued abstinence from heterosexual intercourse or begin acceptable methods of birth control for 28 days prior to prescribing thalidomide, during therapy and for 28 days after the last dose of thalidomide. WOCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a WOCBP even if they have had a successful vasectomy and must agree not to donate semen during study drug therapy and for a period of time after therapy. All patients must abstain from donating blood, agree not to share thalidomide with others and be counseled about the risks of thalidomide

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