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