Multiple Myeloma Stage I Clinical Trial
Official title:
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.
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Active, not recruiting |
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Rivaroxaban or Aspirin As Thromboprophylaxis in Multiple Myeloma
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Phase 2/Phase 3 | |
| Terminated |
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Therapy With Zoledronic Acid in Patients With Multiple Myeloma Stage I
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Phase 3 |