A single agent for multiple myeloma in patients who previously received at least 3 lines of therapy.
Darzalex trade name.
Approved in combination with bortezomib, melphalan, and prednisone to treat patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
The daratumamab, the anti-CD38 antibody, has been approved as a single agent for heavily relapsed/refractory patients, was approved in combination with lenalidomide or bortezomib for patients with 1 to 3 prior lines of therapy, with pomalidomide in more heavily pretreated, and just recently in combination with bortezomib, melphalan, prednisone for newly diagnosed patients.
A human IgG-kappa monoclonal antibody that targets CD38 on surface of malignant plasma cells.
It exerts its effect through antibody dependent cell mediated cytotoxicity, and induction of aptosis.
It has a pivotal role treatment of plasma cell disorders, and is associated with improved outcomes when added to standard backbones for myeloma and light chain amyloidosis
Approval of daratumumab was based on findings from phase 3 of the ALCYONE study showing patients who received treatment with daratumumab experienced a lower risk of disease progression and higher rates of response.
In the above study, 706 patients were randomly assigned to the control group (bortezomib, melphalan, and prednisone) or the daratumumab group (bortezomib, melphalan, and prednisone, plus daratumumab): The study found that the 18-month progression-free survival rate was 71.6% among patients who took daratumumab, compared with 50.2% among patients in the control group, who received bortezomib, melphalan, and prednisone alone.
The study also found a better overall response rate (90.9% with daratumumab vs 73.9% in the control group) and a better rate of complete response (42.6% vs 24.4%).
The most common grade 3 or 4 adverse events were neutropenia (39.9% in daratumumab group and 38.7% in control group), thrombocytopenia (34.4% and 37.6%), and anemia (15.9% and 19.8%).
Combination therapy with daratumumab results in deep and durable responses in newly diagnosed patients with multiple myeloma who are transplant ineligible.
Approved as a single agent for multiple myeloma in patients who previously received at least 3 lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or in patients who are double-refractory to a PI and an immunomodulatory agent.
Approved in combination with pomalidomide and dexamethasone for the third line treatment of patients with myeloma who receive prior therapy with lenalidomide and proteosome inhibitors.
The addition to bortezomib, melphalan and prednisone (VMP) reduced the risk of progression or death compared to VMP alone for newly diagnosided myeloma patients (ALCYONE Trial).
The drug is the first monoclonal antibody to be approved for multiple myeloma therapy.
A human IgG1 antibody that targets the CD-38 transmembrane protein expressed abundantly on malignant plasma cells.
Binds CD 38-expressed in malignant cells with high affinity and induces tumor cell death through diverse mechanisms including complement dependent cytotoxicity, antibody-dependent cell mediated cytotoxicity, anti-body dependent cellular phagocytosis, and induction of apoptosis.
Mechanism to kill CD38 expressed tumor cells by complement dependent cytotoxicity and antibody dependent cellular cytotoxicity.
Causes apoptosis.
The target of CD38 and serves as an antigen, also functions as an enzyme, helping to metabolize nicotinic acid adenine dincucleotide phosphate and cyclic adenosine diphosphate-ribose, both of which help to control intracellular calcium levels.
A treatment option for patients with multiple myeloma who have become resistant to other therapies.
Approval followed a multi-center, open-label study analyzing response rates in 106 patients with relapsed or refractory multiple myeloma administered Daratumumab:
Patients had an objective response rate of 29% with a median response duration of 7.4 months (range: 1.2 to 13.1+ months).
Demonstrted a 65% 1 year overall survival
The recommended dose and schedule for is 16 mg/kg IV once per week for 8 weeks, then once bi-weekly for 16 weeks, then once every 4 weeks until disease progression.
The FDA has approved a split-dosing regimen for patients with multiple myeloma, providing physicians the option to split the first infusion of the CD38-directed monoclonal antibody over 2 consecutive days or complete in a single session.
The approval is based on findings from the phase Ib EQUULEUS (MMY1001) trial, which demonstrated that the pharmacokinetic concentrations of daratumumab at 16 mg/kg were comparable at the end of weekly dosing, regardless of whether it was a split-dose or a single infusion.
The most commonly reported side effects were infusion reactions, fatigue, nausea, back pain, pyrexia, cough, and upper respiratory tract infection.
Can interfere blood bank crossmatching, specifically with Indirect Antiglobulin Tests.
Combining this drug with lenalidomide and dexamethasone reduces the risk of progressive disease by 63% in patients with relapsed/refractory multiple myeloma.
A combination of Daratumumab, lenalidomide and dexamethasone may represent a new standard of care for relapsed or refractory myeloma patients with at least one prior treatment.
A combination of carfilozomib, daratumumab and dexamethasone is highly effective for relapsed to refractory multiple myeloma, especially in patients exposed or refractory to lenalidomide.
Approved in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received ?2 prior therapies including lenalidomide and a proteasome inhibitor (PI).
CASSIOPEIA is an open-label, randomized phase 3 trial that evaluated the addition of daratumumab to the 3-drug regimen of bortezomib, thalidomide, and dexamethasone in 1085 transplant-eligible patients with myeloma: At 100 days after consolidation with autologous stem cell transplant (ASCT), the stringent complete response (sCR) rate was 29% in the Dara-VTd group vs 20% in the VTd group.
After consolidation, more patients receiving Dara-VTd achieved a very good partial response (VGPR) or better (83.4% vs 78%) and measur- able residual disease (MRD) negativity 64% vs 44%.
The GRIFFIN trial evaluated the addition of daratumumab to the standard-of-care regimen lenalidomide, bortezomib, and dexamethasone in 207 transplant-eligible patients.
More patients achieved a CR and MRD negativity with the addition of daratumumab than with standard- of-care treatment alone.
Single-agent daratumumab shows significant activity in smoldering multiple myeloma (SMM).
The 12-month progression-free survival (PFS) rate with a long dosing schedule of daratumumab was 95%, and the median PFS was not yet reached in any of the 3 dosing schedules studied.
The phase 2 clinical trial CENTAURUS support a long dosing schedule of 16 mg/kg intravenously in 8-week cycles from the phase 3 study, AQUILA.
In the international, multi-arm, open-label, nonrandomized EQUULEUS trial investigators evaluated daratumumab in combination with carfilzomib (Kyprolis) and dexamethasone in patients with relapsed/refractory multiple myeloma: Findings also showed that the split and single daratumumab doses have similar pharmacokinetic profiles.
In a randomized trial for Relapsed/ Refractory Multiple Myeloma either daratumamab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone: there was a higher response rate in the daratumamab arm versus RD with 79% of patients showing a very good partial or better response with DRD compared to 53% for RD, and a complete remission rate of 48% with DRD versus 25% for RD.
The median progression free survival was 31.9 months for RD, and not reached for DRD.
There was increased neutropenia and leukopenia, as well as some increased risk of pneumonia with the DRD arm.
Adding daratumamab does seem to improve both depth of response, as well as progression-free survival.
The addition of Daratumumab to bortezomib, dexamethasone, and lenaliomide consistently induced deeper responsesand higher visit minimal residual disease negativity.
With an overall response rate of 98%, more than 69% getting good partial response or better.
In the GRIFFIN trial the addition of CD 38 antibody Daratumumab to bortezomib/lenalidomide/dexamethasone (Dara-VRd) andlenalidomide maintenance produced more and deeper responses: after two years of maintenance 64% of patients withDara-VRd were minimal residual disease negative compared with 30% who receive VRd with a 44% reduction in disease progression.
Daratumumab was administered intravenously (IV) as a single first dose of 16 mg/kg or as a split first dose of 8 mg/kg on days 1 and 2 of cycle 1.
Monteleukast administration decreases infusion reactions.
Darzalex is supplied as 100mg/5mL and 400mg/20mL strength solutions for intravenous (IV) infusion after dilution.
Subcutaneous daratumumab demonstrates noninferiority to intravenous (IV) daratumumab for the treatment of relapsed or refractory multiple myeloma (MM), according to efficacy and pharmacokinetic results from the ongoing phase 3 COLUMBA trial.
Daratumumab that targets CD 38, depletes plasma cells and in SLE is utilized against long-lived plasma cells.
The subcutaneous formulation with hyaluronidase is approved and is administered by injection into the abdomen over 3-5 minutes.
Daratumumab plus hyaluronidase combined with bortezomib, cyclophosphamide, and dexamethasone (VCd) for the treatment of patients with newly diagnosed light chain (AL) amyloidosis.
ANDROMEDA clinical trial. In this study, 388 patients with newly-diagnosed AL amyloidosis, measurable disease, and at least 1 affected organ according to consensus criteria were randomized to receive VCd or D-VCd.
Findings demonstrated hematologic complete response rates of 42.1% and 13.5% for the D-VCd and VCd arms, respectively.
The most common (20%) adverse events among recipients of the D-VCd regimen:
respiratory tract infection, diarrhea, peripheral edema, constipation peripheral sensory neuropathy, fatigue, nausea, insomnia, dyspnea, and cough.
The addition of subcutaneous Daratumumab to bortezomib, lenalidomide, and dexamethasone (VRd) , and lenalidomide maintenance therapy had a significant benefit effect on progression free survival among transplantation eligible patients with newly diagnosed myeloma.
The PERSEUS trial of adding VRd to daratumumab 87% complete response rate and had a progressive free response of 84% at four years follow up.
In, addition in the PERSEUS study the MRD negativity rate was 75%.
Anti-body therapy for myeloma includes: monoclonalanti bodies, antibody-drug conjugates, and bispecific antibodies.
Monoclonal antibodies represent a targeted approach to the treatment of myeloma, with selective killing properties that include complement dependent cytotoxicity (CDC), antibody dependence cell mediated cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP).
In refractory multiple myeloma the tolerability of monoclonal antibodies is better than conventional chemotherapy or stem cell transplant and they can be added without increasing toxicity and can induce more and deeper responses.
Antibody-drug conjugates provide specific cytotoxic drugs to the target cells of interest; bispecific T-cell engagers recruit T cells for the specific targeting of myeloma cells, and checkpoint inhibitors which re-stimulate the immune system by targeting the cell sirface receptor program death 1 and its ligand.
CD38 is a transmembrane glycoprotein expressed on lymphoid and myeloma cells, and acts as the receptor for the transduction of activation signals and serves as a enzyme that catalyzes the production of nucleotides involved in calcium signaling.
Daratumumab is a human IgG kappa monoclonal antibody that targets the plasma cell antigen CD 38 that has safety and efficacy as mono therapy for relapsed and refractory multiple myeloma.
When Daratumumab is added various standard regimens for relapsed multiple myeloma there is improvement in response and survival.
D-VRD compared to VRD shows significant progression free survival: 84.3%, versus 67.7%.
The combination of Daratumumab, lenaliomide, and and dexamethasone (D-VRD) is established as initial therapy for older patients that are transplant ineligible.