On May 29, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the publication of data from the randomized, open-label Phase 3 MAIA (MMY3008) study that showed DARZALEX (daratumumab) plus lenalidomide and dexamethasone (Rd) resulted in a significant increase in progression-free survival (PFS) in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) (Press release, Johnson & Johnson, MAY 29, 2019, View Source [SID1234536670]).1 These data were published today in The New England Journal of Medicine.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
"We continue to see scientific evidence through Phase 3 studies that support the use of daratumumab in combination with standard of care regimens," said Thierry Facon, M.D., Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France, MAIA investigator and author of the study. "As multiple myeloma can become more complex at each relapse, it is important to select an optimal upfront therapy. Results from the MAIA study suggest that this daratumumab combination therapy should be considered for patients with multiple myeloma who are transplant ineligible upon diagnosis."
Results from the MAIA study demonstrated that at a median follow-up of 28 months, DARZALEX, in combination with Rd, reduced the risk of disease progression or death by 44 percent in patients with newly diagnosed multiple myeloma who are ineligible for ASCT, compared to treatment with Rd alone (Hazard Ratio [HR] = 0.56; 95 percent confidence interval [CI]: 0.43-0.73; p<0.001).1 The median PFS for DARZALEX-Rd has not yet been reached, compared to 31.9 months for patients who received Rd alone.1 The overall response rate (ORR) was 92.9 percent in the DARZALEX-Rd arm versus 81.3 percent in the Rd arm (p<0.001).1 The addition of DARZALEX resulted in near-doubling of complete response (CR) or better (47.6 percent vs. 24.9 percent).1 In the MAIA study, treatment with DARZALEX-Rd resulted in a greater than threefold rate of minimal residual disease (MRD) negativity compared to Rd alone (24.2 percent vs. 7.3 percent).1 All patients with MRD-negative status also had a response of CR or better.1 Patients who achieved MRD negativity demonstrated longer PFS than patients who remained MRD-positive, regardless of study treatment.1
The safety of DARZALEX in combination with Rd in this patient population was consistent with previously reported studies.1 The most common Grade 3 or 4 adverse events (AEs) (>10 percent) in the DARZALEX-Rd arm compared to Rd alone were neutropenia (50.0 percent vs. 35.3 percent), lymphopenia (15.1 percent vs. 10.7 percent), pneumonia (13.7 percent vs. 7.9 percent), anemia (11.8 vs. 19.7 percent) and leukopenia (11.0 percent vs. 4.9 percent), respectively.1 AEs leading to treatment discontinuation were less frequent in the DARZALEX-Rd group than with Rd alone (7.1 percent vs. 15.9 percent, respectively), despite the higher rate of neutropenia and pneumonia in the DARZALEX-Rd arm.1 There were fewer patients who discontinued the study treatment due to infections in DARZALEX-Rd versus Rd alone (0.5 percent vs. 1.4 percent, respectively).1 DARZALEX-associated infusion-related reactions (IRR) were reported in 40.9 percent of patients (2.7 percent were Grade 3 or 4); there were no Grade 5 events.1 One patient discontinued treatment with DARZALEX after an IRR.1
"The MAIA study findings demonstrate a consistent and clinically meaningful treatment effect when DARZALEX is incorporated into standard backbone regimens, such as lenalidomide and dexamethasone, for the initial treatment of patients with multiple myeloma who are transplant ineligible," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC. "We have submitted applications to global health authorities in support of the MAIA data and look forward to working with regulators in the hope of bringing a new combination regimen to patients diagnosed with multiple myeloma."
About the MAIA Trial1
The randomized, open-label, multicenter, Phase 3 study included 737 newly diagnosed patients with multiple myeloma ineligible for high-dose chemotherapy and ASCT aged 45 – 90 years old (median age of 73). Patients were randomized to receive either DARZALEX-Rd or Rd alone in 28-day cycles. In the DARZALEX-Rd treatment arm, patients received DARZALEX 16 milligrams per kilogram (mg/kg) IV weekly for cycles 1 – 2, every two weeks for cycles 3 – 6 and every 4 weeks for cycle 7 and thereafter. Patients in the DARZALEX-Rd and Rd treatment arms received 25 mg of lenalidomide on days 1 – 21 of each 28-day cycle, and dexamethasone at 40 mg once a week for each cycle. Patients in both treatment arms continued until disease progression or unacceptable toxicity.
About DARZALEX (daratumumab)
DARZALEX (daratumumab), the first CD38-directed antibody approved anywhere in the world, is the only CD38-directed antibody approved to treat multiple myeloma.2 CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.3 DARZALEX binds to CD38 and inhibits tumor cell growth causing myeloma cell death.2 DARZALEX may also have an effect on normal cells.2 DARZALEX is being evaluated in a comprehensive clinical development program across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.4,5,6,7,8,9,10,11 Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant hematologic diseases in which CD38 is expressed, such as smoldering myeloma.12,13
In the U.S., DARZALEX received initial FDA approval in November 2015 as a monotherapy for patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double refractory to a PI and an immunomodulatory agent.14 DARZALEX received additional approvals in November 2016 in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.15 In June 2017, DARZALEX received approval in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a PI.16 Most recently, in May 2018, DARZALEX received approval in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for ASCT, making it the first monoclonal antibody approved for newly diagnosed patients with this disease.17
In August 2012, Janssen Biotech, Inc. entered into a global license and development agreement with Genmab A/S, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX.18 For the full U.S. Prescribing Information, please visit www.DARZALEX.com.
About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.19,20 When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow.19,20 In 2019, it is estimated that 32,110 people will be diagnosed, and 12,960 will die from the disease, in the U.S.21 While some patients with multiple myeloma have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood counts, tiredness, high calcium levels, kidney problems or infections.22
IMPORTANT SAFETY INFORMATION2
CONTRAINDICATIONS
DARZALEX is contraindicated in patients with a history of severe hypersensitivity (e.g., anaphylactic reactions) to daratumumab or any of the components of the formulation.
WARNINGS AND PRECAUTIONS
Infusion Reactions – DARZALEX can cause severe and/or serious infusion reactions, including anaphylactic reactions. In clinical trials, approximately half of all patients experienced an infusion reaction. Most infusion reactions occurred during the first infusion and were grade 1-2. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.
Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.
To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.
Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion.
Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.
Neutropenia – DARZALEX may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX is recommended. Consider supportive care with growth factors.
Thrombocytopenia – DARZALEX may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions.
Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.
Adverse Reactions – The most frequently reported adverse reactions (incidence ≥20%) in clinical trials were: infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy and upper respiratory tract infection.
In patients who received DARZALEX in combination with bortezomib, melphalan, and prednisone (DVMP), the most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory tract infection (48%), infusion reactions (28%), and peripheral edema (21%). Serious adverse reactions (≥2% compared to the VMP arm) were pneumonia (11%), upper respiratory tract infection (5%), and pulmonary edema (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (58%), neutropenia (44%), and thrombocytopenia (38%).
In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions (≥2% compared to Rd) were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were neutropenia (53%) and lymphopenia (52%).
In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions (≥2% compared to Vd) were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (48%) and thrombocytopenia (47%).
In patients who received DARZALEX in combination with pomalidomide and dexamethasone, the most frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Treatment-emergent hematology Grade 3-4 laboratory abnormalities ≥20% were anemia (30%), neutropenia (82%), and lymphopenia (71%).
In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). The overall incidence of serious adverse reactions was 33%. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (40%) and neutropenia (20%).
DRUG INTERACTIONS
Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab.
Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib or pomalidomide did not affect the pharmacokinetics of bortezomib or pomalidomide.