On November 19, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that the European Commission (EC) has granted marketing authorisation for Darzalex(daratumumab) in combination with lenalidomide and dexamethasone (DRd) for the treatment of newly diagnosed multiple myeloma patients who are ineligible for autologous stem cell transplant (ASCT) (Press release, Janssen Pharmaceuticals, NOV 19, 2019, View Source [SID1234551487]). The approval was based on results from the Phase 3 MAIA (MMY3008) study, published in The New England Journal of Medicine3 earlier this year and presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in 2018.

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"Despite recent therapeutic advances, relapse of multiple myeloma is considered to be almost inevitable, becoming more challenging to treat following each relapse. This makes it even more important that we maximise our best response upfront to extend the first remission," said Professor Thierry Facon, M.D., Service des Maladies du Sang, Hôspital Claude Huriez, Lille, France, and principal investigator of the MAIA study. "This marks an important approval, especially for transplant ineligible patients, a more vulnerable population, for whom outcomes are generally poorer when compared to those who are transplant eligible."

The 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 years).1 Daratumumab in combination with Rd significantly reduced the risk of disease progression or death by 44 percent in patients with newly diagnosed multiple myeloma who are transplant ineligible, compared to treatment with Rd alone (Hazard Ratio [HR] = 0.56; 95 percent confidence interval [CI]: 0.43-0.73; p<0.0001).1 At median follow-up of 28.0 months the median progression-free survival (PFS) for daratumumab-Rd had not yet been reached, compared to 31.9 months for patients who received Rd alone.1 The addition of daratumumab resulted in deeper responses compared to Rd alone, including increased rates of complete response (CR) or better (48 percent vs. 25 percent) and improved rates of very good partial response (VGPR) or better (79 percent vs. 53 percent).1 Daratumumab-Rd induced a >3-fold higher rate of minimal residual disease (MRD) negativity compared to those who received Rd alone (24 percent vs. 7 percent).1

"Every year over 48,000 people in Europe are diagnosed with multiple myeloma, which is considered to be incurable. Older patients who are ineligible for transplant have a limited range of frontline therapeutic options available, so we are pleased that with today’s approval of daratumumab-Rd, these patients now have a new frontline option available to them," said Dr Patrick Laroche, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag.

Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC., commented: "It’s gratifying to see that through our research and development efforts, daratumumab has helped over 100,000 patients globally. With today’s approval and the continued development of daratumumab, we hope to bring this innovative therapy to many more patients in the future."

The most common Grade 3/4 treatment-emergent adverse events (TEAEs) for daratumumab-Rd (≥10 percent) included neutropenia (50 percent), lymphopenia (15 percent), pneumonia (14 percent) and anaemia (12 percent).1 Infusion-related reactions (IRRs) occurred in 41 percent of patients, only 3 percent of which were Grade 3/4.1 Incidence of invasive second primary malignancy was 3 percent in the daratumumab-Rd arm compared to 4 percent with Rd alone.1 TEAEs with an outcome of death were 7 percent in the daratumumab-Rd arm compared to 6 percent in the Rd arm.1 The safety profile of daratumumab was consistent with that of previous studies.1

In Europe, daratumumab is indicated:4

in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant,
in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy,
as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent, and who have demonstrated disease progression on the last therapy.
#ENDS#

About the MAIA (NCT02252172) Trial5

In this open-label and multicentre Phase 3 study patients were randomised to receive either daratumumab-Rd or Rd alone in 28-day Cycles. In the daratumumab-Rd treatment arm, patients received daratumumab 16 (mg/kg) IV weekly for Cycles 1 – 2, every two weeks for Cycles 3 – 6 and every 4 weeks for Cycle 7 and thereafter. The primary endpoint was Progression-Free Survival, defined as the time from date of randomisation to either progressive disease, or death, whichever occurred first. Patients in the daratumumab-Rd and Rd treatment arm 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 daratumumab

Daratumumab is a first-in-class6 biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.7 Daratumumab is believed to induce tumour cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.4 A subset of myeloid derived suppressor cells (CD38+ MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by daratumumab.4 Since launch, it is estimated that 100,000 patients have been treated with daratumumab worldwide.2 Daratumumab is being evaluated in a comprehensive clinical development programme across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.5,8,9,10,11,12,13,14 Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant haematologic diseases in which CD38 is expressed, such as smouldering myeloma.15,16 For more information, please see View Source

For further information on daratumumab, please see the Summary of Product Characteristics at View Source

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive licence to develop, manufacture and commercialise daratumumab.17

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.18 In Europe, more than 48,200 people were diagnosed with MM in 2018, and more than 30,800 patients died.19 Almost 60 percent of patients with MM do not survive more than five years after diagnosis.20

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.21 Refractory MM is when a patient’s disease progresses within 60 days of their last therapy.22,23 Relapsed cancer is when the disease has returned after a period of initial, partial or complete remission.24 While some patients with MM have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.25 Patients who relapse after treatment with standard therapies, including proteasome inhibitors and immunomodulatory agents, have poor prognoses and few treatment options available.26