The Janssen Pharmaceutical Companies of Johnson & Johnson announced the submission of a Type II variation application to the European Medicines Agency (EMA) for Darzalex (daratumumab) in combination with lenalidomide and dexamethasone (Rd) for the treatment of patients newly diagnosed with multiple myeloma who are ineligible for autologous stem cell transplant (ASCT).
“Today’s submission brings us one step closer to our goal of improving treatment outcomes for people newly diagnosed with multiple myeloma,” said José Antonio Burón Vidal, VP Medical Affairs, Europe, Middle East and Africa (EMEA), Janssen-Cilag.
“We are incredibly grateful to the patients and investigators who participated in the MAIA clinical trial programme and look forward to working closely with the regulatory authorities to secure approval of this new combination.”
The submission is supported by data from the Phase 3 MAIA (MMY3008) study, which were presented at the 60th Annual Meeting of the American Society of Hematology.
The study showed that at a median follow-up of 28 months, daratumumab-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).
The median progression-free survival (PFS) for daratumumab-Rd has 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).
Within the study, patient health, functional capacity, symptoms, psychosocial well-being, and life satisfaction were evaluated through measures to assess change in health-related quality of life by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and Euro Quality of Life (EQ-5D-5L) Health State Profile Utility Score.2
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 receiving daratumumab-Rd, 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.
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.1,3,4,5,6,7
Daratumumab-Rd is being reviewed by the U.S. Food and Drug Administration (FDA) under the Real-Time Oncology Review (RTOR) pilot programme.
In Europe, daratumumab is indicated:8
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
as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy
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.
The randomised, open-label, multicentre 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 years).
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.
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.
Daratumumab is a first-in-class biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.
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.
A subset of myeloid derived suppressor cells (CD38+ MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by daratumumab.11 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.
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.
Source: Company Press Release