On December 9, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported overall survival (OS) results from the Phase 3 ALCYONE study, which showed the addition of Darzalex (daratumumab) to bortezomib, melphalan and prednisone (D-VMP) improved OS in patients with newly diagnosed, transplant-ineligible multiple myeloma, with a 40 percent reduction in the risk of death compared to VMP alone (Press release, Janssen Pharmaceuticals, DEC 9, 2019, View Source [SID1234552149]).1 These updated data from the ALCYONE study also demonstrated that the addition of daratumumab to VMP resulted in higher rates of minimal residual disease (MRD) negativity.1 These data are the first OS results from the ALCYONE study and are being featured during an oral session (Abstract #859) at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando. The data were simultaneously published in The Lancet.

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"As a physician treating patients with multiple myeloma, I want to achieve the deepest response in the frontline setting to hopefully provide long-term benefit," said Maria-Victoria Mateos, M.D., Ph.D., Director of the Myeloma Unit at University Hospital of Salamanca-IBSAL, Salamanca, Spain, and a study investigator. "This longer follow-up from the ALCYONE study is encouraging because we see that adding daratumumab to VMP in the frontline setting can provide an important overall survival advantage compared with a current standard of care."

Results of a pre-specified interim analysis, after a median duration of follow-up of more than three years, showed an estimated 42-month OS rate of 75 percent for daratumumab-VMP versus 62 percent for VMP, with a statistically significant improvement in OS observed for daratumumab-VMP versus VMP alone (hazard ratio [HR]=0.60; 95 percent confidence interval [CI], 0.46-0.80; p=0.0003).1 Of note, median OS was not reached in either group and follow-up is ongoing. In addition, daratumumab-VMP resulted in a median progression-free survival (PFS) of 36.4 months versus 19.3 months with VMP alone after a median follow-up of 40.1 months (HR=0.42; 95 percent CI, 0.34-0.51; p<0.0001).1 The results also demonstrated that daratumumab-VMP achieved significantly higher rates of MRD-negativity compared to VMP alone (28 percent vs. 7 percent respectively), at a threshold of one tumour cell per 10-5 white cells.1

The most common Grade 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥3 percent for daratumumab-VMP compared to the VMP arm were neutropenia (40.2 percent vs. 39 percent), thrombocytopenia (34.7 percent vs. 37.9 percent), anaemia (17.3 percent vs. 19.8 percent) and pneumonia (13 percent vs. 4.2 percent).1 Grade 5 TEAEs were 6.9 percent in the daratumumab-VMP treatment arm compared with 5.6 percent in the VMP arm and discontinuation due to TEAEs was 6.9 percent vs. 9.3 percent.1 The rate of invasive second primary malignancy was 4.9 percent in the daratumumab-VMP treatment arm compared with 4.5 percent in the VMP arm.1 No new safety concerns were identified.1

Additional data from longer follow-up (median of 36.4 months) from the Phase 3 MAIA study (Abstract #1875) presented at ASH (Free ASH Whitepaper) 2019 demonstrated daratumumab in combination with lenalidomide and dexamethasone (D-Rd) continued to significantly reduce 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 (HR=0.56; 95 percent CI: 0.44-0.71; p<0.0001), with no new safety concerns after three years of follow-up with daratumumab-Rd.2 Additionally, time from randomisation to progression on next-line treatment or death (PFS2) favoured the daratumumab arm (HR=0.69; 95 percent CI, 0.53-0.91; p=0.0079).2

"Transplant ineligible represents the largest group of newly diagnosed patients with multiple myeloma, and they have the highest unmet need. Accordingly, the advances presented at ASH (Free ASH Whitepaper) on the ALCYONE and MAIA studies for this population are very significant," said Dr Patrick Laroche, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag. "The results show the benefit of adding daratumumab on OS and PFS in the frontline setting – an improvement which could open the door to helping even more patients with multiple myeloma live longer."

The most common Grade 3/4 TEAEs (≥10 percent) for patients in the daratumumab-Rd compared to the Rd arm were neutropenia (51 percent vs. 35 percent), lymphopenia (15 percent vs. 11 percent), pneumonia (15 percent vs. 9 percent), anaemia (14 percent vs. 21 percent), leukopenia (11 percent vs. 6 percent) and hypokalaemia (10 percent vs. 10 percent).2 The most common serious TEAE was pneumonia (14 percent vs. 9 percent) in the daratumumab-Rd arm compared to the Rd arm.2 The most common Grade 3/4 infection rates were 36 percent in the daratumumab-Rd treatment arm compared with 27 percent in the Rd arm.2

#ENDS#

In Europe, daratumumab is indicated:3

in combination with lenalidomide and dexamethasone or 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 and an immunomodulatory agent and who have demonstrated disease progression on the last therapy
About the ALCYONE study (NCT02195479)4

The randomised, open-label, multicentre Phase 3 ALCYONE (MMY3007) study enrolled 706 newly diagnosed patients with multiple myeloma who were ineligible for high-dose chemotherapy with autologous stem cell transplant. The median age was 71 years (range: 40-93).1 Patients were randomised to receive up to nine cycles of either daratumumab-VMP or VMP alone. In the daratumumab-VMP arm, patients received 16 mg/kg of daratumumab once weekly for the first six weeks (Cycle 1), followed by once every three weeks for the next 48 weeks (Cycles 2-9). Following the nine cycles, patients in the daratumumab-VMP arm continued to receive 16 mg/kg of daratumumab once every four weeks until disease progression.

About the MAIA study (NCT02252172)5

In this open-label, multicentre Phase 3 study 737 patients were randomised to receive either daratumumab-Rd or Rd alone in 28-day Cycles. The median age was 73 years (range: 45-90).2 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.3 A subset of myeloid derived suppressor cells (CD38+ MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by daratumumab.3

Since launch, daratumumab has been used to treat more than 100,000 patients worldwide.8 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.9,10,11,12,13,14,15,16 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.17,18 For more information, please see www.clinicaltrials.gov.

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.19

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.20 In Europe, more than 48,200 people were diagnosed with MM in 2018, and more than 30,800 patients died.21 Almost 60 percent of patients with MM do not survive more than five years after diagnosis.22

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.23 Refractory multiple myeloma is when a patient’s disease progresses within 60 days of their last therapy.24,25 Relapsed cancer is when the disease has returned after a period of initial, partial or complete remission.26 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.27 Patients who relapse after treatment with standard therapies, including PIs and immunomodulatory agents, have poor prognoses and few treatment options available.28