On December 3, 2018 The Janssen Pharmaceutical Companies of Johnson & Johnson reported its the long-term results of the Phase 3 ALCYONE study demonstrating that the addition of Darzalex (daratumumab) to bortezomib , melphalan and prednisone (VMP) continued to show significant improvement in progression-free survival (PFS) in patients recently diagnosed with multiple myeloma who are ineligible for autologous stem cell transplantation (GATS) (Press release, Johnson & Johnson, DEC 3, 2018, View Source [SID1234531843]). 1 These data ( Summary No. 156 ), as well as the updates of the LYRA ( Summary No. 152 ) and GRIFFIN ( Summary No. 151)) Phase 2 in patients with multiple myeloma were presented in an oral session on data presentation abstracts at the 60 th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) that was held in San Diego, California.
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Long-term results of the ALCYONE Phase 3 trial for first-line combined treatment with daratumumab 1
With a median follow-up of 27.8 months, the results of the study showed that the addition of daratumumab to the combination of bortezomib, melphalan and prednisone (VMP) reduced the risk of disease progression by 57 percent. or death, in comparison with treatment based solely on the VMP combination (risk ratio [RR] = 0.43, 95 percent confidence interval [CI] 0.35-0.54, p <0, 0001). 1 The combination of daratumumab-VMP resulted in a 24-month PHC rate of 63 percent, compared to 36 percent for VMP alone. 1 The median PFS for the combination of araratumumab-VMP has not yet been reached, and the control group (PMV alone) had a median PFS of 19.1 months.1 In addition, a significantly higher overall response rate (91 percent vs. 74 percent, respectively) was observed for the combination based on daratumumab, compared with the single VMP. 1 The combination of daratumumab-VMP achieved faster responses, with a significant improvement in the rate of very good partial response or higher rate (73 percent versus 50 percent), and a strict complete response rate more than twice as high ( 22 percent vs. 8 percent) to that of the VMP alone. 1 The combination of aratumumab-VMP induced a higher rate of long-term residual residual disease negativity compared to VMP alone (10 percent versus 2 percent, respectively).1 The main results previously announced in this study motivated the European Commission to approve daratumumab in combination with MPV for patients with newly diagnosed multiple myeloma who are not eligible for GATS.
Long-term data from pivotal ALCYONE trial show that combined treatment with daratumumab continued to demonstrate improved progression-free survival and response rates in newly diagnosed patients with multiple myeloma, including patients older people less likely to respond to treatment, "said Meletios A. Dimopoulos, MD, professor and chair of the Clinical Therapies Department at the Faculty of Medicine at the National Capodistrian University of Athens, Greece, and principal investigator. These promising results support the use of daratumumab earlier in the treatment paradigm,
In the ALCYONE study, the most common grade 3/4 adverse events that occurred during treatment with daratumumab-VMP starting in cycle 10 included anemia (4 percent), neutropenia (2 percent), and bronchitis (1 percent). 1 No new safety concerns were observed, and Grade 3/4 infections remained treatable. 1
Data from LYRA and GRIFFIN Phase 2 trials support the efficacy and safety profile of daratumumab in newly diagnosed patients, including those who are eligible for high-dose treatment / GATS, and in patients in relapse 2 , 3
Response rates from the LYRA Phase 2 study were presented for the experimental use of daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients recently diagnosed with multiple and relapsed myeloma. 2 The overall response rate and TBRP or upper rate in 86 newly diagnosed patients, who were 79 and 44 percent, respectively, after 4 cycles, increased to 81 and 56 percent, respectively, at the end of the initial treatment period (average of 6 cycles). 2In addition, the TBRP or higher rate in 14 patients with recurrent multiple myeloma, which was 57 percent after 4 cycles, then increased to 64 percent at the end of induction, while the rate overall response remained stable at 71 percent (average of 7.5 cycles). 2 The 18-month PHC rate was 78 percent in newly diagnosed and ineligible autologous patients, compared with 53 percent in relapsed patients. 2 In addition, this study, which evaluated the fractionation of the first dose of daratumumab to reduce infusion duration on Day 1 of Cycle 1 (C1D1), demonstrated a safety profile consistent with previous studies. . 2Infusion reactions occurred in 49 percent of patients with C1D1, compared to four percent of patients on Day 2 of Cycle 1 (C1D2). Fifty-four percent of newly diagnosed patients experienced infusion reactions, the most common being: chills (14 percent), dyspnoea, pruritus, and nausea (8 percent each), as well as coughing. (7 percent). Fifty-seven percent of relapsed patients experienced infusion-related reactions, the most common of which were: cough (21 percent), hyperhidrosis, dyspnea and chills (7 percent each). Only two patients had a grade 3 infusion reaction, and no grade 4 infusion reaction occurred. has been noted. No interruption of taking daratumumab was necessary because of an infusion reaction. The median infusion time was 4.5 hours at C1D1, compared to 3.8 hours at C1D2.2 Grade 3/4 adverse events that occurred during treatment were reported in 56 percent of patients, the most common (≥10 percent) being neutropenia (13 percent). 2
Data presented in the GRIFFIN Phase 2 study evaluated daratumumab in combination with bortezomib, lenalidomide and dexamethasone (VRd) in a safety group of 16 patients recently diagnosed with multiple myeloma, eligible for high dose treatment and GATS. 3 The results showed that at the end of the GATS consolidation treatment, all patients who participated in the safety preparatory period achieved a TBRP or higher rate, and 63 percent of them achieved complete response (CR) or higher, with 25 percent of patients having achieved SCR. 3In addition, 94 percent of patients remained without progression during the study, at a median follow-up of 16.8 months. 3 In addition, 8 out of 16 patients (50 percent) were negative for the residual disease test, at a level of 10 -5 at the end of consolidation. 3 During grade 3/4 treatment, fourteen patients (88 percent) reported adverse events, including 10 cases (63 percent of patients) related to daratumumab treatment. 3The most common adverse events (≥10 per cent) that occurred during grade 3/4 treatment were neutropenia, pneumonia, thrombocytopenia, lymphopenia, febrile neutropenia, leukopenia, rash, and hypophosphatemia. 3 Thirteen patients (81 percent) had the following infections, all grades: upper respiratory infection (six patients), pneumonia (four patients), bronchitis (two patients), otitis and viral gastroenteritis (two patients each) ). 3 No deaths due to serious adverse events were reported and no patient had to discontinue treatment due to an adverse event. 3These data suggest that induction therapy with daratumumab has no negative impact on stem cell mobilization. All 16 patients had successful stem cell mobilization, followed by GATS. 3
"Daratumumab offers a consistent clinical benefit across multiple therapeutic lines for multiple myeloma, and positive data from the ALCYONE, LYRA, and GRIFFIN studies add to the solid body of evidence supporting daratumumab-based protocols," said Dr. Dr. Catherine Taylor, Head of Hematology Treatments for Europe, Middle East and Africa (EMEA) at Janssen-Cilag Limited. "These are important findings for patients that provide additional information about the most effective methods of managing care," she added.
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About the ALCYONE 4 trial
The randomized, open-label, multi-center Phase 3 ALCYONE (MMY3007) study enrolled 706 patients newly diagnosed with multiple myeloma and ineligible for high-dose GSC chemotherapy. The median age of these patients was 71 years (age range: 40-93). Patients were randomized to receive nine cycles of daratumumab combined with VMP, or VMP alone. In the daratumumab-VMP group, patients received 16 mg / kg of daratumumab once a week for the first week (cycle 1) and then once every three weeks (cycles 2-9). After nine cycles, they continued to receive 16 mg / kg of daratumumab once every four weeks until disease progression.
About the LYRA 5 trial
The ongoing, single-arm, open-label, multi-center LYRA (MMY2012) Phase 2 study enrolled 100 adult patients 18 years of age and older. Patients received 4-8 cycles of combination therapy with daratumumab, including an oral dose of cyclophosphamide 300 mg / m 2 on days 1, 8, 15 and 22; a subcutaneous dose of bortezomib 1.5 mg / m 2 on days 1, 8 and 15; a weekly oral or intravenous dose of dexamethasone 40 mg every 28 days. Daratumumab was administered at 8 mg / kg intravenously at days 1 and 2 of cycle 1, at a weekly dose of 16 mg / kg from cycle 1, at day 8 during cycle 2, at a dose of 16 mg / kg every 2 weeks at cycles 3-6, and at a dose of 16 mg / kg every 4 weeks at cycles 7-8. After the induction treatment, the patients were able to receive a GATS. All patients received 12 cycles of maintenance treatment of 16 mg / kg intravenously every 4 weeks.
About the GRIFFIN 6 trial
The randomized, open-label Phase II GRIFFIN study (MMY2004) recruited and treated more than 200 adults between 18 and 70 years of age, eligible for high-dose treatment / GATS, 7including 16 patients in the safety preparatory phase to evaluate the potential dose limiting toxicities during cycle 1 of daratumumab combined with VRd. The latter patients were treated with four cycles of daratumumab and VRd infusion every 21 days, followed by stem cell mobilization, high-dose treatment and GATS; two consolidation cycles with daratumumab and VRd; as well as maintenance therapy with daratumumab and lenalidomide at cycles 7-32. During induction and consolidation therapy (cycles 1-6), patients received an oral dose of 25 mg lenalidomide on days 1-14, a dose of 1.3 mg / m 2bortezomib subcutaneously on days 1, 4, 8 and 11 and a dose of 20 mg dexamethasone on days 1, 2, 8, 9, 15 and 16 every 21 days. An infusion of daratumumab 16 mg / kg IV was administered on days 1, 8 and 15 of cycles 1-4 and day 1 of cycles 5-6. During the maintenance period (cycles 7-32), patients received a daily dose of 10 mg lenalidomide (15 mg from cycle 10, if tolerated) on days 1-21 every 28 days, and an injection of daratumumab 16 mg / kg every 56 days; this treatment was adjusted every 28 days. Lenalidomide maintenance therapy can be extended beyond cycle 32, according to the local care protocol.7
About Daratumumab
Daratumumab is an advanced biological product targeting the CD38 gene, a surface protein that is overexpressed in multiple multiple myeloma cells, regardless of the stage of the disease. 8 The Daratumumab induce the death of tumor cells via multiple mechanisms of action immunologically mediated, including complement-dependent cytotoxicity (CDC), an antibody-dependent cellular cytotoxicity (CBDC) and dependent cellular phagocytosis of antibody (PCDA) and via apoptosis, during which a series of molecular steps inside the cell leads to the death of the cell. 9A subset of suppressive cells derived from myeloid, CD38 + regulatory T cells and CD38 + B cells was reduced by daratumumab. 9 Daratumumab is being evaluated as part of a comprehensive clinical development program covering a range of treatment protocols for multiple myeloma, including first-line treatment, or recurrence. 10,11,12,13,14,15,16,17 Additional studies are underway or planned to evaluate the potential of this treatment targeting other malignant and pre-malignant haematological conditions in which the CD38 gene is expressed, such as indolent myeloma. 18,19For more information, please visit www.clinicaltrials.gov .
In Europe, daratumumab is indicated for use in combination with bortezomib, melphalan and prednisone for the treatment of newly diagnosed adult patients with multiple myeloma who are ineligible for autologous stem cell transplantation as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, previously treated with a proteasome inhibitor and an immunomodulatory agent, and who experienced disease progression during the last treatment, and in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, and for the treatment of adult patients with multiple myeloma who have benefited fromat least one prior treatment.9 For more information on daratumumab, please see the summary of product characteristics at View Source .
In August 2012 , Janssen Biotech, Inc. and Genmab A / S entered into a worldwide agreement granting Janssen an exclusive license to develop, manufacture and market daratumumab. 20
About multiple myeloma
Multiple myeloma is an incurable cancer of the blood that is found in the bone marrow. The disease is characterized by excessive proliferation of plasma cells. 21 More than 45,000 new cases of multiple myeloma were diagnosed in Europe in 2016, and more than 29,000 patients died. 22 Up to half of newly diagnosed patients do not achieve five-year survival, 23 and nearly 29% of multiple myeloma patients die within one year of diagnosis. 24
Although the treatment may lead to remission, in most cases a relapse will occur because no cure is currently possible. 25 A refractory multiple myeloma is characterized by the fact that the patient’s disease progresses within 60 days following the last treatment. 26,27 A recurrent cancer is characterized by the fact that the disease recurs after a period of initial, partial or complete remission. 28While some patients with multiple myeloma have absolutely no symptoms, the majority of them are diagnosed with symptoms that may include bone problems, low blood counts, increased calcium levels, infections or kidney problems. 29 Patients who have relapsed after treatment with standard therapy, including inhibitors of the proteasome and immunumodulateurs agents have poor prognosis and few treatment options. 30