Efficacy and Tolerability of Daratumumab with Ixazomib and Dexamethasone in Patients with One Prior Lenalidomide-Based Regimen: Preliminary Results of the Phase 2 Daria Study

Introduction: Lenalidomide-based regimens are currently among the standard-of-care treatment options for newly diagnosed patients with multiple myeloma NDMM). Second-line treatment of patients who are refractory to lenalidomide or have relapsed after prior use of lenalidomide is challenging. Daratumumab, an IgG1κ human monoclonal antibody that targets CD38, has shown durable responses and a favorable safety profile in heavily pretreated patients with relapsed/refractory MM (RRMM) as monotherapy, or in combination with other anti-myeloma treatments. Ixazomib, the first oral proteasome inhibitor, has shown deep responses and a positive safety profile in NDMM patients when it is combined with lenalidomide and dexamethasone. The aim of the DARIA study is to evaluate the effectiveness of daratumumab in combination with ixazomib and dexamethasone (DId) as second-line therapy in patients who have received prior treatment with lenalidomide-based regimens.

Methods: DARIA is an ongoing prospective, open-label, multicenter, phase 2 study, which aims to enroll 43 patients who have received one prior line of therapy with a lenalidomide-based regimen. Patients must have a Karnofsky performance status (PS) ≥70. Exclusion criteria include previous daratumumab or anti-CD38, or ixazomib treatment exposure. The treatment phase consists of an induction therapy for 9 cycles, followed by a maintenance period. The induction phase included 28-day treatment cycles with 16 mg/kg intravenous daratumumab (weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter), 4 mg oral ixazomib (Days 1, 8, and 15 of each cycle), and 40 mg oral dexamethasone for the first 9 cycles (weekly, each cycle). During the maintenance phase of the study daratumumab is administered every 4 weeks and ixazomib on the same schedule, until disease progression or unacceptable toxicity whereas dexamethasone is discontinued. The primary endpoint is the overall response rate (ORR). Secondary endpoints include evaluation of the toxicity profile of the study treatment, progression-free survival (PFS), overall survival, and levels of serum bone markers and angiogenic cytokines. All responses are based on investigators' assessment per International Myeloma Working Group criteria. This analysis presents results for patients who received the first dose of study treatment ≥5 months prior to the cut-off date (01/05/2020).

Results: Fifteen patients, enrolled in 4 Sites, are included in the current analysis. Overall, 60% of the patients were refractory to lenalidomide. Median age was 70 years and the majority of patients were male (60%). The median time from diagnosis to first dose of study treatment was 1.3 years. Two patients (13%) had a prior autologous stem cell transplantation. Patients had a Karnofsky PS of 70 (27%), 80 (7%), 90 (53%), and 100 (13%) at baseline. At screening 47%, 26%, and 27% of the patients had an international staging system (ISS) of 1, 2, and 3, respectively, and a revised ISS of 1 (21%), 2 (71%), and 3 (7%). The median number of cycles reached until the cut-off date was 7. The median time from first dose of study treatment until first partial (PR) or very good partial response (VGPR) was 0.9 month. ORR was 60%, with 47% of the patients achieving VGPR and 13% PR. The 12-month PFS rate was 54%, and 8 patients (53%) were still on treatment by the cut-off date. From the patients who discontinued 71% was due to disease progression and 29% due to physician's decision. Overall, 10 patients (67%) had at least one adverse event (AE) grade 3 or 4, the most common being thrombocytopenia (6 patients, 40%). Four patients (27%) had a single SAE each: lower respiratory tract infection (fatal); peritonitis, gastroenteritis; nephrolithiasis.

Conclusions: Rapid (median time to PR or better was 1 month) and deep responses (47% of the patients exhibited VGPR) were observed following treatment with daratumumab, ixazomib and dexamethasone as second-line therapy in patients who were previously treated with a lenalidomide-based regimen, more than half of whom were refractory to lenalidomide. The safety profile of DId combination is very good with one third of the patients not experiencing any grade 3 or 4 AEs, when at the same time the PFS rate at 12 months reached 54%.