Final Results of randomized Phase II study of daratumumab, ixazomib, and dexamethasone (DId, ARM A) vs daratumumab, bortezomib and dexamethasone (DVd) followed by daratumumab, did (Arm B) in newly diagnosed multiple myeloma (DeRIVE) study

Abstract

Abstract Introduction: The safety and efficacy established by daratumumab (a CD38 monoclonal antibody)-based induction therapies for both transplant-eligible myeloma patients (based on PERSEUS, CASSIOPEIA and GRIFFIN trials) and transplant-ineligible patients (based on MAIA trial and CEPHEUS) have cemented the role of daratumumab-based induction therapies. In this context, to find the most optimal non-IMID based daratumumab-combination therapy as induction, we conducted a randomized phase 2 study to evaluate the safety and efficacy for in-class transition from bortezomib to ixazomib, stratified by transplant-eligibility and R-ISS Methods: Patients were randomized to receive Arm A [daratumumab, ixazomib and dexamethasone (DId) X 8 cycles)] or Arm B [(daratumumab, bortezomib and dexamethasone (DVd) x 3) followed by (DId x 5 cycles)] for the primary endpoint of ≥ very good partial response rate (VGPR) rate post-induction cycle 8. Several other secondary endpoints were evaluated including safety, overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Standard dosing schedule was used [DId: daratumumab IV 16 mg/kg on days 1, 8, 15, 22 every 28 days x 2 cycles; then on days 1, 15 every 28 days x 6 cycles and every 28 days during maintenance (or 1800 mg SC at the same schedule), ixazomib - 4 mg PO on Days 1, 8, and 15 every 28 days and dexamethasone - 40 mg PO on days 1, 8, 15 and 22 every 28 days; DVd: daratumumab IV 16 mg/kg on days 1, 8, 15, 22 every 28 days x 2 cycles; then on days 1, 15 every 28 days x 6 cycles and every 28 days during maintenance (or 1800 mg SC at the same schedule), bortezomib - 1.3 mg/m2 SC on days 1, 4, 8 and 11 every 21 day and dexamethasone - 40 mg PO on days 1, 8, 15 and 22 every 28 days]. Transplant eligible patients may receive stem cell collection and transplant after cycle 8. During the maintenance phase, patients receive DId as maintenance therapy for a total of 32 cycles. 52 subjects were enrolled at Winship Cancer Institute of Emory University between 07/2019 and 05/2022. Data cut-off is 5/1/2025, with median follow-up PFS for arm A and Arm B at 53.22 and 55.89 months, respectively; and for OS of 60.22 and 60.97 months, respectively. Results: The median age was 64 years for the 48 evaluable subjects [25 (52%) in arm A, 68 (48-87) and 23 (48%) in arm B, 61 (37-80), p<0.25]. 56% of the cohort was male (64 vs 48%, p=0.20), 48% were black (40% vs 56.5%, p=0.245). 20.8% had t(11;14), 29.2% had 1q abnormalities, 70.8% had hyperdiploidy, 25% had complex karyotype and 10.4% were high-risk [defined as presence of del17p, t(4;14) or t(14;16)]. 38 (81%) patients underwent an autologous stem cell transplant (72% in Arm A and 90.9% in Arm B, p=1.00). The primary endpoint favored arm B (Arm A vs Arm B ≥VGPR rate: 28% vs 56.5%, p<0.043). Similarly, the ORR favored arm B as well (Arm A vs Arm B ORR: 76% vs 95.7%, p<0.062). Post transplant ≥VGPR rates and ORR were 88.9% vs 95%, p=0.458 and 100% vs 100%, p=NS, respectively. Median PFS was not reached in both arms. The 40-month PFS rate was 67% in Arm A and 90% in Arm B (p=0.136). Median OS was not reached in both arms. 52-month OS rate was 83% in Arm A and 100% in Arm B (p=0.052). The adverse event profile was similar across both cohorts (grade 3/4 events related to study occurred in 13 instances in 2 patients in arm A vs 4 instances among 3 patients in Arm B). There was 1 grade 3/4 peripheral neuropathy (PN) event that occurred in Arm A. Grade 1/2 PNs were higher in Arm B. There were two secondary primary malignancies reported in Arm B (prostate cancer and esophageal adenocarcinoma) Conclusion: This is one of the first studies showing the safety and efficacy of non-IMID based daratumumab-combination induction therapies with in-class transition of bortezomib to ixazomib (Arm B) yielding higher response rates post-induction and post-transplant without compromising on the safety. This translated to PFS and OS benefit as well with no survival events for Arm B with more than 60 month follow up.