A phase 2 trial designed by the Nordic Myeloma Study Group (study #23/15) is exploring the response to ixazomib, lenalidomide, and dexamethasone (IRd) induction followed by a single autologous stem-cell transplantation (ASCT), IRd consolidation, and risk-based maintenance with either ixazomib + lenalidomide or lenalidomide alone among patients with newly diagnosed multiple myeloma. Interim safety and response rates are presented following IRd x 4 induction for all patients and for 87% of patients before consolidation.
A total of 120 patients were enrolled across 22 sites. As induction, patients received 4 IRd cycles (ixazomib 4 mg on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; dexamethasone 40 mg weekly) in 28-day cycles. Mobilization and ASCT were performed based on standard practice. All patients receive 2 IRd cycles as consolidation, followed by maintenance therapy at 3 months post-ASCT. Thereafter, patients are stratified to high risk if any aberrations are detected by fluorescence in situ hybridization at inclusion (del17p at least 60%, t[4;14], t[14;16], t[14;20], or +1q), and receive ixazomib 4 mg on days 1, 8, and 15, and lenalidomide 10 mg on days 1 to 21. Patients not classified as high risk receive lenalidomide 10 mg on days 1 to 21, with the dose increasing to 15 mg after 3 cycles. Maintenance therapy continues until disease progression (DP). The primary end point is minimal residual disease (MRD), as determined by an 8-color EuroFlow of <0.01%. Secondary end points include flow-MRD negativity by 10–5, overall response, safety, and progression-free survival. Serologic responses will be assessed before cycles, and flow-MRD sampling will be performed and repeated every 6 months if either stringent complete response (sCR) or complete response (CR) is achieved.
Of 120 patients enrolled in the study, 48% met high-risk criteria. As of December 2020, stem-cell mobilization was performed for 107 (89%) patients. To date, 86 (72%) patients have received ASCT. The overall response rate (ORR) was 93%. After IRd x 4 induction, 2% of patients achieved sCR; 5%, CR; 28%, very good partial response (VGPR); 48%, partial response (PR); 7%, stable disease (SD); and 7% had DP. Response rates before consolidation were 5%, sCR; 14%, CR; 28%, VGPR; 31%, PR; and 2%, DP.
Prior to consolidation, 10 (8%) patients withdrew as a result of DP and 4 (3%) withdrew because of toxicity. Toxicity events included grade 3 cytopenia with liver toxicity, hypersensitivity with hepatorenal failure, and 1 case of unexplained encephalitis. One patient withdrew because of cyclophosphamide toxicity during stem-cell mobilization. Seven additional patients withdrew as per physician’s decision, because of high tumor burden based on M protein level and achieving only SD during induction. One additional patient decided to withdraw. The most common grade 3/4 serious adverse events were neutropenia (22%), infections (22%), and fever (11%). In addition, 12 patients had grade 3 elevated abnormal liver transaminases, 4 had grade 3 peripheral neuropathy, and 61 (51%) patients reported skin reactions (11 of which were grade 3 events). A total of 98 (82%) patients continue in the study, including 80% of the high-risk patients.
In this study, the ORR was 93% after induction treatment. A total of 9 patients only achieved SD, of whom 7 were withdrawn prior to stem-cell mobilization because of high tumor burden. Post-ASCT, ≥VGPR was achieved in 47% of patients. A total of 98 patients of the original 120 (82%) continue in the study, including 80% of the high-risk patients.
Reference
Abstract 144. ASH 2020. December 5, 2020. A Prospective Phase 2 Study to Assess Minimal Residual Disease after Ixazomib, Lenalidomide and Dexamethasone Treatment for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients.