Open-Label Study to Determine the Feasibility of Ixazomib As Maintenance after Allogeneic Stem Cell Transplant for Multiple Myeloma

Introduction: Allogeneic stem cell transplantation is an appropriate treatment option in patients (pts) with high-risk multiple myeloma (MM), but carries a mortality risk as a consequence of graft-versus-host disease (GVHD) and relapsed disease. Proteasome inhibitors have been shown to stimulate allogeneic immune cells to eliminate myeloma cells and at the same time reduce the incidence and severity of GVHD. The use of proteasome inhibitors after stem cell transplant can therefore prolong remissions after transplant and reduce the incidence of GVHD. Ixazomib is an orally bioavailable, reversible inhibitor of the 20S proteasome that has also shown impressive anti-myeloma activity in both the relapsed/refractory and the upfront setting. This is a Phase II, open-label, multicenter, non-randomized study to determine the feasibility of Ixazomib as maintenance after allogeneic stem cell transplant for MM. Here we present results from pts in the three treatment cohorts.

Methods: High risk pts (including chromosome 17p, partial deletion (del(17p), t(4;14), t(14;16), t(14;20), plasma cell leukemia, or progression-free survival of less than 2 years after autologous stem cell transplant) who received an allogenic stem cell transplant and had no evidence of >Grade 2 GVHD or any GVHD requiring methylprednisolone were eligible to enroll between Days 45 and 120 after transplant. Pts received a weekly oral ixazomib dose on Days 1, 8, and 15 of each 28-day cycle for 6 cycles. Pts were treated at 2.3 mg (Cohort 1), 3 mg (Cohort 2), and 4 mg (Cohort 3).

Results: To date, 7 pts were enrolled (3 on Cohort 1, 3 on Cohort 2, and 1 on Cohort 3); median age 49 years; 5 pts (71%) female; 4 pts (57%); International Staging System Grade ≥ 2. The median number of prior systemic regimens was 4 (range 3-8). 100% of pts had received autologous stem cell transplant. Median number of prior autologous transplants was 2 (range 1-3). Conditioning regimen prior to allogeneic stem cell transplant included fludarabine + melphalan (n = 6) and fludarabine + total body irradiation (n = 1). All pts received peripheral blood stem cells, donors included matched related donors (n=2) and unrelated donors (n=5). The median number of weeks of treatment were Cohort 1, 24 wks; Cohort 2, 16 wks; Cohort 3, 6 wks. To date, there have been no dose-limiting toxicities, 1 dose interruption on Cohort 1 due to thrombocytopenia, and 1 dose reduction on Cohort 2 due to rash. 5 pts (71%) have discontinued treatment, 3 pts (43%) due to disease progression and 2 pts (29%) have completed treatment. 2 pts (29%) were still on active treatment at the time of data cut-off. 3 pts (43%) have died due to disease progression. The median time on study overall was 9 months (range 2-28 months). Of the 6 pts (86%) eligible for response analysis, 2 pts (33%) had a stringent complete response, 1 pt (17%) had a complete response, 2 pts (33%) had a very good partial response, and 1 pt (17%) had progressive disease as a best overall response. The most common ≥ Grade 3 adverse events (AEs) were thrombocytopenia (3 pts, 43%) and hypertension (2 pts, 29%). 3 pts (43%) had ≥ Grade 3 treatment-related AEs of thrombocytopenia (3 pts, 43%) and rash (1 pts, 14%). 1 pt (14%) had treatment-related serious adverse events (vomiting and fever). Acute GVHD was reported for 5 pts (maximum Grade 1), chronic GVHD occurred in 4 pts (limited: 2 pts, extensive: 2 pts).

Conclusions: There have been no dose-limiting toxicities on these 3 cohorts. The maximum-tolerated dose has not been reached for this study and enrollment is continuing. Initial response data is promising.