Phase 1/2 trial of ixazomib, cyclophosphamide, and dexamethasone for newly diagnosed multiple myeloma (NDMM)

Background: Ixazomib (Ixa) is an oral proteasome inhibitor, approved for treatment of relapsed myeloma (MM) in combination with lenalidomide and dexamethasone (Dex). The combination of bortezomib with cyclophosphamide (Ctx) and Dex is an effective regimen for initial therapy of MM. The combination of Ixa, Ctx and Dex could provide an effective, all oral regimen for initial therapy of MM. Methods: NDMM patients (pts) with measurable disease, adequate organ function, and an ECOG PS >=2 were enrolled. The primary objective of the phase 1 was to determine the MTD of Ctx that can be combined with Ixa and Dex. Pts received Ixa 4 mg on days 1, 8, 15, dex 40 mg days 1, 8, 15, 22 and cyclophosphamide 300 or 400 mg/m2 days 1, 8, 15, 22; cycles were 28 days. Patients could continue on ixa alone after 12 cycles. The phase 2 portion was designed to determine the complete plus very good partial response rate (>=VGPR) of ixazomib to be used in combination with cyclophosphamide and dexamethasone in ND MM. Results: Fifty-one pts were accrued, 10 to phase 1 and 41 patients to the phase 2 part of the trial, 3 pts were ineligible and were excluded. The median age was 64.5 (41-88); 52% were male. High or intermediate risk FISH was seen in 29% pts. Two patients have died, median (range) follow up for live pts was 8.7 months (2.8-28.3). Nineteen pts continue on treatment; of the 29 who have gone off treatment, majority did so for stem cell transplant, 4 had disease progression. RP2D was 400 mg/m2 of cyclophosphamide weekly, the highest dose tested. Best confirmed response included a partial response or better in 78%, including a VGPR rate of 33%; 2 patients had CR. Response rate at 4-cycle was 71%; the median time to a PR was 1.84 months. Dose modification were mostly in ctx and dex arms; 23 and 13% respectively. A grade 3 or higher adverse events (AE), considered possibly related was seen in 73%. Most common AE included cytopenias, fatigue and GI side effects. Conclusions: The combination of Ixa, Ctx and Dex is well tolerated with high response rates. It offers the opportunity to utilize a completely oral regimen, which also is less expensive compared with the lenalidomide combinations. Future studies should assess its efficacy against other proteasome inhibitor combinations.