Background: AL amyloidosis is an incurable clonal plasma cell disorder characterized by tissue deposits of immunoglobulin light chain fragments leading to organ dysfunction and death. Standard treatment for newly diagnosed patients (pts) has traditionally included oral melphalan + dexamethasone as well as high-dose melphalan + ASCT. Here we report preliminary results of a Phase 1/2, open-label, multi-institution study of ixazomib (I) in combination with cyclophosphamide (Cy) and dexamethasone (D) in newly diagnosed AL amyloidosis. Methods: Eligible pts are ≥18 years with newly diagnosed, untreated biopsy-proven AL amyloidosis. A total of up to 30 pts will be enrolled, with up to 18 in the dose escalation arm (phase 1) and 12 in the maximum tolerated dose (MTD) expansion arm (phase 2) according to a classical 3+3 design. Four dose levels were evaluated in phase 1. I and Cy are given orally (PO) on days 1, 8, 15, and D 20mg PO on days 1, 8, 15, 22 of each 28-day cycle. Treatment continues for a total of 6 cycles or until disease progression, significant toxicity or withdrawal. The primary study objective in phase 1 is to establish the MTD and in phase 2 is to determine hematologic/organ response rate. Results: As of February 2020, 120 pts have been enrolled; 16 in phase 1 and 4 in phase 2. The MTD was established at dose level 3 (I 4mg and Cy 500mg). Median age is 65 years (range 46-79), 12 (67%) are male. Light chain isotype is lambda in 14 (78%). Seven pts (39%) have cardiac, 10 (56%) renal, 4 (22%) gastrointestinal, 1 (6%) hepatic, 2 (11%) soft tissue involvement, with 22% having multi-organ involvement. Four pts (22%) completed 6 cycles of therapy and 6 (33%) remain on study with a median of 3 cycles completed. Eight of 16 pts (50%) had at least 1 drug-related adverse event (AE) (any grade), most commonly edema (19%), fatigue (19%), dizziness/lightheadedness (13%) and lymphopenia (13%). Grade 3/4 AEs were rare with grade 3 lymphopenia, anemia, and hyponatremia occurring in 13%, 6%, and 6% of pts, respectively. Of 18 evaluable pts, 7 (39%) achieved ≥VGPR with the median time to best response 2 cycles (1-5). Conclusions: The combination of ICyD for pts with newly diagnosed AL amyloidosis is safe and well tolerated. Phase 1 is completed and the recommended phase 2 dose has been established. Deep hematologic responses (≥VGPR) have occurred and time to response appears similar to standard of care induction regimens, ie CyBorD. Phase 2 response data will be updated at the meeting.