Background: Melphalan-200 high dose chemotherapy for ASCT has been the standard of care for multiple myeloma (MM) for over 30 years. Newer combination regimens such as Busulfan and Melphalan (BuMel) have demonstrated improved progression free survival (PFS) but with increased transplant related morbidity including mucositis and infections. Our group previously demonstrated that adding a proteasome inhibitor (bortezomib) to BuMel further increased PFS with mucositis ameliorated by Palifermin. Building on this effectiveness, we added carfilzomib to the BuMel backbone in a Phase I/II manner focused on safety and initial effectiveness of this novel regimen. Methods: This phase I/II open-label dose-escalation/expansion study (NCT03795597) enrolled patients with relapsed or high risk first remission MM. Patients received Busulfan over 4 days at a target total AUC of 20,000 mM-min followed by melphalan at 140mg/m2. Patients received 4 total doses of IV carfilzomib, 2 before melphalan and 2 after, with the final 2 doses escalated based on toxicity. Palifermin was given on days -11,-10, 0, and +1. Once MTD was determined, 10 more patients were treated at that level. Primary objective was safety and secondary outcomes were response to treatment at day 100 including MRD, engraftment kinetics, PFS, and OS. Results: Patients were predominantly male (79%) with median age 60.95 years. Median KPS was 80 and median HCT-CI was 2. The carfilzomib MTD was 36 mg/m2. One SAE of grade V ischemic colitis was seen at the 45 mg/m2 dose level. Toxicity at 36 mg/m2 yielded a similar pattern to our prior bortezemib containing regimen with grade 1 NSVT in 2 patients and hypertension in another. With a median follow up of 22 months, only 1 of the 13 MTD patients has progressed at 33mo. 2-year PFS and OS are both 100%. Analysis at D+100 showed 69% of MTD patients were MRD negative regardless of genetics. Conclusions: This novel BuMelCar ASCT regimen is safe and tolerable and appears to lead to a high % of MRD negative disease at D+100, which other studies correlate to a high PFS at 2 years. A comparison study with mel 200 is warranted to test whether BuMelCar can improve transplant outcomes especially in high-risk patients. Clinical trial information: NCT03795597.